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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4567 10.12998/wjcc.v11.i19.4567 Retrospective Study Assessment of functional prognosis of anterior cruciate ligament reconstruction in athletes based on a body shape index Wang YJ et al. Functional prognosis of ACLR in athletes Wang Yun-Jun Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, Shanxi Province, China Zhang Jun-Chang Department of Orthopedics, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China Zhang Yu-Ze Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, Shanxi Province, China Liu Ying-Hai Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, Shanxi Province, China. liuyinghai3699@163.com Author contributions: Wang YJ carried out the acquisition and interpretation of data and was the major contributor to drafting the manuscript; Wang YJ and Zhang JC carried out the clinical partial data collection and analyses; Wang YJ and Zhang YZ participated in drawing tables and diagrams; Zhang YZ was responsible for correcting the language and grammar; Zhang JC was responsible for reviewing and revising some drawings and tables; Zhang JC and Liu YH were responsible for guiding clinical discussions; Liu YH contributed to the ideas of the article and reviewed the manuscript; All authors provided final approval for publishing the manuscript. Corresponding author: Ying-Hai Liu, PhD, Professor, Institutes of Biomedical Sciences, Shanxi University, No. 92 Wucheng Road, Taiyuan 030006, Shanxi Province, China. liuyinghai3699@163.com 6 7 2023 6 7 2023 11 19 45674578 4 5 2023 21 5 2023 24 5 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND A healthy body shape is essential to maintain athletes’ sports level. At present, little is known about the effect of athletes’ body shape on anterior cruciate ligament reconstruction (ACLR). Moreover, the relationship between body shape and variables such as knee joint function after operation and return to the field has not been well studied. AIM To verify the relationship between a body shape index (ABSI) and the functional prognosis of the knee after ACLR in athletes with ACL injuries. METHODS We reviewed 76 athletes with unilateral ACL ruptures who underwent ACLR surgery in the First Hospital of Shanxi Medical University between 2017 and 2020, with a follow-up period of more than 24 mo. First, all populations were divided into a High-ABSI group (ABSI > 0.835, n = 38) and a Low-ABSI group (ABSI < 0.835, n = 38) based on the arithmetic median (0.835) of ABSI values. The primary exposure factor was ABSI, and the outcome indicators were knee function scores as well as postoperative complications. The correlation between ABSI and postoperative knee function scores and postoperative complications after ACLR were analyzed using multifactorial logistic regression. RESULTS The preoperative knee function scores of the two groups were similar. The surgery and postoperative rehabilitation exercises, range of motion (ROM) compliance rate, Lysholm score, and Knee Injury and Osteoarthritis Outcome Score of the two groups gradually increased, whereas the quadriceps atrophy index gradually decreased. The knee function scores were higher in the Low-ABSI group than in the High-ABSI group at the 24-mo postoperative follow-up (P < 0.05). In multifactorial logistic regression, ABSI was a risk factor of low knee joint function score after surgery, specifically low ROM scores (odds ratio [OR] = 1.31, 95% confidence interval [CI] [1.10-1.44]; P < 0.001), low quadriceps atrophy index (OR = 1.11, 95%CI [0.97-1.29]; P < 0.05), low Lysholm scores (OR = 2.34, 95%CI [1.78-2.94]; P < 0.001), low symptoms (OR = 1.14, 95%CI [1.02-1.34]; P < 0.05), low activity of daily living (OR = 1.34, 95%CI [1.18-1.65]; P < 0.05), low sports (OR = 2.47, 95%CI [1.78-2.84]; P < 0.001), and low quality of life (OR = 3.34, 95%CI [2.88-3.94]; P < 0.001). ABSI was also a risk factor for deep vein thrombosis of the lower limb (OR = 2.14, 95%CI [1.88-2.36], P < 0.05] and ACL recurrent rupture (OR = 1.24, 95%CI [0.98-1.44], P < 0.05) after ACLR. CONCLUSION ABSI is a risk factor for the poor prognosis of knee function in ACL athletes after ACLR, and the risk of poor knee function after ACLR, deep vein thrombosis of lower limb, and ACL recurrent rupture gradually increases with the rise of ABSI. A body shape index Anterior cruciate ligament reconstruction Athletes Multifactorial logistic regression Obesity ==== Body pmc Core Tip: A body shape index (ABSI), an excellent body mass index, was used to substitute for the traditional body mass index to more objectively assess the degree of body size/obesity in athletes. Subsequently, multivariate logistic regression analysis was used to determine whether ABSI is a risk factor for poor knee function, lower extremity deep vein thrombosis, and fractures after anterior cruciate ligament surgery. The findings of this study have the potential to narrow the gap in previous research. INTRODUCTION Athletes are at high risk of anterior cruciate ligament (ACL) ruptures, often combined with meniscal and cartilage injuries, which can lead to knee instability and osteoarthritis (OA) if not treated promptly[1]. Due to the high demand for knee function in athletes, ACL reconstruction (ACLR) is generally recommended as early as possible to obtain knee stability after ACL rupture in athletes[2]. Given that good postoperative knee function is the foundation of an athlete's performance on the field[3], it is important to identify the factors that influence an athlete's post-ACLR knee function. A proper body shape plays a central role in athletic performance, and the increasing obesity has a negative impact on athletes' physical performance, such as increased lower limb loading and slower movement speed[4]. As a result, it is important to regularly monitor the obesity of athletes to ensure that the mandatory physical obesity level is kept at a low level[5]. Obesity and overweight have previously been identified as high-risk variables for poor function following ACLR, and a higher body mass index (BMI) tends to predict higher knee loading and OA risk in ACLR patients, especially when the BMI reaches 25 kg/m2[6,7]. Furthermore, a high BMI can also alter post-ACLR gait biomechanics, and increase knee compression and shear forces, as well as patellofemoral pressure and knee extensor moment, which can lead to knee instability[8,9]. Therefore, an increasing number of athletes of all sizes or weights are in need of ACLR, and it is of great importance to identify risk factors that influence the outcomes and complications of ACLR in athletes. BMI is a measurement of a person's weight and height; it is used to determine a person's fat proportion and is also a common clinical indicator for assessing overweight and obesity[10]. BMI does not directly measure body fat composition, but is defined as a positive correlation between weight and obesity at a specific height[11]. Currently, statistics on obesity are mostly based on BMI, which ranges from 18.5 to 24.9 in a healthy person, 25 to 29.9 in an overweight person, and 30+ in an obese person. However, the median distribution of "normal" BMI (approximately 22) differs considerably from the mean BMI of the current population. In addition, the correlation between BMI and the risk of various diseases is not linear[12]. Put another way, a higher BMI does not always reflect an increase in fat, as being overweight may be due to an increase in muscle tissue, especially in athletes with higher levels of musculoskeletal development[13]. ABSI was first proposed by researchers at the City University of New York in 2012[14]. ABSI is calculated from height, weight, and waist circumference (WC), and it standardizes WC with body shape (weight and height), similar to body BMI[15]. ABSI corrects the effect of height and/or body mass to better assesses abdominal fat[16]. There is a paucity of research regarding the association between ABSI and postoperative knee function and complications in athletes with ACLR. Therefore, it is of great significance to identify risk factors associated with poorer postoperative knee function or complications in athletes with ACLR and to emphasize early intervention and guided rehabilitation to allow athletes to return to competition as soon as possible. MATERIALS AND METHODS Research subjects Patients included in this retrospective cross-sectional study were professional athletes with ACL injuries who underwent arthroscopic ACLR between December 2017 and December 2020 at the Department of Orthopedics in the First Hospital of Shanxi Medical University (Shanxi, China), and all patients agreed to participate in this study. According to the Helsinki Declaration, the study was approved by the Ethics Committee of the First Hospital of Shanxi Medical University, and written informed consent was obtained from all patients. Because of the retrospective nature of our study, no additional clinical trial registration was required. Inclusion criteria: (1) Active professional athletes aged 18-years-old to 40-years-old; (2) first-time knee arthroscopy, within 6 mo after ACL injury; (3) intraoperative definite diagnosis of unilateral ACL rupture (may be combined with meniscal or articular cartilage injury); and (4) patients who had no contraindications to surgery and agreed to undergo arthroscopic ACLR surgery and participate in this study. Exclusion criteria: (1) Presence of lower extremity fractures or combined injuries such as medial or lateral collateral ligament or posterior cruciate ligament; (2) previous knee meniscal injury or osteoarthritis; and (3) history of previous knee surgery. Ultimately, a total of 76 ACLR athletes were included in this study through screening. General case information Demographic information was collected through the medical record system and questionnaires including sex, age, type of exercise, smoking and alcohol history, preoperative physical examination (height, weight, BMI, and abdominal circumference), comorbidities (e.g., hypertension, diabetes, cancer, meniscal injury), ACL injury, site of injury, and surgical status (duration of surgery, duration of tourniquet, femoral and tibial fixation). ABSI calculation The exposure variable in this study was ABSI, and it was calculated as follows: BMI = weight/height2, and ABSI = WC/ (BMI2/3 × height1/2)[17]. Grouping First, the ABSI of all ACLR patients was calculated, and then the population was divided into a High-ABSI group (ABSI > 0.835, n = 38) and Low-ABSI group (ABSI < 0.835, n = 38) according to their arithmetic median (0.835). All patients were followed up for more than 24 mo. ACLR surgical technique As previously described[18], all ACLR procedures were performed on ACL patients by the same orthopedic professor under general or combined lumbar and rigid anesthesia using autologous hamstring tendons (semitendinosus and thin femoral muscles). All patients had a thigh tourniquet. Also, all patients had a standard anteromedial femoral and tibial tunnel drilled, with a final fixation of the proximal tendon bundled to the femur with an Endobutton (Smith & Nephew Inc., Memphis, TN, United States) or rounded cannulated interference (RCI) screw (Smith & Nephew, United Kingdom) and the proximal tendon bundled to the tibia with an RCI screw (Smith & Nephew, United Kingdom) or washer (Smith & Nephew UK Ltd., Watford, England, United Kingdom). Postoperatively, all patients followed a standard rehabilitation program. Standard rehabilitation training All patients received standard lower extremity nerve-muscle function training, including quadriceps (anterior thigh muscle group) isometric exercise. They also practiced thigh muscle tensing and relaxation, without significant pain, more than 500 times/d, and had posterior thigh muscle group isometric exercise more than 500 times/d. Furthermore, they had pump exercises such as forceful, slow, full-range flexion and extension of the ankle joints, more than 500 times/d. Patients were clinically reviewed by the surgeon at 3 mo and 12 and 24 mo postoperatively. Functional assessment of the knee joint All patients completed a 24-mo postoperative follow-up to assess the functional recovery of the knees after surgeries. Range of motion compliance rate Range of motion (ROM) is the arc of motion through which the joint moves, and is the most basic method for assessing the motor function of the extremities[19]. Normal knee mobility should be between 140° and 150°, and active knee flexion of 120° or more after surgery is defined as compliance. Quadriceps atrophy index The quadriceps muscle is not only important for the overall health of the knee joint but also plays a key role in ensuring the knee joint’s continued stability[20]. The quadriceps atrophy index is calculated as: atrophy index = (healthy thigh circumference - affected thigh circumference)/healthy thigh circumference × 100%. The smaller the value, the smaller the reduction in quadriceps strength and the better the recovery of muscle strength. Knee Lysholm scale The Lysholm Scale is a condition-specific scale for evaluating ligamentous injuries of the knee, and is also a subjective rating system in the form of a percentage questionnaire[21]. The scale consists of eight items: claudication (5 points), support (5 points), strangulation (15 points), instability (25 points), pain (25 points), swelling (10 points), stair climbing and descending (10 points), and squatting (5 points). A higher score indicates better function. Knee Injury and Osteoarthritis Outcome Score Knee Injury and Osteoarthritis Outcome Score (KOOS) is an assessment of the short- and long-term outcomes of treatment after a knee injury[22]. It consists of five patient-related components: symptoms, pain, activity of daily living (ADL), sports, and knee-related quality of life (QOL). A score of 0 means very poor function of that part of the joint, and a score of 100 means perfectly normal function of that part of the joint. Return to sport According to previous studies[18], “return to sport (RTS)” is defined as an exercise that is considered to return to the same or higher level of return to pre-injury during the follow-up period. Postoperative complications During the follow-up period, patients in both groups were counted for complications, including knee infection, deep vein thrombosis, internal fixation failure, and ACL re-rupture. The patients were analyzed for specific complications, and given symptomatic treatment. Statistical analyses IBM SPSS 27.10 software and GraphPad Prism 9 software were used for statistical analyses. The measurement data are expressed as the mean ± standard deviation, and one-way analysis of variance was used for the comparison between groups. The statistical data are expressed as frequencies (percentages), and the χ2 test was used for the comparison between groups. The median method was used to divide all patients with ACLR into High-ASBI and Low-ASBI groups. The relationship between ABSI and postoperative knee function scores and complications after ACLR was evaluated by multifactorial logistic regression analysis. P < 0.05 was considered statistically significant. RESULTS General information First, survey data were collected from a total of 93 athletes, and 76 ACLR athletes were included in the final analysis after excluding those patients who lacked outcomes, exposure, or did not complete follow-up (Figure 1). Figure 1 Flow diagram of the screening and selection process in this study. ABSI: A body shape index; PCL: Posterior cruciate ligament; ACLR: Anterior cruciate ligament reconstruction. As shown in Table 1, there was no significant difference in age between the High-ABSI group (ABSI > 0.835) and Low-ABS group (ABSI < 0.835) in the preliminary analyses ([25.9 ± 6.3] vs [26.4 ± 7.1]; P = 0.7463). There were 57 male athletes and 19 female athletes, and there was no significant difference in sex composition between the two groups (males: 71.05% vs 78.95%; P = 0.5970), with both groups having a high percentage of males. In terms of types of athletes, soccer players had the most with 37, followed by basketball players with 28 and other athletes with 9. There were no significant differences between the High-ABSI and Low-ABS groups in terms of BMI (24.3 ± 2.2 vs 23.9 ± 2.1), percentage of smoking (10.53% vs 7.895%), and percentage of alcohol consumption (21.05% vs 18.42%) for individuals (all P > 0.05). In terms of surgery, although the High-ABSI group had a lower operative time than the Low-ABSI group, there was no significant difference between them ([88.3 ± 15.7] vs [93.4 ± 16.2]; P = 0.1676). Table 1 Characteristics of participants enrolled in the study, n (%) Characteristics High-ABSI group, n = 38 Low-ABSI group, n = 38 P value Age in yr 25.9 ± 6.3 26.4 ± 7.1 0.7463 Age range in yr 18-38 18-39 Sex 0.5970    Female, n = 19 11 (28.94) 8 (21.05)    Male, n = 57 27 (71.05) 30 (78.95) Athletes 0.8731    Football 18 19    Basketball 16 14    Others 4 5 Body mass index as kg/m2 24.3 ± 2.2 23.9 ± 2.1 0.4201 Side 0.4838    Right 21 24    Left 17 14 Smoker 4 (10.53) 3 (7.895) 0.4446 Alcohol user 8 (21.05) 7 (18.42) 0.8186 Mean follow-up time in mo 26.9 ± 5.9 27.5 ± 6.3 0.6695 Operation time in min 88.3 ± 15.7 93.4 ± 16.2 0.1676 Length of stay in d 6.9 ± 1.9 6.5 ± 1.6 0.3241 Meniscus injury 14 16 0.6388 Duration of tourniquet use in min 45.9 ± 5.9 43.8 ± 6.2 0.1347 Femur fixation method 0.5558    EndoButton 36 37    RCI screw 2 1 Tibial fixation method 0.6422    Screw and washer 21 23    RCI screw 17 15 Comorbidity 0.5488    Diabetes 2 3    Hypertension 2 2    Cancers 1 0 Measurement data are expressed as the mean ± standard deviation. ABSI: A body shape index; RCI: Rounded cannulated interference. There was no significant difference in the duration of the tourniquet (P = 0.1347) or the number of days in the hospital (P = 0.3241) between the two groups. Also, there were no significant differences in the femur (P = 0.5558) or tibia (P = 0.6422) in terms of fixation method. Relationship between ASBI levels and prognosis of knee function in athletes after ACLR surgery Next, the effects of ABSI level and postoperative knee function were explored. Figure 2 shows the functional recovery of the knee joint after surgery in the different ABSI groups. The results showed that the ROM scores of the two groups were similar before surgery (0 mo) and gradually improved with ongoing surgery and postoperative rehabilitation exercises (Figure 2A). Besides, the ROM scores in the Low-ABSI group were higher than those in the High-ABSI group (P < 0.05; Figure 2A), indicating that high ABSI predicted poor knee mobility. The quadriceps muscle also influenced the knee flexion and extension function. The results showed that preoperatively (0 mo), both groups had some short-term atrophy of the quadriceps muscle due to a sudden decrease in motion caused by the ACL rupture (Figure 2B). At 3 mo, 12 mo, and 24 mo postoperatively, the quadriceps atrophy index was higher in the High-ABSI group than in the Low-ABSI group (Figure 2B). This indicates that the higher the ABSI, the lower the muscle strength of the quadriceps. In addition, the Lysholm score is an excellent indicator of knee function after knee ligament injury surgery. As shown in Figure 2C, before surgery, the scores of both groups were low (P > 0.05). With ongoing surgery and rehabilitation exercises, the Lysholm scores of both groups gradually increased, and the Lysholm scores of the Low-ABSI group were consistently higher than those of the High-ABSI group (P < 0.05, Figure 2C). Figure 2 Comparison of knee joint function between High-a body shape index group and Low-a body shape index group after anterior cruciate ligament reconstruction. A: Range of motion (ROM) scores; B: Quadriceps atrophy index; C: Lysholm scores; D: Return to sport (RTS) completion rate. Data are presented as the mean ± standard deviation; aP < 0.05, bP < 0.01 vs Low-a body shape index (ABSI) group. The KOOS score is a comprehensive self-rating measure of postoperative knee surgery outcomes that effectively reflects patients' perceptions of their knee health, symptoms, and function. The KOOS score consists of five subscales: symptoms, pain, ADL, sports, and QOL. As shown in Figure 3, the KOOS scores gradually increased with the ongoing surgery and rehabilitation in each of the five self-scales. At 3 mo postoperatively, the scores in both groups improved rapidly, but there was no significant difference in symptoms, pain, or ADL between the two. This might be attributed to the rapid relief of knee symptoms and pain with the implementation of surgery (P > 0.05, Figure 3). At the last follow-up (24 mo after surgery), all KOOS scores reached their highest values in both groups, and the Low-ABSI group had higher scores than the High-ABSI group (P < 0.05; Figure 3). Figure 3 Comparison of Knee Injury and Osteoarthritis Outcome Score between the High-a body shape index group and Low-a body shape index group after anterior cruciate ligament reconstruction. A: Symptoms; B: Pain; C: Activity of daily living (ADL); D: Sports; E: Quality of life (QOL). Data are presented as the mean ± standard deviation; aP < 0.05, bP < 0.01 vs Low-a body shape index group (ABSI). High levels of ASBI are a risk factor for poorer functional recovery of the knee after ACLR surgery in athletes To determine whether a high level of ASBI is a risk factor for poorer postoperative knee function recovery in ACLR athletes, we performed multifactorial logistic regression analysis with ABSI as the independent variable and each knee function score at the last follow-up as the dependent variable. We turned these continuous variables into dichotomous variables. The median scores of ROM scores, quadriceps atrophy index, Lysholm scores, and KOOS (symptoms, pain, ADL, sports, and QOL) were taken for all groups, and scores greater than the median value were defined as low knee function, specifically low ROM scores (≤ 82 ), low quadriceps atrophy index (≥ 1.2), low Lysholm scores (≤ 83), low symptoms (≤ 88), low pain (≤ 83), low ADL (≤ 87), low sports (≤ 80), and low QOL (≤ 73). As shown in Table 2, the results revealed that high ABSI was a risk factor for patients with low postoperative knee function scores, specifically low ROM scores (odds ratio [OR] = 1.31, 95% confidence interval [CI] [1.10-1.44]; P < 0.001), low quadriceps atrophy index (OR = 1.11, 95%CI [0.97- 1.29]; P < 0.05), low Lysholm scores (OR = 2.34, 95%CI [1.78-2.94]; P < 0.001), low symptoms (OR = 1.14, 95%CI [1.02-1.34]; P < 0.05), low ADL (OR = 1.34, 95%CI [1.18-1.65]; P < 0.05), low sports (OR = 2.47, 95%CI [1.78-2.84]; P < 0.001), and low QOL (OR = 3.34, 95%CI [2.88-3.94]; P < 0.001). Interestingly, while pain scores (higher scores were associated with less pain) were higher in the High-ABSI group than in the Low-ABSI group (P < 0.05; Figure 2C), multifactorial logistic regression showed that high ABSI was not a risk factor for pain (OR = 1.04, 95%CI [0.78-1.44]; P = 0.06) (Table 2). Ultimately, at the final follow-up, the percentage of RTS was significantly higher in the Low-ABSI group (78.95% vs 60.53%; P < 0.05) than in the High-ABSI group (Figure 2D). Table 2 Multifactor logistic regression of low knee joint function score in anterior cruciate ligament reconstruction patients with low a body shape index on last follow-up Items OR (95%CI) P value Low ROM scores 1.31 (1.10-1.44)b < 0.001 Low quadriceps atrophy index 1.11 (0.97-1.29)a < 0.05 Low Lysholm scores 2.34 (1.78-2.94)b < 0.001 Low KOOS scores     Low symptoms 1.14 (1.02-1.34)a < 0.05     Low pain 1.04 (0.78-1.44) 0.06     Low ADL 1.34 (1.18-1.65)a < 0.05     Low sports 2.47 (1.78-2.84)b < 0.001     Low QOL 3.34 (2.88-3.94)b < 0.001 a P < 0.05. b P < 0.001. Compared with the High-a body shape index group. ABSI: A body shape index; ADL: Activity of daily living; CI: Confidence interval; KOOS: Knee Injury and Osteoarthritis Outcome Score; OR: Odds ratio; QOL: Quality of life; ROM: Range of motion. Association between ASBI levels and postoperative complications in ACLR athletes As shown in Table 3, with the exception that the incidence of venous thrombosis of lower limbs (21.04% vs 2.631%; P = 0.0284) in the High-ABSI group was higher than that in the Low-ABSI group, there was no significant difference in the incidence of knee joint infection (5.262% vs 5.262%; P > 0.9999), internal fixation failure (2.631% vs 0.000%; P > 0.9999), and ACL current failure (7.893% vs 2.631%; P = 0.6148) between the two groups. Further multifactorial logistic regression analysis also showed that ABSI was a risk factor for deep vein thrombosis of the lower limb (OR = 2.14, 95%CI [1.88-2.36]; P < 0.05) as well as ACL recurrent rupture (OR = 1.24, 95%CI [0.98- 1.44]; P < 0.05) (Table 4). Table 3 Postoperative complications in the High-a body shape index group and Low-a body shape index group after anterior cruciate ligament reconstruction, n (%) Characteristic High-ABSI group, n = 38 Low-ABSI group, n = 38 P value Knee joint infection 2 (5.262) 2 (5.262) > 0.9999 Internal fixation failure 1 (2.631) 0 (0.000) > 0.9999 Deep vein thrombosis of lower limb 8 (21.04) 1 (2.631)a 0.0284 ACL recurrent rupture 3 (7.893) 1(2.631) 0.6148 Total 14 (36.84) 4 (10.53) 0.0571 a P < 0.05. Compared with the Low-a body shape index group. ABSI: A body shape index; ACL: Anterior cruciate ligament. Table 4 Multifactor logistic regression of complications in anterior cruciate ligament reconstruction patients with high a body shape index on last follow-up Items OR (95%CI) P value Knee joint infection 1.00 (1.10-1.44) > 0.05 Internal fixation failure 1.01 (0.93-1.15) > 0.05 Deep vein thrombosis of lower limb 2.14 (1.88-2.36)a < 0.05 ACL recurrent rupture 1.24 (0.98-1.44)a < 0.05 a P < 0.05. Compared with the Low-a body shape index group. ACL: Anterior cruciate ligament; CI: Confidence interval; OR: Odds ratio. DISCUSSION The current standardized treatment for ACL injury is ACLR, which aims to restore the function and stability of the knee joint, thus promoting RTS[23]. Although most ACL reconstructions restore the mechanical stability of the injured knee joint, the incidence of RTS is different. In 85%-90% of ACLR patients, the prognosis of knee joint function returns to normal or close to normal within 6 mo after surgery[24]. There are also some research reports that only 63% of the people restore their exercise level before the injury at the last follow-up[25]. Our study also showed that the knee joint function scores of most patients with ACLR remained stable from 1 year to 2 years after surgery. In the last follow-up 24 mo after the operation, athletes in the High-ABSI and Low-ABSI groups had 60.53% (23/38) and 78.95% (30/38) RTS completion rates, respectively. This confirms that ACLR is undoubtedly the standard operation to reconstruct the integrity of the anterior cruciate ligament and restore the function of the knee joint. Obesity is also a risk factor for poor function after various knee surgeries[26]. Li et al[27] found that obesity and medial cartilage injury are strong risk factors for osteoarthritis after the first single-beam ACLR. Another prospective study involving 92 patients with ACLR also pointed out that the incidence of postoperative complications in patients with high BMI (BMI > 25 kg/m2) was slightly higher than that in patients with normal BMI[21]. For obese patients with ACLR with BMI higher than 25 kg/m2, the score of the International Knee Documentation Committee was lower after the operation[28]. However, there were also some different results. In addition, another study also confirmed that the preoperative BMI of patients had no significant adverse impact on the KOOS and Lysholm scores, and that there was no significant difference in the postoperative clinical results of these patients[21]. Therefore, the relationship between obesity based on BMI content and the postoperative function of ACLR is complex, because BMI may not be able to effectively measure the content of individual fat and identify muscle and obesity. ABSI has a positive correlation with visceral fat and is not affected by muscle. Thus, it can better display the content of fat than the traditional BMI. The study also confirmed that the knee joint function scores of the High-ABSI population were lower than those of the low-ABSI population. Multivariate logistic analysis also demonstrated that high ABSI was the influencing factor of poor function after ACLR. Similar to a previous study[24], there was no significant difference between the two groups in various functional scores (ROM compliance rate, quadriceps femoris atrophy index, Lysholm score, etc) before surgery (P > 0.05). With the progress of postoperative rehabilitation, the ROM scores, quadriceps femoris atrophy index, and Lysholm score of the two groups were significantly improved compared with those before surgery (P < 0.05). Subsequently, it was gradually revealed that the knee joint function of the High-ABSI group was still lower than that of the Low-ABSI group. At the 6th mo and 12th mo after operation, the knee joint function score of the Low-ABSI group was significantly lower than that of the Low-ABSI group. These results also confirmed the conclusion of previous research[4] that obese people would experience increased load on the lower limbs, thus affecting their recovery of knee joints. Besides, the risk of lower limb deep venous thrombosis after operation in the High-ABSI population was also higher than that in the Low-ABSI population, since obesity is a risk factor for deep venous thrombosis (OR = 1.67, 95%CI: 1.16-2.40; P = 0.006), and Mendel randomization verified the causal relationship between BMI and deep vein thrombosis[29]. Fat plays an important role in the formation of deep venous thrombosis of lower limbs. Studies have shown that lipid metabolism in adipocytes participates in the process of thrombosis, and adipocytes can promote thrombosis by releasing a variety of thrombogenic factors, such as coagulation factors, platelet activating factors, platelet-derived active substances, etc[30]. Therefore, in the process of athletes' rehabilitation, it is necessary to take measures to reduce obesity, thus reducing the incidence rate of deep vein thrombosis. Out investigation had some limitations. This was a retrospective study with a limited number of participants and results that only covered a brief period of time. In addition, this study is part of a larger correlation investigation. To investigate the possible causal connection between ABSI and the postoperative function of ACLR in the future, additional randomized controlled trials or Mendelian randomization will be required. CONCLUSION ABSI is a risk factor for poor prognosis of knee function in ACL athletes after ACLR, and the risk of poor knee function after ACLR, deep vein thrombosis of the lower limb, and ACL recurrent rupture gradually increases with the rise of ABSI. ARTICLE HIGHLIGHTS Research background At present, the indicators of individual obesity only rely on body mass index (BMI) index, but BMI is often not linearly related to body fat content, which limits the research on the association between obesity and other diseases. Research motivation This study introduced a body shape index (ABSI), which is a body type indicator to replace traditional BMI to objectively evaluate the association between athletes' body size/obesity and anterior cruciate ligament reconstruction (ACLR). Research objectives Explore the relationship between knee joint function in athletes with ABSI and anterior cruciate ligament injuries after ACLR. Research methods Multiple logistic regression analysis was used to investigate the relationship between knee joint function scores and postoperative complications after ABSI and ACLR surgery. Research results The knee joint function score of the Low-ABSI group was higher than that of the High-ABSI group (P < 0.05). High ABSI is a risk factor for low score of knee joint function after operation, and also a risk factor for deep vein thrombosis of lower limbs. Research conclusions ABSI is closely related to the prognosis of knee joint function after ACLR. The rise of ABSI is likely to lead to poor knee function after ACLR and deep vein thrombosis of lower limbs. Research perspectives In the future, randomized controlled trials or Mendelian randomization are needed to verify the possible causal relationship between ABSI and postoperative function of ACLR. Data sharing statement The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Institutional review board statement: According to the Helsinki Declaration, the study was approved by the Ethics Committee of First Hospital of Shanxi Medical University. Informed consent statement: The data used in this study were not involved in the patients’ privacy information, so the informed consent was waived by the Ethics Committee of First Hospital of Shanxi Medical University. All patient data obtained, recorded, and managed only used for this study, and all patient information are strictly confidential, without any harm to the patient. Conflict-of-interest statement: The authors have no conflicts of interest to declare. Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: May 4, 2023 First decision: May 12, 2023 Article in press: May 24, 2023 Specialty type: Orthopedics Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): 0 Grade C (Good): C, C Grade D (Fair): 0 Grade E (Poor): 0 P-Reviewer: Baird PN, Australia; Mahmud N, United States S-Editor: Liu JH L-Editor: Filipodia P-Editor: Liu JH ==== Refs 1 van Yperen DT Reijman M van Es EM Bierma-Zeinstra SMA Meuffels DE Twenty-Year Follow-up Study Comparing Operative Versus Nonoperative Treatment of Anterior Cruciate Ligament Ruptures in High-Level Athletes Am J Sports Med 2018 46 1129 1136 29438635 2 Wiggins AJ Grandhi RK Schneider DK Stanfield D Webster KE Myer GD Risk of Secondary Injury in Younger Athletes After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis Am J Sports Med 2016 44 1861 1876 26772611 3 Wilk KE Arrigo CA Rehabilitation Principles of the Anterior Cruciate Ligament Reconstructed Knee: Twelve Steps for Successful Progression and Return to Play Clin Sports Med 2017 36 189 232 27871658 4 Meyer NL Sundgot-Borgen J Lohman TG Ackland TR Stewart AD Maughan RJ Smith S Müller W Body composition for health and performance: a survey of body composition assessment practice carried out by the Ad Hoc Research Working Group on Body Composition, Health and Performance under the auspices of the IOC Medical Commission Br J Sports Med 2013 47 1044 1053 24065075 5 Ackland TR Lohman TG Sundgot-Borgen J Maughan RJ Meyer NL Stewart AD Müller W Current status of body composition assessment in sport: review and position statement on behalf of the ad hoc research working group on body composition health and performance, under the auspices of the I.O.C. 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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4612 10.12998/wjcc.v11.i19.4612 Randomized Controlled Trial Fecal microbiota transplantation in patients with metabolic syndrome and obesity: A randomized controlled trial da Ponte Neto AM et al. Fecal microbiota transplantation da Ponte Neto Alberto Machado Departament of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Serviço de Endoscopia Gastrointestinal do Hospital das Clínicas HCFMUSP, São Paulo 05403-010, SP, Brazil Clemente Aniele Cristine Ott Department of Endocrinology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo 05403-010, SP, Brazil Rosa Paula Waki Department of Endocrinology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo 05403-010, SP, Brazil Ribeiro Igor Braga Departament of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Serviço de Endoscopia Gastrointestinal do Hospital das Clínicas HCFMUSP, São Paulo 05403-010, SP, Brazil. igorbraga1@gmail.com Funari Mateus Pereira Departament of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Serviço de Endoscopia Gastrointestinal do Hospital das Clínicas HCFMUSP, São Paulo 05403-010, SP, Brazil Nunes Gabriel Cairo Departament of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Serviço de Endoscopia Gastrointestinal do Hospital das Clínicas HCFMUSP, São Paulo 05403-010, SP, Brazil Moreira Luana Department of Clinical and Toxicology Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05403-010, SP, Brazil Sparvoli Luiz Gustavo Department of Clinical and Toxicology Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05403-010, SP, Brazil Cortez Ramon Department of Clinical and Toxicology Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05403-010, SP, Brazil Taddei Carla Romano Department of Clinical and Toxicology Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05403-010, SP, Brazil School of Arts, Science and Humanities, University of São Paulo, São Paulo 05403-010, SP, Brazil Mancini Márcio C Department of Endocrinology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo 05403-010, SP, Brazil de Moura Eduardo Guimarães Hourneaux Departament of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Serviço de Endoscopia Gastrointestinal do Hospital das Clínicas HCFMUSP, São Paulo 05403-010, SP, Brazil Author contributions: da Ponte Neto AM contributed to the conception and design of the study, analyzed and interpreted the data, drafted the article; revised the article for important intellectual content, and approved the final version; Clemente ACO analyzed and interpreted the data, revised the article for important intellectual content, and approved the final version; Rosa PW analyzed and interpreted the data, drafted the article, revised the article for important intellectual content, and approved the final version; Ribeiro IB contributed to the conception and design of the study, analyzed and interpreted the data, drafted the article; revised the article for important intellectual content, and approved the final version; Nunes GC analyzed and interpreted the data, revised the article for important intellectual content, and approved the final version; Moreira L analyzed and interpreted the data, and approved the final version; Sparvoli LG analyzed and interpreted the data, drafted the article, revised the article for important intellectual content, and approved the final version; Cortez R analyzed and interpreted the data, drafted the article, revised the article for important intellectual content, and approved the final version; Taddei CR analyzed and interpreted the data, drafted the article, revised the article for important intellectual content, and approved the final version; Mancini M analyzed and interpreted the data, drafted the article, revised the article for important intellectual content, and approved the final version; De Moura EGH: analyzed and interpreted the data, drafted the article, revised the article for important intellectual content, and approved the final version. Corresponding author: Igor Braga Ribeiro, MD, PhD, Associate Research Scientist, Attending Doctor, Doctor, Research Scientist, Departament of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Serviço de Endoscopia Gastrointestinal do Hospital das Clínicas HCFMUSP, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo 05403-010, SP, Brazil. igorbraga1@gmail.com 6 7 2023 6 7 2023 11 19 46124624 10 1 2023 26 1 2023 4 5 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND Metabolic syndrome is a multifactorial disease, and the gut microbiota may play a role in its pathogenesis. Obesity, especially abdominal obesity, is associated with insulin resistance, often increasing the risk of type two diabetes mellitus, vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease. AIM To evaluate the outcomes of fecal microbiota transplantation (FMT) in patients with metabolic syndrome. METHODS This was a randomized, single-blind placebo-controlled trial comparing FMT and a sham procedure in patients with metabolic syndrome. We selected 32 female patients, who were divided into eight groups of four patients each. All of the patients were submitted to upper gastrointestinal endoscopy. In each group, two patients were randomly allocated to undergo FMT, and the other two patients received saline infusion. The patients were followed for one year after the procedures, during which time anthropometric, bioimpedance, and biochemical data were collected. The patients also had periodic consultations with a nutritionist and an endocrinologist. The primary end point was a change in the gut microbiota. RESULTS There was evidence of a postprocedural change in microbiota composition in the patients who underwent FMT in relation to that observed in those who underwent the sham procedure. However, we found no difference between the two groups in terms of the clinical parameters evaluated. CONCLUSION There were no significant differences in biochemical or anthropometric parameters, between the two groups evaluated. Nevertheless, there were significant postprocedural differences in the microbiota composition between the placebo group. To date, clinical outcomes related to FMT remain uncertain. Fecal microbiota transplantation Metabolic syndrome Obesity Endoscopy Diabetes mellitus Endocrinology ==== Body pmc Core Tip: The prevalence of metabolic syndrome is a pandemic that goes hand in hand with obesity and diabetes, affecting almost half of the world's population. Therapeutic approaches targeting dysbiosis and manipulation of the gut microbiome have become options and are being tested. Such approaches include the use of prebiotics, probiotics, synbiotics, antibiotics and fecal microbiota transplantation (FMT). It is known that FMT can alter the intestinal microbiota and increase its diversity, resulting in a microbiome that can help decrease body fat and increase insulin sensitivity, as well as facilitate the treatment of metabolic syndrome and obesity. This was a randomized controlled trial comparing FMT and a sham procedure in patients with the metabolic syndrome. INTRODUCTION The prevalence of metabolic syndrome parallels that of obesity and diabetes—up to 45% of the population worldwide—and is expected to rise as a consequence of increasing longevity and unhealthy lifestyles[1,2]. Obesity has become one of the most important public health problems in the United States and in many other resource-rich countries, as well as in transitional economies. The increase in the prevalence of obesity has resulted in increases in the incidence of associated diseases such as diabetes and hypertension[3,4]. Obesity, especially abdominal obesity, is associated with insulin resistance, often increasing the risk of type two diabetes, vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease[5,6]. Individuals in whom the metabolic risk factors for type two diabetes coexist with those for cardiovascular disease are classified as having metabolic syndrome[7]. There are many treatment modalities for obesity and metabolic syndrome. However, optimal management is still a challenge because multiple factors are involved in its physiopathology, such as genetic predisposition, sedentary lifestyle, and a specific distribution of body fat[8,9]. Therapeutic approaches targeting dysbiosis and manipulation of the gut microbiome have recently been developed. Such approaches include the use of prebiotics, probiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). It is known that FMT can change the gut microbiota and increase its diversity, resulting in a microbiome that could help decrease body fat and increase insulin sensitivity, as well as facilitating the treatment of metabolic syndrome and obesity. The gut microbiota is composed of trillions of microorganisms that can influence the human organism by various mechanisms, having been associated with many diseases and conditions, including obesity and metabolic syndrome[10-14]. The aim of this study was to evaluate the outcomes of FMT in patients with metabolic syndrome. To that end, we performed a randomized placebo-controlled clinical trial. MATERIALS AND METHODS Study design This was a randomized, single-blind, placebo-controlled clinical trial comparing FMT and a sham procedure in patients with metabolic syndrome. We selected patients who had been diagnosed with metabolic syndrome according to the 2006 International Diabetes Federation criteria[2]. Additional inclusion criteria were being female, being between 18 and 70 years of age, and having a body mass index (BMI) of 30–40 kg/m2. Patients who had previously undergone gastrointestinal surgery were excluded, as were those with immunodeficiency, those who had previously undergone treatment for obesity, and those who had used any weight loss medication, antibiotics, or probiotics within the last three months. The primary end point was a change in the gut microbiota. After an initial screening for the characteristics of metabolic syndrome, the patients were referred for consultations with a nutritionist and an endocrinologist. Anthropometric, bioimpedance, and biochemical data were analyzed. The study was approved by the Research Ethics Committee of the Hospital das Clínicas (CAAE: 62319916.9.0000.0068) operated by the University of São Paulo School of Medicine, in the city of São Paulo, Brazil. All participating patients provided written informed consent. Study population Female patients with class I or II obesity were recruited following an advertisement at the entrance of the Hospital das Clínicas. We included 32 female patients (age range, 20–69 years) with class II obesity (BMI 30–40 kg/m2) and metabolic syndrome. Metabolic syndrome was defined as a fasting glucose level > 100 mg/dL or use of antidiabetic medications or insulin, plus at least two of the following criteria: triglycerides ≥ 150 mg/dL; high-density lipoprotein cholesterol < 50 mg/dL (the standard for women); blood pressure ≥ 130/85 mmHg or use of antihypertensive medication; and abdominal obesity, defined as a waist circumference ≥ 80 cm (the standard for women). We chose to use a single feces donor, in an attempt to maintain the same bacterial diversity for all recipients, despite the fact that not all of the donations were made on the same day. To screen the donor, we used the protocol devised by van Nood et al[15]. The donor (a 30-year-old female) was a volunteer and was initially screened with a questionnaire on communicable diseases. Stool and blood samples were collected. The stool sample was screened for parasites, Clostridium difficile, and enteropathogenic bacteria. The blood sample was screened for the following: antibodies to human immunodeficiency virus; human T-cell lymphotropic virus types I and II; hepatitis A, B, and C; cytomegalovirus; Epstein–Barr virus; Treponema pallidum; Strongyloides stercoralis; and Entamoeba histolytica. The screening was repeated every 4 mo during the 1-year donation period. Immediately prior to each donation, another questionnaire was used in order to identify any recent illness[15]. Sample collection On the day of the procedure, a stool sample was collected from each patient. In most cases, the samples were collected from a spontaneous evacuation by the patient prior to the procedure or by digital rectal extraction after the patient had been sedated. In one patient, it was necessary to perform proctoscopy to obtain the stool sample, which was captured with a snare. After the stool samples had been labeled, they were stored at −80°C. Preparation of microbiota solution On the day of donation, the microbiota solution was prepared by diluting 200 g of donor feces in 500 mL of sterile saline. The solution was stirred, after which the supernatant was strained and transferred to a sterile bottle[15]. Immediately after preparation, the microbiota solution was transported from the laboratory to the endoscopy center. Procedure The 32 patients were divided into eight groups of four patients each. All of the patients were submitted to upper gastrointestinal endoscopy. In each group, two patients were randomly allocated to undergo FMT, and the other two patients received saline infusion. All procedures were performed at the endoscopy center of the Hospital das Clínicas. All of the patients underwent upper gastrointestinal endoscopy under sedation. Infusions were performed with an oscope, which was advanced past the ligament of Treitz and released 200 mL of the microbiota or saline solution. In the FMT patients, the solution was infused within 4 h after the feces had been collected from the donor. Follow-up The patients underwent follow-up for one year after the procedure, during which time they had additional consultations with a nutritionist and an endocrinologist: at six weeks, six months, and one year. At each visit, anthropometric parameters, medication use, antibiotic use, and patient complaints were evaluated. Stool samples collected at each time point (baseline, six weeks, six months, and one year) were analyzed. After the procedures, the patients were required to adhere to a standardized diabetic diet (1000 calories/day) and were instructed to keep a food diary for a period of one year. They were also instructed to use no probiotics and to inform the research team if they needed to use antibiotics. DNA extraction and paired-end sequencing A 200-mg aliquot of feces from each patient was analyzed with the QiaAmp DNA Stool Mini Kit (QIAGEN, Hilden, Germany), in accordance with the manufacturer’s protocol. The V4 region of the 16 S rRNA gene was amplified using the primers V4 F (TCGTCGGCAG CCAGTGATGTGTATAAGAGACAGGTGCCAGCMGCC GCGGTAA) and V4 R (GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAGGGACTACHVGGGTWTCTAAT)[16]. Amplification was performed in two steps with a custom Illumina preparation protocol (Illumina, San Diego, CA, USA). The samples were pooled and loaded into an Illumina MiSeq reagent cartridge (Illumina, San Diego, CA) for paired-end, 500-cycle sequencing at a final concentration of 12 pM. The library was clustered at a density of approximately 820 K/mm2. Image analysis, base calling, and data quality assessment were performed on the MiSeq platform. A DNA-free negative control was used, and polymerase-chain-reaction steps were performed. On a gel, no visible amplification signal was observed for the no-template control, indicating that bacterial contamination was minimal. Bioinformatic analysis: The raw reads were demultiplexed and analyzed using QIIME software, version 1.9[17]. The software was used in order to remove barcodes and primer sequences, as well as to extract chimeric artifacts, align sequences, construct distance matrices, define operational taxonomic units (for phylogenetic tree construction), calculate diversity indices, and test hypotheses. After removing the barcodes and primers, we filtered the sequences, discarding the reads that were smaller than approximately 400 bp. We then checked for chimeras, using USEARCH[17], and excluded the sequences identified as chimeric. The sequences of the remaining libraries were grouped into operational taxonomic units, based on 97% similarity to sequences in the SILVA database, version 128[18]. The relative abundance of the bacteria was determined in relation to the main phyla and genera that appeared in at least 1% of the total found in both groups. The alpha and beta diversity indices were calculated for each library. To calculate the alpha diversity, we used the Chao1 richness estimate[19], together with the Shannon and Simpson diversity indices[20,21]. To calculate the beta diversity, we constructed a principal coordinate analysis plot based on the weighted and unweighted UniFrac distance matrices[22,23]. Nucleic acid sequences are available at the Sequence Read Archive (accession number, PRJNA766355). Statistical analysis Initially, all variables were analyzed descriptively. For quantitative variables, we observed the minimum and maximum values, as well as calculating means, standard deviations, and quartiles. For qualitative variables, we calculated absolute and relative frequencies. To compare means between the two groups, we used Student’s t-tests[24]. When the assumption of normality of the data was rejected, we used the nonparametric Mann–Whitney test[24]. To compare the groups over time, we used the nonparametric Mann–Whitney, Wilcoxon, and Friedman tests with Bonferroni correction[24]. The generalized linear model was used in order to compare the two groups, in relation to the clinical data, through linear and ordinal logistic regression. This model was also used in order to evaluate the effect of the independent variable (FMT) on the dependent variables—alpha diversity indices (with gamma distribution) and relative abundance of bacterial phyla and genera (with linear distribution). To detect between-group differences in beta diversity, we used permutational multivariate analysis of variance, with the adonis function for Bray–Curtis distances. For each variable, 999 permutations were used. To study the correlations between the preprocedural and postprocedural periods, we employed Spearman’s correlation coefficient[24]. All statistical analyses were performed with the SPSS Statistics software package, version 17.0 (SPSS Inc., Chicago, IL, USA). The significance level adopted for all tests was 5%. RESULTS Participants We included 32 patients with metabolic syndrome and one feces donor. Of the 32 patients evaluated, four did not complete the study: two withdrew after randomization; one became pregnant during follow-up; and one withdrew during follow-up. Therefore, the final sample comprised 28 patients: 15 in the FMT group and 13 in the placebo group as shown in the CONSORT flow diagram in the Supplementary material. General characteristics and clinical data When we evaluated all 32 patients at baseline, there were no statistical differences between the two groups in terms of the mean age (55.20 + 10.22 years vs 53.62 + 13.09 years, P = 0.722), body weight (94.12 + 8.27 kg vs 89.29 + 5.70 kg, P = 0.867), or BMI (36.69 + 2.94 kg/m2 vs 35.74 + 2.22 kg/m2, P = 0.719). Table 1 shows the change in body weight over the course of the study, by group, among the 28 patients who completed the study. Overall, no significant differences were found between the two groups regarding the general and clinical characteristics at the time of sample collection. Table 1 Body weight over the course of the study, by group Group N Mean SD Range Median IQR FMT (n = 15) Baseline 14 94.18 7.95 82.00–110.00 93.50 87.75–100.38 6 wk 14 93.86 9.94 82.00–114.00 93.00 85.00–100.50 6 mo 14 94.21 11.24 78.00–115.00 94.00 84.50–99.25 1 yr 14 95.79 11.05 81.00–116.00 95.00 86.50–102.25 Placebo (n = 13) Baseline 12 91.28 10.60 82.00–120.00 89.50 83.25–94.50 6 wk 12 89.79 9.53 80.50–112.00 86.50 82.25–96.75 6 mo 12 89.58 10.87 77.00–115.00 88.50 81.25–93.75 1 yr 12 90.50 13.11 73.00–117.00 86.50 81.25–99.75 IQR: Interquartile range; FMT: Fecal microbiota transplantation. No serious adverse events were reported in either group. We also observed no statistical differences between the two groups in terms of biochemical parameters (e.g., hematology, glucose, renal function, and liver chemistry), lean mass, or the percentage of body fat. Clinical follow-up At 6 wk, 6 mo, and one year after the procedures, there were no statistical differences between the FMT and placebo groups for any of the following: body weight; BMI; waist circumference; hip circumference; fasting glucose; insulin; glycated hemoglobin (Table 2); the insulin resistance profile; the respiratory compensation point; and the lipid profile. Table 2 Glycated hemoglobin levels over the course of the study, by group Group N Mean SD Range Median IQR FMT (n = 15) Baseline 11 6.75 1.09 5.60–8.90 6.30 6.10–7.60 6 wk 11 6.65 1.09 5.60–9.10 6.10 6.00–7.60 6 mo 11 6.95 1.19 5.40–9.50 6.50 6.20–7.70 1 yr 11 7.34 1.85 5.60–11.50 6.70 5.80–8.30 Placebo (n = 13) Baseline 11 6.99 1.99 4.80–12.50 6.60 6.00–7.50 6 wk 11 6.75 1.38 5.00–10.20 6.30 6.00–7.40 6 mo 11 6.97 1.98 4.90–12.20 6.40 5.90–7.20 1 yr 11 7.29 2.56 4.90–13.80 6.30 5.90–8.10 IQR: Interquartile range; FMT: Fecal microbiota transplantation. Microbiome analysis In both groups, the predominant phyla were Firmicutes and Bacteroidetes (Figure 1). At 6 wk after the procedures, the relative abundance of Firmicutes was higher in the placebo group than in the FMT group (Figure 1A and Supplementary Table 1). Over the course of the study period, the abundance of Firmicutes in the FMT group increased, whereas that of Bacteroidetes decreased in that group, resulting in the Firmicutes/Bacteroidetes ratio being higher in the FMT group than in the placebo group. In both groups, the most abundant genera were Bacteroides, Prevotella, Ruminococcaceae UCG-002, and Megasphaera (Figure 1B and Supplementary Table 2). Although there were no significant differences in the abundances of genera and phyla between the groups and among the time points, there was a marked increase in Ruminococcus 2 and Phascolarctobacterium in the placebo group, as well as a decrease in Bacteroides in the FMT group. Over the course of the study, the abundances of Prevotella, Ruminococcaceae UCG-002, and Faecalibacterium were higher in the FMT group than in the placebo group. Figure 1 Relative abundance of taxa. A and B: Show the relative abundance of phyla and of the top 15 genera, respectively, in all samples at baseline, as well as in the placebo and fecal microbiota transplantation groups at 6 wk and 1 year after the procedures. FMT: Fecal microbiota transplantation. Alpha and beta diversity There were no significant differences between the FMT and placebo groups in terms of the alpha diversity (Figure 2). However, we observed a significant negative correlation between the Shannon diversity index and the percentage of body fat in both groups. We also found that the Chao1 richness estimate showed a significant negative correlation with fat mass, as did the Shannon and Simpson diversity indices. Figure 2 Alpha diversity indices, by group, over time. A: The Shannon diversity index; B: The Chao1 richness estimate; C: The Simpson diversity index; D: The operational taxonomic units observed, over time, in the placebo and fecal microbiota transplantation groups. FMT: Fecal microbiota transplantation; OTUs: Operational taxonomic units. The beta diversity of the microbial community showed significant differences between the FMT and placebo groups over the course of the study (Figure 3): At baseline (F = 0.83294, R2 = 0.033542, P = 0.603); at 6 wk after the procedures (F = 1.9699, R2 = 0.070431, P = 0.039); and at 1 year after the procedures (F = 3.0656, R2 = 0.15278, P < 0.003). Figure 3 Beta diversity over time. PbO: Placebo; FMT: Fecal microbiota transplantation. DISCUSSION The gut microbiota has been shown to play a role in a number of diseases, including inflammatory bowel disease[25-27], pseudomembranous colitis[28], primary sclerosing cholangitis[29], and cardiovascular disease. The gut microbiota also interacts with obesity, metabolic syndrome, and insulin resistance[30] which have common risk factors and are highly correlated. The gut microbiota appears to be an important factor in the development of obesity and metabolic syndrome, FMT therefore being a possible treatment modality. Controlled studies have shown that FMT alters the gut microbiota of rats and reduces their weight, indicating that the microbiota is directly related to nutrient absorption capacity[12]. In one randomized controlled study of FMT, involving male patients with metabolic syndrome[31], the glycemic profile at six weeks after FMT was found to be better in the patients who received microbiota (from lean individuals) than in those who received autologous microbiota. In another randomized controlled trial[32], 38 obese male patients were randomized to receive autologous microbiota or allogeneic microbiota from lean donors. The authors found that, by six weeks after the procedures, there was a significant (11.5%) increase in insulin resistance among the patients who received allogeneic microbiota, although that increase was not maintained at 18 wk after the procedure, which suggests that FMT has only a short-term effect. In a double-blind randomized controlled study of FMT[33], 20 male patients with metabolic syndrome were allocated to receive autologous or allogeneic (vegan) microbiota. In that study, a slight improvement in insulin resistance was observed at two weeks after FMT in the patients receiving allogeneic microbiota. In a systematic review of FMT in obese individuals with metabolic syndrome[34], the authors evaluated three randomized placebo-controlled studies involving a collective total of 63 patients. They identified no statistical differences between FMT and placebo in terms of the glycemic profile or weight loss. However, the studies evaluated differed in various aspects, including the number of donors, follow-up time, and means of preparation of the microbiota solution. Another systematic review of FMT in patients with obesity and metabolic syndrome[35], published in 2020, evaluated six studies: The three randomized placebo-controlled studies mentioned above[32,33] two randomized double-blind placebo-controlled studies[36] and the prepublication data of the present study. The authors of that review, which involved a collective total of 154 patients, detected no statistical difference between FMT and placebo in terms of the clinical parameters evaluated. In the present study, there were no significant differences in biochemical or anthropometric parameters, between the two groups or at any of the time points evaluated. Nevertheless, there were significant postprocedural differences in the microbiota composition between the placebo group and the FMT group, as evidenced by the beta diversity results, which indicate that FMT is effective in changing the gut microbiome and that such changes can persist for at least one year after the procedure. However, other studies have shown that there is no difference in alpha diversity in the gut microbiome, as assessed with the Shannon diversity index, between patients receiving FMT and those receiving a placebo[33,34]. In one such study[33], the FMT group subjects were divided into two subgroups, based on the insulin sensitivity response observed: Metabolic responders and metabolic nonresponders. Among the metabolic responders, there was a significant increase (in relation to the baseline value) in the relative abundance of Akkermansia muciniphila. Human and animal studies have demonstrated that A. muciniphila is closely associated with improvements in insulin sensitivity[37]. Its beneficial effects may be due to a microbe-induced increase in the intestinal level of endocannabinoids and epithelial expression of Toll-like receptor two, which regulates gut barrier function and inflammation[37]. However, we observed no difference between our FMT group and our placebo group, in terms of the abundance of A. muciniphila, at six weeks or one year. The lack of a statistical difference regarding the abundance of A. muciniphila cannot be evaluated in isolation, as the health of the gut microbiome is defined in terms of diversity, stability, resistance, and resilience[38]. Limitations This trial has some limitations. As gut dysbiosis can be influenced by inflammation, diet, and environmental exposures[39], there was great variability among the individuals evaluated. This variability could be attributed, in part, to the fact that the recommended standardized diet was not followed. All of the patients evaluated were insulin resistant or had diabetes, and it is known that the use of medications such as metformin can change the diversity of the intestinal microbiota[40]. In addition, there is as yet no well-established protocol for preparing the donor intestinal microbiota. Although we followed the protocol devised by van Nood et al[2], it was not possible to ensure that the anaerobic bacteria remained viable until the time of transplantation. The two species most strongly associated with metabolic health—Faecalibacterium prausnitzii and A. muciniphila—are both anaerobic[41,42]. An anaerobic microbiota preparation protocol may be necessary to increase bacterial viability and engraftment success of strict anaerobes in FMT[43]. It would thus be possible to transplant a greater diversity of microbiota and keep the composition of the microbiota solution as close as possible to that of the donor sample. Furthermore, we opted for infusion by colonoscopy, which is just one of the many possible routes of delivery of FMT, and success rates have been shown to vary depending on the route of delivery[44]. Further studies are needed in order to understand the dose and duration of therapy required to maximize the therapeutic effect of FMT, while optimizing patient tolerance and compliance[45]. Moreover, we included only one donor (a female) and our sample comprised only female patients, whereas most comparable studies in the literature have evaluated male patients. Sex is recognized as an important factor in a variety of common conditions, including autoimmune, metabolic, cardiovascular, and psychiatric disorders[46]. Finally, our analysis was also limited not only by the small size of our sample but also by the small number of studies of the topic in the literature and their small sample sizes. As this was a single-center study, our findings may not reflect the outcomes that can be expected across global populations. CONCLUSION In the present study, there were no significant differences in biochemical or anthropometric parameters, between the two groups or at any of the time points evaluated. Nevertheless, there were significant postprocedural differences in the microbiota composition between the placebo group and the FMT group, as evidenced by the beta diversity results, which indicate that FMT is effective in changing the gut microbiome and that such changes can persist for at least 1 year after the procedure. ARTICLE HIGHLIGHTS Research background The prevalence of metabolic syndrome parallels that of obesity and diabetes—up to 45% of the population worldwide. New therapeutic methods have emerged to join efforts in the fight against obesity and metabolic syndrome. Research motivation To investigate new methods for the treatment of metabolic syndrome. Research objectives Evaluate the outcomes of fecal microbiota transplantation (FMT) in patients with metabolic syndrome. Research methods This was a randomized, single-blind, placebo-controlled clinical trial comparing FMT and a sham procedure in patients with metabolic syndrome. The trial was registered at ensaiosclinicos.gov.br (identifier: U1111-1223-6951). Research results There was evidence of a postprocedural change in microbiota composition in the patients who underwent FMT in relation to that observed in those who underwent the sham procedure. However, we found no difference between the two groups in terms of the clinical parameters evaluated. Research conclusions There were no significant differences in biochemical or anthropometric parameters, between the two groups evaluated. Nevertheless, there were significant postprocedural differences in the microbiota composition between the placebo group. To date, clinical outcomes related to FMT remain uncertain. Research perspectives Studies with larger patient samples should be carried out in order to assess the potential effects of fecal microbiota transplantation on clinical parameters. Data sharing statement No additional data are available. Institutional review board statement: The study was approved by the Research Ethics Committee of the University of São Paulo School of Medicine, Approval No. CAAE: 62319916.9.0000.0068. Clinical trial registration statement: The trial was registered at ensaiosclinicos.gov.br (identifier: U1111-1223-6951). Informed consent statement: All subjects agreed to participate in this study after informed consent and ethical permission was obtained. Conflict-of-interest statement: All the authors declare that they have no conflicts of interest related to this manuscript. CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement. Provenance and peer review: Invited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: January 10, 2023 First decision: January 21, 2023 Article in press: May 4, 2023 Specialty type: Gastroenterology and hepatology Country/Territory of origin: Brazil Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): B Grade C (Good): C Grade D (Fair): 0 Grade E (Poor): 0 P-Reviewer: Farhat H, Qatar; Sun SY, China S-Editor: Liu JH L-Editor: Webster JR P-Editor: Ju JL ==== Refs 1 Saklayen MG The Global Epidemic of the Metabolic Syndrome Curr Hypertens Rep 2018 20 12 29480368 2 Alberti KG Zimmet P Shaw J Metabolic syndrome--a new world-wide definition. 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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4544 10.12998/wjcc.v11.i19.4544 Retrospective Study Analysis of characteristic features in ultrasound diagnosis of fetal limb body wall complex during 11-13+6 weeks Ye CH et al. Ultrasound diagnosis of fetal LBWC Ye Cai-Hong Department of Ultrasound, Yijishan Hospital Wannan Medical College, Wuhu 241001, Anhui Province, China. ychyjsyy@163.com Li Shuo Department of Ultrasound, Wannan Medical College, Wuhu 241001, Anhui Province, China Ling Li Department of Obstetrics, Wannan Medical College, Wuhu 241001, Anhui Province, China Author contributions: Ye CH contributed to the conception and design, administrative support, and manuscript writing; Ye CH and Ling L contributed to the provision of study materials or patients; all authors contributed to the data collection and assembly; Li S contributed to the data analysis and interpretation; All authors contributed to the final approval of manuscript. Corresponding author: Cai-Hong Ye, Doctor, MM, Associate Chief Physician, Deputy Director, Department of Ultrasound, Yijishan Hospital Wannan Medical College, No. 2 Zheshan West Road, Wuhu 241001, Anhui Province, China. ychyjsyy@163.com 6 7 2023 6 7 2023 11 19 45444552 14 4 2023 3 5 2023 23 5 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND Limb body wall complex (LBWC) is a fatal malformation characterized by major defects in the fetal abdominal or thoracic wall, visceral herniation, significant scoliosis or spina bifida, limb deformities, craniofacial deformities, and umbilical cord abnormalities (short or absent umbilical cord). Early diagnosis of this condition is of great clinical significance for clinical intervention and pregnancy decision-making. With the rapid development of fetal ultrasound medicine, early pregnancy (11-13+6 wk) standardized prenatal ultrasound examinations have been widely promoted and applied. AIM To explore the value of prenatal ultrasound in the diagnosis of fetal LBWC syndrome during early pregnancy. METHODS The ultrasonographic data and follow-up results of 18 cases of fetal LBWC diagnosed by prenatal ultrasound during early pregnancy (11-13+6 wk) were retrospectively analyzed, and their ultrasonographic characteristics were analyzed. RESULTS Among the 18 fetuses with limb wall abnormalities, there were spinal dysplasia (18/18, 100%), varying degrees of thoracoschisis and gastroschisis (18/18, 100%), limb dysplasia in 6 cases (6/18, 33%), craniocerebral malformations in 4 cases (4/18, 22%), thickening of the transparent layer of the neck in 5 cases (5/18, 28%), and umbilical cord abnormalities in 18 cases (18/18, 100%), single umbilical artery in 5 cases. CONCLUSION Prenatal ultrasound in early pregnancy can detect LBWC as early as possible, and correct prenatal evaluation provides important guidance value for pregnancy decision-making and early intervention. Early pregnancy Ultrasonography Limb body wall complex Fetus ==== Body pmc Core Tip: Limbs-body wall complex (LBWC) is a fatal malformation characterized by severe defects in the abdominal or chest wall of the fetus, resulting in protruding viscera, severe scoliosis or spina bifida, limb deformities, craniofacial malformations, and abnormal umbilical cord (short or absent). Our study focuses on the significance of using prenatal ultrasound in detecting LBWC during early pregnancy, where we also provide a retrospective analysis of ultrasound data and post-abortion consequences of 18 confirmed cases of LBWC. We aim to investigate further and identify the ultrasound characteristics of LBWC in early pregnancy to enhance our knowledge of this condition. INTRODUCTION Limb body wall complex (LBWC) is a fatal malformation characterized by major defects in the fetal abdominal or thoracic wall, visceral herniation, significant scoliosis or spina bifida, limb deformities, craniofacial deformities, and umbilical cord abnormalities (short or absent umbilical cord)[1,2]. Early diagnosis of this condition is of great clinical significance for intervention and pregnancy decision-making. With the rapid development of fetal ultrasound medicine[3,4], early pregnancy (11-13+6 wk) standardized prenatal ultrasound examinations have been widely promoted and applied. However, there are relatively few reports on early pregnancy ultrasound screening for LBWC. In this study, we retrospectively analyzed the sonographic data and post-abortion results of 18 cases diagnosed with LBWC in early pregnancy to explore the ultrasound features of prenatal diagnosis of LBWC in early pregnancy and enhance the understanding of LBWC. MATERIALS AND METHODS Study subjects From March 2015 to October 2022, a total of 35486 pregnant women underwent early pregnancy (11-13+6 wk) fetal nuchal translucency (NT) ultrasound examination at our hospital. Among them, 18 cases of LBWC were detected and confirmed after induced abortion. The pregnant women's ages ranged from 21 years to 39 years, with an average age of 28 years. The gestational age of the fetuses was calculated based on the menstrual cycle, and all were singleton pregnancies. Study methods GE Voluson E8 and Philips EPIQ7 color Doppler ultrasound diagnostic instruments were used in our study, with a 2-8 MHz two-dimensional convex array probe. In accordance with the requirements of the Chinese "Prenatal Ultrasound Screening Guidelines", pregnant women were informed of the appropriate gestational age, content, purpose, importance, and limitations of early pregnancy prenatal ultrasound screening. In this study, all patients were placed in a supine position, and during the examination, in addition to routine checks for the number of fetuses, fetal heartbeat, placenta, and amniotic fluid, the main growth parameters of the fetus and the spectrum of the venous duct were measured. In cases with multiple pregnancies, chorionicity and amnionicity were determined. The focus was on obtaining the fetal mid-sagittal plane and measuring the crown-rump length and NT thickness on this plane, taking the average of three measurements. The presence or absence of the fetal nasal bone was also observed. In addition, the following ultrasound screening planes were included: starting from the fetal head and sequentially examining the skull and brain. The lateral ventricle transverse plane primarily observed the lateral ventricle level cranial halo, cerebral falx, and bilateral choroid plexus in the lateral ventricles. With the abdomen, the umbilical cord abdominal wall entrance transverse plane primarily observed the structure at the umbilical cord abdominal wall entrance. All planes were saved in the workstation. If a defect in the fetal abdominal wall or thoracoabdominal wall was found, it was necessary to carefully observe whether there were abnormal echo masses and the size, shape, and structural echoes of the masses, whether the physiological curvature of the spine had changed, the development of the limbs, and whether there were any abnormalities in the umbilical cord. RESULTS General information of pregnant women As shown in Table 1, the ages of pregnant women ranged from 21 years to 39 years old, with an average of 27-years-old. Gestational age ranged from 11-13+6 wk, with an average gestational age of 12+6 wk. Among the 18 cases, 11 cases of the 18 cases were screened for Down's syndrome in the first trimester and all were found to be low risk. Table 1 General information of pregnant women No. Age Gestational age in wk Pregnancy history, G/P/A/L Embryo transplantation Down syndrome screening status 1 29 13 G1P0 No Unchecked 2 28 13+6 G2P0A1 Yes Unchecked 3 25 13+5 G1P0 No Low-risk 4 21 12+3 G1P0 No Low-risk 5 23 12+4 G1P0 No Low-risk 6 26 12 G2P0A1 No Low-risk 7 30 11+2 G2P0A1 No Low-risk 8 29 13 G1P0 No Low-risk 9 38 11+3 G1P0 Yes Low-risk 10 25 13+2 G1P0 No Low-risk 11 28 12+6 G2P0A1 No Low-risk 12 24 11+6 G1P0 No Low-risk 13 32 12+3 G2P1L1 No Low-risk 14 26 12+4 G1P0 No Unchecked 15 39 13+6 G1P0 Yes Unchecked 16 31 13+5 G2P0A1 Yes Unchecked 17 21 13+2 G1P0 No Low-risk 18 26 13 G1P0 No Low-risk G: Gestation; P: Production; A: Abortion; L: Live. Fetal NT measurement As shown in Table 2, all 18 cases of LBWC fetuses were single live fetuses. Among the 11 cases, 5 had increased NT thickness, 2 had cystic hygromas, and 7 were not measurable. Table 2 Fetal nuchal translucency measurement result No. NT Nasal bone visible Ductus venosus 1 2.0 Yes Visible, no reverse a-wave 2 Unmeasurable No Invisible 3 Unmeasurable No Visible, no reverse a-wave 4 Unmeasurable Yes Invisible 5 Unmeasurable No Invisible 6 2.3 Yes Visible, no reverse a-wave 7 3.8 Yes Invisible 8 Unmeasurable No Visible, no reverse a-wave 9 Unmeasurable Yes Invisible 10 1.3 Yes Visible, no reverse a-wave 11 1.8 Yes Invisible 12 3.4 Yes Visible, no reverse a-wave 13 1.1 Yes Visible, no reverse a-wave 14 4.7 Yes Visible, no reverse a-wave 15 2.8 Yes Visible, no reverse a-wave 16 Unmeasurable No Invisible 17 3.6 Yes Visible, no reverse a-wave 18 2.4 Yes Visible, no reverse a-wave NT: Nuchal translucency. Ultrasound sonographic analysis of LBWC As shown in Table 3, all fetuses had severe thoracoschisis or gastroschisis (18/18, 100%), either spinal scoliosis and torsion (18/18, 100%). Among them, 6 cases (6/18, 33%) had limb developmental abnormalities, 4 cases (4/18, 22%) had cranial malformations, and 1 case had spina bifida. Umbilical cord abnormalities, such as being too short or absent, were observed in 11 cases (11/18, 61%). Color Doppler examination revealed only one umbilical artery in 5 fetuses. None of the fetuses had detectable facial abnormalities (Figure 1). All 18 pregnant women chose to terminate their pregnancies, which was confirmed after induced abortions. Figure 1 Ultrasound sonographic analysis of limb body wall complex. A: The fetus with the absence of the thoracic and abdominal walls and the contents seen floating within the amniotic fluid; B: The baby postdelivery confirming the evisceration of the heart, liver, stomach, large and small bowel loops; C: Fetal umbilical artery blood flow spectrum, no venous catheter blood flow detected; D: Kyphosis of the thoracolumbar spine. Table 3 Ultrasound sonographic analysis of limb body wall complex No. Ultrasonic anomaly Body wall defect and bulge Spine Limbs Brain Umbilical cord Others 1 Gastroschisis (bulge is liver) Torsion Both feet varus - Short 2 Gastroschisis (bulge is liver) Torsion - - Undetectable Cloacal malformation 3 Thoracoschisis and Gastroschisis (bulge are heart, liver, intestinal tube) Twist into angles - Brain herniation Short 4 Gastroschisis (bulge are liver, gastric vesicles and intestinal tubes) Twisted arrangement irregularity - Encephalocele Undetectable Fetal cystic hygroma 5 Gastroschisis (bulge are liver, gastric vesicles and intestinal tubes) Torsion Miss left upper limb Meningoencephalocele Undetectable 6 Gastroschisis (bulge are liver, gastric vesicles and intestinal tubes) Curved, middle and lower segments not shown - Short 7 Gastroschisis (bulge are liver, gastric vesicles and intestinal tubes) Twist into angles Miss one upper limb Undetectable 8 Gastroschisis (bulge are liver, gastric vesicles and intestinal tubes) Abnormal bending, abnormal alignment Short Fetal cystic hygroma 9 Gastroschisis (bulge is liver) Torsion Meningoencephalocele Undetectable 10 Gastroschisis (bulge are liver, gastric vesicle and intestinal tube) Lordotic bending - Short Single umbilical artery 11 Thoracoschisis and gastroschisis (bulge are heart, liver, intestinal tube and gastric vesicle) Lordotic bending - Undetectable 12 Gastroschisis (bulge are liver, intestinal tube) Lordotic bending - Short 13 Gastroschisis (bulge are liver, intestinal tube) Angle the side - Short 14 Gastroschisis and malformation (bulge are liver and intestine) Lordotic bending Miss left upper arm - Short 15 Gastroschisis and malformation (bulge are liver, intestinal tube and gastric vesicle) Side bending and twisting - Short Single umbilical artery 16 Gastroschisis (bulge are liver, gastric vesicles and intestinal tubes) Lordotic bending Lower limb fusion - Undetectable 17 Gastroschisis (bulge are liver, gastric vesicles and intestinal tubes) Torsion Miss right lower limb Short 18 Acromphalus (bulge is liver) Torsion - Short Megacystis DISCUSSION Embryonic development mechanism of fetal LBWC LBWC is an uncommon, intricate, and fatal multi-malformation syndrome characterized by encephalocele and/or craniofacial clefts, thoracoschisis or gastroschisis, and limb deformities. Other features may include spinal scoliosis, genitourinary abnormalities, and short umbilical cords. The initial diagnostic criteria for LBWC were established by Van Allen et al[5] in 1987, and a diagnosis can be confirmed by the presence of two of the following three malformations: any type of limb defect, encephalocele or anencephaly with facial cleft, thoracoschisis or gastroschisis with visceral herniation. The etiology of LBWC remains uncertain, there are three pathogenic mechanisms that have been discussed by foreign scholars[6-10]. Firstly, abnormal folding of the trilaminar embryonic disc during the first 4 wk of embryonic development. Secondly, early amniotic rupture with amniotic band syndrome. Finally, early embryonic vascular rupture leading to widespread blood flow impairment. (1) Abnormal folding of the trilaminar embryonic disc during the first 4 wk of embryonic development, which represents the complete failure of folding along the three axes (cranial, caudal, and lateral) of the body. Abnormal longitudinal folding results in thoracoschisis or gastroschisis, while abnormal transverse folding prompts abdominal contents to protrude into an expansive amniotic sac, which inserts peripherally into the placental chorionic plate, resulting in absent or short umbilical cords. As a result of the compression of abdominal viscera, the spine and thoracic cavity cannot develop symmetrically, leading to severe spinal scoliosis and trunk abnormalities. Poor spinal rotation and incomplete pelvic closure may lead to congenital limb deformities[7]. (2) Early amniotic rupture. Early amniotic rupture caused by mechanical pressure or amniotic bands can lead to severe deformities such as spinal malformations, gastroschisis, and extremely short umbilical cords if the rupture occurs at the caudal end, with the lower half of the embryo entering the extraembryonic cavity through the rupture[8]. This mechanism was questioned by Paul et al[11], who reported a case of intact LBWC at 10 wk of gestation without rupture of the amniotic cavity. And (3) early embryonic vascular rupture or developmental abnormality. Some studies[10] suggest that vascular rupture during early pregnancy (at 4-6 wk of gestation) leads to the interruption of normal blood supply to the developing embryo, resulting in ischemia, hypoxia, hemorrhagic necrosis, and abnormal development of the embryonic disc, which in turn affects the closure of the abdominal wall and extraembryonic cavity. Arshad believes that the pathogenesis of LBWC is more inclined towards the theory of early embryonic abnormal folding[12], with the malformations associated with LBWC depending on the degree of abnormal folding of the embryonic disc. On the other hand, Sahinoglu et al[13] and others believe that due to the complexity of LBWC malformations, all of the above pathogenic mechanisms are possible, leading to different subgroups. LBWC classification There are many literature reports and controversies about the classification of LBWC, and most studies currently divide it into two types based on the characteristic abnormalities of LBWC[13-16]. Type I is based on craniofacial defects, while Type II is based on thoracoschisis or gastroschisis. However, Sahinoglu et al[13] proposed a new phenotypic classification, dividing it into three types, Type I still refers to craniofacial defects, while Type II refers to gastroschisis located above the umbilicus and large chest-abdominal wall defects. Type III pertains to defects located below the umbilicus, while the chest wall remains intact. This article primarily concentrates on thoracoschisis and gastroschisis, which aligns with the research conducted by Akinmoladun et al[17]. Ultrasonographic features of LBWC in early pregnancy At present, early pregnancy ultrasound examination is considered the safest and most reliable imaging technique for screening severe fetal structural malformations. Owing to the relatively large extraembryonic coelom in early pregnancy, it becomes straightforward to distinctly display the extent of thoracoschisis or gastroschisis as well as the protrusion of organs in the thoracoabdominal cavity into the extraembryonic coelom, making the diagnosis relatively easy. With the widespread popularity of early pregnancy (11-13+6 wk) prenatal ultrasound examinations, many severe fetal structural malformations have been detected. Some scholars believe that the most characteristic ultrasonographic clue for LBWC in early pregnancy is spinal curvature[18]. The basis for ultrasound diagnosis of LBWC may be when the fetus has a large abdominal or chest-abdominal wall defect, herniation of the viscera, short or absent umbilical cord combined with spinal abnormalities[19,20]. The sonographic characteristics of the 18 LBWC fetuses in our investigation can be summarized as follows: (1) The most common and severe malformation in LBWC is the thoracoschisis or gastroschisis[21,22]. Due to the absence of abdominal wall development, the defect area is large and may be accompanied by chest wall defects, resulting in the opening of the thoracoabdominal viscera to the amniotic cavity. Prenatal ultrasound shows a large defect at the insertion of the fetal umbilical cord on the abdominal wall, with abnormal echo masses at the defect site, and the fetal liver, stomach bubble, and intestine protruding into the extraembryonic coelom. The umbilical cord is difficult to display or appears too short. Daskalakis et al[23] and others believe that abdominal wall defects can be roughly divided into three types, gastroschisis, umbilical protrusion, and body stalk-like malformation. LBWC can be considered when accompanied by spinal curvature or torsion, anencephaly or encephalocele, facial abnormalities, and limb development abnormalities; (2) All 18 fetuses had spinal developmental abnormalities, manifested as spinal kyphosis, torsion or scoliosis, causing the fetus to be in a flexed or hyperextended state, making it difficult to obtain the mid-sagittal section required for measuring crown-rump length in prenatal ultrasound screening guidelines, and thus unable to accurately determine the gestational age of the fetus by ultrasound. In this study, all cases were calculated by menstrual age. In this group, the earliest large abdominal wall defect was seen at 11+2 wk. In this group, all cases had varying degrees of thoracoschisis or gastroschisis and abnormal spinal curvature; (3) Increased fetal NT, similar to the findings of Daniilidis et al[24]. In our study, 4 cases out of 18 LBWC cases were normal, 5 cases had increased NT, and 9 cases could not be measured due to spinal torsion or concomitant cranial abnormalities. Although LBWC fetuses often have abnormal NT thickening or fetal edema, 8 cases in this group underwent early pregnancy Down syndrome screening and all were classified as low risk. Previous studies[13,25] have shown that fetuses with LBWC have a normal chromosomal karyotype and the recurrence rate in subsequent pregnancies is very low; (4) Cranial abnormalities. In our 18 cases, 3 had encephalocele, and 1 had exencephaly; (5) Limb abnormalities. In our study, limb abnormalities were manifested as clubfoot, limb agenesis, or fusion; and (6) Short or absent umbilical cord. Other associated malformations include megacystis, fetal cystic hygroma, and abnormal development of the cloacal cavity. Differential diagnosis of LBWC Owing to the numerous resemblances in ultrasound manifestations between LBWC and Cantrell's pentalogy[25], the latter primarily encompasses omphalocele, ectopia cordis, lower sternal defects, anterior diaphragmatic defects, and pericardial defects. Its hallmark features are omphalocele and ectopia cordis. Nevertheless, Cantrell's pentalogy does not involve spinal and limb developmental abnormalities, which serve as crucial distinguishing factors from LBWC[26]. CONCLUSION As LBWC is a lethal disease, enhancing early detection is of utmost importance. Prenatal ultrasound should be well-acquainted with the sonographic features of LBWC, such as thoracoschisis and gastroschisis, severe spinal scoliosis, neural tube defects, limb abnormalities, and absence or shortening of the umbilical cord. Furthermore, when spinal scoliosis and omphalocele are observed, the likelihood of LBWC should be strongly considered. In conclusion, early pregnancy ultrasound can effectively diagnose LBWC, and precise prenatal evaluation holds significant value for informing parental decision-making. ARTICLE HIGHLIGHTS Research background There are relatively few reports on early pregnancy ultrasound screening for Limb body wall complex (LBWC). In this study, we retrospectively analyzed the sonographic data and post-abortion results of 18 cases diagnosed with LBWC in early pregnancy to explore the ultrasound features of prenatal diagnosis of LBWC in early pregnancy and enhance the understanding of LBWC. Research motivation In this study, we retrospectively analyzed the sonographic data and post-abortion results of 18 cases diagnosed with LBWC in early pregnancy to explore the ultrasound features of prenatal diagnosis of LBWC in early pregnancy and enhance the understanding of LBWC. Research objectives To explore the value of prenatal ultrasound in the diagnosis of fetal LBWC syndrome during early pregnancy. Research methods The ultrasonographic data and follow-up results of 18 cases of fetal LBWC diagnosed by prenatal ultrasound during early pregnancy (11-13+6 wk) were retrospectively analyzed, and their ultrasonographic characteristics were analyzed. Research results Among the 18 fetuses with limb wall abnormalities, there were spinal dysplasia (18/18, 100%), varying degrees of thoracoschisis and gastroschisis (18/18, 100%), limb dysplasia in 6 cases (6/18, 33%), craniocerebral malformations in 4 cases (4/18, 22%), thickening of the transparent layer of the neck in 5 cases (5/18, 28%), and umbilical cord abnormalities in 18 cases (18/18, 100%), single umbilical artery in 5 cases. Research conclusions Prenatal ultrasound in early pregnancy can detect LBWC as early as possible, and correct prenatal evaluation provides important guidance value for pregnancy decision-making and early intervention. Research perspectives As LBWC is a lethal disease, enhancing early detection is of utmost importance. Prenatal ultrasound should be well-acquainted with the sonographic features of LBWC, such as thoracoschisis and gastroschisis, severe spinal scoliosis, neural tube defects, limb abnormalities, and absence or shortening of the umbilical cord. Furthermore, when spinal scoliosis and omphalocele are observed, the likelihood of LBWC should be strongly considered. In conclusion, early pregnancy ultrasound can effectively diagnose LBWC, and precise prenatal evaluation holds significant value for informing parental decision-making. Data sharing statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Institutional review board statement: The study was approved by Institutional Review Board of Yijishan Hospital, Wannan Medical College. Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment. Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: April 14, 2023 First decision: April 26, 2023 Article in press: May 23, 2023 Specialty type: Pediatrics Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): 0 Grade C (Good): C, C Grade D (Fair): 0 Grade E (Poor): 0 P-Reviewer: Guerriero S, Italy; Matute JD, United States S-Editor: Yan JP L-Editor: Filipodia P-Editor: Yan JP ==== Refs 1 Mandrekar SR Amoncar S Banaulikar S Sawant V Pinto RG Omphalocele, exstrophy of cloaca, imperforate anus and spinal defect (OEIS Complex) with overlapping features of body stalk anomaly (limb body wall complex) Indian J Hum Genet 2014 20 195 198 25400352 2 Baruah P Ray Choudhury P Limb body wall complex with sacrococcygeal mass and agenesis of external genitalia Case Rep Med 2013 2013 218626 23970900 3 Wang J Chen L Zhou C Wang L Xie H Xiao Y Yin D Zeng Y Tang F Yang Y Zhu H Chen X Zhu Q Liu Z Liu H Identification of copy number variations among fetuses with ultrasound soft markers using next-generation sequencing Sci Rep 2018 8 8134 29802277 4 Yang T Li R Liang N Li J Yang Y Huang Q Li Y Cao W Wang Q Zhang H The application of key feature extraction algorithm based on Gabor wavelet transformation in the diagnosis of lumbar intervertebral disc degenerative changes PLoS One 2020 15 e0227894 32101549 5 Van Allen MI Curry C Walden CE Gallagher L Patten RM Limb-body wall complex: II. 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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4655 10.12998/wjcc.v11.i19.4655 Case Report CDKN1C gene mutation causing familial Silver–Russell syndrome: A case report and review of literature Li J et al. Familial Silver–Russell syndrome Li Jie Department of Paediatrics, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu 610000, Sichuan Province, China Chen Li-Na Department of Paediatrics, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu 610000, Sichuan Province, China. linachen9755@163.com He Hai-Lan Department of Paediatrics, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, Chengdu 610000, Sichuan Province, China Author contributions: Li J and Chen LN wrote the study plan, requested ethical approval, and contacted the family; Chen LN examined the patients; Li J wrote the first draft; Li J, Chen LN and He HL performed the corrections on the different versions of the draft, revised the literature, and updated the manuscript; All the authors approved the final version of the manuscript. Supported by the China Foundation for International Medical Exchange, Pediatric Endocrinology Young and Middle-Aged Doctors’ Growth Research Fund, No. Z-2019-41-2101-01. Corresponding author: Li-Na Chen, MD, Doctor, Department of Paediatrics, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, No. 32, West Section 2, Yihuan Road, Qingyang District, Chengdu 610000, Sichuan Province, China. linachen9755@163.com 6 7 2023 6 7 2023 11 19 46554663 1 2 2023 5 5 2023 31 5 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND Cyclin-dependent kinase inhibitor 1C (CDKN1C) is a cell proliferation inhibitor that regulates the cell cycle and cell growth through G1 cell cycle arrest. CDKN1C mutations can lead to IMAGe syndrome (CDKN1C allele gain-of-function mutations lead to intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary malformations). We present a Silver-Russell syndrome (SRS) pedigree that was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). The affected family members had an SRS phenotype but did not have limb asymmetry or adrenal insufficiency. The amino acid changes in this specific region were located in a narrow functional region that contained mutations previously associated with IMAGe syndrome. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants. CASE SUMMARY We describe the case of an 8-year-old girl who initially presented with short stature. Her height was 91.6 cm, and her weight was 10.2 kg. Physical examination revealed that she had a relatively large head, an inverted triangular face, a protruding forehead, a low ear position, sunken eye sockets, and irregular cracked teeth but no limb asymmetry. Family history: The girl’s mother, great-grandmother, and grandmother’s brother also had a prominent forehead, triangular face, and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency. Exome sequencing of the girl revealed a new heterozygous CDKN1C (NM_000076. 2) c.836G>A mutation, resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine (p.Arg279His). The same causative mutation was found in both the proband’s mother, great-grandmother, and grandmother’s brother, who had similar phenotypes. Thus far, we found an SRS pedigree, which was due to a missense mutation affecting the same amino acid position, 279, in the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Although the SRS-related CDKN1C mutation is in the IMAGe-related mutation hotspot region [the proliferating cell nuclear antigen (PCNA) domain], no adrenal insufficiency was reported in this SRS pedigree. The reason may be that the location of the genomic mutation and the type of missense mutation determines the phenotype. The proband was treated with recombinant human growth hormone (rhGH). After 1 year of rhGH treatment, the height standard deviation score of the proband increased by 0.93 standard deviation score, and her growth rate was 8.1 cm/year. No adverse reactions, such as abnormal blood glucose, were found. CONCLUSION Functional mutations in CDKN1C can lead to familial SRS without limb asymmetry, and some patients may have glucose abnormalities. In familial SRS patients, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all patients with functional CDKN1C variants. CDKN1C Gene Silver-Russell syndrome Mutation Case report ==== Body pmc Core Tip: This is the fourth reported case of familial Silver–Russell syndrome (SRS) caused by a new missense mutation in the PCNA-binding domain of CDKN1C.The SRS pedigree, which was due to missense mutation affecting the amino acid position, 279, of the PCNA-binding domain of the CDKN1C gene, resulting in the amino acid substitution p.Arg279His (c.836G>A). Five affected family members also showed SRS phenotypes (small for gestational age, proportionately severe short stature, certain facial features (protruding forehead, triangular face, micrognathia), but without limb asymmetry or adrenal insufficiency. Initial efficacy and safety of growth hormone were observed in the proband treated with growth hormone. INTRODUCTION Cyclin-dependent kinase inhibitor 1C (CDKN1C), also known as p57/Kip2 (OMIM 600856), is active only when inherited maternally. The paternal copy is imprinted on the short arm of chromosome 11 (11p15.4) and is dose-sensitive. By binding to the cyclin/cyclin-dependent kinase complex, the CDKN1C protein prevents DNA replication and cell entry into S phase, arrests the cell cycle in G1 phase, and inhibits cell proliferation[1,2]. Up to 10%–15% of cases of Beckwith–Wiedemann Syndrome (BWS) are familial, and most cases are a result of CDKN1C loss-of-function mutations[3,4]. The clinical features of BWS include macrosomia, hyperinsulinemia, and adrenal tumours[5]. In contrast, gain-of-function variants of CDKN1C have been shown to cause conditions of growth restriction, including IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital malformations) syndrome[6] and familial Silver–Russell syndrome (SRS)[7]. IMAGe syndrome is characterized by foetal/intrauterine growth restriction, adrenal dysplasia, metaphyseal dysplasia, genital abnormalities, and other characteristics, such as hypercalciuria and hearing loss[8,9]. Pathogenic single-nucleotide variations in a specific region of the PCNA-binding domain of CDKN1C have been found in children with IMAGe syndrome. In 2013, Brioude et al[7] identified single-nucleotide variants in the PCNA-binding domain (p.Arg279Leu) of CDKN1C in patients with familial SRS for the first time. This type of SRS has a variety of clinical features, including foetal and postpartum growth restriction, particular facial features (triangular face, protruding forehead) and relative macrocephaly but no adrenal insufficiency or limb asymmetry. Two other familial SRSs resulting from mutations in this region have since been reported (p.Arg279Leu, p.Arg279ser)[10,11]. Inoue et al[12] recently examined the genes of 92 aetiology-unknown SRS patients and reported sporadic SRS cases caused by a new CDKN1C mutation, p.Arg316Gln. These cases met the four criteria of the Netchine–Harbison clinical scoring system, but there was no limb asymmetry and no adrenal insufficiency or metaphyseal dysplasia. Here, we describe in detail a case of familial SRS caused by a new missense mutation in CDKN1C. This mutant gene resulted in an amino acid substitution (p.Arg279His) that was different from previous SRS mutations. CASE PRESENTATION Chief complaints An 8-year-old girl complained of short stature for 8 years. History of present illness She was found to be severely short after birth, there was no vomiting, feeding difficulties, dizziness, headache, polydipsia, and polyuria. the growth rate was less than 5 cm per year. History of past illness There was no history of chronic disease. Personal and family history The proband, born at 36+4 weeks’ gestational age, was delivered by caesarean section due to foetal hypoxia. Her birth weight was 1.44 kg, her body length was 39 cm (-6.22 standard deviation score, SDS), her head circumference was 31 cm, her sitting height was 26 cm, and her head was relatively large at birth. The anterior fontanelle was large (5 cm × 5 cm), and the anterior fontanelle was closed at 4 years of age. The proband could crawl at 10 mo, stand alone at 14 mo, walk at 24 mo, and consciously call her mum and dad at 15 mo. The mother of the proband was 33 years old (IV-2), with an unknown birth history, height 125 cm, weight before pregnancy 18 kg, body mass index (BMI) 11.5 kg/m2, head circumference 50 cm, sitting height 69.9 cm, and sitting height/height 0.56. Gestational diabetes was discovered during pregnancy, and she was later diagnosed with diabetes. The proband’s grandmother’s brother was 58 years old (III-1), with a height of 137 cm, a body weight of 28 kg, a BMI of 14.9 kg/m2, a head circumference of 52 cm, a sitting height of 76 cm, and a sitting height/height of 0.56. He was diagnosed with diabetes at the age of 45. The great-grandmother of the proband was 93 years old (I-1), with a height of 134 cm, body weight of 34 kg, BMI of 18.9 kg/m2, head circumference of 52 cm, sitting height of 73.7 cm, sitting height/height of 0.55, and no diabetes. All of them had an unknown birth history; however, they all mentioned being very thin and small at birth, and all three of them had a prominent forehead, triangular face, and severely proportional dwarfism but no limb asymmetry or adrenal insufficiency (Figure 1). Figure 1 Photographs of the index patient, her affected mother, great grandmother, and grandmother's brother. A: Index patient IV,1 (8 years old); B: Mother of the index patient III,2 (32.0 years old); C: Great grandmother of the index patient I,1 (91.0 years old); D: Grandmother's brother II,1 (58.0 years old). The proband’s late grandmother was 120 cm tall, and her appearance was similar to that of the proband. She passed away 10 years before due to an accident. She had no genetic testing, but we inferred that she had the same pathogenic mutation based on the genetic pedigree (Figure 2). Figure 2 Pedigree of the family. The proband (index IV,1) and her four affected family members (mother III; grandmother II,3; grandmother’s brother II,1; great-grandmother I,1) carried the mutation c.836G>A. The arrow indicates the index patient. Physical examination The girl had a relatively large head, an inverted triangular face, a protruding forehead, a low ear position, sunken eye sockets, and irregular cracked teeth but without limb asymmetry. She was 91.6 cm tall and weighed 10.2 kg, her head circumference was 48 cm, her sitting height was 54 cm, her sitting height/height was 0.58, and her BMI was 12.1 kg/m2. Her motor and language development was normal during treatment. She had no catch-up growth after birth. Laboratory examinations Serum insulin-like growth factor 1 (IGF1) was 244.08 ng/mL, adrenal cortex hormone ACTH was 19.3 pg/mL, cortisol rhythm (8 a.m.) was 6.29 µg/dL, blood glucose was 4.13 mmol/L, the growth hormone provocation test (arginine + levodopa) showed a peak value of growth hormone of 29.9 ng/mL. Exome sequencing revealed a new heterozygous CDKN1C (NM_000076. 2) c.836G>A mutation, resulting in a variant with a predicted evolutionarily highly conserved arginine substituted by histidine (p.Arg279His) (Figure 3). Figure 3 Sequencing map of CDKN1C gene c.836G>A locus. The orange arrow indicates the mutation site. Both the proband and her mother were heterozygous mutations. The proband's father was normal. Imaging examinations Her bone age was 4.6 years, adrenal thin-slice computed tomography and pituitary magnetic resonance imaging were normal. FINAL DIAGNOSIS SRS. TREATMENT She was treated with rhGH. OUTCOME AND FOLLOW-UP After 12 mo of treatment, the patient’s height was 99.7 cm (-5.9 SDS), her height standard deviation score increased by 0.93 SDS, and her growth rate was 8.1 cm/year (Figure 4). Blood glucose, insulin, thyroid function, and IGF-1 Levels were monitored every three months during treatment. No adverse reactions, such as abnormal blood glucose, were found. Figure 4 Growth chart of the index patient. Black dots are postnatal height measurements, black arrows indicate initiation of recombinant human growth hormone treatment, and red dots indicate height measurements after growth hormone treatment. DISCUSSION This is the fourth reported case of familial SRS caused by a missense mutation in the PCNA-binding domain of CDKN1C, which was supported by the onset characteristics and genetic test results of the proband and the pedigree. CDKN1C, CDKN1A, and CDKN1B belong to the Cip/Kip family and are cyclin-dependent kinase (CDK) inhibitors[13]. The CDKN1C protein consists of three functional regions: (1) The N-terminal CDK inhibition domain (CdK); (2) The proline–alanine repeat (PAPA) domain[14,15].; and (3) The C-terminal PCNA-binding domain[1]. The C-terminal PCNA-binding domain binds to PCNA, a cofactor of DNA polymerases that encircles DNA and orchestrates the recruitment of factors to the replication fork[16,17]. CDKN1C mutations cause diseases with gain-of-function mutations such as IMAGe syndrome[6,8] and familial SRS[7,10,11]. These mutations are located in a small, conserved region of the gene (PCNA-binding domain containing 10 amino acid residues), and the common clinical manifestations of the two include foetal and postnatal growth restriction and forehead protrusion. However, none of the familial SRS patients who have been reported thus far have had adrenal insufficiency or limb asymmetry that is common in SRS. The PCNA-binding domain is a linear motif required for PCNA-dependent and crl4cdt2-mediated ubiquitination[18]. The proteins PCNA and CDKN1A associate closely to ensure the gradual ubiquitination and degradation of CDKN1A. The related motifs in CDKN1C are not perfect, resulting in low-affinity binding to PCNA. Low-affinity binding to PCNA is sufficient for monoubiquitination; however, it is not sufficient to carry out the polyubiquitination process required for protein degradation. CDKN1C monoubiquitination may have functions other than protein degradation[16,19]. Gain-of-function mutations affecting the 279th amino acid have been reported in both IMAGe syndrome and familial SRS (p.Arg279Pro, p.Arg279Ser, p.Arg279Leu)[7,10,11]. The Arg279 residue is highly conserved. However, in a flow cytometry study, the SRS-specific mutation p.Arg279Leu did not affect the cell cycle[7]. while the p.Arg279Pro mutation in IMAGe syndrome promoted cell cycle progression[7]. This finding was consistent with Hamajima's results[20]. Further research showed that p.Arg279Leu was associated with increased protein stability. These differences in amino acid changes (arginine to proline vs arginine to leucine) may be associated with a differential loss of binding to PCNA. In a recent study in Japan, the genes of 92 clinically diagnosed SRS patients with unknown aetiology were sequenced again. Sporadic SRS cases caused by the CDKN1C mutation Arg316Gln have been found. The clinical manifestations of the patients were consistent with SRS, but they had no limb asymmetry, adrenal insufficiency, or metaphyseal dysplasia. In vitro studies have shown that amino acid substitution leads to increased protein expression in vitro, and increased CDKN1C protein function leads to related phenotypes[12]. The SRS pedigree mutation (p.Arg279His) reported in this study has not been functionally verified. However, it can be speculated from the above studies that the p.Arg279His mutation increases CDKN1C protein stability. In a study of IMAGe syndrome, mutations in the PCNA domain impaired the binding of PCNA and ubiquitin ligase to CDKN1C, thereby impairing PCDNA-dependent ubiquitination[6]. Monoubiquitination may have some functions in regulating protein localization, protein interaction, and protein chromosome degradation[21-23]; thus, impaired PCDNA-dependent ubiquitination might impair other functions of CDKN1C. Accordingly, it can also be speculated that mutations in the PCNA-binding domain may have different effects on ubiquitination, thereby affecting the regulatory characteristics of the domain. After 1 year of rhGH treatment, the height standard deviation score of the proband increased by 0.93 SDS, and her growth rate was 8.1 cm/year, which was consistent with the first-year rhGH efficacy (growth velocity = 8.8 cm/year) of a proband’s mother (CDKN1C c.835C>T, p.Arg279Ser) reported by Binder et al[11] and was also consistent with the 1-year height standard deviation increase (0.75 ± 0.44 SDS) on rhGH treatment in children younger than gestational age[24]. The growth chart of the index patient is presented in Figure 4. The proband’s grandmother’s brother (III.2) and mother (IV.1) both had diabetes, in line with the report of Kerns et al[25]. They found a variant in a pedigree with short stature syndrome in Ecuador (CDKN1C c.8433G>T, p.Arg281Leu). The affected family members all had intrauterine growth retardation, short stature, and normal adrenal function. Some patients in this pedigree had limb asymmetry, and eight of the 15 affected family members were diagnosed with diabetes before the age of 40. CDKN1C plays a certain role in the proliferation of pancreatic β-cells. The loss of CDKN1C function leads to enhanced β-cell proliferation[26]. CDKN1C is highly expressed in pancreatic β cells, but its expression is absent in the pancreatic cell hyperplasia foci of infantile hyperinsulinemia patients with silencing of CDKN1C due to the loss of maternal 11p15 somatic cells[27]. Transplantation of short hairpin RNA-induced CDKN1C-silenced human islet cells into mice leads to the proliferation of transplanted β cells[28]. In addition, BWS patients often have hyperinsulinemia, and approximately 50% of BWS patients have hypoglycemia at birth[4,29,30]. A pathology study on the pancreas of four patients with BWS and hyperinsulinemia showed that the endocrine cells of the entire pancreas proliferated significantly, and the BWS-related CDKN1C loss-of-function mutation may be the main precipitating factor of β-cell proliferation[31]. CDKN1C (c.836G>A, p.Arg279His) is a gain-of-function mutation, which may be because this mutation leads to increased protein stability and produces the opposite phenotype from above: Decreased β-cell proliferation leads to decreased insulin secretion and the onset of diabetes. CDKN1C (c.836G>A, p.Arg279Leu)- and (c.836G>A, p.Arg279Ser)-induced familial SRS members have not had diabetes[7,10,11]. In this study, the great-grandmother of the proband (I.1) was 91 years old and did not have diabetes. The blood glucose of the proband was normal, but long-term monitoring is needed. Seven of the people with mutations reported by Kerns et al[25] (p.Arg281Ile) were also temporarily free of diabetes. All of these mutations were located in the carboxy-terminal region of the "hot spot" region of the PCNA-binding domain. Kerns et al[25] demonstrated that the PCNA binding irregularities of p.Arg281Ile variants did not interfere with the ability of this CDKN1C mutant to associate with other proteins, such as the stress-activated protein kinase p38/SAPK, believed to interact with the N-terminus of CDKN1C. Missense mutations in the highly conserved PCNA binding domain have been associated with clinical phenotypic heterogeneity (from growth restriction to skeletal abnormalities or no adrenal failure or diabetes in early adulthood)[13]. Further studies are needed to fully elucidate how CDKN1C variants defective only in PCNA binding regions lead to such a wide range of clinical manifestations. CONCLUSION In conclusion, gain-of-function mutations of CDKN1C are a rare cause of familial SRS. Its phenotype is similar to that of SRS, but there is no limb asymmetry, and some cases may be combined with abnormal blood glucose. In familial SRS cases, the PCNA region of CDKN1C should be analysed. Adrenal insufficiency should be excluded in all cases with functional CDKN1C variants. Informed consent statement: We obtained written informed consent from the patients or the patients’ parents to publish patients’ clinical and molecular information as well as facial photographs. Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article. CARE Checklist (2016) statement: The authors have read CARE Checklist (2016), and the manuscript was prepared and revised according to CARE Checklist (2016). Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: February 1, 2023 First decision: April 19, 2023 Article in press: May 31, 2023 Specialty type: Medicine, research and experimental Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): B Grade C (Good): C, C Grade D (Fair): 0 Grade E (Poor): 0 P-Reviewer: Kim BJ, South Korea; Nwabo Kamdje AH, Cameroon S-Editor: Li L L-Editor: A P-Editor: Li L ==== Refs 1 Berland S Haukanes BI Juliusson PB Houge G Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay J Med Genet 2022 59 155 164 33443097 2 Matsuoka S Edwards MC Bai C Parker S Zhang P Baldini A Harper JW Elledge SJ p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene Genes Dev 1995 9 650 662 7729684 3 Brioude F Kalish JM Mussa A Foster AC Bliek J Ferrero GB Boonen SE Cole T Baker R Bertoletti M Cocchi G Coze C De Pellegrin M Hussain K Ibrahim A Kilby MD Krajewska-Walasek M Kratz CP Ladusans EJ Lapunzina P Le Bouc Y Maas SM Macdonald F Õunap K Peruzzi L Rossignol S Russo S Shipster C Skórka A Tatton-Brown K Tenorio J Tortora C Grønskov K Netchine I Hennekam RC Prawitt D Tümer Z Eggermann T Mackay DJG Riccio A Maher ER Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement Nat Rev Endocrinol 2018 14 229 249 29377879 4 DeBaun MR King AA White N Hypoglycemia in Beckwith-Wiedemann syndrome Semin Perinatol 2000 24 164 171 10805171 5 Elliott M Bayly R Cole T Temple IK Maher ER Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases Clin Genet 1994 46 168 174 7820926 6 Arboleda VA Lee H Parnaik R Fleming A Banerjee A Ferraz-de-Souza B Délot EC Rodriguez-Fernandez IA Braslavsky D Bergadá I Dell'Angelica EC Nelson SF Martinez-Agosto JA Achermann JC Vilain E Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome Nat Genet 2012 44 788 792 22634751 7 Brioude F Oliver-Petit I Blaise A Praz F Rossignol S Le Jule M Thibaud N Faussat AM Tauber M Le Bouc Y Netchine I CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome J Med Genet 2013 50 823 830 24065356 8 Schrier Vergano SA Deardorff MA IMAGe Syndrome. 2014 Mar 13. 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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4513 10.12998/wjcc.v11.i19.4513 Retrospective Cohort Study Age, blood tests and comorbidities and AIMS65 risk scores outperform Glasgow-Blatchford and pre-endoscopic Rockall score in patients with upper gastrointestinal bleeding Morarasu BC et al. Pre-endoscopic risk scores in upper GIB Morarasu Bianca Codrina Department of Internal Medicine and Toxicology, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Sorodoc Victorita Department of Internal Medicine and Toxicology, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania. victorita.sorodoc@umfiasi.ro Haisan Anca Department of Emergency Medicine, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Morarasu Stefan Second Department of Surgical Oncology, Regional Institute of Oncology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Bologa Cristina Department of Internal Medicine and Toxicology, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Haliga Raluca Ecaterina Department of Internal Medicine and Toxicology, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Lionte Catalina Department of Internal Medicine and Toxicology, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Marciuc Emilia Adriana Department of Radiology, Emergency Hospital “Prof. Dr. N. Oblu”, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700309, Romania Elsiddig Mohammed Department of Gatroenterology, Beaumont Hospital, Dublin D09V2N0, Ireland Cimpoesu Diana Department of Emergency Medicine, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Dimofte Gabriel Mihail Second Department of Surgical Oncology, Regional Institute of Oncology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Sorodoc Laurentiu Department of Internal Medicine and Toxicology, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700111, Romania Author contributions: Morarasu BC and Sorodoc V contributed equally to this work; Sorodoc L, Dimofte GM, Haisan A, and Morarasu S designed the research study; Haisan A and Marciuc EA performed the research; Bologa C, Haliga RE, and Lionte C contributed to the analytic tools; Morarasu BC, Sorodoc V, Haisan A, Cimpoesu D, and Elsiddig M analyzed the data and wrote the manuscript; and all authors have read and approve the final manuscript. Corresponding author: Victorita Sorodoc, MD, PhD, Associate Professor, Department of Internal Medicine and Toxicology, Saint Spiridon University Regional Emergency Hospital, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, No. 1 BLD Independentei, Iasi 700111, Romania. victorita.sorodoc@umfiasi.ro 6 7 2023 6 7 2023 11 19 45134530 28 3 2023 14 5 2023 30 5 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND Upper gastrointestinal (GI) bleeding is a life-threatening condition with high mortality rates. AIM To compare the performance of pre-endoscopic risk scores in predicting the following primary outcomes: In-hospital mortality, intervention (endoscopic or surgical) and length of admission (≥ 7 d). METHODS We performed a retrospective analysis of 363 patients presenting with upper GI bleeding from December 2020 to January 2021. We calculated and compared the area under the receiver operating characteristics curves (AUROCs) of Glasgow-Blatchford score (GBS), pre-endoscopic Rockall score (PERS), albumin, international normalized ratio, altered mental status, systolic blood pressure, age older than 65 (AIMS65) and age, blood tests and comorbidities (ABC), including their optimal cut-off in variceal and non-variceal upper GI bleeding cohorts. We subsequently analyzed through a logistic binary regression model, if addition of lactate increased the score performance. RESULTS All scores had discriminative ability in predicting in-hospital mortality irrespective of study group. AIMS65 score had the best performance in the variceal bleeding group (AUROC = 0.772; P < 0.001), and ABC score (AUROC = 0.775; P < 0.001) in the non-variceal bleeding group. However, ABC score, at a cut-off value of 5.5, was the best predictor (AUROC = 0.770, P = 0.001) of in-hospital mortality in both populations. PERS score was a good predictor for endoscopic treatment (AUC = 0.604; P = 0.046) in the variceal population, while GBS score, (AUROC = 0.722; P = 0.024), outperformed the other scores in predicting surgical intervention. Addition of lactate to AIMS65 score, increases by 5-fold the probability of in-hospital mortality (P < 0.05) and by 12-fold if added to GBS score (P < 0.003). No score proved to be a good predictor for length of admission. CONCLUSION ABC score is the most accurate in predicting in-hospital mortality in both mixed and non-variceal bleeding population. PERS and GBS should be used to determine need for endoscopic and surgical intervention, respectively. Lactate can be used as an additional tool to risk scores for predicting in-hospital mortality. Glasgow-Blatchford Pre-endoscopic Rockall Age older than 65 Age, blood tests and comorbidities Risk score Gastrointestinal bleeding ==== Body pmc Core Tip: Upper gastrointestinal (GI) bleeding is a life-threatening condition with high mortality rates. It represents one of the main reasons for presentation in the emergency department, having a major impact on both the patient and the clinician. This cohort study evaluates four of the mostly used pre-endoscopic risk scores by comparing them in two populations, variceal and non-variceal upper GI bleeding, highlighting which one should be preferably used depending on the investigated outcome. INTRODUCTION Upper gastrointestinal (GI) bleeding is defined as blood loss from the GI tract above the ligament of Treitz. It is a life-threatening condition with high mortality rates, of up to 15%[1]. This is particularly important as emergency services are struggling with high patient flow[2] and clinicians must promptly decide the need for admission, timing of endoscopy and level of care. It is generally recommended to perform endoscopy within 24 h of presentation[3]. It plays a pivotal role in identifying the source of bleeding and it can achieve haemostasis in most cases. However, endoscopy may not be available in all centers or, if performed in low-risk patients, it may overcrowd the service with unnecessary urgent interventions. European Society of Gastroenterology recommends immediate assessment of patient’s haemodynamic status, transfusion strategy and risk stratification[4]. The latter can be achieved by calculating GI bleeding risk scores which should predict several outcomes such as need for intervention, mortality, rebleeding rate or death[5]. Pre-endoscopy risk scores have been increasingly used as they rely on limited number of parameters and may allow timely sequential decisions. Glasgow-Blatchford score (GBS)[6] has been validated to identify low risk patients which may be managed as outpatients. PERS[7] evaluates the risk of rebleeding and mortality, while albumin, international normalized ratio, altered mental status, systolic blood pressure, age older than 65 (AIMS65)[8], determines the risk of death. Age, blood tests and comorbidities (ABC) is a relatively new risk score used to predict mortality in patients with both upper and lower GI bleeding[9]. These scores have been previously compared, with a certain variability among studies, potentially due to the differences in population included. Moreover, there is limited data for variceal upper GI bleeding, with most of the studies including non-variceal cohorts[10,11]. Venous lactate can be an important tool in critically ill patients, such as those with shock, trauma, or heart failure. It increases as a result of tissue hypoperfusion or hypoxia. Although not routinely used, it can predict in-hospital mortality, need for intensive care or surgical intervention, as well as rebleeding in patients with upper GI bleed[12]. It may be used to improve the performance of existing scoring systems[13] and guide clinicians towards early triage of patients. In this study, we aim to evaluate the performance of pre-endoscopic risk scores (GBS, PERS, AIMS65, and ABC) in patients with variceal and non-variceal upper GI bleeding for predicting the following primary outcomes: In-hospital mortality, type of intervention (endoscopic or surgical) and length of admission (≥ 7 d). We will further evaluate whether the addition of venous lactate improves the score performance in predicting the determined outcomes. MATERIALS AND METHODS We conducted a single centre cohort study, performed in a tertiary emergency hospital, “Saint Spiridon’’ Emergency University Hospital, Iasi, Romania. We retrospectively analyzed all patients above 18 years old presenting to the emergency department (ED) with upper GI bleeding from January 2020 to December 2021. Ethics statement The study was approved by the Hospital’s Ethics Committee. The ‘’Saint Spiridon’’ Institutional Review Board approved this study, approval number 39/30.03.2022. Each patient signed our standard informed consent. We did not require additional consent as patient data is anonymous and the study included standard of care information. Patient management Each patient presenting with upper GI bleed exteriorized as hematemesis, coffee ground vomiting or melena was fully assessed by the emergency medicine physician, including past medical history and complete clinical examination. Immediate venous catheterization and fluid resuscitation was performed as indicated following primary assessment. Subsequent full work-up with blood tests (full blood count, haemoglobin (Hb), platelets, INR, aPTT, albumin, ALT, AST, urea, creatinine, and venous lactate), and other investigations (as indicated) were performed within 24 h from presentation. Hemodynamically stable patients with a Hb ≤ 7 g/dL had at least one unit of red blood cell concentrate transfused, with more than one unit in those with severely lower Hb. A higher Hb threshold (Hb ≤ 8 g/dL) was used for patients with associated cardiovascular disease. Post-transfusion target Hb was between 7-9 g/dL. In case of major transfusion protocol, severe liver disease, drug-induced coagulopathy with active bleeding, patients received both red cell concentrate and fresh frozen plasma. Endoscopy was performed within 24 h of ED arrival in all patients included in analysis. Forrest classification was used to describe peptic ulcer disease, with Baveno and Sarin’s classification for gastroesophageal varices. Those with suspected variceal bleeding had endoscopic evaluation and management within 6 h to 12 h, after initial appropriate fluid resuscitation. In those with non-variceal upper GI bleeding, endoscopy was performed within the first 12 h to 24 h with no patient being postponed more than 24 h. However, we would perform the intervention earlier guided by the patient’s clinical status and the clinician’s preference. Patients with non-variceal upper GI bleeding received an infusion with proton pump inhibitors (PPIs), while those with variceal bleeding were treated with Somatostatin. Endoscopic treatment was performed depending on the cause of bleeding. For non-variceal upper GI bleeding, there was a combined approach with injection therapy (dilute epinephrine) and mechanic therapy (thermal coagulation or haemostatic clip) for FIa, Fib, and FIIa, with clot removal in FIIb lesions. In variceal bleeding, endoscopic ligation was the main approach. Surgical treatment was performed in cases where endoscopic treatment failed, such as actively bleeding malignant lesion, vascular fistula, or in patients with bleeding perforated ulcer. Need for admission was established by the gastroenterology and general surgery teams on-call guided by the patient’s clinical status, comorbidities, and high risk of rebleeding and mortality (GBS score ≥ 2 in non-variceal patients and all patients with stigmata of variceal bleeding irrespective of risk score). Data collection Initially, a ward clerk extracted all data from ED’s computer data. Further exclusion of duplicates/incomplete files was performed. We extracted from the patient’s records and electronic files, the following data: age, gender, comorbidities (heart failure, atrial fibrillation, hypertension, coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease, asthma, liver cirrhosis, active malignancy, hepatocarcinoma, and cerebral vascular disease), symptoms on presentation (hematemesis, melena, coffee ground vomiting, abdominal pain, and syncope), vital signs (systolic blood pressure, heart rate), blood parameters needed to calculate the GBS, PERS, AIMS65 and ABC scores, venous lactate level, source of bleeding if identified by endoscopy (variceal bleeding- oesophageal and/or gastric varices and non-variceal bleeding-gastric/duodenal ulcer, severe/erosive gastritis or duodenitis, severe/erosive esophagitis, Mallory Weiss syndrome, GI malignancy, angiodysplasia, Dieulafoy lesion), type of endoscopic intervention (no intervention, injection therapy, mechanical intervention) or surgical intervention, length of admission (number of days), need for transfusion on admission and in-hospital survival. Venous lactate was measured using Radiometer ABL 90 Series I393-09. Patients were excluded if they were unable to undergo/did not consent for endoscopy or surgical intervention, had a final diagnosis of non-upper GI bleeding, were also diagnosed with sepsis, pregnancy, severe trauma, were taking Metformin, had incomplete data for score calculation or venous lactate was not determined. Statistical analysis Statistical analysis was performed using SPSS software for Windows (v.22.0; SPSS, Chicago, IL, United States). The statistical methods of this study were reviewed by I.L. Rusu, biomedical statistician. Nominal variables are presented as frequencies and percentages, and continuous variables as the mean ± SD. We were able to apply all tests as the score values are homogenous, median value is similar to the mean value and skeweness test had [-2÷ 2] interval. Categorical variables were presented as percentages and compared using Chi-square test. A P value of < 0.05 was considered statistically significant. We determined the scores’ ability to predict each investigated outcome by calculating the area under the receiver operating characteristics curves (AUROCs), including optimal cut-off value with specificity and sensitivity and 95% confidence intervals. AUROCs were determined significant for a value above 0.600. Subsequently, we analyzed through a logistic binary regression model, if addition of lactate to the risk scores increased the probability of previously determined outcomes. RESULTS A total of 1046 medical records were considered eligible (Figure 1). We excluded duplicates or patients with more than one presentation within the study period. After applying the exclusion criteria, the study ended with a cohort of 363 patients with upper GI bleeding with a mean age of 60 years old and a predominance of male sex (n = 240, 66.1%). Non-variceal bleeding was the main cause of presentation (n = 236, 65%). Liver cirrhosis is the most frequent associated comorbidity in the entire group (n = 139, 38.3%), and 2.5% (n = 9) of patients had associated hepatocarcinoma (Table 1). The main symptom of presentation was haematemesis in patients with variceal bleeding and melena in the non-variceal group. Approximately 9% of our patients had chronic treatment with antiplatelets (n = 36, 9.9%) or oral anticoagulation (n = 32, 8.9%). Gastric/duodenal ulcer was the main cause of GI bleeding (n = 151, 41.6%), followed by oesophageal varices (n = 115, 31.7%). Most patients in variceal bleeding group required mechanical endoscopic therapy with band ligation (n = 48, 13.2%) and only 2 patients (0.6%) had variceal sclerotherapy. In the non-variceal bleeding group, dual therapy with thermal anticoagulation and local administration of dilute Adrenaline was the main type of endoscopic intervention (n = 29, 8.0%). Failed endoscopy was recorded in approximately 4.7% (n = 17) of patients. Only 9 patients in the non-variceal group required surgical intervention, in most cases due to actively bleeding perforated duodenal ulcer, inability to achieve local haemostasis in diffuse bleeding induced by malignancy or fistulas. Approximately 31% (n = 112) of the population in both groups required transfusion. In-hospital mortality had an overall rate of 9.4% (n = 34), most cases (n = 16, 12.6%) were in the variceal group (Table 1). The direct cause of death was hypovolaemic shock secondary to upper GI bleeding (in most cases variceal). There were several cases of perforated duodenal ulcer which required emergency surgery, but with poor outcome. One patient developed ventilator associated pneumonia, and another one, acute myocardial infarction, both of them, in the context of major GI bleeding. Figure 1 Flow diagram of patient selection. Table 1 Descriptive analysis of demographical data, clinical findings, type of intervention and outcome by type of bleeding, n (%) Parameters All cases, n = 363 (%) Variceal bleeding, n = 127 (34%) Non-variceal bleeding, n = 236 (65%) P value Demographical data Age, yr; median/interval 60.90; 61/19-93 57.24; 57.50/19-88 62.87; 63/21-93 0.001 > 60 yr 201 (55.4) 56 (44.1) 145 (61.4) 0.002 Male 240 (66.1) 85 (66.9) 155 (65.7) 0.810 Comorbidities Heart failure 75 (20.7) 9 (7.1) 66 (28.0) 0.001 Atrial fibrillation 52 (14.3) 8 (6.3) 44 (18.6) 0.001 Arterial hypertension 119 (32.8) 22 (17.3) 97 (41.1) 0.001 Coronary artery disease 61 (16.8) 4 (3.1) 57 (24.2) 0.001 Diabetes mellitus 49 (13.5) 18 (14.2) 31 (13.1) 0.783 COPD 9 (2.5) 1 (0.8) 8 (3.4) 0.096 Asthma 3 (0.8) 0 (0.0) 3 (1.3) 0.107 Kidney disease 30 (8.3) 2 (1.6) 28 (11.9) 0.001 Liver cirrhosis 139 (38.3) 99 (78.0) 40 (16.9) 0.001 Active malignancy 25 (6.9) 12 (9.4) 13 (5.5) 0.166 Hepatocarcinoma 9 (2.5) 8 (6.2) 1 (0.5) Cerebral vascular disease 24 (6.6) 2 (1.6) 22 (9.3) 0.002 Symptoms Haematemesis 279 (76.9) 115 (90.6) 164 (69.5) 0.001 Melena 267 (73.6) 89 (70.1) 178 (75.4) 0.274 Abdominal pain 60 (16.5) 19 (15.0) 41 (17.4) 0.553 Syncope 12 (3.3) 2 (1.6) 10 (4.2) 0.151 Presyncope 8 (2.2) 2 (1.6) 6 (2.5) 0.539 Other symptoms 36 (9.9) 12 (9.4) 24 (10.2) 0.826 Chronic treatment Antiplatelets 36 (9.9) 0.002 Aspirin 22 (6.1) 1 (0.8) 21 (8.9) Clopidogrel 7 (1.9) 0 (0) 7 (3.0) DAPT (aspirin clopidogrel or aspirin ticagrelor) 6 (1.7) 1 (0.8) 5 (2.1) Ticagrelor 1 (0.3) 0 (0) 1 (0.4) No treatment 327 (90.1) 125 (98.4) 202 (85.6) Anticoagulation 32 (8.9) 0.003 DOAC 22 (6.1) 0 (0) 22 (9.3) VKA 10 (2.8) 3 (2.4) 7 (3.0) No treatment 331 (91.2) 124 (97.6) 207 (87.7) Source of GI bleeding Ulcerative and erosive lesions 25 (6.9) 0 (0) 25 (10.6) 0.001 Severe/erosive esophagitis 27 (7.4) 0 (0) 27 (11.4) Severe/erosive gastritis/duodenitis 151 (41.6) 0 (0) 151 (64) Vascular lesions (angiodysplasia) 6 (1.7) 0 (0) 6 (2.5) Mass lesions 12 (3.3) 0 (0) 12 (5) Traumatic lesions (Mallory Weiss tear) 9 (2.4) 0 (0) 9 (3.8) Lesion unidentified/Dieulafoy 6 (1.6) 0 (0) 6 (2.7) Oesophageal varices 115 (31.7) 115 (90.5) 0 (0) 0.003 Gastric varices 12 (3.3) 12 (9.5) 0 (0) Intervention Injection therapy (dilute epinephrine) with thermal coagulation 29 (8.0) 0 (0.0) 28 (11.9) 0.001 Mechanical endoscopic therapy 59 (16.3) 50 (39.4) 9 (3.8) 0.001 Haemostatic clip 9 (2.5) 0 (0) 9 (3.8) Variceal ligation 48 (13.2) 48 (37.7) 0 (0) Variceal sclerotherapy 2 (0.6) 2 (1.6) 0 (0) Failed endoscopic therapy 17 (4.7) 9 (7) 8 (3.4) 0.001 Surgical interventions 9 (2.5) 0 (0) 9 (3.8) 0.026 Transfusion Transfusions 112 (30.9) 38 (29.9) 74 (31.5) 0.758 In-hospital mortality Death 34 (9.4) 16 (12.6) 18 (7.7) 0.131 COPD: Chronic obstructive pulmonary disease; DAPT: Dual antiplatelets treatment DOAC: Direct oral anticoagulation VKA: Vitamin K antagonist GI: Gastrointestinal. GBS had the highest mean value in the mixed population (12.32), as well as in the two main study groups (12.98 in variceal bleeding and 11.97 in non-variceal bleeding), most patients being at high risk of intervention. ABC score (mean value 5.02) and AIMS65 (mean value 1.52) showed a medium risk of mortality rate. Mean PERS is consistent with an 11% chance of mortality prior to endoscopy (Table 2). Table 2 Mean values of scores in variceal and non-variceal bleed Scores All cases, n = 363, mean Variceal bleeding, n = 127, mean (SD) Non-variceal bleeding, n = 236, mean (SD) P value AIMS-65 1.52 1.74 (0.95) 1.40 (1.05) 0.003 PERS 3.30 3.76 (1.35) 3.06 (1.70) 0.001 ABC 5.02 5.83 (2.42) 4.59 (2.51) 0.001 GBS 12.32 12.98 (2.90) 11.97 (3.74) 0.008 AIMS65: Age older than 65; PERS: Pre-endoscopic Rockall score; ABC: Age, blood tests and comorbidities; GBS: Glasgow-Blatchford score. We have performed linear regression analysis of each pre-endoscopic score against each determined outcome. AIMS65 score is influenced by the following variables: mortality, endoscopic and surgical intervention (Model 4: r = 0.316; P = 0.007), as well as length of stay, with an Y point 3.959-0.961 Death-0.148 Endoscopy + 0.057 Surgery -0.291 d (Table 3). PERS score is influenced by mortality and endoscopic intervention (Model 2: r = 0.243; P = 0.009), with an Y point 6.227-1.961 Death-0.512 Endoscopy (Table 4). ABC score is influenced by mortality and endoscopic intervention (Model 2: r = 0.324; P = 0.006), with an Y point 11.161-2.466 Death-0.815 Endoscopy (Table 5). GBS score is influenced by mortality and endoscopic intervention (Model 2: r = 0.241; P = 0.007), with an Y point 18.557-2.231 Death-1.127 Endoscopy (Table 6). Table 3 Linear regression analysis of age older than 65 score against each determined outcome Model R R square Adjusted R square Std. error of the estimate Change statistics R square change F change df1 df2 Sig. F change 1 0.261 (a) 0.068 0.065 0.994 0.068 260.305 1 361 0.000 2 0.281 (b) 0.079 0.074 0.989 0.011 40.320 1 360 0.038 3 0.286 (c) 0.082 0.074 0.989 0.003 10.010 1 359 0.316 4 0.316 (d) 0.100 0.090 0.981 0.018 70.290 1 358 0.007 Table 4 Linear regression analysis of pre-endoscopic Rockall score against each determined outcome Model R R square Adjusted R square Std. error of the estimate Change statistics R square change F change df1 df2 Sig. F change 1 0.202 (a) 0.041 0.038 10.588 0.041 150.411 1 361 0.000 2 0.243 (b) 0.059 0.054 10.575 0.018 60.987 1 360 0.009 3 0.248 (c) 0.062 0.054 10.575 0.002 0.941 1 359 0.333 4 0.260 (d) 0.068 0.057 10.572 0.006 20.359 1 358 0.125 Table 5 Linear regression analysis of age, blood tests and comorbidities score against each determined outcome Model R R square Adjusted R square Std. error of the estimate Change statistics R square change F change df1 df2 Sig. F change 1 0.294 (a) 0.087 0.084 20.435 0.087 340.206 1 361 0.000 2 0.324 (b) 0.105 0.100 20.413 0.019 70.543 1 360 0.006 3 0.329 (c) 0.108 0.101 20.413 0.003 10.241 1 359 0.266 4 0.334 (d) 0.111 0.101 20.412 0.003 10.183 1 358 0.277 Table 6 Linear regression analysis of Glasgow-Blatchford score against each determined outcome Model R R square Adjusted R square Std. error of the estimate Change statistics R square change F change df1 df2 Sig. F change 1 0.198 (a) 0.039 0.036 30.434 0.039 140.659 1 361 0.000 2 0.241 (b) 0.058 0.053 30.405 0.019 70.250 1 360 0.007 3 0.256 (c) 0.065 0.058 30.396 0.007 20.873 1 359 0.091 4 0.273 (d) 0.075 0.064 30.384 0.009 30.534 1 358 0.061 In-hospital mortality All scores had discriminative ability in predicting in-hospital mortality irrespective of study group (AUROC > 0.600). AIMS-65 score had the best performance for the variceal bleeding group (AUROC 0.772; P < 0.001) (Figure 2A, Table 7), and ABC (AUROC 0.775; P < 0.001) in the non-variceal bleed (Figure 2B, Table 7). Figure 2 Receiver operating characteristics curve of age older than 65, pre-endoscopic Rockall score, age, blood tests and comorbidities, and Glasgow-Blatchford score predictors of in-hospital mortality. A: Variceal bleed; B: Non-variceal bleed; C: Mixed variceal and non-variceal bleeding population; D: Variceal bleeding group; E: Non-variceal bleeding group. Table 7 Analysis of area under the receiver operating characteristics curve, cut-off value, 95% confidence interval for in-hospital mortality Test result variable Area Cut off Std. error(a) Asymptotic Sig.(b) Asymptotic 95% confidence interval Variceal bleed AIMS-65 0.772 1.0 0.051 0.001 0.673-0.871 PERS 0.705 3.5 0.067 0.008 0.573-0.837 ABC 0.744 5.5 0.052 0.002 0.642-0.845 GBS 0.752 10.5 0.067 0.001 0.621-0.883 Non-variceal bleed AIMS-65 0.693 1.5 0.059 0.006 0.577-0.810 PERS 0.680 3.5 0.053 0.011 0.576-0.785 ABC 0.775 5.5 0.051 0.001 0.675-0.874 GBS 0.657 12.5 0.077 0.027 0.505-0.808 AIMS65: Age older than 65; PERS: Pre-endoscopic Rockall score; ABC: Age, blood tests and comorbidities; GBS: Glasgow-Blatchford score. The optimal cut-off value for predicting in-hospital mortality was calculated for each score depending on the type of bleeding. For variceal bleeding, an AIMS 65 score above 1 with sensitivity of 90% and specificity of 73% (AUC = 0.772; 95%CI: 0.673-0.871; P = 0.001) and GBS score above 10.5 with a sensitivity of 93.8% and specificity of 81% (AUC = 0.752; 95%CI: 0.621-0.883; P = 0.001). PERS and ABC scores had similar cut-off values, of 3.5 and 5.5, respectively, irrespective of type of bleeding, but with slight variations in sensitivity (PERS: 87.5% variceal group, 77.8% non-variceal group; ABC: 80% variceal group, 77.8% non-variceal group) and specificity (PERS: 64% variceal group, 56% non-variceal group; ABC: 76.7% variceal group, 65.1% non-variceal group). In the non-variceal bleeding group, the optimal cut-off value for in-hospital mortality was 1.5 for AIMS65 score, with sensitivity of 66.7% and specificity of 57% (AUC = 0.693; 95%CI: 0.577-0.810; P = 0.006), and 12.5 for GBS score with sensitivity of 66.7% and specificity de 52.8% (AUC = 0.657; 95%CI: 0.505-0.808; P = 0.027) (Table 7). We have determined the best scoring system for in-patient mortality in the included population for both variceal and non-variceal bleeding. ABC showed the highest AUROC, 0.770 (Figure 2C), as being the best predictor for in-patient mortality in the entire population, at a cut-off value of 5.5 with a sensitivity of 88.2% and a specificity of 59.6% (95%CI: 0.700-0.840; P = 0.001) (Table 8). Table 8 Analysis of area under the receiver operating characteristics curve, cut-off value, 95% confidence interval for in-patient mortality in mixed variceal and non-variceal bleeding population Scores Cut off Sensitivity Specificity Area Std. error Asymptotic Sig. Asymptotic 95% confidence interval AIMS-65 1.50 82.4 52.6 0.730 0.041 0.001 0.650-0.809 PERS 3.50 82.4 49.2 0.696 0.042 0.001 0.615-0.778 ABC 5.50 88.2 59.6 0.770 0.036 0.001 0.700-0.840 GBS 12.50 76.5 47.7 0.704 0.052 0.001 0.602-0.805 AIMS65: Age older than 65; PERS: Pre-endoscopic Rockall score; ABC: Age, blood tests and comorbidities; GBS: Glasgow-Blatchford score. Type of intervention Endoscopic intervention: For variceal bleeding patients, only PERS score, at a cut-off value above 3.5 was a good predictor for endoscopic treatment with a sensitivity of 76.5% and specificity of 40% (AUC = 0.604; 95%CI: 0.506-0.703; P = 0.046) (Figure 2D). No score performed as a good predictor for endoscopic intervention in non-variceal bleeding group (Table 9). Table 9 Analysis of area under the receiver operating characteristics curve, cut-off value, 95% confidence interval for intervention Test result variable Area Cut off Std. error(a) Asymptotic Sig.(b) Asymptotic 95% confidence interval Endoscopy-variceal bleed AIMS-65 0.538 0.051 0.470 0.437-0.638 PERS 0.604 3.5 0.050 0.046 0.506-0.703 ABC 0.553 0.052 0.313 0.452-0.654 GBS 0.538 0.052 0.468 0.437-0.639 Surgical intervention-non-variceal bleed AIMS-65 0.621 1.5 0.081 0.218 0.461-0.781 PERS 0.624 3.5 0.088 0.208 0.451-0.796 ABC 0.657 5.5 0.079 0.111 0.502-0.811 GBS 0.722 12.5 0.092 0.024 0.541-0.903 AIMS65: Age older than 65; PERS: Pre-endoscopic Rockall score; ABC: Age, blood tests and comorbidities; GBS: Glasgow-Blatchford score. Surgical intervention: In the non-variceal bleeding group, all risk scores were good predictors for surgical intervention, with an AUROC > 0.600 (Figure 2E). However, only GBS score, at a cut-off value above 12.5 with a sensitivity of 66.7% and specificity of 52.8% (AUC = 0.722; 95%CI: 0.541-0.903; P = 0.024), had statistical significance (Table 9). No patient in the variceal bleeding group underwent surgical intervention. Length of admission (> 7 d) No score proved to be a good predictor for length of admission, due to their low AUROC < 600 (Table 10). Table 10 Analysis of area under the receiver operating characteristics curve, cut-off value, 95% confidence interval for length of admission (over 7 d) Test result variable Area Std. error(a) Asymptotic Sig.(b) Asymptotic 95% confidence interval Variceal bleeding AIMS65 0.516 0.053 0.768 0.412-0.619 PERS 0.497 0.054 0.960 0.391-0.604 ABC 0.434 0.053 0.215 0.330-0.538 GBS 0.496 0.053 0.946 0.393-0.600 Non-variceal bleeding AIMS65 0.587 0.037 0.024 0.514-0.660 PERS 0.557 0.038 0.139 0.482-0.631 ABC 0.550 0.039 0.194 0.473-0.627 GBS 0.566 0.038 0.084 0.491-0.641 AIMS65: Age older than 65; PERS: Pre-endoscopic Rockall score; ABC: Age, blood tests and comorbidities; GBS: Glasgow-Blatchford score. Role of venous lactate Logistic regression model showed that lactate is an independent predictor for the determined outcomes. It did not show, however, good performance in predicting variceal or non-variceal bleeding, either due to low sensitivity (64.3%) and specificity (53.2%) or a low AUROC (0.357) (Figure 3, Table 11). For the variceal bleeding population, addition of lactate to AIMS65 score, leads to a 5-fold increase in probability of in-hospital mortality (P < 0.05). For non-variceal bleeding, addition of lactate to GBS score showed a 12-fold increase in probability of in-hospital mortality (P < 0.003). In terms of intervention, higher level of venous lactate increases by 5.5 times the probability of endoscopic intervention and by 2 the probability for surgical intervention (P = 0.001) (Table 12). Figure 3 Receiver operating characteristics curve. Lactate as a predictor for variceal bleed compared to non-variceal bleeding group. Table 11 Analysis of area under the receiver operating characteristics curve, cut-off value, 95% confidence interval of venous lactate in variceal and non-variceal bleed Venous lactate Cut off Area Std. error Asymptotic Sig. Asymptotic 95% confidence interval Variceal bleed 2.05 0.643 0.030 0.001 0.585-0.701 Non variceal bleed 2.45 0.357 0.030 0.001 0.299-0.415 Table 12 Logistic regression model for age older than 65, pre-endoscopic Rockall score, age, blood tests and comorbidities, Glasgow-Blatchford score and lactate Logistic regression models Independent variable Odds ratio (95% confidence interval) P value In-hospital mortality (Yes/No) Adjusted model variceal bleed AIMS-65 1.434 (1.202-1.930) 0.032 PERS 1.028 (0.591-1.789) 0.922 ABC 0.799 (0.608-1.049) 0.106 GBS 0.915 (0.740-1.132) 0.415 Venous lactate 4.944 (2.207-11.008) 0.001 Adjusted model, non-variceal bleed AIMS-65 0.716 (0.374-1.372) 0.314 PERS 0.965 (0.669-1.393) 0.850 ABC 0.824 (0.627-1.084) 0.167 GBS 1.159 (1.053-1.276) 0.003 Venous lactate 11.720 (3.437-39.968) 0.001 Endoscopy (Yes/No) Adjusted model variceal bleed AIMS-65 1.049 (0.688-1.599) 0.823 PERS 0.762 (0.544-1.067) 0.113 ABC 1.025 (0.850-1.236) 0.794 GBS 1.029 (0.905-1.171) 0.659 Venous lactate 2.222 (0.531-9.305) 0.274 Adjusted model non variceal bleed AIMS-65 0.860 (0.533-1.388) 0.537 PERS 1.205 (0.904-1.604) 0.203 ABC 0.931 (0.743-1.166) 0.533 GBS 0.982 (0.891-1.083) 0.721 Venous lactate 5.550 (1.943-15.853) 0.001 Surgical intervention (Yes/No) Adjusted model non variceal bleed AIMS-65 0.928 (0.533-1.388) 0.870 PERS 0.870 (0.904-1.604) 0.663 ABC 1.255 (0.743-1.166) 0.280 GBS 1.214 (0.891-1.083) 0.130 Venous lactate 2.002 (1.002-2.047) 0.001 AIMS65: Age older than 65; PERS: Pre-endoscopic Rockall score; ABC: Age, blood tests and comorbidities; GBS: Glasgow-Blatchford score. DISCUSSION To our knowledge, this is the first study to compare four of the most representative pre-endoscopic risk scores, AIMS65, PERS, GBS and the relatively new ABC score in variceal and non-variceal GI bleeding cohort. Our aim was to identify which score would be preferably used depending on source of bleeding. Prognostic risk scores could be a key step in the initial evaluation of upper GI bleeding patient in order to establish which one is at high risk of death. It should further identify likelihood of blood transfusion, endoscopic or surgical treatment, need for intensive care unit admission and cost of care in an attempt to decrease the burden over ED. Moreover, the routine determination of venous lactate should be used in determining probability of in-patient mortality, both as an independent predictor, and in association with certain risk scores. Our cohort included a total of 363 patients, out of which 9.4% (n = 34) died, most of them (n = 16, 12.6%) in the variceal bleeding group. The mortality rate in our group is high, but similar to the one reported in other studies[14]. The pre-endoscopic risk scores should be considered as a key step to improve these numbers. When we analyzed the performance of risk scores according to in-patient mortality, ABC score had the best performance in both mixed and non-variceal bleeding group, with AIMS65 in variceal bleeding cohort. For endoscopic treatment, only PERS showed good discriminative value in the variceal bleeding group. In terms of surgical intervention, all determined scores had good performance, but only GBS had statistical significance. No score proved to be good in determining length of admission. When comparing the two cohorts and their AUROC values, AIMS65 had the best accuracy in predicting in-patient mortality for patients with variceal bleeding. AIMS65 includes clinical parameters and regular laboratory tests which are fast and simple to be performed in ED settings. We determined an AUROC of 0.772 (95%CI: 0.673-0.871; P = 0.001), which was similar to other studies[15,16], but lower than other cohorts[10,17]. AIMS65 was also reported in other studies as the only score to provide accurate risk assessment for variceal GI bleeding population[18] in comparison to other scores, such as GBS or full Rockall (endoscopic) score. In our research, AIMS65 was superior to GBS, but the latter performed better than ABC or PERS score, which had the lowest AUROC, of 0.705. Previous reports compared both GBS and full Rockall score in predicting outcomes in patients with variceal bleeding, with similar results as ours[19]. The substrate for GBS inferiority in comparison to AIMS65, might be explained by the lack of liver disease history as some patients’ first presentation of liver cirrhosis is with variceal bleeding. Moreover, AIMS65 includes level of serum albumin and INR, which reflect liver function. Other reports comparing several different scores used in patients with liver cirrhosis (MELD-model for end-stage liver disease, APACHE II-acute physiology and chronic health evaluation II, qSOFA-quick sepsis related organ failure assessment) confirmed higher accuracy of AIMS65 in predicting in-hospital mortality[1]. Similar predictive power for in-hospital mortality of AIMS65 score, Child-Pugh score (CTP) and MELD score was found in a metanalysis performed on a variceal bleeding population[20]. The ABC score was recently validated to predict 30 d mortality in patients with both upper and lower GI bleeding. Based on patient’s age, kidney, and liver (albumin) function, and associated comorbidities, it can classify patients at low, medium, or high risk of mortality. Although there is limited literature data, the ABC score showed better performance when compared to AIMS65 and full Rockall score on a mixed population (variceal and non-variceal) GI bleeding[9,21]. Interestingly, in our study, the score had the highest performance (AUROC 0.770) in predicting in-patient mortality in the entire population (variceal and non-variceal), as well as non-variceal bleeding when compared to AIMS65, PERS and GBS. This is particularly important as no previous investigations compared the scores’ ability to predict mortality by type of GI bleeding (variceal vs non-variceal). Our findings also support previous evidence that ABC performs better than GBS or AIMS65 score[22], also outperforming Progetto Nazionale Emorragia Digestive (PNED) and Rockall score[23]. Looking at the other three scores, our results show that AIMS65 is superior to GBS and PERS, but with no significant difference in the AUROC value. In non-variceal upper GI bleeding, other investigators support a better predictive power for AIMS65 when compared to other scores[24]. In contrast, GBS and PERS are the most widely used pre-endoscopic scoring system in clinical practice, with most studies in non-variceal upper GI bleeding cohorts. GBS has been previously reported to perform less than PERS in predicting mortality[25,26], similar to our cohort, where GBS had the lowest AUROC of 0.657. However, for practical reasons, we consider that ABC score, at a cut-off value of 5.5 can be used to determine in-hospital mortality in both populations. The cut-off value of each score was determined as it is a key determinant in predicting outcomes. There are significant variations among different studies, probably due to population characteristics, moment, and type of therapeutic interventions[27]. For in-hospital mortality, we determined a cut-off value of 1 for AIMS65 score in patients with variceal bleeding. This should label the patients as high category of emergency and limit the waiting time until assessment as much as possible. Cut-off values of 1[27], 2[24], or 3[28] were previously reported in different populations, with similar results for European cohorts. For those presenting with non-variceal upper GI bleed, an ABC score of 5.5 classifies them as high risk. Similar to our findings, another study reported a cut-off value of 5.5 for ABC score in predicting 30-d mortality[29] associated with a 13.1% risk of mortality. Regarding endoscopic intervention, no score performed as a good predictor in the non-variceal bleeding group, due to an AUROC < 0.600. This is consistent with previous reports where AUROC levels were around 0.500[30], but other investigators showed better performance (AUROC 0.750, sensitivity 80.4%, specificity 57.4%)[31]. We found that PERS score, at a cut-off value above 3.5 showed good performance for predicting endoscopic treatment in variceal bleeding patients, with a sensitivity of 76.5% and specificity of 40%, and a relatively low AUROC (AUC = 0.604; 95%CI: 0.506-0.703; P = 0.046). Rockall score can be calculated after endoscopy (full Rockall), or prior to it (PERS). The pre-endoscopic score relies on vital signs, patient’s age and comorbidities and it was previously validated to predict in-patient mortality. On the other hand, the full Rockall score can be used as a predictor of endoscopic treatment at a cut-off value > 3.5[32]. This is particularly important as the latter score includes endoscopic findings which plays a major role in the diagnosis and treatment of such patients. All patients included in our cohort have been investigated endoscopically within the first 24 h of presentation. As previously mentioned, timing of endoscopy is of paramount importance in patients with high risk of further bleeding and mortality and it should be performed within 12 h, especially in patients with variceal bleed. On the other hand, very early endoscopy (less than 6 h) does not appear to reduce mortality or further risk of bleeding[33]. Although our AUROC values were low, we agree with most previously reported data which showed better performance of GBS in predicting endoscopic intervention in patients with GI bleeding[20]. We did not find any study to evaluate the ABC score against this outcome. Further larger studies may be needed. Nowadays, less surgical interventions are performed in upper GI bleeding, mainly due to advances in types of endoscopic treatment and interventional radiology. All patients requiring surgical intervention in our population (n = 9) are in the non-variceal group. The main reason is failure of endoscopic treatment and lack of availability of endovascular therapies. All scores showed good predictive value for surgical intervention with an AUROC > 600. Our study is the first to compare such outcome for all investigated scores. However, only GBS score, at a cut-off value above 12.5 with a sensitivity of 66.7% and specificity of 52.8% had statistical significance. GBS has been validated to be a good predictor for need of treatment, which consisted of either endoscopy, surgery or interventional radiology[34]. No risk score proved to be a good predictor for length of stay (> 7 d) as it had poor statistic power, with an AUROC below 0.600. Similar low discriminative abilities were previously reported for PNED, full and PERS, GBS and AIMS65 score, with an AUROC close to 0.600[15]. Lactate is an independent predictor for in-hospital mortality, need for intensive care unit admission, recurrence of bleeding or need for surgical intervention[12,13]. We are of the opinion that lactate could be implemented as a standard test in all patients with upper GI bleeding. In variceal bleeding patients, levels of lactate might be higher due to associated liver insufficiency, large volume of bleeding and subsequent hypovolemia[13,35]. On the other hand, in patients with less dramatic clinical presentation, lactate could be used as a tool for early detection of GI bleeding[36,37]. In our cohort it was an independent predictor of mortality and intervention (endoscopy and surgery). There is, however, disparity among studies evaluating role of lactate in addition to risk scores. It seems that incorporation of arterial lactate in PERS and GBS showed a statistically significant improvement in their ability to predict mortality, but with a low AUROC[38]. In contrast, when taking into account venous lactate level, the power of discrimination for GBS and PERS for in-patient mortality showed better performance and an AUROC > 700. The difference between levels of arterial and venous lactate (which has higher levels) might be a determinant factor for study results variability[39]. In our population, addition of lactate to GBS score showed a 12-fold increase in probability of in-hospital mortality (P < 0.003), but this only applies to the non-variceal bleeding group. In case of patients presenting with variceal upper GI bleeding, addition of lactate to AIMS65 score, leads to a 5-fold increase in determining the probability of in-hospital mortality (P < 0.05). Similar findings are supported by another retrospective study where the modified L-AIMS65 score (AIMS65 combining lactate) had higher AUC for rate of rebleeding and 30 days mortality. Unfortunately, it did not show statistical significance[40]. In terms of type of intervention, adding lactate to the regression model of non-variceal bleeding population does not improve the prediction value of any of the determined scores. There are several limitations of our study. It is a single center, retrospective analysis based on clinical records data which may lead to selection bias. The decision of intervention was based on the clinical judgement of emergency medicine physician. Hospital admission was indicated by the gastroenterologist and surgeon on call. We excluded a large number of patients, mainly due to lack of availability in albumin and venous lactate level. Also, irrespective of their statistical power, risk scores are tools which cannot replace appropriate clinical evaluation, decision making process and the need for an individualized approach of each patient. CONCLUSION ABC score is the most accurate in predicting in-hospital mortality in both mixed and non-variceal bleeding population. AIMS65 had the best performance in predicting in-patient mortality in patients with variceal upper GI bleeding, however, for practicality, we advise the use of ABC score for both populations. In terms of intervention, PERS and GBS should be used to determine need for endoscopic and surgical intervention. Lactate can be used in conjunction to AIMS65 and GBS score to predict in-patient mortality and intervention. Although GBS is currently largely used, further studies are needed to investigate the relatively new ABC score regarding its role in daily clinical practice and possible implementation in guidelines. ARTICLE HIGHLIGHTS Research background Upper gastrointestinal (GI) bleeding patients require immediate assessment at the time of arrival in the emergency department (ED). A comprehensive, however fast approach regarding haemodynamic status, transfusion strategy and need for intervention should be performed. This can be achieved by calculating GI bleeding risk scores which should be able to predict several outcomes such as need for intervention, mortality, rebleeding rate or death. Pre-endoscopy risk scores have proved to be a reliable tool which may allow timely sequential decisions. Glasgow-Blatchford score (GBS) has been validated to identify low risk patients which may be managed as outpatients. Pre-endoscopic Rockall score (PERS) evaluates the risk of rebleeding and mortality, while albumin, international normalized ratio, altered mental status, systolic blood pressure, age older than 65 (AIMS65), determines the risk of death. Age, blood tests and comorbidities (ABC) is a relatively new risk score used to predict mortality in patients with both upper and lower GI bleeding. There is a certain variability among these risk scores, potentially due to the differences in population included. Moreover, there is limited data for variceal upper GI bleeding. Venous lactate is another important tool in critically ill patients, such as those with shock, trauma, or heart failure. It has been shown to predict in-hospital mortality, need for intensive care or surgical intervention, as well as rebleeding rate in patients with upper GI bleed. It may be used to improve performance of existing scoring systems and guide clinicians towards early triage of patients. Research motivation As emergency services are struggling with high patient flow, clinicians must promptly decide appropriate management in patients with upper GI bleeding. A standardized approach and protocols should attempt to quickly assess the need for admission, timing of endoscopy and level of care. It is generally recommended to perform endoscopy within 24 h of presentation as it plays a pivotal role in identifying the source of bleeding and it can achieve haemostasis in most cases. Unfortunately, it may not be available in all centers or, if performed in low-risk patients, it may overcrowd the service with unnecessary urgent interventions. Hence, we need a standardized tool to guide the emergency medicine clinician for appropriate referral and management of patients. This should reduce the burden and costs on the healthcare system and on-call physicians. Research objectives To evaluate the performance of pre-endoscopic risk scores (GBS, PERS, AIMS65, and ABC) in patients with variceal and non-variceal upper GI bleeding for predicting the following primary outcomes: In-hospital mortality, type of intervention (endoscopic or surgical) and length of admission (≥ 7 d). We will further evaluate whether the addition of venous lactate improves the score performance in predicting the determined outcomes. Research methods We retrospectively analyzed all patients above 18 years old presenting to the emergency department (ED) with upper GI bleeding from January 2020 to December 2021. Each patient presenting with exteriorized upper GI bleeding was fully assessed by the emergency medicine physician. Immediate venous catheterization and fluid resuscitation was performed and full work-up with blood tests (full blood count, coagulation parameters, liver, kidney function, venous lactate), and other investigations were performed within 24 h from presentation. Patients with a Hb ≤ 7 g/dL had at least one unit of red blood cell concentrate transfused, with a higher Hb threshold (Hb ≤ 8 g/dL) for patients with associated cardiovascular disease. Post-transfusion target Hb was between 7-9 g/dL. Endoscopy was performed within 24 h of ED arrival in all patients included in analysis. Forrest classification was used to describe peptic ulcer disease, with Baveno and Sarin’s classification for gastroesophageal varices. Patients with non-variceal upper GI bleeding received an infusion with PPIs, while those with variceal bleeding were treated with Somatostatin. Endoscopic treatment was performed depending on the cause of bleeding. A combined approach with injection therapy (dilute epinephrine) and mechanic therapy (thermal coagulation or haemostatic clip) was used for FIa, FIb, and FIIa, with clot removal in FIIb lesions. In variceal bleeding, endoscopic ligation was the main approach. Surgical treatment was performed in cases where endoscopic treatment failed. The need for admission was established by the gastroenterology and general surgery teams on-call. Research results The final study included 363 patients with upper GI bleeding with a mean age of 60 years old and a predominance of male sex. Non-variceal bleeding was the main cause of presentation, liver cirrhosis the most frequently associated comorbidity in the entire group. The main symptom of presentation was haematemesis in patients with variceal bleeding and melena in the non-variceal group. Approximately 9% of our patients had chronic treatment with antiplatelets or oral anticoagulation. Gastric/duodenal ulcer was the main cause of GI bleeding. Most patients in variceal bleeding group required mechanical endoscopic therapy with band ligation and only 2 patients had variceal sclerotherapy. In the non-variceal bleeding group, dual therapy with thermal anticoagulation and local administration of dilute Adrenaline was the main type of endoscopic intervention. Failed endoscopy was recorded in approximately 4.7% of patients. Only 9 patients in the non-variceal group required surgical intervention. In-hospital mortality had an overall rate of 9.4%, most cases were in the variceal group. All scores had discriminative ability in predicting in-hospital mortality irrespective of study group. AIMS65 score had the best performance for the variceal bleeding group and ABC in the non-variceal bleed. The optimal cut-off value for predicting in-hospital mortality was calculated for each score depending on the type of bleeding. For variceal bleeding, an AIMS65 score above 1 with sensitivity of 90% and specificity of 73% and ABC score with a cut-off value of 5.5 and specificity. In the non-variceal bleeding group, the optimal cut-off value for in-hospital mortality was 1.5 for AIMS65 score, with sensitivity of 66.7% and specificity of 57%. We have determined the best scoring system for in-hospital mortality in the included population, both variceal and non-variceal bleeding, with ABC being the best predictor. For variceal bleeding patients, only PERS score, at a cut-off value above 3.5 was a good predictor for endoscopic treatment with a sensitivity of 76.5% and specificity of 40%. Venous lactate did not show good performance in predicting variceal bleeding, due to low sensitivity (64.3%) and specificity (53.2%). However, logistic regression model showed it is an independent predictor for the determined outcomes. For the variceal bleeding population, addition of lactate to AIMS65 score, leads to a 5-fold increase in probability of in-hospital mortality. For non-variceal bleeding, addition of lactate to GBS score showed a 12-fold increase in probability of in-hospital mortality. In terms of intervention, higher level of venous lactate increases by 5.5 times the probability of endoscopic intervention and by 2 the probability for surgical intervention. Research conclusions To our knowledge, this is the first study to compare four of the most representative pre-endoscopic risk scores, AIMS65, PERS, GBS and the relatively new ABC score in variceal and non-variceal GI bleeding cohort. ABC score is the most accurate in predicting in-hospital mortality in both mixed and non-variceal bleeding population. AIMS65 had the best performance in predicting in-hospital mortality in patients with variceal upper GI bleeding, however, for practicality, we advise the use of ABC score for both populations. In terms of intervention, PERS and GBS should be used to determine the need for endoscopic and surgical intervention. Lactate can be used in conjunction to AIMS65 and GBS score to predict in-hospital mortality and intervention. Research perspectives Although GBS is currently largely used, further studies are needed to investigate the relatively new ABC score regarding its role in daily clinical practice and possible implementation in guidelines. Data sharing statement Technical appendix, statistical code, and dataset available from the corresponding author at victorita.sorodoc@umfiasi.ro. Institutional review board statement: The study was reviewed and approved by the ‘’Saint Spiridon’’ Institutional Review Board approved this study (approval No. 39/30.03.2022). Conflict-of-interest statement: The authors declare no conflict of interest. STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items. Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: March 28, 2023 First decision: April 26, 2023 Article in press: May 30, 2023 Specialty type: Gastroenterology and hepatology Country/Territory of origin: Romania Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): 0 Grade C (Good): C, C Grade D (Fair): D, D Grade E (Poor): 0 P-Reviewer: Losurdo G, Italy; Skok P, Slovenia; Treeprasertsuk S, Thailand S-Editor: Chen YL L-Editor: A P-Editor: Cai YX ==== Refs 1 Lai YC Hung MS Chen YH Chen YC Comparing AIMS65 Score With MEWS, qSOFA Score, Glasgow-Blatchford Score, and Rockall Score for Predicting Clinical Outcomes in Cirrhotic Patients With Upper Gastrointestinal Bleeding J Acute Med 2018 8 154 167 32995218 2 Hăisan A Măirean C Lupuşoru SI Tărniceriu C Cimpoeşu D General Health among Eastern Romanian Emergency Medicine Personnel during the Russian-Ukrainian Armed Conflict Healthcare (Basel) 2022 10 3 Stanley AJ Ashley D Dalton HR Mowat C Gaya 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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4640 10.12998/wjcc.v11.i19.4640 Case Report CK5/6-positive, P63-positive lymphoepithelioma-like hepatocellular carcinoma: A case report and literature review Tang HT et al. CK5/6-positive, P63-positive lymphoepithelioma-like HCC Tang Hong-Tao Graduate School of Guangdong Medical University, Zhanjiang 524002, Guangdong Province, China Department of Hepatobiliary Surgery, Zhongshan People’s Hospital, Zhongshan 528400, Guangdong Province, China Lin Wei Graduate School of Guangdong Medical University, Zhanjiang 524002, Guangdong Province, China Zhang Wei-Qiao Graduate School of Guangdong Medical University, Zhanjiang 524002, Guangdong Province, China Qian Jun-Lin Graduate School of Guangdong Medical University, Zhanjiang 524002, Guangdong Province, China Li Kai Graduate School of Guangdong Medical University, Zhanjiang 524002, Guangdong Province, China He Kun Department of Hepatobiliary Surgery, Zhongshan People’s Hospital, Zhongshan 528400, Guangdong Province, China. hekun80@126.com Author contributions: Tang HT analysed the relevant literature and wrote the manuscript; He K led the whole process, including the operation, and directed the writing of the manuscript; Lin W and Zhang WQ participated in the data collection; Qian JL was in charge of the long-term follow-up of the patient. Supported by Zhongshan Bureau of Science and Technology, No. 2017B1044 ; and No. 2017SYF04. Corresponding author: Kun He, MD, PhD, Director, Doctor, Professor, Chief Physician, Department of Hepatobiliary Surgery, Zhongshan People’s Hospital, No. 2 Sunwen East Road, Shiqi District, Zhongshan 528400, Guangdong Province, China. hekun80@126.com 6 7 2023 6 7 2023 11 19 46404647 15 1 2023 11 2 2023 9 6 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND Lymphoepithelioma-like carcinoma (LELC), a rare and unique variant of liver cancer, can be divided into lymphoepithelioma-like hepatocellular carcinoma and lymphoepithelioma-like intrahepatic cholangiocarcinoma. Dense lymphocytic infiltration is its characteristic pathological feature. In recent years, the number of reported cases of this type has increased each year. Studies have shown that lymphoepithelioma-like cholangiocarcinoma occurs more frequently in Asian women; LELC is associated with Epstein–Barr virus infection of liver cells of epithelial origin. Existing research shows that the prognosis of this tumour is good. CASE SUMMARY A 38-year-old female patient was hospitalized after 3 mo of abdominal pain and nausea. She had been infected with hepatitis B virus more than 10 years prior. The patient was hospitalized on January 21, 2022. Magnetic resonance imaging showed a 36 mm × 28 mm mass under the envelope of the left inner lobe of the liver. No metastasis of lymph nodes or other organs was observed. After left hemihepatectomy, biopsy and immunohistochemistry yielded a final diagnosis of lymphoepithelial hepatocellular carcinoma. After 12 mo of outpatient follow-up and chemotherapy, no tumour metastases were found on the latest computed tomography examination. CONCLUSION Herein, the patient was treated surgically and then followed up as an outpatient for 12 mo. This case will further expand our overall knowledge of the diagnosis and treatment of this rare tumor. Liver cancer Lymphoepithelioma-like carcinoma Hepatocellular carcinoma Epstein–Barr virus Literature review Case report ==== Body pmc Core Tip: Primary hepatocellular lymphoepithelioma-like carcinoma (LELC) is a rare disease. We review the relevant literature, and only a few clinical cases have been reported worldwide. The patient in this case report was eventually diagnosed with primary hepatocellular LELC based on her family history, magnetic resonance imaging scans, and immunohistochemical findings. Herein, we summarize and discuss this case and review the pathogenesis, clinical manifestations, diagnosis, and treatment of primary hepatocellular LELC. INTRODUCTION Lymphoepithelioma-like carcinoma (LELC) is a tumor consisting of undifferentiated epithelial cells with a distinct lymphocytic infiltrate. This term was originally used to describe tumors of the nasopharynx[1-5]; however, this tumor has also been reported to be found in the lung, breast, prostate, bladder, uterus, and liver[6]. LELC is a rare and unique variant of hepatocellular carcinoma (HCC) with distinct epidemiological and pathological features possessing a large lymphocytic infiltration. Available studies suggest that this type of tumor has a good prognosis[7,8], and primary LELC of the liver is rare[9]. LELC was recognized as a unique variant of liver cancer by the World Health Organization (WHO) in 2010[10]. As with LELC at most other sites, Epstein–Barr virus (EBV) infection plays a crucial role in the carcinogenesis of liver LELC, and EBV infection can be detected in the vast majority of LELC cases. These results suggest that EBV infection plays an important role in LELC tumorigenesis and development. Lymphoepithelioma-like cholangiocarcinoma (LEL-ICC) formation is closely related to EBV infection[11]. The presence of EBV was also detected in the intrahepatic cholangiocytic LELC in this case. Hepatocellular LELC has no special clinical manifestations; most patients have a history of hepatitis, but a few do not. Histologically, the tumour is infiltrative; specifically, it infiltrates the mucosa in the form of irregular islands, nests, sheets, or single cells. The nests and stroma were filled with mature lymphocytes and plasma cells. Tumour cells have a single vesicular nucleus, a round to ovoid shape, obvious nucleoli, and an eosinophilic cytoplasm. The cells have a syncytial appearance, with no clear boundaries separating them. The tumour cells may also present a thick fusiform shape, and the nuclei may be arranged in a way that resembles flowing water. Most tumour cells are positive for CKL8 and alpha-fetoprotein (AFP). The immunohistochemical markers of infiltrated lymphocytes suggest polyclonal expression. Combining and reviewing the literature on the treatment of LELC, a case of hepatic LELC in a 38-year-old woman is reported here; we hope this report will further improve the diagnosis and treatment of patients with this condition. CASE PRESENTATION Chief complaints A 38-year-old woman was admitted to Zhongshan People's Hospital of Guangdong Province on January 21, 2022, with complaints of dull epigastric pain for 1 wk. History of present illness The patient began to have dull pain in the upper abdomen without any obvious cause. The pain was a persistent sense of distension that did not radiate to any other locations, and there was no actual, palpable distension of the abdomen. The patient had no fever, chills, dizziness, headache, cough, expectoration, diarrhoea, vomiting, bloody or black stools, etc. History of past illness This patient had been infected with hepatitis B virus for more than 10 years and had not been given symptomatic treatment. She had no other significant medical history. Personal and family history There was no other special personal history or family history of disease. Physical examination The patient presented with persistent epigastric pain that did not radiate elsewhere. Laboratory examinations The patient’s laboratory results were as follows: Protein induced by vitamin K absence or antagonist-II (PIVKA-Ⅱ): 38.6 (normal range: 20-40 mAU/mL); AFP: 5 (normal range: 0.0-8.1 ng/mL); carcinoembryonic antigen (CEA): 1.70 (normal range: 0.0-5.0 ng/mL); carbohydrate antigen 125: 93.50 (normal range: 0.0-35.0 U/mL); carbohydrate antigen199 (CA19-9): 165.50 (normal range: 0.0-37.0 U/mL); EBV-DNA: 1.62E+02 copies/mL (normal range: < 100 copies/mL); hepatitis B surface antibody (HBsAb): (+) (normal range: < 10.00 mIU/mL); hepatitis B e antibody (HBeAb): (+) (normal range: > 1.00 cut off index [COI]); hepatitis B core antibody (HBcAb): (+) (normal range: < 1.00 COI); alanine aminotransferase (ALT): 5 (normal range: 7-40 U/L); aspartate aminotransferase (AST): 12 (normal range: 13-35 U/L); albumin(Alb): 37.90 (normal range: 40.0-55.0 g/L). Imaging examinations On magnetic resonance imaging (MRI) examination of the upper abdomen, the shape and size of the liver were as usual. A mass (Figure 1A-D: Maximum diameter 36 mm × 28 mm) was seen under the capsule of the left inner lobe of the liver, which was moderately and inhomogeneously enhanced, with an enhanced capsule and fusion of two nodules. There were no abnormal signals in the parenchyma of the remaining liver. The portal vein and hepatic vein were patent, and there were no signs of filling defects or obstructions. There were no signs of enlarged retroperitoneal lymph nodes. Additionally, there were no signs of effusion in the abdominal cavity. Pharyngorhinoscopy did not reveal any abnormalities in the nasopharynx. Figure 1 Magnetic resonance imaging showed a 36 mm × 28 mm mass under the capsule of the left inner lobe of the liver. A: No abnormal signal was found in the parenchyma of the remaining liver; B: Retroperitoneal lymphadenopathy was not found; C: Slightly elevated signal intensity on T2-weighted imaging; D: No signs of effusion were found in the abdominal cavity. FINAL DIAGNOSIS On the basis of her history, signs, imaging findings, and postoperative pathology (Figure 2B-D) and immunohistochemistry, the patient was ultimately diagnosed with lymphoepithelioma-like HCC. Figure 2 The resected part of the liver measured 16 cm × 9 cm × 5 cm. A: An irregular nodule measuring 3.5 cm × 3.5 cm × 2.5 cm was seen near the resection margin. This nodule was hard, yellow-grey, and well-defined. The tumour did not rupture, and it did not penetrate the liver capsule. The rest of the liver was soft, grey-red, and free of nodules; B: The tumour cells were large, with prominent nucleoli and eosinophilic cytoplasm (H&E, ×200); C: The tumour had an irregular island-like and nest-like morphology, with numerous lymphocytes and plasma cells infiltrating the stroma (H&E, ×200); D: The tumour was infiltrative and indistinguishable from the surrounding liver tissue (H&E, ×200). TREATMENT On January 26, 2022, the patient underwent laparoscopic left hepatectomy plus regional lymphadenectomy based on her medical history, signs, and imaging findings. The hepatectomy encompassed the entire left side of the liver; the lymphadenectomy encompassed the lymph nodes anterior and posterior to the common hepatic artery as well as those posterior to the pancreatic head. OUTCOME AND FOLLOW-UP After the operation, the patient received symptomatic treatment including immune and targeted therapies (lenvatinib mesilate capsules: 8 mg orally once a day; tislelizumab injection: 200 mg given intravenously every 3 wk), and she recovered uneventfully. After discharge, regular outpatient follow-up and drug treatment were continued. At the last outpatient follow-up on December 30, 2022, computed tomography (CT) examination showed no obvious masses in the operative area and no obvious abnormal lymph nodes in the abdominal cavity or retroperitoneum (Figure 3). Tumour marker levels were also reduced (Figure 4). Figure 3 Images of upper abdominal spiral computed tomography performed on December 30, 2022. A: There were no obvious abnormal lymph nodes in the abdominal cavity or retroperitoneum; B: The left lobe of the liver was absent postoperatively; C: A small amount of hydrops was present in the adjacent abdominal cavity, and there was no obvious widening of the portal vein; D: There was no obvious mass lesion in the operative area. Figure 4 Tumour marker levels. A: Alpha-fetoprotein decreaseds from 5 ng/mL to 1.7 ng/mL from January 1 to April 1, 2022; B: From January 1 to August 1, 2022, the carbohydrate antigen 125 value decreased from 93.5 U/mL to 28.2 U/mL. DISCUSSION LELC is believed to have unique epidemiological and pathological characteristics. The prognosis is good compared to typical HCC and ICC. LELC may be associated with a large lymphocytic infiltrate, which in this unique variant of HCC may be associated with an immune response. Overall, the pathogenesis of LELC and the factors affecting its prognosis deserve further investigation. In contrast, the patient's serum levels of AFP were unremarkable, and this may help to differentiate LELC from primary liver tumors, such as HCC and ICC. Positron emission tomography/CT is recommended when LELC is suspected to occur in an uncommon site such as the liver. The clinical presentation and imaging findings of patients with LELC are not specific. Most cases were confirmed by pathological diagnosis and post-surgical immunohistochemistry. The precise diagnosis is made by pathology, and the immunohistochemical findings show numerous large, atypical, poorly differentiated epithelial cells with an eosinophilic cytoplasm and high expression of CK, CK5/6, and P63[12]. Desmin belongs to the intermediate fibronectin family, which connects organelles by forming a cytoskeletal network. During carcinogenesis, an increase in the number of Desmin-positive cells was observed in advanced tumors, consistent with increased angiogenesis and microvascular maturation. Vimentin is among the most common members of mesenchymal cell-specific intermediate filaments. Many proteomic studies have shown that vimentin is a metastasis-associated factor in a variety of malignancies, such as prostate, breast, gastric, and gallbladder cancers. This suggests that vimentin plays an important role in tumor progression and may serve as a potential biomarker of tumor metastasis. The correlation between the expression of vimentin, a canonical marker of epithelial-to-mesenchymal transition (EMT), and malignancy has been extensively studied; however, how vimentin regulates tumor metastasis and survival is still under investigation. These features are confirmed in the present case report. According to an analysis of the current literature, patients with LEL-ICC have a median age of 57 (46–64) years and are mainly Asian women, with 92% of patients overall being Asian[7]. The WHO updated the key histologic feature of LELC in 2019, that is, most areas had more lymphocytes than tumor cells as shown by hematoxylin and eosin staining. Based on this histologic feature, the WHO proposed a new subtype of liver cancer called lymphocyte-enriched HCC[13]. Therefore, pathology is the basic method for the diagnosis of LELC. Microscopically, atypical tumor cells are barely differentiated and have a massive lymphocytic infiltration (Figure 2C). Based on the above pathological features, LELC can be distinguished from typical HCC. In addition, LELC can be divided into two types, namely, LEL-HCC and LEL-ICC, according to microscopic observation and the expression of immunohistochemical factors. However, diagnosis using pathological methods is only used for patients who have undergone hepatectomy, liver puncture, or liver transplantation. The clinical presentation of patients with LELC is nonspecific. Most patients have physical examination findings, while some patients present with symptoms of right upper abdominal pain or chronic cholecystitis[14-16]. Nonetheless, owing to the lack of specific clinical manifestations, it is difficult to diagnose LELC before surgery. The diagnosis and treatment strategy for LELC can be summarized as follows. First, since LELC is a relatively rare HCC variant with a low incidence, it cannot be ruled out in the diagnosis and treatment of HCC. In addition, it is recommended that treatment strategies be developed by a multidisciplinary team. Second, it is best to perform a preoperative EBV test; if the result is positive, it will further support the diagnosis of LELC. Compared to patients with EBV-negative LEL-ICC, those with EBV-associated LEL-ICC usually have favourable postsurgical outcomes. Chan et al[17] found distinctively frequent DNA hypermethylation in seven EBV-associated LEL-CC lesions. Other viruses, such as hepatitis B virus and hepatitis C virus, are not associated with LEL-ICC[18,19]. Third, for advanced liver tumors, a liver biopsy and associated pathological diagnosis are recommended. If LELC is present, it should be treated aggressively. Fourth, when postoperative pathological results indicate the presence of LELC, active intervention and treatment are recommended for long-term survival because, even with local recurrence and metastasis, LELC may have a favourable prognosis. Lymphoepithelioma is a rare cancer originally described in 1982 in the nasopharynx[20]. Since then, cases have been reported in different organs, such as the salivary glands, stomach, lungs, colon, uterus, and ovaries[21], and were designated as LELCs. In 2010, the WHO characterized LELC as undifferentiated cancer cells with markedly infiltrating lymphocytes[22]. The lack of specificity of LELC necessitates a systematic preoperative examination to exclude cancers originating from other organs, especially the nasopharynx[23]. Preliminary analysis suggests that LELC is a unique and rare variant of HCC possessing a large infiltration of lymphocytes, and related studies are still in progress. The diagnosis of LELC mainly depends on pathological methods. In the current study, the positive rates of CK, CK5/6, and CK34βE12 staining were 100% (33/33), 78.13% (25/32), and 78.57% (11/14), respectively, and that of P63 was 81.82% (18/22)[24]. The treatment of LELC mainly depends on surgery. Surgical resection is currently the first choice for the treatment of LEL-ICC. In contrast, advanced or metastatic tumors require a combination of chemotherapy, radiotherapy, and other treatments. Platinum-based chemotherapy can be the first-line treatment for advanced LELC[25]. 5-fluorouracil/folic acid/cisplatin treatment is effective in LELC cases[26]; capecitabine alone can be used as salvage chemotherapy to maintain stable disease[27]. PD-1 inhibitors are increasingly being studied as immunotherapeutic agents. Transcatheter arterial chemoembolization (TACE) combined with a PD-1 inhibitor resulted in decreased CD4+/CD8+ cell ratio and increased PD-1 mRNA expression in HCC patients[28]. Therefore, TACE in combination with PD-1 inhibitors may have potential clinical value in TACE refractory patients. In a phase 1b clinical trial involving patients with unresectable HCC, the combination of a PD-L1 inhibitor (atezolizumab) and a VEGF inhibitor (bevacizumab) has shown excellent antitumor activity and safety[29]. The combined usage of bevacizumab and atezolizumab has also become the new standard of care for first-line treatment of BCLC stage C HCC after the IMbrad-150 study[30,31]. In a randomized phase III trial, the combination of atezolizumab and bevacizumab showed an advantage relative to single-agent sorafenib [median overall survival 19.2 mo vs 13.4 mo (P < 0.001)], and this has led to its recommendation as a first-line treatment in several international guidelines. A good prognosis can be obtained after radical resection, which should be combined with carefully planned adjuvant therapy. CONCLUSION Herein, a rare case of primary hepatocellular LELC is reported. The patient was followed up for 12 mo after surgery and was treated with regular immunotherapy and targeted therapy. No tumour recurrence was found. This case will further expand our overall knowledge of the diagnosis and treatment of this rare tumor. ACKNOWLEDGEMENTS Thanks to Dr. He Yongzhu for his guidance on this article. Informed consent statement: Written informed consent was obtained from the patient for the publication of this report and any accompanying images. Conflict-of-interest statement: All the authors report that they have no conflicts of interest related to this article. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: January 15, 2023 First decision: February 1, 2023 Article in press: June 9, 2023 Specialty type: Oncology Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): B Grade C (Good): 0 Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Elkady N, Egypt; Rizzo A, Italy S-Editor: Liu JH L-Editor: Wang TQ P-Editor: Liu JH ==== Refs 1 Nieto-Coronel MT Perez-Sanchez VM Salazar-Campos JE Diaz-Molina R Arce-Salinas CH Lymphoepithelioma-like carcinoma of breast: A case report and review of the literature Indian J Pathol Microbiol 2019 62 125 128 30706876 2 Sathirareuangchai S Hirata K Pulmonary Lymphoepithelioma-like Carcinoma Arch Pathol Lab Med 2019 143 1027 1030 30672338 3 Venyo AK Primary Lymphoepithelioma-Like Carcinoma of the Prostate Gland: A Review of the Literature Scientifica (Cairo) 2016 2016 1876218 26881187 4 Raphael V Jitani AK Sailo SL Vakha M Lymphoepithelioma-like carcinoma of the urinary bladder: A rare case report Urol Ann 2015 7 516 519 26692678 5 Makannavar JH KishanPrasad HL Shetty JK Lymphoepithelioma-like Carcinoma of Endometrium; A Rare Case Report Indian J Surg Oncol 2015 6 130 134 26405421 6 An SL Liu LG Zheng YL Rong WQ Wu F Wang LM Feng L Liu FQ Tian F Wu JX Primary lymphoepithelioma-like hepatocellular carcinoma: report of a locally advanced case and review of literature Int J Clin Exp Pathol 2015 8 3282 3287 26045853 7 Zhang K Tao C Tao Z Wu F An S Wu J Rong W Lymphoepithelioma-like carcinoma in liver not associated with Epstein-Barr virus: a report of 3 cases and literature review Diagn Pathol 2020 15 115 32967689 8 Labgaa I Stueck A Ward SC Lymphoepithelioma-Like Carcinoma in Liver Am J Pathol 2017 187 1438 1444 28500863 9 Bosman FT Carneiro F Hruban RH Theise ND WHO Classification of Tumours of the Digestive System. Geneva: WHO Press, 2010 10 Verhoeven RJA Tong S Mok BW Liu J He S Zong J Chen Y Tsao SW Lung ML Chen H Epstein-Barr Virus BART Long Non-coding RNAs Function as Epigenetic Modulators in Nasopharyngeal Carcinoma Front Oncol 2019 9 1120 31696060 11 Jeng YM Chen CL Hsu HC Lymphoepithelioma-like cholangiocarcinoma: an Epstein-Barr virus-associated tumor Am J Surg Pathol 2001 25 516 520 11257627 12 Jiang WY Wang R Pan XF Shen YZ Chen TX Yang YH Shao JC Zhu L Han BH Yang J Zhao H Clinicopathological features and prognosis of primary pulmonary lymphoepithelioma-like carcinoma J Thorac Dis 2016 8 2610 2616 27747015 13 Nagtegaal ID Odze RD Klimstra D Paradis V Rugge M Schirmacher P Washington KM Carneiro F Cree IA WHO Classification of Tumours Editorial Board The 2019 WHO classification of tumours of the digestive system Histopathology 2020 76 182 188 31433515 14 Wang JK Jin YW Hu HJ Regmi P Ma WJ Yang Q Liu F Ran CD Su F Zheng EL Li FY Lymphoepithelioma-like hepatocellular carcinoma: A case report and brief review of literature Medicine (Baltimore) 2017 96 e9416 29390565 15 Nemolato S Fanni D Naccarato AG Ravarino A Bevilacqua G Faa G Lymphoepitelioma-like hepatocellular carcinoma: a case report and a review of the literature World J Gastroenterol 2008 14 4694 4696 18698686 16 Filotico M Moretti V Floccari F D'Amuri A Very Rare Liver Neoplasm: Lymphoepithelioma-Like (LEL) Hepatocellular Carcinoma Case Rep Pathol 2018 2018 2651716 30258661 17 Chan AW Tong JH Sung MY Lai PB To KF Epstein-Barr virus-associated lymphoepithelioma-like cholangiocarcinoma: a rare variant of intrahepatic cholangiocarcinoma with favourable outcome Histopathology 2014 65 674 683 24804938 18 Gearty SV Al Jurdi A Pittman ME Gupta R An EBV+ lymphoepithelioma-like cholangiocarcinoma in a young woman with chronic hepatitis B BMJ Case Rep 2019 12 19 Solinas A Calvisi DF Lessons from rare tumors: hepatic lymphoepithelioma-like carcinomas World J Gastroenterol 2015 21 3472 3479 25834311 20 Applebaum EL Mantravadi P Haas R Lymphoepithelioma of the nasopharynx Laryngoscope 1982 92 510 514 7078327 21 Bosman FT Carneiro F Hruban RH Theise ND Editors. 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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4648 10.12998/wjcc.v11.i19.4648 Case Report Edaravone administration and its potential association with a new clinical syndrome in cerebral infarction patients: Three case reports Yang L et al. Exploring the side-effects of edaravone Yang Liu Department of Neurology, Central Hospital Affiliated to Chongqing University, Chongqing 400010, China Xu Xin Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China Wang Liang Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China Zeng Ke-Bin Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China Wang Xue-Feng Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China. wangxfyp@vip.163.com Author contributions: Xu X and Wang XF were responsible for the neurological diagnosis and treatment; Yang L, Wang L, and Zeng KB were major contributors to the writing of the manuscript; All authors have read and approved the final version of the manuscript; Yang L and Xu X are co-authors, they equally contributed to the work. Corresponding author: Xue-Feng Wang, PhD, Professor, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Jiankang Road, Yuzhong District, Chongqing 400010, China. wangxfyp@vip.163.com 6 7 2023 6 7 2023 11 19 46484654 21 1 2023 24 3 2023 13 6 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND Edaravone is a widely used treatment for patients with cerebral infarction and, in most cases, edaravone-induced side effects are mild. However, edaravone-related adverse reactions have been receiving increasing attention. CASE SUMMARY We treated three patients with acute cerebral infarction who died following treatment with edaravone. Edaravone is a widely used treatment for patients with cerebral infarction and, in most cases, edaravone-induced side effects are mild. However, edaravone-related adverse reactions have been receiving increasing attention. CONCLUSION Our cases highlight the importance of educating clinicians regarding the new edaravone-induced clinical syndromes of cerebral infarction as potentially fatal adverse drug reactions. Considering that no laboratory or confirmatory test exists to diagnose edaravone-induced death from cerebral infarction, clinicians’ knowledge is the key element in recognizing this phenomenon. Edaravone Sudden death Patients Cerebral infarction Case report ==== Body pmc Core Tip: We report three patients with acute cerebral infarction who died after edaravone treatment. Edaravone is used to scavenge oxygen free radicals in patients with acute ischemic stroke, and most clinicians are only aware of its damage to kidney function. However, the main symptoms in patients treated with intravenous edaravone, such as rapid disease change, coagulation dysfunction, cardiac arrest and other side effects are rarely reported. The purpose of this paper is to share the experience of edaravone therapy in clinical practice. INTRODUCTION Edaravone is a clinically effective neuroprotective agent and a free radical scavenger that can capture hydroxyl radicals. It was approved for marketing in Japan and China in 2001 and 2005, respectively. Initially indicated for protection against ischemic brain damage, the indications for edaravone have gradually expanded to the treatment of amyotrophic lateral sclerosis[1-5]. However, owing to its widespread clinical application, adverse reactions due to edaravone have also received increasing attention[6-8]. In the earliest randomized controlled trial of edaravone for ischemic stroke treatment, 4 patients in the edaravone and 5 patients in the blank control groups died out of the 125 cases in each group. In the edaravone group, all deaths were caused by cerebral infarction; while in the control group, three patients died of cardiac arrest, pneumonia, and depression suicide, and two patients died of cerebral hernia caused by edema, worsened cerebral infarction, pneumonia, and disseminated intravascular coagulation (DIC) caused by cirrhosis[6]. In 2007, Japanese scholars reported that one patient with cerebral infarction treated with edaravone experienced severe adverse reactions. The patient presented with a sudden disturbance of consciousness and shock 12 d after hospitalization[6]. In 2018, we observed three patients who died of sudden worsening of acute cerebral infarction during treatment with edaravone, which was suspected to be the cause of death. CASE PRESENTATION Chief complaints Case 1: A 63-year-old woman with slurred speech and mental and behavioral abnormalities for ten days was admitted to our hospital. Case 2: A 65-year-old man was admitted to our hospital due to being unconscious for 11 h. Case 3: A 71-year-old man was admitted to our hospital due to sudden twisting of the left corner of his mouth for more than five days and difficulty swallowing for two days. History of present illness Case 1: A 63-year-old woman with slurred speech and mental and behavioral abnormalities for ten days was admitted to our hospital. Case 2: A 65-year-old man was admitted to our hospital due to being unconscious for 11 h. Case 3: A 71-year-old man was admitted to our hospital due to sudden twisting of the left corner of his mouth for more than five days and difficulty swallowing for two days. History of past illness Case 1: No significant history of past illness was noted in the patient. Case 2: The patient had a history of hypertension, diabetes mellitus, and cerebral infarction. Case 3: The patient had a history of hypertension. Personal and family history Personal history and family history were unremarkable. Physical examination Case 1: On admission, the patient’s vital signs were stable. The patient showed dysarthria, lack of cooperation, level V muscular strength in both limbs, and negative Babinski signs in both limbs. Case 2: The patient’s temperature was 36.6°C, blood pressure was 175/91 mmHg, heart rate was 80 beats/min, and respiratory rate was 16 breaths/min. The patient was in a superficial coma. The left nasolabial fold was slightly shallower than the contralateral side. Upon pain stimulation, the patient responded with an expression of pain and lifted his left limbs from the bed surface, but not the right limbs. Muscle tone of the right limb was lower than that of the left limb. Tendon reflexes on the right side were weaker than those on the left side. Case 3: On admission, the patient’s vital signs were stable. The patient was alert and had symmetrical forehead lines and dysarthria. The right nasolabial fold was slightly shallower than its contralateral part, and the patient's tongue deviated to the right when it was protruded. The patient had normal muscular strength and tone in all four limbs and symmetrical sensation and tendon reflexes. Bilateral Babinski signs were negative. Laboratory examinations Case 1: Laboratory examinations, including routine blood tests, liver and kidney function tests, and electrolyte and blood coagulation tests were within normal parameters. Electrocardiography revealed normal sinus rhythm. Case 2: Examination of blood coagulation status, liver and kidney function, and electrolyte levels after admission revealed no obvious abnormalities. Electrocardiography revealed normal sinus rhythm. Case 3: Laboratory examinations were within normal parameters. Electrocardiography revealed normal sinus rhythm. Imaging examinations Case 1: Head computed tomography (CT) scan showed cerebral infarction in the bilateral parietal lobes with multiple small ischemic lesions (Figure 1A). Figure 1 Computed tomography. A: Case 1: Head computed tomography (CT) scan showed cerebral infarction in the bilateral parietal lobes with multiple small ischemic lesions; B: Case 2: The patient’s emergency head CT scan showed cerebral infarction in the left thalamus and right cerebellar hemisphere; C: Case 3: Head CT scan suggested the probability of lacunar infarction in the left brainstem. Case 2: The patient’s emergency head CT scan showed cerebral infarction in the left thalamus and right cerebellar hemisphere (Figure 1B). Case 3: Head CT scan suggested the probability of lacunar infarction in the left brainstem (Figure 1C). FINAL DIAGNOSIS Case 1: Acute cerebral infarction, respiratory failure, and pneumonia. Case 2: Hypertension, diabetes mellitus, and cerebral infarction. Case 3: Hypertension, DIC, and cerebral infarction. TREATMENT Case 1: The following drugs were prescribed: Aspirin (100 mg once a day)[7,8], atorvastatin (20 mg once a day)[8,9], edaravone (30 mg twice a day), and Ginkgo biloba extract[10,11]. On the sixth day after admission, the patient developed dyspnea and showed decreased oxygen saturation. The patient was transferred to the intensive care unit (ICU) for tracheal intubation and mechanical ventilation. Multiple ecchymoses were observed on the patient’s body. DIC was diagnosed based on blood coagulation results, and low-molecular weight heparin (0.2 mL twice a day), tranexamic acid (500 mg once a day), fresh frozen plasma (400 mL), and cryoprecipitate (6 U) were administered to the patient. Blood coagulation status improved gradually after treatment. The patient’s respiratory condition improved after receiving ceftizoxime, and she was released from the ventilator. Case 2: The patient received aspirin (100 mg once a day)[7,8], atorvastatin (20 mg once a day)[8,9], edaravone (30 mg twice a day), Ginkgo biloba extract[10-13], and ceftizoxime (2 g three times a day) to treat the lung infection. Insulin was pumped intravenously based on increased blood glucose levels. Case 3: The patient was administered clopidogrel bisulfate (75 mg once a day), atorvastatin (20 mg once a day)[8,9], edaravone (30 mg twice a day), and ozagrel extract. OUTCOME AND FOLLOW-UP Case 1: On the tenth day after admission, the patient experienced sudden cardiac and respiratory arrest. After external chest compressions and mechanical ventilation, her heartbeat and breathing were restored. However, two further cardiac arrests occurred, and the patient died after the last attempt at resuscitation failed. Case 2: On the third day after admission, the patient's consciousness improved into a lethargic state. However, on the fifth day after admission, the patient lapsed into a deep coma and his heart rate gradually decreased. Resuscitation attempts were ultimately unsuccessful. Case 3: The twisted corner of the mouth rapidly improved. However, sudden cardiac arrest occurred. The heartbeat was restored after external chest compressions, and the patient was alert again. During transfer to the ICU, his heart rate slowed down to 20 beats/min but was restored after external chest compressions. A bedside tracheotomy was performed due to difficulties with orotracheal intubation. Bleeding at the cutting site and urethral bleeding occurred. The coagulation function showed prothrombin time 15.3 s, increased prothrombin time ratio 1.30, increased international normalized ratio 1.31, decreased prothrombin activity 65.2%, activated partial thromboplastin time 32.6 s, thrombin time 18.1 s, and increased D-dimer > 76 mg/L. Fresh frozen plasma (400 mL), cryoprecipitate (6 U), and red blood cell suspension (2 U) were administered to the patient. Compression and carbazochrome sodium sulfonate injection were performed to stop the bleeding, which improved. However, six days after admission, the patient experienced cardiac arrest and died. DISCUSSION Edaravone is a newly developed free radical scavenger, and its administration has been used as a clinical therapeutic option for the management of cerebral infarction[6]. In this case, all three patients had acute cerebral infarction. Therefore, we selected edaravone as the therapeutic option for our patients. The instructions for edaravone clearly suggest that caution should be exercised when using the drug in cardiac patients due to the risk of death[14]. When edaravone was prescribed to elderly patients with cerebral infarction, some experienced a sudden worsening of their condition or died of cardiac arrest[15]. Therefore, we suspected that edaravone may cause serious adverse reactions, although the reason for this remains unknown. Death in patients with cerebral infarction is commonly caused by cerebral hernias in the acute phase of cerebral edema and organ dysfunction resulting from infection accompanied by deterioration of the underlying heart disease[16,17]. This is a noteworthy aspect that should be emphasized, as the acute ischemic stroke etiology in the patients described may also be due to hematological disease[18]. However, in three cases, the patients’ condition deteriorated suddenly and they passed away soon after, which is different from the common cause of death we mentioned above. All these cases had the following characteristics: (1) Elderly patients (aged > 60-year-old); (2) patients with acute cerebral infarction but with a small infarct size, no increase in intracranial pressure, and no serious infection; (3) no history of coronary heart disease, no atrial fibrillation or heart failure, and no abnormal electrocardiography; (4) treatment with edaravone for 4-10 d; (5) rapid deterioration in the patients’ condition, including coagulation dysfunction, severe hepatic and renal damage, or sudden cardiac arrest; and (6) poor response to treatment and difficulty in recovering. Edaravone has also been reported to cause coagulation dysfunctions. In Japan, approximately 400000 patients received edaravone within 4 years of its release in 2001. The registered adverse reactions were 477 cases, including hepatobiliary diseases (0.1%), renal urinary diseases (0.05%), and thrombocytopenia/DIC (0.02%)[5,6]. Both cases 1 and 3 showed coagulation dysfunction, which improved with plasma and cryoprecipitate infusion, and edaravone was discontinued. This suggests that coagulation dysfunction may have occurred before and after cardiac arrest in these aggravated conditions. Therefore, early detection and reasonable treatment of coagulation dysfunction are important. Patients showed tracheal hemorrhage after tracheotomy, massive urethral hemorrhage, and an abnormal coagulation index without a significant decline in platelets, which were in line with the serious adverse reactions of edaravone with a high risk of disseminated or diffuse intravascular coagulation. Cardiac arrest occurred in all three patients during treatment with edaravone. In cases 2 and 3, cardiac arrest was the only manifestation of early exacerbation. Patients 1 and 3 were successfully resuscitated after short-term cardiac arrest, but all three patients ultimately had a worse prognosis. As none of the three patients had prior heart disease, the cardiac arrest could not be attributed to existing heart disease. Based on our clinical observations, other possible causes of the three deaths could be excluded, including concomitant medications such as aspirin, clopidogrel, atorvastatin, Ginkgo biloba extract, ozagrel extract, and ceftizoxime. There were no severe adverse reactions related to sudden cardiac arrest, and there were no warnings for the medications administered for patients with heart disease according to the instructions for these drugs. Therefore, these drugs are unlikely to cause disease progression or cardiac arrest. During this exacerbation, severe hepatic and renal function impairments were observed in case 3, which have been mentioned as severe adverse reactions caused by the edaravone. Therefore, sudden deterioration of the patients may be due to adverse drug reactions caused by edaravone. However, the cause-and-effect relationship between the three patients’ deaths and edaravone’s severe adverse reactions still requires confirmation. In contrast, experimental animal studies have suggested that edaravone treatment improves hepatic injury following ischemia/reperfusion injury, partial hepatectomy, or endotoxin administration[19]. Other researchers have shown that edaravone has beneficial effects on kidney injury induced by ischemia/reperfusion or cisplatin[20-22]. It is possible that edaravone and edaravone-peroxy radicals, which are metabolic products of edaravone, are responsible for these adverse effects; however, the underlying mechanisms remain unclear. Further studies are required to determine the discrepancies between the protective effects observed in previous animal studies and the adverse effects observed in our patients. CONCLUSION In summary, these patients exhibited similar clinical characteristics. Although the characteristics of edaravone use that may lead to sudden death have not yet been identified, this series of cases represent a new clinical syndrome. Thus, further studies are needed to characterize the pathophysiology of this syndrome and determine the underlying causes. Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment. Conflict-of-interest statement: All the authors have no conflicts of interest to declare. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: January 21, 2023 First decision: March 10, 2023 Article in press: June 13, 2023 Specialty type: Clinical neurology Country/Territory of origin: China Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): 0 Grade C (Good): C, C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Ait Addi R, Morocco; Arboix A, Spain; Mishra AK, United States S-Editor: Liu JH L-Editor: Webster JR P-Editor: Liu JH ==== Refs 1 Li LD Zhou Y Shi SF Edaravone combined with Shuxuening versus edaravone alone in the treatment of acute cerebral infarction: A systematic review and meta-analysis Medicine (Baltimore) 2023 102 e32929 36862906 2 Writing Group Edaravone (MCI-186) ALS 19 Study Group Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial Lancet Neurol 2017 16 505 512 28522181 3 Rosenfeldt F Wilson M Lee G Kure C Ou R Braun L de Haan J Oxidative stress in surgery in an ageing population: pathophysiology and therapy Exp Gerontol 2013 48 45 54 22465624 4 Cao S Wei J Cai Y Xiong Z Li J Jiang Z Zhou X Huang B Zeng J Network Pharmacology Prediction and Experimental Verification for Anti-Ferroptosis of Edaravone After Experimental Intracerebral Hemorrhage Mol Neurobiol 2023 5 Warner DS Sheng H Batinić-Haberle I Oxidants, antioxidants and the ischemic brain J Exp Biol 2004 207 3221 3231 15299043 6 Edaravone Acute Infarction Study Group Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters Cerebrovasc Dis 2003 15 222 229 12715790 7 Dengler R Diener HC Schwartz A Grond M Schumacher H Machnig T Eschenfelder CC Leonard J Weissenborn K Kastrup A Haberl R EARLY Investigators Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial Lancet Neurol 2010 9 159 166 20060783 8 Wang G Fang B Yu X Li Z [Interpretation of 2018 guidelines for the early management of patients with acute ischemic stroke] Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2018 30 289 295 29663986 9 Blanco M Nombela F Castellanos M Rodriguez-Yáñez M García-Gil M Leira R Lizasoain I Serena J Vivancos J Moro MA Dávalos A Castillo J Statin treatment withdrawal in ischemic stroke: a controlled randomized study Neurology 2007 69 904 910 17724294 10 Zeng GR Zhou SD Shao YJ Zhang MH Dong LM Lv JW Zhang HX Tang YH Jiang DJ Liu XM Effect of Ginkgo biloba extract-761 on motor functions in permanent middle cerebral artery occlusion rats Phytomedicine 2018 48 94 103 30195885 11 Liu Y Wu X Yu Z Ginkgo leaf extract and dipyridamole injection as adjuvant treatment for acute cerebral infarction: Protocol for systemic review and meta-analysis of randomized controlled trials Medicine (Baltimore) 2019 98 e14643 30813204 12 Abe M Kaizu K Matsumoto K A case report of acute renal failure and fulminant hepatitis associated with edaravone administration in a cerebral infarction patient Ther Apher Dial 2007 11 235 240 17498008 13 Lapchak PA A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother 2010 11 1753 1763 20491547 14 Raymond J Oskarsson B Mehta P Horton K Clinical characteristics of a large cohort of US participants enrolled in the National Amyotrophic Lateral Sclerosis (ALS) Registry, 2010-2015 Amyotroph Lateral Scler Frontotemporal Degener 2019 20 413 420 31131638 15 Jackson C Heiman-Patterson T Kittrell P Baranovsky T McAnanama G Bower L Agnese W Martin M Radicava (edaravone) for amyotrophic lateral sclerosis: US experience at 1 year after launch Amyotroph Lateral Scler Frontotemporal Degener 2019 20 605 610 31364409 16 Zhu L Huang Z Sun X Wu M Xu Y Sun Z The function of mechanical thrombectomy on improving haemodynamics of patients with acute cerebral infarction. Basic & Clinical Pharmacology & Toxicology 2019; 124: 116. Available from: https://www.zhangqiaokeyan.com/journal-foreign-detail/0704028058275.html 17 Chen CJ Wang C Buell TJ Ding D Raper DM Ironside N Paisan GM Starke RM Southerland AM Liu K Worrall BB Endovascular Mechanical Thrombectomy for Acute Middle Cerebral Artery M2 Segment Occlusion: A Systematic Review World Neurosurg 2017 107 684 691 28844911 18 Arboix A Jiménez C Massons J Parra O Besses C Hematological disorders: a commonly unrecognized cause of acute stroke Expert Rev Hematol 2016 9 891 901 27367035 19 Tsuji K Kwon AH Yoshida H Qiu Z Kaibori M Okumura T Kamiyama Y Free radical scavenger (edaravone) prevents endotoxin-induced liver injury after partial hepatectomy in rats J Hepatol 2005 42 94 101 15629513 20 Doi K Suzuki Y Nakao A Fujita T Noiri E Radical scavenger edaravone developed for clinical use ameliorates ischemia/reperfusion injury in rat kidney Kidney Int 2004 65 1714 1723 15086910 21 Satoh M Kashihara N Fujimoto S Horike H Tokura T Namikoshi T Sasaki T Makino H A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo J Pharmacol Exp Ther 2003 305 1183 1190 12649298 22 Koike N Sasaki A Murakami T Suzuki K Effect of edaravone against cisplatin-induced chronic renal injury Drug Chem Toxicol 2021 44 437 446 31064223

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==== Front World J Clin Cases WJCC World Journal of Clinical Cases 2307-8960 Baishideng Publishing Group Inc jWJCC.v11.i19.pg4723 10.12998/wjcc.v11.i19.4723 Case Report Posterior reversible encephalopathy syndrome following uneventful clipping of an unruptured intracranial aneurysm: A case report Hwang J et al. PRES following aneurysm clipping Hwang Joseph Department of Neurosurgery, Biomedical Research Institute, Pusan National University Hospital, School of Medicine, Pusan National University, Busan 49241, South Korea Cho Won-Ho Department of Neurosurgery, Biomedical Research Institute, Pusan National University Hospital, School of Medicine, Pusan National University, Busan 49241, South Korea Cha Seung-Heon Department of Neurosurgery, Biomedical Research Institute, Pusan National University Hospital, School of Medicine, Pusan National University, Busan 49241, South Korea Ko Jun-Kyueng Department of Neurosurgery, Biomedical Research Institute, Pusan National University Hospital, School of Medicine, Pusan National University, Busan 49241, South Korea. redcheek09@naver.com Author contributions: Ko JK and Hwang J contributed to manuscript writing and editing, and data collection; Cho WH and Cha SH contributed to conceptualization and supervision; all authors have read and approved the final manuscript. Supported by Clinical Research Grant from Pusan National University Hospital in 2022. Corresponding author: Jun-Kyueng Ko, MD, PhD, Associate Professor, Department of Neurosurgery, Biomedical Research Institute, Pusan National University Hospital, School of Medicine, Pusan National University, 179 Gudeok-Ro, Seo-Gu, Busan 49241, South Korea. redcheek09@naver.com 6 7 2023 6 7 2023 11 19 47234728 13 4 2023 10 5 2023 6 6 2023 ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved. 2023 https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. BACKGROUND Posterior reversible encephalopathy syndrome (PRES) is characterized mainly by occipital and parietal lobe involvement, which can be reversible within a few days. Herein, we report a rare case of PRES that developed after craniotomy for an unruptured intracranial aneurysm (UIA). CASE SUMMARY A 59-year-old man underwent clipping surgery for the treatment of UIA arising from the left middle cerebral artery. Clipping surgery was performed uneventfully, and he regained consciousness quickly immediately after the surgery. At the 4th hour after surgery, he developed a disorder of consciousness and aphasia. Magnetic resonance imaging revealed cortical and subcortical T2/FLAIR hyperintensities in the parietal, occipital, and frontal lobes ipsilaterally, without restricted diffusion, consistent with unilateral PRES. With conservative treatment, his symptoms and radiological findings almost completely disappeared within weeks. In our case, the important causative factor of PRES was suspected to be a sudden increase in cerebral perfusion pressure associated with temporary M1 occlusion. CONCLUSION Our unique case highlights that, to our knowledge, this is the second report of PRES developing after craniotomy for the treatment of UIA. Surgeons must keep PRES in mind as one of the causes of perioperative neurological abnormality following clipping of an UIA. Clipping Magnetic resonance imaging Posterior reversible encephalopathy syndrome Unruptured intracranial aneurysm Case report ==== Body pmc Core Tip: Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome characterized by predominant parietal and occipital involvement, which can be reversible within a few days. We report a rare case of PRES that developed after clipping surgery for an unruptured intracranial aneurysm (UIA). In our case, the important causative factor of PRES was suspected to be a sudden increase in cerebral perfusion pressure associated with temporary M1 occlusion. Our unique case highlights that, to our knowledge, this is the second report of PRES developing after craniotomy for the treatment of UIA. Surgeons must keep PRES in mind as one of the causes of perioperative neurological abnormality following clipping of an UIA. INTRODUCTION Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity in which reversible changes occur in the central nervous system (CNS), associated with typical features on magnetic resonance imaging (MRI)[1]. The main symptoms of PRES include insidious onset of headache, altered mentality, seizures, and cortical blindness, with edematous changes primarily in the occipital cortex and/or white matter bilaterally on radiological imaging[1,2]. The term ‘PRES’ was first introduced in 1996 by Hinchey and his colleagues[3]. It has been mainly described in relation to the hypertensive crisis—particularly in the setting of renal failure, sepsis, eclampsia, and the use of immunosuppressant drugs, such as calcineurin inhibitors[4]. Since then, many reports have focused on the imaging findings and pathophysiology of this condition. Although various underlying conditions of PRES have been reported, to the best of our knowledge, only one case of PRES that developed after clipping surgery for the treatment of an unruptured intracranial aneurysm (UIA) has been reported[5]. Here, we would like to report the second case of PRES. CASE PRESENTATION Chief complaints Sudden deterioration of consciousness developed at the 4th hour after surgical clipping of an UIA. History of present illness A 59-year-old man who had undergone uneventful coiling for a ruptured anterior communicating artery aneurysm one month ago was readmitted to our hospital for surgical clipping of the left middle cerebral artery (MCA) aneurysm unfavorable for coiling. He recovered uneventfully from the subarachnoid hemorrhage one month ago and had no neurological abnormalities. All other preoperative evaluations, including hematological tests, were unremarkable. Digital subtraction angiography revealed a 5.4 mm-sized aneurysm at the left MCA bifurcation without any other remarkable findings (Figure 1). Left frontotemporal craniotomy for clipping of the UIA was successfully performed under general anesthesia. General anesthesia and operating times were 4 h 25 min and 3 h 7 min, respectively. No intraoperative aneurysm rupture or venous injury occurred. In the course of three temporary M1 occlusions each lasting 8 min, 6 min, and 5 min, we applied various permanent clips to achieve complete obliteration of the UIA. Immediately after surgery, the patient’s condition and the computed tomography (CT) findings were stable. However, sudden deterioration in the level of consciousness and aphasia developed 4 h later. Figure 1 Left internal carotid artery angiography. Preoperative image shows a small aneurysm (arrow) at the left middle cerebral artery bifurcation with an unfavorable dome-to-neck ratio. History of past illness He had no specific medical history other than high blood pressure, which was well controlled by amlodipine (5 mg/d). Personal and family history The patient admitted to smoking ten cigarettes daily for > 20 years. The remaining personal and family histories did not contribute. Physical examination The patient’s vital signs were: Blood pressure, 129/84 mmHg; heart rate, 67 beats per min; body temperature, 37.0°C; and respiratory rate, 21 breaths per min. Neurological examination demonstrated stuporous mentality (Glasgow Coma Scale score of 10) and profound global aphasia. The function of cranial nerves was intact. He had normal tone in all limbs and normal power in the left limbs, but slightly reduced power in (4/5) in the right limbs. Sensory examination was normal. The tendon reflexes of the extremities were normal. Laboratory examinations There were no abnormalities in routine blood tests, blood biochemistry, blood coagulation, and routine urine tests. Imaging examinations After confirming absence of an abnormal finding on non-contrast brain CT performed immediately, MRI was carried out in succession. It showed widespread high signal intensities especially in the cortex and subcortical region of the ipsilateral fronto-parieto-occipital lobes in fluid attenuation inversion recovery images (Figure 2A). The lesions were iso or high signal intensity in diffusion-weighted images (Figure 2B) and high signal intensity in apparent diffusion coefficient maps (Figure 2C) without any signs of diffusion restriction, consistent with vasogenic edema. In contrast-enhanced three-dimensional T1-weighted images, lesions showed patchy enhancement (Figure 2D). Susceptibility-weighted images did not demonstrate hemorrhage. Since major arteries were still clearly depicted on magnetic resonance angiography besides clip artifacts, vascular problems including reversible cerebral vasoconstriction syndrome could be excluded from the diagnosis. The CT perfusion study was negative. Figure 2 Magnetic resonance imaging obtained immediately following deterioration of consciousness A: Axial fluid attenuation inversion recovery image shows extensive hyperintense lesions predominantly in the cortex and subcortical white matter of the left frontoparietal lobe; B: Diffusion-weighted image shows that lesions are iso to hyperintense without any signs of restricted diffusion; C: Apparent diffusion coefficient maps show that lesions are hyperintense, indicating vasogenic edema; D: On the contrast-enhanced three-dimensional T1-weighted image, lesions show patchy enhancement. FINAL DIAGNOSIS The imaging findings were suggestive of PRES in the left hemisphere. TREATMENT The patient gradually recovered with dexamethasone injections and supportive care, without additional neurologic signs. OUTCOME AND FOLLOW-UP He was discharged with a modified Rankin scale score of 0 at 3 wk after surgery. On serial MRI scans, most of the lesions gradually disappeared within few weeks. However, several lesions in the subcortical white matter persisted even after 1 year, despite being reduced in size (Figure 3). Figure 3 Follow-up magnetic resonance imaging. Fluid attenuation inversion recovery image performed at one year after clipping surgery shows that several lesions (arrow heads) in the subcortical white matter persisted, despite being reduced in size. DISCUSSION PRES is a clinicoradiological syndrome characterized mainly by occipital and parietal lobe involvement, which can be recovered within a few days or weeks[1]. In our patient, PRES was diagnosed based on the typical clinical presentation and MRI finding after excluding CNS infections, air embolus, and sinus thrombosis. As clinical symptoms resolve after several weeks in most cases of PRES, neurological abnormalities gradually improved from the 4th day after surgery and our patient fully recovered without any deficit 3 wk after surgery. MRI typically shows symmetrical high signal intensity in both parieto-occipital cortical-subcortical white matter in fluid attenuation inversion recovery images[2]. However, our case showed an atypical finding of unilateral involvement in PRES. The involvement in PRES could be asymmetrical or rarely unilateral. Reports of unilateral lesions include those related to subarachnoid hemorrhage-induced cerebral vasospasm and PRES associated with MCA occlusion[6]. Since PRES was first described in 1996, various MRI findings have been reported. In addition to the typical site of PRES involvement, almost any region of the brain can also be involved[1,6]. Involvement of the basal ganglia or brain stem while sparing the subcortical regions was named “central-variant” PRES accounting for about 4% of the cases, and it was distinctly reported that 10% of the patients were involved in the splenium of the corpus callosum[2,7]. Restricted diffusion is sometimes observed in PRES, and resulted in irreversible cell death[8]. It has been rarely reported that intracranial hemorrhage can also be accompanied by this condition in around 5%–17% of the cases, and it could present as minimal hemorrhages, intraparenchymal hematoma, and subarachnoid hemorrhage[1,9]. However, an intracranial hemorrhage-related finding was not found in our case, even in susceptibility-weighted images. The pathophysiology of PRES remains a mystery nearly 25 years after its initial description. The most well-known and accepted theory is an increase in arterial pressure above the upper limit for cerebral autoregulation, causing vasogenic edema[4]. This theory is supported by hypertension, which is common in patients with PRES. However, this hypertension theory does not explain all situations. Although rare, PRES has been reported in patients with normal or slightly elevated blood pressure, and serious cerebral edema has been reported in PRES without severe hypertension[4,6]. In the present case, the overall intraoperative mean blood pressure was maintained at around 60 mmHg and no blood pressure surge was reported immediately after surgery. Therefore, we hypothesized that a sudden increase in cerebral perfusion pressure associated with temporary M1 occlusion and intracranial hypotension secondary to the cerebrospinal fluid (CSF) leak caused a degree of hyperperfusion that precipitated PRES. These assumptions support the reason for PRES spreading within the brain hemisphere ipsilateral to the treated UIA, and not bilateral involvement. It was also inferred that diffuse subarachnoid hemorrhage, which occurred one month before surgery, partially contributed to increased susceptibility to autoregulation breakdown. Another mechanism to explain the development of PRES is the activation of immune system through cascade as a result of inducing endothelial dysfunction[10]. Kur et al[11] reported three cases of systemic lupus erythematosus (SLE) with PRES, assuming that PRES may be a feature of disease activity with nephritis and hypertension or a result of immunosuppressive therapy in patients with SLE. Patients with autoimmune diseases are more susceptible to endothelial dysfunction and consequently to the occurrence of PRES[12]. To the best of our knowledge, only one case of PRES that developed after clipping surgery for the treatment of UIA has been reported[5]. The authors supposed that the cause of PRES in their case was rapid blood pressure fluctuations accompanying general anesthesia for clipping surgery, and PRES, which occurs after craniotomy, is unilateral and can become severe in the craniotomy area and leave sequelae. Recently, Fukushima et al[13] reported a case of delayed leucoencephalopathy after coil embolization of the UIA, which was supposed to be caused by delayed hypersensitivity to the bioactive polyglycolic-polylactic acid coil. The diagnosis of PRES was excluded as an etiology for the white matter lesion because of unilateral involvement of the lesions. However, their imaging findings are consistent with the current unilateral PRES. Since the causes of PRES are very diverse and difficult to define accurately, it could be assumed that several case reports with different diagnoses for phenomena similar to actual PRES have been reported. According to a report studying cerebral hyperperfusion syndrome and related conditions, such as hypertensive encephalopathy, PRES, and reversible cerebral vasoconstriction syndrome, these syndromes can share similar pathophysiological mechanism such as cerebral vasoconstriction, endothelial damage, blood-brain barrier dysfunction, brain edema, and, sometimes intracerebral hemorrhage, with fatalities described in all reports[14]. Despite knowledge of these syndromes, they still remain unknown. However, it is important to be aware of this condition as it can be cured through early diagnosis and treatment[12]. CONCLUSION Our unique case highlights that, to our knowledge, this is the second report of PRES developing after craniotomy for the treatment of UIA. Although it may be very rare, prolonged temporary occlusion time and CSF leak may cause the development of PRES in the brain with impaired autoregulation. Surgeons must keep PRES in mind as one of the causes of neurological abnormality after clipping of an UIA. Informed consent statement: Written informed consent was obtained from the patient for publication of this report and any accompanying images. We guarantee patient anonymity. Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose. CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016). Provenance and peer review: Unsolicited article; Externally peer reviewed. Peer-review model: Single blind Peer-review started: April 13, 2023 First decision: May 8, 2023 Article in press: June 6, 2023 Specialty type: Neuroimaging Country/Territory of origin: South Korea Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): 0 Grade C (Good): C, C Grade D (Fair): D Grade E (Poor): 0 P-Reviewer: Reis F, Brazil; Shao A, China S-Editor: Liu JH L-Editor: A P-Editor: Liu JH ==== Refs 1 McKinney AM Short J Truwit CL McKinney ZJ Kozak OS SantaCruz KS Teksam M Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings AJR Am J Roentgenol 2007 189 904 912 17885064 2 Hugonnet E Da Ines D Boby H Claise B Petitcolin V Lannareix V Garcier JM Posterior reversible encephalopathy syndrome (PRES): features on CT and MR imaging Diagn Interv Imaging 2013 94 45 52 22835573 3 Hinchey J Chaves C Appignani B Breen J Pao L Wang A Pessin MS Lamy C Mas JL Caplan LR A reversible posterior leukoencephalopathy syndrome N Engl J Med 1996 334 494 500 8559202 4 Bartynski WS Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema AJNR Am J Neuroradiol 2008 29 1043 1049 18403560 5 Chihara H Hatano T Ando M Takita W Tokunaga K Hashikawa T Funakoshi Y Kamata T Higashi E Nagata I A Case of Posterior Reversible Encephalopathy Syndrome After Surgical Clipping of Unruptured Cerebral Aneurysm World Neurosurg 2019 124 323 327 30660882 6 Çamlıdağ İ Cho YJ Park M Lee SK Atypical Unilateral Posterior Reversible Encephalopathy Syndrome Mimicking a Middle Cerebral Artery Infarction Korean J Radiol 2015 16 1104 1108 26356795 7 McKinney AM Jagadeesan BD Truwit CL Central-variant posterior reversible encephalopathy syndrome: brainstem or basal ganglia involvement lacking cortical or subcortical cerebral edema AJR Am J Roentgenol 2013 201 631 638 23971457 8 Covarrubias DJ Luetmer PH Campeau NG Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images AJNR Am J Neuroradiol 2002 23 1038 1048 12063238 9 Hefzy HM Bartynski WS Boardman JF Lacomis D Hemorrhage in posterior reversible encephalopathy syndrome: imaging and clinical features AJNR Am J Neuroradiol 2009 30 1371 1379 19386731 10 Bartynski WS Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features AJNR Am J Neuroradiol 2008 29 1036 1042 18356474 11 Kur JK Esdaile JM Posterior reversible encephalopathy syndrome--an underrecognized manifestation of systemic lupus erythematosus J Rheumatol 2006 33 2178 2183 16960925 12 Ferreira TS Reis F Appenzeller S Posterior reversible encephalopathy syndrome and association with systemic lupus erythematosus Lupus 2016 25 1369 1376 27084028 13 Fukushima Y Nakahara I Delayed leucoencephalopathy after coil embolisation of unruptured cerebral aneurysm BMJ Case Rep 2018 2018 14 Delgado MG Bogousslavsky J Cerebral Hyperperfusion Syndrome and Related Conditions Eur Neurol 2020 83 453 457 33070131

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==== Front RSC Adv RSC Adv RA RSCACL RSC Advances 2046-2069 The Royal Society of Chemistry d3ra02471g 10.1039/d3ra02471g Chemistry Trace determination of disinfection by-products in drinking water by cyclic ion chromatography with large-volume direct injection https://orcid.org/0000-0002-1586-0084 Zhu Haibao ab Ruan Zheng a Wang Han a Liu Danhua a Tang Hongfang a Wang Jiahong c a School of Public Health, Hangzhou Medical College Hangzhou Zhejiang 310013 P. R. China b Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology Hangzhou Zhejiang 310014 P. R. China c Center of Safety Evaluation and Research, Hangzhou Medical College Hangzhou Zhejiang 310013 P. R. China 2020000283@hmc.edu.cn 18 7 2023 12 7 2023 18 7 2023 13 31 2155021557 13 4 2023 5 7 2023 This journal is © The Royal Society of Chemistry 2023 The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ A novel cyclic ion chromatography (IC) system was developed for the simultaneous determination of trace disinfection by-products (DBPs) in drinking water. Five DBPs (chlorite, bromate, chlorate, dichloroacetic acid, and trichloroacetic acid) were sensitively determined by large-volume direct injection, and the interferences of dominant inorganic anions present in water were eliminated online through the cyclic determination of the target analytes. Under optimized conditions, the obtained limits of detection (LODs) were in the range of 0.18–1.91 μg L−1 based on a signal-to-noise ratio (S/N) of 3 and an injection volume of 1.0 mL. The RSDs for peak area and retention time were in the range of 0.13–1.03% and 1.24–4.29%, respectively. Satisfactory recoveries between 92.3% and 106.4% were obtained by adding three concentration gradients of standards to the drinking water samples. The proposed method has advantages such as high sensitivity, facile automation, and no sample pretreatment, and might be a promising approach for routine analysis. A novel cyclic ion chromatography (IC) system was developed for the simultaneous determination of trace disinfection by-products (DBPs) in drinking water. Medical and Health Research Project of Zhejiang Province 10.13039/501100017531 2022PY049 Basic Public Welfare Research Program of Zhejiang Province 10.13039/501100017577 LGC20B050001 pubstatusPaginated Article ==== Body pmc1 Introduction Drinking water disinfection is an indispensable measure to guarantee public health, and can remove viruses, bacteria, and other micro-pollutants as well as provide purified water for human consumption.1–3 Disinfection by-products (DBPs) are a series of contaminants produced by the reaction of disinfectants (chlorine, chlorine dioxide, ozone, etc.) with natural compounds in water during the disinfection process.4 DBPs in drinking water can pose long-term health risks to humans, including potential carcinogenic, mutagenic, and reproductive toxicity, which has attracted considerable public attention.5 Chlorite, bromate, and chlorate are three typical hazardous inorganic oxyhalide DBPs, among which bromate has been identified as a potential carcinogen by the World Health Organization (WHO) and the United States Environmental Protection Agency USEPA.6,7 Haloacetic acids (HAAs) are also another group of DBPs that are detected in drinking water frequently,8 and dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) are two HAAs with the highest concentrations and carcinogenic risk in drinking water.9 Due to their widespread occurrence and potential health risks, some countries have established limit values for the content of oxyhalide DBPs and HAAs in drinking water. Therefore, it is necessary to conduct routine analysis of these DBPs in drinking water to ensure consumer health. Multiple analytical methods have been developed for the determination of DBPs in drinking water. For example, the United States Environmental Protection Agency (USEPA) recommends using gas chromatography (GC) to detect HAAs.10 Before being injected into the GC system, the samples need to undergo pretreatment processes such as acidification, liquid–liquid extraction, and esterification derivatization, which are time-consuming and labor-intensive. Although liquid chromatography coupled with inductively coupled plasma mass spectrometry (ICP-MS) can detect bromate in water, it is limited to determining only one or two compounds, making the simultaneous determination of multiple substances challenging.11 Since chlorite, bromate, and chlorate in drinking water are present in an ionic form, and although DCAA and TCAA exist in a neutral form, their acid-dissociation coefficients (pKa) are low.12 Therefore, ion chromatography (IC) coupled with conductivity detection is a more suitable method for determining these substances. To date, many reports have been published on the use of ion chromatography for determining oxyhalide DBPs and HAAs in drinking water.13,14 Compared with gas chromatography and ICP-MS, IC has obvious advantages such as simple sample treatment, rapid determination, and good reproducibility.15 However, due to the low concentrations of DBPs in water samples, IC with a large-volume injection method is usually adopted, which significantly improves the determination sensitivity of DBPs.16 However, this method also leads to the concentration of dominant inorganic anions (fluoride, chloride, nitrate, sulfate, etc.) present in water samples, causing interference with the DBPs determination.17 This interference is mainly eliminated by optimizing chromatographic conditions and offline pretreatment (e.g., on guard Ag pretreatment column to remove chloride ions and on guard Ba pretreatment column to remove sulfate ions) of water samples before IC injection.18 At present, there is still no universal ideal online IC technology to completely eliminate the influence of this disturbance on DBPs determination. In this study, a novel cyclic ion chromatography system with a large-volume direct injection system was established. Automated and selective online elimination of inorganic anions was achieved by using valve-switching technology and cyclic measurement of the target DBPs. The positions of the enrichment column can be automatically changed by repeatedly switching the valve. After the first separation in the analytical column, the affected target DBPs were concentrated on the enrichment column, and a large amount of interfering components were directly discharged into the waste liquid. Then, DBPs which concentrated on the enrichment column were cut onto the analytical column again by column-switching for secondary separation. The elimination of coexisting interfering anions with high concentrations in the sample was realized by cyclic analysis of the DBPs. This method was successfully applied to the simultaneous determination of five DBPs (chlorite, bromate, chlorate, DCAA, and TCAA) in drinking water. 2 Experimental 2.1 Equipment A Thermo Scientific Dionex ICS 2100 ion chromatograph (Sunnyvale, CA, USA) was employed in this research. It was composed of the following modules: an AS-DV auto-sampler, a dual-piston serial pump, an EG40 eluent generator, a DS6 conductivity detector, and two six-port valves. An ASRS 3000 suppressor (Thermo, Sunnyvale, CA, USA) was used for eluent suppression in the external-water mode. The analytical column was an IonPac AG19 (50 mm × 4 mm i.d., 5 μm) guard column and an IonPac AS19 (250 mm × 4 mm i.d., 5 μm) separation column. Another IonPac AG19 column (50 × 4 mm i.d., 5 μm) was used as the enrichment column. Polyether ether ketone (PEEK) tubes were used to connect all chromatographic modules, and the lengths of the connecting tubes were kept as short as possible to minimize system void volume. The cyclic IC system built with the above modules is shown in Fig. 1. Fig. 1 Chromatographic instrument configurations for the analysis of trace DBPs in drinking water. (a) System balancing and sample injecting; (b) online removal of interfering substances and collection of target components; (c) secondary analysis of target components. 2.2 Reagents and materials Standard solutions, including chlorite, bromate, chlorate, DCAA, and TCAA, with a concentration of 1000 mg mL−1, were purchased from Anpu Experimental Technology Co., Ltd (Shanghai, China), respectively. Other anion standards were prepared from corresponding salts (Sinopharm Chemical Reagent Co. Ltd, China). Experimental water was obtained from a Milli-Q water purification system (Millipore, Bedford, MA, USA). Working standards were prepared by further diluting the above standards to the expected range. The solutions used in the experiment were stored in tightly sealed containers and refrigerated at 4 °C to prevent possible spoilage. Furthermore, stability tests showed that all solutions remained stable for at least three months under the storage conditions of this experiment. Water samples were filtered through a 0.45 μm membrane filter before being injected into the IC system. 2.3 Chromatographic conditions The eluent generator was set to generate a concentration of 12 mmol per L KOH as an eluent to analyze the target compounds. The suppressor current was set at 115 mV. Data acquisition, instrument control, and the switching program of the two six-port valves were all controlled by Chromeleon 6.8 software (Dionex, USA). The positions of the enrichment column could be changed by switching the six-port valves. Correspondingly, the mobile phase of the enrichment column was also varied. In different states, the eluent flowing through the enrichment column was either KOH solution or water, which was converted from KOH liquid by the suppressor. The flow rate of the entire process was 1.0 mL min−1, and the sampling loop was set to a large-volume of 1.0 mL. The temperature of the detector cell and analytical column was 35 °C and 26 °C, respectively. 2.4 Experimental procedure Four steps were involved in eliminating interferences of conventional anions and determining the concentrations of five DBPs: (i) loading the sample into the sample loop via an automatic sampling device, after balancing the chromatographic system; (ii) delivering the sample from the sample loop into the separation column and performing the first separation step; (iii) collecting the disturbed target components by the enrichment column and eliminating the matrix inorganic anions; and (iv) analyzing the disturbed target components for the second time by the analytical column. All these steps were achieved by controlling the cyclic IC system that we constructed in this study. 3 Results and discussion 3.1 Operation procedure of the cyclic IC system Fig. 1 illustrates the configuration diagram of our cyclic IC system. By switching six-port valve 1 and six-port valve 2, the connection patterns of modules in the IC system can be modified to achieve different objectives. Sample injection was accomplished by switching valve 1 (Fig. 1a and b). The collection and secondary analysis of the disturbed components were mainly achieved by switching valve 2. It was worth noting the suppressor in the IC system can convert the KOH eluent to water. When valve 2 was in the “injection” position (Fig. 1b), the enrichment column was connected behind the detector cell. In this condition, water or waste liquid containing sample ions was the mobile phase which flowing through the enrichment column. As the above liquids had no elution capability, target compounds could be concentrated in the enrichment column. Due to the first separation of the analytical column, the target compounds and the interfering matrix have been separated preliminary. By switching valve 2, the disturbed target compounds were concentrated on the enrichment column, and the interfering components were discharged into the waste directly. Then, with valve 2 in the “load” position, the enrichment column was placed at the front of the guard column (Fig. 1c), and the KOH eluent was the mobile phase which flowing through the enrichment column. The components concentrated on the enrichment column can be eluted onto the analytical column under the action of KOH eluent for the secondary separation. Owing to most of the matrix have been discharged into the waste, their effects could be eliminated in the process of secondary analysis. 3.2 Selection of chromatographic parameters Traditional IC methods for the simultaneous determination of oxyhalide DBPs and HAAs have strict requirements on parameters such as the concentration and gradient of KOH eluent, flow rate, and column temperature.19 In contrast, the chromatographic parameters of the cyclic IC in this study were relatively flexible. However, to expand the cyclic IC system applications, we optimized the IC parameters in terms of improving separation, shortening analysis time, and increasing detection sensitivity. We used a large sample loop (1.0 mL) to improve sensitivity. Meanwhile, an isocratic analysis with 12 mmol per L KOH eluent was selected, taking into account both separation efficiency and analysis time. In addition, the columns of the IC system were kept in a constant temperature environment of 26 °C to maintain the stability of the entire process. Based on the above chromatographic parameters, we also focused on optimizing the switching opportunities of the two switching valves (valve 1 and valve 2). 3.3 Interference of the matrix concentration In this study, the influence of inorganic anion matrices on the determination of DBPs were investigated. Drinking water quality standards in China, the EU, and the US EPA all explicitly stipulate the maximum allowable concentrations of common inorganic anions in drinking water.20 The traditional IC method was used to investigate the effect of the concentration of inorganic anion matrix in water samples on the determination of target DBPs. We found that when the concentrations of fluoride and sulfate are at their maximum allowable levels (fluoride: 1.5 mg L−1, sulfate: 250 mg L−1), neither substance interferes with the determination of the five DBPs. Similarly, trace amounts of nitrite and bromide ions in drinking water do not interfere with the measurement of the target DBPs. Nevertheless, due to the lower resolution between the chromatographic peaks of chloride and DCAA, as well as nitrate and TCAA, when the concentrations of chloride and nitrate increase, they may interfere with the determination of DCAA and TCAA, respectively. As shown in Fig. 2a. When the chloride concentration exceeds 1.5 mg L−1 in the determination of drinking water by the traditional IC method, the peak area of DCAA (100 μg L−1) decreases significantly. Likewise, the peak area of TCAA (100 μg L−1) also experiences a significant decrease when the nitrate concentration exceeds 2.0 mg L−1 (Fig. 2b). Therefore, it is necessary to employ the cyclic IC system to eliminate chloride and nitrate interference online. Fig. 2 Effect of inorganic anion matrix content in standard solutions on the peak areas of target sustances using the traditional IC method (n = 6). (a) DCAA, 100 μg L−1; (b) TCAA, 100 μg L−1. Conditions: eluent, 12 mmol per L KOH; flow rate, 1.0 mL min−1; suppressor current, 115 mV; analytical column, IonPac AG19 + AS19; temperature of the detector cell, 35 °C; temperature of the analytical column, 26 °C; sampling volume, 1.0 mL. 3.4 Optimization of switching time Table 1 illustrates the cut windows of the valves and how the system performs clearly. In this study, the cut windows of valve 2 were essential important for the entire experiment, and were strongly associated with the efficiency of matrix elimination and the accurate determination of analytes. Three cut windows of valve 2 were optimized in our study by determining actual tap water samples spiked with five DBPs standards. The first opportunity was from 0.0 min to the time (0.5 min) when the sample was completely washed onto the guard column with KOH eluent, ensuring that the sample was entirely eluted onto the analytical column for the first separation after injecting, and not concentrated on the enrichment column. At this point, under the action of the KOH eluent, fluoride, chlorite, and bromate were completely separated in the analytical column, and sequentially eluted out of the chromatographic column and then into the waste after being detected by the detector. Subsequently, the sequentially eluted species were chloride and DCAA, which could not be baseline separated from each other. Therefore, the second cut window was aimed at eliminating the interference of chloride on DCAA. When DCAA eluted from the chromatographic column (9.7 min), the valve 2 was switched, and the enrichment column was placed behind the detector cell to concentrate DCAA and some chloride ions. We found that if the enrichment column was immediately switched back to the front of the guard column after complete enrichment of DCAA, nitrate ions would interfere with the second analysis of DCAA. To avoid this situation, we set the time of enrichment column cutting back to the front of the guard column at 12.5 min. Nitrite ions were also concentrated on the enrichment column under the conditions of our optimized cut window (9.7–12.5 min) along with all DCAA and a small amount of chloride. System operation procedure Time (min) Valve 1 Valve 2 Position of enrichment column Events −0.5–0.0 Load Load Before the guard column System balancing; sample injecting 0.0–0.5 Inject Inject After the detector cell Washing sample onto the analytical column with KOH eluent 0.5–9.7 Inject Load Before the guard column Separating and analyzing of components with retention weaker than DCAA 9.7–12.5 Inject Inject After the detector cell Collecting of DCAA and nitrite online, eliminating the interfering chloride ions 12.5–18.5 Inject Load Before the guard column Separating and analyzing of components with retention weaker than TCAA and stronger than DCAA, analyzing of DCAA by analytical column secondary 18.5–20.1 Inject Inject After the detector cell Collecting of TCAA online, eliminating the interfering nitrate ions 20.1–50 Inject Load Before the guard column Analyzing of TCAA by analytical column secondary, separating and analyzing of components with retention stronger than TCAA 50–60 Load Load Before the guard column Purification chromatographic system; equilibrium chromatographic system To optimize the second cut window of valve 2 switching, the end time of the switching cut window was set at 12.5 min, while the start time was varied within the range of 9.3 min to 9.9 min. To ensure maximum removal of chloride, it was recommended that the start time of the cut window of valve 2 be delayed as much as possible since the time of the chloride peak is earlier than that of the DCAA. However, after 9.7 min, some of the DCAA could not be entirely collected, resulting in a sharp decrease in peak area (Fig. 3a). As a result, the optimum switching cut window of valve 2 was established at 9.7–12.5 min. Additionally, 18.5–20.1 min was selected as the third cut windows of valve 2. At this point, the DCAA, a small amount of chloride, and nitrite ions concentrated on the enrichment column in the previous stage have been completely eluted out and analyzed for the second time by the analytical column before being discharged into the waste. As shown in Fig. 3b, 18.5 min was the optimal start time for the third cut window. Under the optimized cut window of 18.5–20.1 min, the TCAA was completely concentrated on the enrichment column while minimizing the presence of nitrate matrix as much as possible. Fig. 3 Effect of the switching time of valve 2 on the peak areas of target substances using the cyclic IC method (n = 6). (a) DCAA, 100 μg L−1; (b) TCAA, 100 μg L−1. Conditions: eluent, 12 mmol per L KOH; flow rate, 1.0 mL min−1; suppressor current, 115 mV; analytical column, IonPac AG19 + AS19; enrichment column, IonPac AG19; temperature of the detector cell, 35 °C; temperature of the analytical column, 26 °C; sampling volume, 1.0 mL. Fig. 4 displays the representative chromatogram of actual tap water samples spiked with 5 DBPs standards. As shown in Fig. 4, Chlorite (peak a), bromate (peak b), and chlorate (peak d) were not affected by the coexisting inorganic anions, and they could be directly quantified by the first separation of analytical column. Nevertheless, DCAA (peak c) and TCAA (peak e) were obviously interfered by the tail peaks of chloride and nitrate, respectively. Under the optimized switching windows, the above interferences were eliminated, and baseline separation was achieved (peak c′ and e′) by cycle analysis. Fig. 4 Chromatogram of actual tap water samples spiked with 5 DBPs standards. Peaks for first analysis (add levels): 1 = fluoride; 2 = chloride; 3 = nitrite; 4 = bromide; 5 = nitrate; 6 = carbonate; 7 = sulfate; a = chlorite (0.1 mg L−1); b = bromate (0.02 mg L−1); c = DCAA (0.1 mg L−1); d = chlorate (0.1 mg L−1); e = TCAA (0.1 mg L−1); peaks for secondary analysis: 2′ = chloride; c′ = DCAA (0.1 mg L−1); 3′ = nitrite; 5′ = nitrate; e′ = TCAA (0.1 mg L−1). 3.5 Analytical performances Under the above optimized conditions, five standard solutions containing DBPs at various concentrations ranging from 5.00–100 μg L−1 (1.0–20 for bromate) were analyzed. Each target DBPs exhibited satisfactory linearity within the studied range, with all determination coefficients R ≥ 0.9991. The limits of detection (LODs) and limits of quantification (LOQs), calculated by injecting a 1.0 mL volume of a standard solution with a concentration of 5.0 μg L−1 (bromate: 1.0 μg L−1) and based on signal-to-noise ratios (S/N) of 3 and 10, were calculated to be in the range of 0.18–1.91 μg L−1 and 0.60–6.37 μg L−1, respectively. The precision results of the cyclic IC method were obtained by calculating the relative standard deviation (RSD) values for 6 repetitive injections of 5.0 μg L−1 (1.0 μg L−1 for bromate) standard solutions. The RSD for peak area and retention time ranged from 0.13–1.03% and 1.24–4.29%, respectively. All analytical performances of the proposed method are listed in Table 2. Calibration parameters (five points) for the DBPs in standard solutions (n = 6) Analytes Linear range (μg L−1) Determination coefficient (R) LODsa (μg L−1) LOQsb (μg L−1) RSD (%) Retention time Peak area Chlorite 5.00–100 0.9992 0.18 0.60 0.13 1.24 Bromate 1.00–20.0 0.9991 0.38 1.27 0.25 2.76 DCAA 5.00–100 0.9991 0.59 1.97 0.54 3.05 Chlorate 5.00–100 0.9995 0.43 1.43 0.22 2.17 TCAA 5.00–100 0.9990 1.91 6.37 1.03 4.29 a LODs: limits of detection. b LOQs: limit of quantification. This method was applied for the simultaneous determination of five DBPs in actual drinking water. The anion matrix in the samples has no interference with the determination of target analytes by using the cyclic IC system. Spiked-recovery experiments with three concentration levels were also performed using three typical samples (two tap water and one mineral water) to determine the accuracy of the method. As shown in Table 3, the method had spiking recovery rates of 92.3–105.3% with an RSD of 1.80–3.92% at the low concentration level, 94.8–106.4% with an RSD of 0.95–3.54% at the medium concentration level, and 95.3–102.7% with an RSD of 0.61–3.77% at the high concentration level. These results were satisfactory for trace analysis. Therefore, the complete resolution of chromatographic peaks and accurate quantification of five DBPs with high concentration of anion matrix in drinking water were achieved by the cyclic IC method. Data on analysis of real samples and spiked recoveries of five DBPs Analytes Original (μg L−1) Low level Medium level High level Add level (μg L−1) Recovery (%) RSD (%) Add level (μg L−1) Recovery (%) RSD (%) Add level (μg L−1) Recovery (%) RSD (%) Sample 1 (tap water) Chlorite NDa 5.00 97.4 2.13 20.0 98.3 1.22 50.0 100.3 2.42 Bromate ND 1.00 98.3 3.04 4.00 97.6 1.74 10.0 98.5 1.83 DCAA 10.1 5.00 96.6 3.47 20.0 100.2 0.96 50.0 99.7 1.65 Chlorate ND 5.00 105.3 1.91 20.0 99.4 2.41 50.0 101.4 0.61 TCAA 15.2 5.00 94.7 3.29 20.0 95.2 3.54 50.0 96.2 2.76   Sample 2 (tap water) Chlorite 12.6 5.00 97.8 1.80 20.0 99.4 1.44 50.0 102.7 0.80 Bromate ND 1.00 97.6 2.43 4.00 100.6 1.26 10.0 99.3 2.62 DCAA ND 5.00 102.1 2.46 20.0 98.3 1.78 50.0 98.1 1.14 Chlorate 9.26 5.00 99.4 2.29 20.0 106.4 2.61 50.0 97.4 2.35 TCAA ND 5.00 94.7 2.72 20.0 96.1 3.10 50.0 95.9 3.77   Sample 3 (mineral water) Chlorite ND 5.00 96.4 2.41 20.0 99.4 2.33 50.0 100.4 1.46 Bromate 2.41 1.00 97.0 1.93 4.00 98.9 2.12 10.0 98.6 0.82 DCAA ND 5.00 93.6 2.75 20.0 95.6 0.95 50.0 97.9 1.84 Chlorate ND 5.00 96.1 3.17 20.0 99.4 1.53 50.0 101.6 2.64 TCAA ND 5.00 92.3 3.92 20.0 97.5 2.39 50.0 95.3 3.69 a ND: not detected (lower than the limit of detection). 3.6 Methods comparison To evaluate the applicability of the cyclic IC method for the determination of trace DBPs, we compared the method used in this study with IC methods reported in the literature in terms of method performance and the greenness level. As shown in Table 4, the LODs of the cyclic IC and the literature methods were both in the μg L−1 level. The mobile phase used in the cyclic IC was a KOH solution, which resulted in a lower background conductivity value of the chromatogram baseline than an IC system using Na2CO3 solution as the eluent. Consequently, the LODs of the cyclic IC system were relatively lower. Additionally, the cyclic IC method demonstrated better quantification precision than the literature methods. This is due to the elimination of matrix ions through cyclic analysis, enabling accurate quantification of the target analytes. It should be noted that the retention time precisions of DCAA and TCAA were slightly reduced in the cyclic IC system. In terms of analysis time, the cyclic IC method required a longer duration than the literature methods. Thus, by using two assessment tools (analytical eco-scale and GAPI) to evaluate the level of greenness of the developed method27,28 (Table 5), the cyclic IC system consumed more solvents, reagents and energy than the conventional methods. However, due to the use of a low concentration of KOH solution as the mobile phase instead of organic solvents, the waste generated by the cyclic IC system was relatively less hazardous to the health of the operator and the environment. As a result, the eco-scale assessment shows that both cyclic ion chromatography and conventional IC methods are environmentally friendly. The main advantage of the cyclic IC method, as assessed by GAPI, is that the samples do not require complex pretreatment and can be injected directly into the system for automated analysis. This reduces the time and cost associated with sample pretreatment and manual operation. Overall, the cyclic IC method outperforms traditional IC methods in terms of performance indicators and level of automation. Therefore, this method can be utilized as a green routine approach for the daily detection of water samples. Comparative data for the determination of DBPs by ion chromatography methods Analytes Column(s) Eluent Flow rate (mL min−1) Analysis time (min) Detector Quantification precision (RSD, %) LODs (μg L−1) Ref. BrO3−, ClO3− Metosep A Dual 1 1 mmol per L ortho-phthalic acid, 2% MeCN 1.0 15 UV/Vis 1.31–2.06 5.2–10 21 BrO3−, ClO2−, ClO3−, Br− IonPac AS 19-HC + AG 19-HC 9 mmol per L Na2CO3 1.3 25 Conductivity 0.54–8.81 μg L−1 levels 22 UV/Vis ClO2−, BrO3−, ClO3−, ClO4− IonPac AS 20 + AG 20 5–100 mmol per L NaOH 0.375 18 Conductivity 3.49–6.78 2–27 23 ClO3−, NO2− IonPac AS 19 + AG 19 KOH gradient 1 >30 Conductivity <2 2.2 24 BrO3−, ClO2−, ClO3−, Br− IonPac AS 19-HC + AG 19-HC 9 mmol per L Na2CO3 0.4 25 Conductivity 0.10–3.66 1.32–2.55 25 BrO3−, ClO2−, I− IonPac AS 19-HC 9 mmol per L Na2CO3 1.1 6.5 UV/Vis 0.66–4.60 μg L−1 levels 26 ClO2−, BrO3−, DCAA, ClO3−, TCAA IonPac AS 19 + AG 19 12 mmol per L KOH 1.0 60 Conductivity 0.13–1.03 0.18–1.91 This study Greenness assessment of the proposed method and traditional method according to analytical eco-scale and GAPI Eco-scale assessment GAPI assessment Category Description (per sample) Category Description (per sample) Cyclic IC system Traditional IC method21–26 Cyclic IC system Traditional IC method21–26 Reagents Sample preparation Reagents (g) 28.8 mg NaOH 6.20–23.9 mg Na2CO3/3.6–72 mg NaOH (1) Collection; (2) preservation; (3) transport; (4) storage (1) Off line; (2)—; (3)—; (4) normal conditions (1) Off line; (2)—; (3)—; (4) normal conditions Water (mL) 60 15–30 (5) Type of method: direct or indirect; (6) scale of extraction; (7) solvents/reagents used; (8) additional treatments (5) Direct; (6) no; (7) no; (8) no (5) Indirect; (6) no; (7) no; (8) pretreatment Instrumentation Reagents and solvents Energy (W h) 150 37.5–75 (9) Amount; (10) health hazard; (11) safety hazard (9) 28.8 mg NaOH + 60 mL water; (10) low; (11) safe (9) 6.20–23.9 mg Na2CO3/3.6–72 mg NaOH + 15–30 mL water; (10) low; (11) safe Occupational safety Safe Safe Instrumentation Hazard Low Low (12) Energy (W h) (12) 150 (12) 37.5–75 Waste (mL) 60 15–30 (13) Occupational hazard (13) Safe (13) Safe Total comment Green method Green method (14) Waste; (15) waste treatments (14) 60 mL; (15) no treatment (14) 15–30 mL; (15) no treatment 4 Conclusions In this study, a novel cyclic IC method has been proposed based on valve switching technology. This method achieved the simultaneous determination of five trace DBPs (chlorite, bromate, DCAA, chlorate, and TCAA) in drinking water through large-volume injection. Meanwhile, interferences from chloride and nitrate in the drinking water samples were eliminated online by the cyclic determination of DCAA and TCAA, respectively. Under optimal conditions, the proposed method showed good accuracy, precision, and linearity over a wide range of concentrations. Compared to traditional IC methods, drinking water samples can be injected directly into the cyclic IC system for analysis without pretreatment. Therefore, the cyclic IC method can be a promising alternative for the determination of trace DBPs in drinking water. Additionally, the method can be applied as an online matrix elimination technique to determine trace substances in various samples containing high concentrations of salt matrices. Author contributions Haibao Zhu: writing – original draft, methodology, formal analysis. Zheng Ruan: data curation, formal analysis, investigation. Han Wang: methodology, project administration, writing – review and editing. Danhua Liu: supervision, writing – review and editing. Hongfang Tang: writing – review and editing. Jiahong Wang: methodology, writing – review and editing, supervision. Conflicts of interest The authors declare that they have no conflicts of interest. Supplementary Material This work was supported by the Basic Scientific Research Project of Hangzhou Medical College (YS2021006), Medical and Health Projects of Zhejiang Province, China (2022PY049), and Basic Public Welfare Research Project of Zhejiang Province, China (LGC20B050001). ==== Refs References Wei J. Ye B. Wang W. Yang L. Tao J. Hang Z. Sci. Total Environ. 2010 408 4600 4606 20663540 Dong F. Pang Z. Yu J. Deng J. Li X. Ma X. Dietrich A. M. Deng Y. J. Hazard. Mater. 2022 423 127113 34523488 Khan M. R. Samdani M. S. Azam M. Ouladsmane M. J. King Saud Univ., Sci. 2021 33 101408 Li Z. Song G. 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==== Front Health Sci Rep Health Sci Rep 10.1002/(ISSN)2398-8835 HSR2 Health Science Reports 2398-8835 John Wiley and Sons Inc. Hoboken 10.1002/hsr2.1434 HSR21434 Narrative Review Narrative Review Role of fibrilins in human cancer: A narrative review MAHDIZADEHI et al. Mahdizadehi Mahsa 1 2 Saghaeian Jazi Marie 1 Mir Seyyed Mostafa 1 2 Jafari Seyyed Mehdi http://orcid.org/0000-0003-0483-7505 1 s.meh.jafari@goums.ac.ir 1 Metabolic Disorders Research Center Golestan University of Medical Sciences Gorgan Iran 2 Department of Biochemistry and Biophysics, Faculty of Medicine Golestan University of Medical Sciences Gorgan Iran * Correspondence Seyyed Mehdi Jafari, Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. Email: s.meh.jafari@goums.ac.ir 18 7 2023 7 2023 6 7 10.1002/hsr2.v6.7 e143425 6 2023 02 3 2023 07 7 2023 © 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Abstract Background Fibrillin is one of the extracellular matrix glycoproteins and participates in forming microfibrils found in many connective tissues. The microfibrils enable the elasticity and stretching properties of the ligaments and support connective tissues. There are three isoforms of fibrillin molecules identified in mammals: fibrillin 1 (FBN1), fibrillin 2 (FBN2), and fibrillin 3. Objective Multiple studies have shown that mutations in these genes or changes in their expression levels can be related to various diseases, including cancers. In this study, we focus on reviewing the role of the fibrillin family in multiple cancers. Methods and Results We performed a comprehensive literature review to search PubMed and Google Scholar for studies published so far on fibrillin gene expression and its role in cancers. In this review, we have focused on the expression of FBN1 and FBN2 genes in cancers such as the lung, intestine, ovary, pancreatic ductal, esophagus, and thyroid. Conclusion Altogether various studies showed higher expression of fibrillins in different tumor tissues correlated with the patient's survival. However, there are controversial findings, as some other cancers showed hypermethylated FBN promoters with lower gene expression levels. cancer ECM fibrillin 1 fibrillin 2 source-schema-version-number2.0 cover-dateJuly 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.3.2 mode:remove_FC converted:18.07.2023 Mahdizadehi M , Saghaeian Jazi M , Mir SM , Jafari SM . Role of fibrilins in human cancer: a narrative review. Health Sci Rep. 2023;6 :e1434. 10.1002/hsr2.1434 ==== Body pmc1 INTRODUCTION Identifying novel biomarkers is a foundation for cancer diagnosis and the development of therapeutic strategies. 1 , 2 , 3 Fibrillins (FBNs) are large glycoproteins with supramolecular fibrous structures in the extracellular matrix (ECM). 4 , 5 , 6 Fibrillin proteins with other molecules assemble together to form microfibrils within the ECM. 7 , 8 , 9 In the structure of microfibrils, the fibrillins are connected head‐to‐tail in parallel bundles to form two‐dimensional and three‐dimensional structures. 10 , 11 Fibrillins are multidomain molecules with the two known domains of calcium‐binding epidermal growth factor‐like (cbEGF) and transforming growth factor‐β‐binding protein‐like (TB). 12 There are three different variants of fibrillin molecules in mammals 6 , 10 ; fibrillin_1 (FBN1) and fibrillin_2 (FBN2), and fibrillin_3 (FBN3) genes that encode the human fibrillin proteins. 9 , 13 , 14 All three of them encode proteins with approximately 320–350 kDa. 6 , 15 The human FBN1 gene with 66 exons is located in 15q15‐21.3 15 and encodes for a proprotein named profibrillin‐1. 16 Profibrillin‐1 processed by the furin enzyme proteolytically in the X‐Arg‐X‐Lys/Arg‐Arg‐X consensus sequence in the exon number 65. The products of this cut (exon 1–64 and exon 65–66), respectively, are FBN1 protein which has 2704 amino acids, and asprosin protein which has 140 amino acids. 17 , 18 FBN1 (312 kDa) is a structural ECM glycoprotein that is the main component of 10–12 nm microfibrils and transmits the tensile strength of ECM. 4 , 6 , 18 The FBN1 has a repeated structural domain; for, example, the motif similar to the epidermal growth factor is repeated 47 times in FBN1, 43 of which have a consensus sequence for calcium binding and are called calcium binding repeats. 19 The FBN1 proteins in extracellular microfibrils create the ability to stretch in the ligaments, skin, veins, lens of the eye, nerves, and muscle tissues. 20 , 21 As an essential member of the microfibrils, FBN1 has a role in the formation of elastic fibers. 22 , 23 , 24 To assemble an elastic fiber, fibrillin microfibrils act as a scaffold for the deposition of tropoelastin. 25 Not only playing a role in ECM structure and elasticity, it also can regulate different cellular signaling pathways, including, apoptotic cell death, and proliferation. FBN1 is one of the modulators of the tissue microenvironment and plays important functions in the regulation of the growth and development of vertebrates. 26 , 27 It has been reported that FBN1 induces apoptosis in endothelial cells, and also prevents the proliferation of cells in vitro. 28 Both cellular adhesion and proliferation could be regulated by integrins binding to the Arg‐Gly‐Asp (RGD) motif located at the fourth TB domain of human FBN1, which is an accessible and flexible motif. 29 It should be mentioned that not all RGDs of the ECM are functional 30 ; however, all three fibrillin proteins have RGD domains. An RGD site located at the tail of TB4 is present in all three fibrillins. In addition to this common RGD, FBN2 has an RGD in TB3, and FBN3 has an RGD in cbEGF18. 31 In addition to fibrillins, other glycoproteins, such as latent transforming growth factor‐β‐binding proteins (LTBPs), also can be found in the structure of the microfibrils. 8 , 9 , 13 Fibrillins are structurally related to LTBPs; these are called the fibrillin/LTBP family. 32 FBN1 and LTBP‐1 also interact with each other and cause the repository of transforming growth factor β (TGF‐β) in the ECM. 10 , 33 , 34 In general, TGF‐β binds to LTBP through an interface called LAP, and these bonds are formed between the cysteine residues of LTBP and LAP (Figure 1). 32 Fibrillins serve as scaffolding factors to help the assembly of multiprotein complexes to help maintain tissue homeostasis. 6 They also function in tissue homeostasis through interaction with TGF‐β and the bone morphogenetic proteins. 8 , 9 , 13 , 35 Li et al. reported in a study that FBN1 is upregulated in different chronic kidney diseases and creates a hostile microenvironment for endothelial cells. Fibrillin‐rich microenvironments play an important role in driving endothelial cell damage and vascular rarefaction in CDK. 28 Figure 1 In this figure, the relationship between TGF‐β and human fibrillin 1 is shown. ECM, Extracellular matrix; LAP, latency‐associated propeptide; LTBP, latent transforming growth factor‐β‐binding proteins; TGF‐β, transforming grow factor; TGF‐β R, transforming grow factor receptor. Asprosin, a secreted glucogenic hormone, in mammalian cells, is a 30 kDa protein derived from the c‐terminal cleavage of the profibrillin. 17 , 18 The source of asprosin secretion is adipose tissue. 17 In response to fasting conditions, asprosin stimulates gluconeogenesis leading to glucose secretion in the liver, and it also activates the maintenance of glucose homeostasis with the G protein‐coupled receptor (olfactory receptor family 4 subfamily M member 1). 18 An increment in the serum level of asprosin has been seen in people with type 2 diabetes, insulin resistance, and women with polycystic ovary syndrome (PCOS). 17 In general, mutations in FBN1 and FBN2 lead to fibrinopathies, which are disorders of connective tissue and affect tissues such as eyes, skin, heart, and skeletal tissue. 9 Missense mutations in FBN1 lead to Marfan syndrome, an autosomal dominant connective tissue disorder. 14 , 27 , 36 , 37 This syndrome affects the supporting connective tissue of the joint and body organs. 38 Until today, about 1800 mutations in the FBN1 gene that lead to Marfan syndrome have been identified. Neonatal progeroid syndrome (NPS) is also generated by a mutation in the c‐terminal region of the FBN1 gene resulting in the shortening of the 3′ ends, and ablation of asprosin in NPS patients, 18 , 39 which suffer from severe weight loss. 18 The human FBN2 gene maps to 5q23‐31 and encodes a 315 kDa protein with 2912 amino acid length. 4 , 15 FBN2, a constituent of connective tissue microfibrils, plays a role in the initial process of elastic fiber assembly in the embryo. 40 At first, it was believed that FBN2 has insignificant expression in the postnatal period, but currently, it is determined that FBN2 forms the constructional core of microfibrils and is covered by a layer of FBN1 which means that it also has postnatal expression. 4 , 10 It is said that FBN2 is involved in the assembly of fibronectin around tracheal smooth muscle cells and in the formation of elastic fibers in the tracheal smooth muscle cells. 41 FBN1 and FBN2 are homologous at the nucleotide level, and in comparing 58% of their sequences, 84% similarity was observed between them. 15 There are heterozygous mutations in the FBN2 gene leading to congenital contractile arachnodactyly disease. 40 , 42 In fact, Congenital contractural arachnodactyly or Beals‐Hecht syndrome is a hereditary connective tissue disorder with autosomal dominant inheritance related to Marfan syndrome. 15 , 43 The FBN3, another member of the fibrillins family, is located in 19p13.3‐19p13.2. 15 Unlike FBN1 and FBN2, FBN3 is not well‐known, and even some studies have stated that it exists only in the complementary DNA sequence. The highest level of FBN3 expression has been observed in the fetal tissue. However, FBN3 is observed in the microfibrils of the ECM of tissues such as kidneys, adrenal glands, skin, lungs, skeletal muscles, adult brains, stomach, ovaries, and skeletal elements that are growing. 44 , 45 It also seems that FBN3 participates in the pathogenesis of PCOS. 46 Studies on the lesser‐known member of the fibrillins family, FBN3, have shown that mutations in this gene are related to Bardet–Biedl syndrome. 9 In addition, the homozygous missense variant of FBN3 is related to Klippel–Trenaunay–Weber syndrome. 47 Until now, the mutation of genes encoding fibrillin and its consequences had been given more attention in structural disease of connective tissues; however, considering its various functions in apoptosis modulation, TGF‐β regulation, and tissue microenvironment homeostasis, attention has also been paid to the role of fibrillins in cancers. There are some reports on different human cancers illustrating the association of fibrillin with carcinoma. This review was organized with a focus on investigating the roles of the fibrillin family in cancers. Therefore, fibrillins can be considered new targets for the study of cancers in the future. 2 FIBRILLINS AND CANCERS Cancer progression is significantly related to the condition of the tumor microenvironment. 48 Tumor growth is specially related to the structure and function of the tumor microenvironment, 49 which includes stromal cells, endothelial cells, immune cells, fibroblasts, and ECM. 48 , 49 ECM has a dynamic and three‐dimensional, and noncellular structure 50 ; At the molecular level, ECM not only provides structural support but also supports biochemical reactions in cell, and even ECM constituents have been shown to play dominant roles in tumor development. 51 In addition to their structural roles in the ECM, microfibrils and specially FBN1 contribute to integrin‐mediated signaling, proliferation, and migration, and adhesion of fibroblasts, smooth muscle cells, and endothelial cells. One of the common goals in studies is to check the expression level of genes. 52 The human fibrillin gene is also one of the genes whose role has recently been noticed in cancers. 2.1 Lung cancer There is evidence showing that FBN1 contributes to the migration process of lung and mesenchymal cells. 29 Hong et al. investigated the expression of the FBN2 gene in 97 lung cancer tissues and the effect of FBN2 knockdown in lung cancer cell lines. They reported that the expression level of FBN2 was associated with the patient's TNM stage and lymph node metastasis status. Also, their results showed that the permanence time of patients with high‐FBN2 expression was extremely decreased compared to patients with low‐FBN2 expression, which indicated that higher FBN2 expression is useful for lung cancer prognosis. Also, studies showed that FBN2 knockdown significantly hindered the expansion of PC‐9 and H1640 lung cancer cells with decreased clone formation ability, invasion, and migration. Moreover, in PC‐9 cells, knockdown of the FBN2 gene essentially restrained expression levels of N‐cadherin and vimentin and upregulated levels of E‐cadherin. 53 In a study, Chen et al. reported that abnormal methylation of FBN2 in 55% (6/11) of non‐small cell lung cancer cell lines, but not observed in the small cell lung cancer cell lines. Also, in primary lung cancer, 49% of tumors had FBN2 methylation, but FBN2 methylation was observed in only 7% of nonmalignant lung tissues. Moreover, FBN2 methylation often occurs in large tumors with metastasis or advanced stages. They suggested that the methylation and silencing of FBN2 in tumors can be related to carcinogenesis and metastasis. 54 The outcome of this study shows that the reduction of FBN2 expression has a function in the progression of lung cancer, but the effects of changes in the expression of FBNs in different cancers are contradictory, which we will mention below. 2.2 Colorectal cancer (CRC) Different investigations were carried out on the methylation status of the FBN genes in CRC patients, and they reported aberrant methylation and altered gene expression of the fibrillin genes in colorectal patients. Yi et al. observed that the FBN2 gene promoter is hypermethylated in most CRC cell lines and primary tumors. The reduced FBN2 gene expression, which occurs consequent to the promoter hypermethylation, can be investigated as a biomarker in the early diagnosis of CRC. 55 In relation to further studies in the field of CRC, Hibi et al. observed that 63% of CRC patients showed FBN2 methylation DNA in the tumor tissue. In addition, when measuring the methylation in serum DNA, only 8% of the patients have methylated FBN2 in circulation. Further examination showed that FBN2 methylation was found in the serum DNA of male patients and patients with liver metastasis. 56 In addition to the studies conducted on tumor tissue samples, Guo et al. observed the methylation of the FBN1 gene in stool samples of patients with colon cancer. Methylated FBN1 in the stool samples was observed in 72% of patients and 7.6% of healthy groups in their stool samples. This study also suggested that hypermethylation of FBN1 promoter is a biomarker for CRC. 57 According to the studies, the hypermethylation of FBN1 promoter can be considered a biomarker for CRC. 2.3 Ovarian cancer There are some studies indicating the association of FBNs with tumor progression and metastasis in ovarian cancer cells. As shown by Wang et al., FBN1 silencing resulted in increasing the expression level of E‐cadherin and β‐catenin. Also, adding recombinant FBN1 protein suppressed the expression of E‐cadherin and β‐catenin. Overall, their results showed that FBN1 increases tumorigenesis and metastasis in ovarian cancer. Overexpression of FBN1 can be a reason for the early recurrence of ovarian cancer. 20 The research of Chen et al. shows that FBN1, along with three other genes, can be introduced as a marker to check the survival time of ovarian cancer patients. 58 According to the evidence, it can be concluded that increasing the expression of FBN1 reduces the adhesion between cells in cancer cells, but this effect of FBN1 needs further investigation in other types of cancers as well. 2.4 Other cancers 2.4.1 Pancreatic ductal adenocarcinoma (PDAC) The FBN1 gene can contribute to immune cell infiltration in tumors. For example, Hong Luan showed that FBN1, along with two other genes (SPARC, COL6A3), have a direct relationship with the level of immune cell infiltration, including CD4+ T cells, CD8+ T cells, B cells, neutrophils, macrophages, and dendritic cells in the PDAC. Also, high expression levels at the FBN1 gene showed a positive relationship with a poor prognosis for PDAC. Moreover, it was reported that FBN1 contributes to the regulation of immune cell infiltration in the PDAC; however, more research is needed to investigate its underlying mechanism. 59 2.4.2 Esophageal cancer Studies appear that the level of FBN2 methylation in esophageal tumor tissue was higher than in tumor margin tissue. To determine whether the methylation of FBN2 leads to an increase or decrease in its expression, Tsunoda et al. used 5‐aza‐2'‐deoxycytidine treatment as a demethylation agent, and found a decline in FBN2 gene methylation, leading to an increase in its expression. 60 2.4.3 Thyroid cancer Changes in the level of ECM components have been observed in thyroid cancer, and evidence is reported that ECM modulation can affect thyroid cancer. For example, silencing fibronectin as one of the components of the ECM prevented the proliferation of thyroid cancer cells. 61 Considering the role of fibrillin as one of the ECM proteins, Tseleni‐Balafouta et al. investigated the expression of the FBN1 gene in normal thyroid tissue and thyroid carcinomas. Their results showed that FBN1 immunoreactivity was weak in normal thyroid tissue. But using immunohistochemistry, they identified FBN1 in the cytoplasm of neoplastic thyroid carcinoma cells. Their results confirmed previous studies and showed that fibrillin is produced by epithelial cells and fibroblastic cells. 62 The summary of the research results for the fibrillin family members in different tumor types is shown in Table 1. Table 1 Observation and investigation of fibrillin family members in different tumor types. Gene Location/cell line Observation Intervention Relation with tumor References FBN2 Lung/PC‐9 and H1640 lung cancer cells Relationship between FBN2 with migration and invasion of lung cancer Fibrillin 2 gene Knockdown A. Expression of FBN2 was related to patient's TNM stage and lymph node metastasis B. Knockdown significantly hindered the expansion of PC‐9 and H1640 lung cancer cells [53] FBN2 Non‐small cell lung cancer cell lines/lung Aberrant methylation of FBN2 in cell line and tumor Methylation and silencing of FBN2 in tumors can be related to metastasis [54] FBN2 Colorectal cancer cell lines and colorectal tumors FBN2 gene promoter was hypermethylated The promoter hypermethylation of FBN2 can be investigated as a biomarker in the early diagnosis of colorectal cancer [55] FBN2 Colorectal cancer tumor FBN2 methylation DNA in the tumor tissue [56] FBN1 The stool samples of colorectal cancer Methylation of FBN1 in the stool samples of colorectal cancer patients Hypermethylation of FBN1 promoter is a biomarker for colorectal cancer [57] FBN1 Ovarian cancer cell line Relationship between FBN1 expression and metastasis process in ovarian cancer Silenced the expression of FBN1/adding recombinant FBN1 protein The FBN1 increases tumorigenesis and metastasis in ovarian cancer [20] FBN1 Pancreatic ductal adenocarcinoma (PDAC) FBN1 gene has a direct relationship with the level of immune cell infiltration in the tumor The high expression level of the FBN1 gene has a positive relationship with a poor prognosis for PDAC [59] FBN2 Esophageal cancer tumor FBN2 methylation in tumor tissue A decline in FBN2 gene methylation leads to an increase in its expression [60] Abbreviation: FBN, fibrillin. John Wiley & Sons, Ltd. 3 CONCLUSION Fibrilin, as one of the main integrants of the ECM, can function in the tumor microenvironment affecting cellular proliferation, adhesion, metastasis, and immune cell infiltration in the tumor. Altogether various studies showed higher expression of fibrillins in different tumor tissues correlated with the patient's survival; however, there are controversial findings in this regard, as some other cancers showed hypermethylated FBN promoters with lower gene expression levels. Although studies have been conducted on fibrillin genes in tumors, the exact mechanism of how this protein acts in cancer tissue is unknown. Regarding the potential of fibrillin in cancer progression; for future studies, we suggest investigating its association with its expression level changes in other types of cancer. AUTHOR CONTRIBUTIONS Mahsa Mahdizadehi: Writing—original draft; writing—review and editing. Marie Saghaeian Jazi: Writing—review and editing. Seyyed Mostafa Mir: Writing—review and editing. Seyyed Mehdi Jafari: Supervision; writing—review and editing. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. TRANSPARENCY STATEMENT The lead author Seyyed Mehdi Jafari affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. ACKNOWLEDGMENTS The authors would like to thank the Department of Biochemistry and Biophysics, Faculty of Medicine, Golestan University of Medical Sciences. DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. ==== Refs REFERENCES 1 Mohammadi E , Aliarab A , Babaei G , et al. MicroRNAs in esophageal squamous cell carcinoma: application in prognosis, diagnosis, and drug delivery. 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PMC010xxxxxx/PMC10353533.txt

==== Front Clin J Pain Clin J Pain AJP The Clinical Journal of Pain 0749-8047 1536-5409 Lippincott Williams & Wilkins Hagerstown, MD 37158624 CJP-D-22-00564 10.1097/AJP.0000000000001130 00006 3 Review Articles Identification and Characterization of Pain Processing Patterns Among Patients With Chronic Primary Pain A Replication http://orcid.org/0000-0003-4510-1799 Scheidegger Alina MSc *†scheidegger.alina@gmail.com;alina.scheidegger@insel.ch; alina.scheidegger@students.unibe.ch Jäger Joshua MSc joshua.jaeger@unibe.ch † Blättler Larissa T. MSc *larissa.blaettler@insel.ch Aybek Selma Prof. Dr. med *selma.aybek@insel.ch Bischoff Nina Dr. med *nina.bischoff@insel.ch grosse Holtforth Martin Prof. Dr. phil. *†martin.grosse@unibe.ch * Department of Neurology, Inselspital, Bern University Hospital, University of Bern † Department of Psychology, University of Bern, Bern, Switzerland Reprints: Alina Scheidegger, MSc, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland (e-mail: alina.scheidegger@insel.ch). 8 2023 9 5 2023 39 8 414425 8 12 2022 27 4 2023 30 4 2023 Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Objectives: To develop individual and effective treatment plans for patients with chronic pain, we aimed to replicate Grolimund and colleagues’ empirical categorization of chronic pain patients on a new and larger sample. Moreover, this work aimed to extend previous knowledge by considering various treatment outcomes and exploratorily analyzing which coping skills might be particularly relevant for treatment success in each subtype. Materials and Methods: Latent class analysis was used to identify homogenous subtypes with different pain processing patterns using the pain processing questionnaire (FESV). Results: By analyzing 602 inpatients with chronic primary pain, we identified 3 subtypes: (1) severely burdened individuals with low coping skills, (2) mildly burdened individuals with high coping skills, and (3) moderately burdened individuals with moderate coping skills. Pain interference, psychological distress, and cognitive and behavioral coping skills improved after treatment in all subtypes. Pain-related mental interference significantly improved only in subtypes (1) and (3). Only individuals of subtype (3) reported significant reductions in pain intensity after treatment. Exploratory regression analysis suggested that of subtype (1), the most promising targets in reducing pain interference and psychological distress posttreatment might be to foster relaxation techniques, counteractive activities, and cognitive restructuring. None of the FESV dimensions significantly predicted treatment outcomes among individuals of subtype (2). Individuals of subtype (3) might benefit the most from experiencing more competence during treatment. Discussion: Our findings highlight the importance of identifying and characterizing subtypes of chronic primary pain patients and that these subtypes should be considered for individualized and effective treatment. Key Words: chronic primary pain interdisciplinary pain treatment subtypes pain processing pain coping OPEN-ACCESSTRUE ==== Body pmcChronic pain is a global health problem that profoundly impacts both individuals and society.1 Individuals with chronic pain experience severe physical and psychosocial consequences as their pain is recurrent or persists over 3 months or more.2 Moreover, chronic pain is often accompanied by mental disorders such as depression and anxiety, which may mutually precede and/or increase each other over time.2 As the incidence and prevalence of chronic pain continued to grow over the past few decades, effective treatment for chronic pain is of utmost importance, and tools to better individualize therapy are needed.1,3 Chronic pain treatment aims to increase patients’ physical and psychological functioning by learning and implementing new cognitive and behavioral coping skills or modifying current (potentially inefficient) coping skills.4,5 An interdisciplinary multimodal treatment is considered particularly suitable for chronic pain, as it combines different treatment methods (eg, psychological treatment, physiotherapy, relaxation techniques, occupational therapy). This enables the treatment to be tailored to the specific patient’s needs.6 To prepare an optimally tailored treatment, it is important to identify individual risk and protective factors.4,7 Therefore, it is essential to understand how patients deal with their chronic pain and identify functional and dysfunctional pain processing patterns for an individualized case formulation and treatment planning. Identifying phenotypes that categorize patients according to their pain processing pattern is a pivotal step toward individualized case formulation and might especially help under limited temporal resources.8 Various categorizations of patients with chronic pain based on their pain processing style have been suggested.9–13 Grolimund and colleagues’ categorization seems to have clinical utility for individualized and effective treatment planning, as it takes into account both pain-related mental interference and different coping skills as assessed by the German version of the pain processing questionnaire (FESV).14 For categorizing patients, 3 distinct subtypes of inpatients with chronic pain were identified by a 2-step cluster analysis: (1) individuals with high interference and low coping skills, (2) individuals with low interference and high coping skills, and (3) individuals with high interference and high coping skills. Comparing the different subtypes, Grolimund and colleagues found significant differences in various psychosocial properties such as psychological distress, stress, and social support.9 Grolimund and colleagues’ 3 subtypes also corresponded with 3 of Roditi and colleagues’ 4 subtypes, who focused on the frequency and perceived effectiveness of coping strategies used to cope with chronic pain among patients. Similarly, Wenzel and colleagues, who investigated pain coping types among older community-dwelling care receivers with chronic pain, identified very similar subtypes as Grolimund and colleagues. Considering the importance of identifying and characterizing subtypes of chronic pain inpatients, we aimed to replicate Grolimund and colleagues’ empirical categorization of chronic pain patients. We used latent class analysis on a new and larger sample of inpatients with chronic primary pain receiving inpatient interdisciplinary multimodal pain treatment to improve convergence, correct replications, and reduce parameter bias.15 In extension of the previous study, we considered different treatment outcomes and exploratorily analyzed which coping skills might be particularly important for treatment success among the subtypes. MATERIALS AND METHODS Sample The new and larger sample consisted of 602 patients with chronic primary pain receiving inpatient care in the same tertiary psychosomatic university hospital for 3 weeks where Grolimund and colleagues’ data was collected. Patients received an individualized selection of interventions from various available treatments (ie, psychotherapy, medical interventions, pharmacotherapy, physiotherapy, and occupational therapy).4 Patients were assigned to the different treatment modalities based on indication and availability. They had weekly scheduled sessions, and each therapy was individually tailored to the patient’s complaints, needs, and goals. All patients were considered for inclusion if they fulfilled: (1) the criteria for chronic primary pain (MG30.0) according to the International Classification of Diseases, 11th revision (ICD-11)16; (2) were aged 18 or older; (3) had sufficient German-language proficiency; (4) provided written consent regarding the further use and publication of their anonymized data. Ethics Statement The Ethics Committee of the Canton of Bern approved the study (project ID 2018-00493, ID 2021-02214). The study complies with the Declaration of Helsinki. It was ensured that patients had ample time to get information about the further use of their anonymized data for research and were required to provide written consent if they agreed and wished to participate. Procedures All inpatients receiving interdisciplinary pain treatment between December 2015 and February 2022 were invited for psychometric assessment for quality management and completed self-reported questionnaires within the first 2 days after intake as well as a few days before discharge. Participating patients completed a battery of self-report questionnaires in the presence of a research assistant, who helped with eventual difficulties understanding single items or for providing additional information. This battery included questionnaires on the patient’s overall condition, psychopathological symptoms, clinically relevant behavior and experience, as well as other treatment-related psychological constructs. However, some patients were not able to complete all the questionnaires for various reasons, for example, scheduling conflicts, early (unplanned) discharge, or severe current symptoms. For this study, all inpatients who had completed all questionnaires needed for latent class analysis at intake were included. Thus, fewer data may have been available for the secondary analyses, such as for further characterization of subtypes, pre-post comparisons, and exploratory regression analyses. Measures Sociodemographic and Pain-related Data Age, sex, marital status, and pain duration were assessed at intake. Pain Processing The German pain processing questionnaire (FESV) is one of the most frequently used instruments for assessing core aspects of pain processing.14 In detail, the FESV consists of 38 items and measures 3 basic components of pain processing: cognitive and behavioral pain coping, as well as pain-related mental interference. Each component has 3 sub-dimensions for the cognitive coping component: action planning, cognitive restructuring, and competence experience; for the behavioral coping component: mental distraction, counteractive activities, and relaxation techniques; and for the component of pain-related mental interference: pain-related helplessness and depression, pain-related anxiety, and pain-related anger. Thus, 6 dimensions measure coping skills, and 3 dimensions account for pain-related mental interference. For each item, patients used a 6-point Likert scale ranging from 1=“not at all true” to 6=“completely true” to describe their pain in the last few days. This questionnaire was administered at intake and discharge. Additional Measures of Pain-relevant and Treatment-related Characteristics Various constructs were considered to characterize the individual subtypes further. All additional measures were collected at intake and were considered for the further characterization of patients. The Well-Being Index (WHO-5) was used as a screening tool for depressive symptoms measuring patients’ (lack of) well-being over the last 2 weeks with 5 items, ranging from 0=“at no time” to 5=“all the time.”17 The total score of the Perceived Stress Scale-10 questionnaire was used to assess perceived stress over the previous month, with 10 items ranging from 0=“never” to 4=“very often.”18 Patients’ degree of pain catastrophizing was assessed using the total score of the 13-item Pain Catastrophizing Scale Questionnaire.19 The Pain Catastrophizing Scale uses a 5-point Likert scale from 0=“not at all” to 5=“all the time.” ENRICHD-Social-Support-Instrument (ESSI-D) measures different aspects of social support with 5 items on a 5-point Likert scale from 1=“never” to 5=“always.”20 The German short version of the questionnaire for psychotherapy motivation (FPTM-23) consists of 23 items measuring the 6 scales hopelessness, initiative, denial of the need for psychological help, knowledge of psychological treatment, symptom-related attention, and suffering. 21 Patients use a 4-point Likert scale from 1=“not agree” to 4=“agree.” Illness perception was assessed with the Brief Illness Perception Questionnaire.22 The Brief Illness Perception Questionnaire measures the patient’s perceived consequences, timeline, personal control, treatment control, identity, concern, understanding, and emotional response with one item each, resulting in 8 scales rated on a continuous linear scale from 0 to 10.22 Treatment Outcome Measures In line with the VAPAIN consensus statement6 and Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations,23,24 treatment outcome was operationalized by reductions in pain intensity, pain interference, and psychological distress. Pain intensity and pain interference are 2 scales of the Brief Pain Inventory.25 The mean of 4 items measuring worst, least, average, and current pain on a Likert scale ranging from no pain at all (0) to the worst pain imaginable (10) represents the pain intensity scale. Pain interference can be calculated by averaging 7 items regarding different aspects of life (eg, general activity, mood, relations with other people, normal work) on a Likert scale ranging from no interference (0) to complete interference (10). This questionnaire was administered at intake and discharge. Psychological distress during the last week was measured using the German version of the Hospital Anxiety and Depression Scale (HADS-D).26 This questionnaire consists of 14 items and measures anxiety and depression symptoms as psychological distress on a 4-point Likert scale from 0 to 3, leading to a possible total score of 0 to 42. Patients were asked to complete this questionnaire at intake and discharge. Statistical Analyses Version 27 of IBM SPSS Statistics and version 2021.09.2+382 of RStudio were used to analyze the data.27,28 Other than Grolimund and colleagues, who used 2-step cluster analysis, we used latent class analysis to identify homogenous subtypes with different pain processing patterns using the FESV questionnaire data at intake. In accordance with Weller and colleagues, multiple indicators were considered to determine which class solution fitted best. Bayesian Information Criterion (BIC), which is often considered the most reliable indicator of model fit, was considered alongside the Akaike Information Criterion (AIC), log-likelihood (LL), entropy, and average latent class posterior probability (ALCPP) for best model fit. Lower BIC, AIC, and LL typically indicate better model fits.29 Elbow plots were used to determine changes in the BIC, AIC, and LL indicators and compare different class solutions.30 Values close to 1 for entropy are considered ideal and indicate how accurately the model defines classes. The ALCPP represents the average probability that measures how accurately a person can be assigned to a class. Values for ALCPP between 0.8 and 0.9 are acceptable if other criteria for model fit are met, and values higher than 0.90 are considered ideal.29 In a first step, class solutions for 2 to 6 classes were tested, and model fit indicators were compared to identify the best class solution. To determine the best model fit, we considered lower BIC, AIC, and LL in elbow plots, as well as entropy values close to 1 and ALCPP values above .9 as good model fit indicators.29,30 In a second step, descriptive characteristics for the FESV dimensions, the sociodemographic and clinical characteristics, were investigated and compared for the total sample and the identified subtypes. Furthermore, descriptive characteristics of additional pain-relevant and treatment-relevant measures were analyzed and compared for the total sample and the identified subtypes at intake. The Fisher analysis of variance and Tukey post hoc tests were computed for homogenous variances in the observed variables, whereas the Welch analysis of variance and Games-Howell post hoc tests were computed for not homogenous variances. χ2 tests were used for continuous variables. Next, paired t tests were calculated to assess changes in each subtype from pretreatment to posttreatment in pain intensity, pain interference, psychological distress, cognitive and behavioral coping skills, as well as pain-related mental interference. Finally, exploratory regression analyses using a stepwise elimination strategy were computed for treatment outcome measures that changed significantly during treatment for each subtype to investigate the predictive value of change scores of the single FESV dimensions on treatment outcome measures posttreatment. Bonferroni correction was applied due to multiple comparisons. RESULTS Latent Class Analysis Table 1 summarizes model fit and diagnostic criteria evaluation of the considered class solutions. A model with 3 classes appeared to be the most suitable solution for the observed sample. The characteristics of the different dimensions of the FESV for the respective subtypes are summarized in Table 2 and visualized in Figure 1. Compared with the FESV norm sample of pain patients, most of the subtypes’ mean values of the different FESV dimensions are within the normal value range (±1 SD).14 Following Grolimund and colleagues, the subtypes were named based on their pain processing profiles as (1) severely burdened individuals with low coping skills (N=148; 24.6%), (2) mildly burdened individuals with high coping skills (N=60; 10.0%), and (3) moderately burdened individuals with moderate coping skills (N=394; 65.4%). All dimensions of the FESV differed significantly between the subtypes except the use of counteractive activities, which were only significantly lower in subtype (1) than in subtypes (2) and (3). TABLE 1 Evaluating Class Solutions With Model Fit and Diagnostic Criteria No. latent classes Smallest class count (N) Smallest class size (%) No. parameters estimated (df) LL AIC BIC Entropy ALCPP 2 classes 213 35.3 37 −7228.77 14531.54 14694.35 0.813 0.943 3 classes 60 10 56 −7033.01 14178.01 14424.42 0.901 0.958 4 classes 61 10.3 75 −6906.68 13963.35 14293.37 0.821 0.898 5 classes 60 9.7 94 −6835.36 13858.73 14272.35 0.811 0.877 6 Classes 61 9.6 113 −6792.59 13811.19 14308.42 0.793 0.850 AIC indicates Akaike Information Criterion; ALCPP, average latent class posterior probability; BIC, Bayesian Information Criterion; LL, log-likelihood. TABLE 2 Descriptive Characteristics of the Total Sample and Patient Subtypes for the FESV Dimensions and Patient Subtype Comparisons Mean (SD) F (df1, df2)=F, P FESV Overall sample (N=602) (1) Severely burdened individuals with low coping skills (n=148) (2) Mildly burdened individuals with high coping skills (n=60) (3) Moderately burdened individuals with moderate coping skills (n=394) Fisher ANOVA Welch ANOVA Tukey post hoc test Games-Howell post hoc test Cognitive coping  Action planning 14.9 (5.2) 11.0 (4.8) 18.5 (4.8) 15.8 (4.7) F (2, 147.5)=71.3*** 1<3<2  Cognitive restructuring 13.7 (4.8) 9.0 (3.0) 18.8 (4.0) 14.6 (3.9) F (2, 599)=186.0*** 1<3<2  Competence experience 14.3 (4.9) 9.0 (3.2) 20.3 (2.8) 15.4 (3.8) F (2, 599)=260.1*** 1<3<2 Behavioral coping  Mental distraction 11.8 (5.0) 8.6 (3.3) 15.6 (4.6) 12.4 (4.9) F (2, 599)=61.4*** 1<3<2  Counteractive activities 11.7 (5.3) 7.9 (3.9) 13.4 (5.7) 12.9 (5.0) F (2, 599)=61.4*** 1<3; 1<2  Relaxation techniques 12.0 (5.3) 9.4 (4.1) 15.4 (5.9) 12.5 (5.1) F (2, 599)=35.8*** 1<3<2 Pain-related mental interference  Pain-related helplessness and depression 21.2 (6.4) 26.9 (2.8) 9.5 (3.4) 20.8 (4.9) F (2, 599)=351.1*** 1>3>2  Pain-related anxiety 16.2 (5.4) 20.6 (3.1) 7.0 (2.6) 15.9 (4.4) F (2, 599)=253.8*** 1>3>2  Pain-related anger 16.8 (7.2) 20.0 (6.6) 8.8 (3.6) 16.8 (6.8) F (2, 599)=64.3*** 1>3>2 Range of the cognitive and behavioral coping dimensions: 4 to 24; range of pain-related mental interference dimensions: 5 to 30. ANOVA indicates analysis of variance; FESV, pain processing questionnaire. *** P<0.001. FIGURE 1 Standardized mean values in the pain processing questionnaire (FESV) dimensions of the identified subtypes determined by latent class analysis. The gray area indicates norm values from the reference sample of Geissner (N=401; mean±1 SD; 2001). Sociodemographic and Pain-related Data The mean age of the total sample (n=602) was 47.2±13.7 years. More than 60% of the patients were female (63.6%), married or in a relationship (54.6%), and had suffered from their pain for 1 to 5 years (43.7%). On average, patients stayed for 22.8 days (SD=6.4 d). Additional descriptive results on sociodemographic characteristics and questionnaire data for the entire sample are shown in Tables 2–4. TABLE 3 Descriptive Characteristics of the Total Sample and Patient Subtypes in Sociodemographic and Pain-related Variables and Patient Subtype Comparisons n (%) Fisher exact test χ2 test Fisher ANOVA Overall sample (N=602) (1) Severely burdened individuals with low coping skills (n=148) (2) Mildly burdened individuals with high coping skills (n=60) (3) Moderately burdened individuals with moderate coping skills (n=394) P P (χ2; df) F (df1, df2)=F, P Age, mean (SD) 47.2 (13.7) 46.4 (12.7) 50.6 (15.3) 46.9 (13.7) F (2, 599)=2.36 Sex  female 383 (63.6) 100 (67.6) 43 (71.7) 240 (60.9) 0.148  male 219 (36.4) 48 (32.4) 17 (28.3) 154 (39.1) Marital status  In a relationship 67 (11.1) 17 (11.5) 6 (10.0) 44 (11.2) 0.939 (2.92; 8)  Married 262 (43.5) 64 (43.2) 26 (43.3) 172 (43.7)  Divorced/separated 135 (22.4) 35 (23.7) 17 (28.3) 83 (21.1)  Widowed 18 (3.0) 5 (3.4) 2 (3.3) 11 (2.8)  Single 120 (19.9) 27 (18.2) 9 (15.0) 84 (21.3) Pain duration  0-3 mo 8 (1.3) 1 (0.7) 2 (3.3) 5 (1.3) 0.312 (11.60; 10)  4-6 mo 28 (4.7) 9 (6.1) 4 (6.7) 15 (4.7)  7-11 mo 31 (5.1) 8 (5.4) 1 (1.7) 22 (5.2)  1-5 y 263 (43.7) 64 (43.2) 29 (48.3) 170 (43.7)  6-10 y 96 (15.9) 18 (12.2) 13 (21.7) 65 (16.0)  >10 y 176 (29.2) 48 (32.4) 11 (18.3) 117 (29.2) Stay duration, mean (SD) 22.8 (6.4) 22.9 (6.7) 21.9 (6.9) 22.9 (6.1) F (2, 599)=0.496 ANOVA indicates analysis of variance. TABLE 4 Descriptive Characteristics of the Total Sample and Patient Subtypes in Additional Pain-relevant and Treatment-relevant Variables and Subtype Comparisons Overall sample Mean (SD) F (df1, df2)=F, P N Mean (SD) (1) Severely burdened individuals with low coping skills (n=148) (2) Mildly burdened individuals with high coping skills (n=60) (3) Moderately burdened individuals with moderate coping skills (n=394) Fisher ANOVA Welch ANOVA Tukey post hoc test Games-Howell post hoc test Brief Pain Inventory  Pain intensity 602 5.4 (1.7) 6.1 (1.7) 5.1 (1.7) 5.2 (1.7) F (2, 599)=14.5*** 1>2; 1>3  Pain interference 602 5.9 (1.9) 7.2 (1.5) 4.4 (1.8) 5.8 (1.7) F (2, 599)=95.3*** 1>3>2  Psychological distress HADS-D 602 11.3 (3.1) 13.2 (2.9) 8.8 (2.6) 10.9 (2.9) F (2, 599)=57.9*** 1>3>2  WHO-5 416 8.7 (5.4) 5.3 (4.1) 15.7 (4.9) 8.9 (4.8) F (2, 98.8)=73.3*** 1<3<2  Perceived Stress Scale-10 460 22.4 (7.5) 28.0 (5.2) 12.9 (7.1) 21.8 (6.7) F (2, 106.3)=98.0*** 1>3>2  Pain Catastrophizing Scale 407 26.9 (11.7) 36.6 (8.8) 13.9 (8.6) 25.4 (10.4) F (2, 404)=81.3*** 1>3>2  ENRICHD social support instrument 448 24.2 (5.7) 22.3 (6.7) 26.9 (4.3) 24.4 (5.4) F (2, 97.0)=11.2*** 1<3<2 Questionnaire for therapy motivation FPTM-23  Hopelessness 334 2.0 (0.7) 2.4 (0.7) 1.6 (0.6) 2.0 (0.7) F (2, 331)=19.2*** 1>3>2  Initiative 334 2.6 (0.9) 2.5 (1.0) 2.7 (1.0) 2.7 (0.9) F (2, 331)=1.3  Denial of psychological need 334 1.7 (0.7) 1.8 (0.7) 1.7 (0.9) 1.6 (0.6) F (2, 65.1)=0.8  Symptom-related attention 334 2.4 (0.8) 2.3 (0.8) 2.2 (0.8) 2.5 (0.8) F (2, 331)=2.8  Knowledge about psychological treatment 334 2.9 (0.9) 3.0 (0.8) 2.9 (0.9) 2.8 (0.9) F (2, 331)=1.2  Suffering 334 2.7 (0.8) 3.3 (0.5) 1.8 (0.8) 2.7 (0.7) F (2, 73.1)=61.6*** 1>3>2 Brief Illness Perception Questionnaire  Consequences 393 7.7 (1.9) 8.7 (1.5) 6.1 (2.0) 7.6 (1.9) F (2, 90.8)=31.1*** 1>3>2  Timeline 393 7.2 (2.5) 8.3 (1.9) 6.5 (2.8) 7.0 (2.6) F (2, 91.5)=14.8*** 1>3; 1>2  Identity 393 7.9 (1.8) 8.7 (1.4) 7.1 (1.9) 7.8 (1.8) F (2, 391)=16.9*** 1>3; 1>2  Concern 393 6.8 (2.7) 8.5 (1.9) 4.3 (2.9) 6.6 (2.6) F (2, 90.7)=45.6*** 1>3>2  Understanding 393 5.9 (3.1) 4.5 (3.3) 7.4 (2.5) 6.2 (3.0) F (2, 93.6)=15.5*** 1<3<2  Emotional response 393 7.2 (2.5) 8.7 (1.6) 3.9 (2.7) 7.1 (2.2) F (2, 89.7)=65.7*** 1>3>2  Personal control 393 4.3 (2.5) 2.8 (2.5) 6.6 (2.0) 4.4 (2.3) F (2, 391)=37.0*** 1<3<2  Treatment control 393 6.2 (2.5) 4.7 (2.5) 7.6 (1.7) 6.5 (2.3) F (2, 391)=28.4*** 1<3<2 ANOVA indicates analysis of variance; FPTM-23, German short version of the questionnaire for psychotherapy motivation; HADS-D, Hospital Anxiety and Depression Scale—German version; WHO-5, 5-item World Health Organization Well-Being Index. *** P<0.001. Comparison of Patient Subtypes Regarding Sociodemographic and Pain-related Variables Table 3 summarizes the descriptive characteristics of the total sample and patient subtypes in sociodemographic and pain-related variables and illustrates patient subtype comparisons. Age, sex distribution, marital status, and pain duration did not differ significantly between the different patient subtypes. Table 4 summarizes descriptive characteristics of the total sample and the patient subtypes in additional pain-relevant and treatment-relevant variables, as well as the results of their comparison. Class comparisons revealed that individuals in subtype 1 (severely burdened individuals with low coping skills) experience higher pain intensity and pain interference than individuals in subtypes 2 (mildly burdened individuals with high coping skills) and 3 (moderately burdened individuals with moderate coping skills). Furthermore, individuals in subtype (1) experience the most psychological distress, stress, as well as pain catastrophizing, followed by individuals from subtype (3), then subtype (2). Similarly, individuals in subtype (1) report the lowest well-being and social support, followed by subtypes (3) and (2). Significant differences in therapy motivation could only be found for the scales of hopelessness and suffering. Individuals in subtype (1) showed the highest values in the scales of hopelessness and suffering, followed by individuals in subtype (3) and subtype (2). The identified subtypes did not differ significantly regarding the therapy motivation scales initiative, denial of psychological need, symptom-related attention, and knowledge about psychological treatment. Comparisons of illness perception scores revealed that individuals of subtype (1) indicated more strongly that their illness burdened their lives than the other subtypes. Furthermore, subtype (1) experienced most strongly that symptoms were related to their illness, followed by subtype (3) and (2). Similarly, individuals in subtype (1) believed most strongly that their illness would last for a long time than patients in the other 2 subtypes did. Moreover, this subtype reported the least control or influence over their symptoms and believed most strongly that the treatment would not help them. In addition, patients in subtype (1) reported understanding their symptoms the least, followed by individuals of subtypes (3) and subtype (2). Furthermore, this subtype reports being most concerned and emotionally burdened by their pain condition, and subtype (2) reports being less concerned and emotionally burdened by their illness than subtype (3). Comparisons Between Pretreatment and Posttreatment More detailed evaluations of the individual subtypes show that pain interference and psychological distress were significantly reduced during treatment in all subtypes, and patients’ cognitive and behavioral coping skills improved significantly over all subtypes (Table 5). TABLE 5 Number of Patients, Mean, SD, Pre-Post Comparison, and Effect Size of Different Outcome Measures and FESV Dimensions of Patient Subtypes Mean (SD) N Pretreatment Posttreatment t d (1) Severely burdened individuals with low coping skills  Pain intensity BPI 115 6.1 (1.8) 5.9 (1.8) −1.3 −0.12  Pain interference BPI 115 7.0 (1.7) 5.8 (2.1) −7.5*** −0.70  Psychological distress HADS-D 115 13.1 (3.1) 11.7 (3.6) −6.0*** −0.55  Cognitive coping FESV 94 9.6 (2.4) 12.3 (3.6) 6.8*** 0.70  Behavioral coping FESV 94 8.6 (2.3) 10.6 (3.5) 5.8*** 0.60  Pain-related mental interference FESV 94 23.1 (2.9) 20.0 (4.8) −6.6*** −0.68 (2) Mildly burdened individuals with high coping skills  Pain intensity BPI 48 4.9 (1.6) 4.6 (2.0) −1.4 −0.21  Pain interference BPI 48 3.4 (1.4) 2.7 (1.5) −3.9*** −0.57  Psychological distress HADS-D 48 8.3 (2.5) 7.3 (3.0) −3.5*** −0.50  Cognitive coping FESV 47 19.4 (2.7) 20.4 (2.4) 2.3* 0.33  Behavioral coping FESV 47 15.4 (3.7) 16.6 (3.6) 2.2* 0.33  Pain-related mental interference FESV 47 8.6 (1.9) 8.1 (3.0) −1.2 −0.18 (3) Moderately burdened individuals with moderate coping skills  Pain intensity BPI 324 5.2 (1.6) 5.0 (1.9) −3.3** −0.18  Pain interference BPI 324 5.7 (1.7) 4.3 (1.9) −14.3*** −0.79  Psychological distress HADS-D 324 10.9 (2.8 9.3 (3.3 −11.2*** −0.62  Cognitive coping FESV 284 14.6 (2.8) 16.6 (3.5) 8.7*** 0.52  Behavioral coping FESV 283 12.3 (3.1) 14.0 (3.4) 8.99*** 0.53  Pain-related mental interference FESV 283 17.9 (3.9) 15.0 (5.1) −10.9*** −0.65 BPI indicates Brief Pain Inventory—German version; d, Cohen d; FESV, pain processing questionnaire; HADS-D, Hospital Anxiety and Depression Scale—German version. * P<0.05. ** P<0.01. *** P<0.001. Subtype (1) ie., being severely burdened with low coping skills, did not show significant reductions in pain intensity. Moreover, mildly burdened individuals with high coping skills (subtype 2) did not report significant reductions in pain intensity and pain-related mental interference after treatment. According to the IMMPACT criteria, a reduction in pain intensity of >30% can be regarded as an at least moderate clinically relevant decrease during treatment, which is found in 15.8% of this sample’s patients. However, 57.5% of all patients reported a clinically significant reduction in pain interference across treatment, measured by a 1-unit decrease on the Numerical Rating Scale.23 Overall, only 4.9% of patients indicated meaningful improvements regarding psychological distress from pretreatment to posttreatment according to the reliable change index of at least a difference of 5.96 for the subscale of anxiety and 5.25 for the subscale of depression. Exploratory Regression Analyses Exploratory regression analyses using a stepwise elimination strategy were conducted to determine which FESV dimensions were associated with treatment outcomes in reducing pain intensity, pain interference, and psychological distress. Regression analyses were performed for these treatment outcomes that changed significantly during treatment for each subtype. FESV dimensions that changed significantly in each subtype were included as predictors. Bonferroni correction was applied due to multiple comparisons. Change scores were computed separately for all FESV dimensions, pain intensity, and pain interference. Tables 6–8 summarize the exploratory regression analyses regarding the prediction of different treatment outcomes posttreatment by change scores of the separate FESV dimensions with Bonferroni correction. TABLE 6 Exploratory Regression Analysis With Stepwise Elimination for Treatment Outcomes Posttreatment for Subtype 1 With Bonferroni Correction Subtype 1 B SE β t R2 Adjusted R2 R2ch Pain interference posttreatment  Step 1: Control variable 0.26 0.25  Step 2: FESV dimensions 0.53 0.51 0.26***   Control variable    Pain interference pretreatment 0.58 0.09 0.46 6.17***   FESV dimensions    Change in relaxation techniques −0.10 0.03 −0.25 −3.08**    Change in pain-related helplessness and depression 0.10 0.03 0.27 3.44***    Change in counteractive activities −0.09 0.03 −0.22 −2.88** Psychological distress posttreatment  Step 1: Control variable 0.46 0.46  Step 2: FESV dimensions 0.62 0.60 0.14***   Control variable    Psychological distress pretreatment 0.79 0.09 0.68 8.83***   FESV dimensions    Change in cognitive restructuring −0.16 0.05 −0.23 −3.09**    Change in relaxation techniques −0.16 0.05 −0.25 −3.29** B indicates unstandardized beta; β, standardized beta; FESV, pain processing questionnaire. ** P<0.01. *** P<0.001. TABLE 7 Exploratory Regression Analysis With Stepwise Elimination for Therapy Outcomes Posttreatment for Subtype 2 With Bonferroni Correction Subtype 2 B SE β t R2 Adjusted R2 R2ch Pain interference posttreatment  Step 1: Control variable 0.27 0.26   Control variable    Pain interference pretreatment 0.54 0.13 0.52 4.05*** Psychological distress posttreatment  Step 1: Control variable 0.48 0.47   Control variable    Psychological distress pretreatment 0.82 0.13 0.69 6.37*** B indicates unstandardized beta; β, standardized beta; FESV, pain processing questionnaire. *** P<0.001. TABLE 8 Exploratory Regression Analysis With Stepwise Elimination for Therapy Outcomes Posttreatment for Subtype 3 With Bonferroni Correction Subtype 3 B SE β t R2 Adjusted R2 R2ch Pain intensity posttreatment  Step 1: Control variable 0.40 0.40  Step 2: FESV dimensions 0.43 0.42 0.02***   Control variable    Pain intensity pretreatment 0.74 0.06 0.63 13.46***   FESV dimensions    Change in pain-related anxiety 0.07 0.02 0.18 3.85*** Pain interference posttreatment  Step 1: Control variable 0.25 0.25  Step 2: FESV dimensions 0.48 0.47 0.22***   Control variable    Pain interference pretreatment 0.57 0.06 0.50 9.57***   FESV dimensions    Change in competence experience −0.12 0.02 −0.27 −5.72***    Change in pain-related anxiety 0.08 0.02 0.19 3.74***    Change in pain-related anger 0.06 0.02 0.18 3.54*** Psychological distress posttreatment  Step 1: Control variable 0.37 0.37  Step 2: FESV dimensions 0.51 0.50 0.13***   Control variable    Psychological distress pretreatment 0.74 0.06 0.61 12.70***   FESV dimensions    Change in competence experience −1.53 0.04 −0.19 −4.08***    Change in pain-related anxiety 0.12 0.04 0.18 3.55***    Change in pain-related helplessness and depression 0.67 0.30 0.12 2.32* B indicates unstandardized beta; β, standardized beta; FESV, pain processing questionnaire. * P<0.05. *** P<0.001. As individuals in subtype (1) significantly improved in pain interference, and psychological distress, as well as in cognitive coping skills, behavioral coping skills, and pain-related mental interference, exploratory regressions were calculated to predict these outcome measures posttreatment by the mentioned FESV dimensions. Due to multiple comparisons of these 9 FESV dimensions, Bonferroni correction was applied. The adjusted P-value <0.006 marked statistical significance. In the first step, the prediction of posttreatment pain interference [F (1, 90)=31.03, P<0.001] and psychological distress [F (1, 90)=77.93, P<0.001] was significant, including pretreatment scores of these measures as predictors. In the second step, the various cognitive and behavioral coping and pain-related mental interference dimensions of the FESV questionnaire were added. This second analysis reached significance for predicting posttreatment scores of pain interference [F (4, 91)=24.74, P<0.001] and of psychological distress [F (3, 91)=47.27, P<0.001]. The added dimensions uniquely accounted for 26% of the variance in mean pain interference and 14% in mean psychological distress. Findings suggested that improvements in relaxation techniques and counteractive activities predicted lower levels of both, pain interference and psychological distress posttreatment. In addition, increased levels of pain-related helplessness and depression predicted higher levels of pain interference posttreatment. Similarly, as individuals from subtype (2) showed significant reductions in pain interference and psychological distress, as well as significant improvements in cognitive and behavioral coping skills, exploratory regressions were calculated to predict these outcome measures posttreatment by the mentioned FESV dimensions. Due to multiple comparisons of these 6 FESV dimensions, Bonferroni correction was applied, and the adjusted P-value <0.008 marked statistical significance. In the first step, the prediction of posttreatment pain interference [F (1, 45)=16.39, P<0.001] and psychological distress [F (1, 45)=40.52, P<0.001] was significant, including pretreatment levels of the outcome variables. The second step, including the 6 dimensions of the FESV coping skills, did not reach significance and, therefore, did not suggest that any dimension of the FESV coping skills predicted pain interference or psychological distress levels posttreatment in this subtype (2). Individuals from subtype (3) showed significant improvements in pain intensity, pain interference, and psychological distress, as well as improvements regarding cognitive coping, behavioral coping, and pain-related mental interference. Therefore, exploratory regression analyses were calculated for all outcome measures using all 9 dimensions of the FESV questionnaire as potential predictor variables. The adjusted P-value <0.006 marked statistical significance due to multiple comparisons of the FESV dimensions. The first analysis reached significance for the prediction of pain intensity [F (1, 276)=181.28, P<0.001], pain interference [F (1, 276)=91.66, P<0.001], and psychological distress [F (1, 276)=161.24, P<0.001] levels posttreatment, including outcome variable levels pretreatment as control variables. In the second analysis, the separate cognitive and behavioral coping dimensions and the pain-related mental interference dimensions of the FESV questionnaire were added. This second analysis reached significance for predicting pain intensity [F (2, 276)=102.60, P<0.001], pain interference [F (4, 276)=62.27, P<0.001] and psychological distress [F (4, 276)=71.09, P<0.001] levels posttreatment. The added dimensions uniquely accounted for 2% of the variance in mean pain intensity, 22% in mean pain interference, and 13% in mean psychological distress. In this subtype, increased levels of pain-related anxiety seemed to predict higher levels of pain intensity and psychological distress posttreatment. Furthermore, higher levels of pain-related anger predicted higher pain interference levels posttreatment, and higher levels of pain-related helplessness and depression predicted higher psychological distress levels posttreatment. Improvements in the competence experience dimension predicted reduced pain interference and psychological distress posttreatment. DISCUSSION In the present replication study, we aimed to identify and describe subtypes of inpatients with chronic primary pain by latent class analysis of patient ratings of pain processing characteristics. We based our work on the findings of Grolimund and colleagues but critically extended their study by analyzing a new and larger sample, using a more advanced clustering method (latent class analysis), investigating a wider range of outcomes, and exploring the relative outcome prediction by the different coping skills. Exploratory regressions were calculated to determine the change of which FESV dimensions might be particularly predictive of treatment outcome in each subtype, potentially generating suggestions for differential indications based on the assessed subtype. We identified 3 distinct subtypes of inpatients with chronic primary pain: (1) severely burdened individuals with low coping skills, (2) mildly burdened individuals with high coping skills, and (3) moderately burdened individuals with moderate coping skills. Despite using a different statistical method (2-step cluster analysis) for analyzing data of a smaller sample (N=166 inpatients), the 3 subtypes identified by Grolimund and colleagues are very similar to the subtypes identified in the current study. The subtypes also correspond well with the 3 subtypes found by Wenzel and colleagues, as well as with 3 of the 4 subtypes identified earlier by Roditi and colleagues. In line with Grolimund and colleagues, the subtypes differed significantly in measures of other constructs. In addition, values in these measures corresponded meaningfully to the characterization of each subtype regarding pain coping and pain-related interference. By this, the relevance of the FESV questionnaire and the identified subtypes go beyond pain processing alone so that the FESV might be used for screening and preparing an individualized treatment planning. Posttreatment, all subtypes showed significant reductions in pain interference and psychological distress, as well as improvements in cognitive and behavioral coping skills. However, pain intensity significantly changed only in subtype (3) ie, individuals with moderate interference and moderate coping skills. Furthermore, pain-related mental interference did not improve significantly among individuals in subtype (2) ie, patients with mild interference and high coping skills. Thus, the large majority of outcome measures improved significantly in each subtype of patients after treatment, which generally supports the general suitability of an interdisciplinary multimodal inpatient treatment of chronic primary pain.6 Whether the differences in pain intensity and psychological distress are clinically meaningful is debatable since only 15.8% of inpatients reported an at least 30% difference in pain intensity, and only 4.9% of inpatients reported improvements according to the reliable change index. In the following, we discuss the findings of this study with regard to each subtype. Individuals in subtype (1) report being highly burdened by their pain and report low cognitive and behavioral coping skills. Individuals in this subtype experienced more intense pain than the other 2 types and experienced the most pain interference. Moreover, patients of this subtype reported the strongest psychological distress, suffering, and perceived stress, the lowest well-being, as well as receiving the least social support. Comparisons of illness perception revealed that individuals of the first subtype felt more strongly than the other 2 subtypes that their illness burdened their life and experienced stronger symptoms attributed to their illness. Similarly, these individuals felt most strongly of all subtypes that their illness would last for a long time. Moreover, patients of this subtype perceived the least control or influence over their symptoms and believed most strongly of all subtypes that the treatment would not help them. In addition, patients of this subtype seemed to understand their symptoms the least and reported being more concerned and emotionally burdened than the other 2 subtypes. Feeling insufficiently able to cope with their pain might explain why these individuals catastrophized their pain the most and had the least hope regarding treatment compared with the other 2 types. As pain interference is reported as being very high and coping skills as very low, particularly individuals of this subtype could be expected to benefit from the inpatient treatment. In accordance with these expectations, pain interference, psychological distress, as well as pain-related mental interference were reduced, and cognitive and behavioral coping skills improved significantly. However, the reduction of pain intensity after treatment was not significant. Given that patients with chronic primary pain had suffered from pain and associated interferences for several years, the 3-week duration of this inpatient treatment could have been simply too short to reduce pain intensity in this subtype of highly burdened patients. Moreover, large reductions in pain intensity are not expected after an interdisciplinary multimodal pain treatment, as it has been shown to be very challenging to alleviate pain intensity among patients with chronic primary pain.6,31,32 Thus, interdisciplinary multimodal pain treatment usually focuses more on improving physical and psychological functioning despite the pain so that reducing pain interference and psychological distress can be considered more adequate outcomes in short-term pain treatment.6,31,32 Exploratory regression analyses predicting reduced pain interference and psychological distress revealed that the most promising targets to address in the treatment of individuals of subtype (1) might be relaxation techniques, counteractive activities, and engaging in cognitive restructuring, which are already known effective strategies in the treatment of patients with chronic pain.33,34 Therefore, incorporating these strategies into the treatment plan for patients of subtype may improve treatment outcomes and could be a valuable area for further investigation. Moreover, as individuals of this subtype were highly burdened, it is important to explicitly address pain-related helplessness and depression in treatment. These targets can be integrated into pain-related psychotherapy, allowing patients of this subtype to learn and practice specific new skills to cope with pain and pain-related mental interference,4,6 as also Grolimund and colleagues recommended. Only 10% of all patients were assigned to subtype (2), representing patients being only mildly burdened by their pain and having high cognitive and behavioral coping skills. Moreover, individuals of this subtype reported receiving the most social support compared with the other 2 subtypes. Patients in subtype (2) reported a lower pain intensity than individuals of subtype (1), experienced the least pain interference of all patient groups, reported being the least burdened by psychological distress, stress, and suffering, and experienced the lowest level of illness-related symptoms. In addition, patients of subtype (2) assumed less strongly than patients of subtype (1) that their pain burdened their life and that it would last as long as patients of subtype (1) believed. Furthermore, patients of subtype (2) thought that the treatment would help them, were generally hopeful, reported the most control and/or influence over their symptoms, seemed to understand their symptoms the most, and were less concerned and emotionally burdened by their illness than the other 2 subtypes. Being only mildly burdened by pain at intake might partially explain why individuals of this subtype did not show significant decreases in pain intensity and pain-related mental interference after treatment. Whereas individuals of this subtype showed significant reductions in pain interference and psychological distress as well as improvements in cognitive and behavioral coping skills after treatment, the according effect sizes were not as big as in other subtypes. Given the generally lower values at intake, there might have been limited room for decreases in the sense of a bottom effect. As individuals of subtype (2) obviously were not able to benefit as much from inpatient treatment as individuals of other subtypes, it is also of no surprise that none of the changes in FESV dimensions predicted posttreatment outcome variables. Also, because this subtype contains very few patients, these results should be interpreted cautiously. Generally, individuals of this subtype might benefit most from supportive and resource-oriented interventions, optimizing their reportedly already efficient coping skills.9 Subtype (3) includes moderately burdened individuals with moderate coping skills. In almost all measures examined, this subtype fell between the severely and the mildly burdened individuals. Even though these individuals reported having some coping skills, they still suffered from pain, which might indicate the presence of some dysfunctional coping patterns. After treatment, patients reported significant reductions in pain intensity, pain interference, psychological distress, and pain-related mental interference. Furthermore, they were able to improve their cognitive and behavioral coping skills. Regression analyses revealed that in this subtype, especially reductions in pain-related anxiety, anger, helplessness, and depression were related to reductions in pain intensity, pain interference, and psychological distress. These results are rather unsurprising since these constructs largely overlap. Nonetheless, these patient experiences might qualify as indicators of symptom improvement during treatment or even as treatment targets themselves. Also, experiences of competence might be particularly relevant for patients of this subtype since improvements in this cognitive coping skill predicted reductions in pain interference and psychological distress posttreatment. A similar concept is self-efficacy, which has also been studied in relation to chronic pain. Improvements in self-efficacy (ie, perceived ability to successfully cope with chronic pain) have been found to be associated with reduced interference among patients with chronic pain independently of changes in pain intensity.35 Thus, it seems particularly worthwhile to elicit from these individuals exactly which strategies they use, to identify effective and ineffective coping strategies, and to foster and optimize effective skills.4,6 At the same time, it could be beneficial for individuals of this subtype to learn and build new coping skills via pain management training to experience more competence and self-efficacy regarding pain coping. Limitations It must be taken into account that the analyzed sample might not be representative of all inpatients with chronic pain, since our sample included only inpatients with chronic primary pain, consent was required for inclusion, and the studied patients were all from the same clinic in one country. Moreover, it was the same clinic where Grolimund and colleagues had previously conducted their study. Therefore, the identified subtypes might be specific for the investigated samples. Relatedly, the values on the scales used for classification generated from these 2 samples cannot be used for defining general cutoffs for example, severely, moderately, and mildly burdened individuals. Future research in more diverse samples is needed for such generalizations. Similarly, different coping questionnaires should also be used to replicate similar patterns among patients with chronic primary pain, as the FESV questionnaire is mainly used in German-speaking parts of the world. Although this sample is already quite large and provides robust statistics, even larger samples would allow for a more detailed analysis of subtypes, as well as changes within the subtypes and in subtype membership. For example, pain processing patterns of an individual patient might change over time depending on the pain symptomatology or other factors. Furthermore, due to the naturalistic design of this study, it is not possible to attribute identified changes to specific interventions. Vice versa, specific interventions may have had differential effects on pain coping, psychological distress, or pain outcomes. Overall, future studies should implement longitudinal designs to observe the time course of pain processing patterns and inform on the sustainability of treatment effects. Future studies should also use controlled and experimental designs to allow for drawing causal conclusions for the treatment of patients with chronic primary pain. Moreover, future research should consider other clinically meaningful changes in treatment-related outcome measures in more detail to better understand the clinical utility of these subtypes. CONCLUSIONS We identified 3 subtypes of chronic primary pain inpatients according to their pain-related mental interference and coping patterns. Thereby we replicated Grolimund and colleagues’ findings. The 3 subtypes are based on values assessed with the FESV but have been shown to be significantly related to differences in various other self-report measures. This suggests that the relevance of FESV measurements might go beyond pain processing. Identification and characterizing subtypes of chronic primary pain inpatients seems to be a critical step towards individualized and effective treatment. The authors declare no conflict of interest. ==== Refs REFERENCES 1 Mills SEE Nicolson KP Smith BH . Chronic pain: a review of its epidemiology and associated factors in population-based studies. 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==== Front Clin J Pain Clin J Pain AJP The Clinical Journal of Pain 0749-8047 1536-5409 Lippincott Williams & Wilkins Hagerstown, MD 37166199 CJP-D-22-00560 10.1097/AJP.0000000000001129 00003 3 Original Articles An Analysis of How Herpes Zoster Pain Affects Health-related Quality of Life of Placebo Patients From 3 Randomized Phase III Studies http://orcid.org/0000-0001-7427-7326 Matthews Sean MSc sean.f.matthews@gsk.com * Curran Desmond PhD †desmond.x.curran@gsk.com Sabater Cabrera Eliazar MSc †ELIAZAR.X.SABATERCABRERA@GSK.COM Boutry Céline PhD †celine.x.boutry@gsk.com Lecrenier Nicolas PhD †nicolas.lecrenier@gsk.com Cunningham Anthony L. MD ‡tony.cunningham@sydney.edu.au Schmader Kenneth MD §kenneth.schmader@duke.edu * Freelance c/o GSK, Wavre, Belgium † GSK, Wavre, Belgium ‡ The Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia § Duke University Medical Center and Durham VA Health Care System, Durham, NC Reprints: Sean Matthews, MSc, Avenue Fleming 20, 1300 Wavre, Belgium (e-mail: sean.f.matthews@gsk.com). 8 2023 11 5 2023 39 8 386393 8 12 2022 18 4 2023 27 4 2023 Copyright © 2023 GSK. Published by Wolters Kluwer Health, Inc. 2023 https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Objectives: Herpes zoster (HZ) is a painful condition caused by the reactivation of the varicella-zoster virus, negatively affecting the lives of patients. In this post hoc analysis, we describe the impact of HZ pain on the health-related quality of life (HRQoL) and activities of daily living (ADL) of immunocompetent individuals 50 years of age and older and in hematopoietic stem cell transplantation (HSCT) recipients age 18 years of age and older. Materials and Methods: ZOE-50 (NCT01165177), ZOE-70 (NCT01165229), and ZOE-HSCT (NCT01610414) were phase III, randomized studies conducted in immunocompetent adults 50 years of age and older and 70 years of age and older and in HSCT recipients age 18 years of age and older, respectively. This analysis was performed on patients who experienced an HZ episode in the placebo groups. The impact of varying levels of HZ pain on HRQoL and ADL was analyzed using data from the Zoster Brief Pain Inventory (ZBPI) and the Short Form Health Survey 36 (SF-36) and EQ-5D questionnaires. Results: A total of 520 immunocompetent and 172 HSCT individuals with HZ were included. SF-36 and EQ-5D domain scores showed a significant relationship between increased HZ pain and worsening HRQoL. For every increase of 1 in the ZBPI pain score, the estimated mean decrease (worsening) in score in the ZOE-50/70 and ZOE-HSCT, respectively, was 2.0 and 2.4 for SF-36 Role Physical; 2.1 and 1.8 for SF-36 Social Functioning; and 0.041 and 0.045 for EQ-5D utility. Sleep and General activities were the ADL components most affected. Discussion: Moderate and severe HZ pain had a substantial negative impact on all aspects of HRQoL and ADL. This impact was independent of age and immunosuppression. Key Words: HZ pain quality of life patient-reported outcomes SF-36 EQ-5D SDCT OPEN-ACCESSTRUE ==== Body pmcHerpes zoster (HZ) or shingles generally presents as a skin rash caused by reactivation of the varicella-zoster virus that blisters and scabs over a period of 7 to 10 days. The vast majority of people who get shingles will experience pain that typically lasts for 2 to 4 weeks; however, pain can persist beyond the acute phase (≤30 d post rash-onset) and subacute phase (30 to 90 d post rash-onset). Up to 30% of HZ patients develop postherpetic neuralgia (PHN, defined as pain persisting or appearing beyond 90 d post rash-onset), a chronic condition of debilitating pain that may last for months or even years and is very difficult to treat.1,2 One in 3 people in the United States will develop shingles in their lifetime, resulting in an estimated 1 million new cases annually.3 A few qualitative studies4,5 have described the patient experience of having HZ and PHN and the impact on health-related quality of life (HRQoL) at an individual level. Participants who developed HZ used words such as burning, sharp/shooting, sensitive to touch, and extreme/intense to describe their pain. These studies demonstrated that HZ has an impact on physical, emotional, social, and cognitive functioning, as well as sleep, hobbies, and work. Most publications of quantitative research describe HZ pain, but fewer publications describe how this pain impacts HRQoL. Schmader and colleagues detailed how increasing HZ pain and discomfort in older adults adversely affect a wide range of activities of daily living (ADL) as measured by the Zoster Brief Pain Inventory (ZBPI),6,7 whereas another study8 demonstrated that SF-36 Social Functioning and functional domains, Role Physical and Role Emotional, are substantially affected by HZ pain by comparing the scores to the normative values during the acute phase of the HZ episode. Pickering et al9 carried out an extensive literature review in which they confirmed that acute HZ pain and PHN generate a significant impairment of HRQoL in the general population and more specifically in older persons, but also highlighted the scarcity of large-scale surveys such as analysis from clinical trials. In this post hoc analysis, we describe the impact of HZ pain on HRQoL and ADL of both immunocompetent and immunocompromised participants during the acute phase using patient-reported outcomes (PROs) (see Graphical Abstract, Supplemental Digital Content, http://links.lww.com/CJP/B3). MATERIALS AND METHODS Study Design The analysis is based on data from 3-multinational phase III randomized trials in which the primary endpoint assessed the vaccine efficacy of the recombinant zoster vaccine (RZV, Shingrix; GSK). The trials were conducted using similar methods in 2 adult populations: (1) the ZOE-50 study (NCT01165177), which included patients 50 years of age and older, and the ZOE-70 study (NCT01165229), which included patients 70 years of age and older; and (2) the ZOE-HSCT study (NCT01610414), which included an immunocompromised population of autologous hematopoietic stem cell transplantation (HSCT) recipients.10–12 Analysis of the characteristics of the HZ pain and the vaccine efficacy in reducing pain and the burden of illness are presented elsewhere.13,14 Our analysis includes only placebo recipients from the above clinical trials. The characteristics of the HZ episode in the same cohort of placebo participants are presented elsewhere.15 Outcome Measures Patients with a suspected HZ episode were asked to complete the ZBPI daily for a minimum of 28 days after rash onset and then weekly until either the patient had been pain-free for 4 consecutive weeks or 90 days had elapsed after rash onset and for a maximum of 182 days. The ZBPI asks the participant to rate 4 categories of pain (least, worst, and average “in the last 24 hours,” and “right now”) on 11-point Likert-type scales (0 to 10, with 10 signifying the worst imaginable pain). The ZBPI questionnaire also assesses the degree to which the HZ pain interferes with 7 ADLs: general activity, mood, walking ability, work, relation with others, sleep, and enjoyment of life. These are all rated on 11-point Likert-type scales with 0 signifying ‘does not interfere’ and 10 ‘completely interferes’. A summary ADL score is calculated by averaging the scores for the 7 activities.13,14 HRQoL was assessed using 2 standard questionnaires, the Short Form Survey (SF-36)16 and the EuroQoL EQ-5D.17 Details of the SF-36 and EQ-5D can be found elsewhere but briefly, the SF-36 contains 36 questions from which 8 domain scores are calculated: Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), Social Functioning (SF), Vitality (VT), General Health (GH), Role Emotional (RE) and Mental Health (MH). Each domain is scored on a 0 to 100 scale in which a higher score indicates a higher level of functioning/quality of life (QoL). A brief explanation of each domain score can be found in the Supplementary Text (Supplemental Digital Content, http://links.lww.com/CJP/A964). The EQ-5D-3L questionnaire is a generic measure of health status that defines health in terms of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. From these 5 categories, a single index or utility value is obtained. The United Kingdom time trade-off 18 was used to map the 5 responses to the corresponding utility value. The utility score ranges from −0.54 to 1, a higher score indicating a higher level of functioning/QoL. A Visual Analog Scale (VAS) was also included as part of the EQ-5D in which a value in the range from 0 (worst imaginable health) to 100 (best imaginable health) is obtained. Both SF-36 and EQ-5D questionnaires were completed by all enrolled patients before the first vaccination and then at months 14, 26, and 38 in the ZOE-50 and 70 trials and at months 2 and 13 in the ZOE-HSCT trial. The latest SF-36 and EQ-5D questionnaires completed before the onset of the HZ episode served as the baseline values in our analysis. During the HZ episode, the SF-36 and EQ-5D questionnaires were to be completed at the onset (day 0) and then on a weekly basis until the resolution of the episode. To analyze the effect of HZ pain on HRQoL, we paired the ZBPI and SF-36/EQ-5D when both were completed on the same day. SF-36 and EQ-5D questionnaires that were not completed on the same day as the ZBPI were excluded from our analysis. Although the completion of questionnaires continued until the resolution of the HZ episode, we restricted our analysis to the time period between the day of onset of the episode and day 35. Data from the ZOE-50 and ZOE-70 studies were combined for our analysis, whereas the ZOE-HSCT study was analyzed separately. This is justified as the ZOE-50 and ZOE-70 phase III randomized, placebo-controlled clinical trials were conducted concurrently at the same study sites using the same methods with patients 70 years of age and older randomly assigned to the ZOE-50 or ZOE-70 study. Summary descriptive statistics of the domain scores and change from baseline in the SF-36 and EQ-5D domains were calculated by week (0, 1, 2, 3, 4, 5) and ZBPI Worst Pain Category (None [ZBPI Worst Pain Score=0], Mild [Score=1, 2, 3], Moderate [Score=4, 5, 6, 7] and Severe [Score=8, 9, 10]). This categorization of ZBPI worst pain follows exactly that used in the study by Schmader et al.6 We analyzed the change from the baseline of each SF-36/EQ-5D domain score over time using a repeated measures mixed effects model, adjusting for age and sex. Both the intercept and slope (ie, day of assessment) were allowed to vary per patient. The corresponding ZBPI worst pain score was included as a covariate. We derived the area under the curve (AUC) during the acute phase (first 30 d) of the HZ episode of each SF-36 and EQ-5D domain (adjusted for baseline value) and ZBPI worst pain score using a trapezoidal approximation of the observed scores.19 The Spearman correlation coefficient between each domain score AUC and the ZBPI worst pain AUC was estimated. RESULTS In the ZOE-50, ZOE-70, and ZOE-HSCT studies, 280, 240, and 172 HZ cases occurred among the patients receiving placebo, respectively. The patient demographics by study group are presented in Table 1 (Supplemental Digital Content, http://links.lww.com/CJP/A965). The baseline (pre-HZ episode) SF-36 and EQ-5D domain scores are presented in Table 2 (Supplemental Digital Content, http://links.lww.com/CJP/A966) for ZOE-50/70 combined and ZOE-HSCT separately. The baseline mean scores were consistently lower across all domains for patients in the HSCT study compared with the ZOE-50/70 combined, notably for Role Physical (mean: 78.3 vs. 64.2) and Social Functioning (mean: 87.6 vs. 79.9). Adherence to completion of questionnaires during the HZ episode was high (Table 3, Supplemental Digital Content, http://links.lww.com/CJP/A967). In the first 35 days of the HZ episode, 1257 SF-36 and ZBPI questionnaires were jointly completed on the same day by 277 (98.9%) patients in the ZOE-50, 1058 questionnaires by 237 patients (98.8%) in the ZOE-70 and 668 questionnaires by 163 (94.8%) patients in the ZOE-HSCT. Figures 1 and 2 and Tables 4 (http://links.lww.com/CJP/A968) and 5 (http://links.lww.com/CJP/A969) of Supplemental Digital Content present the mean change from baseline for all SF-36 domain and EQ-5D utility and VAS scores across all timepoints categorized by ZBPI Worst Pain category for both the ZOE-50/70 and ZOE-HSCT. In the ZOE-50/70 analysis, in general, large changes from baseline (ie, worsening) were observed across all SF-36 and EQ-5D domains and across all timepoints for patients experiencing moderate and severe HZ pain. For example, on day 7, patients with severe pain reported a mean decrease of 32.7 in Role Physical score, a mean decrease of 19.5 in Mental health score, and a mean reduction of 0.4002 in EQ-5D utility score. FIGURE 1 SF-36 Domain Scores by corresponding ZBPI Worst Pain Category at day 0 and day 14 of HZ episode. ZOE-50/70 and ZOE-HSCT. ZOE-50/70=Placebo participants from the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) studies who had an HZ episode. ZOE-HSCT=Placebo participants from the ZOE-HSCT study (NCT01610414) who had an HZ episode. SF-36=Short Form Survey 36, ZBPI=Zoster Brief Pain Inventory. Pain categories: No Pain=ZBPI Worst pain score=0; Mild Pain=ZBPI pain score=1, 2, 3; Moderate Pain=ZBPI pain score=4, 5, 6, 7; Severe Pain=ZBPI pain score=8, 9, 10. N=Number of participants with a baseline (pre-HZ episode) SF-36 questionnaire and an SF-36 and ZBPI questionnaire at the relevant time point during the HZ episode. HSCT indicates hematopoietic stem cell transplantation; HZ, herpes zoster. FIGURE 2 Change from baseline in EQ-5D Utility Score during HZ episode by corresponding ZBPI Worst Pain Category and time point. ZOE-50/70 ZOE-HSCT. ZOE-50/70=Placebo participants from the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) studies who had an HZ episode. ZOE-HSCT=Placebo participants from the ZOE-HSCT study (NCT01610414) who had an HZ episode. EQ-5D=EuroQoL EQ-5D. Pain categories: None=ZBPI Worst pain score=0; Mild Pain=ZBPI pain score=1, 2, 3; Moderate Pain=ZBPI pain score=4, 5, 6, 7; Severe Pain=ZBPI pain score=8, 9, 10. N=Number of participants with a baseline (pre-HZ episode) EQ-5D utility assessment and both an EQ-5D utility and ZBPI worst pain score assessed at the relevant time point during the HZ episode. HSCT indicates hematopoietic stem cell transplantation; HZ, herpes zoster; ZBPI, Zoster Brief Pain Inventory. Similar reductions were also observed late in the acute phase. On day 28, 83 patients were still reporting moderate or severe worst pain with a corresponding mean worsening in Role Physical of 25.5 for patients with moderate pain and 29.3 for those with severe pain. Similarly, a mean worsening in Mental Health score of 23.6 was observed for the 26 patients with severe pain on day 28. Worsening of scores was also observed in patients with mild ZBPI pain, but negligible changes were observed across all timepoints and SF-36/EQ-5D domains for patients reporting no ZBPI pain. Similar results were observed in the ZOE-HSCT patients regarding the Bodily Pain, Role Physical, and EQ-5D utility domains, but less effect on Mental Health and Role Emotional domains was observed compared with the ZOE-50/70. Only 7 patients had reported severe pain by day 28. The 28 patients with moderate pain had a mean decrease in Role Physical of 22.5 and mean decrease in Social Functioning of 26.8. Table 1 presents the estimates of the coefficient of the ZBPI worst pain score from the repeated measures mixed model. The estimate of −3.6 for Bodily Pain (ZOE-50/70) indicates that, for every 1-point increase in the ZBPI worst pain score, the corresponding mean decrease (worsening) in SF-36 Bodily Pain from the baseline score (pre-HZ episode) was 3.6. TABLE 1 Estimates of the Mean Reduction in SF-36/EQ-5D Domain Scores for Every Increase of 1 Point in the ZBPI Worst Pain Score Estimate SE t value P ZOE-50/70  SF-36   PF −1.50 0.141 −10.65 <0.0001   RP −2.00 0.197 −10.18 <0.0001   BP −3.63 0.181 −20.11 <0.0001   GH −0.84 0.113 −7.44 <0.0001   VT −1.64 0.155 −10.58 <0.0001   SF −2.07 0.186 −11.13 <0.0001   RE −1.36 0.198 −6.87 <0.0001   MH −1.52 0.134 −11.37 <0.0001  EQ-5D   Utility −0.041 0.002 −20.87 <0.0001   VAS −1.94 0.136 −14.30 <0.0001 ZOE-HSCT  SF-36   PF −1.57 0.307 −5.11 <0.0001   RP −2.35 0.387 −6.06 <0.0001   BP −3.78 0.367 −10.30 <0.0001   GH −0.60 0.203 −2.93 0.036   VT −1.56 0.298 −5.24 <0.0001   SF −1.84 0.376 −4.89 <0.0001   RE −1.02 0.361 −2.84 0.0048   MH −0.97 0.254 −3.81 0.0002  EQ-5D   Utility −0.044 0.0040 −11.12 <0.0001   VAS −2.31 0.271 −8.55 <0.0001 ZOE-50/70 combines participants from the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) studies. ZOE-HSCT=participants from the ZOE-HSCT study (NCT01610414). Estimates, SE, t values, and P-values obtained from the repeated measures, mixed effects model, adjusting for age and sex with random intercept and slope (ie, day of assessment) and ZBPI worst pain score included as a covariate. SF-36 domains and EQ-5D VAS are scored on a 0 to 100 scale, the range of the EQ-5D utility is (−0.5, 1). A higher score indicates a higher level of functioning/quality of life. BP indicates Bodily Pain; EQ-5D, EuroQoL EQ-5D; GH, General Health; HSCT, hematopoietic stem cell transplantation; MH, Mental Health; PF, Physical Functioning; RE, Role Emotional; RP, Role Physical; SF, Social Functioning; SF-36, Short Form Health Survey 36; Utility, Utility Score; VAS, Visual Analog Scale; VT, Vitality; ZBPI, Zoster Brief Pain Inventory. All SF-36 and EQ-5D domain scores showed a significant relationship between increased HZ pain and worsening HRQoL (both ZOE-50/70 and ZOE-HSCT). The domain scores that showed the highest absolute impact from HZ pain were SF-36 Bodily Pain (3.6 in the ZOE-50/70, 3.8 in the ZOE-HSCT), Role Physical (2.0 and 2.4, respectively), Social Functioning (2.1 and 1.8, respectively) and EQ-5D utility (0.041 and 0.045, respectively). The domain score showing the smallest absolute impact was General Health (0.8 and 0.6, respectively). The domain scores associated with Mental Health and Role Emotional functioning were also impacted, with scores of 1.5 and 1.4, respectively, reported in the ZOE-50/70; a smaller absolute impact of 1.0 in both domains was observed in the ZOE-HSCT. Day of assessment was not a significant factor in each model apart from Bodily Pain, indicating that the effect of HZ pain on HRQoL was the same regardless of when in the acute phase the ZBPI pain was experienced. In the ZOE-50/70 studies, sex was only significant in the model of Role Emotional over time. By contrast, in the ZOE-HSCT study, sex was a significant factor in the decrease in Physical Functioning, General Health, Vitality, Role Emotional, and Mental Health, with females experiencing larger average reductions in HRQoL from baseline. Age was not a significant factor in any of the models apart from change in EQ-5D utility over time in the ZOE-50/70 analysis. The AUC analysis provided similar results to the repeated measures mixed model. Table 6 (Supplemental Digital Content, http://links.lww.com/CJP/A970) presents the AUC for each domain score adjusted for baseline categorized by the corresponding ZBPI Worst Pain AUC and Table 2 presents the corresponding correlation coefficients. The ZBPI AUC is highly correlated with all SF-36 and EQ-5D domain AUC values. TABLE 2 Spearman Correlation Coefficients Between ZBPI Worst Pain Score AUC and Each Corresponding SF-36 Domain and EQ-5D Utility Score AUC During First 30 Days of Herpes Zoster Episode Correlation coefficient/P/(N) Domain ZOE-50/70 ZOE-HSCT SF-36 PF −0.485/<0.0001/N=499 −0.425/<0.0001/N=152 RP −0.571/<0.0001/N=499 −0.491/<0.0001/N=151 BP −0.785/<0.0001/N=498 −0.757/<0.0001/N=152 GH −0.372/<0.0001/N=499 −0.319/<0.0001/N=152 VT −0.536/<0.0001/N=499 −0.428/<0.0001/N=151 SF −0.596/<0.0001/N=498 −0.421/<0.0001/N=152 MH −0.483/<0.0001/N=499 −0.357/<0.0001/N=151 RE −0.510/<0.0001/N=499 −0.374/<0.0001/N=151 EQ-5D Utility −0.701/<0.0001/N=498 −0.615/<0.0001/N=151 VAS −0.557/<0.0001/N=498 −0.486/<0.0001/N=151 ZOE-50/70=Placebo participants from the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) studies who had an herpes zoster episode. ZOE-HSCT=Placebo participants from the ZOE-HSCT study (NCT01610414) who had an herpes zoster episode. N=Number of participants with a nonmissing ZBPI AUC and domain AUC during the first 30 days of the herpes zoster episode. AUC indicates area under curve; BP, Bodily Pain; EQ-5D, EuroQoL EQ-5D; GH, General Health; HSCT, hematopoietic stem cell transplantation; MH, Mental Health; PF, Physical Functioning; RE, Role Emotional; RP, Role Physical; SF, Social Functioning; SF-36, Short Form Health Survey 36; Utility, Utility Score; VAS, Visual Analog Scale; VT, Vitality; ZBPI, Zoster Brief Pain Inventory. Effects of HZ Pain on ZBPI Components Figure 3 shows the mean ADL component scores at the onset of the HZ episode (day 0) categorized by ZBPI worst pain score for both the ZOE-50/70 and ZOE-HSCT studies. The correlation between increasing pain and the negative impact on ADL was clear across both analyses. The components most affected were Sleep and General Activities, but the negative impact was seen in all components. FIGURE 3 ZBPI ADL components at day 0 by Worst Pain Score. ZOE-50/70=Placebo participants from the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) studies who had an HZ episode. ZOE-HSCT=Placebo participants from the ZOE-HSCT study (NCT01610414) who had an HZ episode. ADL indicates activities of daily living; HSCT, hematopoietic stem cell transplantation; HZ, herpes zoster; N, number of participants by ZBPI worst pain score at day 0; ZBPI, Zoster Brief Pain Inventory. Table 3 presents the estimates of the coefficient of the ZBPI worst pain score from the repeated measures mixed model of the ADL components. The components with the highest coefficient were General Activities (0.57 in the ZOE-50/70, 0.76 in the ZOE-HSCT) and Sleep (0.57 in the ZOE-50/70, 0.68 in the ZOE-HSCT). It is worth noting that the estimates appear to be higher in the ZOE-HSCT, indicating that HZ pain appeared to have a larger impact on ADL in HSCT recipients. TABLE 3 Estimates of the Mean Increase (Worsening) in ZBPI ADL Individual Component and Total Score for Every Increase of 1 Point in ZBPI Worst Pain Score ZBPI ADL component Estimate SE t value P ZOE-50/70 General activities 0.57 0.0137 41.13 <0.0001 Mood 0.51 0.0137 37.22 <0.0001 Walking ability 0.27 0.0121 22.21 <0.0001 Normal work 0.47 0.0142 33.04 <0.0001 Relations with other people 0.33 0.0140 23.88 <0.0001 Sleep 0.57 0.0147 39.08 <0.0001 Enjoyment of life 0.49 0.0148 32.84 <0.0001 ADL Total 0.43 0.0098 44.11 <0.0001 ZOE-HSCT General activities 0.76 0.0215 35.46 <0.0001 Mood 0.65 0.0214 30.51 <0.0001 Walking ability 0.51 0.0225 22.84 <0.0001 Normal work 0.71 0.0237 29.78 <0.0001 Relations with other people 0.54 0.0235 22.99 <0.0001 Sleep 0.68 0.0227 29.93 <0.0001 Enjoyment of life 0.63 0.0241 26.16 <0.0001 ADL Total 0.64 0.0168 37.90 <0.0001 ZOE-50/70=Placebo participants from the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) studies who had an herpes zoster episode. ZOE-HSCT=Placebo participants from the ZOE-HSCT study (NCT01610414) who had an herpes zoster episode. The ZBPI Worst Pain score and ADL component and total scores all range from 0 to 10 with a higher score indicating increased pain/negative impact on quality of life. Estimates, SE, t values, and P-values obtained from the repeated measures, mixed effects model, adjusting for age and sex with random intercept and slope (ie, day of assessment) and ZBPI worst pain score included as a covariate. ADL indicates activities of daily living; HSCT, hematopoietic stem cell transplantation; ZBPI, Zoster Brief Pain Inventory. DISCUSSION In this study, we presented the PRO data from patients who experienced an HZ episode in the placebo groups of the ZOE-50, ZOE-70, and ZOE-HSCT studies. We have shown that increasing HZ pain is highly correlated with worsening HRQoL. A strength of our analysis is the large sample size and the quality of the data reflected in the high completion rate of questionnaires throughout the acute phase of the HZ episode. Another strength is the fact that each patient had a baseline PRO assessment before the HZ episode. This eliminates the need to compare domain scores during the HZ episode to population normative values. We were therefore able to run a repeated measures mixed model for the combined ZOE-50/70 analysis and ZOE-HSCT separately which gave robust estimates of the association between HZ pain and summary measures of HRQoL and ADL. We have previously shown in another study that for this same cohort of placebo patients that pain was experienced by 491 of 520 patients (94.4%) in the combined ZOE-50/70 studies and by 163 of 172 of patients (93%) in the ZOE-HSCT study.15 The median duration of clinically significant pain (ie, a ZBPI worst pain score of at least 3) was estimated to be 17 days in the ZOE-50 study, 22 days in the ZOE-70 study, and 30 days in the HSCT study. The impact of increasing HZ pain was observed across all SF-36 domains, but the Bodily Pain, Role Physical and Social Functioning domains showed the greatest impact in absolute terms of HZ pain in both the ZOE-50/70 and ZOE-HSCT. This is a similar finding to that observed in Lydick et al.8 The effect on the Bodily Pain domain may seem obvious at first, but it is nevertheless an important indication of the cross-validity of the ZBPI and SF-36. It is also relevant to highlight that SF-36 Bodily Pain covers both the magnitude of pain and also the interference of pain with normal work activities. The negative impact of increasing HZ pain on the EQ-5D utility score was also apparent. This is similar to the effects seen in patients with PHN in both Oster et al20 and Serpell et al.21 The impact of increasing HZ pain on participants’ ADL, as measured solely by the ZBPI, was also evident from our analysis. In particular, we observed a large negative effect on Sleep, Mood, General Activities, and ability to carry out normal work activities. We also observed that these negative effects were consistently higher for immunocompromised participants in the ZOE-HSCT analysis. The absolute impact on HRQoL as assessed by the SF-36 and EQ-5D questionnaires was similar across both ZOE-50/70 and ZOE-HSCT analyses but it is worth mentioning that patients in the ZOE-HSCT study had lower baseline values for all domain scores, suggesting a lower level of functioning/QoL. Thus the relative impact of the worsening of QoL may have been greater for the immunocompromised patients. We observed a minimal effect on HRQoL for patients who reported no HZ pain. We may have expected a negative impact on HRQoL or interference with ADL related to rash or itching, independent of pain. In the analysis by Schmader et al,6 such an association was described. It is important to mention, however, that in the ZOE-50/70 and ZOE-HSCT studies, patients with no pain were not required to complete the rest of the ZBPI questionnaire detailing ADL but were still nonetheless required to complete the SF-36 and EQ-5D. We also observed that the changes in domain scores were independent of time, that is, given a certain level of pain (moderate or severe pain), the impact on HRQoL was similar at the beginning and the end of the acute phase. It is well known that the majority of HRQoL domains decrease (worsen) with age but we observed that the mean reduction from baseline conditional on the level of HZ pain was independent of age. However, it should be mentioned that an absolute reduction in, for example, Physical Functioning of 20 points may have more of an impact (ie, greater relative reduction) in a frail older person with a lower normal/baseline value than the same absolute reduction in a healthier younger patient. To put our results into context, it is worthwhile examining minimally important differences (MID) in HRQoL measures across other conditions/disease areas. Several authors have suggested using Cohen d “medium” effect size (ie, half an SD) as a threshold for defining MIDs in HRQoL instruments.22–24 A threshold of 0.3 times the SD has also been proposed by others25 who commented that, although this method may be flawed, it does give us an indication of what may be considered an important change. Our observed changes are, for patients with moderate and severe HZ pain, almost always much greater than 0.5 times the SD across every SF-36 and EQ-5D domain at every time point. Spiegel et al26 proposed a MID of 4.2 points (range from 3 to 5) for the SF-36 Vitality domain in individuals with compensated hepatitis C virus, based on an expert panel assessment using a modified Delphi technique. The vitality domain was also the focus of an analysis performed on data across multiple conditions from a medical outcomes study.27 MID of 5 points was estimated in patients with anemia, and of 6 points in patients with either congestive heart failure or chronic obstructive pulmonary disorder. Based on these values, the vitality score was impacted overall by an important difference in patients with HZ, in particular on day 0 and day 7, and for most weeks when patients had even just mild HZ pain. HZ patients with moderate or severe pain reported values that were on average consistently much higher than MID values of 5 to 6 points (Tables 4, Supplemental Digital Content, http://links.lww.com/CJP/A968 and 5, Supplemental Digital Content, http://links.lww.com/CJP/A969). MIDs of 5.3 in Physical Functioning and 7.2 in the Bodily Pain domains were estimated for patients with worsening symptoms of osteoarthritis of the lower extremities.28 Mean MIDs of 9.3 for Social Functioning, 7.8 for Vitality, and 15.6 for Role Physical domains were observed in patients reporting an improvement in symptoms of rheumatoid arthritis.29 In a retrospective analysis of patients receiving chemotherapy for different types of cancers, MIDs for the EQ-5D UK utility scores ranging from 0.10 to 0.12 and VAS scores ranging from 8 to 12 were estimated.30 MIDs of 14.4 for the VAS score and 0.109 for the EQ-5D utility were estimated in patients with deteriorating health from inflammatory bowel disease.31 It is notable that the differences we observed across all domains in our analysis were consistently higher than the MIDs detailed above not only in patients with severe HZ pain but also in those patients who report moderate pain. Qualitative research can help contextualize the findings of this quantitative research. Few studies examine the qualitative impact of HZ pain on HRQoL. In a recent study,4 a total of 32 patients with a mean age of 61 years with HZ participated in concept elicitation interviews by telephone and were asked to describe in their own words the impact of HZ. Overall, 97% of patients described an effect on Emotional Functioning, using words such as “self-conscious/embarrassed” and “stress/anxiety.” Effects on Social Functioning were reported by 63% of patients, with the majority citing social isolation and an inability to carry out normal hobbies. In the study of Weinke et al,5 280 patients with HZ with a mean age of 63.5 years were interviewed by telephone. A total of 80% of patients cited feelings of stress, 68% cited the impact on moderate physical efforts and 37% cited a lack of enjoyment in leisure activities caused by HZ. The effect of vaccination with RZV in reducing the impact on HRQoL of HZ pain was evaluated in both the ZOE-50/70 pooled and ZOE-HSCT phase III clinical trials. In the ZOE-HSCT analysis, significant differences between the vaccinated and placebo groups were observed at week 1 of the HZ episode in the SF-36 Bodily Pain, Social Functioning, Role Emotional, Mental Health, and EQ-5D utility domains (see table 4 of Curran et al13). Similar trends were observed in the ZOE-50/70 studies14; however, as there were few breakthrough HZ episodes among the vaccinated cohort, none of the comparisons resulted in statistical significance. However, the data suggest a clear trend, that vaccination with RZV not only maintains QoL by preventing HZ episodes, but it also reduces the burden of HZ pain and consequently the negative impact of this pain on HRQoL in individuals who develop disease despite vaccination. CONCLUSIONS The pain associated with an HZ episode has a large impact across all aspects of HRQoL. The magnitude of impact increases with increasing pain. DATA SHARING STATEMENT GSK makes available the anonymized individual participant data and associated documents from interventional clinical studies which evaluate medicines, upon approval of proposals submitted to www.clinicalstudydatarequest.com. To request access to patient-level data and documents for this study, please submit an enquiry via HYPERLINK “http://www.clinicalstudydatarequest.com/”www.clinicalstudydatarequest.com. Information on GSK's data sharing commitments and requesting access to anonymized individual participant data and associated documents can be found at HYPERLINK “http://www.clinicalstudydatarequest.com/”www.clinicalstudydatarequest.com. Supplementary Material ACKNOWLEDGMENTS The authors thank the investigators of the ZOE studies for their support in the conception of the studies. They also thank the Business and Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. D.C., K.S., and N.L. were involved in the conception and/or the design of the study. A.L.C., C.B., D.C., K.S., and N.L. participated in the collection/generation of the study data. A.L.C., C.B., D.C., E.S.C., K.S., N.L., and S.M. were involved in the analysis and/or the interpretation of data. All authors had full access to the data and gave approval before submission. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The work described was carried out in accordance with the recommendations of the International Committee of Medical Journal Editors for conducting, reporting, editing, and publication of scholarly work in medical journals. Some of the data in this study have been presented as a poster at IDWeek 2021 (from September 29 to October 3, 2021, virtual event). GlaxoSmithKline Biologicals SA (Brentford, United Kingdom) funded this study (GSK study identifiers: 110390, 113077) and was involved in all stages of study conduct, including the analysis of the data. GlaxoSmithKline Biologicals SA also took charge of all costs associated with the development and publication of this article. C.B., D.C., E.S.C., and N.L. are employed by/hold shares in GSK. A.L.C. reports a grant from GSK and received honoraria paid to his institution Merck Serono (Merck, Darmstadt, Germany), and BioCSL/Sequirus (Melbourne, Australia) outside the submitted work. S.M. reports personal fees from GSK during the conduct of the study and outside the submitted work. N.L. reports patents planned, issued, or pending outside the submitted work. The remaining authors declare no conflict of interest. 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==== Front 7807270 22115 Environ Int Environ Int Environment international 0160-4120 1873-6750 37307604 10.1016/j.envint.2023.108001 nihpa1909948 Article Effects of ambient fine particulates, nitrogen dioxide, and ozone on maturation of functional brain networks across early adolescence Cotter Devyn L. ab Campbell Claire E. ab Sukumaran Kirthana b McConnell Rob b Berhane Kiros c Schwartz Joel d Hackman Daniel A. e Ahmadi Hedyeh b Chen Jiu-Chiuan bf Herting Megan M. bg* a Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA b Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA c Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY, USA d Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA e USC Suzanne Dworak-Peck School of Social Work, University of Southern California, Los Angeles, CA, USA f Department of Neurology, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA g Children’s Hospital Los Angeles, Los Angeles, CA, USA * Corresponding author at: Department of Population and Public Health Sciences, University of Southern California, 1845 N. Soto Street, Room 225N, Los Angeles, CA 90089, USA. herting@usc.edu (M.M. Herting). 21 6 2023 7 2023 01 6 2023 18 7 2023 177 108001108001 https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Background: Air pollution is linked to neurodevelopmental delays, but its association with longitudinal changes in brain network development has yet to be investigated. We aimed to characterize the effect of PM2.5, O3, and NO2 exposure at ages 9–10 years on changes in functional connectivity (FC) over a 2-year follow-up period, with a focus on the salience (SN), frontoparietal (FPN), and default-mode (DMN) brain networks as well as the amygdala and hippocampus given their importance in emotional and cognitive functioning. Methods: A sample of children (N = 9,497; with 1–2 scans each for a total of 13,824 scans; 45.6% with two brain scans) from the Adolescent Brain Cognitive Development (ABCD) Study® were included. Annual averages of pollutant concentrations were assigned to the child’s primary residential address using an ensemble-based exposure modeling approach. Resting-state functional MRI was collected on 3T MRI scanners. First, developmental linear mixed-effect models were performed to characterize typical FC development within our sample. Next, single- and multi-pollutant linear mixed-effect models were constructed to examine the association between exposure and intra-network, inter-network, and subcortical-to-network FC change over time, adjusting for sex, race/ethnicity, income, parental education, handedness, scanner type, and motion. Results: Developmental profiles of FC over the 2-year follow-up included intra-network integration within the DMN and FPN as well as inter-network integration between the SN-FPN; along with intra-network segregation in the SN as well as subcortical-to-network segregation more broadly. Higher PM2.5 exposure resulted in greater inter-network and subcortical-to-network FC over time. In contrast, higher O3 concentrations resulted in greater intra-network, but less subcortical-to-network FC over time. Lastly, higher NO2 exposure led to less inter-network and subcortical-to-network FC over the 2-year follow-up period. Conclusion: Taken together, PM2.5, O3, and NO2 exposure in childhood relate to distinct changes in patterns of network maturation over time. This is the first study to show outdoor ambient air pollution during childhood is linked to longitudinal changes in brain network connectivity development. Air pollution Brain development Functional magnetic resonance imaging Resting-state Functional connectivity Longitudinal Adolescence ==== Body pmc1. Introduction Ambient air pollutants are increasingly being recognized as consequential neurotoxicants, in addition to their link to adverse cardiovascular and pulmonary health (reviews by Castagna et al. 2022; Herting et al. 2019). The Environmental Protection Agency (EPA) tracks pollutants, including particulate matter (PM) of different size fractions, specifically particulate matter (PM) with diameter < 10 μm (PM10) and < 2.5 μm (PM2.5). Among these, the World Health Organization’s (WHO) Global Burden of Disease Project recognizes PM2.5 as a leading cause of adverse health outcomes; its small size allows for particles to be inhaled deeply into the lungs and enter the bloodstream, causing systemic inflammation and affecting multiple biological systems (Cohen et al. 2005). Outdoor PM2.5 comes primarily from combustion of gasoline, oil, diesel fuel, coal, or wood. Other pollutants of neurological concern tracked by the EPA include ground level ozone (O3), a key component of smog formed from the reaction between sunlight and nitrogen oxides, as well as nitrogen dioxide (NO2), an important fraction of PM2.5 and the main source of nitrate aerosols (WHO, 2022). While the toxic neurological effects of ambient air pollution may impact individuals at all ages (Livingston et al. 2020; Russ, Reis, and van Tongeren 2019; Jayaraj et al. 2017), children are thought to be particularly vulnerable given their higher respiratory rates compared to adults (Buka, Koranteng, and Osornio-Vargas 2006) and the rapid and dynamic neural change that occurs during childhood (Sunyer 2008). Furthermore, the transition from childhood to adolescence represents a sensitive period of neurodevelopment, suggesting that exposures at this time may have an impact on long-term cognitive and emotional functioning (Kessler et al., 2005; Paus et al., 2008; Casey et al., 2008). Using magnetic resonance imaging (MRI), evidence suggests a number of neurodevelopmental consequences of outdoor air pollution exposure, including aberrations in gray and white matter volumes and microstructure, cortical thickness, and brain function (for review, see Herting et al. 2019; Peterson et al. 2015; Pujol, Martínez-Vilavella, et al. 2016; Pujol, Fenoll, et al. 2016; Mortamais et al. 2017; Guxens et al. 2018; Alemany et al. 2018; Cserbik et al. 2020; Lubczyńska et al. 2020; 2021; Burnor et al. 2021; Pérez-Crespo et al. 2022; Peterson et al. 2022; Sukumaran et al. 2023). Although initial MRI studies focused on prenatal exposure, emerging research suggests exposure to ambient PM2.5 and its constituents during childhood is also associated with differences in cortical thickness and subcortical volumes (Mortamais et al. 2017; Alemany et al. 2018; Cserbik et al. 2020; Lubczyńska et al. 2021) as well as altered white matter microstructural integrity (Lubczyńska et al. 2020; Burnor et al. 2021) and subcortical gray matter microarchitecture (Sukumaran et al. 2023). Potential mechanisms through which air pollution can cause neurotoxicity include systemic and neuro-inflammation, induced oxidative stress and the resulting increase in free radicals, as well as damage to neurovascular units, endothelial cells, and all tissue barriers in the body, including nasal, lung, gastrointestinal, and blood–brain barriers (for reviews, see Calderón-Garcidueñas et al. 2016 & You, Ho, and Chang 2022). However, the impact of air pollution exposure on functional brain network maturation during this critical period of early adolescence is not well understood. One in vivo method that can be leveraged for studying air pollution and functional brain maturation is resting-state functional magnetic resonance imaging (rs-fMRI), which quantifies the temporal correlation of activity across different brain regions at rest, revealing robust large-scale resting-state functional networks (Beckmann et al. 2005; Yeo et al. 2011). These core brain networks continue to mature across childhood and adolescence (Grayson and Fair 2017), including the frontoparietal network (FPN), the default mode network (DMN), and the salience network (SN), which are involved in emotional regulation, acute stress response, and executive function (Seeley et al. 2007; Hamilton et al. 2011; Hermans et al. 2014). Specifically, these three networks are part of the triple-network model, with each network working in tandem to successfully produce a variety of cognitive tasks (Seeley et al. 2007; Sridharan, Levitin, and Menon 2008; V. Menon and Uddin 2010). The FPN is anatomically anchored in the dorsolateral prefrontal cortex (dlPFC) and the posterior parietal cortex (PPC) and is functionally described as a task-positive network involved in executive functions like attention, problem solving, and working memory (Marek and Dosenbach 2018). The DMN is anatomically anchored in the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), precuneus, and the angular gyrus and is functionally described as a task-negative network that is active in passive rest, mind-wandering, and day-dreaming (Raichle 2015). The SN is anatomically anchored in the insula and dorsal anterior cingulate cortex (dACC) and is theorized to mediate the switch between the FPN and DMN in response to salient stimuli (Seeley et al. 2007; Goulden et al. 2014). As Menon (2019) eloquently states, together these three networks consolidate past and present sensory, affective, and cognitive inputs (SN), integrate this information into an individualized narrative (DMN), and respond accordingly by executing emotional reactions and/or planned, goal-directed activities (FPN). These networks form the basis for a range of important cognitive and emotional functions integral to everyday life, with dysfunction of this triple network likely to contribute to an array of complex brain disorders, including psychopathologies that commonly emerge during adolescence. Patterns of integration and segregation within and between intrinsic brain networks tend to mirror functional developmental milestones. For example, sensorimotor and visual networks reach maturation by early childhood, whereas networks involved in higher order cognitive and emotional functions (i.e., FPN, SN, DMN) experience dynamic restructuring in later childhood and into adulthood (Kiviniemi et al. 2000; Redcay, Kennedy, and Courchesne 2007; Lin et al. 2008; Xiao et al. 2016; Grayson and Fair 2017). In addition to network maturation, subcortical regions like the hippocampus and amygdala experience a period of significant plasticity during childhood and adolescence (Curlik, Difeo, and Shors 2014; DiFeo and Shors 2017; for reviews, see Scherf, Smyth, and Delgado 2013 & Tottenham and Galván 2016). Children exhibit increased subcortical-cortical connectivity compared to young adults, where there is more prominence among cortical connections (Grayson and Fair 2017). This neural maturation and increased subcortical-cortical connectivity is likely important for the development of executive functions, memory, and emotional regulation, and is thought to represent a period of particular vulnerability to insult from a myriad of exposures, including neurotoxicants like air pollution (Hedges et al. 2019). However, despite several existing studies on the topic, questions remain about the exact developmental profiles of intrinsic brain networks given inconsistencies in the literature. For example, while the intrinsic functional network hierarchy is largely in place as early as 1 year of age, important networks undergo differential patterns of between- and within-network integration and segregation (Gilmore, Santelli, and Gao 2018). In normative healthy neurodevelopment there is evidence that both the FPN and DMN have well-connected local (e.g., brain regions close together) within-network patterns early in development, with longer-range connections between more distal brain regions continuing to develop in late childhood (Long et al. 2017). In contrast, longitudinal reductions are seen in within-network SN connectivity during adolescence (Teeuw et al. 2019). Results from a more recent cross-sectional study by Sanders et al. (2023) further supports the tenet that age-related increases in within-network connectivity occur in DMN and FPN but decreases occur in within-network connectivity in the SN during childhood and into early adolescence. As for between-network connectivity, current evidence points to segregation for all canonical networks, namely those within the triple network model (FPN, SN, DMN) (DeSerisy et al. 2021; Thomson et al. 2022). For example, a recent study by DeSerisy et al. (2021) found connectivity between DMN and FPN brain regions were increasingly anticorrelated in older participants (age range: 7–25 years), suggesting between-network segregation in these networks. Additionally, Thomson et al. (2022) found decreased SN-FPN and SN-DMN network connectivity in children. As such, a tenet in the existing literature is that by adulthood brain regions within-network show stronger correlations with each other, whereas brain regions that are from different networks show weaker correlations, respectively. However, it is important to note that not all studies find the same degree of large-scale network reorganization across development (Sylvester et al. 2018) and accelerated cohort studies suggest that the transition from childhood to adolescence may in fact be a sensitive period hallmarked by greater, and possibly more dynamic, changes in functional connectivity (FC). For example, in a cross-sectional study conducted by Marek et al. (2015), both within- and between-network connectivity was lower during childhood to early adolescence (10–15 years of age); later in development, between-network integration was higher in young adulthood. The authors posit that the observed between-network increases may explain increased ability for cognitive control during the transition to young adulthood. However, Sanders et al. (2023) found no significant age-related differences in between-network dynamics involving our three networks of interest (i.e., SN-DMN, SN-FPN, or FPN-DMN). Discrepancies among the literature could likely be attributed to methodological differences, such as study design (cross-sectional vs longitudinal), analysis (i.e., pairwise correlations, graph theory, independent component analysis), scanner hardware and software differences, and differences in how head motion was handled. Thus, although patterns exist in children versus adults, few studies have examined longitudinal changes in these networks during the transition to early adolescence, highlighting the need for additional longitudinal neuroimaging studies aimed at characterizing intrinsic functional network connectivity (Stevens 2016; Grayson and Fair 2017; Thomson et al. 2022; Cao et al. 2016; Ernst et al. 2015, Supekar, Musen, and Menon 2009; Qin et al. 2012) as well as examining to what degree these patterns may be altered by outdoor air quality. To date, only three studies have described cross-sectional associations between exposure to air pollution and functional brain network connectivity (Pujol, Martínez-Vilavella, et al. 2016; Pujol, Fenoll, et al. 2016; Pérez-Crespo et al. 2022) and no studies have examined whether air pollution exposures affect longitudinal changes in FC development over time. In a sample of 236 children aged 8–12 years old from Barcelona, Spain, Pujol, Martínez-Vilavella, et al. (2016) found that air pollution exposure during childhood in the form of a combined estimate of NO2 and elemental carbon was significantly associated with decreased intra-DMN FC, indicative of lower within-network integration in the DMN. FC between the medial frontal cortex and the frontal operculum at the lateral boundary of the DMN was higher in more exposed children, suggestive of lower between-network segregation. A second study from the same group found that exposure to airborne copper, as measured via PM2.5, was related to decreased FC between the caudate and frontal lobe operculum in children aged 8–12 years (Pujol, Fenoll, et al. 2016). More recently, Pérez-Crespo et al. (2022) utilized a large longitudinal cohort of children (N = 2,197) from the Generation R Study to investigate the association between air pollution exposure during discrete developmental windows (i.e., pregnancy, birth to 3 years, 3 to 6 years, and 6 to 12 years of age) on network FC at age 12 years old. Higher levels of NO2, nitrogen oxides (NOx, and PM2.5 absorbance (a proxy for black carbon – also known as “soot”, a major component of PM (Cyrys et al. 2003)) were found to be related to greater between-network FC, albeit the associations between the exposure and the outcome varied for each pollutant depending on the timing of exposure. Specifically, PM2.5 absorbance had the most associations with brain network FC, demonstrating that higher exposure was associated with higher within- and between-network measures of FC and thus, higher within-network integration and lower between-network segregation. NO2 and NOx exposure demonstrated similar relationships - higher NO2 and NOx exposure and higher between-network FC (i.e., decreased between-network segregation) was observed. These studies found that pollutants interfered with expected between-network segregation but results regarding effects on within-network integration were mixed. While these three cross-sectional analyses of Western European children represent important advances in the investigation of ambient air pollution exposure and functional network outcomes during childhood and adolescence, additional large-scale and longitudinal studies from diverse geographical regions are needed. The current exploratory longitudinal study aimed to understand how exposure to ambient air pollutants, including PM2.5, O3, and NO2, at ages 9–10 years are associated with changes in FC over a 2-year follow-up period from late childhood into early adolescence using data from the longitudinal Adolescent Brain Cognitive DevelopmentSM (ABCD) Study® cohort. By utilizing ABCD’s geographically diverse and large sample size, we are more likely to detect nuanced effects of air pollution xposure on pediatric brain maturation across the United States. We chose to focus on the potential effects of air pollution on the FC of the FPN, DMN, and SN, as well as subcortical regions of interest (ROI) due to their aforementioned development during this time period and their potential relative importance for emotional regulation and executive functioning. Considering most of the literature on resting-state brain maturation is based on cross-sectional studies, we first examined developmental changes in FC patterns over the 2-year period (in absence of any pollutant) to aid in the interpretation of our findings. We hypothesized that higher levels of outdoor air pollution exposure during late childhood would associate with altered FC development in the networks of interest over time. 2. Methods 2.1. Study population The ABCD Study® is the largest long-term study of adolescent brain development from 21 communities throughout the United States, with 11,867 9–10-year-old children enrolled between years 2016 and 2018; these children are followed annually for over ten years with up to two brain imaging timepoints currently available (Volkow et al. 2018). ABCD Study inclusion criteria included age (≤10.99 years old at initial visit) and English language proficiency, whereas exclusion criteria included major medical or neurological conditions, history of traumatic brain injury, diagnosis of schizophrenia, moderate/severe autism spectrum disorder, intellectual disability, alcohol/substance use disorder, premature birth (gestational age <28 weeks), low birthweight (<1200 g), and contraindications to MRI scanning; detailed recruitment procedures can be found in Garavan et al. 2018. ABCD’s study procedures are approved under a centralized institutional review board from the University of California, San Diego; each study site also obtained approval from their own institutional review boards. All parents or caregivers provided written informed consent; children provided written assent. For the current analyses, data were obtained from the ABCD’s 4.0 Data Release and included 9497 subjects across 21 sites with air pollution exposure estimates from baseline and good quality scans from baseline and/or year-two follow-up visit dates (9/2016 – 2/2020) (see below for quality control details). One subject from each family was randomly selected to reduce the number of hierarchical levels from three (subject, family, site) to two (subject, site), in that the number of both siblings and twins vary by site as part of the planned study design. Participants were 9–10 years old during the baseline assessment and 11–13 years old at the follow-up assessment approximately two years later. Of the total 9497 participants, 4327 (45.6%) had two time points of good quality imaging data, and the remainder (N = 5170, 54.4%) had one time point of good quality imaging data, either from the baseline or year-two follow-up visit (see additional details below and Table 1). Moreover, the final sample used here represents children with complete exposure and imaging data collected before March 1, 2020 to remove any potential confounding effects of stress inherent to the COVID-19 pandemic. 2.2. Ambient air pollution estimates Annual ambient air pollution concentration for PM2.5, O3, and NO2 were assigned to primary residential addresses of each child as described in detail in Fan et al. (2021). Briefly, daily estimates of PM2.5 and NO2 as well as daily 8-hour maximums of ground-level O3 were derived at a 1-km2 resolution across the United States using hybrid spatiotemporal models, which utilize satellite-based aerosol optical depth models, land-use regression, meteorological data, and chemical transport models (Di et al. 2019; 2020; Requia et al. 2020). These daily estimates were averaged over the 2016 calendar year, corresponding to onset of ABCD Study enrollment. These concentrations were then assigned to the primary residential address at the baseline study visit when children were aged 9–10 years. The cross-validation of these models with EPA-monitored levels across the country were as follows: R2 Root Mean Square Error (RMSE) of 0.89 for PM2.5 annual averages (Di et al., 2019); 0.84 for NO2 annual averages (Di et al., 2020); 0.90 for daily 8-hour maximum O3 (Requia et al., 2020). PM2.5 was reported in μg/m3 and O3 and NO2 were originally reported in parts per billion (ppb). Prior to analysis, O3 and NO2 were converted from ppb to μg/m3 (O3: 1 ppb = 1.97 μg/m3; NO2: 1 ppb = 1.88 μg/m3). 2.3. Imaging 2.3.1. Image acquisition and Processing: rs-fMRI Each scan was collected in accordance with harmonized procedures on Siemens Prisma, Philips, or GE 750 3T MRI scanners. Imaging acquisition protocols specific to ABCD have been described by Casey et al. (2018). Twenty cumulative minutes of resting-state data was collected across two sets of two five-minute acquisition periods, while subjects were instructed to keep their eyes open and fixed on a crosshair. This increased the probability of collecting enough data with low motion per ABCD’s standards (>12.5 min of data with framewise displacement (FD) < 0.2 mm) (Power et al. 2014). Resting-state scans were acquired using an echo-planar imaging sequence in the axial plane, with the following parameters: TR = 800 ms, TE = 30 ms, flip angle = 90°, voxel size = 2.4 mm3, 60 slices. Only images without clinically significant incidental findings (mrif_score = 1 or 2) that passed all ABCD quality-control parameters (imgincl_rsfmri_include = 1) were included in analysis. Image processing steps have been previously described by Hagler et al. (2019). 2.3.2. Gordon parcellation and functional connectivity analysis Networks of interest included the SN, FPN, and DMN; subcortical ROIs included right and left amygdalae and hippocampi. Networks were functionally defined using resting-state FC patterns according to methods described by Gordon et al. (2016). Intra-network correlations were calculated by averaging the pairwise correlations for ROIs belonging to that network; inter-network correlations were calculated by averaging the pairwise correlations between ROIs within the first network and ROIs within the second network; subcortical-network correlations were calculated by averaging the pairwise correlations between ROIs within a network and a given subcortical ROI (Gordon et al. 2016). 2.4. Covariates Covariates included demographic and socioeconomic variables, including race/ethnicity (White, Black, Hispanic, Asian, or Other), average household income in USD (≥100 K, ≥50<100 K, <50 K, or Don‘t Know/Refuse to Answer), and highest household education (Post-Graduate, Bachelor, Some College, High School Diploma/GED, or < High School Diploma), since pollution levels are higher in minority communities and those from disadvantaged social status backgrounds (Hajat, Hsia, and O’Neill 2015). We also included precision variables related to both the child and MRI collection, including the child’s sex at birth (male or female) and handedness (right, left, or mixed), as well as scanner manufacturer (Siemens, Philips, GE) to account for differences in both scanner hardware and software, and average framewise displacement (mm) due to fMRI’s sensitivity to head motion (Ciric et al. 2018). 2.5. Statistical model building approach Given that linear mixed-effects (LME) modeling can handle correlated data (i.e., hierarchical structure of subjects within study sites and longitudinal data), as well as handle missing data, it has been widely used in the MRI literature to model neurodevelopmental trajectories using all available data (Mills et al. 2016; Tamnes et al. 2017; Herting et al. 2018). LME models were used to examine developmental changes in FC patterns as well as the effects of exposure to PM2.5, O3, and NO2 on these changes in FC over time. In each model, subjects (i.e., individuals) were nested within ABCD sites, and modeled as random effects. Age was z-scored using the scale() function in base R (R Core Team, 2020), resulting in a z-score of 0 equivalent to 10.69 years. Given the ability of LME models to handle a differing number of time points per subject data (Mills et al. 2016; Tamnes et al. 2017; Herting et al. 2018), all 9497 subjects with a total of 13,824 scans were included in the following analyses, without data imputation. All analyses were conducted using the R statistical software including the lmerTest::lmer() package in R (Version 4.1.2.) for LME models (Kuznetsova, Brockhoff, and Christensen 2017). 2.5.1. Developmental models To put the putative air pollution exposure effects in the context of normal development, we first examined longitudinal changes in FC in a model that included age (in months) as the time variable as well as all covariates previously mentioned. 2.5.2. Single pollutant models Single pollutant models included one pollutant (PM2.5, O3, or NO2) used as a continuous variable, age in months also used as a continuous variable, sex used as a binary variable (male or female), a three-way interaction term of age-by-sex-by-pollutant to allow testing for the impact of pollutants on changes over time as well as sex as a potential moderator of how each pollutant affects brain networks over time – previous research demonstrated both sex and age associations with brain network maturation (Satterthwaite et al. 2015; Schulz and Sisk 2016; Grayson and Fair 2017; Sanders et al. 2023) – plus all covariates previously mentioned. Nonsignificant interaction terms were then removed to achieve a more parsimonious model. Terms of interest in the final single-pollutant models included the fixed effects of age, pollutant, and the age-by-pollutant interaction term, respectively. 2.5.3. Multi-pollutant models Finally, we built a multi-pollutant model to help address confounding effects of co-exposure to multiple pollutants on our outcomes which included age-by-PM2.5, age-by-O3, and age-by-NO2 interaction terms, the main effects of each pollutant (PM2.5, O3, and NO2) and age, and all previously mentioned covariates. 2.5.4. Sensitivity analyses Due to the potential seasonality of pollutant concentrations, we performed an additional sensitivity analysis including meteorological season of the MRI scan as an additional time-varying covariate for each multi-pollutant model. Additionally, we performed a sensitivity analysis to examine effects in the subset of participants that had both waves of MRI data (N = 4327). 2.5.5. Correction for multiple comparisons Given we conducted models for multiple brain outcomes, including 3 intra-network outcomes (SN, DMN, FPN), 3 inter-network outcomes (SN-DMN, SN-FPN, DMN-FPN), 6 amygdala (right and left) to network (SN, DMN, FPN) outcomes, and 6 hippocampus (right and left) to network (SN, DMN, FPN) outcomes, we corrected for multiple comparisons using false discovery rate (FDR) correction for the coefficients of interest across the 18 tests. We also denote in our tables which findings pass a more stringent Bonferroni-correction (i.e., 90 tests (18 tests * 5 models); p = 0.0005). 3. Results Participant demographic and socioeconomic characteristics for the final study sample can be found in Table 1 and Supplemental Table 1. Data from 9497 participants with 1–2 waves of neuroimaging data were included in the final analyses. Excluding age at visit, subjects scanned at the baseline visit and the year-2 follow-up visit did not differ significantly on socioeconomic, demographic, or MRI variables. The discrepancy in N at the baseline visit compared to the year-2 follow-up visit can partially be explained by the onset of the COVID-19 pandemic, which interrupted data collection, and our decision to exclude scans collected after March 2020. The mean (SD) annual pollutant concentrations across all sites are as follows: PM2.5: 7.65 (1.53) μg/m3 (range, 1.72–15.9 μg/m3); O3: 81.2 (8.67) μg/m3 (range, 58.5 – 111 μg/m3); and NO2: 35.1 (10.9) μg/m3 (range, 1.16–69.7 μg/m3). PM2.5 and O3 were weakly negatively correlated (r = −0.17) and PM2.5 and NO2 were weakly positively correlated (r = 0.18); there was no correlation between O3 and NO2 (r = 0.003) (Supplemental Fig. 1). Below we outline the results from the developmental models (Table 2) as well as the multi-pollutant models (Tables 3–4 and Figs. 1–2). Notably there were no significant age-by-sex-by-pollutant or sex-by-pollutant interactions across the initial single-pollutant models (see Supplemental Tables 2–4). Results of both sets of single-pollutant models were nearly identical to the multi-pollutant models and are therefore not discussed; however, results for the single pollutant models can be found in Supplemental Tables 2–7. 3.1. Intra-network cortical functional connectivity In developmental models, intra-SN FC decreased, whereas intra-DMN and intra-FPN FC increased over the 2-year follow-up period from age 9 - 13 (Table 2, Fig. 1a). In fully adjusted multi-pollutant models, there was a significant age-by-O3 interaction, demonstrating that with higher O3 concentrations, greater intra-DMN integration was seen over the two-year follow up period from age 9 - 13 (Table 3, Fig. 1b). There were no significant age-by-PM2.5 or age-by-NO2 interactions on intra-network FC over the 2-year follow-up period. There was a main effect of NO2 on intra-FPN connectivity, such that higher NO2 concentrations were related to less intra-FPN FC at age 9 (Table 3). 3.2. Inter-network cortical functional connectivity In developmental models, SN-FPN FC increased with age over time, demonstrating inter-network integration. There were no significant changes in SN-DMN or FPN-DMN FC over the 2-year follow-up period from age 9 - 13 (Table 2, Fig. 1a). In fully adjusted multi-pollutant models, there were significant age-by-pollutant interactions for PM2.5 and NO2 (Table 3, Fig. 1b). Specifically, with higher PM2.5 concentrations, increases in SN-DMN and FPN-DMN inter-network FC were seen over the 2-year follow-up period from age 9 - 13 (Table 3, Fig. 1b). In contrast, higher NO2 exposure was associated with decreasing SN-FPN and FPN-DMN inter-network FC over the 2-year follow-up period from age 9 - 13 (Table 3, Fig. 1b). There were no significant main effects or interactions of O3 on inter-network FC. 3.3. Subcortical-network functional connectivity 3.3.1. Amygdala In developmental models, right amygdala-FPN and bilateral amygdala-SN FC decreased with age over time, demonstrating amygdalae-to-network segregation (Table 2, Fig. 2a). There were no significant changes in amygdala-DMN FC over the 2-year follow-up period from age 9 - 13 (Table 2). In fully adjusted multi-pollutant models, there were several significant age-by-pollutant interactions (Table 4, Fig. 2b). Higher PM2.5 concentrations were associated with decreasing left amygdala-DMN and right amygdala-FPN FC, but increasing left amygdala-FPN and bilateral amygdala-SN FC over time from age 9 - 13. On the other hand, higher O3 levels were related to decreasing right amygdala-DMN FC, whereas higher O3 and NO2 levels were associated with decreasing left amygdala-FPN FC over the 2-year follow-up period from age 9 - 13. No significant main effects of pollutants were seen for amygdala-to-network FC (Table 4). 3.3.2. Hippocampus In developmental models, FC decreased between the bilateral hippocampus-DMN, -FPN, and -SN over time, demonstrating hippocampal-to-network segregation from age 9 - 13 (Table 2, Fig. 2a). In fully adjusted multi-pollutant models, higher PM2.5 concentrations were related to increasing left hippocampus-DMN, bilateral hippocampal-SN, and bilateral hippocampal-FPN FC over the 2-year follow-up period from age 9 - 13 (Table 4, Fig. 2b). Higher O3 concentrations were associated with decreasing left hippocampus-DMN, right hippocampus-FPN, and left hippocampus-SN FC over time (Table 4, Fig. 2b). Lastly, higher NO2 levels were associated with decreasing bilateral hippocampal-FPN and left hippocampus-SN FC over the follow-up period from age 9 - 13 (Table 4, Fig. 2b). No significant main effects of pollutants were detected in hippocampal-to-network FC (Table 4). 3.4. Sensitivity analyses In models including the season in which the MRI was collected, the previously noted findings all remained significant (Supplemental Table 8). Similarly, magnitude and direction of effects (standardized ß’s) were nearly identical in the subset of participants with both waves of MRI data as compared to the full analytic sample that included all individuals with one or two waves of MRI data (Supplemental Table 9). 4. Discussion In this study, we leveraged longitudinal LME modeling and resting-state fMRI data to assess how one year of exposure to PM2.5, O3, and NO2 during childhood changes large-scaled cortical network and subcortical-to-cortical FC over a 2-year follow-up period. PM2.5 was found to relate to a greater number of changes in FC (i.e., 2 inter-network and 10 subcortical-to-cortical changes) over the transition from late childhood into early adolescence as compared to O3 (i.e., 1 intra-network and 5 subcortical-to-cortical changes) and NO2 (i.e., 2 inter-network and 4 subcortical-to-cortical changes). The current findings of differential FC development in children exposed to higher levels of air pollution expand upon the previous cross-sectional studies to show that ambient air pollution exposure during late childhood contributes to differential, within-subject changes in FC development as measured over a 2-year period. 4.1. Longitudinal trajectories of intrinsic functional network development In terms of large-scaled network dynamics, previous literature, largely focused on comparing children versus adults, suggests that individual networks segregate from each other, while also displaying increased connectivity within each network (i.e., integration) to increase efficiency across childhood and adolescence (Grayson and Fair 2017). However, Marek et al. (2015) found that both within- and between-network FC decreases in early adolescence (ages 10–15 years), followed by between-network integration increasing later as individuals transition into adulthood. Sanders et al. (2023), however, found linear and non-linear age-related differences in both intra- and inter-network connectivity in a cross-sectional analysis using child and adolescent data from the Human Connectome Project (HCP). Given that most of the developmental resting-state FC studies to date have been limited by cross-sectional study design, small N, and/or inclusion of a wide age-range (for review, see Stevens 2016), we first sought to characterize age-related intra-, inter-, and subcortical-to-network FC trajectories within the large longitudinal ABCD sample. We found increasing intra-network integration for both the FPN and DMN from ages 9–13 years-old, which suggests increased communication or connectivity between regions in the same network. This finding is consistent with previous literature demonstrating increased intra-network integration with age in developmental cohorts, even those with wider age ranges. However, we also observed decreased intra-network connectivity in the SN as well as increased inter-network connectivity between the SN-FPN, at odds with most of the literature to date but more consistent with the findings of Sanders et al. (2023) and Teeuw and colleagues (2019) as it relates to intra-network dynamics, as well as Marek et al. (2015) to an extent. We also did not find age-related changes in inter-network connectivity between the FPN-DMN or SN-DMN. Thus, longitudinal changes seen between the narrow developmental window of ages 9–13 years within our sample are incongruent with the simplistic theory of intra-network integration and inter-network segregation throughout development which has largely been based on group differences between children and adults (Supekar, Musen, and Menon 2009; Qin et al. 2012; DeSerisy et al. 2021; Stevens 2016). Our findings highlight more nuanced patterns of large-scaled FC development during the transition from childhood to adolescence. Beyond cortical FC, we also found distinct segregation patterns between subcortical-to-cortical FC over the 2-year follow-up period. The amygdala was found to segregate from SN and FPN, whereas the hippocampus segregated from all three networks of interest. The current findings are inconsistent with others that have reported the PFC and hippocampus integrate over the course of development from ages 8 to 32 years (Calabro et al. 2020). Inconsistencies in the literature could be due to issues with head motion resulting in spurious results or subcortical signal dropout, both common issues in rs-fMRI methodology (Boubela et al. 2015; Grayson and Fair 2017). Additionally, these other studies have focused on smaller and more homogenous samples or used different study designs (i.e., cohort-sequential or cross-sectional). Taken together, our findings in a large and diverse sample point to dynamic changes to SN connectivity, namely intra-SN segregation and SN-FPN integration; intra-network integration in FPN and DMN; and subcortical-to-cortical network segregation broadly from ages 9 to 13 years of age. These findings support previous studies suggesting that the transition from childhood into early adolescence may be a time characterized by more dynamic change in network FC, within the overall intra-network integration and inter-network segregation noted to occur by adulthood (Heyn et al. 2019; Jalbrzikowski et al. 2017; Peters et al. 2017; Wendelken et al. 2017). 4.2. Distinct changes in functional network organization during the transition to adolescence by pollutant type Building from these developmental changes in FC, our results suggest that outdoor air pollution exposure is associated with distinct differences in functional organization during the transition from childhood to early adolescence depending on the pollutant type. For instance, PM2.5 had opposite effects as compared to O3 and NO2 on inter-network and subcortical-to-network changes over time. Importantly, we implemented a multi-level model analytic framework which accounted for study site differences, controlled for potential seasonality in sensitivity analyses, and examined both single and multi-pollutant models to try to disentangle these complex multiple exposure challenges. Thus, while the opposing effects of PM2.5 compared to O3 and NO2 may initially seem counterintuitive, it is feasible that these differences may reflect varying underlying mechanisms and/or be the result of compensatory restructuring of crosstalk between brain regions resulting from exposure. Moreover, our findings also suggest patterns of change for large-scaled networks during the transition from childhood to early adolescence may be exaggerated or diminished depending on the type of pollutant. For example, higher O3 exposure was related to greater increases in intra-network FC above increases seen with age alone, suggestive of exaggerated connectivity in this network over time. In contrast, higher PM2.5 exposure was linked to greater integration between cortical networks and subcortical regions, which may reflect impairments in the otherwise expected subcortical-to-network segregation seen in our sample during this developmental stage. This disruption of developmental change in functional network organization from ambient air pollution may have important implications, as an optimal balance in the synchrony within the triple network model is vital for various cognitive and emotional processes (for reviews, see Menon 2011; van Oort et al. 2017), with potential consequences related to the emergence of psychopathologies (for review, see Menon 2019). Therefore, additional research is warranted to determine whether these notable exposure-related changes in the functional balance of intrinsic brain networks during the transition to early adolescence may subsequently contribute to various mental health disorders that typically emerge during mid- to late adolescence (Kessler et al. 2005). 4.3. Potential effects of pollutant composition, dose, and timing of exposure Similarities and differences between the current study and the three previous studies also suggest that examining the chemical composition, dose of pollutant, and timing of exposure are likely important to consider in future research. PM2.5 effects on FC development were most prominent in the current study, yet Pérez-Crespo et al. (2022) did not find any associations between PM2.5 exposure and functional brain connectivity outcomes in their study sample. Pérez-Crespo et al. (2022) also found that higher NO2 exposure from birth to age 3 was linked to lower between-network segregation at age 12 years, whereas we found higher NO2 exposure at ages 9–10 years was related to greater between-network segregation over time, up to age 13 years. It is possible that chemical composition or source differences in exposures as well as differential doses of exposure between the studies may account for such discrepancies. For example, PM2.5 is known to carry heavy metals as well as include sulfate, nitrate, ammonium, black and organic carbon, and other materials, with composition varying regionally (Hyslop 2009). In the Generation R project, local traffic emissions within Rotterdam, Netherlands were responsible for the vast majority of NO2 exposure, whereas NO2 sources in the ABCD project are likely more complex and vary as a function of regional differences across the U.S. Moreover, we utilized a multi-pollutant approach, and our average levels of exposure were relatively low as compared to the other studies to date that have focused either on single pollutant or summary exposure estimates. Thus, it is possible there may be differential dose dependent effects that warrant further investigation. Moving forward, the timing of exposure is likely a key piece in fully characterizing how air pollution exposure affects FC development across childhood and adolescence. Although the exact biological mechanisms linking ambient air quality and neurodevelopmental outcomes remain unclear, animal studies suggest both prenatal and childhood exposure lead to changes in oxidative stress, neuroinflammation, microglial activation, and neuronal structure and function (Morgan et al. 2011; Yan et al. 2015; Levesque et al. 2013; 2011; Li et al. 2012). However, the routes and degree by which prenatal and childhood exposures impact these processes may be distinct. Specifically, prenatal exposure to air pollution is expected to activate maternal immune function, leading to systemic changes in oxidative stress and inflammation as well as impairment of placental function and epigenetic modification (Johnson et al. 2021; Ha 2021). In addition to systemic inflammation and oxidative stress, childhood exposure may also damage the blood–brain barrier (BBB), making the brain more vulnerable to many exogenous toxins (Ha 2021; Kang et al. 2021; Lilian Calderón-Garcidueúas et al. 2008). Moreover, regardless of the mechanism(s) at play, prenatal and childhood exposure may present unique neurodevelopmental deficits based on the differential timing of various neurodevelopmental processes (i.e., neurulation, proliferation, migration, differentiation, synaptogenesis, gliogenesis, and myelination) and known spatial differences in periods of plasticity across various brain regions (e.g., visual and sensory systems develop earlier than the prefrontal cortex) (Herting et al. 2019). Thus, it is reasonable to hypothesize that prenatal and childhood exposures may also have varying consequences on developmental trajectories of intrinsic brain network development. In this regard, the current findings, suggesting one-year annual average exposure during childhood is linked to changes in FC patterns as the brain matures into early adolescence, is congruent with those of Pujol et al. (2016a, 2016b). They reported similar associations as seen with PM2.5 in the current study – namely decreased within-network and increased between-network FC – when the timing of child’s exposure and the brain outcomes coincide at ages 8–12 years old (Pujol et al., 2016a,b). In contrast, however, the associations between air pollution exposure and differential FC at age 12 years reported by Pérez-Crespo et al. (2022) were only apparent when the exposure occurred in early life (i.e., birth to age 3 years and age 3 to 6 years), whereas no association was found between more recent exposures in relation to the time of the brain scanning. Interestingly, however, despite differences in the timing of exposure, both Pérez-Crespo et al. (2022) and the current study found air pollution exposure to relate more broadly to inter-network as compared to intra-network FC; which is also congruent with the between-network differences noted in both studies by Pujol et al. (2016a, 2016b). Taken together, it seems ambient air pollution during childhood development may directly interfere with the diverging activation and communication between functional networks, which is thought to be necessary to support increased ability of cognitive and emotional functioning (for reviews, see Menon 2011; van Oort et al. 2017). As such, more research is necessary to understand the nuances in the relative importance of both the potential concurrent, delayed, and/or cumulative effects of exposure periods on intra-network brain maturation. Again, given the transition from childhood to adolescence may in fact be a sensitive period with dynamic changes in FC development (Thomson et al. 2022; Long et al. 2017; Heyn et al. 2019; Jalbrzikowski et al. 2017; Peters et al. 2017; Wendelken et al. 2017), it will be important for future research to also consider how air pollution influences the underlying developmental profile of FC that may exist within the age ranges studied. Hence the current study aimed to examine developmental patterns of change in FC, as to better understand how air pollution may influence developmental processes captured from ages 9–13 years. Future cross-sectional and longitudinal air pollution and FC studies should consider examining age, especially in samples with wider age ranges of children (i.e., 8–12 years), as well as how air pollution may interact with those age-related patterns, to more fully characterize how air quality may influence the potential dynamic changes that likely occur during this period of early adolescent neurodevelopment in addition to the amount of change in pollution over time. 4.4. Potential neurobiological mechanisms of pollutants’ effects on network connectivity While mechanistically the neurobiology that contributes to patterns of resting-state FC remain unknown, experimental studies have quantified several immune- and cerebral vasculature-related effects of pollution exposure that may be relevant to how air pollution contributes to altered patterns of synchrony between large-scaled cortical networks and subcortical-to-cortical connectivity. For example, a study using human cerebral endothelial cells to create an in-vitro BBB model demonstrated that PM2.5 can cross the BBB and induce an upregulation of pro-inflammatory cytokines, illustrating a potential mechanism for neurotoxicity (Kang et al. 2021). Beyond PM2.5, O3 exposure has also been shown to increase the expression of pro-inflammatory cytokines near brain capillaries (Araneda et al. 2008). Animal studies of the effects of NO2 exposure reveal associated endothelial and inflammatory responses and a corresponding increased risk for ischemic stroke (Zhu et al. 2012) as well as weakened synaptic plasticity and increased risk for vascular dementia (Li and Xin 2013) in rodent stroke models. Additionally, the same group reported induced excitotoxicity in healthy rats (L ind Xin 2013). In terms of subcortical-to-cortical findings, changes in patterns of hippocampal and amygdalar connectivity development by ambient air pollution is supported by evidence from rodent models investigating the neurodevelopmental consequences of traffic-related air pollution. Patten et al. (2020) have shown traffic-related air pollution upregulates microglial expression in the CA1 region of the hippocampus, as well as impacts hippocampal neurogenesis in rodents. Additionally, the cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein and brain derived neurotrophic factor (BDNF) signaling pathway in the hippocampus has demonstrated vulnerability to the neurotoxic effects of PM2.5 (J. Liu et al. 2019; 2021; F. Liu et al. 2021). BDNF expression occurs in both the amygdala and the hippocampus, and is responsible for regulating synaptic plasticity, neurogenesis, proliferation, and dendritic spine morphology (Miranda et al. 2019). Thus, outdoor air pollution exposure may lead to dysregulation of various neural processes and pathways that could lead to aberrations in the maturation of brain networks across childhood and adolescence as captured by resting-state FC. Future translational work is needed that integrates human and experimental MRI imaging and histological approaches in animal models to clarify the mechanisms underlying air pollution effects on FC maturation. 4.5. Limitations, future directions, and conclusions Limitations of our study include those inherent in rs-fMRI methodology, namely its extreme sensitivity to signal noise. To guard against this, we controlled for all available variables that could affect image quality, such as motion artifacts and incidental findings, and covaried for motion using framewise displacement. Another limitation is that the ABCD Study currently lacks air pollution exposure during the prenatal period, early life, and beyond the 9–10-year age period for participants, as well as more acute measures of air pollutant concentrations from the day of MRI scan. Recent evidence suggests acute effects of diesel exhaust exposure on intrinsic brain network FC (Gawryluk et al. 2023), albeit levels of exposure tested were very high as part of this randomized controlled cross-over design study. Nonetheless, it will be important for future studies to investigate potential acute versus chronic effects of ambient air pollution exposure on brain connectivity. In addition, the availability of up to only two neuroimaging time points, while a significant advance in the field and covering a relatively wide age range, limits the ability to fully examine the effects of air pollution on longitudinal brain health outcomes over a longer follow-up period, including potential non-linear exposure-outcome relationships that can only be accurately quantified with three or more time points of data per subject. Future studies are warranted in deciphering how lifetime pollution may impact brain development as the data becomes available in the ABCD Study cohort and other publicly available datasets. It will also be warranted for future studies to examine the effects of exposure during vulnerable windows of development, such as those identified by Pérez-Crespo et al. (2022), on longitudinal brain outcomes to evaluate the persistence of the observed altered connectivity. Lastly, this is the fourth study and the first longitudinal analysis to our knowledge examining effects of ambient air pollution and FC in childhood and adolescence, with low levels of exposures. Therefore, our findings warrant validation in other large, representative cohorts. Moreover, future studies should aim to connect cognitive and emotional functions to alterations in brain network maturation related to air pollution. In conclusion, we find compelling evidence that exposure to ambient air pollution is associated with differences in the maturation of functional brain networks as measured by rs-fMRI in children as they transition into early adolescence. Of note, the level of exposures in the current study are well below EPA’s national standards (US EPA 2014), yet the current study shows even low level exposures are correlated with changes in longitudinal resting-state FC development in children across the U.S. Moreover, while the effect sizes seen are small – which could be in part because levels of exposure were low – it is also feasible that cumulative exposure to these low levels may have larger and/or persistent health effects on a population level (Funder et al., 2019). As such, our results may provide further support for new guidelines with more stringent recommendations, such as those recommended by the WHO in September 2021 (PM2.5 = 5 μg/m3; O3 = 100 μg/m3; NO2 = 10 μg/m3) (WHO 2021). Thus, the current findings should be taken into consideration by regulatory bodies as they set guidelines for acceptable levels of pollutants for the general population to optimize public health. Supplementary Material Supplemental Material Acknowledgements Research described in this article was supported by the National Institutes of Health [NIEHS R01ES032295, R01ES031074, P30ES007048-23S1, 3P30ES000002-55S1] and EPA grants [RD 83587201, RD 83544101]. Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9-10 and follow them over 10years into early adulthood. The ABCD Study is supported by the National Institutes of Health Grants [ U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147]. A full list of supporters is available at https://abcdstudy.org/nih-collaborators. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/principal-investigators.html. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. The ABCD data repository grows and changes over time. The ABCD data used in this report came from 10.15154/1523041. Additional support for this work was made possible from NIEHS R01-ES032295 and R01-ES031074. Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Megan Herting, PhD reports financial support was provided by National Institute of Environmental Health Sciences. Dr. Rob McConnell, MD reports financial support was provided by National Institute of Environmental Health Sciences. Dr. Joel D. Schwartz, PhD reports financial support was provided by United States Environmental Protection Agency. Dr. Rob McConnell, MD reports financial support was provided by United States Environmental Protection Agency. Data availability Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study, held in the NIMH Data Archive (NDA) and can be found at DOI https://doi.org/10.15154/1523041. The NDA study for this project can be found at https://dx.doi.org/10.15154/1528391. Abbreviations: ABCD Adolescent Brain Cognitive Development BDNF Brain-Derived Neurotrophic Factor BBB Blood-Brain Barrier BOLD Blood Oxygen Level Dependent cAMP Cyclic Adenosine Monophosphate CREB cAMP Response Element-Binding Protein dACC Dorsal Anterior Cingulate Cortex dlPFC Dorsolateral Prefrontal Cortex DMN Default Mode Network FDR False Discovery Rate FC Functional Connectivity FPN Frontoparietal Network HCP Human Connectome Project LME Linear Mixed Effects mPFC Medial Prefrontal Cortex NO2 Nitrogen Dioxide O3 Ozone PM Particulate Matter PPC Posterior Parietal Cortex ROI Region of Interest rs-fMRI Resting-State Functional Magnetic Resonance Imaging SD Standard Deviation SN Salience Network TE Echo Time TR Repetition Time Fig. 1. A) Longitudinal changes seen with age from 9 to 13 years in large-scaled cortical functional connectivity. B) Significant associations between the age-by-pollutant interaction term and intra- and inter-network rs-fMRI outcomes (FDR corrected). Red lines indicate the age-by-PM2.5 interaction term; blue lines indicate the age-by-O3 interaction term; green lines indicate the age-by-NO2 interaction term. Solid lines represent network integration, or increased functional connectivity as measured by BOLD rs-fMRI; dashed lines represent network segregation, or decreased functional connectivity as measured by BOLD rs-fMRI. For ease of interpretation, graphs depict significant interactions between pollutant and age per intra- and inter-network outcome for both the 0.75 quartile (dashed line) (PM2.5 = 8.68 μg/m3; O3 = 89.26 μg/m3; NO2 = 41.91 μg/m3) and 0.25 quartile (solid lines) (PM2.5 = 6.66 ϋg/m3; O3 = 75.14 μg/m3; NO2 = 28.14 μg/m3) of each pollutant. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 2. A) Longitudinal changes seen with age from 9 to 13 years in cortical-to-subcortical functional connectivity. B) Significant associations between the age-by-pollutant interaction term and subcortical-to-network rs-fMRI outcomes (FDR corrected). Red lines indicate the age-by-PM2.5 interaction term; blue lines indicate the age-by-O3 interaction term; green lines indicate the age-by-NO2 interaction term. Solid lines represent network integration, or increased functional connectivity as measured by BOLD rs-fMRI; dashed lines represent network segregation, or decreased functional connectivity as measured by BOLD rs-fMRI. Graphs depict significant interactions between pollutant and age per subcortical-to-network outcome. For ease of interpretation, graphs depict significant interactions between pollutant and age per subcortical-to-network outcome for both the 0.75 quartile (dashed line) (PM2.5 = 8.68 μg/m3; O3 = 89.26 μg/m3; NO2 = 41.91 μg/m3) and 0.25 quartile (solid lines) (PM2.5 = 6.66 μg/m3; O3 = 75.14 μg/m3; NO2 = 28.14 μg/m3) of each pollutant. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Table 1 Cohort demographic and socioeconomic characteristics, baseline pollutant levels, and MRI information, including manufacturer and head motion as measured by average framewise displacement (FD). Cohort Characteristics N total unique subjects 9497 Baseline Year 2 N (%) subjects with one timepoint 5170 (54.4%) N (%) subjects with one timepoint 4292 (83%) 878 (17%) N (%) subjects with two timepoints 4327 (45.6%) Mean Pollutant Levels in 2016, μg/m3 (SD) PM2.5 7.65 (1.54) 7.64 (1.52) O3 81.3 (8.72) 80.9 (8.58) NO2 35.3 (10.9) 34.8 (10.9) Mean Age, months (SD) 119 (7.52) 143 (7.68) Sex, N (%) Female 4264 (49.5%) 2449 (47.1%) Race/Ethnicity, N (%) White 4662 (54.1%) 2957 (56.8%) Black 1120 (13%) 592 (11.4%) Hispanic 1752 (20.3%) 1037 (19.9%) Asian 175 (2%) 102 (2%) Other 910 (10.6%) 517 (9.9%) Handedness, N (%) Right 6943 (80.6%) 4154 (79.8%) Left 590 (6.8%) 356 (6.8%) Mixed 1086 (12.6%) 695 (13.4%) Highest Household Education, N (%) Post Graduate Degree 3068 (35.6%) 1845 (35.4%) Bachelor 2249 (26.1%) 1401 (26.9%) Some College 2198 (25.5%) 1348 (25.9%) HS Diploma/GED 730 (8.5%) 401 (7.7%) < HS Diploma 374 (4.3%) 210 (4%) Overall Income, N (%) ≥100 K 3465 (40.2%) 2044 (39.3%) ≥50 K & <100 K 2291 (26.6%) 1471 (28.3%) <50 K 2190 (25.4%) 1304 (25.1%) Don’t Know or Refuse 673 (7.8%) 386 (7.4%) MRI Characteristics N total MRI scans 13,824 N (%) MRI scans per timepoint 8619 (62.3%) 5205 (37.7%) MRI Manufacturer, N (%) Siemens 5616 (65.2%) 3213 (61.7%) GE 2125 (24.7%) 1419 (27.3%) Philips 878 (10.2%) 573 (11%) Mean FD, mm (SD) 0.23 (0.22) 0.17 (0.16) Table 2 Results from developmental models examining the fixed effect of age over time, including Cohen’s f-squared, standardized betas, and 95% confidence intervals for each rs-fMRI outcome of interest. Main Effect of Age (over time) f2 β CI (95%) Intra-Network Intra-SN 7.28E-03 −0.06 * −0.08, −0.05 Intra-DMN 4.81E-03 0.05 * 0.03, 0.06 Intra-FPN 0.01 0.07 * 0.05, 0.08 Inter-Network SN-DMN 3.12E-05 0.004 −0.01, 0.02 SN-FPN 0.01 0.08 * 0.06, 0.09 FPN-DMN 2.96E-08 −0.0001 −0.02, 0.02 Subcortical to Network L amyg-DMN 3.20E-05 0.01 −0.01, 0.02 R amyg-DMN 1.77E-04 −0.01 −0.03, 0.005 L amyg-FPN 7.52E-05 −0.01 −0.02, 0.009 R amyg-FPN 6.70E-03 −0.07 * −0.09, −0.06 L amyg-SN 0.01 −0.10 * −0.11, −0.08 R amyg-SN 1.26E-03 −0.03 * −0.05, −0.01 L hippo-DMN 7.72E-03 −0.08 * −0.09, −0.06 R hippo-DMN 5.27E-03 −0.07 * −0.08, −0.05 L hippo-FPN 1.27E-03 −0.03 * −0.05, −0.02 R hippo-FPN 3.92E-04 −0.02 −0.03, −0.001 L hippo-SN 7.37E-04 −0.02 −0.04, −0.007 R hippo-SN 6.36E-04 −0.02 −0.04, −0.005 Significant models are bolded (FDR-p < 0.05); * denotes passing a more stringent Bonferroni correction (p < 0.0005). Abbreviations: salience network (SN), default-mode network (DMN), frontoparietal network (FPN), left (L), right (R), amygdala (amyg), hippocampus (hippo). Table 3 Results from multi-pollutant models, including Cohen’s f-squared, standardized betas, and 95% confidence intervals for each intra- and inter-network rs-fMRI outcome of interest. Multi-Pollutant Model PM2.5 Age-by-PM2.5 O3 Age-by-O3 NO2 Age-by-NO2 f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) Intra-Network Intra-SN 1.17E-03 −0.01 −0.04, 0.02 2.05E-04 0.01 −0.005, 0.03 4.15E-05 0.004 −0.02, 0.03 6.20E-05 −0.01 −0.02, 0.009 7.78E-04 −0.01 −0.04, 0.02 3.10E-04 −0.01 −0.03, 0.002 Intra-DMN 7.22E-05 0.003 −0.03, 0.03 6.72E-06 −0.002 −0.02, 0.01 1.08E-05 −0.002 −0.02, 0.02 9.15E-04 0.02 0.006, 0.03 6.45E-04 0.01 −0.02, 0.04 4.72E-09 0.00 −0.01, 0.01 Intra-FPN 0.01 0.02 −0.009, 0.04 6.40E-06 0.002 −0.01, 0.02 1.81E-04 −0.003 −0.03, 0.02 2.68E-04 0.01 −0.003, 0.02 0.11 −0.04 −0.07, −0.02 6.37E-04 −0.02 −0.03, −0.002 Inter-Network SN-DMN 3.13E-05 −0.001 −0.03, 0.03 2.33E-03 0.04 * 0.02, 0.05 6.41E-04 0.01 −0.01, 0.04 1.05E-04 −0.01 −0.02, 0.007 4.99E-05 0.002 −0.03, 0.03 2.36E-04 −0.011 −0.03, 0.004 SN-FPN 0.07 0.04 0.02, 0.06 3.74E-04 0.01 −0.001, 0.03 4.95E-03 0.02 −0.003, 0.04 7.40E-05 −0.01 −0.02, 0.008 8.75E-03 −0.01 −0.04, 0.01 1.14E-03 −0.02 −0.04, −0.009 FPN-DMN 7.36E-04 0.01 −0.02, 0.04 2.14E-03 0.03 * 0.02, 0.05 1.51E-04 0.01 −0.01, 0.04 4.30E-05 −0.005 −0.02, 0.01 2.14E-05 0.003 −0.03, 0.03 2.33E-03 −0.03 * −0.05, −0.02 Significant models are bolded (FDR-p < 0.05); * denotes passing a more stringent Bonferroni correction (p < 0.0005). Abbreviations: salience network (SN), default-mode network (DMN), frontoparietal network (FPN). Table 4 Results from multi-pollutant models, including Cohen’s f-squared, standardized betas, and 95% confidence intervals for each subcortical-network rs-fMRI outcome of interest. Multi-Pollutant Model PM2.5 Age-by-PM2.5 O3 Age-by-O3 NO2 Age-by-NO2 f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) f2 β CI (95%) Subcortical to Network Lamyg-DMN 2.83E-04 0.005 −0.02, 0.03 4.86E-04 −0.02 −0.04, −0.004 4.94E-04 −0.01 −0.04, 0.01 8.04E-06 −0.003 −0.02, 0.01 9.15E-05 0.003 −0.02, 0.03 2.05E-04 0.01 −0.004, 0.03 Ramyg-DMNL 0.02 −0.02 −0.05, 0.006 1.32E-04 0.01 −0.006, 0.03 5.36E-05 0.002 −0.02, 0.02 1.45E-03 −0.03 * −0.05, −0.02 8.57E-04 −0.005 −0.03, 0.02 1.44E-04 −0.01 −0.03, 0.006 Lamyg-FPN 7.53E-05 0.003 −0.03, 0.03 1.21E-03 0.03 * 0.01, 0.05 4.67E-04 −0.01 −0.04, 0.006 7.39E-04 −0.02 −0.04, −0.007 4.43E-03 0.03 0.0002, 0.05 1.03E-03 −0.03 −0.04, −0.01 Ramyg-FPN 2.87E-03 −0.01 −0.04, 0.02 1.10E-03 −0.03 * −0.05, −0.01 3.61E-05 −0.002 −0.02, 0.02 3.73E-04 0.02 0.001, 0.03 1.78E-03 0.008 −0.02, 0.03 6.20E-05 0.007 −0.009, 0.02 Lamyg-SN 0.02 −0.03 −0.06, −0.004 6.15E-04 0.02 0.005, 0.04 2.30E-04 −0.01 −0.03, 0.02 3.18E-05 0.005 −0.01, 0.02 8.12E-04 0.01 −0.02, 0.03 5.79E-07 0.00 −0.02, 0.02 Ramyg-SN 1.22E-04 0.003 −0.02, 0.03 5.02E-04 0.02 0.003, 0.04 7.80E-04 −0.02 −0.04, 0.006 4.94E-05 −0.01 −0.02, 0.01 6.46E-05 −0.003 −0.03, 0.02 3.36E-04 −0.02 −0.03, 0.0005 Lhippo-DMN 0.01 −0.03 −0.06, −0.007 7.HE-04 0.02 0.007, 0.04 2.60E-04 0.01 −0.01, 0.03 9.65E-04 −0.03 −0.04, −0.01 1.62E-03 0.02 −0.01, 0.04 7.20E-06 −0.002 −0.02, 0.01 Rhippo-DMN 0.01 0.02 −0.004, 0.05 2.73E-05 −0.005 −0.02, 0.01 7.07E-04 0.01 −0.01, 0.03 1.83E-06 0.001 −0.02, 0.02 2.32E-03 0.01 −0.02, 0.03 1.84E-05 0.004 −0.01, 0.02 Lhippo-FPN 1.39E-03 −0.02 −0.05, 0.007 1.19E-03 0.03 * 0.01, 0.05 1.59E-06 −0.001 −0.02, 0.02 4.32E-04 −0.02 −0.03, −0.002 1.80E-04 0.01 −0.02, 0.04 5.74E-04 −0.02 −0.04, −0.005 Rhippo-FPN 2.96E-05 −0.01 −0.04, 0.02 1.24E-03 0.03 * 0.02, 0.05 5.08E-05 −0.01 −0.03, 0.02 2.16E-03 −0.04 * −0.06, −0.02 9.91E-06 0.003 −0.02, 0.03 5.60E-04 −0.02 −0.04, −0.005 Lhippo-SN 1.64E-04 0.01 −0.02, 0.04 7.58E-04 0.02 0.007, 0.04 9.51E-05 0.01 −0.01, 0.03 7.35E-04 −0.02 −0.04, −0.007 4.92E-04 0.01 −0.02, 0.04 6.36E-04 −0.02 −0.04, −0.005 Rhippo-SN 2.77E-03 −0.01 −0.04, 0.02 1.20E-03 0.03 * 0.01, 0.05 9.88E-05 0.004 −0.02, 0.03 2.55E-05 0.004 −0.01, 0.02 1.91E-03 0.01 −0.02, 0.03 2.05E-04 −0.01 −0.03, 0.004 Significant models are bolded (FDR-p < 0.05); * denotes passing a more stringent Bonferroni correction (p < 0.0005). Abbreviations: salience network (SN), default-mode network (DMN), frontoparietal network (FPN), left (L), right (R), amygdala (amyg), hippocampus (hippo). CRediT authorship contribution statement Devyn L. Cotter: Formal analysis, Writing – original draft, Writing – review & editing, Visualization. Claire E. Campbell: Writing – review & editing, Visualization. Kirthana Sukumaran: Project administration, Writing – review & editing. Rob McConnell: Methodology, Writing – review & editing. Kiros Berhane: Methodology, Writing – review & editing. Joel Schwartz: Methodology, Data curation, Resources, Writing – review & editing. Daniel A. Hackman: Methodology, Writing – review & editing. Hedyeh Ahmadi: Supervision, Writing – review & editing. Jiu-Chiuan Chen: Conceptualization, Methodology, Writing – review & editing. Megan M. Herring: Funding acquisition, Conceptualization, Methodology, Supervision, Project administration, Writing – review & editing. Appendix A. 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==== Front Open Access J Contracept Open Access J Contracept oajc Open Access Journal of Contraception 1179-1527 Dove 418820 10.2147/OAJC.S418820 Original Research Uptake and Associated Factors of Male Contraceptive Method Use: A Community-Based Cross-Sectional Study in Northern Uganda Tumwesigye et al Tumwesigye et al http://orcid.org/0000-0003-4656-4496 Tumwesigye Raymond 1 http://orcid.org/0000-0001-9748-693X Kigongo Eustes 2 Nakiganga Stella 3 Mbyariyehe Godfred 3 http://orcid.org/0000-0002-4406-7309 Nabeshya Joel 1 Kabunga Amir 4 Musinguzi Marvin 5 Migisha Richard 6 1 Department of Emergency Nursing and Critical Care, Faculty of Nursing and Midwifery, Lira University, Lira City, Uganda 2 Department of Environment Health and Disease Control, Faculty of Public Health, Lira University, Lira City, Uganda 3 Department of Nursing, Faculty of Nursing and Midwifery, Lira University, Lira City, Uganda 4 Department of Psychiatry, Faculty of Medicine, Lira University, Lira City, Uganda 5 Department of Community Health, Faculty of Public Health, Lira University, Lira City, Uganda 6 Department of Physiology, Mbarara University of Science and Technology, Mbarara City, Uganda Correspondence: Raymond Tumwesigye, Department of Emergency Nursing and Critical Care, Faculty of Nursing and Midwifery, Lira University, Lira City, Uganda, Tel +256 782810567, Email rtumwesigye@lirauni.ac.ug 14 7 2023 2023 14 129137 26 4 2023 09 7 2023 © 2023 Tumwesigye et al. 2023 Tumwesigye et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Background Uganda has one of the highest fertility rates in Sub-Saharan Africa (SSA). Improving contraceptive uptake in all genders, including males, may be critical to meeting family planning goals in such a setting. Yet, data on male contraception uptake and associated factors in SSA, including Uganda, are limited. We determined the uptake and associated factors of male contraception use in Lira City, Northern Uganda. Methods We conducted a community-based cross-sectional study from November 12, 2022, to December 12, 2022, among men aged ≥18 years. We used multi-stage sampling to select participants from 12 cells of Lira City divisions of East and West. Data were collected using interviewer-administered structured questionnaires. We defined uptake in males who had used any contraceptive method, including periodic abstinence, withdrawal, condoms, and vasectomy in the previous four weeks. We performed modified Poisson regression to identify associated factors of male contraception uptake. Results We recruited 401 participants with mean age of 30.4 (±9.3) years. Male contraceptive uptake was 46.4%, 95% CI: 41.5–51.3%. Ever heard about male contraception (adjusted prevalence ratio [aPR] =1.73, 95% CI: 1.172–2.539, p=0.006), willingness to use novel methods (aPR=2.90, 95% CI: 1.337–6.293, p=0.007), both partners being responsible for contraception (aPR: 1.53, 95% CI: 1.113–2.119, p=0.009) were the factors associated with male contraception uptake. Conclusion We found that nearly half of the men surveyed had used male contraceptive methods in Lira City. Factors associated with the uptake of male contraception included having heard about male contraception, joint couple decision regarding contraception, and the use of novel methods of male contraception. We recommend comprehensive education and awareness campaigns to promote male contraception, with a particular emphasis on encouraging shared decision-making within couples and introducing innovative contraceptive options. Keywords knowledge male contraception practices uptake Uganda funding from the Center for International Reproductive Health Training University of Michigan, United States. This research work was supported by the Center for International Reproductive Health Training the University of Michigan, it mainly supported the process of proposal development, data collection, and processing. The funder does not have any influence on the study findings or its processes This research was supported by seed funding from the Center for International Reproductive Health Training (CIRTH) at the University of Michigan, United States. This research work was supported by the Center for International Reproductive Health Training (CIRHT-UM), at the University of Michigan, it mainly supported the process of proposal development, data collection, and processing. The funder does not have any influence on the study findings or its processes. ==== Body pmcBackground Globally, male contraceptive use stands at 12.5% and about 60.0% of males are indirectly involved in family planning through spousal communication and approval.1 There is a paucity of literature concerning male contraceptive use in Africa; however, a recent systematic review reported a low level of willingness to use novel male hormonal contraceptives of 34.0%.2 According to the Uganda Demographic and Health survey of 2016, 35.9% of men were using a modern contraceptive method, an increase from 10.4% in 1995.3 Yet, the country is grappling with the highest fertility rate in the region and it stands at 5.4.4 Male partners play a key role in family planning/contraceptive uptake and use. This is influenced by different dimensions that include personal, organizational, spiritual, cultural, and political.2 Henceforth, increasing access to and uptake of male contraceptive methods (periodic abstinence, withdrawal, condoms, and vasectomy) is paramount in reducing abortion rates and unintended pregnancies.5 Additionally, contraception helps in healthy timing and spacing of pregnancies, hence regulating fertility. This correlates with a fall in infant, child, and maternal mortality.1 A recent review reported that male contraception has the potential to shift societal gender dynamics and provide males with gender control over their production.4,6 However, recent clinical trials have reported that men are less willing to use male contraceptives with a level as low as 13.6%.2 If not addressed, this is likely to compromise the achievement of Sustainable Development Goal 3.8 which targets health for all by the year 2030. In Lira City, there has been a recurrent resistance to family planning by men due to widespread misconceptions about the use of family planning with frequent cases of domestic violence towards their female counterparts.7 Furthermore, a recent study in Uganda found that for men, a lack of knowledge, fear of their partners experiencing side effects, and dissatisfaction with male contraceptive methods have been key barriers to their involvement in their reproductive health.8 Hence, male contraception has been underutilized due to a myriad of factors. Thus far, male contraceptive behavior has been a largely understudied area in Uganda, yet male involvement in family planning both as clients and partners remains a key focus of reproductive health programs.9 Therefore, the purpose of this study was to determine the uptake and associated factors of male contraception use in Lira, Northern Uganda. Methods Study Setting The study was conducted in Lira City from November 12, 2022, to December 12, 2022. Lira city is located in the central part of northern Uganda about 343km from Kampala, well known as one of the regions in northern Uganda with a poor contraceptive non-use prevalence of 50%.10 The city comprises four major divisions, namely: Lira City West, East Division, Central, and Adyel division. The current uptake of male modern contraceptives in Lira City is unknown; however, recent studies found that the prevalence of utilization of modern contraceptives among postpartum women at two health centers in Lira City was 49.4%.11 Study Design This was a community-based cross-sectional study. Study Population and Eligibility Criteria We included males aged 18 years and above, who were residing in the selected divisions of Lira City during the study period. The study excluded male health workers because they have good knowledge of male contraceptives and were likely to skew the data. Additionally, individuals who declined to consent were excluded. Sampling Criteria A multi-stage sampling technique was used to select the participants from the Lira City Divisions of East and West. The 12 selected cells were Bar-onger Central and Go-down, Railway Quarters, Boroboro East, Baridike, Owinyo church, Ayago (a and b) and Kirombe Central and West, Teso A and Lira Modern Primary School. The two divisions, East and West were selected. Within each of the two divisions, two sub-counties were selected by simple random sampling. From each sub-county, two parishes were selected by a simple random sampling technique. A consecutive sampling technique was used to select the participants who gave written consent. In the technique, participants meeting the inclusion criteria and willing to participate were selected for the study. Participants who at the time of data collection were emotionally or psychologically unstable or had difficulty communicating or had cognitive impairment were excluded. Sample Size Estimation The study estimated sample size using the Kish formula (1965), assuming a variability (p=0.13), 95% Confidence interval, 5% margin of error, and Z=1.96. In order to account for the non-response rate, the sample size was increased by 10% to 193 participants. By factoring in the design effect of 2, this doubled the calculated minimum sample size to generate a total estimate of 386. Data Collection Five research assistants who were social scientists and good in both English and local dialect were recruited and trained to guide participants in filling in the questionnaire. Data for the present study was collected using a researcher-formulated questionnaire. The instrument had two sections, A and B. Section A captured demographic information such as age, education, marital status, and others. Section B captured information on awareness of, knowledge of, and practices of male contraceptive use and had 15 items. Such items included, “Have you ever heard about male contraception?” It captured information on the basis of “yes” and “no.” The uptake of male contraception, or self-reported use of male contraceptives in the prior month, was the study’s outcome variable and was assessed as a yes/no response. The independent variables included sociodemographic characteristics, knowledge about, and practices regarding male contraception. Pretesting of the questionnaire was done on 10% of the respondents, giving a Cronbach's alpha of 0.89. Data Analysis Every questionnaire was checked for completeness. Data were collected using Open Data Kit (ODK) software and thereafter exported to Microsoft excel for cleaning and editing, which was later exported to STATA version 17 (STATACorp LLC, Texas, USA). Descriptive statistics including frequencies and percentages were used to summarize the participants’ characteristics. Univariate analysis was done to generate frequencies and percentages for male contraceptive uptake variables related to knowledge and practices. Bivariate and multivariate analysis with a well-constructed regression model of predictors of male contraception was done. The outcome variable was extracted from the question, have you ever used any male contraception in the previous four weeks? Responses were Yes or No. We utilized prevalence ratios by way of a modified Poisson regression method employing a generalized linear model with Poisson as family and log link without an offset and integrating robust standard errors.12,13 Given the high prevalence (46.4%), odds ratios could have overestimated the effect size, hence they were not employed.14 Results Socio-Demographic Characteristics We analyzed data from 401 male participants, with an average age of 30.4 (±9.3) years with an average of 3 children. Most participants had completed tertiary education (37.7%; n=151), were married (60.6%; n=243), and were peasants (46.3%; n=155). Most of the respondents were Anglican (47.4%; n=190) and lived in an urban setting (91.5%; n=367) (Table 1).Table 1 Socio-Demographic Characteristics of Respondents (N=401) Variable Category Frequency (n) Percentage (%) Age (years) 18–24 103 25.69 25–35 207 51.75 36–45 68 17.00 >45 22 5.50 Education No formal education 18 4.49 Primary 94 23.44 Secondary 138 34.41 Tertiary 151 37.66 Marital status Married 243 60.6 Not married 158 39.4 Occupation Businessman 119 35.52 Engineer 23 6.87 Health worker 7 2.09 Peasant 155 46.27 Politician 4 1.19 Teacher 27 8.06 Religion Anglican 190 47.38 Catholic 180 44.89 Muslims 31 7.73 Employment status Employed 80 19.95 Self employed 277 69.08 Student 44 10.97 Have children No 147 36.66 Yes 254 63.34 Number of children 1–3 187 73.62 4–6 53 20.87 >6 14 5.51 Desire to have children No 141 35.16 Yes 260 64.84 Average monthly income (UGX) <50,000 62 17.0 50,000–100,000 68 18.7 >100,000 234 64.3 Abbreviation: UGX, Ugandan shillings. Male Contraceptive Uptake Variables Related to Knowledge and Practices Out of the total sample of 401 male participants, the uptake of male contraceptives was 46.4% (n=186) with a 95% confidence interval of 41.5% to 51.3%. The majority of the respondents had heard about male contraceptives (61.9%; n=248) and knew condoms as a male contraceptive method (68.8%; n=275). Most of the respondents had obtained this information from friends (48.9%; n=108) and had talked to their spouses about using male contraceptives (53.1%; n=213). However, most of the respondents were not willing to use novel contraceptives (61.6%; n=247) and their spouses had not approved of the use of male contraceptives (51.4%; n=206) (Table 2).Table 2 Knowledge and Practices Regarding Male Contraceptive Use Among Respondents (N=401) Variable Attribute Frequency Percentage Heard about male contraceptive No 153 38.2 Yes 248 61.9 Willingness to use novel method No 247 61.6 Yes 154 38.4 Discussion with spouse No 188 46.9 Yes 213 53.1 Spousal approval No 206 51.4 Yes 195 48.6 Responsible for contraception Husband 139 34.7 Wife 68 17.0 Both 194 48.3 Source of information Friend 108 48.9 Social media 71 32.1 Television 13 5.9 Workmate 29 13.1 Reasons for non-use* Side effects 60 44.1 Do not know any method 25 18.4 Religious prohibition 18 13.2 Contraception is for women 15 11.0 Others 11 8.1 Desire for more children 7 5.2 Notes: *Reasons for non-use were assessed among 135 respondents, who answered this question. Factors Associated with Male Contraceptive Use At Multivariate analysis (Table 3), ever hearing about male contraception (adjusted prevalence ratio [aPR]=1.73, 95% CI: 1.172–2.539, p=0.006), willingness to use novel methods (aPR=2.90, 95% CI: 1.337–6.293, p=0.007), both partners responsible for contraception (aPR: 1.53, 95% CI: 1.113–2.119, p=0.009) were significantly associated with uptake of male contraceptives. Participants who had heard about male contraceptives were 1.73 times more likely to use male contraceptives compared to those who had not heard of male contraceptives. Respondents who were willing to use novel methods of male contraceptives were 2.9 times more likely to use male contraceptives compared to those who were not willing to use novel methods. Males who reported that both partners are responsible for contraceptive use were 1.53% more likely to use male contraceptives (Table 3).Table 3 Bivariate and Multivariate Analysis for Factors Associated with Male Contraceptive Use, Lira City, Uganda Variable Male Contraceptive Use Bivariate Analysis Multivariate Analysis No n (%) Yes n (%) PR 95% CI P value aPR 95% CI P value Age (years) 18–24 59(27.6) 44(23.7) Ref 25–35 98(45.8) 109(58.6) 1.23 0.869–1.750 0.24 2.49 0.636–9.766 0.19 36–45 40(18.7) 28(15.1) 0.96 0.600–1.548 0.88 1.48 0.358–6.152 0.59 >45 17(7.9) 5(2.7) 0.53 0.211–1.342 0.18 0.93 0.171–5.118 0.94 Education  None 11(5.1) 7(3.8) Ref Primary 64(29.8) 30(16.1) 0.82 0.360–1.868 0.61 Secondary 83(38.6) 55(29.6) 1.02 0.467–2.250 0.95 Tertiary 57(26.5) 94(50.5) 1.60 0.743–3.450 0.23 Marital status In a marital relationship 131(60.9) 112(60.2) Ref Not in a marital relationship 84(39.1) 74(39.8) 1.02 0758–1.363 0.92 Occupation Businessman 46(26.4) 73(45.3) Ref Engineer 5(2.9) 18(11.2) 1.28 0.762–2.137 0.36 1.15 0.743–1.771 0.54 Health worker 3(1.7) 4(2.5) 0.93 0.340–2.549 0.89 1.33 0.659–2.675 0.43 Peasant 107(61.5) 48(29.8) 0.50 0.351–0.727 <0.001 0.81 0.567–1.150 0.24 Politician 2(1.2) 2(1.2) 0.82 0.200–3.321 0.78 1.01 0.457–2.362 0.99 Teacher 11(6.3) 16(9.4) 0.97 0.562–1.651 0.90 1.23 0.707–2.132 0.47 Anglican 91(42.3) 99(53.2) Ref Catholic 105(48.8) 75(40.3) 0.80 0.592–1.079 0.14 0.85 0.621–1.157 0.30 Muslims 19(8.8) 12(6.5) 0.74 0.408–1.352 0.33 0.56 0.281–1.133 0.12 Employment Employed 37(17.2) 43(23.1) Ref Self employed 149(69.3) 128(68.8) 0.86 0.609–1.214 0.39 1.06 0.654–1.727 0.81 Student 29(13.5) 15(8.1) 0.63 0.352–1.142 0.13 3.92 0.856–17.916 0.08 Have children No 78(36.3) 69(37.1) Ref Yes 137(63.7) 117(62.9) 0.98 0.729–1.321 0.90 Number of children 1–3 98(71.0) 89(76.7) Ref 4–6 27(19.6) 26(22.4) 1.03 0.666–1.595 0.14 1.09 0.792–1.498 0.60 >6 13(9.4) 1(0.9) 0.15 0.021–1.077 0.06 0.27 0.048–1.494 0.13 Income Below 10,000 32(16.1) 7(4.2) Ref Ref 10,000–50,000 15(7.5) 8(4.9) 1.64 0.873–3.085 0.12 1.35 0.687–2.640 0.39 >50,000 152(76.4) 150(90.9) 2.17 1.271–3.714 0.05 1.37 0.740–2.511 0.32 Heard about male contraceptive No 116(54.0) 37(19.9) Ref Yes 99(46.1) 149(80.1) 2.48 1.733–3.561 <0.001 1.73 1.172–2.539 0.006 Willingness to use novel method No 148(68.8) 99(53.2) Ref Yes 67(31.2) 87(46.8) 1.72 1.272–2.334 <0.001 2.90 1.337–6.293 0.007 Discussion with spouse No 125(58.1) 63(33.9) Ref Yes 90(41.9) 123(66.1) 1.72 1.272–2.234 <0.001 Spousal acceptance of contraception No 131(60.9) 75(40.3) Ref Yes 84(39.1) 111(59.7) 1.56 1.166–2.095 0.003 0.92 0.516–1.651 0.79 Responsible for contraception Man 191(42.3) 48(25.8) Ref Both 89(41.4) 105(56.5) 1.57 1.114–2.205 0.01 1.53 1.113–2.119 0.009 Woman 35(16.3) 33(17.7) 1.41 0.902–2.189 0.13 1.43 0.093–2.203 0.110 Source of information Friend 49(49.5) 59(48.4) Ref Social media 31(31.3) 40(32.8) 1.03 0.690–1.540 0.88 Television 8(8.1) 5(4.1) 0.70 0.283–1.754 0.45 Workmate 11(11.1) 18(14.8) 1.14 0.670–1.925 0.64 Abbreviations: PR, prevalence ratio; aPR, adjusted prevalence ratio; CI, confidence interval; Ref, reference category. Discussion We conducted a study to determine the uptake and associated factors of male contraceptive method use in Northern Uganda. We found the uptake of male contraceptives was 46.4%. The findings report an improvement in the uptake of modern male contraception contrary to the previously reported uptake of 35.9% by a recent cross-sectional population survey conducted in Uganda.6 This is most likely due to the increase in massive campaigns on virtual communication platforms, radios, and TVs regarding male contraception use in the study setting. Moreover, in the current study, men who had ever heard about male contraception were more likely to use male contraception compared to their counterparts who did not get any information regarding male contraception. The uptake of male contraceptives in the current study is consistent with previous reports from Cameroon and Ghana, which documented rates of 46.4% and 42.6%, respectively.15,16 However, the uptake is higher than 38.4% reported in urban Uganda.17 This discrepancy may be attributed to differences in sample size and geographic settings. The results further revealed that 53.1% had talked to their spouses about using male contraceptives and the couple jointly consented to it. The findings of this study align with recent research conducted in Malawi and Tanzania, which reported a prevalence of male involvement in family planning decisions of 53.0% and 26.6%, respectively.18 This is further supported by a study conducted in Indonesia, which found that the approval of the family planning method by spouses positively influenced the uptake of male contraception.19 This study also revealed decreased willingness for uptake in situations where only male partners were responsible for contraception. Couples need to make a joint decision regarding contraception because it involves both individuals and affects their relationship, well-being, and future plans. Making a joint decision together ensures that both partners are comfortable and in agreement with the chosen method and promotes communication, mutual trust in the relationship and overall quality of life. Our findings show that participants who were willing to use novel methods of male contraceptives were more likely to use male contraceptives compared to those who were not willing to use novel methods. This finding aligns with the results of a recent qualitative survey conducted in Uganda and Burkina Faso, which indicated a greater level of acceptance and positive attitudes towards novel hormonal contraceptive methods in Uganda compared to Burkina Faso.20 These findings categorically indicate that there is growing awareness about men taking responsibility for contraception and will most likely accept and utilize these novel methods once available, given the fact that traditional hormonal female contraceptive methods have been associated with serious lifelong side effects in women. Our results revealed that those who had not heard of male contraceptives and were not willing to use novel methods were less likely to use male contraceptive methods. Both of these circumstances negatively affect male contraceptive uptake rates, because men are not educated on the different options of male contraception and may not consider using them as a viable option for family planning. This can lead to deadly complications that include unintended pregnancies which can have long-term consequences for individuals, families, and communities. This result mirrors the findings of the study conducted in 2017 in Uganda.21 In a nutshell, the improved male contraceptive uptake has public health implications, as this will most likely reduce the burden of contraceptive uptake on women and potentially lower the magnitude of unintended pregnancies and the overall burden of maternal morbidity and mortality. The factors associated with male contraception such as having heard about male contraception could have been indirectly influenced by increasing male literacy levels, socioeconomic status, exposure to sexual reproductive health and rights services in schools, and media exposure. Therefore, such efforts and many others should be continuing to exist and be supported by the government of Uganda and other development partners. Lastly, joint couple decision-making around contraception use could lead to increased contraception use in general and better decision-making around family planning. The factors that could impact this decision-making process could include the level of couple communication, gender norms, power dynamics within the relationship, and individual attitudes towards contraception. Strengths and Limitations of the Study The study helped provide evidence of acceptability regarding further plans to roll out novel male contraception methods. However, it was limited in scope and only focused on male contraceptive uptake in Lira City Northern Uganda; hence, our findings can only be generalized to the population of men in Lira City in Northern Uganda and other similar peri-urban settings. Because the study was cross-sectional, we cannot establish causality, its limited to one point in time and does not provide information on temporal relationships. Additionally, we could not rule out under-reporting of male contraception given that it is a culturally sensitive issue that is subject to social desirability bias and the Hawthorne effect. Despite its limitations, this study produced data that will help researchers better understand the magnitude of male contraception is low and the factors associated with the uptake. Conclusion We found that nearly half of the men surveyed had used male contraceptive methods in Lira City. The factors associated with the uptake of male contraception included having heard about male contraception, joint couple decision regarding contraception, and use of novel methods of male contraception were significantly implicated in increasing willingness for uptake. We recommend increasing efforts to create more awareness and education around male contraceptive methods with a focus on joint decision-making between couples and the use of novel methods. This could potentially lead to an increase in the adoption of male contraceptives and ultimately contribute to more effective family planning and reproductive health outcomes. Acknowledgments We thank everyone who participated in this study. We are also grateful for the support from the Center for International Reproductive Health Training (CIRTH) at the University of Michigan, United States, in conducting this study. Abbreviations aPR, adjusted prevalence ratio; CI, confidence interval; CIRTH, Center for International Reproductive Health Training; ODK, Open Data Kit; PR, prevalence ratio; SD, standard deviation. Data Sharing Statement The Principal Investigator is the custodian of the datasets and other materials of this study. For confidentiality reasons, the datasets are not publicly available. However, the data sets can be availed upon reasonable request from the corresponding author. Ethics Approval and Consent to Participate The ethical approval was granted by Gulu University Research Ethics Committee under approval number GUREC-2022-330. We sought and obtained written informed consent from respondents during data collection. The participants indicated their consent by checking an appropriate box for consent before filling out the questionnaires. Participants were told that their participation was voluntary and that there would be no negative consequences if they refused to participate (none declined). During data collection, respondents were assigned unique identifiers instead of names to protect their confidentiality. Information was stored in password-protected computers and was not shared with anyone outside the investigation team. Additionally, we obtained permission from Local council Chairpersons of the selected wards of Lira City where the study was conducted. Author Contributions All authors (RT, EK, SN, GM, JN, AK, MM and RM) made substantial contributions to the conception and design of the study, acquisition, analysis, and interpretation of the data. All the authors took part in drafting and revising the article critically for important intellectual content; all the authors agreed to submit the manuscript to the current journal; all authors gave final approval of the version to be published, and agreed to be accountable for all aspects of the work. Disclosure The authors of this work report no conflicts of interest. However, it is important to note that Lira University had not yet established its own Research Ethics Committee at the time of our study (REC). Therefore, we sought ethical approval for our research protocol from the nearby institution, Gulu University. Initial establishment of Lira University was as a constituent college affiliated with Gulu University. ==== Refs References 1. Shiferaw WS, Akalu TY, Aynalem YA. Prevalence of erectile dysfunction in patients with diabetes mellitus and its association with body mass index and Glycated hemoglobin in Africa: a systematic review and meta-analysis. Int J Endocrinol. 2020;2020 :1–10. doi:10.1155/2020/5148370 2. Reynolds-Wright JJ, Cameron NJ, Anderson RA. Will men use novel male contraceptive methods and will women trust them? A systematic review. J Sex Res. 2021;58 :838–849. doi:10.1080/00224499.2021.1905764 33900134 3. UDHS. Uganda Demographic and Health Survey 2016; 2016. 4. ICF&UBOS. No the DHS program—Uganda: DHS, 2018—final report title; 2018. 5. Kriel Y, Milford C, Cordero J, et al. Male partner influence on family planning and contraceptive use: perspectives from community members and healthcare providers in KwaZulu-Natal, South Africa. Reprod Health. 2019;16 :1–15. doi:10.1186/s12978-019-0749-y 30621726 6. Namasivayam A, Lovell S, Namutamba S, Schluter PJ. Predictors of modern contraceptive use among women and men in Uganda: a population-level analysis. BMJ Open. 2020;10 :e034675. doi:10.1136/bmjopen-2019-034675 7. The daily Monitor. Lira men reject family planning; 2021. 8. Namasivayam A Understanding unmet need for contraception in Uganda: a mixed methods study of contraceptive use among women and men; 2020. 9. Okalo P, Arach AA, Apili B, Oyat J, Halima N, Kabunga A. Predictors of unintended pregnancy among adolescent girls during the second wave of COVID-19 pandemic in Oyam District in Northern Uganda. Open Access J Contracept. 2023;Volume 14 :15–21. doi:10.2147/OAJC.S399973 10. Otim J. Contraceptive nonuse among women in Uganda: a comparative assessment of predictors across regions. BMC Womens Health. 2020;20 (1 ):1–14. doi:10.1186/s12905-020-01148-6 31898500 11. Isoke R, Kunihira I, Apili F. Prevalence, barriers and facilitators influencing modern contraceptive use among postpartum mothers at ober and barapwo health centre III, Lira City: a cross sectional design; 2022. 12. Cook TD. Advanced statistics: up with odds ratios! A case for odds ratios when outcomes are common. Acad Emerg Med. 2002;9 :1430–1434. doi:10.1197/aemj.9.12.1430 12460851 13. Barros AJD, Hirakata VN. Alternatives for logistic regression in cross-sectional studies: an empirical comparison of models that directly estimate the prevalence ratio. BMC Med Res Methodol. 2003;3 :1–13. doi:10.1186/1471-2288-3-21 12515580 14. Migisha R, Ario AR, Kwesiga B, et al. Risk perception and psychological state of healthcare workers in referral hospitals during the early phase of the COVID-19 pandemic, Uganda. BMC Psychol. 2021;9 :195. doi:10.1186/s40359-021-00706-3 34920763 15. Tsegaye R. Family planning need of people living with HIV/AIDS in antiretroviral therapy clinics of Horro Guduru Wollega zone, Ethiopia. BMC Res Notes. 2017;10 :1–6. doi:10.1186/s13104-017-2914-0 28057050 16. Melaku YA, Zeleke EG. Contraceptive utilization and associated factors among HIV positive women on chronic follow up care in Tigray Region, Northern Ethiopia: a cross sectional study. PLoS One. 2014;9 :e94682. doi:10.1371/journal.pone.0094682 24743241 17. Mbabazi L, Nabaggala MS, Kiwanuka S, et al. Factors associated with uptake of contraceptives among HIV positive women on dolutegravir based anti-retroviral treatment-a cross sectional survey in urban Uganda. BMC Women's Health. 2022;22 :262. doi:10.1186/s12905-022-01842-7 35761248 18. Osuafor GN, Akokuwebe ME, Idemudia ES. Male Involvement in family planning decisions in Malawi and Tanzania: what are the determinants? Int J Environ Res Public Health. 2023;20 :5053. doi:10.3390/ijerph20065053 36981959 19. Irawaty DK, Pratomo H. Socio-demographic characteristics of male contraceptive use in Indonesia. Malaysian J Public Heal Med. 2019;19 :152–157. doi:10.37268/mjphm/vol.19/no.1/art.47 20. Cartwright AF, Lawton A, Brunie A, Callahan RL. What about methods for men? A qualitative analysis of attitudes toward male contraception in Burkina Faso and Uganda. Int Perspect Sex Reprod Health. 2020;46 :153. doi:10.1363/46e9720 32985988 21. Thummalachetty N, Mathur S, Mullinax M, et al. 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==== Front J Multidiscip Healthc J Multidiscip Healthc jmdh Journal of Multidisciplinary Healthcare 1178-2390 Dove 429655 10.2147/JMDH.S429655 Letter Viewpoint on “The Frail Scale – A Risk Stratification in Older Patients with Acute Coronary Syndrome” [Letter] Li Li Li Xinyue 1 1 Department of Cardiovascular Disease, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China Correspondence: Xinyue Li, Department of Cardiovascular Disease, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding Great Wall North Street No 320, Baoding, Hebei, People’s Republic of China, Tel +8615633144512, Email lxy013579@sina.com 14 7 2023 2023 16 19371938 08 7 2023 11 7 2023 © 2023 Li. 2023 Li. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). ==== Body pmcDear editor We appreciate the authors’ paper titled “Evaluation of the Frail Scale - A Risk Stratification in Older Patients with Acute Coronary Syndrome” by Anh Phuong et al.1 We acknowledge the significance of their findings in the field of health education. As readers, we would like to share our perspectives on this study and offer input that can contribute to the further development of this research for future researchers interested in testing the frail scale. The study conducted by Anh Phuong et al aimed to investigate the influence of frailty on in-hospital adverse outcomes and net adverse clinical events (NACE) in older patients diagnosed with acute coronary syndrome (ACS). The authors aimed to demonstrate the association between frailty in ACS patients and an elevated risk of in-hospital adverse outcomes and NACE. The study’s findings have provided promising insights into the potential use of the simple FRAIL scale for risk stratification in older ACS patients. However, in addition to the noteworthy findings, it is important to consider certain aspects when evaluating the FRAIL scale. The baseline data of the patients included in this study are generally classified appropriately, but the specific details still require further elaboration. Firstly, chronic kidney disease (CKD) had not been included in the comorbidity part listed in Table 1. However, CKD patients have a higher prevalence of frailty, particularly those with end-stage renal disease, and even higher among dialysis patients.2 Recent studies have also demonstrated that frailty is an independent risk factor for elderly patients with CKD.3 Secondly, the categorization of BMI in Table 1 was also inaccurate, as it failed to include data for obese individuals in addition to patients with underweight, normal weight, and overweight. Thirdly, the category of in-hospital adverse outcomes in Table 1 did not include acute kidney injury (AKI). Historically, AKI had been a well-known complication among hospitalized patients and was frequently observed as a severe complication of acute myocardial infarction.4 Elderly patients with ACS were more susceptible to developing AKI, which often signifies a poor prognosis.5 Additionally, Table 1 in the description of in-hospital adverse outcomes and NACE in this study, both of them included stroke and major bleeding, which may result in overlapping. Lastly, some statistical analyses in this study deserve further discussion. Firstly, variables in Table 3, such as gender, age, LVEF, and angiography, when including them in the regression analysis, each variable should be separately set with a designated reference and the odds ratio (OR) value for the reference should normally be set as 1. Secondly, the regression analysis presented in Table 4, as the number of variables included increased, the OR values became larger. However, in general, the OR values should tend to decrease with the inclusion of additional variables. This result contradicts the usual principles of statistics. Therefore, we recommend that the authors make adjustments to the aforementioned issues, as failing to do so may have varying degrees of impact on the statistical results, ultimately making it difficult to establish valid clinical conclusions. In conclusion, we acknowledge that Anh Phuong’s study can serve as a valuable reference for reviewing and uncovering intriguing insights into the potential role of the simple FRAIL scale in risk stratification for older patients with ACS in coronary care settings. However, it is important to consider the need for extensive experience and evidence across various subgroups of populations. To ensure broader applicability and generalizability, it is crucial to validate the findings in diverse populations, including different racial and ethnic backgrounds, as the prevalence of these patients varies. Disclosure The author reports no conflicts of interest in this communication. ==== Refs References 1. Pham HM, Nguyen AP, Nguyen HTT, et al. The frail scale - a risk stratification in older patients with acute coronary syndrome. J Multidiscip Health C. 2023;16 :1521–1529. doi:10.2147/JMDH.S409535 2. Wilkinson TJ, Miksza J, Zaccardi F, et al. Associations between frailty trajectories and cardiovascular, renal, and mortality outcomes in chronic kidney disease. J Cachexia Sarcopenia Muscle. 2022;13 (5 ):2426–2435. doi:10.1002/jcsm.13047 35851589 3. Chang J, Hou W, Li Y, et al. Prevalence and associated factors of cognitive frailty in older patients with chronic kidney disease: a cross-sectional study. BMC Geriatr. 2022;22 (1 ):681. doi:10.1186/s12877-022-03366-z 35978304 4. Oweis AO, Zeyad HN, Alshelleh SA, Alzoubi KH. Acute kidney injury among patients with multi-drug resistant infection: a study from Jordan. J Multidiscip Healthc. 2022;15 :2759–2766. doi:10.2147/JMDH.S384386 36504497 5. Cosentino N, Resta ML, Somaschini A, et al. Acute kidney injury and in-hospital mortality in patients with ST-elevation myocardial infarction of different age groups. Int J Cardiol. 2021;344 :8–12. doi:10.1016/j.ijcard.2021.09.023 34537309

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==== Front Neuropsychiatr Dis Treat Neuropsychiatr Dis Treat ndt Neuropsychiatric Disease and Treatment 1176-6328 1178-2021 Dove 424382 10.2147/NDT.S424382 Letter Neurological manifestations of long COVID: a single-center one-year experience [Letter] Li et al Li et al Li Xingling 1 2 * http://orcid.org/0000-0001-8759-5083 Hu Hantong 1 2 * Cheng Yingying 1 2 1 Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China 2 Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou City, People’s Republic of China Correspondence: Yingying Cheng, Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Hangzhou City, 310000, People’s Republic of China, Email cyysince@163.com * These authors contributed equally to this work 14 7 2023 2023 19 16051606 05 6 2023 09 6 2023 © 2023 Li et al. 2023 Li et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Zhejiang Province Public Welfare Technology Application Research The work was supported by the Zhejiang Province Public Welfare Technology Application Research (grant number: LTGY23H270003) and Zhejiang Provincial Famous Traditional Chinese Medicine Experts Inheritance Studio Construction Project (grant number: GZS2021027). ==== Body pmcDear editor We read with great interest a recently published study by Lisa Taruff et al in Neuropsychiatric Disease and Treatment.1 This study found that for patients who developed a previous mild form of COVID-19, the majority of them would present persistent neurological and neuropsychological symptoms.1 Specifically, various neuropsychological disorders have been frequently reported in patients with long COVID, such as anxiety, depression, and sleep disorders. Thus, this paper discusses the potential value of acupuncture and moxibustion as adjunctive therapy for alleviating neuropsychological disorders associated with long COVID in the post-epidemic era. As an important component of traditional Chinese medicine (TCM), acupuncture and moxibustion have been frequently used as complementary treatments for COVID-19 and related complications. To note, several published TCM guidelines and consensuses for COVID-19 in the past three years have specifically focused on the adjunctive use of acupuncture for COVID-19 treatment. Moreover, a recently published scoping review2 demonstrated that evidence from case reports, clinical trials, and randomized controlled trials (RCTs) supporting the use of acupuncture and moxibustion in COVID-19-associated neuropsychological disorders is growing. For instance, RCTs have shown that, compared with controls, acupuncture and moxibustion can significantly improve anxiety and depressive symptoms in long-COVID patients.2 In a RCT by Yang et al,3 auricular acupuncture combined with Baduanjin was found to have a better effect on improving sleep quality, anxiety, and depression conditions in COVID-19 patients with insomnia than pharmacotherapy (ie, oral administration of estazolam). Another encouraging study 4 revealed that adopting a mobile internet-based moxibustion technique for COVID-19 treatment is feasible. Through a mobile internet platform, patients were instructed to perform self-administered moxibustion for COVID-19-related symptoms at home. This internet-based mode of self-administered moxibustion can not only relieve respiratory symptoms such as cough and fatigue and improve neuropsychological state but also potentially protect front-line medical professionals against COVID-19. Additionally, several ongoing systematic reviews and meta-analyses are investigating the efficacy and safety of acupuncture and/or moxibustion for treating COVID-19-related neuropsychological disorders,2 and their results are eagerly anticipated. Apart from the aforementioned clinical trials, experimental studies are emerging to explore the possible mechanisms underlying acupuncture and moxibustion for alleviating COVID-19-associated symptoms. Notably, a study5 based on bioinformatics and topology systematically revealed the multi-target mechanisms of acupuncture therapy for COVID-19. In this study,5 180 protein targets and two active compounds produced were identified, in which the results suggested that the effect of acupuncture for COVID-19 was associated with suppression of inflammatory stress, improvement of immunity, and regulation of nervous system function, including activation of neuroactive ligand–receptor interaction, calcium signaling pathway, cancer pathway, viral carcinogenesis, and Staphylococcus aureus infection. Taken together, it is feasible and valuable to apply acupuncture and moxibustion as adjunctive therapy for long-COVID-19-associated neuropsychological disorders. Especially, in the post-epidemic era, acupuncture and moxibustion are likely to play an important role and deserve further application in clinical practice. Acknowledgment Xingling Li and Hantong Hu contributed equally to this work as co-first authors. Disclosure The authors declare that they have no competing interests in this communication. ==== Refs References 1. Taruffi L, Muccioli L, Mitolo M, et al. Neurological manifestations of long COVID: a single-center one-year experience. Neuropsychiatr Dis Treat. 2023;19 :311–319. doi:10.2147/NDT.S387501 36761395 2. Ren M, Liu Y, Ni X, et al. The role of acupuncture and moxibustion in the treatment, prevention, and rehabilitation of patients with COVID-19: a scoping review. Integr Med Res. 2022;11 (4 ):100886. doi:10.1016/j.imr.2022.100886 35967901 3. Yang C, Ma Y, Mei JH, Gong X, Wang M, Liu K. Observation of therapeutic effect on coronavirus disease 2019 with insomnia in treatment with baduanjin and auricular point sticking therapy. Chin Acupuncture Moxibust. 2021;41 (3 ):243–246. doi:10.13703/j.0255-2930.20200327-0002 4. Chen X, Huang W, Liu BY, et al. Moxibustion therapy in prevention and treatment of coronavirus disease 2019 (COVID-19): construction and application of non-contact diagnosis and treatment mode. Chin Acupuncture Moxibust. 2020;40 (10 ):1027–1033. doi:10.13703/j.0255-2930.20200428-k0006 5. Han Z, Zhang Y, Wang P, Tang Q, Zhang K. Is acupuncture effective in the treatment of COVID-19 related symptoms? Based on bioinformatics/network topology strategy. Brief Bioinform. 2021;22 (5 ):bbab110. doi:10.1093/bib/bbab110 33866350

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==== Front Clin Exp Gastroenterol Clin Exp Gastroenterol ceg Clinical and Experimental Gastroenterology 1178-7023 Dove 417644 10.2147/CEG.S417644 Case Report A Case of Pathologically Complete Response After Nivolumab Combined with Chemotherapy in a Gastric Cancer Patient with Virchow’s Lymph Node Metastasis Izumo et al Izumo et al http://orcid.org/0000-0001-7348-1616 Izumo Wataru 1 Hosoda Kei 1 Kuramochi Hidekazu 2 Nakajima Go 2 http://orcid.org/0000-0001-8262-8122 Maeda Shinsuke 1 http://orcid.org/0000-0002-8850-4566 Ito Shunichi 1 Nagashima Yoji 3 Itabashi Michio 1 1 Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, 162-8666, Japan 2 Department of Chemotherapy and Palliative Care, Tokyo Women’s Medical University, Tokyo, 162-8666, Japan 3 Department of Surgical Pathology, Tokyo Women’s Medical University Hospital, Tokyo, 162-8666, Japan Correspondence: Wataru Izumo, Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan, Tel +81-3-3353-8111, Fax +81-3-5269-7507, Email izumo.wataru@twmu.ac.jp 14 7 2023 2023 16 107115 18 4 2023 10 7 2023 © 2023 Izumo et al. 2023 Izumo et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Abstract Gastric cancer with Virchow’s lymph node metastasis (LNM) is not indicated for initial curative surgery. Although there have been some case reports of curative resections after pre-operative treatment, including immune checkpoint inhibitors (ICIs), there is no consensus regarding the optimal timing of surgery. We describe a rare case of initially unresectable gastric cancer treated preoperatively with nivolumab combined chemotherapy, which achieved a pathologically complete response. An 82-year-old man was referred for gastric cancer treatment. Contrast-enhanced computed tomography revealed stomach wall thickening and swollen left supraclavicular LN. This gastric cancer was assessed as unresectable due to the presence of Virchow’s LNM; therefore, chemotherapy and ICI using S-1 plus oxaliplatin plus nivolumab were administered. After three courses of treatment, the primary tumor and Virchow’s LN showed a marked reduction in size. The patient underwent Virchow’s LNM resection as a preliminary step to determine indications for curative surgery. A pathological examination revealed no viable cancer cells were found inside the resected LN. The patient underwent distal gastrectomy. Pathological examination revealed complete degeneration of the primary tumor and regional LN without residual carcinoma. The patient did not receive adjuvant chemotherapy and survived with no evidence of recurrence for one year after the initial treatment. Keywords gastric cancer Virchow’s lymph metastasis complete response pre-operative treatment nivolumab ==== Body pmcPlain Language Summary We describe a rare case of initially unresectable gastric cancer treated preoperatively with nivolumab combined chemotherapy, which achieved a pathologically complete response. An 82-year-old man was referred for gastric cancer treatment. Contrast-enhanced computed tomography revealed stomach wall thickening and swollen left supraclavicular LN. This gastric cancer was assessed as unresectable due to the presence of Virchow’s LNM; therefore, chemotherapy and ICI using S-1 plus oxaliplatin plus nivolumab were administered. After three courses of treatment, the primary tumor and Virchow’s LN showed a marked reduction in size. The patient underwent Virchow’s LNM resection as a preliminary step to determine indications for curative surgery. A pathological examination revealed no viable cancer cells were found inside the resected LN. The patient underwent distal gastrectomy. Pathological examination revealed complete degeneration of the primary tumor and regional LN without residual carcinoma. The patient did not receive adjuvant chemotherapy and survived with no evidence of recurrence for one year after the initial treatment. Introduction Gastric cancer was the fifth most common malignancy and the second leading cause of cancer-related deaths worldwide in 2018.1 In particular, there is no indication for initial surgical resection for stage IV gastric cancer, and the prognosis of these patients remains poor, with their median survival time reported to be 8.8–14.1 months.2,3 Recently, the efficacy in prolonging the prognosis for unresectable gastric cancer patients by immune checkpoint inhibitors (ICIs) have been demonstrated.4–6 Although there have been some case reports of conversion surgery after pre-operative treatment, including ICIs, for stage IV gastric cancer,7–9 there is no consensus regarding the optimal timing of curative gastrectomy. In this case, the indication for conversion surgery in a patient with stage IV gastric cancer was determined based on prior pathological diagnosis of unresectable factors. Moreover, the present study presents a rare case of initially unresectable gastric cancer with Virchow’s lymph node metastasis (LNM) treated preoperatively with nivolumab combined chemotherapy, which achieved a pathologically complete response. Case Report An 82-year-old man was referred for the treatment of gastric cancer. The patient had abdominal pain, nausea, and vomiting for several weeks. He had no medical or family history of gastric cancer. Physical examination revealed mild anemia in the palpebral conjunctiva. The serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19–9 (CA19-9), and Krebs von den lungen-6 (KL-6) were within the normal limits, but the serum levels of hemoglobin and albumin declined to 10.1 g/dL and 3.2 g/dL, respectively. The Helicobacter pylori antibody test result was positive in the blood. Esophagogastroduodenoscopy (EGD) revealed an irregular ulcerative tumor in the middle to lower region of the stomach, and the pyloric ring was constricted such that the EGD could barely pass through it (Figure 1). Endoscopically, the lesion was diagnosed as a type 3 advanced gastric cancer. Pathological examination of the endoscopic biopsy specimen from this region indicated poorly differentiated adenocarcinoma, and immunostaining for human epidermal growth factor type 2 (HER2) was negative (Figure 2a and b). Microsatellite instability (MSI) test results were MSI-stable In addition, the result of the combined positive score (CPS), which indicates the expression of the programmed cell death-ligand 1, was more than 5%. Figure 1 Endoscopic finding before treatment. On esophagogastroduodenoscopy before treatment, an irregular ulcerative tumor in the middle to lower stomach and the pyloric ring was constricted so that the scope could barely pass through it. Figure 2 Histopathological findings of biopsied primary gastric cancer. (a) On hematoxylin and eosin staining, alveolar and solid proliferation of tumor cells with hyperchromatic and enlarged nuclei with occasional glandular lumina were detected. (b) On immunostaining, the tumor cells were negative for HER2. Contrast-enhanced computed tomography (CT) revealed thickening of the wall of the middle to lower stomach and a swollen left supraclavicular LN (Figure 3a and b). However, no distant metastasis to any other organs, including the liver, lung, peritoneal dissemination, or paraaortic LN, was observed. The patient did not undergo PET-CT at this time. Figure 3 Radiological findings before treatment. (a and b) On contrast-enhanced computed tomography before treatment, a thickening of the wall of the middle to lower stomach (black arrows) and a swollen left supraclavicular lymph node (white arrows) were detected. Initially, gastric cancer was classified as unresectable because of Virchow’s LNM, and a laparoscopic gastrojejunostomy with partial gastric partitioning was performed to improve the gastric obstruction. Subsequently, the patient received chemotherapy combined with ICI treatment using S-1 plus oxaliplatin (SOX) plus nivolumab fifteen days after gastrojejunostomy with partial gastric partitioning. Anthropometric measurements were as follows: height: 177.5 cm, weight: 63.6 kg, and body surface area: 1.79 m². The patient was administered S-1 (120 mg/body/day) orally on days 1–14, a 0.5-h intravenous infusion of nivolumab at a dose of 360 mg/body, and then a 2-h intravenous infusion of oxaliplatin at a dose of 130 mg/m2, at 3-week intervals. After the first course, the patient experienced an adverse event of fatigue (grade 2), so the doses of S-1 and oxaliplatin were reduced from the next course. S-1 (100 mg/body/day) was administered orally on days 1–14, a 0.5-h intravenous infusion of nivolumab at a dose of 360 mg/body, followed by a 2-h intravenous infusion of oxaliplatin at a dose of 100 mg/m2. The patient did not experience any grade 2 or higher adverse event during or after the second course of treatment. After three courses of treatment, EGD revealed that the primary gastric cancer had shrunk, and no mucosal irregularities were observed (Figure 4a). Pathological examination of the endoscopic biopsy specimen revealed regenerative atypia without malignant features. Contrast-enhanced CT detected decreased gastric wall thickening and reduced size of the swollen Virchow’s LN (Figure 4b and c). PET-CT showed that mild accumulation was still present in the stomach (SUVmax 3.33); however, there was no abnormal accumulation in Virchow’s LN (Figure 4d and e). As an adverse effect, chest CT revealed grade 1 interstitial pneumonia (Figure 4f), and the serum level of KL-6 increased to 1162 U/mL, but no clinical respiratory symptoms were present. Figure 4 Endoscopic and radiological findings after pre-operative treatment. (a) On esophagogastroduodenoscopy after 3 courses of pre-operative treatment, an irregular ulcerative tumor had shrunk, mucosal irregularities had disappeared, and scarring was observed. (b and c) On contrast-enhanced computed tomography after 3 courses of pre-operative treatment, a thickening of the gastric wall (black arrows) and the size of swollen left supraclavicular lymph node (white arrows) were decreased. (d and e) On PET-CT after 3 courses of pre-operative treatment, a mild accumulation was still present in the stomach (SUVmax 3.33: black arrows) and there was no abnormal accumulation in a left supraclavicular lymph node (white arrows). (f) On plain chest computed tomography after 3 courses of pre-operative treatment, a mild ground glass opacity was detected. At this point, we determined that continued SOX plus nivolumab therapy was at risk for exacerbation of interstitial pneumonia. First, the patient underwent Virchow’s LN resection as a preliminary step to determine indications for curative resection. Thus, if Virchow’s LN is cancer-negative, it will be determined that the unresectable factor is controlled, and curative conversion surgery will be performed, but if not, drug therapy will be continued. Histopathological examination revealed that the insides of the resected Virchow’s LNs were entirely necrotic, and histiocytes were conspicuous around them. Furthermore, these necrotic parts were positive for AE1/AE3 staining and were thought to be previously present with metastasis from epithelial malignancy but are now thought to be only ghostly cancerous cells. No viable cancer cells were found inside the resected LN (Figure 5a and b). Figure 5 Histopathological findings of Virchow’s lymph nodes and primary gastric cancer by the resected specimen. (a) On hematoxylin and eosin staining of the resected Virchow’s lymph nodes, there is coagulation necrosis (*) surrounded with histiocyte. There are no viable cancer cells. (b) On immunohistochemical staining for cytokeratin (clone AE1/AE3) of the resected Virchow’s lymph nodes, the necrotic regions were stained, indicate of necrotic change of cancer cells. (c, d) On hematoxylin and eosin staining of the resected stomach, mucosa (c) and muscularis propria (d) failed to show any viable cancer cell. Therefore, in the second phase, the patient underwent robot-assisted distal gastrectomy with D2 regional LN dissection because on preoperative PET-CT, a mild accumulation was still present in the stomach (SUVmax 3.33). Histopathological examination revealed complete degeneration of the primary tumor and regional LN without any residual carcinoma (Figure 5c and d), and the histological response of the tumor was categorized as grade 3. The patient had no post-operative complications, survived without a recurrence for one year after the initial treatment, and did not receive adjuvant chemotherapy. Therefore, a treatment strategy that evaluates unresectable factors pathologically in advance to determine the indications for curative conversion surgery may be useful for initially unresectable gastric cancer after pre-operative treatment. Discussion Gastric cancer is the fifth most common malignant neoplasm and the second leading cause of cancer-related deaths worldwide.1 In particular, the incidence and mortality rate of gastric cancer are highest in Eastern Asia. In Japan, gastric cancer is still the third most common malignant cancer and the third leading cause of cancer-related deaths.10 Although surgical resection is usually the most suitable treatment for resectable gastric cancer, there is no indication for gastrectomy in patients with distant metastases, including liver, lung, peritoneal dissemination, and distant LN. Therefore, chemotherapy is the standard treatment for stage IV gastric cancer. Patients with stage IV gastric cancer still have a poor prognosis, with a five-year overall survival rate of 8.8 to 14.9%.2,11 These survival rates were still unsatisfactory. A left supraclavicular LN was first described by Rudolf Ludwig Karl Virchow as a frequent metastasis from gastric cancer.12 Subsequently, a left supraclavicular LN is called Virchow’s LN, and metastasis to this site is considered the final stage of lymphatic progression of cancer, with a very poor prognosis. The prognostic significance of non-curative surgery for reducing the tumor burden of stage IV gastric cancer has been denied in previous clinical trials.13 However, with the progression of anticancer drug therapy, some case reports state that curative surgery for stage IV gastric cancer becomes possible after pre-operative treatment.7–9,14–16 An international multicenter retrospective study verified the significance of conversion surgery and found that the median survival time of all resected patients who received pre-operative treatment for stage IV gastric cancer was 36.7 months. Those of R0, R1, and R2 resection were 56.6, 25.8, and 21.7 months, respectively.17 In addition, the incidence of Clavien–Dindo grade 3 or higher post-operative complication and mortality rates in conversion surgery patients were 10.3 and 0.2%, respectively.17 These results were relatively favorable and have been considered a treatment option for stage IV gastric cancer when R0 resection is possible after pre-operative treatment.18 However, there is still no clear consensus on conversion surgery for stage IV gastric cancer, and the optimal criteria and duration of pre-operative treatment for which conversion surgery should be performed remain unclear. Moreover, it has not yet been concluded at this time whether curative resection or continued chemotherapy for stage IV gastric cancer after pre-operative treatment is superior, and comparative clinical trials (The RENAISSANCE trial) are being conducted,19 the results of which should be watched closely. In recent years, a small number of metastases in a small number of metastatic organs is called oligo metastasis. This case is thought to be an oligo metastasis. In gastric cancer, the efficacy of radical resection after preoperative treatment has been suggested for a small number of localized aortic lymph node metastases.20 In addition, the significance of surgical resection has been suggested for single liver metastasis.21,22 Although there are no comprehensive reports on Virchow’s LNM, considering the same as aortic lymph node metastasis, radical resection after preoperative treatment as in this case may lead to improved prognosis. In patients with gastric obstruction, there are some options for improving gastric obstruction: gastrojejunostomy, stents, naso-enteric nutrition tubes, and gastrostomy. Gastrojejunostomy is considered to be preferable to stenting for gastric obstruction if the patient has a certain amount of survival time and is able to tolerate the surgery, and the site of gastric cancer is amenable to anastomosis.23,24 In addition, previous literatures reported that up to 50% of patients who underwent gastrojejunostomy developed delayed gastric emptying postoperatively and also showed that the addition of gastric partitioning improved postoperative gastric emptying.25–27 Therefore, we think that gastrojejunostomy with partial or complete gastric partitioning is currently the first choice for patients with gastric obstruction. In addition, decompression via a nasogastric tube or gastrostomy should be considered for patients with a fairly limited prognosis.18 In recent years, ICIs have been shown to prolong the prognosis of various unresectable malignant tumors.28–30 Concerning gastric cancer, it was reported that nivolumab, which is a fully human IgG4 monoclonal antibody targeting programmed cell death 1, improved the prognosis.4–6 First, nivolumab monotherapy as third-line therapy improved overall survival time compared to placebo treatment in patients with previously treated unresectable gastric cancer.4 Subsequently, nivolumab with chemotherapy as the first-line therapy offered a prognostic benefit compared with chemotherapy alone.5,6 Therefore, the combination of nivolumab plus chemotherapy is currently recommended as a first-line treatment for HER2-negative unresectable gastric cancer with a CPS of more than 5%.31 Some case reports of conversion surgery use these agents.7–9 However, the prognostic effect of pre-operative treatment using chemotherapy plus ICI for stage IV gastric cancer is still unclear, as with chemotherapy alone. Since surgical resection is a local treatment, we believe that distant unresectable factors need to be controlled in advance when performing conversion surgery. This is because patients with active distant metastases are not candidates for local treatment and require systemic therapy. In this case, imaging studies revealed that Virchow’s LN decreased in size, and no abnormal accumulation was detected at the same site. Therefore, confirmation that Virchow’s LNM was pathologically cancer-negative by pre-operative treatment was performed prior to curative gastrectomy. This was because we think that if a pathological complete response is obtained in the largest metastatic lesion, there is a high possibility that all other microscopic metastases that may be present have been controlled and disappeared; therefore, primary resection will lead to complete curative treatment. However, we believe that this is a necessary but insufficient condition for conversion surgery. This factor strictly describes only the disappearance of aggregated cancer and does not indicate the absence of microscopic cancer cells in the veins or lymphatics. It was thought that if the serum levels of CEA and CA19-9, which were reported to be associated with prognosis in gastric cancer,32,33 were elevated at the time of pre-treatment, it would be one of the judgment indicators. However, these tumor markers also do not sensitively reflect the existence of a microscopic disease. Recently, it was reported that the detection of minimum residual disease using blood-derived circulating tumor DNA (ctDNA) effectively predicted the prognosis of gastric cancer.21,22,34,35 Moreover, for colorectal cancer, a prospective study using ctDNA to predict recurrence and indications for adjuvant therapy in curative resected colorectal cancer is being conducted.36 However, at present, there is no insurance approval for using ctDNA as a predictive marker for gastric cancer patients in routine clinical practice in Japan. It may be a future task to examine the usefulness of such technology and to establish factors that predict the appropriate timing to shift from systemic therapy to local treatment. However, at this time, a multistep process that evaluates unresectable distant factors and determines curative resection is considered desirable in patients with stage IV gastric cancer. In previous reports, conversion surgery was performed based on the improvement in distant metastases on imaging studies.7–9,14–16 Curative gastrectomy and adjuvant chemotherapy prolong the prognosis of patients with resected stage II and III gastric cancer compared to curative surgery alone37–40 and have become standard treatments. In addition, in stage IV gastric cancer patients, adjuvant chemotherapy is weakly recommended in the Japanese gastric cancer treatment guidelines.18 However, there is no clear evidence regarding the indications for adjuvant therapy in patients with stage IV gastric cancer who eventually achieve pathological complete remission after chemotherapy and ICI. However, as adjuvant chemotherapy has certain adverse effects,37–40 it is necessary to assess the benefits and harms of adjuvant treatment. In this case, a good prognosis was obtained without adjuvant therapy; however, the indication of adjuvant therapy for such cases may be an issue for future consideration. In conclusion, the present study reports a rare case of initially unresectable gastric cancer with Virchow’s LNM showing a pathologically complete response to pre-operative chemotherapy combined with ICI. A treatment strategy that evaluates distant metastasis, aiding in the decision on whether to perform curative conversion surgery, may be effective for unresectable gastric cancer. Abbreviations CEA, Carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; CT, computed tomography; EGD, Esophagogastroduodenoscopy; ICI, immune checkpoint inhibitor; LNM, lymph node metastasis; PET-CT, positron emission tomography-CT. Ethics Statement Written informed consent was obtained from the patient for the publication of this report and accompanying images. Institutional ethics committee approval was not required to publish this manuscript. All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Author Contributions Wataru Izumo contributed to conception and design. Wataru Izumo, Kei Hosoda, Hidekazu Kuramochi, Go Nakajima, Shinsuke Maeda, Shunichi Ito, Yoji Nagashima and Michio Itabashi contributed to the development of methodology and data acquisition. Wataru Izumo, Kei Hosoda, Yoji Nagashima, and Michio Itabashi contributed to the analysis and interpretation of data, writing, review, and revision of the manuscript. All authors have read and approved the final manuscript. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Disclosure Wataru Izumo, Kei Hosoda, Hidekazu Kuramochi, Go Nakajima, Shinsuke Maeda, Shunichi Ito, Yoji Nagashima, and Michio Itabashi declare no conflicts of interest. ==== Refs References 1. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144 :1941–1953.30350310 2. Kim SG, Seo HS, Lee HH, et al. Comparison of the Differences in Survival Rates Between the 7th and 8th Editions of the AJCC TNM Staging System for Gastric Adenocarcinoma: a Single-Institution Study of 5507 Patients in Korea. J Gastric Canc. 2017;17 :212–219. 3. Yamada Y, Higuchi K, Nishikawa K, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol. 2015;26 :141–148.25316259 4. Boku N, Ryu MH, Kato K, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, Phase 3 trial. Lancet Oncol. 2022;23 :234–247.35030335 5. Janjigian YY, Shitara K, Moehler M, et al. 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Izumo W, Furukawa K, Katsuragawa H, et al. A case of advanced gastric cancer with tumor embolus in the portal vein and liver metastasis responding to S-1 plus cisplatin chemotherapy. Nihon Shokakibyo Gakkai Zasshi. 2014;111 :2131–2139.25373374 15. Terashima T, Yamashita T, Takabatake H, et al. Successful second conversion surgery after trastuzumab deruxtecan for recurrent HER2-positive gastric cancer. Clin J Gastroenterol. 2023. doi:10.1007/s12328-023-01764-3 16. Iwazawa T, Kinuta M, Yano H, et al. An oral anticancer drug, TS-1, enabled a patient with advanced gastric cancer with Virchow’s metastasis to receive curative resection. Gastric Cancer. 2002;5 :96–101.12111585 17. Holen KD, Klimstra DS, Hummer A, et al. International Retrospective Cohort Study of Conversion Therapy for Stage IV Gastric Cancer 1 (CONVO-GC-1). Ann Gastroenterol Surg. 2021;6 :227–240.35261948 18. Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2021. Gastric Cancer. Kanehara Publishing Co, Ltd; 2021. 19. Al-Batran SE, Goetze TO, Mueller DW, et al. The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction - a phase III trial of the German AIO/CAO-V/CAOGI. BMC Cancer. 2017;17 :893.29282088 20. Tsuburaya A, Mizusawa J, Tanaka Y, et al. Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis. Br J Surg. 2014;101 :653–660.24668391 21. Marker SR, Mikhail S, Malietzis G, et al. Influence of Surgical Resection of Hepatic Metastases From Gastric Adenocarcinoma on Long-term Survival: systematic Review and Pooled Analysis. Ann Surg. 2016;263 :1092–1101.26797324 22. Kodera Y, Fujitani K, Fukushima N, et al. Surgical resection of hepatic metastasis from gastric cancer: a review and new recommendation in the Japanese gastric cancer treatment guidelines. Gastric Cancer. 2014;17 :206–212.24022130 23. Bian SB, Shen WS, Xi HQ, et al. Palliative Therapy for Gastric Outlet Obstruction Caused by Unresectable Gastric Cancer: a Meta-analysis Comparison of Gastrojejunostomy with Endoscopic Stenting. Chin Med J. 2016;129 :1113–1121.27098799 24. Ahmed O, Lee JH, Thompson CC, et al. AGA Clinical Practice Update on the Optimal Management of the Malignant Alimentary Tract Obstruction: expert Review. Clin Gastroenterol Hepatol. 2021;19 :1780–1788.33813072 25. Oida T, Mimatsu K, Kawasaki A, et al. Modified Devine exclusion with vertical stomach reconstruction for gastric outlet obstruction: a novel technique. J Gastrointest Surg. 2009;13 :1226–1232.19333659 26. Ramos MFKP, Barchi LC, de Oliveira RJ, et al. Gastric partitioning for the treatment of malignant gastric outlet obstruction. World J Gastrointest Oncol. 2019;11 :1161–1171.31908721 27. Lorusso D, Giliberti A, Bianco M, et al. Stomach-partitioning gastrojejunostomy is better than conventional gastrojejunostomy in palliative care of gastric outlet obstruction for gastric or pancreatic cancer: a meta-analysis. J Gastrointest Oncol. 2019;10 :283–291.31032096 28. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J. 2015;373 :123–135. 29. Ferris RL, Blumenschein G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J. 2016;375 :1856–1867. 30. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373 :1803–1813.26406148 31. Japanese Gastric Cancer Association. Comment of Japanese gastric cancer treatment guidelines committee. Available fron: chromeextension://efaidnbmnnnibpcajpcglclefindmkaj/http://www.jgca.jp/pdf/news202112_1.pdf. Accessed July 11, 2023. 32. Song YX, Huang XZ, Gao P, et al. Clinicopathologic and prognostic value of serum carbohydrate antigen 19-9 in gastric cancer: a meta-analysis. Dis Markers. 2015;2015 :1–11. 33. Deng K, Yang L, Hu B, et al. The prognostic significance of pretreatment serum CEA levels in gastric cancer: a meta-analysis including 14651 patients. PLoS One. 2015;10 :1–23. 34. Leal A, van Grieken NCT, Palsgrove DN, et al. White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer. Nat Commun. 2020. doi:10.1038/s41467-020-14310-3 35. Slagter AE, Vollebergh MA, Caspers IA, et al. Prognostic value of tumor markers and ctDNA in patients with resectable gastric cancer receiving perioperative treatment: results from the CRITICS trial. Gastric Cancer. 2022;25 :401–410.34714423 36. Taniguchi H, Nakamura Y, Kotani D, et al. CIRCULATE-Japan: circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer. Cancer Sci. 2021;112 :2915–2920.33931919 37. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011;29 :4387–4393.22010012 38. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012;379 :315–321.22226517 39. Yoshida K, Kodera Y, Kochi M, et al. Addition of Docetaxel to Oral Fluoropyrimidine Improves Efficacy in Patients With Stage III Gastric Cancer: interim Analysis of JACCRO GC-07, a Randomized Controlled Trial. J Clin Oncol. 2019;37 :1296–1304.30925125 40. Park SH, Lim DH, Sohn TS, et al. 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==== Front Patient Prefer Adherence Patient Prefer Adherence ppa Patient preference and adherence 1177-889X Dove 416024 10.2147/PPA.S416024 Original Research A Cross-Sectional Evaluation of Parents’ Awareness Towards Testicular Torsion and Their Response to a Potential Torsion: A Northern Saudi Study Alenzi et al Alenzi et al Alenzi Mohammed Jayed 1 * Alshalash Ahmed S 1 Al-enzi Abdulmohsen Nayef 2 Al-anazi Fahad Suhayman 2 Al-anzi Nawaf Mohammed 2 Alsharari Khalid Omar 2 Alanazi Abdulhadi Abdullah 2 Alanazi Sultan Mohammed 2 Thirunavukkarasu Ashokkumar 3 * 1 Department of Surgery, College of Medicine, Jouf University, Sakaka, Aljouf, Saudi Arabia 2 Medical Student, College of Medicine, Jouf University, Sakaka, Aljouf, Saudi Arabia 3 Department of Community and Family Medicine, College of Medicine, Jouf University, Sakaka, Aljouf, Saudi Arabia Correspondence: Ashokkumar Thirunavukkarasu, Department of Community and Family Medicine, College of Medicine, Jouf University, Sakaka, 72388, Saudi Arabia, Tel +966-599739619, Email ashokkumar@ju.edu.sa * These authors contributed equally to this work 14 7 2023 2023 17 16711678 09 4 2023 24 6 2023 © 2023 Alenzi et al. 2023 Alenzi et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Background Assessment of parents’ awareness of testicular torsion (TT) is essential to plan for necessary awareness-raising campaigns by policymakers. Hence, the preventable loss of testis due to inadequate awareness can be avoided. We aimed to evaluate the awareness of TT amongst parents from the Aljouf region, KSA, and to assess their response to a potential torsion. Methods We conducted a cross-sectional study among parents from the Aljouf region. The sample population was obtained using a consecutive sampling method. The present study used a pretested Arabic questionnaire. We used a statistical package for social science software for data analysis. Results There were 320 parents who participated in different public places for the present study. Of the respondents, 10.6% of their children had sudden pain in the scrotum. More than half (52.2%) had never heard of testicular torsion, and 72.5% of parents agreed that they would seek immediate medical attention for severe testicular pain, but a low (42.5%) proportion of parents responded that they would seek help immediately. Nearly one-fourth of them responded that less than 6 hours is the critical time for repair. Parents who were knowledgeable at the critical time had more odds of presenting to a healthcare facility immediately for both mild (OR = 2.77, CI = 1.55–4.03, p = 0.001) and severe (OR = 1.92, CI = 1.03–3.63, p = 0.032). Conclusion We found a lack of awareness of TT among Saudi parents. It is suggested to improve the knowledge among them through awareness-raising campaigns by the concerned health authorities through feasible methods. Furthermore, we recommend conducting a futuristic multicenter and exploratory study to find province-specific awareness. Keywords testicular torsion awareness Saudi pain parents critical time ==== Body pmcIntroduction Scrotal-related problems are relatively common in the emergency unit, comprising a minimum of 0.5% of all emergency cases. Testicular torsion (TT) happens when the testicle rotates and twists the spermatic cord, blocking blood circulation to the testicles.1,2 TT is a pediatric urologic emergency, and timely diagnosis is essential, as early assessment can help in necessary intervention to prevent the loss of testicles.3–5 This scenario worsened during the COVID-19 pandemic, as a multicenter study by Pogorelić et al stated that significantly higher pediatric patients presented in the emergency department with late presentation of TT and a higher rate of orchidectomy were done among them.6 The patients affected by TT commonly present with the symptoms of acute and excruciating pain in the scrotum, swollen scrotum, fever, vomiting, and abdominal pain.1,5,7 Even though previous studies have explored several causes for TT, the most common cause is the improper attachment of testicles with the scrotum at birth. Although TT can occur at any age, the incidence rate is comparatively higher among the age group of 1–17 years than in the older age group.8,9 On assessing the epidemiological factors of TT, Greear GM et al reported that the predicted annual incidence rate of TT was 5.9 per 100,000 males in the age group of 1–17 years, while it was 1.3 per 100,000 males among 18 years and above.10 Timely recognition of symptoms of TT by the parent (s) is crucial as they would be the first person whom the children present with the complaints. In a survey conducted in the Riyadh region of Saudi Arabia (KSA) by Alyami et al, the awareness about TT is very low in their study, which means that they should spend more time and invest more in raising awareness to increase knowledge and avoid the consequences of TT. The media, with its diverse tools, would play a significant role in raising awareness because they provide a lot of information that is easy to access for the whole community. On the other hand, awareness campaigns would also give another aspect of the interaction between healthcare providers and the community, resulting in well-informed parents.11 Another survey conducted among Irish parents by Yap LC et al found that only 56% of the parents were aware of TT. They also found that the parents with an understanding of TT were four times more likely (OR = 4.2, p<0.01) to come to the emergency department immediately in case their child showed symptoms of TT than those who were unaware of TT. Those who responded correctly to the crucial period were three times (OR = 3.0, P=0.08) more probability of coming to the emergency department immediately than those who did not respond correctly.12 Friedman et al looked at the parent awareness of TT in urology and ear, nose, and throat (ENT) clinics. They found no statistically significant difference in the awareness of TT between the parents in the urology and ENT clinics (34.2 vs 35.6%). In Friedman et al survey, 34% of parents had heard of testicular twisting/torsion, most commonly through friends, relatives, or knowing someone with torsion (35%).13 Assessment of parents’ awareness of TT is very much essential to plan for necessary awareness-raising campaigns by the policymakers. Hence, the preventable loss of testis due to inadequate awareness can be avoided.14 However, the authors did not find sufficient published research, especially in the northern regions. Hence, this survey aimed to evaluate the awareness of testicular torsion and its association with the presentation time amongst parents from the Aljouf region, KSA. Furthermore, we assessed their response to potential torsion. Materials and Methods Study Design and Settings The present population-based study is a cross-sectional study conducted from December 2022 to March 2023 in the Al Jawf province of KSA. Al Jawf province is located close to Jordan in northern KSA, and the total population of this province is around half a million. Sampling Strategy We measured the minimum required participants for this survey using the WHO sample size calculation formula (n = z2pq/d2). In this equation, we considered the TT awareness (p = 0.19) among the parents as 19% according to Alyami et al,11 q = 1–0.19, z = 1.96 at 95% confidence interval, 5% acceptable precision (d = 0.05). Additionally, we considered taking 25% to increase the present study’s power. Hence, the final estimated sample was 320. Participants’ Details, Inclusion, and Exclusion Criteria By applying the consecutive sampling method, we invited the parents who visited public places such as malls, parks, and masjids. In order to include the participants on all days in the week, we will restrict the participants to 50 per day. The present study included all parents (male and female) aged 18 to 49 years, those willing to participate, and those from Al jawf province included study settings. We excluded those parents with a child who already had an episode of TT. Furthermore, this study will exclude non-Aljouf province participants. Data Collection Method Firstly, we obtained the necessary permissions and ethical clearance from the concerned authorities (Jouf University ethical committee approval no: 1-04-44). Our study followed all the ethical consideration that complies with the Declaration of Helsinki. The present study used the data collection proforma prepared by the research team from a focus group discussion of experts from urology and family medicine departments and previously published studies (2, 11). We used the Arabic version of the questionnaire. Initially, we pretested with 30 parents to understand local adaptability and suitability. Furthermore, the Cronbach value for the data collection tool of the data collection tool was 0.79. Firstly, we briefed the TT awareness survey to the selected parents and obtained informed consent. Then, we requested the invited parents to complete the prepared TT awareness assessment proforma in the google form given to the data collectors’ own electronic devices. The data collection form inquired about the participants’ sociodemographic characteristics, parents’ responses to their child’s scrotal pain, the major source of information on TT, and the knowledge regarding the critical time to fix the TT-related complaints. Data Analysis We used the statistical pack for social sciences (SPPS, V.23) for data entry, coding, and analysis. We presented the descriptive data as frequency, proportion, and diagrams. We executed binary logistic regression analysis to identify the factors associated with TT awareness (No vs Yes). All the analytical results were interpreted based on a two-tailed test with a significant value (p<0.05). Results Of the 320 studied parents, the majority (37.2%) belonged to the age group of 30 to 40 years (mean ± SD = 34.32 ± 9.1), male gender (60.6%), studied university and above (72.2%), and working in the government sector (40.9%) (Table 1).Table 1 Background Characteristics of the Parents (n = 320) Variables Frequency (n) Proportion (%) Age (mean ± SD) 34.32 ± 9.1 Less than 30 108 33.8 30 to 40 119 37.2 More than 40 93 29.0 Gender Male 194 60.6 Female 126 39.4 Education status Up to high school 89 27.8 University and above 231 72.2 Occupation Government 131 40.9 Private 92 28.8 Self-employed/business 60 18.7 Unemployed 37 11.6 Number of children 2 or less 104 32.5 3 to 4 160 50.0 More than 4 56 17.5 Nearly three-fourths of the participants responded that they would take the baby immediately during working hours (72.5%) and non-working hours (75.6%). However, some parents answered that they would take the baby to a regular urology clinic after arranging an appointment (Table 2).Table 2 Participants’ Response if Their Child Gets Scrotal Pain (n = 320) Responses During Working Hours n (%) During Weekends and Non-Working Hours n (%) Take him to hospital immediately 232 (72.5) 242 (75.6) Give him pain medications 26 (8.1) 34 (10.6) Take him to urology clinic after arranging appointment 40 (12.5) 35 (10.9) Home remedies such as ice fermentation 22 (6.9) 9 (2.8) Figure 1 depicts the parents’ responses to the child’s scrotal pain on taking them to a healthcare facility. Of the responded parents. 47.5% and 72.5% answered that they would immediately take the baby to healthcare facilities for mild and severe scrotal pain, respectively. Figure 1 Parents’ response regarding waiting time for mild and severe testicular pain (n = 320). The present study revealed that less than half (47.8%) of participants were aware of the TT condition (Figure 2). Figure 2 Aware of testicular torsion (TT) among the participants (n = 320). We further inquired about the source of information on TT to the participants who were aware of TT. The major (39.2%) source of information they received about TT was from the ministry of health activities, followed by family and friends (22.9%), and media (15%) (Table 3).Table 3 Major Source of Information Regarding Testicular Torsion (TT) (n = 153) Source Frequency (n) Proportion (%) Friends and family members 35 22.9 Ministry health activities 60 39.2 School 15 9.8 Media (including social media) 23 15.0 Other sources 20 13.1 Among the 320 respondents, 27.8% correctly answered that less than 6 hours after developing scrotal pain is the critical time frame to take the child to a healthcare facility to fix the problem (Figure 3). Figure 3 Participants’ knowledge regarding critical time to fix the TT (N = 320). Parents who were knowledgeable at the critical time had more odds of presenting to a healthcare facility immediately for both mild (OR = 2.77, CI = 1.55–4.03, p = 0.001) and severe (OR = 1.92, CI = 1.03–3.63, p = 0.032). Similarly, parents who were aware of TT also had higher odds of presenting to a healthcare facility for mild (OR = 2.36, CI = 1.11–3.18, p = 0.003) and severe (OR = 3.53, CI = 2.11–4.96, p < 0.001) (Table 4).Table 4 Correlation Between Parents’ Awareness with the TT, Critical Time (CT) Span, and Presentation at Healthcare Facilities Mild Pain: Odds Ratio (OR)/95% Confidence Interval (CI) p-value Severe Pain: OR (95% CI) p-value Knowledge on CT span – Present immediately 2.77 (1.55–4.03) 0.001 1.92 (1.03–3.63) 0.032 Knowledge on CT span – Present within a few hours 3.81 (1.94–6.37) <0.001 1.89 (1.37–3.03) 0.007 Aware of TT – Present immediately 2.36 (1.11–3.18) 0.003 3.53 (2.11–4.96) <0.001 Aware of TT – Present within a few hours 1.91 (1.38–2.73) 0.001 2.54 (0.81–3.59) 0.001 Discussion Public health education regarding important health problems is essential for the community. To explore the necessary programs, it is critical to evaluate the current health literacy and awareness of the target population. The present study assessed the parents’ awareness to TT and their response to potential torsion. The commonest reason for testicular loss during TT is not seeking emergency attention immediately and promptly.3,15 One of the major reasons for not seeking attention immediately could be due to a lack of awareness. The present study reported that less than half (47.8%) of the parents were aware of TT in the Aljouf province. A survey conducted among Irish parents reported a higher proportion (56%) of parents were aware of TT.12 Similarly, Abelson et al also reported a higher proportion of awareness among their study participants.16 However, Friedmann et al and Alyami et al reported a lower proportion of awareness among their participants.11 The variation from our TT awareness survey and other research might be study settings, our study was population-based, and the latter studies were done in hospital settings. These findings emphasize the need for education targeted the parents, as it is a powerful tool. One of the best methods of delivering to the targeted population is through role play and open discussion.17,18 Interestingly, some Nigerian studies reported that the awareness level of TT and testicular self-examination was poor, even among undergraduate medical students.19,20 The right source of health information is critical to impart essential medical knowledge to the general population.21,22 Non-authenticated health information not only decreases knowledge but also leads to a negative impact on health. Hence, it is crucial to follow the authorized health authorities’ information.22 However, the present study found that only 39.2% responded that the ministry of health, KSA was their major source of information about TT. Similar to the present study, Yap et al found that healthcare workers were the primary source of information related to TT.12 Interestingly, the general Saudi population considers more credible information for some other information pertaining to health.21,23 This indicates that concerned healthcare managers to focus on this subject with special consideration to the sociocultural situation. Testicular viability significantly decreases after 6 hours of TT; hence, this period is crucial to salvaging the twisted testis.9,24 Nonetheless, the present study findings explored that only 27.8% of the parents were aware of the critical time frame to fix the TT, and those who were aware had significantly higher odds of bringing their children in the event of mild and severe testicular pain. Similar to the present findings, other authors also found poor knowledge among the parents on the critical time frame to bring the children if their children present with scrotal pain.12,14 Strengths and Weakness of the Present Survey Our study is the first of its kind conducted in the northern KSA that evaluated one of the least explored topics in pediatric urology. However, we assessed parents’ awareness of TT through the cross-sectional study. Hence, the readers to consider the constraints of this method, such inability to find the temporal association. Since we used a questionnaire-based survey, we may consider biases related to recall and self-reported. Finally, the present survey findings may not reflect parents’ awareness of TT in other regions of KSA. Conclusion We found a lack of awareness of TT among Saudi parents. We also found that knowledgeable parents had higher odds of presenting to the healthcare facility immediately in the event that the child develops mild or severe testicular pain. It is suggested to improve the knowledge among them through awareness-raising campaigns by the concerned health authorities through feasible methods. Furthermore, we recommend conducting a futuristic multicenter and exploratory study to find province-specific awareness. Acknowledgments The authors want to thank the parents who participated in the present survey. Furthermore, we extend our sincere thanks to the scientific committee of the college of medicine, Jouf university for their immense help for the research. Disclosure The authors report no conflicts of interest in this work. ==== Refs References 1. Laher A, Ragavan S, Mehta P, Adam A. Testicular torsion in the emergency room: a review of detection and management strategies. Open Access Emerg Med. 2020;12 :237–246. doi:10.2147/oaem.S236767 33116959 2. 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==== Front J Asthma Allergy J Asthma Allergy jaa Journal of Asthma and Allergy 1178-6965 Dove 417117 10.2147/JAA.S417117 Original Research 1-Year Prospective Study of the Relationship of Serial Exhaled Nitric Oxide Level and Asthma Control Ko et al Ko et al http://orcid.org/0000-0001-8454-0087 Ko Fanny Wai San 1 Chan Ka Pang 1 Ng Joyce Ka Ching 1 Ngai Jenny C L 1 Yip Wing Ho 1 Lo Rachel Lai Ping 1 Chan Tat On 2 http://orcid.org/0000-0003-4382-2445 Hui David Shu Cheong 1 1 Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong, People’s Republic of China 2 The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China Correspondence: David Shu Cheong Hui, Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, NT, Hong Kong, Tel +852 35053128, Email dschui@cuhk.edu.hk 14 7 2023 2023 16 725734 13 4 2023 30 6 2023 © 2023 Ko et al. 2023 Ko et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Background and Objective Previous studies found that the fractional nitric oxide concentration in exhaled breath (FeNO) levels in healthy Chinese adults was higher than in White adults. More understanding of serial changes of FeNO levels with asthma control in a real-life clinical setting would be important to explore the utility of this biomarker in routine asthma management. This study assessed the FeNO levels of Chinese asthma subjects with different levels of asthma control and the serial changes with respect to the changes in asthma control over 1 year. Methods A 12-month prospective study (subjects recruited between November 2019 and January 2021) with serial measurement of FeNO levels at baseline, 4, 8 and 12 months. Asthma control was assessed by the Global Initiative for Asthma classification, Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ). Results Altogether, 136 subjects (mean age 51.51±15.09 years, 46[33.8%] male) had successful baseline FeNO measurements. At baseline, the FeNO levels did not show a statistically significant difference for controlled, partly controlled and uncontrolled asthma according to GINA classification, ACT and ACQ. FeNO levels decreased with improving asthma control and stayed at similar levels with unchanged or worsening asthma control for all subjects. For subjects with baseline blood eosinophil levels ≥300 cells/µL(n=59), FeNO levels decreased with improving asthma control, stayed similar without change for asthma control and increased with worsening asthma control. Receiver operating characteristic (ROC) analysis with the highest area under curve (AUC) for changes in FeNO levels for improving asthma control was between ≤ −10 to −25 ppb at various time points in the 12-month study. Conclusion Changes in FeNO levels over time were associated with changes in clinical asthma control, particularly in those with higher blood eosinophil count and are likely more useful than a single time point measurement in managing asthma. Keywords asthma FeNO serial measurement the Hong Kong Lung Foundation Gran This study is supported by the Hong Kong Lung Foundation Grant. ==== Body pmcIntroduction Measurement of fractional nitric oxide concentration in exhaled breath (FeNO) has been shown to be a non-invasive, quantitative biomarker for eosinophilic airway inflammation. FeNO levels correlated with features of T2 inflammation, in particular with the eosinophil levels in induced sputum and peripheral blood.1–3 Both the innate immune system and the adaptive immune system drive T2 inflammation. The former is triggered by pollutants or infections involving type 2 innate lymphoid cells and the latter is activated by contact with allergens involving type 2 T-helper cells.4 Our recent study found that about 70% of moderate and severe asthma patients had features of type 2 inflammation indicated by elevated blood eosinophils and/or immunoglobulin E (IgE) levels.5 FeNO is now used as a biomarker for guiding the initiation of biologic therapy in asthma.6,7 It can also support the diagnosis of asthma.8,9 A meta-analysis found that when compared to clinical symptoms, tailoring asthma medications based on FeNO levels decreased the frequency of asthma exacerbations. However, FeNO-based approach did not impact day-to-day clinical symptoms, end-of-study FeNO levels, lung function or inhaled corticosteroid (ICS) dose. The studies included in this meta-analysis ranged from 18 to 52 weeks in duration. In addition, the FeNO cutoff values among the studies were variable.10 The latest American Thoracic Society (ATS) guideline on FeNO has made a conditional recommendation that in patients with asthma in whom treatment is being considered, FENO is beneficial and should be used in addition to usual care.8 More understanding of serial changes of FeNO levels with asthma control in a real-life clinical setting would be important to explore the utility of this biomarker in routine asthma management. Previous studies of FeNO and asthma control were limited to retrospective11 or single-time point assessments.12,13 There are limited prospective adult data on serial FeNO levels and asthma control, with some studies focusing on the relationship with asthma exacerbations and some on children.14,15 Our previous study on FeNO in healthy Chinese populations observed a higher level of FeNO than in the Caucasian population.16 To the best of our knowledge, correlation between changes in FeNO level and changing levels of asthma control among Chinese has not been studied. The latest ATS FeNO guideline has suggested a need for larger trials that evaluate the use of FENO testing to monitor therapy with serial measurements once the FeNO level is established.8 The primary aim of this study was to assess the FeNO levels of Chinese asthma subjects with different levels of asthma control. The secondary aim was to assess serial changes in levels of FeNO in Chinese asthma patients with respect to the changes in asthma control in a real-life clinical setting over 1 year. Understanding the baseline and serial changes in FeNO would contribute more to the potential role of this biomarker. Methods This was a prospective study of FeNO levels and asthma control over a period of 12 months. Subjects were recruited between November 2019 and January 2021 from the respiratory clinic of the Prince of Wales Hospital, Hong Kong. The study (ClinicalTrial.gov registration number NCT04125316) was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC 2019.395). All recruited subjects had signed informed written consent. The manuscript complied with the Declaration of Helsinki. Chinese subjects aged between 18 and 90 years who had a diagnosis of asthma were recruited. Asthma was defined as those with a consistent history and prior documented evidence of variable airflow obstruction, with evidence of an increase in FEV1 greater than 12% or 200mL following bronchodilator or bronchial hyperresponsiveness on bronchial provocation testing when stable Exclusion criteria were patients with other known respiratory diseases, including chronic obstructive pulmonary disease, bronchiectasis, tuberculosis with destroyed lung parenchyma, history of lung resection and lung cancer, individuals older than 40 years with a smoking history of more than 10 pack-years, current smokers (smoking in the past 12 months), patients currently randomised in other clinical studies and pregnant women. Demographic characteristics of the subjects were collected, including age, gender, weight, height, medications, co-morbidities and asthma exacerbations in the past 12 months. Blood tests (including eosinophil count and total IgE levels), spirometry and skin prick tests were performed at baseline. Spirometry (pre- and post-bronchodilator) was performed according to the American Thoracic Society and European Respiratory Society standards.17 The updated predicted spirometry values for Hong Kong Chinese were used to calculate the predicted lung function.18 Skin prick test was performed with a panel of allergen extracts including cat, dog, Dermatophagoides pteronyssinus and Dermatophagoides farinae, aspergillus, mould mix, tree mix and cockroach (ALK, USA and Greer, USA). A minimum wheal size of 3 mm was defined as a positive response. FeNO levels and asthma control were assessed at baseline, 4, 8 and 12 months. FeNO levels were measured online using a NIOX VERO (Circassia, Uppsala, Sweden) according to ATS/ERS recommendations19 before spirometry. Subjects were tested in a sitting position (with no nose clip), exhaled to residual volume, inserted a mouthpiece, inhaled to total lung capacity, and then exhaled for 10 seconds at a constant flow rate of 50mL/s. The measurement was repeated until three FeNO values varied less than 10% or two values varied less than 5%. The mean FeNO (in ppb) was recorded. Subjects with any upper or lower respiratory tract infection in the past 4 weeks would need to re-scheduled the testing to a later date. Asthma control in the past 4 weeks was assessed by GINA classification,7 Asthma Control Test (ACT),20 and Asthma Control Questionnaire 5 (ACQ).21 For GINA classifications, subjects were classified as having controlled, partly controlled or uncontrolled asthma based on symptoms.7 For ACT, the scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting better asthma control. A score between 20 and 25 represents controlled asthma, while a score of 19 or below represents not well-controlled asthma (partly controlled), and a score less than 16 indicates very poorly controlled asthma (uncontrolled asthma).22 For ACQ5, scores range from 0 to 6 (higher is worse). ACQ ≤0.75 indicated asthma was well-controlled; 0.75–1.5 as a “grey zone” (partly controlled asthma); and ≥1.5 has a high probability that asthma is poorly controlled (uncontrolled asthma).23 We defined changes in levels of asthma control as follows: Improved (improved in at least one level of asthma control, ie, from partly controlled or uncontrolled to controlled, or from uncontrolled to partly controlled), no change (stayed at same level of control), worsened (worsened in at least one level of asthma control, ie, from controlled to partly controlled or uncontrolled, or from controlled to partly controlled). The asthmatic attacks that required treatment of systemic corticosteroids or hospitalization at 12 months were documented (by asking the patient and checking with health records). Sample size determination is shown in the Supplementary Document, and the minimal sample size required to assess the primary outcome of the study was 132 subjects. Data were analysed by the Statistical Package of the Social Science Statistical software (SPSS) for Windows, Version 28.0.1.0 (IBM SPSS Inc, IL, USA). The clinical characteristics of the subjects were expressed as mean (SD) or median [IQR]. Kruskal–Wallis test was used for between-group comparisons in changes of asthma control. Categorical data were analysed by Fisher’s exact or Chi-square tests. In addition, Receiver Operating Characteristic (ROC) analyses with the calculation of Area Under Curve (AUC) were used to assess the predictive value of FeNO for changes in asthma control. A p-value <0.05 was considered statistically significant. Results Altogether, 141 subjects were recruited for this study. Among them, 5 subjects failed the FeNO baseline assessment as they could not master the technique. Only those with successful baseline FeNO values (n = 136) were included in subsequent analyses. Demographic characteristics are shown in Table 1. The mean age of the subjects was 51.51±15.09 years, with 46 (33.8%) male subjects. The mean pre-bronchodilator FEV1% predicted and FEV1/FVC was 80.80 ±20.71 and 70.68±13.54%, respectively. Over 90% of the subjects were on ICS, and no subjects received biologics therapy. At 4, 8 and 12 months, 101, 92 and 94 subjects had successful FeNO measurements, respectively. At 12 months of follow-up, 13 (9.6%) and 3 (2.2%) subjects had asthma exacerbations requiring oral steroids and hospital admissions, respectively, during the study period.Table 1 Demographic Data of the Subjects (n = 136) Age 51.51 ± 15.09 Gender (Male) 46 (33.8%) Body mass index (kg/m2) 24.95 ± 4.80 Baseline medication use  ICS alone 9 (6.62%)  ICS + LABA 116 (85.3%)  LAMA 41 (30.1%)  Montelukast 59 (43.4%)  Theophylline 14 (10.3%) Dose of ICS: (n=125)  Low 21 (16.8%)  Medium 50 (40.0%)  High 54 (43.2%) Eosinophil count (X109/L) (n=135) 0.34 ± 0.44 Eosinophil (%) (n=135) 4.69 ± 4.26 IgE (IU/mL)(n=134) 118.5 [41–312] Skin prick test (n=133)  Positive 83 (62.4%) Spirometry Pre-bronchodilator(n=121)  FEV1 (L) 1.98 ± 0.67  FVC (L) 2.80 ± 0.75  FEV1/FVC % 70.68 ± 13.54  FEV1% predicted 80.80 ± 20.71  FVC % predicted 91.81 ± 16.50 Post-bronchodilator(n=133)  FEV1 (L) 2.03 ± 0.66  FVC (L) 2.81 ± 0.77  FEV1/FVC (%) 72.36 ± 12.97  FEV1% predicted 83.41 ± 19.12  FVC % predicted 92.64 ± 16.70 Comorbidities  Rhinitis 97 (71.3%)  Eczema 20 (14.7%)  Sleep apnoea 20 (14.7%)  Heart failure 1 (0.7%)  Hypertension 33 (24.3%)  Diabetes 17 (12.5%)  Ischaemic heart disease 1 (0.7%)  Gastroesophageal reflux 17 (12.5%)  Psychiatric disorder 10 (7.4%) Number of asthma exacerbations in the past 12 months 0.14 ± 0.91 Note: Data were presented as mean ± SD, median [IQR] or number (%). Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting anti-cholinergic agent. The baseline FeNO levels are shown in Table 2. There was no statistically significant difference in FeNO values in the different levels of asthma control according to GINA, ACT and ACQ at baseline. Cutoff levels of <25, 25 to 50 and >50 ppb of the FeNO for low, intermediate and high FeNO level8 with respect to the different levels of asthma control by GINA, ACT and ACQ are shown in Supplementary Table 1. There were no statistically significant differences in the asthma control for GINA, ACT and ACQ among the suggested cutoff levels of FeNO by the American Thoracic Society.8 Asthma control according to GINA classification, ACT and ACQ at baseline did not have statistically significant differences based on blood eosinophil count at cutoff values of 0.3X109/L and 0.15X109/L (Supplementary Table 2). Baseline inhaled corticosteroid dose had no association with asthma control (Supplementary Table 3) and FeNO levels (Supplementary Table 4).Table 2 FeNO Levels and Asthma Control at Baseline Visit n Mean (SD) ppb Median [IQR] ppb p value* GINA  Controlled 48 36.8 (26.4) 27.5 [19.0–46.5] 0.157  Partly controlled 49 41.3 (34.7) 28.0 [14.0–55.0]  Uncontrolled 39 53.8 (41.4) 34.0 [21.0–84.5] ACT  20–25 85 39.0 (29.6) 29.0 [17.0–53.0]_ 0.302  19–16 31 51.6 (38.5) 35.0 [20.5–85.5]  <16 20 48.7 (45.9) 29.0 [18.0–66.5] ACQ  ≤0.75 79 42.1 (31.4) 32.0 [18.50–58.0] 0.991  0.75–1.5 30 41.2 (33.6) 31.5 [17.0–52.0]  ≥1.5 27 49.1 (44.6) 26.0 [17.5–84.5] Note: P* value by comparisons of the median levels using Kruskal-Wallis Test. Abbreviations: GINA, Global Initiative of Asthma level of asthma control; ACT, Asthma Control Test; ACQ, Asthma Control Questionnaire. Serial changes of the changes in FeNO levels for changes in asthma control are shown in Table 3 and Figure 1. Those with improvement in asthma control according to the GINA classification had a statistically significant decrease in FeNO levels, while those with the same or worsened asthma control had not much change in FeNO levels, at 4, 8 and 12 months compared to baseline. For asthma control by ACT, subjects with improved asthma control at 4 months had a decrease in FeNO levels compared with baseline, but that was not statistically significant at 8 and 12 months. For asthma control by ACQ, subjects with improvement in asthma control at 4 and 8 months had a decrease in FeNO levels compared to those with the same or worsened asthma control, but the changes were not statistically significant at 12 months.Table 3 Changes in Asthma Control and FeNO Levels Over Time Change of Level of Control n Mean (SD) Median [IQR] P# n Mean (SD) Median [IQR] P# n Mean (SD) Median [IQR] P# Changes from Baseline to 4 Months Changes from Baseline to 8 Months Changes from Baseline to 12 Months GINA Worsened 18 3.21 (21.1)ppb 2.0 [−4.0–12.0]ppb 0.021* 12 8.5 (21.8)ppb 1.5 [−4.5–12.0]ppb 0.048* 14 4.9 (10.5)ppb 3.5 [−5.0–12.0]ppb 0.036* 18.6 (63.6)% 6.6 [−25.0–60.0]% 0.034* 43.1 (84.5)% 13.1[−15.7–83.1]% 0.116 32.7 (71.8)% 14.1 [−20 – 69.2]% 0.112 No change 43 0.7 (24.4)ppb −1.0 [−10.5–9.0] ppb 39 0.5(19.4)ppb −1 [−11.5–10.0]ppb 32 2.3 (21.0)ppb −0.5 [−9.0–10.0]ppb 18.5 (102.2)% −8.0 [−34.9–34.6]% 19.9 (79.5)% −7.1 [−40.4–44.5]% 40.2 (130.1)% −1.6 [−25 – 41.4]% Improved 38 −16.8 (28.4)ppb −7.0 [−32.0–3.0]ppb 36 −17.7 (36.6)ppb −6.5 [−35.5–6.5]ppb 39 −16.2 (35.7)ppb −7.0 [−25.5–6.0]ppb −17.3 (44.0)% −27.5[−43.8–11.6]% −4.6 (64.0)% −16.1 [−53.8–32.8]% −2.2 (64.9)% −13.8 [−42.5–29.0]% ACT Worsened 13 −2.6 (22.7)ppb −3.0 [−5.0–5.0]ppb 0.016* 12 2.0 (24.9) ppb −3 [−12.5–10.5]ppb 0.149 11 3.8 (21.4)ppb 1.0 [−5.5–17.0]ppb 0.129 3.1 (63.8)% −16.7[−33.3–19.8]% 0.007* 13.2 (73.4)% −9.6 [−39.4–36.9]% 0.165 73.1 (183.7)% 5.9 [−31.0–57.5]% 0.194 No change 61 0.7 (22.43)ppb 0 [−10.0–9.0]ppb 53 −2.2 (24.5)ppb 0.0 [−1.02–11.0]ppb 55 −2.2 (23.3)ppb −1.0 [−9.0–9.0]ppb 18.5 (90.2)% 0 [−28.6–37.5]% 22.1 (78.6)% 0.0 [−41.7–50]% 19.1 (78.3)% −3.5 [−25.0–38.0]% Improved 25 −22.5 (31.8)ppb −15.0 [−45.0–3.0]ppb 22 −19.3 (39.1)ppb −9.5 [−35.0–3.0]ppb 19 −21.6 (41.7)ppb −12.0 [−36.5–2.0]ppb −27.6 (38.2)% −35.5 [−57.0–6.7]% −9.1 (65.8)% −22.7 [−55.8–12.5]% −10.4 (62.3)% −18.2 [−61.2–12.4]% ACQ5 Worsened 14 3.9 (15.3)ppb 2.0 [−4.0–9.0]ppb 0.003* 12 −6.5 (39.0)ppb −7.5 [−11.0–10.5]ppb 0.004* 17 −1.5 (34.5)ppb −4.0 [−7.0–12.0]ppb 0.295 15.1 (57.8)% −4.00 [−20 – 31.25]% 0.004* 3.3 (77.4)% −19.9 [−42.4–24.7] <0.001* 54.8 (167.2)% −6.3 [−28.6–34.9]% 0.160 No change 61 −1.0 (24.8)ppb 0.0 [−11.0–9.0]ppb 51 2.1 (18.5)ppb 2.0 [−8.5–12.0]ppb 47 −0.2 (14.7)ppb −1.0 [−10.5–9.5]ppb 16.0 (91.3)% 0.0 [−33.3–34.6]% 32.9 (76.4)% 20 [−25.4–62.8]% 21.1 (69.1)% −3.23 [−23.6–47.6]% Improved 24 −22.9 (29.9)ppb −14.5 [−40.0–0.5]ppb 24 −22.8 (37.1)ppb −17.0 [−43.0–1.0]ppb 21 −21.7 (42.1)ppb −7.0 [−49.0–7.0]ppb −29.7 (35.0)% −36.6 [−52.6–1.9]% −24.5 (56.4)% −47.8 [−61.8–3.3]% −12.8 (61.8)% −17.1 [−63.4–25.9]% Notes: Changes in FeNO levels were presented as observed FeNO at certain time points minus baseline level (ppb) and the results were illustrated as absolute change (SD) in ppb and percentage change (SD) in %. #Kruskal–Wallis test. *p < 0.05. Changes in levels of control: Improved (improved in at least one level of asthma control, ie, from partly controlled or uncontrolled to control or from partly controlled to controlled), no change (stayed at same level of control), worsened (worsened in at least one level of asthma control, ie, from controlled to partly controlled or uncontrolled, from partly controlled to uncontrolled). Figure 1 Boxplot of change in FeNO levels at 4, 8 and 12 months compared with baseline (all subjects). (A) Global Initiative of Asthma level of asthma control (GINA), (B) Asthma Control Test (ACT), (C) Asthma Control Questionnaire (ACQ). Changes in FeNO levels were presented as observed FeNO at certain time point minus baseline level (ppb). p value was calculated by Kruskal–Wallis test. * = p < 0.05. The solid line represents the median level, the box represents the IQR and the upper / lower whiskers are from the upper/lower quartile to the highest/lowest actual value within the 75th percentile/25th percentile ± 1.5 × IQR. Changes in levels of control: Improved (improved in at least one level of asthma control, ie, from partly controlled or uncontrolled to control, or from uncontrolled to partly controlled), no change (stayed at same level of control), worsened (worsened in at least one level of asthma control, ie from controlled to partly controlled or uncontrolled, from controlled to partly controlled). Subjects with eosinophils ≥150 or ≥300 cells/µL were separately analysed, and their results are shown in Supplementary Tables 5 and 6 and Supplementary Figures 1 and 2. A similar pattern was noted, but it was observed for subjects with blood eosinophils ≥300 cells/µL, worsening of asthma control was associated with an increase in FeNO level. ROC analyses were performed using different cutoffs for changes in FeNO to predict improvement in asthma control. For GINA classification of asthma control, AUCs were highest for these cutoffs for changes in FeNO levels: ≤ −15ppb, ≤-25 ppb and ≤-10 ppb, respectively, for improvement in asthma control at baseline vs 4 months, 8 months and 12 months, while for ACT were ≤ −15 ppb, ≤-25 ppb and ≤-10 ppb respectively and that for ACQ5 were ≤-25 ppb at all time points (p all <0.05) (Supplementary Table 7). Their respective ROC curves are shown in Figure 2. As the ROC analyses for identifying cutoffs for changes in FeNO for worsening asthma control were mostly statistically non-significant, they were not reported. Figure 2 ROC curves for predicting the improvement for asthma control at different time points. (A) Global Initiative of Asthma level of asthma control (GINA), (B) Asthma Control Test (ACT), (C) Asthma Control Questionnaire (ACQ). Discussion This is a real-life study to assess the FeNO values of Chinese asthma subjects at various levels of asthma control and the serial changes of FeNO with asthma control over time. At the baseline visit, FeNO levels did not differ among the different groups of asthma control by GINA, ACT or ACQ scores. It was observed that FeNO levels decreased with improving asthma control and stayed at similar levels with unchanged or worsening asthma control for all subjects. For those with baseline blood eosinophil levels ≥300 cells/µL, FeNO levels decreased with improving asthma control, stayed similar without change for asthma control and increased with worsening asthma control. ROC analysis with the highest AUC for changes in FeNO level for improving asthma control was between ≤ −10 to −25 ppb at various time points in the 12-month study. There are no clear reference values for FeNO for different levels of asthma control. Some previous studies that used FeNO levels to adjust ICS treatment had various cutoffs. For example, in a study involving asthma patients on regular ICS, FeNO levels of ≥24ppb in women and ≥26 ppb in men were used as a guide for stepping up ICS treatment.24 In another study, if the FeNO was >26 ppb (this cutpoint was chosen as this corresponded to a sputum eosinophil count of >2%), ICS treatment was increased; if it was <16 ppb or <26 ppb on two consecutive occasions, treatment was decreased.25 The main idea was to use FeNO as a marker of inflammation, and thus above or below certain points, ICS was titrated to control the inflammation. If we take the median levels of FeNO and GINA classification of asthma control as a reference in this study, those who had controlled asthma had a median value of 27.5ppb and mean value of 36.79ppb, while partly-controlled and uncontrolled asthma had higher levels. Our patients with controlled asthma had FeNO levels above the cutoff used for titrating up ICS in other studies. We did not perform sputum eosinophil assessment for our subjects, which probably could help identify patients with eosinophil airway inflammation and give a better guide for the cutoffs for titration of asthma medications. Our previous studies on Chinese healthy subjects found that the FeNO levels were higher than in the Caucasian population.16 Results in this study might suggest FeNO levels in Chinese asthma subjects were higher than in the Caucasian populations. Further studies with a comparison of the levels of asthma control with control of the amount of anti-inflammatory therapy used would be needed. Overall, the range of FeNO levels measured for various levels of asthma control using symptom scores in this study was very wide, making that interpretation using a single time point challenging. Some studies found one-off high FeNO level and/or blood eosinophil count had positive associations with asthma symptoms and exacerbations.26–28 Studies on serial FeNO studies with respect to asthma control had variable results. A study found that daily FeNO score at home did not correlate with symptom level.29 Some studies found that FeNO changed with improving or deteriorating asthma control. For example, in patients who received emergency therapy for asthma, repeated measurements of mixed expired NO levels during treatment with glucocorticoids showed a reduction in FeNO levels with an improvement in airway obstruction.30 On the other hand, patients with mild/moderate asthma with their ICS withdrawn and observed for loss of asthma control, increase in FeNO of 10 ppb, 15 ppb or >60% over baseline had positive predictive values that ranged from 80% to 90% for predicting the loss of control.31 There is not much information on the longitudinal study of FeNO in unselected patients. A prospective trial with post hoc data analysis of study of serial FeNO levels using ACQ score 0.75 as the cutoff for well-controlled asthma found that FeNO decreased by 40% and increased by 30% with asthma control optimisation or deterioration, respectively. The serial measurements ranged from 10 to 1129 days. The prediction of FeNO on change of asthma control was better for patients on low-dose ICS compared with those on higher doses.32 In the current study, we found that FeNO decreased with improving asthma control and stayed at similar levels for those with no change or worsening asthma control when all subjects were analysed together. It appeared that only in those with higher blood eosinophil counts, increased FeNO levels were observed with deteriorating asthma control. FeNO levels are affected by many factors,8 including age, height, smoking, and anti-inflammatory medications, and these have to be taken into account during the interpretation. Serial levels of FeNO appeared to reflect changes in levels of asthma control. FeNO is a marker of type 2 inflammation, and it is uncertain if serial FeNO levels are more helpful in detecting changes in asthma control in type 2 high compared to type 2 low subjects. More studies in well-phenotyped patients with a sufficient sample size can give more information on how to interpret the FeNO level changes with respect to asthma control. We found that a decrease in FeNO level (at a range of between ≤ −10 to −25 ppb) had both a positive predictive value (PPV) and negative predictive value (NPV) of about 70% for improvement in asthma control in our cohort. A previous study found that a cutoff of FeNO level at −15% had similar PPV and NPV for predicting improvement in asthma control as in our study. We were unable to find suitable cutoff values of FeNO for predicting the worsening of asthma control in our study.32 We had a relatively smaller number of subjects with worsening asthma control than those with no change or improved asthma control. In addition, many subjects were on ICS, which would affect the FeNO levels. For asthma control, ACT and ACQ have data on the minimal important difference and were used in clinical trials for assessing the response to therapy.22,33 For FeNO, the clinically important change of FeNO in individual patients is not certain. The latest ATS Clinical Practice Guideline on FeNO suggested at least a 20% change to indicate a significant rise or fall in FENO over time or following an intervention.8 While this study assessed the real-life FeNO changes over time in a Chinese cohort, it was limited by being a single-centre study. In addition, this study was in a tertiary referral centre, and thus the results might not be applicable to asthma patients managed in the general practice. Furthermore, the study was limited by the relatively small sample size with no normal subjects as control. The sample size was based on assessing the single-time measurement of FeNO in Chinese asthma subjects to assess if there was a difference from Caucasian values. We had extended the analyses to assess serial changes in the FeNO levels. We did not assess the serial changes in FeNO level according to the ICS dose in this study as many subjects were on an anti-inflammatory reliever for their asthma control. Without electronic monitoring in a real-life study, the amount of the dose of ICS used could not be recorded accurately. Age and gender of an individual can also affect the FeNO level,16 and these factors were not assessed in this study. Conclusion The single-time point measurement of FeNO levels in Chinese patients with controlled asthma appeared higher than that of the cutoffs recommended by clinical trials to step up anti-inflammatory therapy for asthma. When managing asthma, a single measurement of FeNO was not associated with the level of asthma control. However, a serial measure of FeNO showed a decrease in levels with improvement in asthma control as measured by GINA, ACT or ACQ in real-life asthma patients. FeNO levels were observed to increase with worsening asthma control in those with blood eosinophils ≥300 cells/µL. Changes in FeNO level over time were associated with changes in clinical asthma control, particularly in those with high blood eosinophil count and is likely to be more useful than a single time point measurement in the management of asthma. Data Sharing Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Disclosure All authors have no conflicts of interest to declare in relation to this manuscript. ==== Refs References 1. Riise GC, Toren K, Olin A-C. Subjects in a population study with high levels of FENO have associated eosinophil airway inflammation. ISRN Allergy. 2011;2011 :792613. doi:10.5402/2011/792613 24977053 2. Silkoff PE, Lent AM, Busacker AA, et al. Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma. J Allergy Clin Immunol. 2005;116 :1249–1255.16337453 3. Fleming L, Tsartsali L, Wilson N, Regamey N, Bush A. Longitudinal relationship between sputum eosinophils and exhaled nitric oxide in children with asthma. Am J Respir Crit Care Med. 2013;188 :400–402.23905533 4. Maspero J, Adir Y, Al-Ahmad M, et al. Type 2 inflammation in asthma and other airway diseases. ERJ Open Res. 2022;8 :56. 5. Ko FW, Wang JKL, Hui DSC, et al. A multi-center study of the prevalence and characteristics of eosinophilic phenotype and high ige levels among Chinese patients with severe asthma. J Asthma Allergy. 2023;16 :173–182.36721738 6. Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J Med. 2022;386 :157–171.35020986 7. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention; 2022. Available from: www.ginasthma.org. Accessed May 1, 2023. 8. Dweik RA, Boggs PB, Erzurum SC, et al. American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels for Clinical A. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184 :602–615.21885636 9. British Thoracic Society. British guideline on the management of asthma; 2019. Available from: https://www.sign.ac.uk/media/1773/sign158-updated.pdf. Accessed December 20, 2022. 10. Petsky HL, Cates CJ, Kew KM, Chang AB. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax. 2018;73 (12 ):1110–1119. doi:10.1136/thoraxjnl-2018-211540 29858277 11. Sato S, Saito J, Fukuhara A, et al. The clinical role of fractional exhaled nitric oxide in asthma control. Ann Allergy Asthma Immunol. 2017;119 :541–547.29110960 12. Khalili B, Boggs PB, Shi R, Bahna SL. Discrepancy between clinical asthma control assessment tools and fractional exhaled nitric oxide. Ann Allergy Asthma Immunol. 2008;101 :124–129.18727466 13. Visitsunthorn N, Prottasan P, Jirapongsananuruk O, Maneechotesuwan K. Is fractional exhaled nitric oxide (FeNO) associated with asthma control in children? Asian Pac J Allergy Immunol. 2014;32 :218–225.25268339 14. Abe Y, Suzuki M, Kimura H, et al. Annual fractional exhaled nitric oxide measurements and exacerbations in severe asthma. J Asthma Allergy. 2020;13 :731–741.33380812 15. Garcia E, Zhang Y, Rappaport EB, et al. Patterns and determinants of exhaled nitric oxide trajectories in schoolchildren over a 7-year period. Eur Respir J. 2020;56 :2000011.32299857 16. Ko FW, Leung TF, Wong GW, Chu JH, Sy HY, Hui DS. Determinants of, and reference equation for, exhaled nitric oxide in the Chinese population. Eur Respir J. 2013;42 :767–775.23180587 17. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26 :319–338.16055882 18. Ip MS, Ko FW, Lau AC, et al. Updated spirometric reference values for adult Chinese in Hong Kong and implications on clinical utilization. Chest. 2006;129 :384–392.16478856 19. American Thoracic Society, European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171 :912–930.15817806 20. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004;113 :59–65.14713908 21. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14 :902–907.10573240 22. Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally important difference of the Asthma Control Test. J Allergy Clin Immunol. 2009;124 :719–23 e1.19767070 23. Juniper EF, Bousquet J, Abetz L, Bateman ED, Committee G. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006;100 :616–621.16226443 24. Syk J, Malinovschi A, Johansson G, et al. Anti-inflammatory treatment of atopic asthma guided by exhaled nitric oxide: a randomized, controlled trial. J Allergy Clin Immunol Pract. 2013;1 :639–48 e1–8.24565712 25. Shaw DE, Berry MA, Thomas M, et al. 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==== Front J Pain Res J Pain Res jpr Journal of Pain Research 1178-7090 Dove 406498 10.2147/JPR.S406498 Clinical Trial Report Assessment of Ultrasound-Guided Continuous Low Serratus Anterior Plane Block for Pain Management After Hepatectomy: A Randomized Controlled Trial Jiang et al Jiang et al Jiang Fei 1* Wu Ailing 1 Liang Yan 1 Huang Hui 1 Tian Wei 1 Chen Bogang 1 http://orcid.org/0000-0002-1142-0313 Liu Di 1* 1 Department of Anesthesiology, The First People’s Hospital of Neijiang, Neijiang, Sichuan, People’s Republic of China Correspondence: Di Liu, Department of Anesthesiology, The First People’s Hospital of Neijiang, No. 1866 Han’an Dadao West Section, Shizhong District, Neijiang, Sichuan, People’s Republic of China, Tel +86 3541633502, Email liudimzk@126.com * These authors contributed equally to this work 14 7 2023 2023 16 23832392 31 1 2023 06 7 2023 © 2023 Jiang et al. 2023 Jiang et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Purpose Adequate postoperative analgesia is a key to earlier recovery from open surgery. This work investigated the pain control and quality of patient recovery after hepatectomy to evaluate the modified continuous serratus anterior plane block (called low SAPB) for postoperative analgesia. Patients and Methods This single-center, blinded, randomized, controlled study included 136 patients who underwent hepatectomy under general anesthesia. For postoperative analgesia, the patients in the SAPB group were given a continuous low SAPB at the 7th intercostal space in the right mid-axillary line, and the patients in the control group were given continuous intravenous opioid analgesia. The numeric pain rating scale (NPRS) was used for pain assessment. The postoperative assessment focused on the remedial drug consumption, the occurrence of adverse postoperative analgesic reactions, and the quality of patient recovery evaluated with the QoR-15 questionnaire. Results Compared to the controls, the SAPB patients had significantly lower NPRS scores at 12 h and 24 h at rest and 6 h, 12 h, and 24 h in motion, and a longer time to first use of remedial analgesics at 24 h, and higher overall QoR-15 scores at 24 h [124 (121, 126) vs 121 (120, 124)] and 48 h [129 (126, 147) vs 126 (125, 128)], after surgery. There was no significant difference in the incidence of analgesia-related adverse reactions between the two groups. Conclusion The continuous low SAPB could achieve superior pain control, especially for motor pain, to intravenous opioid analgesia during the first 24 h post-surgery. Even with no significant difference in the incidence of postoperative adverse reactions, patients with continuous low SAPB appeared to have a higher quality of recovery in the first two days post-surgery than patients with continuous intravenous analgesia. Keywords liver resection postoperative analgesia serratus anterior plane block the Research Program of the Sichuan Provincial Health Commission, Sichuan, China the Sichuan Medical Association Youth Research Innovation Fund Project This work was supported by the Research Program of the Sichuan Provincial Health Commission, Sichuan, China (No. 20PJ288), and the Sichuan Medical Association Youth Research Innovation Fund Project (No. Q22022). ==== Body pmcIntroduction Liver cancer is one of the most frequent fatal malignancies that threaten human health.1 Liver resection remains the optimal choice for the treatment of liver cancer in current clinical practice.2 Due to the invasive procedure, drainage tube placement, liver regeneration following damage or resection, and inflammatory response, patients commonly experience moderate-to-severe acute pain (defined as a visual analogue scale score greater than 3) lasting several days after hepatectomy.3,4 The incidence of moderate-to-severe acute pain in patients on day 1 after hepatectomy is as high as 72%.4,5 The stress response to painful surgical trauma is associated with the increased release of inflammatory factors and hormones including cortisol and adrenocorticotropic hormones, which can induce cardiovascular and metabolic adverse effects. These pains reduce patients’ quality of life, raise postoperative stress, prolong surgical wound healing time, aggravate patients’ anxiety and depression, and even evolve into chronic postsurgical pain, which hinders the rapid recovery and rehabilitation process.5 As reported, 55–80% of patients undergoing hepatectomy have inadequate postoperative analgesia.6 Multimodal analgesia after open surgery is essential.4 Intravenous analgesia, epidural analgesia, and peripheral nerve blocks are common postoperative analgesia modalities in clinical practice.7–9 Systemic intravenous analgesia could contribute to side effects including respiratory depression, nausea, vomiting, and pruritus.10,11 Whereas sympathetic blockade (hypotension, bradycardia) or patient coagulation dysfunction limits its use, epidural analgesia may provide better pain management.5 Ultrasound-guided serratus anterior plane block (SAPB) provides accurate ultrasound localization for block catheter placement and has been gradually applied for pain management after upper abdominal surgery as a new fascial plane block technique in recent years.12–14 It was first described by Blanco in 2013 and has a high block success rate in contrast to thoracic epidural analgesia and paravertebral block. Ultrasound-guided SAPB not only reduces surgical stress response, inflammatory factor release, and opioid use15 but also avoids hemodynamic fluctuations and serious respiratory and intraspinal sequelae.12,16–18 In clinical practice, 30 mL of 0.25% ropivacaine is administered via an injection into the deep fascial plane under the serratus anterior muscle at the 7th intercostal space in the mid-axillary line for SAPB, which provides good analgesia to the anterolateral chest wall and upper abdominal wall. Analgesic evaluation of such a modified low SAPB after hepatectomy in terms of pain management and quality of patient recovery has not been reported to date. Therefore, this prospective, randomized, controlled study aimed to evaluate the clinical analgesic efficacy and safety of ultrasound-guided continuous low SAPB after hepatectomy to provide a clinical reference. Materials and Methods This prospective, randomized, controlled, single-blind trial was approved by the Institutional Ethics Committee (Approval number: 2021-01) of the First People’s Hospital of Neijiang (Sichuan Province, China) and was conducted following the principles outlined in the Declaration of Helsinki. This trial was preregistered on clinicaltrials.gov (Trial registration number: NCT05531864). Written informed consent was obtained from all participants for the enrolment and interventions in the study. Participants and Grouping The patients diagnosed with hepatocellular carcinoma who were scheduled for hepatectomy (open surgery) between June 18, 2021 and July 24, 2022 in our hospital were included in the present study. All diagnoses met the World Health Organization’s diagnostic criteria for liver cancer. The included patients were aged 25 to 75 years with an ASA (American Society of Anesthesiologists) level of I, II, or III, and a body mass index (BMI) of 18.5 to 29 kg/m2. Patients with cardiac, cerebral, hepatic, or renal failure, comorbid psychiatric or neuromuscular disorders, or coagulation disorders were excluded. Other exclusion criteria included a history of allergy to anesthetic drugs or local anesthetics, a history of long-term opioid or drug use, an inability to cooperate with the researchers in this study for various reasons, and participation in other synchronous clinical or drug trials. Participants were randomized into two groups: the SAPB group (general anesthesia with continuous low SAPB) and the control group (general anesthesia with continuous intravenous opioid analgesia). Each patient was randomly assigned to the SAPB group or control group according to a random number table. Random numbers were generated using IBM SPSS 26.0 software. Group allocations were kept in serially numbered opaque envelopes and sealed. After baseline assessment and recruitment, one patient’s envelope was sent to an anesthetist. The anesthetist opened the envelope to determine the group allocation and performed the interventions pre-established for the indicated group. The anesthetist who performed the blocks did not participate in the intraoperative pain management of the patients. General Anesthesia and Postoperative Analgesia General anesthesia and surgical technique were the same for all patients included. General anesthesia was actively induced by administering 0.02 mg/kg midazolam, 0.4 μg/kg sufentanil, 0.3 mg/kg cis-atracurium, and 0.3 mg/kg etomidate, and maintained by propofol, remifentanil, cis-atracurium, and sevoflurane. In the SAPB group, continuous low SAPB and patient-controlled nerve analgesia (0.25% ropivacaine hydrochloride, 5 mL/h) were used. In the control group, patient-controlled continuous intravenous analgesia (100 mL dilution containing 2 μg/kg sufentanil, 0.25 mg/kg dezocine, and 10 mg toltestrone) was given. The analgesia pump parameters were set as background dose 2 mL/h, patient-controlled analgesia dose 0.5 mL, and locking time 15 min. At the end of the surgery, the patients were monitored in the recovery room and received pain assessment using the 11-point NPRS (the numeric rating scale for clinical pain measurement), which ranges from “0” (indicating “no pain”) to “10” (indicating “pain as bad as you can imagine”). When the postoperative NPRS score was greater than 3, remedial analgesia (100 mg tramadol) was administered by a ward physician who was blind to the grouping information. SAPB patients were treated in the supine position with the right upper limb abducted at 90°, and the nerve block catheter was positioned at the 7th intercostal space in the right mid-axillary line, which could block the lateral cutaneous branches of the 4th to 11th intercostal nerves (T4–T11) and provide good analgesia to the anterolateral chest wall and upper abdominal wall. In detail, after routine skin preparation, the linear ultrasound transducer probe (S9, SonoScape, Shenzhen, China) was placed over the thoracic cage in a sagittal plane to identify the superficial latissimus dorsi and the deep serratus anterior muscle (as shown in Figure 1). Subsequently, using an in-plane approach, a nerve block puncture needle (Stimuplex, B. Braun Medical, Melsungen, Germany) was inserted caudally from the skin above the 6th or 7th rib to the 8th intercostal space in the right mid-axillary line, namely, through the latissimus dorsi and the serratus anterior muscle to reach the deep fascial plane between the serratus anterior muscle and the external intercostal muscles and ribs in the 7th intercostal space. About 2 mL of normal saline solution was used for the injection test. After a black appearance of fluid spreading caudally along the rib surface was visible on ultrasound and no blood or gas was found after pulling back the plunger, 30 mL of AstraZeneca 0.25% ropivacaine was injected into the deep fascial plane. Besides, a puncture needle was inserted caudally along the 6th, 7th, or 8th rib surface through the external and internal intercostal muscles in the 6th, 7th, or 8th intercostal space, respectively, to reach the plane between the internal and the innermost intercostal muscles. About 2 mL of 0.25% ropivacaine was injected into the plane each in the 6th, 7th, and 8th intercostal spaces after an injection test as above described. Afterward, a nerve block puncture needle was inserted caudally as above described, and the nerve block catheter was kept at the deep fascial plane (a depth of approximately 5 cm; T7) in the 7th intercostal space for continuous postoperative analgesia. At the end of one surgery, the patient-controlled analgesia pump (0.25% ropivacaine, 5 mL/h) was connected to the nerve block catheter. The patient-activated dose was 8 mL per time, and the lockout interval was set at one hour. Figure 1 Sonographic anatomy of the low serratus anterior plane block. 7th rib, the seventh rib. Primary and Secondary Endpoints The primary outcomes were the numeric pain rating scale (NPRS) scores at rest and in motion at various postoperative time points (0 h, 2 h, 6 h, 12 h, 24 h, and 48 h). The secondary outcomes included the quality of patient recovery after surgery which was evaluated with the global Quality of Recovery-15 (QoR-15) questionnaire,19 time to the first use of remedial analgesics (tramadol) after various postoperative analgesia interventions, adverse postoperative analgesic reactions, or nerve block-related complications (nausea, vomiting, etc.) within the postoperative 24 h. Statistical Analysis All data were collected by an Excel program and then analyzed using GraphPad Prism 9.0. The Shapiro–Wilk test was used to determine if the data followed a normal distribution. The normally distributed data (including age, height, BMI, duration of anesthesia, and duration of surgery) were expressed as mean ± standard deviation (SD) and analyzed using an independent samples t-test. Fisher’s exact test was used for non-normally distributed quantitative data (eg, gender). The skewed data were expressed as the median and interquartile range (IQR). The Mann–Whitney U-test was applied to detect the between-group differences in NPRS scores at 0 h, 2 h, 6 h, 12 h, 24 h, and 48 h after surgery. The relationship between qualitative variables and independent samples (eg, ASA classification) was analyzed using a chi-square test. P values <0.05 were considered statistically significant. Results After random allocation and several rounds of exclusion, a total of 136 participants were included in our analysis. Of the 139 patients who were eligible and underwent open surgery for hepatocellular carcinoma, there were two patients lost to follow-up, and one was excluded due to the occurrence of postoperative thrombosis (Figure 2). Basic information about the enrolled patients is detailed in Table 1.Table 1 Patient Demographic and Clinical Parameters Variable SAPB Group (N = 69) Control Group (N = 67) P Age (years) 55.63 ± 3.03 54.94 ± 4.98 0.547 Sex (N/%)  Female 30 (43.5%) 27 (40.3%) 0.509  Male 39 (56.5%) 30 (59.7%) 0.632 Body mass index 22.37 ± 2.35 22.59 ± 2.41 0.748 ASA physical status  ASA I 8 5 0.089  ASA II 45 43 0.646  ASA III 16 19 0.751 Duration of surgery (min) 290.23 ± 19.02 283.01 ± 16.20 0.582 Duration of anaesthesia (min) 395.01 ± 22.50 388.25 ± 18.62 0.773 Intraoperative fluid intake [mL; mean (SE)] 3592.2 (134.5) 3710.4 (202.4) 0.134 Estimated blood loss [mL; mean (SE)] 465.0 (52.9) 450.9 (83.0) 0.331 Hypoproteinaemia (N/%) 25 (36.2%) 23 (34.3%) 0.281 QoR-15 score 141.63 ± 4.02 140.94 ± 3.19 0.313 Notes: QoR-15 refers to the 15-item quality of recovery scale for patient-reported, global outcome measures of quality of recovery after surgery and anaesthesia. Abbreviations: ASA, American Society of Anaesthesiologists; SE, standard error. Figure 2 CONSORT (Consolidated Standards of Reporting Trials) flow diagram. The SAPB group underwent general anesthesia and continuous low serrate anterior plane block, while the control group underwent general anesthesia and continuous intravenous opioid analgesia. Notes: Adapted from Schulz KF, Altman DG, Moher D, CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials. PLoS Med. 2010;7(3): e1000251. Copyright: © 2010 Schulz et al. Creative Commons Attribution License.20 Abbreviations: SAPB, serratus anterior plane block; control, the control group. As shown in Table 2 and Figure 3, after various postoperative analgesia interventions, the patients with continuous low SAPB (SAPB group) had a significantly greater reduction in NPRS scores at rest and in motion compared to the control patients within 24 h post-surgery (p<0.05). In addition, we also used a survival curve to depict the time to the first use of remedial analgesics after various postoperative analgesia interventions (Figure 4). We found a significant difference between the two groups in the time to the first use of remedial analgesics (p=0.017). Besides, as shown in Table 3, there was no significant difference between the two groups in terms of complications such as incisional infection and hypotension (requiring intervention), implying that continuous low SAPB did provide better pain control on the first postoperative day than other analgesia modalities. The SAPB patients had fewer postoperative adverse reactions (nausea, vomiting, and pruritus) than the control patients.Table 2 Assessment of Numeric Pain Rating Scale Scores of the Two Groups at Different Postoperative Time Points Postoperative Time Point Numeric Pain Rating Scale Score [Min–Max (Median)] At Rest In Motion SAPB Group Control Group P SAPB Group Control Group P 2 h 0–1 (0) 0–1 (0) 0.059 0–1 (1) 0–2 (1) 0.003 6 h 1–3 (1) 0–2 (1) 0.062 1–3 (1) 1–3 (1) 0.041 12 h 1–3 (1) 1–3 (1) 0.018 1–3 (2) 1–4 (3) 0.033 24 h 1–4 (2) 1–4 (2) 0.025 1–4 (2) 1–4 (3) 0.014 48 h 0–3 (2) 1–3 (2) 0.301 1–3 (2) 1–3 (2) 0.266 Table 3 Comparison of Incidence of Adverse Effects Between the Two Groups SAPB Group (N = 69) Control Group (N = 67) P-value* Nausea 7 (10.14) 12 (17.91) 0.034 Vomiting 6 (8.70) 8 (11.94) 0.043 Incisional infection 1 (1.45) 1 (1.49) 0.98 Hypotension requiring intervention in recovery 3 (4.34) 4 (5.97) 0.87 Pruritus 1 (1.45) 3 (4.48) 0.041 Total 18 (26.08) 28 (41.79) 0.032 Notes: Data are shown as N (%). *Fisher exact test. P < 0.05 vs control group. Figure 3 NPRS scores of the two groups at different postoperative time points (0 h, 2 h, 6 h, 12 h, 24 h, and 48 h) after surgery. (A) NPRS scores at rest. (B) NPRS scores in motion. The SAPB group underwent general anesthesia and continuous low serrate anterior plane block, while the control group underwent general anesthesia and continuous intravenous opioid analgesia. *p<0.05 versus the control group. Abbreviations: SAPB, serratus anterior plane block; NPRS, numerical pain rating scale. Figure 4 Kaplan-Meier plots of the observed probability of postoperative use of remedial analgesia (seconds) for the two intervention groups. p=0.033. Abbreviation: SAPB, serratus anterior plane block. As shown in Figure 5, the SAPB patients had significantly higher QoR-15 scores at 24 h [124 (121, 126) vs 121 (120, 124)] and 48 h [129 (126, 147) vs 126 (125, 128)] post-surgery than the control patients; both groups of patients also had significantly higher QoR-15 scores in the first two postoperative days compared to their baseline levels (p<0.05). However, such significant differences were not maintained on the third postoperative day. Figure 5 The overall QoR-15 scores of the SAPB group and control group at postoperative day 1 (POD1), day 2 (POD2), and day 3 (POD3). The data were represented by the median (horizontal bar), interquartile range (box), maximum and minimum values (upper and lower edges), and outliers (dots). #p<0.05 versus the control group. Abbreviations: SAPB, serratus anterior plane block; QoR-15, Quality of Recovery-15 scale; ns, not significant. Discussion This prospective, randomized, controlled study evaluated the analgesic effect of ultrasound-guided continuous low SAPB and the quality of patient recovery after hepatectomy. We found that ultrasound-guided continuous low SAPB significantly reduced pain at 12 h and 24 h post-surgery at rest and in motion and reduced the administration of remedial analgesics at 24 h post-surgery compared to intravenous analgesia alone. The patients with continuous low SAPB had higher global QoR-15 scores at 48 h post-surgery, indicating a clinically meaningful improvement in the quality of recovery. However, there was no statistically significant difference in analgesia-related adverse reactions between SAPB patients and control patients. In the present study, the ultrasound-guided continuous low SAPB used as an analgesic protocol for postoperative pain management after hepatectomy is a modified SAPB modality. Unlike Blanco’s classical SAPB with the puncture points located at the 4th and 5th intercostal spaces in the mid-axillary line, the puncture points in our study were located above the 6th or 7th rib in the mid-axillary line, and the analgesic (ropivacaine) was injected into and the nerve block catheter was placed into the deep fascial plane between the deep surface of the serratus anterior muscle and external intercostal muscles and ribs at the 7th intercostal space in the mid-axillary line. Our SAPB modality used a lower concentration (0.25%) and a higher dose (30 mL) of ropivacaine. Our continuous low SAPB could maximize the spread of local anesthetic to the lateral cutaneous branches, mainly T4–T11, of the intercostal nerves. The hyperalgesia of dermatomal block levels T4–T11 can be examined in the lateral region of the abdomen at 30 min. Previous studies17,21–24 have shown that SAPB is more frequently used in thoracic anesthesia, and relatively few studies have reported its application in hepatectomy. Elsharkaw et al25 reported a case series of the application of rhomboid intercostal and sub-serratus plane blocks for postoperative pain management in upper abdominal surgery, which could better block the lateral cutaneous branches of the thoracic intercostal nerves and be used for thoracic and upper abdominal analgesia in various clinical situations. This block modality is highly similar to the SAPB. In the present study, we put forward our modified continuous low SAPB for postoperative analgesia. We chose the puncture point and the block catheter placement site more distant from the hepatic region to avoid their contributing surgical incisional contamination. Besides, the local anesthetic was injected into the plane between the internal and innermost intercostal muscles to achieve a selective block of the anterior cutaneous branch of the 6th, 7th, and 8th intercostal nerves. This would avoid unnecessary medical disputes caused by incision infections caused by the rectus abdominis sheath block. Our study showed that the block levels of ultrasound-guided unilateral SAPB at the 7th or 8th intercostal space were concentrated at T4–T11, which provided good postoperative analgesia of incisions for liver resection. With our modified SAPB, the SAPB patients had significantly lower NPRS scores at rest and in motion than the control patients at 12 h and 24 h after hepatectomy for hepatocellular carcinoma. Besides, the SAPB patients had no significantly lower resting NPRS scores at 6 h post-surgery than the control patients, which may be attributed to the small sample size. In addition, the median NPRS scores at rest and in motion after surgery were less than 4 at most times in both groups, indicating clinically acceptable analgesia could be achieved in both groups using the multimodal analgesia protocol in this study. Of note, SAPB with ropivacaine alone could only control the incisional pain and did not improve the outcome of postoperative visceral pain, so flurbiprofen ester was administered intravenously 30 min before the end of surgery to achieve better postoperative analgesia. With survival curve analysis, we investigated the time to the first use of remedial analgesia after various postoperative analgesia interventions in the two groups and found a statistically significant difference between the two groups. The SAPB patients required significantly less opioid analgesia after the same procedure since our study used a higher dose of local anesthetic (30 mL ropivacaine). Notably, the trigger points for postoperative analgesia intervention by the anesthetists differed between studies. The patients in our study had an NPRS score greater than 3 as the intervention threshold, and the other studies used different intervention thresholds and anesthetics. This may partially explain the significant difference in opioid use between the studies. In any case, the administration of analgesics should not be the main criterion for assessing patient comfort in the perioperative period. Therefore, unlike previous studies that simply assessed postoperative pain severity and the use of postoperative remedial analgesics, this study also assessed patients’ QoR-15 scores on the three postoperative days, which is an internationally recognized and validated patient-centered instrument for assessing the quality of patient postoperative recovery. This study found that the SAPB patients had significantly higher QoR-15 scores on the first and second postoperative days than the control patients, and there was no difference in the scores on the third postoperative day between the two groups, mainly due to the good analgesic effect of SAPB on the first postoperative day and the reduction in the use of postoperative remedial analgesics and less resulting nausea and vomiting and other adverse effects, thus improving the quality of recovery and patient satisfaction. Ropivacaine is a long-acting amide local anesthetic and has a longer duration of action, a more rapid onset of action, a higher maximal dose, and lower toxicity to the central nervous system and cardiovascular system compared with other local anesthetics. With the available reports and our clinical practice, this study selected 30 mL of 0.25% ropivacaine for ultrasound-guided low SAPB and 5 mL/h of 0.25% ropivacaine for continuous SAPB pump after surgery. It was found that ropivacaine could alter the growth, apoptosis, and proliferation of cancer cells through a variety of mechanisms.26–28 Ropivacaine reduced the mRNA levels of key cell cycle regulators and the expression of MK167, a marker of cell proliferation, in hepatocellular carcinoma cells.26 It could promote apoptosis and inhibit the development of hepatocellular carcinoma by targeting the IGF-1 R/PI3K/AKT/mTOR signaling pathway.27 It could also disrupt mitochondrial function and activate caspase-3 activity to promote apoptosis in hepatocellular carcinoma cells.28 Taken together, ropivacaine can inhibit the biological properties of tumors by blocking sodium channels and is suitable for analgesia after surgery for liver cancer. Our study is a single-center study, and further confirmation of our findings in other centers is required, although the team of surgeons and anesthetists ensured the standardization and consistency of all procedures. Besides, due to ethical constraints, 0.9% saline was not used in this study as a negative control in control patients. As SAPB for postoperative analgesia after hepatic lobectomy is less studied at present, the low SAPB we applied was slightly modified from the traditionally described modality and was compared with patient-controlled analgesia in the present study to observe whether such SAPB was effective in postoperative analgesia. It may be better to compare it with the classical thoracic paravertebral nerve block for pain management after hepatectomy. Given the small sample size, larger relevant studies are warranted to assess the analgesic effect of SAPB more accurately in hepatocellular carcinoma patients undergoing hepatectomy and the quality of patient recovery. Conclusion In this work, our continuous low SAPB within the first 24 h post-surgery provided better postoperative analgesia compared to continuous intravenous analgesia. Continuous low SAPB appears to be superior to continuous intravenous analgesia regarding postoperative analgesia and quality of patient recovery from hepatectomy in the first two days post-surgery, while no significant difference exists between both in the incidence of postoperative adverse effects. More randomized controlled trials with larger samples need to be conducted to confirm these observations. Data Sharing Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics Approval and Informed Consent This prospective, randomized, controlled, single-blind trial was approved by the Institutional Ethics Committee (approval number: 2021-01) of the First People’s Hospital of Neijiang (Sichuan, China) and was conducted in accordance with the principles outlined in the Declaration of Helsinki. This trial was preregistered on clinicaltrials.gov (Trial registration number: NCT05531864). Disclosure The authors report no conflicts of interest in this work. ==== Refs References 1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71 (3 ):209–249. doi:10.3322/caac.21660 33538338 2. Anwanwan D, Singh SK, Singh S, et al. Challenges in liver cancer and possible treatment approaches. Biochim Biophys Acta Rev Cancer. 2020;1873 (1 ):188314. doi:10.1016/j.bbcan.2019.188314 31682895 3. Joshi GP, Kehlet H. Postoperative pain management in the era of ERAS: an overview. Best Pract Res Clin Anaesthesiol. 2019;33 (3 ):259–267. doi:10.1016/j.bpa.2019.07.016 31785712 4. Agarwal V, Divatia JV. Enhanced recovery after surgery in liver resection: current concepts and controversies. Korean J Anesthesiol. 2019;72 (2 ):119–129. doi:10.4097/kja.d.19.00010 30841029 5. Dieu A, Huynen P, Lavand’homme P, et al. Pain management after open liver resection: procedure-specific postoperative pain management (PROSPECT) recommendations. Reg Anesth Pain Med. 2021;46 (5 ):433–445. doi:10.1136/rapm-2020-101933 33436442 6. Chou R, Gordon DB, De Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17 (2 ):131–157. doi:10.1016/j.jpain.2015.12.008 26827847 7. Mungroop TH, Geerts BF, Veelo DP, et al. Fluid and pain management in liver surgery (MILESTONE): a worldwide study among surgeons and anesthesiologists. Surgery. 2019;165 (2 ):337–344. doi:10.1016/j.surg.2018.08.013 30314727 8. Dudek P, Zawadka M, Andruszkiewicz P, et al. Postoperative analgesia after open liver surgery: systematic review of clinical evidence. J Clin Med. 2021;10 (16 ):3662. doi:10.3390/jcm10163662 34441958 9. Zhou L, Huang J, Chen C. Most effective pain-control procedure for open liver surgery: a network meta-analysis. ANZ J Surg. 2018;88 (12 ):1236–1242. doi:10.1111/ans.14456 29534349 10. Salicath JH, Yeoh EC, Bennett MH. Epidural analgesia versus patient-controlled intravenous analgesia for pain following intra-abdominal surgery in adults. Cochrane Database Syst Rev. 2018;8 (8 ):Cd010434. doi:10.1002/14651858.CD010434.pub2 30161292 11. Bongiovanni T, Lancaster E, Ledesma Y, et al. Systematic review and meta-analysis of the association between non-steroidal anti-inflammatory drugs and operative bleeding in the perioperative period. J Am Coll Surg. 2021;232 (5 ):765–790.e1. doi:10.1016/j.jamcollsurg.2021.01.005 33515678 12. Tiwari AK, Mar AA, Fairley MA. Serratus anterior plane block for upper abdominal incisions. Anaesth Intensive Care. 2019;47 (2 ):197–199. doi:10.1177/0310057x19842461 31116015 13. FernÁndez MT, LÓpez S, Aguirre JA, et al. Serratus intercostal interfascial plane block in supraumbilical surgery: a prospective randomized comparison. Minerva Anestesiol. 2021;87 (2 ):165–173. doi:10.23736/s0375-9393.20.14882-x 33319949 14. Fernández Martín MT, López Álvarez S, Mozo Herrera G, et al. Ultrasound-guided cutaneous intercostal branches nerves block: a good analgesic alternative for gallbladder open surgery. Rev Esp Anestesiol Reanim. 2015;62 (10 ):580–584. doi:10.1016/j.redar.2015.02.011 25896736 15. Lillemoe HA, Marcus RK, Day RW, et al. Enhanced recovery in liver surgery decreases postoperative outpatient use of opioids. Surgery. 2019;166 (1 ):22–27. doi:10.1016/j.surg.2019.02.008 31103198 16. Semyonov M, Fedorina E, Grinshpun J, et al. Ultrasound-guided serratus anterior plane block for analgesia after thoracic surgery. J Pain Res. 2019;12 :953–960. doi:10.2147/jpr.S191263 30881105 17. Finnerty DT, Mcmahon A, Mcnamara JR, et al. Comparing erector spinae plane block with serratus anterior plane block for minimally invasive thoracic surgery: a randomised clinical trial. Br J Anaesth. 2020;125 (5 ):802–810. doi:10.1016/j.bja.2020.06.020 32660716 18. Blanco R, Parras T, Mcdonnell JG, et al. Serratus plane block: a novel ultrasound-guided thoracic wall nerve block. Anaesthesia. 2013;68 (11 ):1107–1113. doi:10.1111/anae.12344 23923989 19. Myles PS, Shulman MA, Reilly J, et al. Measurement of quality of recovery after surgery using the 15-item quality of recovery scale: a systematic review and meta-analysis. Br J Anaesth. 2022;128 (6 ):1029–1039. doi:10.1016/j.bja.2022.03.009 35430086 20. Schulz KF, Altman DG, Moher D, CONSORT Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials. PLoS Med. 2010;7 (3 ):e1000251.20352064 21. Jack JM, Mclellan E, Versyck B, et al. The role of serratus anterior plane and pectoral nerves blocks in cardiac surgery, thoracic surgery and trauma: a qualitative systematic review. Anaesthesia. 2020;75 (10 ):1372–1385. doi:10.1111/anae.15000 32062870 22. Kim D-H, Oh YJ, Lee JG, et al. Efficacy of ultrasound-guided serratus plane block on postoperative quality of recovery and analgesia after video-assisted thoracic surgery: a randomized, triple-blind, placebo-controlled study. Anesth Analg. 2018;126 (4 ):1353–1361. doi:10.1213/ane.0000000000002779 29324496 23. Fernández Martín MT, López Álvarez S, Fajardo Pérez M, et al. Serratus-intercostal interfascial plane block: alternative analgesia for open nephrectomy? Minerva Anestesiol. 2018;84 (7 ):872–873. doi:10.23736/s0375-9393.18.12808-2 29479932 24. Xiao Y-K, She S-Z, Xu L-X, et al. Serratus anterior plane block combined with general analgesia and patient-controlled serratus anterior plane block in patients with breast cancer: a randomized control trial. Adv Ther. 2021;38 (6 ):3444–3454. doi:10.1007/s12325-021-01782-y 34021888 25. Elsharkawy H, Maniker R, Bolash R, et al. Rhomboid intercostal and subserratus plane block: a cadaveric and clinical evaluation. Reg Anesth Pain Med. 2018;43 (7 ):745–751. doi:10.1097/aap.0000000000000824 30169476 26. Le Gac G, Angenard G, Clément B, et al. Local anesthetics inhibit the growth of human hepatocellular carcinoma cells. Anesth Analg. 2017;125 (5 ):1600–1609. doi:10.1213/ane.0000000000002429 28857796 27. Zhang R, Lian Y, Xie K, et al. Ropivacaine suppresses tumor biological characteristics of human hepatocellular carcinoma via inhibiting IGF-1R/PI3K/AKT/mTOR signaling axis. Bioengineered. 2021;12 (2 ):9162–9173. doi:10.1080/21655979.2021.1995103 34696683 28. Wang W, Zhu M, Xu Z, et al. Ropivacaine promotes apoptosis of hepatocellular carcinoma cells through damaging mitochondria and activating caspase-3 activity. Biol Res. 2019;52 (1 ):36. doi:10.1186/s40659-019-0242-7 31300048

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==== Front Int Med Case Rep J Int Med Case Rep J imcrj International Medical Case Reports Journal 1179-142X Dove 422426 10.2147/IMCRJ.S422426 Case Report Pituitary Macroadenoma with Optic Cupping Masquerading as Normal Tension Glaucoma Cheng et al Cheng et al http://orcid.org/0000-0001-7035-8567 Cheng Anny M 1 2 3 * http://orcid.org/0009-0002-8472-6572 Schecter Scott 4 * Komotar Ricardo Jorge 5 Tsai Joby 1 2 Gupta Shailesh K 1 2 1 Department of Ophthalmology, Broward Health, Fort Lauderdale, FL, USA 2 Specialty Retina Center, Coral Springs, FL, USA 3 Department of Ophthalmology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, USA 4 South Florida Vision, Fort Lauderdale, FL, USA 5 Department of Neurosurgery, University of Miami, Miami, FL, USA Correspondence: Shailesh K Gupta, Department of Ophthalmology, Broward Health, Fort Lauderdale, FL & Specialty Retina Center, 6280 W Sample Road# 202, Coral Springs, FL, 33067, USA, Tel +1 561 322-3588, Fax +1 754 812-5993, Email sgupta@specialtyretina.com * These authors contributed equally to this work 14 7 2023 2023 16 419423 22 5 2023 05 7 2023 © 2023 Cheng et al. 2023 Cheng et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Abstract When non-glaucomatous disease with disc cupping mimics normal-tension glaucoma (NTG), diagnosis is challenging. The typical optic disc features of glaucomatous disease are often subjective, and often overlap with disc changes in compressive intracranial lesions. Ancillary diagnostic testing such as retinal nerve fiber layer (RNFL) analysis and visual field testing can elevate the index of suspicion of an underlying non-glaucomatous process. We present a case of a nonfunctional macroadenoma coexisting with NTG, although it is unclear if the concurrent brain lesion aggravated or caused it. This case highlights the diagnostic challenge of recognizing optic cupping and non-matching abnormalities in the visual field from a coexisting intracranial lesion, even in the absence of other neurological signs. Keywords cupping normal tension glaucoma pituitary macroadenoma visual field defects not supported by any grant This study was not supported by any grant. ==== Body pmcIntroduction Normal-tension glaucoma (NTG) is characterized by optic nerve head cupping, retinal ganglion cell (RGC) loss, and visual field defects, whereas intraocular pressure (IOP) is within the normal range. Diagnosis is challenging when normal pressure non-glaucomatous disorders with disc cupping mimic NTG. Optic nerve cupping is an important diagnostic feature of glaucoma; however, it is not pathognomonic and may occur in non-glaucomatous diseases. The typical characteristics of glaucomatous changes include deepening of the optic cup, appearance of the optic nerve head, neuroretinal rim notching, disc hemorrhage, parapapillary atrophy, and symmetric retinal nerve fiber layer loss.1,2 Cupping with out-of-proportional neuroretinal rim pallor is more common in non-glaucomatous eyes. However, all of these funduscopic signs are subjective, and similar clinical cupping observations have been found in glaucoma and compressive intracranial lesions. Patients with intracranial tumors have been reported to have normal IOP but glaucomatous-like optic discs.3–6 Studies show that the neuroradiological presence of a mass lesion in patients diagnosed with glaucoma varies from 0 to 14.2%.2,7 While part of the possible work-up, routine neuroimaging is not recommended for patients with presumed NTG, because of the low yield of intracranial pathological detection.2,8 Instead of imaging studies, the pattern of the visual field defect can be a diagnostic clue to identify the intracranial etiology if optic disc neuroretinal rim pallor is absent in examinations.6 Studies show that visual field defects related to vertical alignment are significantly associated with compressive intracranial pathology.2,6 This is an important clinical finding in isolated or coexisting intracranial masses and glaucoma, where the diagnosis of brain lesions may be overlooked. Therefore, a detailed record of visual field pattern changes is crucial. Herein, we present the identification of an associated brain mass in a NTG patient with significant optic disc cupping. Institutional approval was waived as our single case report involves retrospective medical record review of one patient and the only interaction with the patient has been for purposes of treating the patient and does not meet the Common Rule definition of research (45 CFR 164.501). Although institutional approval was not required to publish the case details, we obtained written informed consent from the patient for the publication of his case and any accompanying images. Case Report A healthy 65-year-old man presented with occasional blurred vision for one week. At the initial presentation, his best-corrected visual acuity was 20/25 bilaterally, and intraocular pressure was 16 mmHg in both eyes. Motility revealed a slight limitation of abduction in the left eye. Pupils were round and reactive without a relative afferent pupillary defect. Slit-lamp examination revealed mild bilateral nuclear cataracts. Fundus examination revealed clear media, normal color, and asymmetric optic nerve head cupping of 0.55 horizontally in the right eye and 0.85 horizontally in the left eye (Figure 1A). An initial diagnosis of “normal tension glaucoma” was made, and he was not treated with any topical glaucomic medications at the initial presentation. Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) showed bilateral superior and inferior thinning, which is consistent with glaucomatous changes; however, the left eye also showed temporal thinning (Figure 1B). Automated perimetry revealed bilateral nasal steps associated with temporal defects with respect to the vertical meridian (Figure 1C and D), raising the suspicion of an intracranial lesion other than glaucomatous change. Magnetic resonance imaging (MRI) of the brain (Figure 2) confirmed a 3.1×2.3 x 2.8 cm mass arising from the pituitary fossa, consistent with a macroadenoma, with mass effect on the optic chiasm, protrusion into the left cavernous sinus, and lateral displacement of the left internal carotid artery. The brain tumor was removed uneventfully after evaluation by a neurosurgeon (R.J.K.). Postoperative best-corrected visual acuity was 20/25 bilaterally, and visual field testing demonstrated resolution of bitemporal defects. Follow-up evaluation at 12 months revealed an intraocular pressure of 12 mmHg bilaterally under Lumigan (bimatoprost ophthalmic solution 0.01%, Allergan, AbbVie, USA) treatment for NTG, and cupping remained 0.55 in the right eye and 0.85 in the left eye, respectively. Figure 1 Asymmetric optic nerve head cupping of 0.55 horizontally in the right eye (left panel) and 0.85 horizontally in the left eye (right panel) (A). Optical coherence tomography of the retinal nerve fiber layer showed atrophy of the left optic nerve not only in the superior and inferior but also in the temporal portion (B). Pre-operative automated perimetry showed a bitemporal visual field defect respect to vertical meridian associated with nasal steps in the left eye (C) and right eye (D). Figure 2 MRI sagittal (A) and coronal (B) T1 showed heterogeneous enhancing mass arising from pituitary fossa consistent with macroadenoma. Discussion We present a case of a nonfunctional macroadenoma coexisting with glaucoma that highlights the importance of identifying nonglaucomatous visual field defects in the presence of concurrent glaucomatous changes. To avoid mismanagement of glaucoma, in particular NTG, we emphasize the importance of considering more than merely the morphology of the optic disc. It is not uncommon to interpret intracranial optic lesions as glaucomatous changes based on fundus examinations and, therefore, miss the diagnosis.9 Patients may have signs that raise suspicion about the presumptive diagnosis of NTG. Clinically differentiating glaucomatous and non-glaucomatous etiologies can be challenging, especially in NTG, like in our patient, who presented with cupping and normal IOP without pallor.2,8 Although pallor of the neuroretinal rim is a hallmark non-glaucomatous finding,10 a recent study suggests that the absence of pallor can be due to the difficulty in evaluating patients with little neuroretinal rim left in glaucoma.8 This may explain why we did not appreciate the rim pallor in our patient. In addition, our patient did not present with clinical manifestations such as reduction in central visual acuity, rapid afferent pupillary defect (RAPD), or optic disc edema that have been more easily associated with intracranial lesions. In addition to studying the appearance of the optic disc and other clinical clues, ancillary diagnostic tests such as RNFL and visual field testing can help increase the index of suspicion for non-glaucomatous disease. A detailed assessment of the optic nerve in relation to visual field defects is critical, as glaucomatous cupping is correlated with visual field deficits. Therefore, non-glaucomatous lesions should be suspected in patients with cupping non-matching visual field defects. Importantly, it is critical to distinguish patients with visual field defects with respect to the vertical meridian from those with typical glaucomatous defects with respect to the horizontal midline. Although unilateral NTG is possible, unilateral or asymmetric cupping may favor a non-glaucomatous cause, such as in our patient. One published report showed that the laminal cribrosa in NTG undergoes significant remodeling, promoting damage to axons that precedes IOP-induced retinal nerve fiber layer loss.11 This suggests that pathologic changes in NTG are more generalized and less likely to be asymmetric or caused by local factors. Additional examinations, such as MRI, can be employed to confirm and localize the underlying cause. Intriguingly, it is unclear whether the coexisting brain macroadenoma, in our case, aggravated or caused NTG. NTG development in our patient may be caused by optic nerve susceptibility to intraocular pressure and/or macroadenoma-induced compression. Regardless of whether the mechanism of NTG in our patient is incidental or casually related, this case highlights the importance of carefully analyzing the visual field deficiency induced by brain lesions that simulate glaucoma cupping, which also coexists with glaucoma, for better time management and surgical planning. Disclosure None of the authors have conflicts of interest. ==== Refs References 1. Jonas JB, Budde WM. Optic nerve head appearance in juvenile-onset chronic high-pressure glaucoma and normal-pressure glaucoma. Ophthalmology. 2000;107 (4 ):704–711. doi:10.1016/S0161-6420(99)00172-4 10768332 2. Greenfield DS, Siatkowski RM, Glaser JS, Schatz NJ, Parrish RK. The cupped disc. Ophthalmology. 1998;105 (10 ):1866–1874. doi:10.1016/S0161-6420(98)91031-4 9787356 3. Pellegrini F, Marullo M, Zappacosta A, Liberali T, Cuna A, Lee AG. Suprasellar meningioma presenting with glaucomatous type cupping. Eur J Ophthalmol. 2021;31 (6 ):NP36–NP40. doi:10.1177/1120672120937674 4. Karl D, Gillan SN, Goudie C, Sanders R. Giant prolactinoma mimicking low-tension glaucoma at presentation. Case Rep. 2015;2015 (feb06 1 ):bcr2014207634–bcr2014207634. 5. Drummond SR, Weir C. Chiasmal compression misdiagnosed as normal-tension glaucoma: can we avoid the pitfalls? Int Ophthalmol. 2010;30 (2 ):215–219. doi:10.1007/s10792-009-9308-9 19352595 6. Choudhari N, Neog A, Fudnawala V, George R. Cupped disc with normal intraocular pressure: the long road to avoid misdiagnosis. Indian J Ophthalmol. 2011;59 (6 ):491. doi:10.4103/0301-4738.86320 22011496 7. Kosior-Jarecka E, Wróbel-Dudzińska D, Pietura R, et al. Results of neuroimaging in patients with atypical normal-tension glaucoma. Biomed Res Int. 2020;2020 :1–8. doi:10.1155/2020/9093206 8. Donaldson L, Dezard V, Margolin E. Yield of investigations in patients with questionable nonglaucomatous optic neuropathy. Can J Ophthalmol. 2022;58 :219–223. doi:10.1016/j.jcjo.2022.01.013 35123944 9. Trobe JD, Glaser JS, Cassady J, Herschler J, Anderson DR. Nonglaucomatous excavation of the optic disc. Arch Ophthalmol. 1980;98 (6 ):1046–1050. doi:10.1001/archopht.1980.01020031036004 7387507 10. Lee AG. Differentiating glaucomatous from nonglaucomatous optic atrophy. Ophthalmology. 1999;106 (5 ):855. doi:10.1016/S0161-6420(99)10109-X 10328372 11. Kim JA, Kim TW, Lee EJ, Kim JM, Girard MJA, Mari JM. Intereye comparison of lamina cribrosa curvature in normal tension glaucoma patients with unilateral damage. Invest Ophthalmol Vis Sci. 2019;60 (7 ):2423. doi:10.1167/iovs.19-26828 31158274

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==== Front J Multidiscip Healthc J Multidiscip Healthc jmdh Journal of Multidisciplinary Healthcare 1178-2390 Dove 421089 10.2147/JMDH.S421089 Short Report A Cross-Sectional Survey of Pulmonologists Working at Non-ILD Centers in the United States Biehl et al Biehl et al http://orcid.org/0009-0001-4802-6723 Biehl Rodney 1 Jeganathan Niranjan 1 2 Imperio Michelle 2 3 Becerra Benjamin J 1 4 López David 1 http://orcid.org/0000-0002-7844-8943 Alismail Abdullah 1 3 1 Department of Cardiopulmonary Sciences, School of Allied Health Professions, Loma Linda University, Loma Linda, CA, USA 2 Department of Pulmonary and Critical Care Medicine, Loma Linda University Health, Loma Linda, CA, USA 3 Department of Medicine, School of Medicine, Loma Linda University, Loma Linda, CA, USA 4 Department of Information and Decision Sciences, California State University of San Bernardino, San Bernardino, CA, USA Correspondence: Abdullah Alismail, Department of Cardiopulmonary Sciences, Department of Medicine, Loma Linda University Health, Loma Linda, CA, USA, Email aalismail@llu.edu 14 7 2023 2023 16 19391942 12 5 2023 11 7 2023 © 2023 Biehl et al. 2023 Biehl et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Abstract The purpose of this cross-sectional short report study was to evaluate the perception of pulmonologist working in noninterstitial lung disease centers on challenges (COE) encountered in daily practice. Results of this survey revealed that only 40% of their patients are referred to an ILD COE, out of 69% who have access to an ILDCOE. Of these patients who were referred, the perceived benefits were rated high when it comes to having an accurate diagnosis. Keywords ILD interstitial lung disease idiopathic pulmonary fibrosis multidisciplinary discussion funding There is no funding to report. ==== Body pmcIntroduction Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, interstitial lung disease (ILD) and the most common of the numerous ILDs.1,2 Although heterogeneity exists in the natural history of IPF, the overall prognosis is poor, with a median survival of 3–4 years.3 Early and accurate diagnosis of IPF is challenging, and delays in both diagnosis and treatment initiation are associated with worse survival.4–6 Unfortunately, many patients experience a significant delay in diagnosis and multiple misdiagnoses prior to the actual diagnosis of IPF.7 Studies show improved accuracy of diagnosis and earlier initiation of treatment in patients treated at specialized ILD centers.4,8–10 Additionally, the use of multidisciplinary discussion (MDD) among specialists from different disciplines such as radiology, pathology, and rheumatology has been shown to improve diagnostic confidence and may produce better prognostic separation in diagnosis.8,11,12 Clinical guidelines currently recommend the use of MDD in the diagnosis of IPF.3,13,14 However, data on the availability and utilization of important resources in the diagnosis of IPF by pulmonologists working at non-ILD centers is scarce. Currently, there are 81 ILD Care Centers in the United States (https://www.pulmonaryfibrosis.org/docs/default-source/media/ccn-fact-sheet-2022.pdf?Status=Master&sfvrsn=942f276d_3/%20CCN-Fact-Sheet-2022%20.pdf). We conducted a social and behavioral survey to gain insight into the challenges encountered by non-ILD center pulmonologists in establishing a diagnosis of IPF and assess their referral patterns to ILD centers. In this short report, we report our findings of this cross-sectional study of physicians within the United Stated of America. Methods The Loma Linda University Institutional Review Board examined the study and exempted it from full review since it is an anonymous survey. The survey included background questions (ie, primary work setting, experience/training in ILD) and questions related to survey participants’ perceptions with the level of difficulty with components of IPF diagnosis and the benefits of referral to an ILD center. The survey was emailed to pulmonologists throughout the United States as an anonymous questionnaire using a proprietary medical database. Data collection began in March 2020 and ended in May 2020. The target participants were pulmonary physicians working at a non-ILD center. We excluded those self-identifying as working in an ILD center. The survey content was validated by pulmonologists specializing in IPF, respiratory therapists, and statisticians. Once the respondents opened the survey, the first question was the consent to participate. If they select “yes, I am interested to participate”, survey started; when selecting “No, I do not want to participate”, survey ended. We reported descriptive statistics in numbers and percentages, and continuous variables in medians and interquartile ranges (IQR, 25–75th percentiles). Results A total of N=65 pulmonologists working at non-ILD centers have responded to the survey. The number of years in practice varied widely (the median was 25 (IQR 5–42)). Only 30.8% reported having any recent training in ILD (conference/CME 18.5%, fellowship 6.2%, other 6.1%). The average number of patients diagnosed with IPF also varied (median of 5 (IQR 1–75) in the past year and 20 (IQR 3–250) in the past three years). The majority (81%) agreed on the importance of early diagnosis of IPF. Next, we evaluated the perceived level of difficulty with components of IPF diagnosis on a scale of 1–5 (least to most difficult) (Figure 1a). The median difficulty score for access to MDD was 3.00 (IQR 1–4), access to High resolution computed tomography (HRCT) of the chest was 1.00 (IQR 1.0–2.5), patient compliance was 2.0 (IQR 1.0–3.0), and disease/guidelines familiarity was 2.0 (IQR 1.0–3.0). The median percent of the time respondents indicated utilizing MDD was 45% (IQR 0–100). Figure 1 (a) Difficulty level with diagnostic components of IPF. Each bar represents the percentage of non-ILD center pulmonologists responses based on a Likert scale: 1 to 5 (least difficult to most difficult). (b) Benefits of Referral to an ILD Center. Each bar represents the percentage of non-ILD center pulmonologists responses based on a Likert scale: 1 to 5 (least beneficial to most beneficial). Abbreviations: HRCT, High resolution computed tomography; MDD, multidisciplinary discussion. Only 69.2% of the respondents reported having access to an ILD center. The median for the percentage of time the respondents referred suspected IPF patients to an ILD center was 40.5% (IQR 20–67.5) for those with access to an ILD center. For the group with access, there was no difference in baseline factors (recent ILD training, number of years in practice, number of ILD patients seen) between those more likely to refer (median and above, ≥ 40.5% of the time) to an ILD center and those less likely to refer to an ILD center (below median, <40.5% of the time). Next, we evaluated the perceived benefits of referral to an ILD center on a scale of 1–5 (least beneficial to most beneficial) (Figure 1b). The median for access to specialized care was 5.0 (IQR 4.0–5.0), an accurate diagnosis was 4.0 (IQR 3.0–4.75), and management was 4.0 (IQR 3.0–4.75). Supplementary Table 1 shows a list of the total survey questions and response count and % of each question. Discussion A significant percentage of patients do not have access to an ILD center and are cared for by pulmonologists at non-ILD centers. In this pilot study, we examined the non-ILD center pulmonologists perspective on the challenges with IPF diagnosis and perceived benefits of referring patients to an ILD center. The median number of patients diagnosed with IPF by non-ILD center pulmonologists was only 5 per year. Similarly, prior studies have shown that most pulmonologists treat only a small number of IPF patients per year. We examined the difficulty level with the important components in IPF diagnosis. The percentage of pulmonologists rating the difficulty level as high (4 or 5 on a scale of 1 to 5) was 30.2% for access to MDD, 15% for HRCT access, 15.1% for patient compliance and 20.8% for disease familiarity. Although the majority stated that access to MDD was not difficult, the utilization was low (used in less than half of the IPF cases). ILD centers have shown to be beneficial for IPF patients as they are equipped and designed to manage a large volume of these patients. The percentage of pulmonologists rating the benefits of referring to an ILD center as high (4 or 5) was 83% for access to specialized care, 63.5% for management and 51.9% for accurate diagnosis. However, even for those with access to an ILD center, utilization was much lower than expected (median percent was 41% for suspected IPF patients). There are likely various reasons for the underutilization of MDD and referral to an ILD center. Most physicians in this study had not recently received any formalized training in ILD, perhaps indicating a knowledge gap in both the importance of early diagnosis and best practices in making the diagnosis. Additionally, a significant percentage did report having difficulties with access to MDD and access to an ILD center, highlighting the need for improvement in the availability of these resources and infrastructure. We strongly recommend providers to have enhance MDD access as it will improve IPF related outcomes. Furthermore, utilizing uptodate methods such as online conferences, networking with IPF specialists at ILD centers would improve the diagnosis as well as access, especially for general physicians working at Non-ILD centers. This study has several limitations. First, the sample size is small. The reason for the low sample size and response is most likely the timeframe of the data collection, as it took place at the beginning of the COVID-19 pandemic. The self-reported design of this survey may also limit the conclusions that can be drawn from the results, as answers are subject to various forms of bias, including desirability and recall biases. Additional studies using objectively collected data on the frequency of ILD center referral and MDD usage would be useful. Further research is needed to expand our understanding of the reasons for underutilization of ILD centers and MDD by non-ILD center pulmonologists. In addition, we believe that future studies should focus on addressing ways to utilize MDD in terms access to improve IPF related outcomes. Disclosure All authors report no conflict of interest. ==== Refs References 1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188 (6 ):733–748. doi:10.1164/rccm.201308-1483ST 24032382 2. Oliveira DS, de Araújo Filho JA, Paiva AFL, Ikari ES, Chate RC, Nomura CH. Idiopathic interstitial pneumonias: review of the latest American Thoracic Society/European Respiratory Society classification. Radiol Bras. 2018;51 (5 ):321–327. doi:10.1590/0100-3984.2016.0134 30369660 3. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2023. doi:10.1164/rccm.2009-040GL 4. Lamas DJ, Kawut SM, Bagiella E, et al. Delayed access and survival in idiopathic pulmonary fibrosis | a cohort study. Am J Respir Crit Care Med. 2023. doi:10.1164/rccm.201104-0668OC 5. Hoyer N, Prior TS, Bendstrup E, Shaker SB. Diagnostic delay in IPF impacts progression-free survival, quality of life and hospitalisation rates. BMJ Open Respir Res. 2022;9 (1 ):e001276. doi:10.1136/bmjresp-2022-001276 6. Kolb M, Richeldi L, Behr J, et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2017;72 (4 ):340–346. doi:10.1136/thoraxjnl-2016-208710 27672117 7. Cosgrove GP, Bianchi P, Danese S, Lederer DJ. Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey. BMC Pulm Med. 2018;18 (1 ):9. doi:10.1186/s12890-017-0560-x 29343236 8. Flaherty KR, Andrei AC, King TE, et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am J Respir Crit Care Med. 2007;175 (10 ):1054–1060. doi:10.1164/rccm.200606-833OC 17255566 9. Maher TM, Swigris JJ, Kreuter M, et al. Identifying barriers to idiopathic pulmonary fibrosis treatment: a survey of patient and physician views. Respiration; International Review of Thoracic Diseases. 2018;96 (6 ):514–524. doi:10.1159/000490667 30114692 10. Marijic P, Schwarzkopf L, Maier W, Trudzinski F, Kreuter M, Schwettmann L. Comparing outcomes of ILD patients managed in specialised versus non-specialised centres. Respir Res. 2023. doi:10.1186/s12931-022-02143-1 11. Flaherty KR, King TE, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med. 2004;170 (8 ):904–910. doi:10.1164/rccm.200402-147OC 15256390 12. Fujisawa T, Mori K, Mikamo M, et al. Nationwide cloud-based integrated database of idiopathic interstitial pneumonias for multidisciplinary discussion. Eur Respir J. 2019;53 (5 ):1802243. doi:10.1183/13993003.02243-2018 30880283 13. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198 (5 ):e44–68. doi:10.1164/rccm.201807-1255ST 30168753 14. Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205 (9 ):e18–47. doi:10.1164/rccm.202202-0399ST 35486072

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==== Front 101280339 33033 Transl Res Transl Res Translational research : the journal of laboratory and clinical medicine 1931-5244 1878-1810 36070840 10.1016/j.trsl.2022.08.014 nihpa1913027 Article Inflammasome activation in traumatic brain injury and Alzheimer’s disease Johnson Nathan H. 2 de Rivero Vaccari Juan Pablo 135 Bramlett Helen M. 134 Keane Robert W. 12 Dietrich W. Dalton 135* 1 The Miami Project to Cure Paralysis, Miami, FL, USA 2 Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA 3 Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA 4 Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL, USA 5 Center for Cognitive Neuroscience and Aging, University of Miami Miller School of Medicine, Miami, FL, USA * Reprint requests: W. Dalton Dietrich, PhD, Scientific Director, The Miami Project to Cure Paralysis, Professor of Neurological Surgery, Neurology, Biomedical Engineering and Cell Biology, University of Miami, Leonard M. Miller School of Medicine, 1095 NW 14th Terrace, Suite 2-30, Miami, FL 33136-1060. ddietrich@med.miami.edu (W.D. Dietrich). 12 7 2023 4 2023 05 9 2022 18 7 2023 254 112 https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Traumatic brain injury (TBI) and Alzheimer’s disease (AD) represent 2 of the largest sources of death and disability in the United States. Recent studies have identified TBI as a potential risk factor for AD development, and numerous reports have shown that TBI is linked with AD associated protein expression during the acute phase of injury, suggesting an interplay between the 2 pathologies. The inflammasome is a multi-protein complex that plays a role in both TBI and AD pathologies, and is characterized by inflammatory cytokine release and pyroptotic cell death. Products of inflammasome signaling pathways activate microglia and astrocytes, which attempt to resolve pathological inflammation caused by inflammatory cytokine release and phagocytosis of cellular debris. Although the initial phase of the inflammatory response in the nervous system is beneficial, recent evidence has emerged that the heightened inflammatory response after trauma is self-perpetuating and results in additional damage in the central nervous system. Inflammasome-induced cytokines and inflammasome signaling proteins released from activated microglia interact with AD associated proteins and exacerbate AD pathological progression and cellular damage. Additionally, multiple genetic mutations associated with AD development alter microglia inflammatory activity, increasing and perpetuating inflammatory cell damage. In this review, we discuss the pathologies of TBI and AD and how they are impacted by and potentially interact through inflammasome activity and signaling proteins. We discuss current clinical trials that target the inflammasome to reduce heightened inflammation associated with these disorders. ==== Body pmcIntroduction Traumatic Brain Injury (TBI) is a significant source of disability and death in the United States,1 with an average of 1.7 million Americans. It is reported that 30% of people who suffer a moderate TBI report worsening symptoms over a 5 year period, with deficits in learning and memory as one of the major disabling results.2,3 These symptoms are a result of the initial acute trauma to the brain as well as homeostatic changes in the central nervous system (CNS) and chronic inflammation.4 TBI presents as a potent risk factor for the development of additional pathologies throughout the CNS and systemically.5–7 For instance, TBI is a potent underlying contributor to the pathology of Alzheimer’s disease (AD).8 AD is a neurodegenerative and psychiatric disorder that is one of the most common forms of dementia.8 AD pathology is driven by a combination of genetic and environmental factors.9 There are 2 major pathological hallmarks of AD; the formation and accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles (pTau) that result in chronic inflammation and neuronal loss.10 According to the United States Centers for Disease Control and Prevention (CDC), individuals with a history of moderate TBI have a 2.3 times greater risk of developing AD,3 and this risk may be due to the chronic nature of neuroinflammation after TBI. Moreover, there are numerous pathological features shared between TBI and AD, but most notable is the chronic neuroinflammatory response that is mediated in part by persistent inflammasome activation of the innate immune response. The inflammasome is a multi-protein complex that activates the proinflammatory cytokines interleukin (IL)-1β and IL-18 upon activation of caspase-1, resulting in the cell death process of pyroptosis. In TBI, several recent studies have documented increased inflammasome activity after injury, primarily occurring in activated microglia.9,11 In AD, Aβ accumulation within the CNS activates microglia resulting in the release of IL-1β.12 Furthermore, Aβ plaques form as a result of Aβ monomers binding to inflammasome components.13 Recent studies demonstrate that formation and accumulation of tau is linked to secretion of inflammasome components from microglia.14 These findings collectively suggest that the main pathomechanisms of AD may be contributed in part by the inflammasome and suggest that disruption of inflammasome activation could be targeted to ameliorate AD pathology. In this review, we discuss the pathophysiology of TBI and introduce relevant clinical and experimental findings involved with TBI induced inflammasome activity and pathology. Furthermore, we discuss TBI as a risk factor for AD development, and how these 2 pathologies interact mechanistically via inflammasome activity. Finally, we discuss current translational studies and potential therapeutic pathways for development of therapeutics that target inflammasome activation in TBI and AD pathologies. The innate immune system The pathophysiological processes underlying trauma are diverse and complex. Cell death, structural damage, inflammation, swelling, and infection often result from physical trauma and are either transitory components of the initial trauma and recovery or alter homeostasis in more chronic pathology. The effects of TBI are not transient, but result in chronic alterations to the CNS environment, including structural changes and a persistent elevation of inflammatory activity.15–18 One such physiological process that has been shown to be involved in acute and chronic pathology is the innate immune response. Evolutionarily speaking, the innate immune system is one of the oldest forms of defense from invading organisms and cellular damage and is conserved in all forms of complex cellular life.19 The innate immune system is composed of both physical defenses, such as the skin and epithelia, and cellular agents, such as macrophages and neutrophils.20 The innate immune system utilizes genetically encoded pattern recognition receptors (PRR) to detect infectious pathogens, unwanted foreign matter, and cellular damage. PRR such as Toll-like receptors (TLR) and nucleotide oligomerizing domain (NOD)-like receptors (NLR) facilitate the innate immune system to recognize damage associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs), which induce macrophages to immediately react and shift to a mobile and inflammatory phenotype thus mediating phagocytosis of invaders and the secretion of inflammatory signaling proteins to alert nearby cells of potential harm.12,20 Similarly, other cells express PRR and recognize DAMPs and PAMPs, triggering activation of the innate immune response, including inflammasomes in neurons,21–24 astrocytes,25 microglia11,15 and oligodendrocytes.26 Immunological moderators of CNS injury and disease The CNS environment has been traditionally considered to be immunologically privileged.27,28 The blood-brain barrier (BBB), numerous antigen presenting cells, and a wide range of anti-inflammatory modulators participate in the brain’s immune response in which inflammation is highly regulated.27 Recent studies identified that a large array of neuroimmune interactions occurs at the CNS borders in the meningeal lymphatic system and that dysfunction of this system exacerbates TBI pathologies.28,29 Of all these mechanisms, microglia have been identified as key players in the CNS response to trauma. Interestingly, these cells play dual roles as first responders to CNS illness and injury, but also act to maintain neural homeostasis and plasticity.30,31 In the healthy CNS environment, microglia are in a “resting” state and are identified morphologically by long processes, which sample the environment to detect deleterious changes to homeostasis.32 It is in the resting state microglia also clear cellular debris and contribute to the overall plasticity of the CNS through the maintenance of neuronal connections, regulation of neurogenesis, and pruning of synapses.33 After trauma, TLRs and NLRs on microglia detect PAMPs and DAMPs released by injured cells, and quickly shift to an “activated” state in which they assume a more ameboid morphology and migrate towards the site of injury.32,33 Microglia are important for maintaining the health of the CNS and aid in the removal of damaged neurons and infections. In addition, they play important roles in secondary pathomechanisms of a variety of CNS disorders and interact with astrocytes and neurons in response to CNS trauma.34 Microglia are a well-established source of inflammatory activity within the CNS that is primarily regulated by activation and formation of inflammasomes. Activated microglia have traditionally been classified into 2 phenotypes. The M1 form is proinflammatory and expresses pro-inflammatory cytokines and chemokines, while the M2 form is neuroprotective and expresses anti-inflammatory cytokines, neurotropic factors, and resolves the inflammatory activity of the M1 form.33,35 Although these forms are complimentary, studies have shown that the M2 form is short lived after injury, and that the M1 form plays a prevailing role in chronic inflammatory activity after injury.33,36 However, recent research has shown that these traditional phenotypic classifications of microglia are not all inclusive, and alternative and intermediate forms may exist.31,34 Studies investigating microglia activation after CNS injury or illness have noted that the M1/M2 microglial classification is simplistic, as multipurpose and alternative forms have been identified after injury.37,38 For example, the anti-inflammatory and regenerative M2 form has been further subdivided into M2a, M2b, M2c33,39,40 and M2d subtypes.38,41 The M2a form is activated by IL-4 and IL-13 and plays a role in anti-parasitic responses in that it increases scavenger receptors and induces phagocytosis, IL-10 secretion, and tissue growth and repair.33,39,41 The M2b form is activated by IL-1R ligands and may form intermediate types that expresses pro- or anti-inflammatory activity through secretion of IL-1β, TNF-α, and IL-10. M2b interacts with B cells and regulates the M2 response that also shares characteristics of M1 microglia.33,39 The M2c form, activated by IL-10 and glucocorticoids, is considered to resolve inflammation in that it promotes the cleanup of tissue after inflammatory activity is reduced.33,39,41 The M2d form is unique in that it is derived from the M1 form and is alternatively activated through IL-6 and adenosine receptors and is anti-inflammatory and angiogenic in nature.41,42 Beyond the classical M1/M2 classifications, recent studies have indicated that microglia classification may be better defined along a shifting spectrum of inflammatory activity, and that microglia should instead be defined by multiple factors such as genetic expression or by the identification of multiple surface markers.43,44 Although, many current studies still use the M1/M2 classification colloquially to refer to pro-inflammatory vs anti-inflammatory microglia, new classifications are especially important in AD pathology. A new form of disease associated microglia (DAM), defined by the expression of multiple AD associated genes, is thought to play an integral role in AD pathology progression.44 (Table I). Microglia interact with astrocytes and neurons in response to CNS trauma. Astrocytes and microglia maintain CNS homeostasis and modulate inflammatory cytokine expression regulated by assembly of the inflammasome. Astrocytes are the most numerous cell type in the brain45 and function in maintaining the CNS environment45 and together with neurons maintain ionic and water balances, regulate blood flow, maintain the BBB, and modulate synaptic transmission.45–47 Interestingly, astrocytes are similar to microglia in that they also have long processes that sample their environments for changes in homeostasis. Astrocytes form complex networks of gap junctions and closely adhere to neurons, and through unique end-feet adhere to blood vessels forming the BBB.29,46 Astrocytes maintain homeostasis through crosstalk with neurons via glutamatergic and GABAergic neurotransmission, calcium signaling, and ionic buffering.45–47 In the event of trauma or infection, astrocytes become activated (astrogliosis), as indicated by an increase of the cytoskeletal protein glial fibrillary acidic protein (GFAP), and like microglia, secrete numerous inflammatory products, including cytokines and chemokines such as IL-1β, TNF-α, growth factors and reactive oxygen species.46,48 There are numerous triggers of astrogliosis such as DAMPs from damaged cells, cytokines from microglia, Aβ from neurons, albumin from BBB disruption, and synaptic glutamate and adenosine triphosphate (ATP), the exact nature of astrocytic activation is still not well understood.48,49 Inflammasome activation and assembly The inflammasome (Fig 1) is a multi-protein complex formed as part of the innate immune response. Inflammasomes are identified by their sensor protein, which contains either an NLR, an absent in melanoma 2 (AIM2) like receptor (ALR), or pyrin.50,51 The NLR group of inflammasomes includes NLRP1, NLRP3, and NLRC4, and is further classified by whether their nucleotide binding regions have a pyrin (NLRP) or caspase (NLRC) activation and recruitment domain.51 The inflammasome complex is composed of caspase-1 and typically contains an adaptor protein known as apoptosis-associated speck-like protein containing a caspase recruiting domain (ASC).52 Upon inflammasome activation, the oligomerization of ASC allows for the binding and subsequent activation of pro-caspase-1.50,52,53 Caspase-1 activation leads to the cleavage and activation of IL-1β and IL-18, along with the formation of the pyroptotic pore through cleavage of gasdermin-D (GSDMD).53,54 The end result is pyroptotic cell death and the release of inflammatory cytokines along with the components of the intercellular environment into the extracellular space (Fig 1). Activation of the inflammasome is specific to the respective sensor’s trigger. The NLRP1 sensor contains a function-to-find domain, and a C terminus caspase recruitment domain (CARD) and is activated by microbial associated agents such as Bacillus anthrax lethal toxin, changes in cellular ATP levels, and double stranded RNA.55 NLRP1 binds caspase-1 directly or with the adapter, ASC.50,51,56,57 The NLRP3 sensor is unique in that it is activated through numerous triggers and by 2 distinct pathways. Traditional activation is through the canonical pathway in response to the detection of numerous triggers including PAMPS, DAMPS, extracellular ATP, increases in intracellular calcium, mitochondrial dysfunction, and cellular potassium efflux.50,58–60 The alternative pathway of activation or noncanonical pathway is activated by lipopolysaccharide (LPS), utilizing caspase-4/5 in humans or caspase 11 in mice.50,61 LPS detection results in the caspase cleavage of GSDMD and formation of the pyroptotic pore which results in ATP release and potassium efflux and subsequent activation of NLRP3.50,62 The NLRC4 sensor is activated indirectly by proteins that detect bacterial components such as flagellin and needle proteins and binds caspase-1 directly to the CARD or with ASC.51,52,57,63 NLRP6 is activated by gram positive bacteria, such as listeria and S. aureus, and has been shown to form an inflammasome complex containing ASC, caspase-1 and caspase-11.64,65 Outside of the NLR family is AIM2, which is activated by cytosolic double stranded DNA, is classified by its N terminal pyrin domain and C terminus hematopoietic interferon-inducible nuclear protein with a 200 amino acid repeat domain and requires ASC to bind caspase-1.51,52,66 Along with pyrin which is activated through Ras homolog family member A (RhoA) inactivation and contains a pyrin domain, 2 B-boxes, a coiled-coil domain, and C terminus B30.2 domain.50–52 Regardless of the unique trigger or the particular inflammasome in action, the main result of inflammasome activation is to reduce infection through pyroptotic cell death of the affected cell and alert neighboring cells to potential danger. The ASC speck ASC is a component of the inflammasome that acts as a scaffold of the inflammasome complex. ASC is expressed via the PYCARD gene and is structurally composed of pyrin and CARD domains that mediate binding of the inflammasome sensor protein and caspase-1, respectively.50,67 Upon inflammasome activation ASC self-oligomerizes into a 1 μm aggregate known as the ASC speck. ASC speck formation is accompanied by the binding of pro-caspase-1, to amplify the inflammatory activity and inflammatory cytokine production.50,67,68 Nagar and colleagues found that blocking ASC speck formation using colchicine in cells dosed with nigericin did not prevent inflammasome activation or subsequent cytokine maturation, but rather higher doses of nigericin were required to elicit an inflammasome response.68 These findings suggest that ASC may not be necessary for inflammasome activation, it increases the efficiency of the inflammasome by lowering the stimulus threshold necessary to induce an inflammasome response. This feature allows for a swifter and stronger response to inflammasome triggers. ASC specks are secreted extracellularly and amplify the inflammasome response. In the CNS, ASC specks are taken up by activated microglia that also secrete inflammasome mediated cytokines.69 Thus, extracellular ASC specks propagate inflammation after release by pyroptotic cells and are ingested by activated microglia that secrete inflammatory cytokines. Moreover, ASC specks may stimulate and perpetuate inflammation after uptake by neighboring cells through recognition by TLRs. Recent studies by Cyr and colleagues show that increased ASC protein expression in the cortical tissue is associated with the progression of the inflammatory response in aging (inflammaging).22 Similarly, Kerr and colleagues showed increased ASC protein expression and speck oligomerization in the lung tissue of mice within 4 hours after brain injury that was associated with lung damage after CNS trauma.6 Johnson and colleagues also observed increased ASC protein expression in the blood serum of patients with diabetic kidney disease and lupus nephritis and showed that ASC protein levels was a reliable biomarker for predicting respective pathological outcomes with increased levels linked to more deleterious outcomes.70 Within the CNS, Johnson et al further observed this same phenomenon in the blood serum collected from hospitalized TBI patients in which ASC and other inflammasome proteins were likewise elevated after injury.71 Furthermore, Chen and colleagues identified increased levels of ASC proteins in the thrombolytic cores of patients who suffered ischemic stroke,72 and Keane and colleagues observed increased ASC and caspase-1 protein expression in patients with multiple sclerosis and that both represented potential biomarkers of pathology.73,74 Lastly, Scott et al showed that ASC protein levels was increased in the blood serum of patients diagnosed with either AD or mild cognitive impairment, and that ASC protein levels was also a reliable biomarker of the early stages of AD pathology.75 Taken together the ASC protein, and the inflammasome appears to play a pivotal role in many CNS diseases and insults, including TBI and AD. Pathophysiology of TBI TBI includes many different forms of CNS injury. These include concussions from sports, trauma from motor vehicle accidents, pressure damage from explosions, and penetrative trauma from gunshot wounds, and all forms of TBI may possess various levels of severity. The pathology of TBI is traditionally viewed as a 2-part event. The initial impact of trauma is termed the primary injury, while the more chronic damage is known as the secondary injury.35 Primary injury involves the damage caused by the physical blow to the brain, with the effects of injury both focal and diffuse and occurring in a relatively short period of time.35 Upon injury (Fig 2), blunt-force trauma causes immediate cell loss at the epicenter of the injury lesion, along with potential vascular injury, glymphatic/lymphatic dysfunction, edema, and diffuse injury to axons and neuronal networks.29,76 It is during the primary injury that PAMPS and DAMPS are released from damaged and dying cells that play an important role in secondary injury. During secondary injury, the multiple pathophysiological cascades are activated by the primary injury that results in disruption of CNS homeostasis and cognitive function, chronically. At the cellular level, (Fig 2) there is a disruption in the ionic balance, resulting in energy shortfalls, dysfunctional microglia, and reactive oxygen species (ROS) production.59 After moderate or more severe TBI, errant depolarization from injured neurons results in the release of neuroexcitatory glutamate.58 Increased glutamate release is associated with worsened pathological outcomes, and results in increased intracellular sodium levels and the release of glutamate at the synaptic bouton which in turn cause a post-synaptic release of potassium ions.58,76,77 Potassium efflux is met with calcium influx resulting in an increase in extracellular potassium and sodium potassium pump activity in an attempt to restore ionic balance.58,77 Resulting pump activity draws on cellular stores of ATP which may be depleted and not restored as mitochondria attempt to store the large influx of intracellular calcium and in turn become dysfunctional, resulting in hyperglycolysis and buildup of lactate.58,77 With the combination of increased calcium and decreased ATP, the cell undergoes the enzymatic processes necessary to induce cell death.58 PAMPs and DAMPs released by injured or necrotic cells trigger the activation of microglia (Fig 2), which attempt to address the injury through the dual application of increased inflammatory activity to clear damaged cells, along with phagocytic activity and neurotrophic factor release to remove and repair damaged structures.34 Astrocytes become activated by DAMPs and release inflammatory cytokines, while also migrating to the site of injury forming a densely packed astrocytic scar.48,76 Additionally, disruption of the BBB allows for the invasion of monocytes from outside of the CNS environment, which contribute to overall inflammatory activity from injury.35 BBB damage and vascular inflammation also contributes to TBI pathology through the infiltration of blood directly into the cerebral tissue, resulting in excitotoxicity and oxidative stress from iron-rich red blood cells along with the infiltration of non-resident immune cells, resulting in increased inflammation, oxidative stress, and cell death.76 Finally, disruption of the glymphatic and lymphatic systems is thought to reduce clearance of neurotoxic proteins from the CNS after injury resulting in worsened inflammatory pathology, edema, and cell death.28,29 Although these effects are seen in traumatic injury settings, they often remain present months to years after injury with chronic inflammatory activity leading to increased neurodegeneration and increased risk for the development of comorbid pathologies. Studies have shown that damage to the CNS environment from TBI or stroke have been linked to not only loss of cognitive function, but also to psychiatric and sleep disorders, lung damage, cardiovascular disorders, and disruptions to gastrointestinal system functionality.6,78–80 Moreover, although TBI is mainly a pathology imposed from an external source, genetic predisposition has also been implicated as a contributor to primary and secondary injury effects. For example, a recent longitudinal study involving U.S. service members observed increased rates of self-reported decline in cognitive function and psychological wellbeing in participants who sustained a mild TBI and were positive for AD-associated apolipoprotein E-4 (ApoE4).81 Additionally, the AD-associated microglia gene triggering receptor expressed on myeloid cells 2 (TREM2) was shown to be upregulated after TBI in rats and potentially linked to TBI neuropathology along with ApoE.82 These findings implicate the importance of genetic predisposition on TBI outcomes while also demonstrating how pathological outcomes are very much dependent on the individual, thus making the TBI population extremely heterogenous. TBI and inflammasome activity Changes in the extracellular environment, the release of PAMPs and DAMPS, the disruption of the BBB, and activation of microglia, all contribute to the chronic inflammatory response after TBI (Fig 2). PAMPS, DAMPS, increased intracellular calcium, potassium efflux, mitochondrial dysfunction, and extracellular ATP may trigger formation of the NLRP3 inflammasome.50,59 TLRs detect DAMPS released by injured cells and upregulate the NLRP3 sensor and IL-1β RNA transcription through nuclear factor-κB (NF-kB) signaling.74 In addition, changes to the intracellular environment such as K+ efflux and ROS, as well as ionic changes like Cl−, activate the inflammasome.59 However, although the NLRP3 inflammasome has been shown to play a major role in TBI pathology, it is not the only inflammasome that contributes to the innate immune inflammasome response after TBI. For example, the AIM2 and the NLRP1 inflammasome are also activated following TBI.23,66,83 Inflammasome proteins are released into the blood and CSF following TBI and these circulating inflammasome proteins are reliable biomarkers for determining injury severity and probable pathological outcomes after TBI.71,83,84 For instance, Adamczak et al observed increased ASC, caspase-1, and NLRP1 in the CSF of moderate and severe TBI patients, respective amounts correlated with 5-month Glasgow Outcome Scale scores, and elevated protein levels were associated with worsened outcomes.85 Kerr and colleagues identified that in human TBI patients, blood serum taken at 1 and 2 days post injury showed levels of ASC and caspase-1 that were elevated after injury, and that increased ASC levels were associated with worsened pathological outcomes.83 In support of these findings, Pérez‑Bárcena et al determined that blood serum levels of caspase-1 taken at 24 hours after hospital admission for TBI reliably predict pathological outcomes 6 months later with increased caspase-1 levels associated with more severe injury and worsened pathological outcomes.84 In a previous study, they also observed that caspase1 levels were elevated in the CSF of TBI patients with increased intracranial pressure, and that increased levels within the CSF were also associated with worsened pathological outcomes.86 In addition, Johnson et al observed that increased caspase-1 and IL-10 in the blood serum of TBI patients collected between 1 and 12 hours was associated with worsened outcomes after TBI, and that IL-13 levels could be used to determine injury severity.71 Moreover, in a murine model of TBI, Lee et al showed that NLRP3, ASC, caspase-1, and IL-1β were all significantly increased within tissue of the injured cerebral cortex at 24 and 48 hours after penetrating injury, and that this was accompanied by increased GSDMD expression and ASC speck oligomerization.15 These results not only indicate that the NLRP3 inflammasome was activated after trauma, but that it also resulted in increased pyroptotic activity and subsequent cytokine release. Interestingly, IL-18 was also seen to be increased at 48 hours post injury and continued to be increased as late as 72 hours post injury.15 The majority of PAMP and DAMP expression after TBI is evident within the first minutes to hours after injury, whereas the activation of microglia and the infiltration of immune cells into the injured tissue occurs later after TBI, primarily within the first few days to a week.35,76 As microglia become more activated, the levels of cellular ASC increase,11,15 thus supporting the idea that microglia are major contributors to inflammasome activity after primary injury. Indeed, TBI studies investigating the effectiveness of reducing microglia activity via chemical inhibition and replacement have observed subsequent reductions in inflammatory activity and brain injury.29 Although the most deleterious impacts of primary and secondary injury are seen within the first week after injury, continuous deleterious inflammation continues well past the traditional convalescent period.35,76 Chronic loss of learning and memory functionality and changes to personality and overall mental health have been observed in patients after TBI.87 Pathophysiologically, chronically activated microglia, autoimmunity, and inflammation are present months to years after the initial injury.29,76 Therefore, TBI is considered a risk factor for numerous CNS disorders including dementia-like disorders such as AD. Hallmarks and pathophysiology of AD AD, like many neurological and psychiatric disorders, involves a combination of genetic predisposition and environmental/lifestyle triggers that orchestrate the pathological onset and development of the disease.88 Increasing numbers of genetic mutations have been linked to AD pathological development. However, alterations to the genes amyloid precursor protein (APP), presenilin (PSEN1, PSEN2), and ApoE (ApoE4) are among the most widely reported, which alter normal protein functionality resulting in the development of the hallmarks of AD pathology.89,90 The Aβ plaque is a primary hallmark of AD and results from an alternative method of amyloid precursor protein (APP) cleavage and subsequent oligomerization of the released non-soluble product.91 APP is a transmembrane protein which is typically cleaved by α-secretase. However, in AD, APP is cleaved by β-secretase (BACE) and then released via γ-secretase as a longer, stickier peptide between 40 to 44 amino acids long, that aggregates to form neurotoxic plaques.89,91,92 Moreover, this description of Aβ plaque formation is overly simplified because other products of APP are generated by cleavage through caspases and other secretases into soluble forms that mediate other physiological functions.93 Although the physiological role of APP in the healthy CNS environment is still not fully understood, studies suggest that it may play a role in cell growth, motility, and survival.89 Interestingly, some studies have suggested that Aβ in its monomeric form may be neuroprotective and found in those individuals without AD symptomology.94 In pathological AD, however, the insoluble Aβ plaques are deleterious, resulting in CNS cell death, microglia and astrocyte activation, and inflammation. Damage to healthy neurons has been attributed to Aβ disruption of cellular homeostasis, resulting in increased levels of intracellular calcium, increased synaptic glutamate release, and increased excitatory activity in neurons which is in turn compensated by an increase in long term depression and a reduction in post-synaptic glutamate receptors.82 Furthermore, Aβ plaques also affect intracellular potassium levels through the disruption of potassium channels and the increased expression and activation of voltage gated potassium channels.69 Although Aβ has been the focus of many studies of AD, it does not adequately parallel the pathological properties of AD pathology progression.91,93 pTau tangles are considered another key hallmark of AD pathology and have been shown to elicit a deleterious response within the CNS similar to Aβ. In the healthy CNS, tau serves as a cytoskeletal protein and is utilized in the construction of microtubules, the growth of neurons, potential maintenance of DNA, and axonal transport.95,96 Tau is expressed via the microtubule associated protein tau (MAPT) gene and is found primarily within neurons but is also present in glia and extracellularly in small amounts.95 Tau has multiple isoforms and tau phosphorylation plays a role in maintaining healthy function and development of the CNS.96 Mutations to the MAPT gene and other environmental factors are linked to increases in Tau isoforms that are more susceptible to hyperphosphorylation and other tau pathologies such as frontotemporal dementia.95,96 In the disease state, tau does not adequately maintain DNA within the cell nucleus, contributing to cell damage, and tau hyperphosphorylation results in microtubule destruction and migration of pTau to the presynaptic terminal, causing dysfunction, vesicle release reductions, and loss of synapse and dendrites.95 In AD, the hyperphosphorylation of Tau makes it less efficient in binding to microtubule associated proteins and instead self-aggregates, forming pTau tangles.96 Thus, Aβ plaques and pTau tangles form the pathological hallmarks of AD and elicit damage to the cells of the CNS through the disruption of ionic and cytoskeletal homeostasis, activation of microglia, and induction of inflammation, leading to subsequent cell death. Altered microglia in AD Microglia play an important role in the pathology of AD through the recognition and clearance of AD-associated DAMPs and subsequent inflammatory activity. Oligomerized Aβ is detected by the surface antigen receptors of microglia and astrocytes as a DAMP.9,49 Microglia scavenger receptors identify and mediate Aβ uptake, resulting in microglia activation and inflammatory cytokine release.69 About 25% of genes associated with immunity alterations in AD are associated with microglia.49 Genetic mutations, such as PSEN and TREM2 are thought to cause microglia to become dysfunctional, impacting microglial autophagy and lysosomal function.9,97 Interestingly, recent evidence suggests that a new type of microglia known as disease associated microglia (DAM) may be upregulated by AD-associated genes such as TREM2 and ApoE as well as by downregulation of genes associated with microglia homeostasis.98–100 DAM also show altered autophagy activity, and are present in regions close to Aβ plaques and contain Aβ intracellularly in murine and human samples.100 In addition, PSEN and TREM2 genetic alterations may increase DAM autophagy activity to increase phagocytotic clearance of Aβ plaques.100,101 DAM may contribute to AD pathology through the excessive pruning of healthy dendrites and by becoming “frozen” in an activated state in order to increase inflammatory cytokine expression, resulting in a self-driving and perpetually continuous loop of inflammatory activity.9,99,100 Additionally, PSEN mutations may contribute to a loss of microglia lysosomal functionality in non-DAM, reducing the capacity of microglia to break down oligomerized Aβ that results in reduced Aβ clearance and increased inflammasome activation.102 Studies in murine models have implicated that microglia may also transport Aβ to unaffected regions of the CNS, thus increasing inflammatory activity and overall AD pathology.103 Inflammasome and AD interactions The inflammasome has emerged in recent years as a key player in a number of CNS diseases and conditions, particularly AD. As noted, Aβ alters the cellular ionic balance in neurons, but acts as a DAMP in microglia and astrocytes (Fig 3).49,69,82 Microglia attempt to clear Aβ by phagocytosis. However, in AD, Aβ endocytosis does not result in proper degradation by lysosomes, resulting in numerous alterations of microglia morphology and functionality. Aβ aggregates are crystalline in nature, and once endocytosed, they trigger NLRP3 inflammasome activation, resulting in lysosomal damage and potassium efflux.69,92 NLRP3 activation leads to formation of the inflammasome and release of cytokines, inducing oligomerization of ASC into ASC specks. Importantly, ASC specks may act as “seeds” to encourage further polymerization of Aβ that form ASC/Aβ aggregates, which are highly toxic to neurons.13,69 Moreover, Aβ and ASC interactions increase NLRP3 activity, and Aβ/ASC aggregates hinder Aβ clearance, but also induce microglial pyroptosis.104 These events result in heightened microglial inflammatory activity and release of inflammatory cytokines, thereby inducing pyroptosis and accumulation of ASC and Aβ into the extracellular space that perpetuates inflammation by inducing inflammasome activation and pyroptosis in neighboring CNS cells and microglia.92,104 Additionally, murine studies observe that inflammatory cytokines such as IL-1β hamper the clearance activities of microglia, potentially reducing Aβ clearance and the removal of other cellular debris by microglia.105 Furthermore, IL-18 appears to increase BACE activity and alter the processing of APP, potentially increasing production of Aβ.106 In addition, pTau has been shown to induce inflammasome activity. Studies in murine models of AD demonstrate that reduction of NLRP3 activity may lead to a reduction in the formation of pTau and pTau tangles.14 On the other hand, murine models have also shown that pTau activates NLRP3 in microglia and that tau pathology is reduced in ASC knockout mice.107 Interestingly, Aβ deposition appears to precede tau pathology in AD, suggesting that pTau deposition may represent a downstream product of Aβ pathology.14,100 Indeed, microglia and astrocytic activation, potentially from Aβ or other sources, is thought to encourage pTau formation through the release of inflammatory cytokines such as the inflammasome product IL-1β.49 However, tau pathologies occur in human AD that are separate of Aβ, and human imaging and postmortem studies have demonstrated alterations in microglial inflammatory activity in patients with tau pathology without the presence of Aβ.107 Lastly, it should be noted that other inflammasomes beside NLRP3 have been implicated to play a role in AD. A recent study found that NLRP1 knockout in AD mouse models resulted in reduced Aβ plaque load, normalized hippocampal dendritic spines, and resulted in improved spatial and episodic memory testing performance.108 Increased NLRC4 expression and decreased learning and memory functionality was observed in a rat model simulating AD like pathology utilizing streptozotocin injections.109 AIM2 knock out in murine models was associated with decreased Aβ load and reduced microglia activity, but not with improvements in memory function.12 Taken together, these findings indicate that several inflammasomes contribute to the inflammatory response present in AD. TBI as an AD risk factor AD is a chronic neurodegenerative disorder, and like TBI, AD is known for structural damage, neuronal loss, chronic inflammation, and behavioral abnormalities. As such, the shared aspects, and potential interactions between these 2 pathologies (Fig 3) are of paramount interest, as trauma could potentially be the pathological facilitator to AD onset in the AD predisposed brain. This is especially true as studies suggest that TBI can lead to the earlier onset of AD pathology in as much as 4 to10 years earlier than the traditional onset.110,111 The effects of trauma on the CNS are interesting when considering that they induce similar disruptions to cellular homeostasis, microglia and astrocyte activation, and inflammatory activity that is seen in AD pathology. For instance, NLRP1, NLRP3, AIM2, ASC speck activity, inflammatory cytokine release, pyroptosis, chronic microglia activation, and neuronal damage have all been observed after TBI in numerous studies and experimental models.11,12,15,23,83 Likewise, similar observations have been observed in and are thought to contribute to the progression of AD pathology.13,69,99,105 Experiments involving TBI have observed increased levels of AD-associated proteins after injury, and human observations suggest that about 30% of TBI patients develop Aβ after injury.112,113 In addition, TBI induced reductions to CNS glymphatic/lymphatic functionality have been shown to reduce Aβ and tau clearance and increase microglia in murine AD models.28,29 Murine model studies of AD in the 3XTg model have seen increased Aβ levels within 24 hours following TBI, though it should be noted that these levels often returned to sham levels at 7 days after injury112 (Table II). Shishido and colleagues investigating the 3XTg AD mouse model observed increased Aβ levels within the hippocampus of injured mice 28 days post injury with accompanying decreased spatial memory function114 (Table II). In a more chronic injury model, Zysk and colleagues observed worsened learning and memory function and evidence of earlier onset of Aβ pathology in tg-ArcSwe AD mice after injury at 12 and 24 weeks post injury when compared to uninjured AD mice.8 In the R1.40 AD mouse model, Kokiko-Cochran and colleagues observed increased tissue loss and continued inflammatory activity after TBI when assessed at 3 and 120 days post injury115 (Table II). In the APP/PS1 AD mouse model, Collins and colleagues observed increased Aβ levels in the cortex of injured 3-month-old mice. However total Aβ load, though not fibrillar Aβ load, was decreased in mice injured at 6 months of age when compared to uninjured controls at 30 days post-injury.116 Interestingly, opposite results were obtained in a subclinical blast injury model with 20-week-old APP/PS1 mice in which repeated blasts over an 8 week period, 3 times per week, did not reduce overall plaque load but did reduce oligomerized Aβ levels and improved behavioral outcomes.117 Tau pathology has been identified in as many as 1/3 of TBI patients after single and multiple injuries.118 Interestingly, a U.S. Department of Defense study led by Clark and colleagues identified increased pTau load in the CSF of Vietnam era veterans who had undergone a TBI but did not see increased Aβ expression.119 pTau is also seen in murine models after TBI, and has been demonstrated to be phagocytosed by and able to activate microglia.120 Edwards and colleagues observed increased pTau aggregation after TBI in the P301S Tau mouse model as early as 1 day after injury and noted decreased learning and memory function at 6 months post injury accompanying increased pTau aggregation.121 Additionally, disruption of the BBB secondary to TBI is also of interest as studies have shown increased plaque formation near areas of BBB damaged due to age.19 All points considered, TBI represents a potential trigger of AD development through the initiation of neuronal cell death, diffuse axonal injury, BBB disruption, microglia activation, and inflammasome activity, all of which are seen as major drivers of AD pathology and represent current areas of therapeutic research. New therapeutic opportunities and current clinical trials Numerous studies and potential therapeutic interventions are currently being investigated in order to prevent, reduce, or reverse the effects of TBI and AD pathology. In both conditions, the inflammasome pathway offers attractive therapeutic targets for the reduction of damaging inflammatory secondary injury cascades. These may include the prevention of the priming phase or step 1 through targeting NF-κB, blocking the activity of the inflammasome sensor protein, such as NLRP3, prevention of ASC speck oligomerization, targeting caspase-1 activity, or blockage of GSDMD pyroptotic activity.122–124 Therapeutics that target NLRP3 activity such as MCC950 showed initial promising results through the reduction of NLRP3 and microglia activation and increased Aβ phagocytosis in AD, and reduced caspase-1 and IL-1β activity in TBI.125 Studies with the caspase-1 inhibitor VX-765 have demonstrated reduced inflammatory cytokine and GSDM-D activity in a murine model of TBI, as well as delayed inflammatory onset in an AD murine models though without altering plaque load.126,127 Studies involving an anti-ASC drug called IC100 show exciting results in reducing inflammatory activity and improving functional outcomes in murine models of inflammaging, multiple sclerosis, and CNS injury induced acute lung injury.6,22,123 Additionally, targeting ASC lowered the expression of caspase-1 and reduced pyroptotic cell death in rats after TBI.11 Given the unique role of ASC in the inflammasome and its interactions with AD proteins, ASC represents an interesting target in both pathologies, as hindrance of ASC speck activity could reduce plaque progression, inflammasome activation, and reduce inflammatory signaling in both AD and TBI pathologies. Beyond the bench, numerous human clinical trials are investigating the effectiveness of targeting the inflammasome in reducing the progression of inflammatory linked pathologies within and outside of the CNS (Table III). Due to current research targets, a majority of current inflammasome clinical trials are primarily focused on treating COVID-19 infections and related pathologies such as pneumonia and lung damage. A NLRP3 antagonist known as DFV890 developed by Novartis has just finished a phase 2 clinical trial investigating its effectiveness in treating severe respiratory infections of COVID-19. Provided data suggests that patients who were administered DFV 890 along with standard medical care had no higher chance of dying in the intensive care unit than patients that received standard medical care alone.128 Interestingly, researchers noted that slightly less of the patients that received DFV890 required ventilator intervention and also that slightly more of these patients had reduced COVID-19 pathology.128 Another study, which instead targeted NLRC4 with the drug MAS825 also investigated the effectiveness of inflammasome targeting in treating COVID-19 patients. Results suggest that patients administered MAS825 along with standard of care had decreased levels of the inflammatory biomarker C-reactive protein (CRP) compared to placebo at 15 days post treatment.129 However, these results did not translate to an improvement in clinical outcomes or reduce the need for other interventions.129 OLT1177 (dapansutrile), a NLRP3 inhibitor developed by Olatec has undergone a few clinical trials which have shown positive results and is currently being investigated for treating COVID-19 symptoms. In a clinical trial investigating use in systolic heart failure, patients administered dapansutrile 2,000mg had improved left ventricular ejection fraction and exercise time compared to placebo controls at day 14 and was deemed safe for use.130 When used for the treatment of gout, which is linked to IL-1β expression secondary to NLRP3 activation from monosodium urate crystals, patients administered dapansutrile reported reduced joint pain when compared to controls.131 Additional inhibitors of NLRP3 activity analogous to MCC950, such as IZD334 and Inzomelid developed by Inflazome (Roche) are currently being assessed for safety and clinical effectiveness in autoinflammatory disease trials that have just recently been completed.132 Although these studies are not investigating CNS pathologies, given how damage to 1 organ system such as the brain and spinal cord has been shown to secondarily impact other organ systems such as the lungs or gut through inflammasome activity, any effective compound in reducing the pathology of one could be potentially effective in reducing the pathology of another.6,78 As such, attention should be paid to all types of inflammasome clinical trials, and their findings should be considered for potential application to CNS pathologies such as TBI and AD. Additionally, since numerous studies show that inflammasome inhibitors are well tolerated and safe, continued investigation of new targets for inflammasome inhibition are encouraged. Currently, a search of clinicaltrials.gov utilizing the term “inflammasome” returns 45 studies, none of which are or have investigated inflammasome interactions in either TBI or AD pathologies, or combinations of the 2 pathologies. Future studies and drug investigations should consider the role of the inflammasome in CNS pathology, as well as more than just the products of inflammasome maturation, such as IL-1β and IL-18 but also to the individual proteins that are produced in order to build the inflammasome such as ASC specks. Conclusion The pathologies of TBI and AD are diverse, chronic, and psychologically debilitating for patients. Research of these 2 pathologies is of paramount interest and importance as incidences of both are increasing with the aging population. Emerging evidence has accumulated describes a link between TBI and AD pathologies. Cell injury in the simplest sense is the 1 true linker of AD and TBI, as the products of cell injury are represented in both pathologies. Neuronal injury from trauma or from Aβ and pTau activity result in cell death and the release of DAMPs, excitatory proteins, and disruptions to ionic homeostasis. These disturbances to CNS homeostasis in turn trigger the activation of the innate immune system, microglia, and the inflammasome, resulting in continued inflammatory activity as heightened inflammasome activation induces pyroptotic cell death. In this scenario, heightened inflammation becomes perpetual. In AD, the continued production and lack of Aβ clearance, and pTau activity feeds this inflammatory cycle thereby producing DAMPs and neuronal ionic unbalancing agents to trigger neuronal inflammasome activity and inflammatory astrocytic and microglial activation. This cycle becomes more amplified in AD in which microglia in the AD brain assume a self-perpetuating inflammatory morphology. Additionally, inflammasome products, such as ASC and IL-18 encourage Aβ pathology and in turn induces pTau pathology downstream. Taken together, TBI represents a risk factor in AD development by enhancing inflammation and promoting AD pathological onset. Furthermore, the genetic predisposition associated with AD may impact TBI pathological and functional outcomes. TBI can be an inflammatory trigger through tissue damage, astrocyte and microglia activation and therefore it is not surprising that TBI would be considered a risk factor for AD. However, although these pathologies have many similarities, they also have unique signatures. Injury severity and location are major factors in determining the degree of damage and cognitive abnormalities. On the other hand, AD is associated with numerous genetic mutations and potentially can be the result of environmental factors. As such, it should be noted that one does not necessarily always precede the other, and that individual genetic predisposition and environmental factors must be considered when determining overall risk for chronic pathology after CNS injury. Given the inconsistent results using murine models of AD, and that numerous AD genetic models and TBI experimental models currently exist, we must be cautious not to overgeneralize observations and extrapolate these results to humans. Regardless, the inflammasome represents a viable target for reducing the impact of each pathology, as well as reducing crosstalk between them. Current results have shown that inflammasome inhibitors appears to be a safe and potentially effective in reducing pathology in TBI and AD, and a wide variety of inflammatory associated disorders such as MS, kidney disease, stroke, lung damage, and aging. Although current clinical trials have focused on inflammasome sensor inhibition, future studies will need to focus on other proteins associated with formation of the inflammasome complex. Given the interactions between ASC and Aβ or IL-18 and BACE in AD, and that numerous inflammasome sensors exist and are implicated in TBI and AD, future clinical studies should consider targeting multiple inflammasome sensors or adaptor molecules. In addition, neuroimmune interactions involving the meningeal lymphatic system at the CNS borders will likely provide information about the immune responses in the CNS; and potentially yield therapeutic strategies to treat neurological disorders, including TBI and AD. In conclusion, AD and TBI individually represent complex disorders with numerous factors that play into pathological onset, development, and prognosis. As such, researchers and medical professionals must take into consideration all factors in an experimental study or individual patient’s environment in an attempt to evaluate the related pathology holistically. Since genetic predisposition has been implicated as a major factor in AD pathology and could likewise influence TBI pathology, these variables should be taken into consideration along with environmental factors when evaluating potential experimental models and injury methods. As such, while TBI represents a known source of cognitive decline, inflammatory activity, and potential AD protein development, it is not a guaranteed cause of AD. Additionally, while AD predisposition could potentially impact inflammatory activity within the CNS, it does not guarantee AD pathological development with or without TBI. Regardless, the inflammasome represents a shared characteristic of numerous pathologies and a promising target for the development of novel and effective therapeutic interventions. This is especially the case when considering the role of inflammasome-derived cytokines, activated microglia and astrocytes, as well as pyroptotic cell death induced by trauma or AD pathology. Acknowledgments This research was funded by an R01 grant from the NIH/NINDS to RWK and JPdRV (R01NS113969-01), a FDOH grant (21A13) to WDD and an RF1 grant from the NIH/NINDS/NIA (1RF1NS125578-01) to WDD and JPdRV. We would like to thank Karen Cashmere who assisted with compiling clinical trial data investigating therapeutics targeting the inflammasome. All figures were created with BioRender.com. All authors have read the journal’s authorship agreement and that the manuscript has been reviewed by and approved by all named authors. Abbreviations: Aβ amyloid beta AD Alzheimer’s disease AIM2 absent in melanoma 2 ALR AIM2 like receptor ApoE4 apolipoprotein E-4 APP amyloid precursor protein ASC apoptosis-associated speck-like protein containing a caspase recruiting domain ATP adenosine tri-phosphate BACE β-secretase BBB blood-brain barrier CARD C terminus caspase recruitment domain CDC U.S. Centers for Disease Control and Prevention CNS central nervous system CRP C-reactive protein DAM disease associated microglia DAMPs damage associated molecular patterns GFAP glial fibrillary acidic protein Glu glutamate GSDMD gasdermin-D IL interleukin LPS lipopolysaccharide MAPT microtubule associated protein tau NF-κB nuclear factor-κB NOD nucleotide oligomerizing domain NLR NOD-like receptor NLRC NLR- containing caspase domain NLRP, NLR- containing pyrin domain PAMPs pathogen associated molecular patterns PRR pattern recognition receptors PSEN presenilin pTau hyperphosphorylated tau ROS reactive oxygen species RhoA Ras homolog family member A TBI traumatic brain injury TLR Toll-like receptors TREM2 triggering receptor expressed on myeloid cells 2 Fig 1. Inflammasome activation and formation. The NLRP3 inflammasome is activated by numerous triggers and by 2 distinct pathways. The canonical pathway is activated first by TLRs that detect the priming signal (dashed lines) which increases transcription of an inflammasome sensor and cytokine RNA through NF-kB signaling. This is followed by an activating signal including: PAMPs, DAMPs, crystalline matter, K+ efflux, ROS, and external ATP (solid lines) which activates the inflammasome sensor protein, pro-caspase-1, and ASC to form the inflammasome complex. Complex formation allows for the self-activation and cleavage of caspase-1 which in turn cleaves pro-IL-1β and pro-IL-18. Additionally, caspase-1 will cleave GSDMD allowing the N terminus to form the pyroptotic pore after which the cell undergoes pyroptosis, releasing its cellular contents, including the IL-1 inflammatory cytokines. Non-canonical activation occurs through detection of LPS or gram-negative bacteria which also induces transcriptional upregulation and caspase activation. However, this pathway utilizes caspase-4/5 in humans or caspase-11 in murine species, and unlike caspase-1, only cleaves GSDMD to form the pyroptotic pore. Pore formation allows for the release of ATP which activates pannexin channels, resulting in K+ efflux and subsequent NLRP3 activation. Fig 2. TBI and inflammasome pathology. TBI is a chaotic event in which one strike results in major changes to CNS homeostasis. Upon moderate or severe injury, the cells at the epicenter of the trauma will be destroyed and their contents will be spilled out into the extracellular space as DAMPs. Damaged vasculature at the epicenter will result in breakdown of the BBB, allowing for the infiltration of peripheral immune cells and blood vessels carrying excitatory products such as iron, resulting in oxidative stress. DAMPs will prime neurons for pyroptotic activity while also activating microglia and astrocytes to secrete inflammatory cytokines, encouraging inflammasome formation. Trauma induced depolarization will result in the imbalance of ionic homeostasis, encouraging the uptake of Na+, Ca++, efflux of K+ and resulting Na+/K+ pump activity and inflammasome activation. Ca++ uptake and pump activity results in mitochondrial dysfunction, energy loss and the release of ROS. Encouraging excitatory cell death and/or inflammasome formation resulting in GSDMD pore induced pyroptosis and cytokine release. Fig 3. TBI effects and inflammasome activation linked to AD pathology. TBI and AD are unique pathologies of the CNS, resulting in damage to CNS structures, homeostatic disturbances, and cognitive decline. The inflammasome is seen activated in both pathologies and represents a potential link between the 2 pathologies (black lines), allowing for one to potentially exacerbate the other. In TBI, (pink lines) the inflammasome is activated by DAMPs released by injured and dead cells, while in AD (green lines) the inflammasome is activated by oligomerized Aβ, resulting from BACE cleavage of APP. In both pathologies, the respective proteins are recognized by microglia and astrocytes, which become activated and secrete inflammatory cytokines matured through inflammasome formation. Cytokine release results in pyroptotic activity in neighboring cells and successive release of additional DAMPs, excitatory proteins, ASC specks, and inflammatory cytokines, inducing the inflammatory cascade. Additionally, AD pathology is potentially exacerbated by TBI inflammasome activation through IL-18-induced increased BACE activity, ASC speck interactions with Aβ, and increased pTau formation. Table I Microglia classifications Microglia type Activators Functionality Physiological response Sources M1 LPS, IFN-γ Proinflammatory IL-1β, TNF-α, ROS 33,35,39 M2a IL-4, IL-13 Anti-inflammatory Increased scavenger receptors 33,39,41 IL-10 M2b IL-1R ligands Both IL-1β, TNF-α, IL-10 33,39 B cell class switching 39 M2c IL-10, glucocorticoids Anti-inflammatory Increased phagocytosis 33,39,41 Promote structural repair M2d IL-6, Adenosine Anti-inflammatory Pro-angiogenic 38,41,42 DAM TREM2, PSEN, ApoE Dysfunctional Increased autophagy and Aβ phagocytosis Increased cytokine expression 97_102 Excessive dendritic pruning Table II TBI outcomes in AD murine models AD model Time post TBI Observations Sources 3XTg 24h Increased Aβ levels 112 7d Sham Aβ levels 28d Increased Aβ levels 114 Decreased spatial memory tg-ArcSwe 12w and 24w Decreased learning and memory 8 Earlier Aβ onset R1.40 3d and 120d Increased tissue loss 115 Inflammatory activity APP/PS1 30d 3m: Increased Aβ levels 116 6m: Decreased total Aβ, same fibrillar Aβ levels 8w* Same total Aβ, reduce oligomerized Aβ load 117 Reduced anxiety behavior, improved cognition P301S (PS19) 1d, 1w, 2m, 6m Increased Tau aggregation 121 6m: Decreased learning and memory Abbreviations: d, days; h, hours; m, months; w, weeks. * Repeated subclinical blast model. Table III Recent clinical trials targeting the inflammasome Drug name Inflammasome target Disorder Study type Results Source DFV890 NLRP3 COVID-19 Clinical Trial Reduced COVID pathology 128 Reduced ventilator intervention MAS825 NLRC4 COVID-19 Clinical Trial Decreased C-reactive protein 129 No change in clinical outcomes OLT1177 NLRP3 Heart Failure Clinical Trial Improved left ventricular ejection fraction 130 Dapansutrile Gout Clinical Trial Reduced joint pain 131 IZD334 NLRP3 Autoinflammatory Disease Clinical Trial Trial complete 132 Inzomelid NLRP3 Autoinflammatory Disease Clinical Trial Trial complete 132 MCC950 NLRP3 AD Animal Study Increased Aβ phagocytosis 125 TBI Animal Study Reduced caspase-1 and IL-1β activity 125 Rheumatoid Arthritis Clinical Trial Severe side effects 125,133 VX765 Caspase-1 TBI Animal Study Reduced cytokine and GSDM-D activity 127 Alzheimer’s Disease Animal Study Delayed inflammatory onset 126 No change in plaque load IC-100 ASC Aging Animal Study Reduced Caspase-1,8, Il-1β, ASC, NLRP-1 expression 22 Multiple Sclerosis Animal Study Reduced T cell, myeloid cell, and microglia activation 123 CNS induced Lung Injury Animal Study Reduced Il-1β, ASC, caspase-1, AIM2 expression 6 Reduced lung tissue damage TBI Animal Study Reduced caspase-1 and pyroptosis 11 The inflammasome represents a promising target in the treatment of numerous inflammatory fueled pathologies. Current clinical studies have shown that therapeutics that target inhibition of the inflammasome sensor are safe, well tolerated, and potentially effective in numerous inflammatory pathologies. Conflicts of Interest: JPdRV, HMB, RWK, and WDD are co-founders and managing members of InflamaCORE, LLC and have licensed patents on inflammasome proteins as biomarkers of injury and disease as well as on targeting inflammasome proteins for therapeutic purposes. JPdRV, HMB, RWK, and WDD are Scientific Advisory Board Members of ZyVersa Therapeutics. NHJ declares no conflicts of interest. ==== Refs References 1. Coronado VG , Xu L , Basavaraju SV , Surveillance for traumatic brain injury-related deaths–United States, 1997–2007. MMWR Surveill Summ 2011;60 :1–32. 2. Lew HL , Poole JH , Guillory SB , Salerno RM , Leskin G , Sigford B . Persistent problems after traumatic brain injury: the need for long-term follow-up and coordinated care. J Rehabil Res Dev 2006;43 :vii–x. 3. Prevention CfDCa. 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==== Front Cancer Manag Res Cancer Manag Res cmar Cancer Management and Research 1179-1322 Dove 416366 10.2147/CMAR.S416366 Case Report Personalized Brachytherapy for a Herlyn-Werner-Wunderlich Syndrome Patient with Endometrial Cancer: A Case Report Zeng et al Zeng et al Zeng Zheng 1 * Lu Yuanyuan 2 * http://orcid.org/0000-0002-6856-2320 Zhang Fuquan 3 Zhang Jie 1 Zhang Wenjun 1 Luo Chunli 1 Guo Yuping 4 http://orcid.org/0009-0008-8785-9948 Yan Junfang 1 Yu Lang 1 1 Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China 2 Department of Radiation Oncology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, People’s Republic of China 3 Department of Radiation Oncology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China 4 Gynecological Radiotherapy Ward, The Third Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China Correspondence: Junfang Yan; Lang Yu, Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86-10-6915-5485, Fax +86-10-6512-4875, Email yanjunfang@pumch.cn; Lay227215@163.com * These authors contributed equally to this work 14 7 2023 2023 15 691697 01 5 2023 06 7 2023 © 2023 Zeng et al. 2023 Zeng et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Purpose Endometrial carcinoma (EC) is a common gynecological malignancy. Vaginal cuff brachytherapy (VBT) is an adjuvant treatment for EC. Since a single-channel cylinder sometimes delivers inadequate dose coverage to the vaginal apex, three-dimensional (3D) printing technology can be used to achieve satisfactory dose distribution. Here, we report the first case of an EC patient with Herlyn-Werner-Wunderlich syndrome (HWWS) treated with VBT using 3D-printed applicators. Case Presentation Here, we present a case study of an endometrial cancer patient with HWWS who underwent surgery. During adjuvant radiotherapy, 3D-printed applicators were used in VBT. To accomplish the reconstruction of the source pathways on magnetic resonance imaging, catheters with copper sulfate were placed in two 3D-printed applicators. The early tolerance of this treatment was positive. During the 6-month follow-up, locoregional recurrence was not detected. Conclusion Our findings strongly indicate that VBT with 3D-printed applicators may be a reasonable treatment option for EC with HWWS. Keywords personalized brachytherapy Herlyn-Werner-Wunderlich syndrome endometrial cancer 3D-printed applicator National Key R&D Program of China, Ministry of Science and Technology of the People’s Republic of China This work was supported by National High Level Hospital Clinical Research Funding (grant number 2022-PUMCH-B-052) and National Key R&D Program of China, Ministry of Science and Technology of the People’s Republic of China (Grant No. 2022YFC2407100, 2022YFC2407101, 2022YFC2407102). ==== Body pmcIntroduction Endometrial carcinoma (EC) is the seventh most common cancer in women, with a high mortality rate.1 Vaginal cuff brachytherapy (VBT) has become the standard adjuvant treatment for EC, with a high risk of recurrence after resection.2 Vaginal applicators are tools for performing VBT and are the most commonly used single-channel cylinders (SCC).3 However, SCC sometimes delivers inadequate dose coverage to the vaginal apex, owing to source anisotropy.4 Creating individualized applicators for different patients using three-dimensional (3D) printing technology achieves satisfactory dose distribution.5,6 Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare disease often discovered at menarche and consists of anomalies of the female reproductive tract. It comprises the three most common forms of anomalies, including uterus didelphys, unilateral blind hemivagina, and ipsilateral renal agenesis.7 This case report describes a patient with HWWS who was admitted to our hospital with postoperative EC and provides insights into a personalized treatment approach that has resulted in satisfactory clinical outcomes. Case Presentation A middle-aged woman with irregular vaginal bleeding was admitted to another hospital. Routine blood test results, liver function, kidney function, and electrolyte levels were within normal ranges. The patient’s serum cancer antigen (CA) 125 (CA125) level was elevated to 182.0 IU/mL (0–35.0 IU/mL), and CA199 and carcinoembryonic antigen levels were within the normal range. Pelvic magnetic resonance imaging (MRI) revealed that the uterus was poorly formed and showed bi-cavitary changes. The left uterine volume was significantly increased, the myometrial signal was significantly heterogeneous, multiple nodules were observed, and some protruded from the uterine contour; the largest size was 7.4×7.3 cm. Sagittal T2-weighted imaging of the right uterus showed a normal structure and signal intensity in the three layers of the uterus. Chest and abdominal computed tomography (CT) revealed no tumor metastasis. Subsequently, hysteroscopic bilateral endometrial biopsy was performed. Pathology, in combination with immunohistochemistry, revealed that the left uterus was an adenocarcinoma, which is considered a high-grade serous carcinoma. Total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, para-aortic lymph node dissection, omentectomy, abdominopelvic adhesiolysis, and peritoneal brush cytology were performed. Postoperative histology revealed that the left uterus and ovary had mixed high-grade adenocarcinomas, including some serous carcinomas and some endometrial carcinomas, with a focal invasion of the myometrium. Multiple uterine myomas with adenomyosis were also observed in the left uterus. Tumor invasion of uterine blood vessels was also observed. Adenomyosis with some epithelial dysplasia was observed in the right uterus, but no carcinoma was observed in the parametrium. One of the 16 lymph nodes in the left pelvic cavity was positive, while 10 lymph nodes in the right pelvic cavity and six para-aortic lymph nodes showed no lymph node metastasis. No malignant tumor cells were found on peritoneal cytology. Using the International Federation of Gynecology and Obstetrics (FIGO) Staging System, version 2018, the tumor was classified as Stage IIIC1. Using the American Joint Committee on Cancer TNM Staging System version 8, the tumor was classified as T3aN1M0 (Stage IIIC1). Immunohistochemical examination of the tumor revealed positivity for Vimentin, P53, P16, ER, and CD34 were positive. However, the napsin A, WT-1, and HNF-1B tests were negative. The Ki-67 proliferation index was ~70%. A definitive diagnosis of EC was confirmed based on the histopathological and immunohistochemical results. Genetic testing revealed a TP53 exon7 mutation with an abundance of 41.14%. Molecular typing was classified as having a high copy number. The patient received three cycles of chemotherapy with paclitaxel and carboplatin. The patient was admitted to our hospital for adjuvant radiotherapy. External beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) were performed. For EBRT, the clinical target volume (CTV) included the lower half of the vaginal, parapodium, and pelvic lymphatic drainage areas. The planning target volume was defined as a 6‒10 mm margin added to the CTV in all directions. The prescribed dose was 50.4 Gy to at least 95% of the planning clinical target volume in 28 fractions. High-dose-rate ICBT generally begins after intensity-modulated radiation therapy with 192 Ir. For ICBT, to show the shape of the vagina, two inflated balloons with sterile physiological salt solution filled the double vagina for MRI (Figure 1A and B). As shown in Figure 1C and D, MRI was used to create a 3D-printed ICBT applicator. Figure 1 (A and B) Images of two inflated balloons with a sterile physiological salt solution. (C and D) T2-weighted magnetic resonance images were obtained after two inflated balloons with sterile physiological salt solution filled the double vagina. A 3D-printed applicator was designed and sent to a 3D printer (Eden260VS; Stratasys, Inc, Gilbert, AZ, USA). Examples are shown in Figure 2A. Applicators are available for clinical use after quality assurance. As shown in Figure 2B, catheters with copper sulfate were placed in two 3D-printed applicators to show the needle paths in the applicators. As shown in Figure 2C and D, a planning MRI scan was performed. CTV included the lower half of the vaginal wall. The dose calculations were performed using the Oncentra Brachy Treatment Planning System (Elekta, Stockholm, Sweden). A prescribed dose of 10 Gy was delivered in two fractions. The CTV and organs at risk (OARs) doses were converted to an equivalent dose of 2 Gy (EQD2). The final goal was a cumulative dose to the CTV of 65.89 Gy in the 3D-printed plan. The cumulative doses of the D2cc of the bladder, rectum, and sigmoid were 4858, 4362, and 5293 cGy, respectively. A multichannel cylinder (MCC) simulation plan is developed. As shown in Table 1, the dosimetric indices were superior in the 3D-printed plan than in the MCC plan. In Figure 3A and B, when evaluating the CTV from the vaginal apex, the isodose curve of 100% cover was better than that in the MCC plan. Figure 3C and D show a 100% isodose curve covering a larger volume range of the urethra and rectum, respectively. Comparing the two groups of plans, these results favor the 3D-printed plan. The patient’s follow-up time was 6 months, with an Eastern Cooperative Oncology Group score of 0 and no reported acute urinary or lower digestive tract events.Table 1 Dosimetric Comparison of Organs at Risk Between Multichannel Cylinder (MCC) and Three-Dimensional (3D)-Printed Plan Dosimetric Parameters MCC Applicator 3D-Printed Applicator D98 (cGy) 417.76 435.55 D90 (cGy) 586.87 586.12 Bladder D2cc (cGy) 480.29 221.83 Rectum D2cc (cGy) 513.04 396.17 Sigmoid D2cc (cGy) 98.46 180.00 Small intestine D2cc (cGy) 89.93 80.18 Urethra D0.1cc (cGy) 730.38 424.49 Figure 2 (A) Photographs of the three-dimensional (3D)-printed applicators. (B) Catheters with copper sulfate were placed in two 3D-printed applicators. (C and D) T2-weighted magnetic resonance images were obtained after the catheters with copper sulfate were placed in two 3D-printed applicators. The catheters with copper sulfate are represented by blue arrows. Figure 3 (A and B) Vaginal apex treatment plans using a multichannel cylinder (MCC) and 3D printer. (C and D) Midvaginal treatment plans using MCC and 3D-printer. Discussion To our knowledge, this is the first reported case of EC with HWWS that was treated with VBT. Moreover, this is the first study on VBT using 3D-printed applicators in patients with HWWS. In this case, copper sulfate was used as a photographic developer for the 3D-printed applicator reconstruction in MRI. Abnormal development of the Müllerian and Wolffian ducts caused HWWS. It is a rare genital malformation, with a true incidence of approximately 0.1–3.8%.8 The development of EC associated with HWWS is not yet clear. Research has shown that women with endometriosis and adenomyosis have an increased risk of developing EC.9 In our case, postoperative pathology revealed adenomyosis in both uteri, suggesting that EC may be associated with HWWS. According to European Society for Medical Oncology (ESMO) (Version 2022) guidelines, for the FIGO stage IIIC patients with EC who had regional lymph node involvement, the treatment methods included radical surgery with postoperative adjuvant treatment.1 Adjuvant chemotherapy with or without postoperative radiotherapy is the treatment of choice for these patients. Pelvic EBRT with VBT and EBRT alone is a common radiotherapy treatments.1 The vaginal vault is a common relapse site for patients with EC undergoing radical surgery.10 Given the pattern of EC failure, VBT alone is regarded as the standard adjuvant therapy for high-intermediate-risk endometrial cancer.10 However, the role and utilization of a VBT boost in EBRT are less clear in patients with stage III EC.11 Bingham et al evaluated 12,988 patients with stage III EC using the National Cancer Database.12 They found that EBRT plus VBT had a significantly improved 5-year survival rate compared to EBRT alone (69% vs 66%, respectively; P < 0.01) for patients with cervical stromal involvement. Rossi et al analyzed 611 women with stage IIIC EC.13 They found that EBRT plus VBT had a significantly improved 5-year survival rate compared to EBRT alone (63% vs 47%, respectively; P < 0.001) for patients with direct local disease extension. For patients with stage III EC, the ESMO guidelines (Version 2022) list the optional inclusion of a VBT boost.1 Uterine serous carcinoma is an aggressive histological subtype of endometrial cancer, with a high relapse rate.14 Hong et al evaluated 5432 women with uterine serous carcinoma and found that VBT was associated with a significant survival advantage.15 In this case, the patient was staged IIIC1 with uterine serous carcinoma, and a boost in VBT to EBRT was administered. In this case, different treatments were considered. Interstitial brachytherapy is often used in specific situations, including large tumors, asymmetric tumors, organs at risk proximity, and patient anatomy considerations.16 Owing to irregular dose distribution and special anatomy, interstitial brachytherapy may increase the risk of side effects such as bleeding, urethritis, and cystitis. In the case of postoperative endometrial cancer, the most commonly used brachytherapy is the intracavitary techniques.17 The patient was diagnosed with complete vaginal septum and required removal of the entire vagina if surgical excision was necessary. It results in significant surgical trauma and affects the quality of life. In this case, a patient who received VBT for personalized applicators may be a suitable choice. MCC applicators have become more popular for VBT treatment because of their dose flexibility.4 However, the vagina may not be cylindrical because of surgery and anatomic irregularities.5 Furthermore, MCC applicators are limited to various applications owing to air gaps. Air spaces cause a 1–2 mm displacement of the vaginal wall, which can reduce the dose to the vaginal mucosa by more than 10%.18 Personalized vaginal applicators are one choice to overcome the limitations of MCC applicators.19 Yan et al showed that 3D-printed applicators obtained significant improvements in CTV-1 cm V100 (by 13%) and D90 (by 11%) compared to MCC; 3D-printed applicators demonstrated superiority over MCC in terms of OARs protection.5 The advantages of 3D-printing technology include versatility, cost-effectiveness, and accuracy.20 In this case, the doses to the bladder, rectum, urethra, and small intestine in the 3D-printed plan were lower than those in the MCC plan were. Meanwhile, the apex of the vagina was better covered by the CTV in the 3D-printed plan. With the development of imaging technology, brachytherapy based on imaging modalities has increased the precision and accuracy of treatment.21 MRI can provide better soft tissue contrast than CT and is already used for some gynecologic cancers.22 The vaginal cuff can be visualized using MRI, which provides better images for defining the gross disease.22 The introduction of brachytherapy by MRI has led to a new era of increasingly effective treatments.23 One challenge of which is the reconstruction of the source pathways on MRI. Applicator reconstruction inaccuracies lead to dosimetric uncertainties in target volumes and OARs.24 Schindel et al evaluated seven MRI marker agents and found that the CuSO4 marker was feasible for MRI-guided gynecological brachytherapy.25 In this case, custom-made plastic catheters with CuSO4 solution were inserted into the source channels of MRI-compatible applicators. This method can provide accurate source pathway reconstruction. In cases in which conventional treatments are complex; a personalized approach is essential for the patient to have the broadest range of medically reasonable options. Currently, there is a report on EC with HWWS treated with VBT using 3D-printed applicators. Reconstruction of titanium applicators using MRI is complex. CuSO4 has been used as an MRI marker in brachytherapy, achieving relatively good dose distribution and no relevant acute toxicity reaction. This unique, personalized treatment approach has provided satisfactory outcomes for patients. Patients treated with personalized brachytherapy are expected to achieve long-term survival. Acknowledgments We would like to thank Editage (www.editage.cn) for English language editing. Data Sharing Statement All data generated or analyzed during this study are included in this published article. Ethics Approval and Consent to Participate Approval was obtained from the Institutional Review Board of Peking Union Medical College Hospital. Consent Statements The patient has provided informed consent for case details of this manuscript and accompanying images to be published. Disclosure The authors report no conflicts of interest in this work. ==== Refs References 1. Oaknin A, Bosse TJ, Creutzberg CL, et al. Endometrial cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33 (9 ):860–877. doi:10.1016/j.annonc.2022.05.009 35690222 2. Zakem SJ, Robin TP, Smith DE, et al. Evolving trends in the management of high-intermediate risk endometrial cancer in the United States. Gynecol Oncol. 2019;152 (3 ):522–527. doi:10.1016/j.ygyno.2018.12.010 30876498 3. Harkenrider MM, Grover S, Erickson BA, et al. Vaginal brachytherapy for postoperative endometrial cancer: 2014 survey of the American brachytherapy society. Brachytherapy. 2016;15 (1 ):23–29. doi:10.1016/j.brachy.2015.09.012 26620818 4. Hou X, Liu A, Zhang F, Wong J, Chen YJ. Dosimetric advantages of using multichannel balloons compared to single-channel cylinders for high-dose-rate vaginal cuff brachytherapy. Brachytherapy. 2016;15 (4 ):471–476. doi:10.1016/j.brachy.2016.03.002 27066994 5. Yan J, Qin X, Zhang F, Hou X, Yu L, Qiu J. Comparing multichannel cylinder and 3D-printed applicators for vaginal cuff brachytherapy with preliminary exploration of post-hysterectomy vaginal morphology. J Contemp Brachytherapy. 2021;13 (6 ):641–648. doi:10.5114/jcb.2021.112115 35079250 6. Wiebe E, Easton H, Thomas G, Barbera L, D’Alimonte L, Ravi A. Customized vaginal vault brachytherapy with computed tomography imaging-derived applicator prototyping. Brachytherapy. 2015;14 (3 ):380–384. doi:10.1016/j.brachy.2014.12.006 25630618 7. Horst W, de Melo RC, Theilacker G, Schmitt B, de Melo RC. Herlyn-Werner-Wunderlich syndrome: clinical considerations and management. BMJ Case Rep. 2021;14 (3 ):e239160. doi:10.1136/bcr-2020-239160 8. Tong J, Zhu L, Lang J. Clinical characteristics of 70 patients with Herlyn-Werner-Wunderlich syndrome. Int J Gynaecol Obstet. 2013;121 (2 ):173–175. doi:10.1016/j.ijgo.2012.11.023 23465857 9. Hermens M, van Altena AM, Velthuis I, et al. Endometrial cancer incidence in endometriosis and adenomyosis. Cancers. 2021;13 (18 ):4592. doi:10.3390/cancers13184592 34572823 10. Nout, RA, Smit, V, Putter, H, et al Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet. 2010;375(9717):816-823. doi:10.1016/S0140-6736(09)62163-2. 11. Wortman BG, Creutzberg CL, Putter H, et al. Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer. 2018;119 (9 ):1067–1074. doi:10.1038/s41416-018-0310-8 30356126 12. Bingham B, Orton A, Boothe D, et al. Brachytherapy improves survival in stage III endometrial cancer with cervical involvement. Int J Radiat Oncol Biol Phys. 2017;97 (5 ):1040–1050. doi:10.1016/j.ijrobp.2016.12.035 28332987 13. Rossi PJ, Jani AB, Horowitz IR, Johnstone PA. Adjuvant brachytherapy removes survival disadvantage of local disease extension in stage IIIC endometrial cancer: a SEER registry analysis. Int J Radiat Oncol Biol Phys. 2008;70 (1 ):134–138. doi:10.1016/j.ijrobp.2007.05.048 17855014 14. Bogani G, Ray-Coquard I, Concin N, et al. Uterine serous carcinoma. Gynecol Oncol. 2021;162 (1 ):226–234. doi:10.1016/j.ygyno.2021.04.029 33934848 15. Hong JC, Foote J, Broadwater G, Gaillard S, Havrilesky LJ, Chino JP. Impact of chemotherapy and radiotherapy on management of early stage clear cell and papillary serous carcinoma of the uterus. Int J Gynecol Cancer. 2017;27 (4 ):720–729. doi:10.1097/IGC.0000000000000926 28375927 16. Kamrava M, Alrashidi SM, Leung E. Interstitial brachytherapy for gynecologic malignancies: complications, toxicities, and management. Brachytherapy. 2021;20 (5 ):995–1004. doi:10.1016/j.brachy.2020.12.008 33789823 17. Prisciandaro JI, Zhao X, Dieterich S, Hasan Y, Jolly S, Al-Hallaq HA. Interstitial high-dose-rate gynecologic brachytherapy: clinical workflow experience from three academic institutions. Semin Radiat Oncol. 2020;30 (1 ):29–38. doi:10.1016/j.semradonc.2019.08.001 31727297 18. Hassouna A, Bahadur YA, Constantinescu C. Assessment of air pockets in high-dose-rate vaginal cuff brachytherapy using cylindrical applicators. J Contemp Brachytherapy. 2014;6 (3 ):271–275. doi:10.5114/jcb.2014.45436 25337128 19. Lindegaard JC, Madsen ML, Traberg A, et al. Individualised 3D printed vaginal template for MRI guided brachytherapy in locally advanced cervical cancer. Radiother Oncol. 2016;118 (1 ):173–175. doi:10.1016/j.radonc.2015.12.012 26743833 20. Mohammadi R, Siavashpour Z, Aghdam SRH, Fazli S, Major T, Rohani AA. Manufacturing and evaluation of multi-channel cylinder applicator with 3D printing technology. J Contemp Brachytherapy. 2021;13 (1 ):80–90. doi:10.5114/jcb.2021.103590 34025740 21. Fokdal L, Tanderup K, Nielsen SK, et al. Image and laparoscopic guided interstitial brachytherapy for locally advanced primary or recurrent gynaecological cancer using the adaptive GEC ESTRO target concept. Radiother Oncol. 2011;100 (3 ):473–479. doi:10.1016/j.radonc.2011.08.016 21924784 22. Chapman CH, Prisciandaro JI, Maturen KE, et al. MRI-based evaluation of the vaginal cuff in brachytherapy planning: are we missing the target? Int J Radiat Oncol Biol Phys. 2016;95 (2 ):743–750. doi:10.1016/j.ijrobp.2016.01.042 27020110 23. Westerveld H, Nesvacil N, Fokdal L, et al. Definitive radiotherapy with image-guided adaptive brachytherapy for primary vaginal cancer. Lancet Oncol. 2020;21 (3 ):e157–e167. doi:10.1016/S1470-2045(19)30855-1 32135119 24. Viswanathan AN, Dimopoulos J, Kirisits C, Berger D, Potter R. 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==== Front Vet Med (Auckl) Vet Med (Auckl) vmrr Veterinary Medicine : Research and Reports 2230-2034 Dove 410904 10.2147/VMRR.S410904 Original Research Sero-Prevalence and Associated Risk Factors of Peste Des Petits Ruminants in Dera and Gerar Jarso Districts of Oromia Region, Ethiopia Ejigu et al Ejigu et al Ejigu Eyoel 1 http://orcid.org/0000-0002-4492-688X Tolosa Tadele 1 http://orcid.org/0000-0001-5828-5609 Begna Feyissa 1 http://orcid.org/0000-0002-3801-2619 Tegegne Hailehizeb 2 1 Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine Jimma University, Jimma, Oromia, Ethiopia 2 Department of Veterinary Science, College of Agriculture and Environmental Science, Debre Tabor University, Debre Tabor, Amhara, Ethiopia Correspondence: Eyoel Ejigu, Email eyoelabi7@gmail.com 07 7 2023 2023 14 111123 31 3 2023 01 7 2023 © 2023 Ejigu et al. 2023 Ejigu et al. https://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Introduction Peste des petits ruminants is a transboundary disease of major economic importance and imposes significant constraints on small ruminant production. Methods A cross-sectional study was employed in Dera and Gerar Jarso districts of the North Shewa zone, Oromia Region from February 2021 to March 2022, to estimate the antibody of PPRV and assess the associated risk factors. Blood samples (n = 662) were collected from sheep and goats. Cluster sampling strategy was employed to collect the data. Villages/Kebeles and individual small ruminants were randomly selected, while households were designated using a systematic random sampling method. Results An overall individual animal and flock level sero-prevalence was 10.3% (95% CI = 8.2–12.8) and 100% (95% CI = 96.3–100), respectively, from the c-ELISA test result. A sero-prevalence of 11.2% (95% CI = 8.7–14.4) in Dera and 8% (95% CI = 5–12.7) in Gerar Jarso districts was recorded. Discussion Flock size, age, sex, communal grazing, and watering system, new small ruminant introduction into a flock, and mixed rearing were significantly associated with PPR sero-positivity in sheep and goats. The chance of PPR occurrence in goats was 4 times (OR = 4; P = 0.000) more than sheep. Female sheep and goats were more likely to be sero-positive to PPR by 3 times (OR = 3.2; P = 0.003) than males. The newly introduced small ruminants had 4 times more odds (OR = 4.4; P = 0.000) of sero-positivity than animals being born at home. Small ruminants kept under communal grazing and watering system were nearly 12 times (OR = 11.5; P = 0.024) more likely sero-positive than privately managed small ruminants. Likewise, sheep and goats reared together were almost 9 times (OR = 9.4; P = 0.000) a higher chance of being sero-positive compared with separately reared small ruminants. Conclusion The finding of PPR virus antibodies in small ruminants from all study areas indicates endemic circulation of the virus. The implementation of regular vaccination could minimize the occurrence of PPR. Keywords PPR prevalence risk factor small ruminant North Shewa ==== Body pmcIntroduction Ethiopia possesses the largest population of small ruminants, with an estimated 42.9 million sheep and 52.5 million goats1 in Africa. Livestock ownership currently contributes to the livelihoods of an estimated 80% of the rural population.2 There are 39,854 sheep, 123,675 goats in Dera, 50,564 sheep, and 19,750 goats in Girar Jarso. Despite production and the disease challenges in Ethiopia, farmers prefer to rear sheep and goats for their low cost of production, prolificacy, adaptive capacity to the environment through dynamic feeding behavior, and fast reproduction cycle and growth rate.3 The degree to which sheep and goats survive to marketable age is one of the key indicators of the efficiency of their production. They also play an important role in food security and livelihood resilience in many parts of the country, but several constraints are reducing productivity in this sector. Peste des petits ruminants are considered a major restriction factor causing direct losses, such as death and decreased production, and indirect losses, such as, animal movement restriction and trade banns.4–6 Peste des petits ruminants (PPR) is one of the transboundary diseases of major economic importance and imposes significant constraints on small ruminant production due to its high mortality rate. It is an acute, highly contagious, and frequently fatal disease of sheep and goats caused by PPR virus, a member of the genus morbillivirus of the family Paramyxoviridae.7,8 Therefore, it is considered one of the most damaging animal diseases in Africa, the Middle East, and Asia. It is also one of the priority diseases indicated in the FAO-OIE Global Framework for the Progressive Control of Trans-boundary Animal Diseases.3 PPR is more pronounced in goats than in sheep, and mortality approaches 100% when associated with other disease complications. Following infection via the respiratory tract, PPRV replicates in the oropharynx and mandibular lymph node. The incubation period of PPRV is about three to four days before the onset of clinical disease.8,9 Pyrexia (40–41°C), nasal and ocular discharge, respiratory tract infection, and inflammation of the gastrointestinal tract that resulted in severe diarrhea are the disease clinical manifestation.10 Viremia may develop within 2–3 days and via blood, it spreads to other organs and tissues like the spleen, lungs, bone marrow, and mucosa of the gastrointestinal tract.11 Morbidity and case fatality rates vary depending on factors such as immune status, age, species, and the presence of other co-infections. The disease can cause mortality rates as high as 90–100% in naive sheep and goat populations. In clean flocks, sheep and goats of all ages can be affected during an outbreak.10,11 However, in endemic areas, the most susceptible ages are between 4 and 24 months. The disease has been associated with an increased animal movement for commercial and trade purposes, transhumance and nomadic customs, climatic changes, and extensive farming practices.12 The control of PPR requires an effective mass vaccination of small ruminants, where the virus is endemic and farmers are unable to afford and implement the strict sanitary control measures, including the stamping out policy, required to contain the virus. Mass vaccination campaigns must achieve high levels of herd immunity (70% to 80%) to block the epidemic cycle of the virus.10 With the tools currently available, disease control and subsequent eradication programs for PPR may be feasible options. An understanding of the cultural and socio-economic circumstances of goat and sheep owners and a keen watch on the endemic nature of PPR in neighboring countries will enhance the success of this approach. Coordinated efforts from all stakeholders, combined with proper funding and execution of control programs, will be needed to achieve the goal of PPR-free zones.13 As a result, Ethiopia has developed a strategy for the progressive control of PPR that builds upon the lessons learned from rinderpest eradication.14,15 However, the control campaign based on repeated vaccination of all susceptible small ruminants is not an easy way to implement. Hence, an epidemiologically based targeting of endemic populations and high-risk zones is essential. Among the highly risky zones of Oromia’s Regional State of Ethiopia is North Shewa, where there is no report on epidemiological and socio-economic studies, even though a large number of small ruminants are raised in the smallholder production system. Therefore, there is a need to assess the prevalence of the disease under village conditions to recommend possible prevention and control strategies that enhance poverty alleviation programs in the area. Materials and Methods Study Area Descriptions The study was conducted in two districts (Dera and Girar Jarso) of the North Shewa zone of the Oromia region. The North Shewa has an area of 8990 km2 and accounts for about 2.5% of the total area of Oromia Region. It is located between 9.05°–10.23° N and 37.57°–39.28 E. It is bordered on the south by Oromia special zone surrounding Addis Ababa, on the southwest by West Shewa, on the north by Amhara Region, and the southeast by East Shewa. The total area of the zone is covered by 20.7% Kola (tropical), 42.6% Woyna Dega (Sub-tropical), and 36.7% Dega (temperate) agro-climatic zones, respectively (Figure 1). Temperate climate prevails in areas having elevation ranging from 1750 to 2700 meter above sea level. Crop-livestock production is the major farming practice in the zone.16Figure 1 Map showing the location of the study sites. Dera is the largest district in the North Shewa zone (Oromia region) with 42 administrative PAs. It is situated north of Addis Ababa at 220 km. It is bordered on the south by the Jemma River, which separates it from Hidabu Abote and Wara Jarso districts, the Abay River defines the Western boundary with the East Gojjam zone, on the north and east by South Wollo zone as well as on the southeast by North Shewa of Amhara region. The district falls between 38.66° and 39.28° E and between 8.31° and 10.23° N. The agroecology of the district is mostly characterized by Kola with an altitude ranging from 1500 m to 1860 m. It receives an annual rainfall of 894 mm. Gerar Jarso is located 114 km north of Addis Ababa at 8.54°–10.23° N and 37°.56–39.24° E. The district has 18 PAs including the zonal administrative town Fiche. The total area of the district is 42,763 hectares. Yaya Gulale and Debrelibanos districts border it on the south, on the west by Degem district, on the east by Amhara region (Ensaro district), and share a border with Hidabu Abote district on the north. The maximum altitude of the district is 2542 m, and the minimum is 1080m. The average minimum and maximum rainfall are 793 mm and 1443 mm, respectively. Study Population The study was done on some small ruminants found in Dera and Girar Jarso districts of North Shewa zone, Oromia region. Small ruminants considered for sampling in this study were those animals that were not vaccinated against PPR before. This was to eliminate the chance of being sero-positive due to vaccination. Small ruminants of both sex and greater than six months (0.5 years) old were included in the study. Study Design It was a cross-sectional study design that was conducted. Individual animal bio-data was collected using the appropriate format, and flock-level information was collected using a semi-structured questionnaire. Sample Size Determination The sample size for the study was determined based on the formula described by Abraham et al,17 using a 95% confidence interval at 5% desired absolute precision and considering a conservative prevalence of 50% to have a maximum sample size. \documentclass[12pt]{minimal} \usepackage{wasysym} \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs} \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n} \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $${\rm{n}} = {{{{1.96}^2}p\left( {1 - p} \right)} \over {{d^2}}}$$ \end{document} Where n = required sample size, P = expected prevalence, and d = desired absolute precision. Substituting each value gives n = 384. Given that cluster sampling was employed, the sample size was recalculated to get a closer accuracy to that of simple random sampling by considering the design effect. The design effect was determined using a formula described by Dohoo et al.18 Thus, the design effect = 1+ ρ (m − 1), where ρ is the intra-cluster correlation coefficient and m is the number of small ruminants sampled per cluster. A flock of sheep/goats in one village was considered a cluster. Rho of 0.029 was used, which was obtained from the national survey of PPR in 1999 in Ethiopia.19 The average number of sheep and goats to be sampled from each cluster (m) was estimated to be 26 according to,20 formula. \documentclass[12pt]{minimal} \usepackage{wasysym} \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs} \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n} \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $${\rm{m }} = \sqrt {{\rm{C}}1/{\rm{C}}2{\rm{}} \times \left( {1{\rm{}} - {\rm{\rho }}} \right)/{\rm{\rho }}} $$ \end{document} Where C1 is the cost of sampling a cluster, C2 is the cost of sampling a sheep or a goat within a cluster and ρ is the intra-cluster correlation coefficient (0.029). C1 was estimated to be 20 times more than C2 by considering the distance between the clusters. \documentclass[12pt]{minimal} \usepackage{wasysym} \usepackage[substack]{amsmath} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage[mathscr]{eucal} \usepackage{mathrsfs} \DeclareFontFamily{T1}{linotext}{} \DeclareFontShape{T1}{linotext}{m}{n} {linotext }{} \DeclareSymbolFont{linotext}{T1}{linotext}{m}{n} \DeclareSymbolFontAlphabet{\mathLINOTEXT}{linotext} \begin{document} $${\rm{m }} = \sqrt {20{\rm{C}}2/{\rm{C}}2{\rm{}} \times \left( {1{\rm{}} - 0.029} \right)/0.029}\ {= 26\ {\rm{small\ ruminants\ per\ cluster}}}$$ \end{document} Design effect = 1+0.029(26–1) =1.725 The new sample size (n’) was calculated by multiplying n = 384 by the design effect.21 Hence, n’ = n × Design effect. Therefore, n’ = 384 × 1.725 = 662. The number of clusters/villages to be sampled (25) in the seven kebeles was calculated by dividing the total sample size of small ruminants (662) by the average sample size per cluster (26). Sampling with probabilities proportional to the number of small ruminants in each district was used to determine the number of small ruminants included in the study in each district and Kebele. Similarly, the number of villages and PAs were proportionally allocated per district.20 Sampling Techniques A cluster sampling strategy with probability sampling was used to meet the objectives of this study. Two districts (Dera and Gerar Jarso) from the North Shewa zone of Oromia were purposively selected from thirteen districts. Information on the general distribution of small ruminants was taken from the respective district livestock and fishery development offices. Further sampling was done according to the local administrative partition (Kebele, village, household) of the district. A total of seven Kebeles were selected randomly from Dera (4 Kebeles) and Gerar Jarso (3 Kebeles). Villages (25); 19 villages from Dera and 6 villages from Gerar Jarso were randomly selected. Averagely, nine households per village were designated using a systematic random sampling method. In this sampling technique, the total number of households found in a village (N = 27) was divided by the desired sample size (n = 9) to get the sampling interval (k=27/9). Thus, the households were sampled at every 3rd after randomly selecting the starting point of selection. Individual small ruminants were randomly selected (in average three animals per household). Villages were considered as a single-level cluster of small ruminants (epidemiological unit) concerning disease risk, because the residents of the village are living very close to each other and had common watering and browsing/grazing lands. The number of small ruminants sampled from each district and Kebeles was proportional to the sheep and goats population in the district and Kebele. Accordingly, 463/163,529 and 199/70,314 small ruminants per district were sampled from Dera and Gerar Jarso, respectively. A total of 25 clusters/villages (considered as flocks of sheep and/or goats) were sampled from both districts. Thus, districts, Kebeles, species, flock size (small; 26–45 and large; >45), sex, age group, grazing and watering management, housing system, new animal introduction (mixing of the newly bought or brought animal to the flock) and mixed species rearing (rearing of sheep and goats together) were recorded being hypothesized as risk factors. Three local agroecological classifications (highland, midland, and lowland with an altitude range of >2300–3700, >1500–2300, and 500–1500 meters, respectively) were also included. Age was classified as young (>0.5–2 years) and adult (>2 years) and determined using dentition. Laboratory Protocols Sample Collection, Transportation, and Storage Before collection of a sample, the small ruminant from which the sample was going to be taken was identified for vaccination history, and animals were handled in humane manner during sample collection to ensure the ethical treatment of animals and obtain accurate results, and to promote animal welfare, scientific integrity, and ethical conduct in research. We have used appropriate restraining techniques, providing a calm and quiet environment, and minimizing the duration of the procedure to minimize the stress and discomfort experienced by animals during the sample collection process. We confirm that the animals were treated with best practice of veterinary care. Then, blood samples for serological analysis were aseptically collected. Accordingly, the jugular vein area was disinfected using alcohol and about 2mL blood was collected from the vein using a venoject needle and plain vacutainer tube. Then, the collected blood samples were labeled with the date of collection, specific identification number, age, sex, agroecology, and species of the animals. In Selale University’s laboratory, the blood samples were allowed to stand in a slant position for 24 hours at room temperature. After 24 hours, the serum was harvested using clean sterile test tubes and centrifuged at 1500 rpm for 10 minutes to remove the remaining red blood cells. The serum was transferred into a sterile cryovials tube bearing the identification number, transported to the National Animal Health Diagnostic and Investigation Center (NAHDIC), Sebeta, Ethiopia, for laboratory analysis, and then stored at −20◦C until analyzed. Serological Examination All the 662 serum samples were analyzed in NAHDIC using the nucleoprotein-based competitive ELISA platform, ID Screen® PPR Competition (IDvet Innovative Diagnostics, Montpellier, France) according to the manufacturer’s OIE reference lab recommended technique. The kit micro-plates were coated with PPRV recombinant nucleoprotein. The reagents were allowed to come to room temperature (21 ± 5°C) before use and homogenized by the vortex. First, 25µL of dilution buffer 13 was added to all wells. Next, 25µL of the positive control was distributed to wells A1 and B1, and 25µL of the negative control was added to wells C1 and D1. Then, 25µL of each serum to be tested was added to the rest wells and incubated for 45 ± 4 minutes at 37± 3°C using a micro-plate incubator shaker (AQS manufacturing, LTD, UK). Each well was washed three rounds, using 300 µL of prepared wash solution. Next, 100µL of the conjugate 1× diluted in dilution buffer 4 was added to each well. After incubating for 30 ± 3 minutes at 21± 5°C, each well was washed three rounds with 300µL of the wash solution. Then, 100µL of the substrate solution was added to each well and incubated for 15 ± 2 minutes at 21± 5°C in the dark. Finally, 100µL of H2SO4 (stop solution) was added to all wells; the OD was read at 450 nanometers using the ELISA reader (Highland Park, USA). The cut-off points were calculated as competition percentages from the OD values using the following formula.22 Competition percentage = (OD Sample)/(OD Negative Control) x 100 If the percentage of competition (S/N %) was less or equal to 50% the sample was taken as positive, samples presenting the S/N% greater than 60% were negative and those showing S/N% between the negative and positive values were said to be uncertain (50%< S/N% ≤60%). Questionnaire Survey Verbal consent was obtained from the interviewees (respondents) who were willing to give information. Interviews were performed in Afan Oromo and Amharic. At the start of our research, we attempted to obtain an ethical approval letter from the office responsible for such tasks. Unfortunately, the director in charge of providing the letter had passed away from Covid-19, and as a result, all the staff members were forced to isolate themselves. The office was closed for more than two months, causing possible delays in our research. Therefore, to avoid any further delays, we decided to acquire the ethical approval letter from the district where the research was being carried out. Verbal consensus was taken after being approved from Dera district Fishery and livestock development office Ethics Committee coordinator Mr Usman Yasin Ahmed. Verbal consensus was taken because 95% of the farmer in Ethiopia neither read nor write the local language and as a result consent was taken to ensure that farmers who cannot read and write are able to access and understand key information, receive the same level of support as their literate counterparts, and be active participants in decision-making processes. We preferred verbal consent because it is important to be able to conduct interviews quickly and efficiently. Additionally, taking verbal consent provides a platform for these farmers to express their opinions while expanding their knowledge base through education. The objective of the survey was also explained to them. The survey was conducted by administering the semi-structured questionnaires to 225 household representatives (143 males and 82 females) for identifying risk factors. The contents of the questionnaire were mainly focused to collect information about age, vaccination history, housing system, grazing and watering management, animal marketing, movement of animals, raising system, and flock size. Interviewing and sampling were done in collaboration with the two district veterinary offices; the veterinary assistant and Asella regional laboratory field workers were present at all sampling sites. Data Analysis Data obtained from the questionnaire and laboratory results were recorded, coded, and stored in a Microsoft Excel sheet. Microsoft Excel sheet format of the animal and flock level data was transferred to IBM SPSS version 25. Descriptive statistics were used to summarize the data and analytical statistics were used as appropriate. The units of analysis were individual sheep and goats, and flocks. Animal-level seroprevalence was calculated for all categories of assumed risk factors as the number of PPR-infected individuals divided by the number of individuals sampled and for flock-level sero-prevalence, the number of positive flocks for at least one sheep/goat divided by the total number of flocks tested. Univariable analysis was performed and factors with p-value <0.25 were taken forward for multivariable analysis to correct for confounding effects. Associations between PPR sero-positivity and risk factors for all units of analysis were investigated by using multivariable logistic regression. The strength of the association between PPR seropositivity and the potential risk factors (explanatory variables) was assessed using the adjusted odds ratios (AOR). For all analyses, the confidence level is at 95%, and P ≤ 0.05 was set for significance. The collinearity of the variables was analyzed using Spearman-correlation coefficient. Interaction between the factors taken to multivariable analysis was tested and turned with no interaction. Results In this study, 662 small ruminants (319 sheep and 343 goats) were sampled; among which 68 of them were sero-positive. An overall sero-prevalence of 10.3% (95% CI = 8.2–12.8) was estimated (Table 1). A flock with at least one positive animal was considered a positive flock for PPR; 100% (95% CI = 94–100) flock-level sero-prevalence was found.Table 1 Univariable Logistic Regression Analysis of Individual Animal-Level Sero-Prevalence and Possible Risk Factors Variables Category Sample Examined Positive Sample Prevalence in % (95% CI) COR (95% CI) P-value District Gerar Jarso(Ref) 199 16 8 (5–12.7) Dera 463 52 11.2 (8.7–14.4) 1.45 (0.81–2.60) 0.217 Kebele Keru Suba(Ref) 167 15 9 (5.5–14.3) Menkata Wariyo 138 11 8 (4.5–13.7) 0.88 (0.39–1.98) 0.753 Gebro 81 13 16 (9.6–25.6) 1.94 (0.87–4.29) 0.103 Amoma Gendo 77 13 17 (10–26.8) 2.06 (0.93–4.57) 0.076 Gerar Geber 84 5 6 (2.6–13.2) 0.64 (0.23–1.83) 0.406 Torban Ashe 45 4 9 (3.5–20.7) 0.99 (0.31–3.14) 0.985 Wedesa Amba 70 7 10 (5–19.2) 1.13 (0.44–2.89) 0.805 Agro-eclogy High-land (Ref) 251 20 8 (5.2–12) Mid-land 183 15 8.2 (5–13.1) 1.03 (0.51–2.07) 0.931 Low-land 228 33 14.5 (10.5–19.6) 1.96 (1.09–3.52) 0.025 Species Ovine(Ref) 319 16 5 (3.1–8) Caprine 343 52 15.2 (11.8–19.3) 3.38 (1.89–6.06) 0.000 Flock size Small (26–45) (Ref) 361 24 6.6(4.5–9.7) Large (>45) 301 44 14.6(11–19) 2.4(1.4–4.1) 0.001 Sex Male (Ref) 197 9 4.6 (2.4–8.5) Female 465 59 12.7 (10–16) 3.04 (1.47–6.25) 0.003 Age >0.5–2(Ref) 345 24 7 (4.7–10) >2 317 44 14 (10.5–18) 2.16 (1.28–3.64) 0.004 New animal introduction No(Ref) 554 41 7.4 (5.5–10) Yes 108 27 25 (17.8–34) 4.17 (2.43–7.15) 0.000 Housing system Fenced Stable (Ref) 37 2 5.4 (1.5–17.7) House Barn 625 66 10.6 (8.4–13.2) 2.07 (0.49–8.79) 0.326 Grazing and watering Management Private(Ref) 77 1 1.3 (0.2–7) Communal 585 67 11.5 (9.1–14.3) 9.98 (1.37–72.93) 0.023 Raising Together No (Ref) 167 3 1.8 (0.6–5.2) Yes 495 65 13.1 (10.4–16.4) 8.26 (2.56–26.66) 0.000 Overall 662 68 10.3 (8.2–12.8) Abbreviations: Ref, reference; COR, crude odds ratio; CI, confidence interval. Risk Factors for Individual Sero-Positivity of Small Ruminants Among sampled sheep (n = 319), 70.2% were females (n = 224) and 29.8% were males (n = 95). Similarly, 70.3% female (n = 241) and 29.7% male (n = 102) goats were sampled. The age distribution (including both sheep and goats) was 52% more than six months to two years of age (>0.5–2) (n = 345) and 48% more than two years old (>2) (n = 317). Based on this study result, the highest district-based sero-prevalence was found in Dera (11.2%; P = 0.217) compared to the Gerar Jarso district 8%. At the Kebele level, the highest sero-prevalence was recorded in Amoma Gendo (17%; P = 0.076) and the lowest was in Gerar Geber (6%). The higher (15.2%; P = 0.000) and the lower (5%) sero-positivity were detected in goats and sheep, respectively. The disease was more prevalent in females (12.7%; P = 0.003) than in males (4.6%). Sheep and goats greater than two years old showed a higher prevalence of PPR (14%; COR = 2.16) than those more than six months to two years old (7%). In newly introduced animals 25% (P = 0.000) sero-prevalence was estimated and 7.4% was recorded in permanently stayed small ruminants. Small ruminants sampled from communal grazing and watering system were in higher prevalence of the PPR antibody (11.5%; COR = 9.98) than those found in private (1.3%). The study also showed that larger flock sizes had higher sero-positivity (14.6%; P = 0.001) than the smaller flock sizes (6.6%) (Table 1). The univariable logistic regression analysis on individual animal-level risk factors showed that the district (P = 0.217), species (P = 0.000), sex (P = 0.003), age (P = 0.004), new animal introduction (P = 0.000), grazing and watering management (P = 0.023), and raising the two species together (P = 0.000) had a statistically significant effect on sero-prevalence of PPR (P < 0.05). Accordingly, they were selected for the final model (Table 2).Table 2 Multivariable Logistic Regression Analysis in Animal-Based Sero-Prevalence of PPR in Association with Potential Risk Factors Factors Sample Examined Positive Sample Prevalence in % (95% CI) AOR (95% CI) P-value Species  Caprine 343 52 15.2 (11.8–19.3) 4.0 (2.1–7.4) 0.000  Ovine (Ref) 319 16 5 (3.1–8) Flock size  Large (>45) 301 44 14.6 (11–19) 2.0 (1.1–3.6) 0.019  Small (26–45) (Ref) 361 24 6.6 (4.5–9.7) Sex  Female 465 59 12.7 (10–16) 3.2 (1.5–6.8) 0.003  Male (Ref) 197 9 4.6 (2.4–8.5) Age  >2 317 44 14 (10.5–18) 2.7 (1.5–4.9) 0.001  >0.5–2 (Ref) 345 24 7 (4.7–10) New animal introduction  Yes 108 27 25 (17.8–34) 4.4 (2.4–8.1) 0.000  No (Ref) 554 41 7.4 (5.5–10) Grazing and watering management  Communal 585 67 11.5 (9.1–14.3) 11 (1.4–89) 0.024  Private (Ref) 77 1 1.3 (0.2–7) Reared Together  Yes 495 65 13.1 (10.4–16.4) 9.4 (2.8–31.7) 0.000  No (Ref) 167 3 1.8 (0.6–5.2) Overall 662 68 10.3 (8.2–12.8) Abbreviations: Ref, reference; AOR, adjusted odds ratio; CI, confidence interval. In the final model analysis result, the factor species (P = 0.000), flock size (P = 0.019), sex (P = 0.003), age (P = 0.001), new animal introduction (P = 0.000), grazing and watering management (P = 0.024), and rearing of the two species together (P = 0.000) were shown as statistically significantly (P < 0.05) associated with the sero-prevalence of PPR. Goats were 4 times (OR = 4.0) more likely sero-positive to PPR antibody compared to sheep. The larger flock sizes had the odds of 2 times being sero-positive than the smaller flock size (Table 2). As shown in Table 2, female sheep and goats were more likely to be sero-positive to PPR by 3 times (OR = 3.2) than males. Small ruminants with an age of greater than two years had almost 3 times more odds (OR = 2.7) of sero-positivity for the disease than those aged greater than six months to two years. The newly introduced small ruminants were statistically, strongly significant with p-value=0.00 and had the odds of 4-times (OR = 4.4) sero-positivity than animals being born at home. As illustrated in Table 2, sheep and goats kept under communal grazing and watering system were nearly 12 times (OR = 11.5) more likely sero-positive than privately managed small ruminants. Small ruminants reared together were almost 9 times (OR = 9.4) at a higher chance of being seropositive compared with separately reared small ruminants (Table 2). Associated Risk Factors for Sheep and Goat Sero-Positivity In the separate univariable logistic regression analysis of sheep and goat data, the possible risk factors for PPR sero-positivity were identified. The new animal introduction was the only risk factor that had strong statistical association (P = 0.000) for being sero-positive in sheep (Table 3). While in goats, flock size (P = 0.001), sex (P = 0.003), age (P = 0.001), new animal introduction (P = 0.000), and rearing of goat and sheep together (P = 0.003) were found to be the significant risk factors (Table 4).Table 3 Variables Associated with the Sero-Positivity in Univariable Models of Sheep Data Variables Category Sample Examined Positive Sample Prevalence in % (95% CI) COR (95% CI) P-value Flock size Small (26–45) (Ref) 178 8 4.5 (2.3–8.6) Large (>45) 141 8 5.7 (2.9–10.8) 1.3 (0.5–3.5) 0.632 Sex Male (Ref) 95 3 3.1 (1.1–8.9) Female 224 13 5.8 (3.4–9.7) 1.9 (0.5–6.8) 0.330 Age >0.5–2(Ref) 161 8 5 (2.5–9.5) >2 158 8 5.1 (2.6–9.7) 1 (0.4–2.8) 0.969 New animal introduction No (Ref) 269 7 2.6 (1.3–5.3) Yes 50 9 18 (9.8–30.8) 8.2 (2.9–23.3 0.000 Housing system Fenced Stable (Ref) 24 0 0 (0–13.8) House Barn 295 16 5.4 (3.4–8.6) 1 (-) 0.998 Grazing and watering Management Private(Ref) 41 1 2.4 (0.4–12.6) Communal 278 15 5.4 (3.3–8.7) 2.3 (0.3–17.8) 0.431 Raising Together No (Ref) 83 0 0 (0–4.4) Yes 236 16 6.8 (4.2–10.7) 1 (-) 0.997 Overall 319 16 5 (3.1–8) Abbreviations: Ref, reference; COR, crude odds ratio; CI, confidence interval. Table 4 Variables Associated with the Sero-Positivity in Univariable Models of Goat Data Variables Category Sample Examined Positive Sample Prevalence % (95% CI) COR (95% CI) P-value Flock size Small (26–45) (Ref) 183 16 8.7 (5.5–13.7) Large (>45) 160 36 22.5 (16.7–29.6) 3 (1.6–5.7) 0.001 Sex Male (Ref) 102 6 5.9 (2.7–12.2) Female 241 46 19.1 (14.6–24.5) 3.8 (1.6–9.2) 0.003 Age >0.5–2(Ref) 184 16 8.7 (5.4–13.7) >2 159 36 22.6 (16.8–29.8) 3.1 (1.6–5.8) 0.001 New animal introduction No (Ref) 285 34 11.9 (8.7–16.2) Yes 58 18 31 (20.6–43.8) 3.3 (1.7–6.4) 0.000 Housing system House Barn (Ref) 330 50 15.2 (11.7–19.4) Fenced Stable 13 2 15.4 (4.3–42.2) 1 (0.2–4.7) 0.998 Grazing and watering Management Private (Ref) 37 0 0 (0–9.4) Communal 306 52 17 (13.2–21.6) 1 (-) 0.998 Rearing Together No (Ref) 84 3 3.6 (1.2–10) Yes 259 49 18.9 (14.6–24) 6.3 (1.9–20.80) 0.003 Overall 343 52 15.2 (11.8–19.3) Abbreviations: Ref, reference; COR, crude odds ratio; CI, confidence interval. In the final model analysis result (Table 5), flock size (P = 0.012), sex (P = 0.007), age (P = 0.000), new animal introduction (P = 0.001), and rearing the two species together (P=0.002) were the potential risk factors for the sero-positivity of goats. Hence, goats that had a large flock size were 2 times (OR = 2.4) more likely to be sero-positive for PPR antibody than the smaller flock size. Female goats had nearly 4 times (OR = 3.6) odds of being sero-positive compared to males. Goats, aged greater than two years, were almost 4 times (OR = 3.7) at a higher chance to have PPR antibodies than those aged between greater than six months and two years. Newly introduced goats were in the odds of almost 4 times (OR = 3.6) compared to those born in the flock. Goats reared with sheep were 7 times (OR = 7.1) more seropositive than those raised separately (Table 5).Table 5 Multivariable Logistic Regression of Potential Risk Factors Associated with Sero-Prevalence of Goats Factors Sample Examined Positive Sample Prevalence in % (95% CI) AOR (95% CI) P-value Flock size  Large (>45) 160 36 22.5 (16.7–29.6) 2.4 (1.2–4.8) 0.012  Small (26–45) (Ref) 183 16 8.7 (5.5–13.7) Sex  Female 241 46 19.1 (14.6–24.5) 3.6 (1.4–9) 0.007  Male (Ref) 102 6 5.9 (2.7–12.2) Age  >2 159 36 22.6 (16.8–29.8) 3.7 (1.8–7.5) 0.000  >0.5–2(Ref) 184 16 8.7 (5.4–13.7) New animal introduction  Yes 58 18 31 (20.6–43.8) 3.6 (1.7–7.7) 0.001  No (Ref) 285 34 11.9 (8.7–16.2) Raising Together  Yes 259 49 18.9 (14.6–24) 7.1 (2–24.9) 0.002  No (Ref) 84 3 3.6 (1.2–10) Abbreviations: Ref, reference; AOR, adjusted odds ratio; CI, confidence interval. Discussions In this study, the overall individual animal-based sero-prevalence of peste des petits ruminants was 10.3%. This finding is comparable with the result of 6.8% by Abraham et al,17 from Afar and Borena, 8% by Waret-Szkuta et al,19 in Benishangul, 7.93% and 13.62% by Fentie et al,22 in East Gojjam and North Gondar, respectively. It is also slightly in agreement with Wegayehu et al,16 who reported 5.71% from Horo Guduru Zone, Oromia region. This finding was higher than the result of Waret-Szkuta et al,19 who reported 1.7%, 4.6%, and 1.8%, from Oromia, Amhara, and Southern Nations Nationalities and Peoples Region, respectively. It is also higher than the result reported by 2.1% by Gebre et al,23 from Bench Maji and Kefa Zones, SNNPR. However, it is lower than Delil et al24 who documented 36.6% from Awash Fentale, OIE4 who reported 27.3% and 38.3% from Itang (Gambella) and Adar (Afar), respectively, Afera et al25 who reported 47.5% from Tigray, and Gari et al26 who reported 48.43% in East Shewa and Arsi areas. This variation might be due to the geographical location and climatic differences between the localities, variation in the production system, and proportion of sample size.7,8,15,19 Species-specific prevalence was determined in this study. Goats were observed to have significantly (P < 0.005) greater sero-prevalence (15.2%) than sheep (5%). This finding was in agreement with Fentie et al,22 who documented higher sero-positivity in goats than sheep (21.57% in goats and 14.89% in sheep). Other findings as Abubakar et al and Waret-Szkuta et al7,19 (49.5% in sheep and 56.3% in goats) and Delil et al24 (7.3% sheep and 42.6% goats) were reported a higher sero-prevalence of PPR in goats than sheep. On contrary, the findings of Abraham et al17 from Afar and Borena, Saeed et al27 from Sudan, Abdalla et al28 from the Kordofan state of Sudan, and Gelana et al14 from Horo Guduru zone of Ethiopia documented higher seroprevalence in sheep than goats. The difference in prevalence might be due to the difference in the proportion of sampled animals, management system, and geospatial location of the study areas. An outbreak with high mortality in sheep was also reported that sheep possessed an innate resistance to the clinical effects of the disease, but occasional field strains could overcome this resistance and produce high mortality.25,26,29,30 Goats are affected more severely by PPR virus exposure compared to sheep, and they exhibit easily noticed clinical signs while sheep undergo a mild form of the disease as documented by Delil et al, Libeau et al and Farougou et al.24,31,32 The multivariable logistic regression analysis result showed that females were more likely to be sero-positive than males. It was also indicated that females (12.7%) had significantly higher sero-positivity than the male counterparts (4.6%). This observation agrees with the result of OIE, Gebre et al, Wondimagegn and Libeau et al.4,23,29,31 This might be due to sampling size variation and the physiological differences where females reveal some degree of predominance infection because of production and reproduction-related stresses. This could be also due to male small ruminants are not stayed long in the flock (sold or slaughtered) while the females remain for breeding.4,16,17,19,25 This result reflection disagrees with the findings of Alemu et al33 from East Amhara Region and Swai et al34 from Tanzania who stated that males had higher seroprevalence than female small ruminants. In considering the two species’ sex, female goats had more sero-prevalence (19.1%) than female sheep (5.8%) as described in Table 5 and Table 4, respectively. This finding is in line with OIE and Libeau et al,4,31 who reported a higher PPR antibody sero-prevalence in female goats compared with female sheep. A similar comparison was observed in male goats, which recorded, a slightly higher sero-prevalence (5.9%) compared with male sheep (3.1%). This could also be due to the fact that male small ruminants usually not allowed to stay long in the flock. This increased PPR prevalence in goats in both sexes might be the difference in the proportion of sampling and variation in recovery rate on sheep and goats. Sheep’s recovery is usually higher than goats’.26 From the multivariable logistic regression, the chance of being sero-positive was higher in the age group >2 years (adults). The adult small ruminants had higher sero-prevalence (14%) than the younger age group (7%). The reports of Abubakar et al, Waret-Szkuta et al, Abdalla et al, Wondimagegn and Alemu et al7,19,28,29,33 documented high prevalence in adults, which agreed with this result. In contrast, Farougou et al32 from Niger and Afera et al25 reported high sero-prevalence in young (>0.5–2) small ruminants. Libeau et al31 reported that the natural infection of the PPR virus at a very young age might have the probability to carry antibodies for 1–2 years following exposure and remains positive for a long time. In this research, we also found that communal grazing and watering systems were significantly associated with the transmission of PPR virus infection among sheep and goats than private grazing management. In agreement with this result, Abubakar et al7 from Pakistan documented that continued year-round circulation of the virus was enhanced by frequent animal-to-animal contact on the grazing pasture. Wegayehu et al16 also indicated communal sharing of grazing land probably increases small ruminant vulnerability to infection. Even though the aerosol route is the main transmission way for PPRV, oral transmission is possible by contact with secretions or excretions (saliva, feces, urine, and vaginal, nasal or ocular discharges) of infected animals from the communal pasture.15,17,22 The introduction of new small ruminants appears to be a risk factor for seropositive status, in the multivariable logistic regression analysis. Bello et al35 from Nigeria, Clarke et al9 from Bangladesh, and De Nardi et al36 from Algeria stated that the introduction of new animals purchased from the live animal market was a means of disease transmission. Wondimagegn and Alemu et al29,33 also reported that newly introduced small ruminants were in a higher chance of being sero-positive than the home-born ones. This might be due to the absence of practicing isolation and quarantine of newly bought animals before mixing into the flock.23 In contrast to this result, Saeed et al27 reported that newly introduced animals had lower sero-positivity in Sudan. The result of multivariable logistic regression showed that flock size was statistically significant (P = 0.019). The large flock size had the odds of 2 times being sero-positive. This finding is in agreement with the works of OIE, Gelana et al, Gebre et al and Gari et al4,14,23,26 while the report of Saeed et al27 stands in contrast to this result. The overcrowding or the stocking density of small ruminants might have increased the spread of the virus due to direct contact with the animals.15 Dera district had slightly higher seroprevalence (11.2%) than Gerar Jarso (8%) district. The seroprevalence result variation between the districts might be due to the contagious nature of the disease in wide geographic areas and infecting perhaps most of the susceptible animals in affected villages.8,29,33 The sample size difference, geographical and seasonal effects, host population density, disease control programs, and the social environment that can influence the contact rates and husbandry practices may explain the differences with other areas.4,25,28,31 In the agro-ecology-based sero-prevalence, lowland areas were statistically significant (P = 0.025) and had the highest sero-prevalence. The finding of this study agrees with the report of Waret-Szkuta et al, Fentie et al, Afera et al and Abdalla et al.19,22,25,28 The documents29,33 reported higher seroprevalence of PPR in lowland areas of Somali and Eastern Amhara region, respectively. This might be due to different production systems with exchanges and movements in areas of lowland being more frequent and involving larger numbers of animals. Abdalla et al28 from Sudan and Bello et al35 from Nigeria documented that lowland agroecology was the risk factor for PPR sero-positivity. In Ethiopia, small ruminants mainly thrive on free-range grazing lands, shrubs, and forest grounds. Agro-climatic conditions influence the availability of these resources and the movement of animals becomes necessary to ensure the provision of fodder and water. This is particularly important during the dry season and in low-altitude areas where resources are scarce. However, in the report of Wegayehu et al,16 the highest PPR prevalence was found in the midland agro-ecology from Horo Guduru Zone, Western Ethiopia. Conclusion and Recommendations The present study confirmed the presence of PPR antibodies in sheep and goats in our study areas (Dera and Gerar Jarso districts). The fact that antibodies of PPR virus were detected in studied Kebeles and districts suggests, the infection has been circulating/endemic. The disease was found to be more prevalent in Dera than Gerar Jarso district. This study has indicated that sero-prevalence of PPRV in goats was higher than that of sheep. Flock size, species sex, age, the introduction of a new animal to the flock, utilization of communal grazing and watering system, and mixed species rearing were found to be the higher disease predictors or risk factors for the occurrence and distribution of PPR infection. Based on the concluding remarks, the following recommendations are forwarded: Mass vaccination programs should be mandatory. Further studies are needed, to establish the disease situation in other animals in the study area. Disclosure The authors report no conflicts of interest in this work. ==== Refs References 1. CSA (Central Statistical Authority). 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==== Front 101316957 35616 Stem Cell Res Stem Cell Res Stem cell research 1873-5061 1876-7753 36965406 10.1016/j.scr.2023.103078 nihpa1906527 Article Generation of two induced pluripotent stem cell lines with heterozygous and homozygous amyotrophic lateral sclerosis-causing mutation R521G (c.1561C > G) in FUS gene http://orcid.org/0000-0002-7111-5222 Akter Masuma Cui Haochen Hosain Abir Md http://orcid.org/0000-0002-2149-2599 Ding Baojin * Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences, Center at Shreveport, Shreveport, LA 71130-3932, USA * Corresponding author. Baojin.Ding@lsuhs.edu (B. Ding). 29 6 2023 6 2023 21 3 2023 18 7 2023 69 103078103078 https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Mutations in the RNA-binding protein FUS (fused in sarcoma) are linked to amyotrophic lateral sclerosis (ALS), but the pathogenesis is not fully understood. For modeling ALS, here we generated two induced pluripotent stem cell (iPSC) lines carrying the heterozygous and homozygous R521G (c.1561C > G) mutation in the FUS gene via genetic modification of a healthy hiPSC line (WTC11, UCSFi001-A). Both lines show normal stem cell morphology and karyotype, express pluripotent markers, and can differentiate into three germ layers, providing a valuable resource in determining the pathological mechanisms underlying the FUS mutation of R521G in ALS. ==== Body pmc1. Resource utility The R521G mutation in the FUS gene is associated with familial ALS, a neurodegenerative disorder without cure so far. Generation of human neurons from iPSCs containing ALS-causing mutations will overcome the limited access to patient neurons and provide an unprecedented approach in disease modeling and novel therapeutic development. 2. Resource details Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons and typically leads to death within 3–5 years from diagnosis. Mutations in the FUS gene, such as R521G (c.1561C > G) are implicated in familial ALS. The mutated FUS protein shows abnormal accumulation and aggregation in the cytoplasm of affected neurons and may disrupt a variety of biological processes such as RNA metabolism, nucleocytoplasmic transport, and cytoskeleton dynamics etc. (Szewczyk et al., 2023). However, the molecular mechanism underlying FUS mutations in ALS is not fully understood. Generation of human motor neurons from hiPSCs carrying disease-causing mutations has emerged as one critical approach in modeling movement disorders and for developing novel therapeutic interventions (Akter and Ding, 2022; Sepehrimanesh and Ding, 2020). In this study, we generated two iPSC clones carrying the heterozygous (LSUHSi004-A-72) and homozygous (LSUHSi004-A-73) mutation c.1561C > G (p.R521G) in the FUS gene via genetic modification of a well-characterized healthy hiPSC line (WTC11, UCSFi001-A) with CRISPR/Cas9 method. Both lines showed a typical pluripotent stem cell morphology with a high nucleus/cytoplasm ratio (Fig. 1A). Sanger DNA sequencing of polymerase chain reaction (PCR) products (Fig. 1B) and deep sequencing analysis (Supp. Fig. S1A) confirmed that these iPSC lines contain heterozygous (LSUHSi004-A-72) and homozygous (LSUHSi004-A-73) c.1561C > G (p.R521G) mutation in the FUS gene. Chromosomes from 20 metaphase cells of each clone were harvested and analyzed using the GTW banding method, and all cells are characteristic of a chromosomally normal male karyotype, 46, XY (Fig. 1C). Short tandem repeat (STR) analysis at 18 loci indicated that LSUHSi004-A-72 and LSUHSi004-A-73 clones completely matched the parental hiPSC line (UCSFi001-A) identity (Supp. Fig. S1B). Immunocytochemistry analysis indicated that these iPSCs highly expressed pluripotency markers of OCT4, NANOG, SOX2, and SSEA4 (Fig. 1D). Quantitative RT-PCR analysis demonstrated that the pluripotency markers of OCT4, SOX2, NANOG, and KLF4 were expressed at similar levels as their parental line (UCSFi001A) (Fig. 1E). Following spontaneous differentiation, embryoid bodies (EBs) (Fig. 1F) derived from LSUHSi004-A-72 and LSUHSi004-A-73 displayed dramatic upregulation of markers of the ectoderm (PAX6, OTX1), mesoderm (DCN, IGF2, GATA2) and endoderm (SOX7, SOX17) lineages. The expression levels of these trilineage markers were consistent with their parental line UCSFi001A (Fig. 1G). Mycoplasma test using MycoAlter PLUS kit verified that LSUHSi004-A-72 and LSUHSi004-A-73 were negative for mycoplasma (Fig. S1C). 3. Materials and methods 3.1. Generate and culture of iPSCs Human FUS R521G mutant clones were generated from a healthy hiPSC line by Genome Engineering and iPSC Center (GEiC) at Washington University in St. Louis. Briefly, approximately 1 × 106 single cells were resuspended in P3 primary buffer (Lonza) with gRNA/Cas9 ribo-nuclease protein (RNP) complex (200 pmol synthetic gRNA and 80 pmol SpCas9 protein) and hFUS mutant ssODN (Table 2). Subsequently, cells were electroporated with a 4DNucleofector (Lonza) using CA-137 program. Following nucleofection, the editing efficiency was confirmed by targeted deep sequencing using primer sets specific to target regions and then the pool was single-cell sorted. Single-cell clones were screened with targeted deep sequencing analysis. All iPSCs were cultured with mTeSR Plus (STEMCELL Technology) on Matrigel-coated plates at 37 °C in a humidified, 5% CO2 incubator and passage at a 1:6 ratio using gentle cell dissociation reagent (Versene, Gibco). 3.2. Embryoid bodies (EB) formation Cultured hiPSCs were dissociated with Versene and transferred to low attachment 10-cm petri dishes in KOSR medium (DMEM/F12 medium containing 20% KnockOut Serum Replacement, 1% GlutaMax, 1% non-essential amino acids, 50 μM β-mercaptoethanol and 1% penicillin-streptomycin) supplemented with 10 μM Y-27632. The medium was changed every other day and EBs gradually formed. After 7 days of suspension culture, EBs were digested with 0.25% Trypsin and cultured on gelatin-coated plates with KOSR medium for another 7 days. The total RNAs were extracted for RT-PCR analysis. 3.3. Immunostaining and confocal microscopy Briefly, Cultured iPSCs (P5) were fixed with 4% paraformaldehyde (PFA) in PBS for 15 min at room temperature and incubated in blocking buffer (3% bovine serum albumin in PBS) with (for nuclear markers) or without (for a cell surface marker SSEA4) 0.2% Triton X-100 for 1 h. Cells were then incubated with primary antibodies (Table 2) in blocking buffer at 4 °C overnight, followed by washing and incubating with fluorophore-conjugated corresponding secondary antibodies at room temperature for 2 hrs. Nuclei were stained with Hoechst 33,342 (ThermoFisher Scientific). Images were obtained with a Leica SP5 confocal microscope. 3.4. Quantitative PCR analysis As previously described (Akter et al., 2021; 2022), iPSCs (P5) and EBs were collected from cultured plates and lysed in TRIzol (Invitrogen). A phenol/chloroform extraction method was used to isolate total RNAs and then perform reverse-transcription to synthesize cDNAs with the Superscript™ III Reverse Transcriptase (Invitrogen). SYBR Green PCR Master Mix (Applied Biosystems) was employed to perform quantitative PCR analysis using the StepOne qPCR machine (Applied Biosystems). The gene expression data were analyzed using the ΔΔCT method and the values were shown as the relative expression level to the housekeeping gene GAPDH. Primers used in this study were listed in Table 2. 3.5. Karyotyping Chromosomes from iPSC clones were analyzed using the GTW banding method at GEiC at Washington University in St. Louis. 3.6. STR analysis Short tandem repeat (STR) analysis of 18 loci (Fig. S1B) were performed at GEiC at Washington University in St. Louis. 3.7. Mycoplasma test Mycoplasma test was performed at GEiC Washington University in St. Louis using MycoAlert PLUS Mycoplasma Detection Kit. Supplementary Material Supp.Figure 1 Acknowledgment We thank Genome Engineering & iPSC Center (GEiC) at Washington University in St. Louis for their excellent services, and members of the Ding laboratory for help and discussion. Funding This work was supported by National Institute of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) (NS112910 to B.D.), Department of Defense (DoD) Peer Reviewed Medical Research Program (PRMRP) Discovery Award (W81XWH2010186 to B.D.), and LSU Health Shreveport Center for Brain Health (CBH) Grant in Aid (Spring 2022 to B.D.). Fig. 1. Characterization of LSUHSi004-A-72 and LSUHSi004-A-73 iPSC lines. Resource Table Unique stem cell lines identifier LSUHSi004-A-72 LSUHSi004-A-73 Alternative names of stem cell lines FUS-R521G HET 2B10 FUS-R521G HOM 1D9 Institution Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA USA Contact information of the reported cell line distributor Baojin Ding (baojin.ding@lsuhs.edu) Type of cell lines iPSC Origin Human Additional origin info (Applicable for human ESC or iPSC) Age: 30YR Sex: Male Ethnicity: Asian Cell Source Skin fibroblasts. Method of reprogramming N/A Clonality Clonal Evidence of the reprogramming transgene loss (including genomic copy if applicable) RT/q-PCR Cell culture system used Serum-free and feeder-free medium Type of Genetic Modification Induced mutation Associated disease Amyotrophic Lateral Sclerosis Gene/locus FUS c.1561C > G (p. R521G)/Chromosome 16p11.2 Method of modification/user-customisable nuclease (UCN) used, the resource used for design optimisation CRISPR/Cas9 User-customisable nuclease (UCN) delivery method Electroporated with a 4D-Nucleofector (Lonza) using CA-137 program. All double-stranded DNA genetic material molecules introduced into the cell gRNA vector MLM3636 (Addgene #43860) Cas9 vector p3s-Cas9HC (Addgene #43945) Analysis of the nuclease-targeted allele status Sequencing of the targeted allele Method of the off-target nuclease activity surveillance Targeted PCR/sequencing Descriptive name of the transgene N/A Eukaryotic selective agent resistance (including inducible/gene expressing cell-specific) N/A Inducible/constitutive system details N/A Date archived/stock creation date February 3, 2023 Cell line repository/bank https://hpscreg.eu/cell-line/ LSUHSi004-A-72 https://hpscreg.eu/cell-line/ LSUHSi004-A-73 Ethical/GMO work approvals Genetic modification was performed at Genome Engineering and iPSC Center (GEiC) at Washington University in St. Louis. Addgene/public access repository recombinant DNA sources’ disclaimers (if applicable) N/A Table 1 Characterization and validation. Classification Test Result Data Morphology Brightfield microscopy Typical human pluripotent stem cell morphology Fig. 1 Panel A Pluripotency status evidence for the described cell line Qualitative analysis Immunocytochemistry showed expression of pluripotency markers: OCT4, SOX2, NANOG, SSEA-4. Fig. 1 Panel D Quantitative analysis Compared to DAPI, % of positive cell (LSUHSi004-A-72, LSUHSi004-A-73) OCT4: 97%, 98%; SOX2: 99%, 96%; NANOG: 98%, 97%; SSEA-4: 97%, 98%. RT-PCR showed highly express OCT4, SOX2, NANOG, KLF4 Fig. 1 Panel D and E Karyotype Karyotype (G-banding) and resolution 46, XY, Resolution 400 Fig. 1 Panel C Genotyping for the desired genomic alteration/allelic status of the gene of interest PCR across the edited site and deep sequencing analysis Heterozygous or homozygous c. 1561C < G in FUS gene Fig. 1 Panel B and Supplementary Fig. S1A. Transgene-specific PCR N/A N/A Verification of the absence of random plasmid integration events PCR/Southern Off Target Analysis of gRNA showed 100% minus a weighted sum of off target hit-scores in the target genome. N/A Parental and modified cell line genetic identity evidence STR analysis, microsatellite PCR (mPCR) or specific (mutant) allele seq STR analysis of 18 loci, all matched. Supplementary Fig. S1B Mutagenesis / genetic modification outcome analysis Sequencing (genomic DNA PCR or RT-PCR product) The sequencing results of genomic DNA all matched with parent line. Fig. 1 Panel B and Supplementary Fig. S1A. PCR-based analyses The sequencing results PCR products all matched with parent line. Fig. 1 Panel B and Supplementary Fig. S1A. Southern Blot or WGS; western blotting (for knock-outs, KOs) N/A N/A Off-target nuclease analysis PCR across top 5/10 predicted top likely off-target sites, whole genome/exome sequencing N/A N/A Specific pathogen-free status Mycoplasma Tested by MycoAlert PLUS kit: Negative Fig. S1C Multilineage differentiation potential Embryoid body formation, RT-PCR Typical embryoid body formed. Upregulation of trilineage markers PAX6, OTX1 (ectoderm), DCN, IGF2, GATA2 (mesoderm), and SOX7, SOX17 (endoderm). Fig. 1 Panel F and G Donor screening (OPTIONAL) HIV 1 + 2 Hepatitis B, Hepatitis C N/A N/A Genotype additional info (OPTIONAL) Blood group genotyping N/A N/A HLA tissue typing N/A N/A Table 2 Reagents details. Antibodies used for immunocytochemistry Antibody Dilution Company Cat # and RRID Pluripotency Markers Mouse anti-OCT4 1:200 Santa Cruz Cat# sc-5279, RRID: AB_628051 Mouse anti-SOX2 1:200 Santa Cruz Biotechnology Cat# sc-365823, RRID: AB_10842165 Mouse anti-SSEA4 1:200 Abcam Cat# ab16287, RRID: AB_778073 Rabbit anti-Nanog 1:100 Abcam Cat# ab21624, RRID: AB_446437 Secondary antibodies Donkey anti-Mouse IgG (H + L), Alexa Fluor 488 1:500 Jackson ImmunoResearch Labs Cat# 715-545150, RRID: AB_2340846 Donkey Anti-Rabbit IgG (H + L), Alexa Fluor 594 1:500 Jackson ImmunoResearch Labs Cat# 711-585152, RRID:AB_2340621 Nuclear stain Hoechst33342 1 μg/mL Invitrogen Cat # H3570. RRID: NOT FOUND Site-specific nuclease Nuclease information Cas9 Cas9 vector p3s-Cas9HC (Addgene #43945) Delivery method electroporation 4D-Nucleofector (Lonza, Cat # AAF-1002B) Selection/enrichment strategy sorted into 96-well plates with one cell per well Single cell clones were screened and expanded Primers and Oligonucleotides used in this study Target Forward /Reverse primer (5′-3′) Pluripotency marker OCT 3/4 CGAGAGGATTTTGAGGCTGC/ CGAGGAGTACAGTGCAGTGA Pluripotency marker SOX 2 AGGATAAGTACACGCTGCCC/ TTCATGTGCGCGTAACTGTC Pluripotency marker NANOG TGTCTTCTGCTGAGATGCCT/ CAGAAGTGGGTTGTTTGCCT Pluripotency marker KLF4 TCTCCAATTCGCTGACCCAT/ CGGATCGGATAGGTGAAGCT Differentiation marker PAX6 GGGCGGAGTTATGATACCTACA/ ATATCAGGTTCACTTCCGGGAA Differentiation marker OTX1 TACGCCCTCCTCTTCCTACT/ GCATGTGGGTGGTGATGATG Differentiation marker DCN CTGAAGAACCTTCACGCATTGA/ GGCAATTCCTTCAGCTGATTCT Differentiation marker IGF2 CAATATGACACCTGGAAGCAGT/ GTAGAGCAATCAGGGGACGG Differentiation marker GATA2 ACCTGTTGTGCAAATTGTCAGA/ ATCCCTTCCTTCTTCATGGTCA Differentiation marker SOX7 ACTCCACTCCAACCTCCAAG/ TTCATTGCGATCCATGTCCC Differentiation marker SOX17 ATCGGGGACATGAAGGTGAA/ TCCTTAGCCCACACCATGAA Housekeeping Genes GAPDH CAAATTCCATGGCACCGTCA/ GGACTCCACGACGTACTCAG Genotyping-PCR FUS GGCTAGGTGGAAAGACCTGAGGTTG/ AGGAAAGTGAAAAGGGGGAAGAGG Sequencing FUS AGTGAATCTGTAGACCCACTTGAG/ GAAGAGGAACAAAATTTAAC hFUS gRNA (IDT) FUS ACAGACAGGATCGCAGGGAG hFUS ssODN (IDT) FUS AATATAATGGATACTTAATTTTTTTTTTTTTTTTTGCA GGGGTGAGCACAGACAGGATGGCAGGGAGAGGCCG TATTAATTAGCCTGGCTCCCCAGGTTCTGGAACAGCT TTTTGTCCTGTAC Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.scr.2023.103078. ==== Refs References Akter M , Cui H , Chen YH , Ding B , 2021. Generation of two induced pluripotent stem cell lines with heterozygous and homozygous GAG deletion in TOR1A gene from a healthy hiPSC line. Stem Cell Res. 56 , 102536 10.1016/j.scr.2021.102536.34536661 Akter M , Cui H , Chen YH , Ding B , 2022. Generation of gene-corrected isogenic control cell lines from a DYT1 dystonia patient iPSC line carrying a heterozygous GAG mutation in TOR1A gene. Stem Cell Res. 62 , 102807 10.1016/j.scr.2022.102807.35533513 Akter M , Ding B , 2022. Modeling Movement Disorders via Generation of hiPSC-Derived Motor Neurons. Cells 11 (23 ), 3796.36497056 Sepehrimanesh M , and Ding B (2020). Generation and optimization of highly pure motor neurons from human induced pluripotent stem cells via lentiviral delivery of transcription factors. American Journal of Physiology-Cell Physiology 319 , C771–C780.32783653 Szewczyk B , Günther R , Japtok J , Frech MJ , Naumann M , Lee HO , Hermann A , 2023. FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration. Cell Rep. 42 (2 ), 112025.36696267

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-98 10.33546/bnj.1322 Original Research Social stigma towards nurses taking care of patients with COVID-19 in Indonesia: A mixed-methods study https://orcid.org/0000-0001-5865-8452 Manik Marisa Junianti * Natalia Siska Theresia Faculty of Nursing, University of Pelita Harapan, Tangerang, Indonesia * Corresponding author: Marisa Junianti Manik, MN, Faculty of Nursing, University of Pelita Harapan, FK UPH Building-Soedirman Boulevard, 15, Lippo Village, Tangerang, Indonesia. Telp. +6281519704427. Email: marisa.manik@uph.edu Cite this article as: Manik, M. J., Natalia, S., & Theresia. (2021). Social stigma towards nurses taking care of patients with COVID-19 in Indonesia: A mixed-methods study. Belitung Nursing Journal, 7(2), 98-106. https://doi.org/10.33546/bnj.1322 29 4 2021 2021 7 2 98106 19 1 2021 18 2 2021 05 3 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The condition of the Indonesians’ unpreparedness for the COVID-19 pandemic has caused anxiety and fear. The public’s fears of COVID-19 cases have led to a negative stigma. As part of health workers in disaster management’s main pillars in health services, nurses are most vulnerable to infection and not free from the stigma. Objective This study aimed to describe the social stigma against nurses taking care of patients with COVID-19 and experiencing suspected or probable or confirmed COVID-19 cases in Indonesia. Methods This study was a mixed-method study using a sequential explanatory design-participant selection model. The selection of respondents used the convenience sampling technique. The number of respondents in the quantitative stage was 118 respondents. For qualitative data, selected participants were respondents with a stigma score of more than 21 nurses and willing to continue the interview process. There were 11 participants in the qualitative stage. This study used the modified Stigma Scale of the Explanatory Model Interview Catalog for quantitative data and four semi-structured questions to obtain qualitative data. Quantitative data were processed in descriptive statistics, and a thematic analysis was performed to analyze the qualitative data. Results The highest stigma score of 118 respondents was 37, and the lowest score was zero. The stigma score had a mean of 12.28 (SD ± 7.9). The higher the score obtained leads to a higher level of stigma received. From a total of 11 participants interviewed, four main themes emerged: rejection, feeling down and afraid, sources of support, and professional vigilance. Conclusion The social stigma experienced by nurses comes from colleagues and society and impacts psychological distress. Support from families and colleagues strengthens nurses in facing social stigma. Nevertheless, nurses uphold the values to remain grateful and carry out professional responsibilities in taking care of patients. Nurses should be provided with psychological support and be prepared for disasters to provide excellent health services and reduce adverse mental health. coronavirus COVID-19 Indonesia nurses social stigma ==== Body pmcThe world, including Indonesia, deals with a non-natural disaster in the form of an outbreak of Coronavirus Disease (COVID-19), an infectious disease caused by a type of newly discovered coronavirus. The genetic sequence of the new virus, called COVID-19, was officially announced by the World Health Organization (WHO) on 12 January 2020. The first status of COVID-19 was a global epidemic and then upgraded to a pandemic status just within ten weeks after the first case was reported (WHO, 2020b). The disease outbreak has become a pandemic that can impact people’s mental and psychosocial health conditions (Ministry of Health of Indonesia, 2020). The first case in Indonesia had been officially announced on 2 March 2020 (Nuraini, 2020). The condition of the Indonesian public’s unpreparedness for this pandemic was evident in the first week of the first cases publicly announced. There is growing anxiety in the community living around the first suspects confirmed with COVID-19 cases (Nuraini, 2020). The public feared the suspected and probable COVID-19 cases, which led to a negative stigma against them. This stigma took the form of exclusion and discrimination from the community. Health workers, such as nurses, who are part of COVID-19 disaster management’s main pillars in health services, are also not free from the stigma. The stigma experienced by health workers was in the form of rejection by the community around the neighborhood or the nearby rented or boarding house. The most evident negative stigma reported was when the corpse of a dead nurse confirmed with COVID-19 was rejected by the community around the public cemetery in Central Java, Indonesia. Health workers are most vulnerable to infection from patients who come to health care facilities because exposures from patients with COVID-19 are unavoidable (Tosepu, Effendy, & Ahmad, 2020; Wibowo, 2020). Besides, hospital care service flows for COVID-19 cases were still unclear in the pandemic’s early days. The COVID-19 testing tools such as rapid tests were still limited, placing a higher risk of being exposed to health workers. The increasing number of health workers infected with COVID-19 is associated with the rising number of confirmed COVID-19 cases and patients’ dishonesty with their previous travel history or symptoms (Tosepu et al., 2021; Wibowo, 2020). Research on the health workers’ mental health in handling COVID-19 in Singapore and India shows that one of the psychological distresses found was a social stigma (Chew et al., 2020). The experience shared by several health workers indicated that the stigma comes from the other health workers or friends. Health workers’ mental health is essential in providing excellent health services, especially during a pandemic. Therefore, it is crucial to uncover the pictures of stigma to develop mental health support according to health workers’ needs. Social stigma in the health context is a negative relationship between a person or group of people with specific characteristics and diseases. In the pandemic context, this stigma means that people are labeled, stereotyped, discriminated against, treated separately, or experience loss of status because of their perceived relationship with the disease (WHO, 2020a). Literature studies suggest that health workers are at significant risk of adverse mental health during the COVID-19 pandemic. The reasons include long working hours, risk of infection, lack of personal protective equipment, loneliness, physical exhaustion, and separation from family (Rajkumar, 2020). Another study focusing on mental health challenges during the COVID-19 pandemic found that mental health challenges, such as anxiety or fear of infection to depression, are in line with increased health workers’ workload (Kar, Arafat, Kabir, Sharma, & Saxena, 2020). One descriptive study in several health centers in India and Singapore found that 48 respondents (5.3%) experienced moderate to severe depression, 79 respondents (8.7%) mild to severe anxiety, 20 respondents (2.2%) very severe stress, and 34 respondents (3.8%) moderate to heavy levels of psychological stress (Chew et al., 2020). A possible contributing factor was social stigma, resulting in individuals having a higher tendency to express their psychological distress with physical symptoms (Chew et al., 2020). Literature studies emphasize the imbalance and mismatch between stigma mitigation, prevention, and containment of COVID-19. Those studies suggested short-term and long-term strategies for building empathy and social justice in current and future pandemics. Although the research in COVID-19 is relatively new, the stress from the stigma of COVID-19 may have similar mental health impacts with the previous research, including healthcare workers. Therefore, a strategy is needed to consider various health conditions and social identities to understand and reduce the stigma of COVID-19 (Logie & Turan, 2020). At the beginning of the COVID-19 pandemic, few studies reveal the stigma experienced by nurses. Many studies have discussed the stigma among health workers but are still limited to survey studies. No research has explored the stigma experienced by nurses as health care providers who are at the same time experiencing the COVID-19 itself. This study aimed to uncover the pictures of the stigma against nurses taking care of clients with COVID-19 and experiencing as suspects or probable suspects or confirmed COVID-19 cases. Methods Study Design This study was a mixed-method study using a sequential explanatory design-participant selection model established in two phases. The first phase was conducted with the quantitative methods, followed by the second phase of exploration with qualitative methods. The qualitative phase was emphasized and connected to the result of the first phase, with the intent is to purposefully select participants to best address the qualitative research questions (Creswell, 2018). The consideration for using mixed methods was to get a comprehensive and more detailed picture of the phenomena that occurred within the participants in the target population. Participants and Study Setting Quantitative strand Respondents in this study were nurses taking care of COVID-19 patients in several private hospitals in Indonesia. The selection of respondents used the convenience sampling technique because it was difficult to reach the population in the pandemic situation, particularly at the beginning of the outbreak. The inclusion criteria were nurses taking care of COVID-19 patients and once experienced as probable suspect or confirmed COVID-19 cases. The number of participants who took part in quantitative research in this study was 118 respondents. Qualitative strand For qualitative data, selected participants were respondents with a stigma score of more than 21 nurses and willing to continue the interview process. After the researchers collected the quantitative data, a stigma score was established. The researchers identified 17 nurses who had more than a 21-stigma score. They were invited to participate in the second phase by email. 11 participants were interviewed. Data Collection Quantitative strand The quantitative data were collected using a modified questionnaire from the Stigma Scale of the Explanatory Model Interview Catalog (EMIC Stigma Scale). This instrument was utilized after obtaining consent from the original author. The questionnaire was previously intended to measure the social stigma of stigmatized people for having leprosy and tuberculosis. The questionnaire was also translated into the Indonesian language (De Korte, Vellacott, Pongtiku, Rantetampang, & Van Brakel, 2018). There were 14 questions with four answer choices: yes, maybe, do not know, and no. Question number two was the only question with a reverse score (InfoNTD, 2020; Morgado et al., 2017). Each item was rated on a 4-point Likert scale, options being three = yes to zero = no. A total score of a stigma was computed by adding up individual items’ scores. The maximum score is 42, and the minimum score is zero. The higher the score obtained by a respondent, the greater the indication of stigma. There is no stigma categorization of the total score (InfoNTD, 2020; Morgado et al., 2017). The EMIC stigma scale was confirmed to have good internal consistency and high item-total correlation (Chung & Lam, 2018). The research instrument was reliable, with a Cronbach’s Alpha value of 0.88. The researcher collected quantitative data by compiling the survey into an online form using the Google platform and distributing a link by WhatsApp Messenger application to the nursing leaders in 13 private hospitals in Indonesia. The nursing leaders shared the survey link with their nursing staff. The quantitative data were collected in the first week of May 2020. Qualitative strand The qualitative data collection used an online semi-structured interview. Interview sessions were conducted in the third and fourth week of May 2020. The research instrument for obtaining qualitative data was semi-structured interview guidelines developed from the EMIC Stigma Scale to explore participants’ stigma experiences. Two researchers with a nursing background conducted the interview using semi-structured interviews. The interview questions included (1) How was your experience as a nurse who is also a suspected or probable or confirmed COVID-19? (2) How did you experience working with other health workers when you had experienced as suspected or probable or confirmed COVID-19? (3) How were the support of colleagues, family, and the people around you toward your profession and your experience? (4) Can you share the value that you get from this experience? The online interview was conducted by the WhatsApp voice call or Zoom application according to the participants’ preference. The interviews took 45 to 60 minutes and were digitally audio-recorded to be transcribed verbatim in Indonesian. Data Analysis Quantitative strand Quantitative data were summarized using descriptive statistics (mean, standard deviation, frequency) and processed in percentages based on each question’s answers and each respondent’s total stigma score. Data analysis was conducted using the IBM SPSS Statistics version 27. Qualitative strand The researchers performed a thematic analysis for the qualitative data. Data analysis processes included familiarizing with data, generating initial codes, searching for themes, reviewing themes, and defining and naming themes (Vaismoradi, Turunen, & Bondas, 2013). To establish this qualitative data’s trustworthiness, the researchers employed member-checking by sending the transcripts to the participants to verify the data accuracy. Ethical Consideration This study obtained ethical clearance from the Institutional Review Board of the Mochtar Riady Institute for Nanotechnology (approval no. 2005005-04). In this light, the researchers gave the respondents the right to participate, and they could also stop participating during the research process. Permission to record the conversation was obtained after considering the participants’ consent. Results Quantitative Results The respondents’ characteristics in this study were in the age range of 17-25 years old (60.2%), and 56.8% of the participants have been working for one to three years at the current hospital (Table 1). Table 1 Distribution of respondents’ characteristics by age and length of employment in their current hospital (N = 118) Category n % Age  17 – 25 years 71 60.2  26 – 35 years 32 27.1  36 – 45 years 13 11.0  46 – 55 years 2 1.7 Length of work  Less than one year 24 20.3  1 – 3 year 67 56.8  More than three year 27 22.9 Most respondents, or around 72%, underwent both rapid tests for antibody and swab-polymerase chain reaction (PCR). In March 2020, 29.7% of respondents became suspected, and 6.8% were confirmed COVID-19 (Table 2). Table 2 Distribution of respondents’ characteristics based on COVID-19 test and their status related to COVID-19 from March to May 2020 (N = 118) Category n % COVID-19 test  Rapid test (Antibody) 15 12.7  PCR (Swab) 18 15.3  Rapid test and PCR 85 72 Status of COVID-19  Suspected/ Probable cases   March 35 29.7   April 23 19.5   May 13 11   Not answer 47 39.8  Confirmed cases   March 8 6.8   April 3 2.5   May 10 8.5   Never 97 82.2 The respondents’ highest stigma score was 37, and the lowest score was zero. The mean score was 12.28 (SD ± 7.9). The distribution of the respondents who answered each item of the stigma questionnaire varies (Table 3). Table 3 Distribution of respondents based on question items of the EMIC Stigma Scale (N = 118) No Question Yes Maybe No Do Not know 1 Do you choose so that other people do not know about the COVID-19 that you are experiencing? 29 25 62 2 2 Have you discussed this issue with close people, people you can easily talk to? Example: close friend, family 110 1 5 2 3 Do you think you will be underappreciated or less respected because of this health problem? 21 40 53 4 4 Have you been humiliated because of this health problem? 11 17 87 3 5 Do your neighbors, coworkers, or the community disrespect you because of your health problems? 17 24 69 8 6 Do you think that coming into contact with you will be bad for those around you even after being treated? 21 35 59 3 7 Do you feel that other people are avoiding you because of this problem? 22 34 59 3 8 Has anyone refused to visit your home because of this condition even after you have been treated? 15 26 66 11 9 If they know about your health problems, will the people in your community have less respect for your family? For example, neighbors, coworkers 12 36 64 6 10A If you have children, is your illness causing social problems for your child? 1 3 20 1 10B If you have children in the future, can your illness cause social problems for your child? 7 25 53 8 11A If you are not married, does this disease make it difficult for you to get married? 3 18 57 12 11B If you are married, is this a disease-causing problem in your marriage? 2 3 23 0 12 Do you feel that this disease can make it difficult for people in your family to get married? Example: children, grandchildren, or siblings 17 29 61 11 13 Have you been asked to stay away from work or social groups? 28 9 78 3 14 Did you decide to quit your job or stay away from community groups? 24 7 85 2 Qualitative Results In the second phase, 11 out of 17 participants had more than 21 stigma scores and were willing to be interviewed. Most of the interviewed nurses were female (82%) and were between 20 and 40 years old. More than half of the participants (82%) have been working for one to three years at the current hospital. The purpose of the qualitative phase is to gain a deeper understanding of the stigma experienced by nurses taking care of clients with COVID-19 and at the same time experiencing as suspected or probable or confirmed COVID-19 cases at the beginning of the pandemic in March to May 2020. Four major themes emerged from the qualitative data, including (1) rejection, (2) feeling down and fatigue, (3) sources of support, and (4) professional vigilance. Rejection Participants experienced rejection from the social environment. Participants stated that they got cross-infection from the workplace, and the experience was exacerbated by rejection from others. Participants expressed feelings of being feared and avoided by colleagues and people in their neighborhood. Stigma in the form of rejection was obtained from colleagues and other officers in the hospital. Participants stated that they felt both verbal and nonverbal rejection when being suspected or probable COVID-19 cases. The experiences were described in the following statements: “Yes, they said, you cannot come here” (p10) “Do not come close to me, or I will be positive too” (p10) “You do not come near us, get away from us” (p7) Participant 2 conveyed discrimination from friends who were quarantined because he was placed in a different room. “so, my friends were isolated, but I was isolated different from them” (p2) Several participants expressed rejection by other professions. There were hospital employees who were openly evasive and keeping their distance away. “There are also other health workers who underestimated us; they wanted to go out like when we were in the same waiting room with us” (p8) “It feels like we are filthy, and that person keeps his distance, not entering the ICU” (p9) This social stigma was also found in the adverse treatment of other health workers. “Yes, I feel rejected, my diagnosis has not been confirmed, it is still early, why are they so terrified” (p3) “We feel shunned even though we are fellow health workers” (p8) “(Hospital employee) when he met us, he avoided us” (p8) Most participants also experienced rejection from the boarding house owner in the community because most of the participants lived in a boarding or rent house. “Suspicion arose from the boarding house owner. Yes, I informed them that I am taking care of the COVID-19 suspects. There is a stigma in the society; it looks like I will be expelled from the boarding house” (p5) “I could not go back to the boarding house because the owner was afraid that we would come home with the virus, afraid that other residents of the boarding house would be worried if, for example, they know that we are nurses caring for COVID patients” (p11) The rejection was also obtained from the local people, online taxi drivers; some were indirectly conveyed to their families. “They (the local community) are afraid of me” (p1) “Stigma from them, wow there are positive people, you have to get out of this environment” (p5) “The taxi driver was shocked knowing I was a nurse. Then he pointed out the nurse should stay in isolation” (p11) “There was an incident where the community leader and my neighbor, not directly to me but my family, to my sister and my mother, said that I should not go home because I will spread the virus” (p3) Feeling Down and Afraid The stigma experienced by nurses caused psychological distress, such as being down, sad, and fearful. Some of the participants chose to hide their status as nurses. These stigmatized nurses also think about the adverse effects that could happen to their families and loved ones. The participants expressed fear and sadness because they felt they were treated differently after becoming suspected or probable for COVID-19 cases. “I am upset, even though I felt no symptoms, right” (p1) “I am also in a position to feel down right away. I Feel down. I am not accepted in this environment” (p5) “I feel despicable” (p6) “So sad, I am there to work, nothing else” (p7) “Feeling even more disappointed because when we were quarantined, there were also nursing colleagues and other health workers who avoided us” (p8) “It feels like we are filthy” (p9 & p11) In this study, participants stated that they were afraid and anxious to reveal their identity as nurses because they were considered in close contact with COVID-19 patients. “It is because I do not want him to know my status, my job, so I have to lie” (p1) “I lose confidence too, feel afraid to use an online taxi, I am afraid to get questions” (p1) “Moreover, news began to appear that health workers were being kicked out from their boarding houses. I am cautious when I go outside. I am more afraid of the boarding house owner’s response” (p2) “Well, I was asked, where are you going? I do not dare to answer. If I said I was assigned to a COVID hospital, I could be kicked out, so I just said, Yeah Ma’am, I am leaving for home” (p2) “At the time, there was news that a nurse was kicked out from her boarding house, so I was afraid of being rejected by my new boarding house. I had the thought of wanting to lie and hide my status as a nurse. I am afraid of being rejected in a new environment” (p9) “Yes, there was a feeling of fear, fear of not being accepted; people do not know that I am a nurse” (p9) “I heard that the boarding house owner said that I shouldn’t stay there. I feel dizzy, wondering where to live and continue to quarantine in the hospital, but it means I would stay with others. I am afraid, and I have mixed feelings” (p11) Source of Supports This study indicated that participants felt discriminated when exposed to COVID-19, and they needed support. The support was considered as a reinforcement and counter-attack due to the stigma experienced. Participants felt affirmative relief from fellow health workers who gave encouragement and offered prayers. The participants’ most valuable support was from family, parents, and siblings who openly accepted, protected, and offered prayers for them. “Yes, I got prayers of support; the prayers from parents are powerful” (p1) “Family support, they always support, come to give vitamins, give support like that” (p5) “From my family, my parents who are in the village, usually they call me once a week, but now, they call me every night” (p7) “Support from family, siblings, friends who are also on duty here” (p8) “I feel most strengthened from the family, from my mother” (p9) Another support comes from other professions, such as doctors and the hospital’s Human Resource Department (HRD). “So far, there is support from the HRD, so we have been given a vitamin package. Also, every few days we get fresh milk, there are also lunch boxes, all kinds of things” (p3) “The support from colleagues is excellent. Support from a cardiologist, he cares so much” (p5) “Our intensivist is the best. He is very understanding. He desperately asked so that nurses are quarantined here so he can see them” (p6) “We must support each other. Prayer is the most important one” (p1) Professional Vigilance In general, participants interpreted this experience as a valuable experience and made them find values in life, even though they experienced the negative impact of stigma. Some of the values obtained are described in terms of spiritual values, increased self-awareness, and a responsibility to serve patients. Spirituality in this study did not focus on the sole relation about God but was also interpreted as the wisdom obtained through unpleasant experiences, making a person alive again and leading to satisfaction in understanding life. Almost all the participants expressed gratitude for this experience and grew closer to God. “I realized that this COVID also made me closer to God” (p1) “As long as God still gives a chance, as long as God still gives a healthy condition, opportunities, just do our part” (p11) “I feel even more grateful” (p3) They also expressed gratitude to understand self-care and appreciate little things as stated: “Because I am a nurse, maybe I am more grateful because I can care about my patient more. Not being careless” (p6) “I even think of appreciating small things which are invisible, never considered.” (p2) “I am more grateful because we appreciate the importance of cleanliness, the importance of taking care of each other” (p10) A health protocol for risk management increased the sense of security for health workers and reduced disease transmission. Participants stated that this experience made them more aware of the health protocol standards. “Because our caring and attention are honed, even more, our alertness is honed more, more than usual” (p3) “First, maybe it should be safe. Just stay safe, do hand washing, drink vitamins, do the social distance with friends, to take care of them. So yes, we still use the N95, and I also ask everyone to do the health protocols when we take care of patients” (p5) “Be more vigilant, be more vigilant, do hand washing and keep distance, keep wearing a mask everywhere” (p9) Participants stated that they continued to serve patients professionally even though they had experienced the impact of stigma, once felt afraid and anxious, and now are still at risk of being re-exposed to the COVID-19. “Because we are nurses to care for others, so I think we will treat the patient with the same action. Just like before, before this COVID-19. We continue to treat patients with the determination as it has been before” (p8) Participants also stated that they had more empathy and compassion because of their personal experience of stigma. They were aware that patients and families could also experience social stigma because they were considered to transmit disease. “I care my patient even better, no more careless” (p6) “The patient cannot be visited; I see the family in front of ICU hoping with anxiety, waiting for the patient, but they cannot go inside the room, but they still stay in front of the door. It makes me sad” (p2) “Because of this situation, we know that this is our struggle, where our job leads us, what challenges will we face, how to embrace those around us” (p7) Discussion The quantitative and qualitative results indicate that COVID-19 causes some nurses to experience stigma. This result is in line with the statement of WHO regarding the social stigma caused by COVID-19. Individuals tend to be afraid of something new, and fear is associated with other straightforwardly (WHO, 2020a). The stigma associated with COVID-19 varies from the transmission, examination or testing, pain level, comorbid disease levels affect, newly appearing symptoms, and treatment. An incomplete explanation of the symptoms causes individuals suffering from this disease to experience segregated and labeled/ stigmatized (Bhattacharya, Banerjee, & Rao, 2020). The stigma has several components, namely (1) differentiating and labeling differences, (2) associating human differences with negative attributions or stereotypes, (3) separating ‘us’ from ‘them,’ (4) experiencing loss of status and discrimination (Pescosolido & Martin, 2015). The data show that in question items of 1, 3, 6, 7, 13, and 14, more than 20 respondents answered ‘yes.’ These question items are in line with the exposure to the dimensions related to stigma as a multidimensional thing. Some of these dimensions are associated with stigma, namely social distance, covering facts or disclosures, negative influences, and danger perceptions (Pescosolido & Martin, 2015). The answer ‘yes’ to question number one means the respondent chose not to let others know about the COVID-19 status; this is a disclosure dimension. The meaning of the disclosure dimension is to hide the COVID-19 examination results, in line with the understanding that an individual diagnosed with a disease will conceal his condition from the public (Ashby, 2016). This dimension focuses on the negative consequences of disclosing the status or results of the COVID-19 examination. The disclosure aspect may also be increased when asking the closest people and family not to reveal secrets to avoid them feeling embarrassed and hoping that they will still be accepted in society (COVID-19 Response Acceleration Task Force, 2020). The third question is about the feeling of disrespect, which is most often experienced by patients of other diseases with high stigma scores, such as leprosy (Adhikari, Kaehler, Chapman, Raut, & Roche, 2014). COVID-19, as a new disease, also causes a decrease in self-esteem, even in health workers who are infected with COVID-19. The sixth question is related to the dimension of stigma based on fear of danger, such as stigma against patients with psychiatric illness or stigma on criminal behavior (Adhikari et al., 2014). Respondents who answered “yes” to this question item experienced internalized stigma (Pescosolido & Martin, 2015). Respondents stated that other people around them who met them would be adversely affected. COVID-19, as an airborne disease, is one of the facts that came to the respondents’ minds for this question. The seventh question is associated with the stigma dimension of social distance or maintaining an interpersonal distance that usually occurs in patients with psychiatric disorders (Ashby, 2016). This dimension’s rationale depends on the party giving the stigma, whether to accept or refuse to interact with people who have certain diseases or disabilities. Question number 13 is quite similar to question number 14. Simultaneously, these two questions have differences in the words ‘ask’ or ‘decide for themselves.’ These items’ dimensions are still related to social distance, which is discussed in the seventh question. So, questions number 7, 13, and 14, especially on the word ‘avoiding’ or ‘social distancing,’ will be further explored in the context of the stigma caused by COVID-19 because social and physical distancing is part of health protocols for the prevention of this disease. For this reason, these items will be explained in more detail in the qualitative discussion of several participants. From the results of the interview transcript analysis, four main themes emerged, including (1) rejection, (2) feeling down and afraid, (3) sources of support, and (4) professional vigilant. These negative response to stigma is consistent with the research, which states that exposure to this virus can negatively stigmatize labels, leading to negative responsive behavior (Ashby, 2016). The study shows that 140 from 2050 Indonesian nurses have felt humiliated by others because they work as the nurse of COVID-19 patients, and 135 nurses have been asked to leave their homes (Humasfik, 2020). The forms of rejection were the threat of eviction and avoidance by closing their doors when they see the nurse. The community also stays away from the nurse’s family (Humasfik, 2020). The results in this study also follow the statement that health workers at the forefront who risk their lives have experienced stigma and are socially shunned because they are in contact with COVID-19 patients and are vulnerable to experiencing discrimination (Ashby, 2016). The participant’s fear is the stigma’s impact. Participants feel anxious because of the conversations with colleagues and thus grow the fear of themselves and others. The stigma’s impact can increase the risk of mental disorders. As stated by Adom and Adu Mensah (2020), people affected by stigma are continually fighting the stress they experience from anxiety, depression, and fear. Stigma is a reaction to disease and cannot be avoided. Through the values expressed by the participants, those experiences provide awareness that the real opponent is the virus and not the patient of COVID-19 (Earnshaw, 2020). Based on those themes’ interpretation, participants experienced social stigma from both the work environment and community. From the rejection experienced, psychological distress appears in the form of fear and anxiety. The results show that the participants receive support from their families and people around them, and this is a steady source of support in facing their crisis period. Later, even though they experience stigma, they still carry out professional responsibilities as health workers and get the value of life. Those values include being more vigilant and maintaining self-health, and even spirituality related matters, where participants could be grateful in bad situations. The previous study revealed that stigma is an essential predictor of burnout and compassion fatigue in health workers, so the health workers need support to deal with the stigma (Ramaci, Barattucci, Ledda, & Rapisarda, 2020). In this study, nurses receive help from other health workers, such as doctors and staff. Nurses are the largest group in the health profession. Therefore, it is essential to raise awareness to face stigma from other professionals and meet negative behavior (Ashby, 2016). This study’s limitation includes the limited number of samples representing nurses from several private hospitals in Indonesia. This study does not analyze the participant’s coping mechanisms and does not measure the level of anxiety or distress. There could also be an accidental assumption in the discussion when combining quantitative data sets and qualitative data without considering each data’s type and depth. The existence of a presumption in combining the two methods is a weakness of mixed methods. This study tries to initiate the scope of stigma in the COVID-19 pandemic experienced by health workers. Although it only describes the stigma conditions experienced and does not statistically measure the variables’ effect or relationship, this study is meaningful. Future studies should pay more focus on this topic. Conclusion Stigma is an issue that needs to be controlled by the health system because it is a crisis in the health sector and can impact health workers’ mental health. There comes a need to provide psychological support and prepare an effective hospital disaster plan policy to improve health workers’ safety and promote mental health. The psychological support can be given in mental health services accessible to nurses, implementation of mechanisms to assess nurses’ mental wellness in real-time, establish a hotline staff for any type of needs or concerns, and any other forms. Future studies obtaining the presentation of psychological distress and coping with health workers are also needed. Health workers, especially nurses and doctors, need to be supported in carrying out their roles and responsibilities, especially during a pandemic, as the frontline of patient care. Acknowledgments The researchers express thanks to the University of Pelita Harapan, Indonesia, for its funding support in this study. Special thanks go to the nurses who were voluntarily interviewed. Their honesty was essential in carrying out this study. Declaration of Conflicting Interest The authors declare no conflict of interest. Funding The University of Pelita Harapan funded the study with the number: 321/LPPM-UPH/VI/2020. Authors Contribution All authors have equal contributions in this study started from the proposal, data collection (quantitative and qualitative data), data analysis, final report, and development of the manuscript. Data Availability Statement The databases generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Author Biographies Marisa Junianti Manik, MN is a Full-time Nursing Lecturer at the Faculty of Nursing, Pelita Harapan University, Indonesia. Siska Natalia, MSN-Palliative Care is a Part-time Nursing Lecturer at the Faculty of Nursing, Pelita Harapan University, Indonesia. Theresia, BN is a Clinical Educator at the Faculty of Nursing, Pelita Harapan University, Indonesia. ==== Refs References Adhikari, B., Kaehler, N., Chapman, R. S., Raut, S., & Roche, P. (2014). Factors affecting perceived stigma in leprosy affected persons in western Nepal. PLoS Neglected Tropical Disease, 8 (6 ), e2940. 10.1371/journal.pntd.0002940 Adom, D., & Adu Mensah, J. (2020). The psychological distress and mental health disorders from COVID-19 stigmatization in Ghana. Social Sciences & Humanities Open. 10.2139/ssrn.3599756 Ashby, N. J. (2016). Student nurses, stigma and infectious diseases. A mixed methods study. (PhD Thesis), University of Birmingham, England. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-107 10.33546/bnj.1268 Original Research Knowledge and healthcare-seeking behavior of family caregivers of children with pneumonia: A qualitative study in an urban community in Indonesia https://orcid.org/0000-0002-3104-3498 Purwati Nyimas Heny 1* https://orcid.org/0000-0002-3369-2694 Rustina Yeni 2 https://orcid.org/0000-0001-6953-9141 Supriyatno Bambang 3 1 Faculty of Nursing, Universitas Muhammadiyah Jakarta, Jakarta, Indonesia 2 Faculty of Nursing, Universitas Indonesia, Jakarta, Indonesia 3 Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia * Corresponding author: Ns. Nyimas Heny Purwati, M.Kep., Sp.Kep.An, Faculty of Nursing, Universitas Muhammadiyah Jakarta, Jl. Cemp. Putih Tengah I No.1, RT.11/RW.5, Cemp. Putih Tim., Kec. Cemp. Putih, Kota Jakarta Pusat, Jakarta, Indonesia, 10510. E-mail: nyimas.heny@umj.ac.id Cite this article as: Purwati, N. H., Rustina, Y., & Supriyatno, B. (2021). Knowledge and healthcare-seeking behavior of family caregivers of children with pneumonia: A qualitative study in an urban community in Indonesia. Belitung Nursing Journal, 7(2), 107-112. https://doi.org/10.33546/bnj.1268 29 4 2021 2021 7 2 107112 11 12 2020 04 1 2021 25 3 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Childhood pneumonia is the leading cause of death. Family caregivers may have a poor understanding of pneumonia, especially related to prevention and treatment. It is crucial to understand country-specific knowledge and healthcare-seeking behaviors of caregivers of children with pneumonia before planning programmatic responses, particularly in an urban community where the culture-social economic status is diverse. Objective This study aimed to describe the knowledge and healthcare-seeking behavior of family caregivers of children with pneumonia in Indonesia’s urban community. Methods A descriptive qualitative study was conducted at a public hospital in Jakarta, Indonesia, from 10 December 2019 to 28 January 2020. Ten family caregivers of children with pneumonia were included, and a semi-structured interview was conducted for data collection. The audio recording was transcribed verbatim, and the data were analyzed using content analysis. Results The emerged data indicated low knowledge of the family caregivers, especially mothers, which considered pneumonia a common cold only, and they failed to understand the risk of its transmission. Using traditional medicines was the first stage of healthcare-seeking behavior. If the symptoms worsened, the caregivers brought their children to the nearest health center. If there was no change in the symptoms, they headed to the hospital. The health center’s location, condition, services, and staff attitude were considered factors to choose the services. Conclusion Living in an urban area does not guarantee the family caregivers have better knowledge and good healthcare-seeking behavior. Therefore, nurses should provide comprehensive education about pneumonia, its symptoms, and treatment management to improve family care and prevent pneumonia-related deaths. Integrated management of children with illness is recommended to help the family caregivers of children with pneumonia receive treatment as quickly as possible. caregivers healthcare-seeking behavior mothers knowledge common cold pneumonia nursing Indonesia ==== Body pmcPneumonia is the leading infectious cause of death among children under five; about 2,400 children die every day (UNICEF, 2016). In 2016, Indonesia ranked as the sixth-highest number of pneumonia in the world (Ministry of Health, 2017). Unlike in other countries in Southeast Asia, the number of under-five deaths caused by pneumonia increases about 0.12% from 2016 to 2017 (Ministry of Health, 2017). High mortality due to pneumonia is associated with malnutrition, poor sanitation, air pollution, and lack of access to health care facilities (UNICEF, 2016). The Indonesian government provides integrated childhood illness management but only 60% of children receiving appropriate care from the public health centers (Ministry of Health, 2015). Family is critical in treating pneumonia in children, as they cannot take care of themselves. Their main problems were high levels of stress, anxiety, adverse family environment, and financial hardship (Pahlavanzadeh, Mousavi, & Maghsoudi, 2018). Also, poor coping skills and a lack of social support have contributed to the child’s health issues (Le Roux & Zar, 2017). A previous systematic review has shown a significant association between the role of the family caregiver and the readmittance (McLeod-Sordjan, Krajewski, Jean-Baptiste, Barone, & Worral, 2011). Therefore, ensuring family caregivers’ knowledge and behavior in health care is very important in providing appropriate care for children. Previous studies reported that family caregivers, particularly mothers, have inadequate knowledge about the etiology and symptoms of pneumonia, and many of them treat their children with pneumonia as a common cold and provide the children with traditional medicine to solve one of the symptoms, such as cough or fever that could be a reason for delay treatment (Abbey, Chinbuah, Gyapong, Bartholomew, & van den Borne, 2016; Ndu et al., 2015). A study conducted in six sub-Saharan African Countries reported that only 30% of caregivers were aware of at least one of the two pneumonia symptoms (i.e., fast or difficulty breathing) (Noordam, Carvajal-Velez, Sharkey, Young, & Cals, 2015). Additionally, household wealth-status, maternal and paternal education, and religion were associated with the inequality in the use of child health services (Ayalneh, Fetene, & Lee, 2017; Noordam et al., 2015). Pneumonia in An Urban Community in Indonesia In Indonesia, pneumonia, together with diarrhea, is the leading cause of death for children under five. Based on the diagnosis, the prevalence of pneumonia in 2018 was 2%, while in 2013, it was 1.8%. From 2015-2018 confirmed pneumonia cases in children under five years increased by about 500,000 per year. In Jakarta in 2018, 42,305 children under five were found and treated with a diagnosis of pneumonia, approximately 95.53 percent of the 44,285 children under five who are estimated to be sufferers spread across six districts/cities (Ministry of Health, 2018). Jakarta is included in the metropolitan city, or urban area, which is also the capital of Indonesia. Jakarta is the second-most populous urban area globally, after Tokyo, and covers 6.392 square kilometers. It has a population of around 35,934 million by 2020 (it occupies 6,392 kilometers square (2,468 sq mi). Pneumonia is a lung infection caused by bacteria, fungi, and viruses. The disease is often called a multifactorial disease. Apart from the condition, cleanliness and population density in residence also affect the proliferation of the disease (Ministry of Health, 2015). While population density is very crowded, that potential to be one of the significant risks for the rising factors of pneumonia. Jakarta has many of the best public and private health facilities (National Statistics Center, 2020). However, people living in Jakarta are diverse. They came from around the province in Indonesia with different socio-economic statuses. Therefore, it is crucial to understand country-specific understanding and health care-seeking behaviors for children with pneumonia before planning programmatic responses, particularly in an urban community where the culture-social economic status is diverse. Also, the family caregiver may have a poor understanding of pneumonia, especially related to prevention and treatment. This study was conducted to explore the knowledge and healthcare-seeking behaviors of family caregivers of children with pneumonia in Indonesia’s urban community. Methods Study Design and Participants This descriptive qualitative study involved family caregivers of children with pneumonia referred to a general public hospital in Jakarta, Indonesia. Participants were selected using purposive sampling. The inclusion criteria were mothers or primary caregivers of a child with pneumonia under five years of age, able to communicate verbally, and not having any addictions, and not using any psychological drugs. A total of ten participants were recruited. According to Colvin et al. (2013), at least three to ten participants are recruited in qualitative research. The participants were recruited during children’s clinical visits, and a head nurse provided the name lists of the potential participants. Data Collection This study was conducted at a general public hospital in Jakarta, Indonesia, from 10 December 2019 to 28 January 2020. The primary method of data collection was semi-structured interviews with open questions. Interviews were conducted in a private and quiet room individually as schedule with the participants. At the beginning of the interview, an introduction conversation was conducted to explain and obtain written consent and build trust with participants. After obtained approval from the participants, the researcher and participants made an appointment for an interview. The interviews were recorded with permission from the participants. The interview began with questions, “How long did your child get sick?” “Could you describe the symptoms complained by your child?”. After receiving the answers to the above questions, exploratory and in-depth questions, such as “Could you explain what you have done to help your child recovery?” were asked by the researcher and continued until no new data were described or the same things were repeatedly explained. The mean duration of the interviews was 30 to 45 minutes. All of the interviews were conducted by one person (NHP). The interview was audio recorded. Data Analysis Data were analyzed using content analysis (Creswell, 2012). In qualitative research, data analysis involves planning and organizing data (such as transcripts or photographs), followed by reducing the data into themes through coding and condensing the codes. Data are presented in figures, charts, or a discussion. In this study, the interviews were transcribed verbatim and reviewed every word to extract the codes. Then the codes were categorized into general topics. Based on their similarities, codes were put into the classified themes. Trustworthiness/Rigor Several evaluation methods were used to ensure the reliability and accuracy of the study. Responses were confirmed by subjects (member check) and experts (external check by a nursing expert in a qualitative study with a doctoral degree). To measure the fittingness, the results were shared with family caregivers of children with pneumonia who did not join this study, and they were agreed with the fittingness of data. Some of the observers examined the study findings and agreed that the data collection methodology was appropriate. To ensure the conformity and consistency of the study, the researcher also correctly documented the whole analysis process to allow others to follow. Ethical Consideration Ethical permission was obtained prior to data collection from the Institutional Review Board of the Universitas Muhammadiyah Jakarta, Jakarta, Indonesia (approval number: 078/III/UMJ/2019) and the studied hospital. Each participant was asked to sign a written informed consent prior to data collection, and they could withdraw from the study without any penalty. Results Characteristics of the Participants The average age of the participants was 26.57 years old, with a standard deviation of 2.34. All of the participants in this study were mothers of children with pneumonia, and the onset of a child’s disease was between the age of one and four years. Of all participants, the majority of their educational level was senior high school. The duration of the children having the disease ranged between 12 and 20 days. Analytical Findings The findings of this study emerged from data representing knowledge and healthcare-seeking behavior of family caregivers of children with pneumonia (Table 1). Table 1 Themes and subthemes of knowledge and health care seeking behaviors of family caregivers of children with pneumonia Themes Subthemes Knowledge of pneumonia ■ Just a common cold ■ Risk of transmission Healthcare-seeking behavior ■ Using traditional medicines ■ The nearest health center first, hospital second Theme 1: Knowledge of pneumonia Just a common cold The family’s knowledge about pneumonia experienced by their children in this study was considered low. The majority of the participants perceived that the illness experienced by their children as a common cold, as described by the participants: “What I know, my child is sick of a common cold” (P2) “I do not really know, but my child has a cold cough and must be treated” (P3) Also, although several triggers of pneumonia symptoms were identified by some participants, such as drinking too much ice, being exposed to cigarette smoke, and not having time to play, and eating too much, along with different combinations of external influences, some participants did not recognize the conditions that triggered the symptoms. It is described by the participants: “I certainly don’t know, but my child likes to eat a snack, likes drinking ice, eating is difficult. There is no coughing at home” (P2) “My husband smoked, sometimes he smoked near his son, sometimes outside too. Sometimes the windows at home are opened if the heat is opened” (P2) Risk of transmission While their children got sick, the parents and children did not provide or use a mask to prevent the transmission. It is described by the participants: “My kid is usually cheerful. Now he is sick, and does not want to play. He just wants to be held all the time” (without using a mask seen from the observation”) (P5) “During the sickness, she only played in bed, no mask. She kept silent, looked soft, not cheerful” (P9) Theme 2: Healthcare-seeking behavior The healthcare-seeking behaviors of the family for their children with pneumonia could be seen in the two following subthemes: Using traditional medicines The majority of the participants used traditional medicines to take care of their children at home, such as using a red onion, hot water, and saga leaves. This is usually based on their previous experience and suggestions from other family members. This is explained in the following statements: “My father-in-law uses hot water using eucalyptus or scraped using onions so can help the body getting warm or hot” (P1) “I gave herbal first such as saga leaves to reduce cough” (P2) The nearest health center first, hospital second The majority of the participants preferred to bring the children to the nearest public health center or clinic than the hospital if traditional medicines are not effective. The location, condition, services, and staff attitude have become the factors of choosing health care services, as stated in the following statement: “Immediately, I took my kid to the public health center if there was an emergency at home, or if traditional medicine is not working” (P4) “I bring my kid to the clinic or public health center first, then if it cannot guarantee recovery, I bring to the hospital” (P8) It’s even better service in a good public health center. Sometimes the nurses are friendly, and some are not. In the hospital, there are many people” (P2 & P3) Discussion This study found that most of the family caregivers considered pneumonia as a common cold. They did not know the symptoms of pneumonia correctly, even dangerous symptoms, and also a condition that might trigger symptoms became more severe. It is similar to previous research conducted in Africa, Uganda, and Thailand to more than four hundred mothers and caregivers of children with pneumonia reported their knowledge of causes, symptoms, and danger signs of pneumonia were poor (Ndu et al., 2015; Tuhebwe, Tumushabe, Leontsini, & Wanyenze, 2014). Parents perceive the symptoms are ordinary and harmless so they can treat themself (Ferdous et al., 2014; Pajuelo et al., 2018). However, proper knowledge of pneumonia, including its dangerous symptoms, is essential to prevent death from pneumonia (Ferdous et al., 2014). Therefore, increasing health education to society in Indonesia about pneumonia is very important using a more comprehensive approach. In our study, it has been shown that the majority of the family preferred the traditional way to take care of their sick children, such as scraping with red onion and other traditional medicines. They chose to deal directly with the disease based on their previous knowledge of child-related symptoms. If the symptoms worsened, the parent brought their children to the first or primary healthcare center. And finally, if the symptoms were no better, they headed to the hospital. The existence of a spiritual belief in the prohibition of the use of medical treatment has led to the emergence of traditional healing practices (Bedford & Sharkey, 2014; Colvin et al., 2013). Another reason is parents’ mistrust of the health-care system, which they believe is not providing proper care for their children, as well as the poor standard of service provided by government hospitals and a shortage of qualified staff (Colvin et al., 2013; Ferdous et al., 2014; Pajuelo et al., 2018). Delays in obtaining appropriate treatment occur when health service providers, especially at the primary care level, are unable to provide the right diagnosis and treatment. Care-seeking is one of the keys to managing children with pneumonia. According to a previous study, the average parent delay in seeking treatment for children with pneumonia ranges from three to 14 days after the onset of symptoms in children, especially fever and cough (Pajuelo et al., 2018). The primary reason for the delay in the treatment of children with pneumonia was a spiritual belief, low quality of service in government hospitals, lack of professionally qualified staff (Colvin et al., 2013; Ferdous et al., 2014; Noordam et al., 2015; Pajuelo et al., 2018). Parents perceived that symptoms appear to be common and not dangerous so that they can be self-resolved or treated on their own. If the condition does not improve, the child comes to health care at an advanced stage of the disease (Ferdous et al., 2014; Pajuelo et al., 2018). The previous study has shown that the lack of knowledge of the mother regarding signs and symptoms and the severity of the disease has resulted in ineffective treatment, i.e., either delayed treatment or unnecessary treatment (Ferdous et al., 2014). The findings of this study indicated that a program to help parents of children with pneumonia receive treatment as soon as possible is needed through integrated management of children with illness. Nurses, especially family nurses and pediatric nurses, should provide information and education to parents about home care and ensure urgent follow-up in general practice clinics or outpatient care. The primary health education subjects are mothers and child caregivers, while secondary subjects are health workers, decision-makers, and other related sectors. However, health promotion aims to ensure that people adopt behaviors that comply with health requirements. The study was limited to the individual differences that could have influenced caregivers’ pursuing behavior between religious, moral, social, cultural, and mental beliefs. To an extent, this would compensate for the inequality in ability levels between the participants. The study’s limitations were also more directed towards collecting data concerning the availability of the patients under five years of age. In general, children treated with pneumonia are infants and are accompanied by other comorbidities such as congenital heart disease and malnutrition. During the interview, distraction sometimes occurred because the child was mischievous, mainly if left behind, so that data might not be optimally collected. Finally, a follow-up interview must be conducted at the patient’s home. Conclusion This study found that the family caregivers had insufficient knowledge of pneumonia and its symptoms even though living in the urban area. They considered pneumonia the same as a common cold. Thus, this condition affected their healthcare-seeking behaviors, in which many of the family preferred to apply traditional ways in caring for their children with pneumonia. Therefore, it is crucial for nurses, especially pediatric nurses or family nurses, to provide comprehensive and continuous education about pneumonia, its symptoms, and treatment management to enhance the family caregivers’ healthcare-seeking behavior and prevent death caused by pneumonia. Our study highlights the need for more serious efforts to increase the knowledge about pneumonia in primary and other health services levels. This new information could contribute to new conceptualizations or question existing ones; it could provide data that could improve practice. Future studies exploring other potential factors that may contribute to the caregivers’ knowledge and barrier to provide care for their children with pneumonia are essential. Acknowledgment We thank all participants for joining this study. Declaration of Conflicting Interest All authors declare no conflict of interest. Funding This study was funded by Universitas Muhammadiyah Jakarta, Indonesia Authors’ Contribution NHP contributed to all the study steps, including data collection, data analysis, data interpretation, drafted and critically revised the article. YP and BS contributed to data analysis and interpretation, wrote and revised the paper critically. All authors agreed with the final version of the manuscript. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Authors’ Biographies Ns. Nyimas Heny Purwati, M.Kep., Sp.Kep.An is a Lecturer at the Faculty of Nursing, Universitas Muhammadiyah Jakarta, Indonesia. Yeni Rustina, S. Kp., M.App.Sc., Ph.D is a Professor at the Faculty of Nursing, Universitas Indonesia, Indonesia. DR. dr. Bambang Supriyatno, Sp. A(K) is a Professor at the Faculty of Medicine, Universitas Indonesia, Indonesia. ==== Refs References Abbey, M., Chinbuah, M. 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(2015). Danger signs of childhood pneumonia: Caregiver awareness and care seeking behavior in a developing country. International Journal of Pediatrics, 2015 , 167261. 10.1155/2015/167261 26576161 Noordam, A. C., Carvajal-Velez, L., Sharkey, A. B., Young, M., & Cals, J. W. L. (2015). Care seeking behaviour for children with suspected pneumonia in countries in sub-Saharan Africa with high pneumonia mortality. PloS One, 10 (2 ), e0117919. 10.1371/journal.pone.0117919 25706531 Pahlavanzadeh, S., Mousavi, S., & Maghsoudi, J. (2018). Exploring the needs of family caregivers of children with attention deficit hyperactivity disorder: A qualitative study. Iranian Journal of Nursing and Midwifery Research, 23 (2 ), 149. 10.4103/ijnmr.IJNMR_16_17 29628964 Pajuelo, M. J., Huaynate, C. A., Correa, M., Malpartida, H. M., Asayag, C. R., Seminario, J. R., … Paz-Soldan, V. A. (2018). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-008 10.33546/bnj.1279 Original Research Holistic nursing care among operating room nurses: Strengthening the standard of practice in Saudi Arabia https://orcid.org/0000-0001-9749-9669 Albaqawi Hamdan Mohammad 1 https://orcid.org/0000-0002-7847-9635 Butcon Vincent Edward 2 https://orcid.org/0000-0002-6246-210X Albagawi Bander Saad 1 https://orcid.org/0000-0002-3321-174X Dayrit Richard Dennis 1 https://orcid.org/0000-0002-6370-0739 Pangket Petelyne 1* 1 College of Nursing, University of Ha’il, Saudi Arabia 2 Tallahasse Memorial Healthcare Inc., Florida, USA Corresponding author: Dr. Petelyne Pangket, College of Nursing, University of Ha’il, Saudi Arabia. Aja Road, P.O.Box 2440, Ha’il, 81481, KSA. Cell phone: +9665032376884. Email: phetz75@yahoo.com Cite this article as: Albaqawi, H. M., Butcon, V. E., Albagawi, B. S., Dayrit, R. D., & Pangket, P. (2021). Holistic nursing care among operating room nurses: Strengthening the standard of practice in Saudi Arabia. Belitung Nursing Journal, 7(1), 8-14. https://doi.org/10.33546/bnj.1279 22 2 2021 2021 7 1 814 28 12 2020 26 1 2021 01 2 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Holistic practices have been found beneficial for patients as well as nurses. They increase both the nurses and the patients’ health-promoting behaviors, spirituality, and interpersonal relationships. Objective This study aimed to determine holistic nursing care and compare its differences based on individual characteristics. Methods This study employed a quantitative-cross sectional approach. It was conducted at the hospitals of Hail region, Kingdom of Saudi Arabia, from February 2020 to March 2020. Selected through convenience sampling, 154 operating room nurses participated in the study. Frequency and percentages were used to analyze the demographic information, and t-tests and analysis of variance were used to test for differences. Results Holistic nursing dimensions such as physiological (4.72 ± 0.40), socio-cultural (4.53 ± 0.45), psychological (4.66 ± 0.32), and spiritual aspects (4.22 ± 0.73) were consistently carried out in the operating room. On the physiological dimension, no significant differences were found in years of experience [(t) -0.073; p > 0.942], gender [(t) -1.113; p > 0.27], or age [(F) 0.558; p > 0.57), but there was a significant difference with nationality [(t) -3.328; p < 0.001]. On the socio-cultural dimension, the length of experience [(t) 0.599; p > 0.550], gender, [(t) -1.420; p > 0.158], and age [(F) 0.148; p > 0.862] were not significant, but a significant difference was found with nationality [(t) -7.516; p < 0.001]. Regarding the psychological dimension, the length of experience [(t) -1.101; p > 0.276], gender [(t) -1.545; p > 0.129], and age [(F) 1.259; p > 0.287] were not significant, but there was a significant difference with nationality [(t) -5.492; p < 0.001]. Finally, with the spiritual dimension, no significant difference was found on length of experience [(t) -1.101; p > 0.276] or age [(F) 0.584; p > 0.559], but there were significant differences on gender [(t) -3.890; p < 0.001] and nationality [(t) -3.653; p < 0.001]. Conclusion Nationality is a causal factor to physiological, socio-cultural, psychological, and spiritual dimensions, while gender is significant to spiritual aspect. Regardless of nationality or gender, nurses must be knowledgeable regarding the significance of adopting holistic care to improve the quality of their care to their patients. holistic nursing operating room nursing spirituality Saudi Arabia ==== Body pmcCaring has been continually regarded as the heart of the nursing profession. Nurses are expected to provide professional and competent nursing skills with exceptional care and compassion for patients. Accordingly, nurses integrate compassionate behavior with the condition of the patients by supporting those patients, forming mutual relationships, and making a difference in their lives, thus portraying nursing as both an art and a science (Henry, 2018). It is assumed that it always transforms to quality care when nurses engage in professional principles and the application of professional expertise. To Kinchen (2015), caring in nursing traditionally employs a holistic approach. Holistic nursing care goes back to the time of Florence Nightingale when the healing process was influenced by the patient’s environment. This concept has expanded as aspects of the physical, social, psychological, and spiritual have been taken into consideration (Tjale & Bruce, 2007). Holistic nursing care is integrally composed of therapeutic interactions by the nurse and the patient, the communication patterns, and the patient preference (Dossey, 2009). According to Mariano et al. (2013), holistic nursing heals the whole person with the incorporation of caring. Holistic practices are beneficial for the patients and the nurses, increasing the health-promoting behaviors, spirituality, interpersonal relations, and nutrition (Mcelligott et al., 2010). Although care is essential in all nursing fields, the operating room poses the most difficulty in terms of rendering holistic nursing care. The operating room is a fast-paced hospital area; in constant change, it is highly demanding and schedule-driven. These characteristics present a challenge for perioperative nurses to possess good critical thinking and decision-making skills while simultaneously delivering holistic nursing care (Cohen, 2008). Consequently, in managing operating room employees, nursing managers must strategize for an excellent workforce (Alshammari et al., 2020; Gunawan et al., 2020). Operating room nurses face numerous challenges in the operating room arena; they are pressured physically, mentally, and emotionally, which leads to increased pressure and high medical risks (Higgins & Macintosh, 2010). A range of different problems (e.g., technical, equipment/patient) results in an increase in stress to operating room personnel, ultimately affecting their performance and care (Arora et al., 2010). Communication failures among the surgical team and equipment problems result in procedure delays and inefficiencies (Halverson et al., 2011). Incontrovertibly, perioperative nurses have a multitude of concerns that compromise the value of the care given to the patient. Patient safety breaches, for instance, have been the result of system failures, including failure of the equipment due to design and use, inadequate staffing, miscommunication, and poor team coordination inside the operating room (Van Beuzekom et al., 2012). Since holistic nursing care in the operating room context starts from the time the patient consents for surgery until his or her discharge in the hospital, the Joint Commission established steps to prevent surgical errors and promote patient safety (Joint Commission, 2009). Perioperative nurses aim to avert physical and psychological complications related to surgery and assist in the resumption of the patient to normal (Selimen & Andsoy, 2011). Albaqawi et al. (2017) note that the diversity of cultures poses a difficulty for nurses in achieving holistic caring expectations in the Arab context. These problems are due to values considerations, gender segregation among the patients and staff, and family and tribal relationships. Jasemi et al. (2017) postulated that holistic care is an unfamiliar concept in Iran and that a philosophical shift is needed to encourage nurses to reflect on their roles. This is both within the healthcare team, and it is to enhance their contributions to patient care beyond that of being assistants to doctors. To Holt-Waldo (2011), an observable change in the interventional methods can be seen once holistic nursing is employed. While holistic care is assumed to be an all-inclusive context, previous studies demonstrate that nurses do not apply holistic care well (Zamanzadeh et al., 2015). This study is important because it deals with the determination of holistic care practice in the Arab context. Exploring the holistic care employed by the nurses helps to determine what needs to be improved in their caring practices that use this model. To this end, the nurses engaged themselves in using holistic care in examining themselves through this study. The study aimed to determine holistic nursing care and to compare its differences based on individual characteristics. Methods Study Design This study employed a quantitative-cross sectional design. Setting The study was conducted in the operating rooms of the hospitals of the Hail region of Saudi Arabia. The researchers utilized the total population sampling for the hospitals. The hospitals were King Khalid Hospital, Hail General Hospital, Maternity Hospital, King Salman Hospital, and Saudi German Hospital. Participants The study participants were operating room nurses, 154 in total. The researchers set the inclusion criteria as nurses who had been assigned to the operating room permanently and who had direct contact with the patients for surgery. Intern nurses, regular employee nurses who were on leave, and nurses who were not willing to participate were excluded from the study. The non-probability sampling, specifically convenience sampling, was utilized in this investigation due to participants’ accessibility. The Raosoft sample size calculator (http://www.raosoft.com/samplesize.html) was used to determine the sample needed in this study. Through convenience sampling, using a 5% margin of error and a 95% level of confidence, of 254 operating room nurses, only 154 served as participants. Instrument The researchers utilized a researcher-made tool because there is no explicit tool available to determine the holistic practices of nurses in the operating room. The composition of the tool was based on the holistic care theory, literature from similar studies, and the opinions of experts. The tool was composed of a 20-item statement that was divided into four dimensions. These included the physiological dimension with five statements (e.g., Do you identify the patient for operation accurately?), the socio-cultural with five statements (e.g., Do you respect cultural differences that may affect opinions, values, and beliefs of the patient and his or her family?), the psychological dimension with five statements (e.g., Do you assess the patient’s knowledge and understanding of the surgery?), and the spiritual with five statements each (e.g., Do you encourage patients to pray before surgery?). These statements were rated using a five-point Likert scale with the corresponding verbal interpretations: 5 – Every time, 4 – Almost every time, 3 – Sometimes, 2 – Almost never, and 1 – Never. Higher mean scores indicate a consistent demonstration of holistic care. The scale measurement and verbal interpretations utilized in the analysis of data were 1–1.5 (Never), 1.51–2.5 (Almost never), 2.51–3.5 (Sometimes), 3.51–4.5 (Almost every time), and 4.51–5 (Every time). Since most nurses can comprehend and speak English, the researcher-made questionnaire was in the English language. The tool was subjected to face validity by five experts in the field. Two had a doctorate in psychology and work as psychometricians in a university; one is a doctor of nursing practice working in the hospital, and the other two are nursing directors of continuing nursing education. Suggestions were implemented in the final draft. Content validity was conducted, resulting in 0.77 for the relevance score of 0.78 for clarity. These results indicate a high level of content validity. The tool was tested with 15 operating room nurses for reliability, resulting in a reliability coefficient of 0.70. This means that the tool was reliable. Data Collection With the approval of the hospital authorities, the researchers conducted a face-to-face orientation with the operating room nurses to explain the purpose of the study, their rights, the benefits, and the extent of their participation. The researchers personally handed the questionnaires to the participants, and they were given two days to answer it considering the nature of their work and their schedule. The data was gathered from February 2020 through March 2020. Data Analysis The data were examined using SPSS version 25. The normality test using the Kolmogorov-Smirnov test revealed 0.73, which means that data are normally distributed. The frequency distribution and percentages were used to determine the demographic profile of the respondents. The weighted mean was used to determine the holistic nursing care practices of the respondents in the operating room. The t-test and the analysis of variance (ANOVA) were used to determine the presence of a significant difference, if any, between the holistic nursing care practices of the respondents when grouped according to the demographic variables included in the study. Ethical Consideration This research received ethical clearance from the University of Ha’il. Written informed consent was included in the survey instrument, which the participants need to sign before they can proceed to answer. The rights, benefits, anonymity, and confidentiality of the participants were all fully ensured throughout the entire course of the research process. Results Most of the participants were in the age range of 31 to 35 (48.7 %), followed by 36 years and above (31.8%). The majority were female (83.1%); 50 percent were Saudi, and 50 percent were non-Saudi. Regarding the length of experience, 76 percent of the participants had six or more years of experience (Table 1). Table 1 Demographic information of the participants Demographic Information Frequency Percentage Age (years)  25-30 30 19.5  31-35 75 48.7  36 and above 49 31.8 Gender  Male 26 16.9  Female 128 83.1 Nationality  Saudi 77 50  Non-Saudi 77 50 Length of experience (years)  Less than five years 37 24  Six years and above 117 76 The participants perceived that holistic dimensions such as physiological (4.72 ± 0.40), socio-cultural (4.53 ± 0.45), psychological (4.66 ± 0.32), and spiritual (4.22 ± 0.73) were consistently carried out in the operating room (Table 2). Table 2 Overall mean and standard deviation of the holistic dimension Holistic Dimension Mean SD Remarks Physiological 4.72 0.40 Every time Socio-cultural 4.53 0.45 Every time Psychological 4.66 0.32 Every time Spiritual 4.22 0.73 Every time SD= standard deviation Table 3 shows the differences in the demographic information of the participants regarding the physiological, socio-cultural, psychological, and spiritual dimensions. On the physical dimension, no significant differences were found in years of experience [(t) -0.073; p > 0.942], gender [(t) -1.113; p > 0.27], or age [(F) 0.558; p > 0.57), but there was a significant difference regarding the nationality of the participants [(t) -3.328; p < 0.001]. Table 3 Differences on the demographic information as to physical, social, psychosocial, and spiritual dimension Mean SD Test Value df p Physiological dimension Length of experience (years) Less than five years 4.72 0.44 (t) -0.073 152 0.942 Six years and above 4.72 0.39 Gender Male 4.63 0.51 (t) -1.113 30.82 0.274 Female 4.74 0.37 Nationality Saudi 4.62 0.47 (t) -3.328 129.54 0.001* Non-Saudi 4.83 0.29 Age 25-35 4.71 0.44 (F) 0.558 153 0.573 36-45 4.76 0.36 46 and above 4.68 0.44 Socio-cultural dimension Length of experience (years) Less than five years 4.57 0.44 (t) 0.599 152 0.550 Six years and above 4.52 0.46 Gender Male 4.42 0.45 (t) -1.420 152 0.158 Female 4.56 0.45 Nationality Saudi 4.77 0.33 (t) -7.516 140.77 0.001 * Non-Saudi 4.53 0.32 Age 25-35 4.58 0.42 (F) 0.148 153 0.862 36-45 4.52 0.47 46 and above 4.53 0.45 Psychological dimension Length of experience (years) Less than five years 4.73 0.29 (t) 1.463 152 0.145 Six years and above 4.64 0.33 Gender Male 4.59 0.24 (t) -1.545 46.45 0.129 Female 4.68 0.34 Nationality Saudi 4.53 0.32 (t) -5.492 152 0.001* Non-Saudi 4.80 0.28 Age 25-35 4.62 0.34 (F) 1.259 153 0.287 36-45 4.70 0.29 46 and above 4.62 0.36 Spiritual dimension Length of experience (years) Less than five years 4.09 0.86 (t) -1.101 51.57 0.276 Six years and above 4.26 0.69 Gender Male 3.73 0.78 (t) -3.890 152 0.001* Female 4.32 0.69 Nationality Saudi 4.01 0.78 (t) -3.653 145.15 0.001* Non-Saudi 4.43 0.63 Age 25-35 4.21 0.69 (F) 0.584 153 0.559 36-45 4.29 0.75 46 and above 4.22 0.74 * significant at 0.05; df= degrees of freedom Regarding the socio-cultural dimension, the length of experience [(t) 0.599; p > 0.550], gender, [(t) -1.420; p 0.158], and age [(F) 0.148; p >.862] were not significant. However, a significant difference was found regarding the nationality [(t) -7.516; p < 0.001] of the participants. Regarding the psychological dimension, there were no significant differences regarding length of experience [(t) -1.101; p > 0.276], gender [(t) -1.545; p > 0.129], or age [(F) 1.259; p > 0.287], however, there was a significant difference with nationality [(t) -5.492; p < 0.001]. With the spiritual dimension, no significant difference was found on the length of experience [(t) -1.101; p > 0.276] or age [(F) 0.584; p > 0.559], but there were significant differences on gender [(t) -3.890; p < 0.001] and nationality [(t) -3.653; p < 0.001]. Discussion This study aimed to determine the level of demonstration of holistic nursing among the staff nurses in the operating rooms of the hospitals of Hail, Saudi Arabia. Overall, the staff nurses perceived that holistic dimensions such as the physiological, socio-cultural, psychological, and spiritual were consistently demonstrated. This indicates that the staff nurses provide care to patients based on a mutual comprehension of their physical, psychological, socio-cultural, and spiritual aspects. This supports a study conducted previously in which nurses received performance ratings of “very good” and “excellent” in their holistic care (Albaqawi et al., 2017). In this study, the nurses were mindful of the realities of physiological care and that nurses and patients collaborate on healthcare demands that lead to recovery. Regarding the socio-cultural dimension, the nurses understood that reverence of culture is required for the patients and their families. This validates the studies of both Sevinç et al. (2016) and Almutairi et al. (2015), wherein values, language, and norms are essential for the nurses to communicate and understand their patients. Since the patient is unconscious, the psychological aspects of holistic care may not be apparent in an operating room. Nevertheless, important concerns must be taken into consideration before the surgery. For instance, nurses conveyed the essential instructions regarding the post-operation management of pain (Panlican et al., 2020). In this context, nurses were obliged to enlighten the patients regarding their illness, to assess their psychological capacity, and to inform them of accessible alternatives to handling their illness (Al‐Mutair et al., 2014). Spiritual care focuses on the patients’ belief that nurses are mindful of its importance in line with delivering holistic care. According to Gore (2013), addressing spiritual care includes active listening, therapeutic touch, and assistance on spiritual activities. The demographic traits, working environment, and educational system are the primary aspects when caring for a patient holistically. These provisions of holistic care have been demonstrated in earlier studies (Shiao et al., 2019; Zamanzadeh et al., 2015). Such a finding indicates the need for closer attention to the educational system, including adjustment and modification of the course in the nursing curriculum to intensify the holistic care. In addition, nurses should create an atmosphere capable of providing holistic treatment, understand the socio-cultural and social condition of the patient, and be intimately familiar with their family and living environment. To develop holistic caring, the congruence between the identities of the nurses and their discipline, the development of their communicative abilities, and the promotion of involvement in the practice of nurses and nursing students must be appreciated. Nurses can utilize holistic nursing care to enhance the lives of the patients and their own lives. The key is not necessarily about how long the nurses spend interacting with a patient, but about how the nurses use their time with them. In this study, no significant differences were found in the physiological, socio-cultural, or psychological with years of experience, gender, and age; however, a significant difference was found with nationality. The difference regarding nationality means that there could be a language barrier and marginalization in the system among the nurses or even among the patients. Studies found that, because of the immense diversity in culture, language barriers, and lack of support, nurses had difficulties understanding and remembering cultural preferences (Hart & Mareno, 2014; Mcfarland & Wehbe-Alamah, 2014). Saudi Arabia’s healthcare system relies heavily on immigrant nurses hired from over 52 countries (Alyami & Watson, 2014). Differences in faith, culture, social values, and language can build barriers between patients and immigrant nurses (Al-Mahmoud et al., 2012). The nurses were consistently concerned with meeting language barriers (Hadziabdic et al., 2015). Communi-cating health information is additionally challenging in a setting where the patients and healthcare professionals speak different languages, and English is the language of the healthcare practice. The findings on these dimensions provide awareness to nursing administration to create policies and procedures. Nurses who speak the language can, for instance, be partnered with nurses who are still learning it. This serves to provide consistent direction by eliminating misunderstandings and establishing a well-meaning working environment (Atanga & Ayong, 2017). It becomes easier to solve nursing care problems when protocols and guidelines are clearly followed by nurses and patients. Holistic nursing care should consider the principles and beliefs that affect people, families, and groups. To provide reliable, fulfilling, and culturally appropriate treatment, it must be focused on the patients’ cultural way of life (Zamanzadeh et al., 2015). By understanding these differences, nurses will resist stereotyping and recognize that not all patients can react to the values or traditions of nursing care (Mcfarland & Wehbe-Alamah, 2014). On the spiritual dimension, the length of experience and age were not significant. However, a significant difference was found in the nationality and gender of the participants. This difference was there because most of the nurses delivering health care are immigrant nurses and Christians, and they are assumed to adjust, especially regarding their religion. Saudi Arabia is known to be an absolute Muslim country where Christian nurses might have difficulty expressing their faith. Almutairi et al. (2015) pointed out that, while Saudi Arabia gives freedom to non-Muslims to practice their religion, it has to be in private. The significant difference in gender implies that the nurses’ gender could create a deficiency in capability and confidence in them to provide spiritual care. This result may be attributed to the extreme working conditions and obligations of mothers and housewives, as determined by their culture (Alshehry, 2018). As Almutairi et al. (2015) maintained, spiritual care could be associated with personal features such as gender, which can lead to disparities in the nurses’ capability to deliver spiritual care. These results could contribute to nursing education, provided that the development of an effective cultural and language training program is added before immigrant nurses leave their home country. Moreover, the introduction of guidance programs to help immigrant nurses benefit tremendously from the provision of spiritual care (Alshammari et al., 2019). Similarly, education curriculums can deal with gender disparities and inequality to provide nurses with practical learning opportunities (Jradi et al., 2013). Decreased levels of spiritual suffering are seen when spiritual demands are met (Kitchener, 2019). Moreover, there are reports that sufficiently attending to spiritual needs can enable healing (Willemse et al., 2018). Overall, the implications of this study give a better perspective for nurses about the value of more comprehensive and structured treatment being implemented and provided. Indeed, the findings of this study provide operating room nurses the need to continue offering systematic nursing, not just in Saudi Arabia but also in the international context, taking into account the beliefs, cultures, and viewpoints of patients. The findings of this study highlighted the causal factors affecting holistic treatment and prompting other nurses and nursing stakeholders globally to look for ways to improve holistic nursing further. This helps nurses to understand better the use of holistic care in improving the condition of their patients. Of note, regardless of the nurses’ demographics, this research is a compelling reminder that holistic nursing improves the overall outcomes of care. The authors acknowledged the limitations of this study. Some of the limitations include; the use of convenience sampling, which lacks clear generalizability, the non-inclusion of the construct validity, which may enhance to strengthen the instrument’s validity, and the non-translation of the instrument to the Arabic version. These limitations can be addressed in future studies such that investigators will consider using probability sampling (e.g., simple random sampling) and re-validate the instrument within the investigator’s locality with construct validity when using the developed tool. Translation of the instrument to include non-English speakers is highly recommended to future investigators conducting the same study focus. Conclusion Nationality plays a role in the physiological, socio-cultural, psychological, and spiritual dimensions, while gender is a factor of the spiritual aspect. In addressing these variables in the continuing nursing education, it is assumed that nurses deliver more holistic and comprehensive care. Regardless of nationality or gender, nurses must be knowledgeable regarding the significance of adopting holistic care to improve the quality of their care to their patients. Acknowledgment The authors would like to acknowledge the support of the Scientific Research Deanship of the University of Ha’il Saudi Arabia to this research endeavor. Declaration of Conflicting Interest The authors declare no conflict of interest. Funding This research has been funded by the Scientific Research Deanship of the University of Ha’il Saudi Arabia with project number RG-191236. Author Contribution HMA and VEB conceptualized and drafted the research, BSA and RDD performed data collection, data management, and analysis. PP focused in developing the questionnaire and validation. All of the authors read and approved the final draft. Data Availability Statement The data that support the findings of this study are available upon request to the corresponding authors. Author Biographies Dr. Hamdan Mohammad Albaqawi is a Former Dean and Faculty Member at the College of Nursing, University of Ha’il, Saudi Arabia. Mr. Vincent Edward Butcon is a Staff Nurse at Tallahasse Memorial Healthcare Inc., Florida, USA. Dr. Bander Saad Albagawi is a Dean and Faculty Member at the College of Nursing, University of Ha’il, Saudi Arabia. Dr. Richard Dennis Dayrit is a Vice Dean and Faculty Member at the College of Nursing, University of Ha’il, Saudi Arabia. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-186 10.33546/bnj.1427 Original Research Lived experiences of Overseas Filipino Worker (OFW) nurses working in COVID-19 intensive care units Pogoy Jane Marnel https://orcid.org/0000-0003-3227-4543 Cutamora Jezyl C. * Cebu Normal University, Philippines Corresponding author: Jezyl C. Cutamora, PhD, Cebu Normal University, Block 2 lot 13 888 Acacia Drive Subdivision Capitol Site Cebu City 6000 Philippines. Mobile: +63 032 254 4837 / +63 9195044984. Email: cutamoraj@cnu.edu.ph Cite this article as: Pogoy, J. M., & Cutamora, J. C. (2021). Lived experiences of Overseas Filipino Worker (OFW) nurses working in COVID-19 intensive care units. Belitung Nursing Journal, 7(3), 186-194. https://doi.org/10.33546/bnj.1427 28 6 2021 2021 7 3 186194 16 3 2021 18 4 2021 03 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Limited studies focus on the effects of the pandemic on the nurses' overall risks and wellbeing. At present, no single study has been published on Filipino nurses’ experiences outside the country during the COVID-19 pandemic. Objective This descriptive phenomenological study explored the Overseas Filipino Worker (OFW) nurses’ experiences working in COVID-19 intensive care units. Methods The study was conducted in Dubai, United Arab Emirates, where there is a high number of COVID-19 cases. This study utilized a qualitative Husserlian phenomenological approach to describe and explore the lived experiences of the OFW nurses’ caring for COVID-19 critically ill patients. The research key interview informants were eight ICU nurses who cared for COVID-19 patients in Dubai hospitals. Data saturation was reached. Data collection was done in 2020, and Collaizi’s method of data analysis was utilized. Results A total of 135 significant statements were extracted from the interview transcripts. There were 36 formulated meanings generated, and four themes emerged from this study. The first theme is Challenges During the Pandemic with the following subthemes: Away from Home, Caring for the COVID-19 Patients, and Fear of the Unknown. The second theme is Patient Care during COVID-19 with the following subthemes: COVID-19 ICU Patient Care and The Nursing Profession. Third, Adapting to Change with the subthemes: Living the New Normal and Protecting One’s Self from COVID-19. Lastly, Resilience Amidst the Pandemic with the following subthemes: Being with Others and Seeing Oneself. Conclusion Despite the existing challenges like cultural differences and homesickness faced by these OFW nurses and the new challenges they are faced with the pandemic today, they were still able to continue living and do what is expected of them. From the hassle of wearing the PPEs, shortage of PPE, and being transferred from one unit in the hospital to another, the OFW nurses were able to adapt to these changes. The nurses already got used to the routine, but the fear of getting infected by the virus is still there. lived experiences OFW nurses COVID-19 intensive care units hospitals United Arab Emirates patient care ==== Body pmcAccording to the World Health Organization (WHO, 2020a), COVID-19 is a highly transmissible disease caused by a SARS-CoV 2 strain. Literature has shown that nurses need to sacrifice their own needs to prioritize the crisis management strategies and a need to make selfless and significant contributions out of moral and professional responsibility (Aliakbari et al., 2014). There are limited studies focusing on the effects of the pandemic on the nurses' overall risks and wellbeing. At present, no single study has been published on Filipino nurses’ experiences outside the country during the COVID-19 pandemic. Thus, this descriptive phenomenological study will describe and explore Overseas Filipino Workers (OFW) nurses working in COVID-19 Intensive Care Units. COVID-19 infection has quickly spread globally, and due to the sudden outbreak, nurses are faced with a lot of pressure and new challenges like being transferred to new units or wards and adjusting to what is presently called the new normal (Sun et al., 2020). Some studies have shown that when nurses are caring for patients with highly transmissible diseases such as SARS (Chung et al., 2005) and MERS-Cov (Kim, 2018), nurses tend to suffer from psychological issues such as loneliness, anxiety, fear, fatigue, sleep disorders, and other physical and mental health problems. A study found the prevalence rate of psychological effects among nurses involved in the treatment of infectious disease (such as SARS patients), namely: depression at 38.5%, insomnia at 37%, and post-traumatic stress at 33% (Sun et al., 2020). Furthermore, among the psychological status of Ebola patients’ caregivers, 29% of respondents felt lonely, and 45% received psychological counseling. On the contrary, the positive experience and growth brought by the collective anti-epidemic efforts were also demonstrated (Sun et al., 2020). Presently, many studies are published on how the COVID-19 pandemic has strained the world’s healthcare systems that include nurses. As cited by Mo et al. (2020), among the healthcare workers, nurses are found to be the most anxious and stressed in caring and treating patients infected with the COVID-19. Nurses who provided direct patient care seemed to be more stressed, overworked, and psychologically disturbed and less fulfilled in their job compared to nurses in other areas of assignment (Zerbini et al., 2020). Hospital women nurses who performed diagnosis, care, treatment, and management of patients with COVID-19, have shown psychological disturbances such as anxiety, lack of sleep, and depression (Lai et al., 2020). For many years, Filipino nurses have been migrating abroad to meet the very high demand in other countries. The Philippine Overseas Employment Administration estimates more than 13,000 health care professionals leave the country every year. Many Filipino families view the nursing profession as their ticket to a better life earning 15 times more than their salary while working in our local hospitals (Lorenzo et al., 2007). As other countries have a shortage of nurses, they began hiring Filipino nurses because it is more cost-effective than training their own nurses (Lorenzo et al., 2007). With Filipinos being fluent in English, innately caring for the elderly and the sick, being adept in adjusting to new cultures and learning new languages, and not minding working longer hours, they perfectly fit the bill for nursing. The ongoing COVID-19 pandemic poses great pressure, most especially in the critical care areas due to the large number of patients requiring critical care (Shang et al., 2020). As observed, Filipino nurses assigned in these areas face a lot of struggles in managing these critical patients in terms of implementing new practices, frequent changes in the medical and nursing management, and the virus is not readily studied yet. On top of the mentioned challenges, these nurses also are worried about their families in the Philippines, adjusting to the environment, interacting with people with different cultures, and so much more. Overseas Filipino Workers (OFW) nurses are already faced with challenges every day, especially because they are working away from their country. They worry about their safety while working and at the same time worry about their families back at home. A lot of changes have been implemented in the hospital to address staffing problems. Some of the nurses are being pulled out to other units, and leaves were canceled. In this time of the pandemic, they are forced to find means to adapt to the present situation. As nurses are placed in demanding situations, fulfilling their roles on the frontline while at higher risk just to save others, this study will explore and describe the lived experiences of the OFW nurses working in COVID-19 Intensive Care Units. This study can help hospital administrators and government agencies understand the situation of OFW nurses and serve as a basis for them to develop new or revised policies that are beneficial to the welfare of the nurses and the patients. Methods Study Design This study utilized the qualitative Husserlian phenomenological approach to describe and explore the meaning of OFW nurses’ lived experiences caring for critically-ill patients with COVID-19. Descriptive phenomenology was used for it has laid the foundation for theoretical knowledge and methodological clarity and rigor in qualitative nursing research Abalos et al. (2016) and Norlyk and Harder (2010). Husserlian phenomenology allows the researchers to explore and describe the structures of consciousness as experienced from the first-person point of view. Key Informants The key informants are OFW nurses assigned in the COVID-19 intensive care units and interviewed at their houses and hospitals. The researcher used purposive sampling in choosing the participants or key informants of this study. Purposive sampling is a strategy selected that will give information necessary for the needs of the study (Polit & Beck, 2017). In this study, the research participants were eight ICU nurses who cared for COVID-19 patients in Dubai hospitals. Exclusion criteria of the study included the unwillingness to participate in the study and nurses with a COVID-19 diagnosis. Data Collection The main instrument of this study is the researchers, as cited by Polit and Beck (2017). This highlighted the role of the researcher during interviews and observations. An English and vernacular semi-structured interview guide made by the researcher was utilized and expert-validated. The language used was based on informants’ preference. This interview guide comprises three parts: warm-up questions, main questions, and follow-up or probing questions. Sample grand tour question is “Can you describe to me your experiences as a Filipino nurse caring for patients with COIVD-19 in ICU in another country?”. Probing was done to encourage the respondents to give more information. Probes were neutral to avoid bias. Open-ended questions were used to provide the respondents with ample opportunity to express their feelings. Prior to starting the interview, bracketing was done. This is important to mitigate the preconceptions or biases that may taint the research process. During the interview, the standard COVID-19 safety protocols were followed. Important aspects of the research were explained and discussed with the key informants, such as the use of a tape recorder, the interview venue, and the time that can be devoted to the interview. Then informed consent was obtained from the key informants. The researcher remained neutral throughout the interview process. The researcher started the interview with the list of semi-structured interview questions the researcher has prepared through one-on-one, face-to-face interviews. The average interview duration was one hour and 30 minutes and was duly recorded. The interview was conducted by JMP, spending one day per informants. Translation and back-translation with the help of a language expert were done to ensure the accuracy of the translation. Data Analysis Colaizzi’s method of data analysis is deemed most fitting and was utilized. This method uses components of Husserlian phenomenology, putting a premium on the description of the lived experience (Morrow et al., 2015). Colaizzi’s method of data analysis consists of seven steps. The first is to read and re-read all the participants’ verbatim transcripts of the phenomena to acquire a feeling. Second, significant statements or phrases are extracted from participants’ transcripts pertaining directly to the research phenomena. Then, formulated meanings are constructed from the significant statements. Fourth, formulated meanings are arranged into cluster themes which evolve into emergent themes. Then the results were incorporated into a rich and exhaustive description of the lived experience. Sixth, the thorough description from the participants involved in the research was validated. Lastly, new or pertinent data obtained from participants’ validation was incorporated and adapted to attain congruence with the lived experience of the participants studied. This study is rooted in the phenomenological framework to explore the OFW ICU nurses’ experiences in caring for the COVID-19 patients to develop a composite description of the essence of the experience for all the participants. Data was collected and analyzed using the steps from Colaizzi’s descriptive phenomenological method. Significant themes and meanings were interpreted through rigorous analysis of data to formulate the composite findings for this research study. Rigor of the Study Multiple semi-structured interviews per informant were done in different time-points to facilitate qualitative research rigor. To enhance the trustworthiness of this study, the following steps were done. First, person triangulation was done where auxiliary informants confirmed the statements made by the key informants or participants. Other colleagues not included in the key informants were also interviewed for confirmation of the key informants’ statements. The second is time triangulation, where the same questions were asked at different time points during the interview. Lastly, method triangulation wherein aside from multiple individual interviews, observation was done by the researcher to confirm statements and the researcher’s reflection. Observations were done by looking at the congruency of the verbalizations and the facial expressions and non-verbal cues. Ethical Consideration The researcher assures that the study adhered to the basic ethical considerations. The COVID-19 safety protocols were implemented throughout the research process. The data gathering was done after the participants were informed of the purpose of the study and have provided informed consent. It was made clear to the OFW COVID-19 ICU nurses that their participation is voluntary and that they can choose not to complete the interview without any consequence. Further, the participants were informed of their anonymity and that the data provided will be kept confidential. This study was reviewed and approved by Cebu Normal University – Ethics Review Committee with an approval code of 606/2020-11. Results Characteristics of Key Informants Table 1 shows the profile of the informants of the study, including the code name, age, sex, civil status, and length of time they were working in the COVID-19 ICU. It shows that the informants are between 28 and 32 years old, and most are married. The shortest length of time they spent in the COVID-19 ICU is six months, and the longest is 11 months. They are all registered nurses. Some are master’s degree holders. Table 1 Profile of the Informants Code Name Age Sex Civil Status Length of time Working in COVID-19 ICU SN01 29 Female Married Eight months SN02 29 Female Married Six months SN03 29 Male Single Ten months SN04 30 Female Married Six months SN05 32 Female Married Six months SN06 32 Female Married 11 months SN07 31 Male Single Seven months SN08 28 Male Married 11 months Thematic Analysis A total of 135 significant statements were extracted from the interview transcripts from the eight informants. There were 36 formulated meanings generated from these significant statements, and four themes emerged from this study. The first theme is Challenges During the Pandemic with the following subthemes: (a) Away from Home, (b) Caring for the COVID-19 Patients, and (c) Fear of the Unknown. The second theme is Patient Care during COVID-19 with the following subthemes: (a) COVID-19 ICU Patient Care and (b) The Nursing Profession. Third, Adapting to Change with the subthemes: (a) Living the New Normal, and ( b) Protecting One’s Self from COVID-19. Lastly, Resilience Amidst the Pandemic with the following subthemes, (a) Being with Others and (b) Seeing One self. These themes will be discussed further in the following. Theme 1. Challenges During the Pandemic This discusses the problems faced by the key informants assigned in COVID-19 ICUs during the pandemic. According to Sadang (2020), the COVID-19 health crisis caused an unforeseen paradigm shift in nurses’ life in healthcare systems, resulting in stressful and overwhelming challenges in their daily battle against this illness. Subtheme 1. Away from Home This is about the challenges faced by the key informants working abroad. It includes the feeling of homesickness, being away from the family, the cultural differences that they have observed, and the cancellation of plans due to the pandemic. SN01 stated that SS2 “Aside from that, being a nurse overseas means being away from your family and loved ones, so you miss out on special occasions and holidays.” She added that “Uhmm, actually church wedding namin dapat ng husband ko but because of this travel ban, di natuloy.” (Because of this travel ban, my church wedding was postponed). SN04 also mentioned that SS39 “Di naman nawawala yung pagiging homesick” (Homesickness is always there) and added, “Miss ko na anak ko” (I miss my child). SN07 mentioned that SS95 “Pero di gihapon mawa ang kamingaw uy samot nag close jud kaayo mos imong family.” (But the feeling of missing your family is always there, especially if you have a close relationship with them). Lastly, SN08 said SS19 “Kanang homesickness ug cultural differences given naman.” (Homesickness and cultural differences are given). The issue of homesickness has not been addressed by international human resource management for a long time. Despite the recognition in the literature that expatriates go through the critical issue of adjustment (Haslberger et al., 2014) triggers the feelings of disconnection and missing home and has been a not-easy-to-achieve situation (Ward et al., 2001). Subtheme 2. Caring for the COVID-19 Patients This discusses the concerns faced by ICU nurses assigned to care for COVID-19 patients. This includes the hassle of wearing personal protective equipment (PPE), feeling of anxiety of possibly getting infected, not meeting the standards of care, and thinking about their families back home worrying about their safety. According to SN01, SS4 “At first, I was very anxious to handle COVID-19 positive patients because I was worried that I might also contract the disease.” SN03 also stated that “Mas kapoy lang sad ang sa COVID-19 kay mag PPE kag taas na time.” (It’s more tiring in COVID-19 units because you have to wear PPE for a longer period). SN05 said, SS60 “Naa baya koy newborn sa balay nya simbako matakdan ko ig duty.” (I have a newborn at home, and I’m scared to get infected). She also added that “Kapoy pud kay the usual na daghan na layers na PPE, init kaayo maski aircon pa. Then if naay procedures sa bedside, lisod pud kay di kaayo ka kaklaro tungod sa face shield.” (It’s tiring because of the PPE. It feels really hot wearing them even with the air conditioner. If there are bedside procedures, it is difficult because you can’t see properly because of the face shield). Lastly, SN07 verbalized that SS100 “Hadlok ko uy sa akong safety.” (I was scared for my safety). Front-line nurses experience an enormous amount of work, long-term exhaustion, infection risk, and frustration with the death of patients they care for. They also face anxiety or even disagreement among patients and their family members (Shen et al., 2020). Subtheme 3. Fear of the Unknown This tackles the fears of the informants regarding the disease, the unpreparedness for this pandemic, and the uncertainty of the future. SN01 stated that SS5 “Also, it is a new illness so little is known about the virus, its transmission and effects on different types of people.” SN02 verbalized that, SS20 “Kuyaw pud kay mas higher imong chance ma infect unya handtud karon, wala pay mga certain treatment jud na makaingon kag effective jud plus if ever, simbako, matakdan ka, layo pa jus imong family.” (It is risky to get infected because until now there is no certain effective treatment, and if ever you get infected, you are very far from your family). According to SN03, SS34 “In some aspects siguro kay diri sa UAE naa man jud silay disaster plan and kani na pandemic considered man na disaster but for sure di jud emotionally prepare ang tanan.” (In some aspects, because here in the UAE, they really have a good disaster plan and this pandemic is considered to be a disaster but one thing is for sure, we are not all emotionally prepared). SN04 said, SS42 “Mahirap kasi wala naman talagang nakapagprepare for this pandemic.” (It’s hard because nobody was really prepared for this pandemic). The current COVID-19 pandemic presents a considerable occupational vulnerability for the health care team, causing fear or anxiety. These can be brought about by knowing or having more information and fear of the unknown related to the virus (Coelho et al., 2020). Fear of the unknown appears to be a fundamental fear and is a core component of anxiety (Carleton, 2016; Gallagher et al., 2014). Theme 2. Patient Care During COVID-19 Averting a nosocomial outbreak of COVID-19 through transmission from patients to healthcare workers is essential. New and improved policies have been implemented to protect the healthcare worker and the patient. This section discusses about the changes in the care provided to the COVID-19 patients and the roles and responsibilities of nurses. Subtheme 1. COVID ICU Patient Care This tackles about the care provided to the COVID-19 ICU patients in comparison to non-COVID-19 ICU patients. This also includes the support given by the nurses to the patients. According to SN01, SS6 “Sa COVID-19 positive patients, mas clustered yung care na binibigay sa kanila.” (In COVID-19 patients, we provide clustered care). She also added that SS7 ”Dapat as much as much as possible, ilessen yung time sa loob ng patient’s room, to lessen also your exposure.” (As much as possible, we spend less time inside the patient’s room to lessen our exposure). SN02 mentioned, SS24 “Ipafeel nako nila na makarely sila nako sa scariest time sa ilang life.” (I will let them feel that I am there at the scariest part of their life). SN05 verbalized, SS71 “Ang ako lang is ikeep nako in mind na atimanon lang jud sila ug tarong. Mo empathize lang jud ta nila.” (I keep in mind to properly take care of them. We should empathize with them). SN07 said, SS102 “And kailangan sad jud tas mga patients especially karon.” (And the patients need us especially nowadays). Although nursing care of patients with COVID-19 is largely supportive, it should include a strong emphasis on alleviating the spread of contamination to staff, other patients, and the community (Deitrick et al., 2020). The first priority of any nurse should be to protect themselves with the appropriate PPE. Nursing care should focus on limiting the exposure and spread of the virus. The whole experience of COVID-19 infection, in the form of staying in isolation wards, could be very traumatic, even for patients who are minimally symptomatic or asymptomatic (Sahoo et al., 2020). It is important to provide support to these patients, especially during this time. Subtheme 2. The Nursing Profession Nurses are very valuable in the healthcare systems and are crucial to health promotion, disease prevention, and treatment (Robertson-Malt, 2020). The World Health Organization (WHO, 2020b) considers nurses and midwives as the cornerstone in helping countries meet their commitments to Universal health coverage. SN03 stated that SS38 “It also made me realize how noble the nursing profession is, and I am proud that I have pursued it.” SN04 mentioned SS58 “Also, dapat din natin alagaan sarili natin para mafulfill natin ang ating duty.” (We need to take care of ourselves to fulfill our duties). SN05 verbalized, SS61 “Worried kaayo ko all the time pero unsaon ta man, part man nis atong trabaho.” (I am worried all the time but this is part of our job). SN07 said, SS117 “And kita nurses di ta dapat moundang ug educate sa mga taw and should lead by example.” (And we nurses should not stop educating the others and should lead by example). Nurses are usually in the front line of care. They make a difference in individual patients’ lives and the community as a whole. Due to their sheer numbers and the locations where they often work, nurses are key players in improving public health outcomes around the world (Robertson-Malt, 2020). Theme 3. Adapting to Change Change is inevitable, but a drastic one has happened during this pandemic. The way we live nowadays is different, and people around the world are starting to adapt to these changes. But until a safe and effective coronavirus vaccine is available, there will always be a risk of infection, especially now that people are starting to go back to work. Businesses are re-opening, and classes at some schools were resumed. This part discusses about the present situation, adjustments made, and self-protection. Subtheme 1. Living the New Normal This talks about the experiences of the key informants with our present situation in this time of the pandemic. SN03 stated, SS33 “Sauna mogreet with a smile jud kas imong patients, tabi sa mga kauban, party2x, but karon? Di ka kastorya sa uban without a mask and social distancing.” (Before, we used to greet the patients with a smile, talk with our colleagues and attend parties. But now, we can’t even talk with others without a mask and social distancing). SN04 said, SS51 “Wala na din kasi masyadong gala sa labas.” (We don’t go out that much anymore). SN05 verbalized, SS77 “Then mask jud bisag asa kay aside sa protection sa imong self, makabayad tag fine.” (We wear the mask all the time not only to protect ourselves but also to avoid paying the fine). SN06 mentioned about always wearing a mask, SS85 “Wearing a mask is part of my outfit every day since it is now mandatory.” Ever since the WHO declared this pandemic, we were forced to change the way we live. According to the Centers for Disease Control and Prevention (2021), we have to practice physical distancing, wearing masks all the time, and doing hand hygiene all the time to help prevent the spread of infection. These practices were followed by the key informants. The present pandemic pushed the key informants to look for ways to connect with their families in the Philippines even if they are far from them and discover new activities while staying at home most of the time. SN02 said, SS25 “Ngita jud ug paagi na connected gihapon mi despite sa distance.” (We find ways to stay connected despite the distance). SN03 stated, SS36 “Physical activities and constant communication lang jud with the family.” (Physical activities and constant communication with the family). SN04 verbalized about adjusting to the present situation, SS45 “Ngayon, nakapag adjust naman na.” (I have adjusted now). She also added that she got more attached to her family, SS48 “Mas attached ako sa kanila ngayon. Sila kasi yung source of inspiration ko at strength.” (I’m more attached to them now because they are my source of inspiration ang strength). SN05 mentioned about constant communication, SS65 “Video call video call lang kada adlaw.” (We just call each other through video call every day). She also mentioned, “Kailangan sad jud mo adapt.” (We need to adapt). SN07 stated, SS94 “Pero naanad ra sad kadugayan.” (But I got used to it eventually). Due to the present situation, the key informants looked for alternative ways to connect with their families in the Philippines using different platforms for this will give them strength while working abroad. They also did more enjoyable activities with their friends in their respective residences or accommodation to pass the time and verbalized that they have already adjusted to the present situation. Subtheme 2. Protecting One’s Self from COVID-19 The following statements made by the key informants are indicative of ways on how to protect themselves from being infected with COVID-19. SN01 stated, SS17 “Aside from religiously drinking vitamins and minerals, during this pandemic, I sanitize everything that I brought outside including bags, cards, and cell phone.” She also added, SS18 “Every after duty, I make sure to take a bath and disinfect properly the uniform I used in the hospital as well as clothes worn outside of the accommodation.” SN04 mentioned, SS54 “As much as possible, healthy diet na din to boost my immunity.” (As much as possible, I make sure to have a healthy diet to boost my immunity). SN07 said, SS116 “Di nato itake for granted ang policies to prevent infection.” (We should not take for granted the policies to prevent infection). Lastly, SN08 stated about the value for health and having a healthy lifestyle, SS131 “Mas givalue nako akong health ron. SS132 Di na ko magsmoke. SS133 Maningkamot ko ug tug jud at least 8 hours a day, and magstart nag kaon ug vegetables.” (I value my health more. I don’t smoke anymore. I try to sleep at least 8 hours a day and started eating vegetables). According to WHO (2020b), good nutrition and hydration are very important. People who eat a well-balanced diet be likely to be healthier with stronger immune systems and reduced risk of chronic illnesses and infectious diseases. As mentioned by the key informants, they are doing steps to protect themselves from the virus by observing health protocols and boost their immune systems. Theme 4. Resilience Amidst the Pandemic Resilience is an extensive concept that encompasses individual and social resources to thrive from challenging circumstances (Callueng et al., 2020). Because Filipinos often experience different calamities and disasters, they remain resilient and seemingly immune to such circumstances (Ang & Diaz, 2018). The current pandemic arises numerous psychological stressors due to health-related, social, economic, and individual consequences and may cause psychological distress (Petzold et al., 2020). Strategies such as keeping a healthy lifestyle and social contacts, recognizing anxiety and negative emotions, and nurturing self-efficacy may help with these stressors (Petzold et al., 2020). Having a good support system and being more positive and appreciative is helpful for OFWs to be more resilient in this time of the pandemic. Subtheme 1. Being with Others This section discusses the key informants’ support system, including their relationship with their colleagues during the pandemic and how this helped maintain their positive attitude despite being away from home. SN01 stated about the bond with her colleagues, SS12 “Uhmm mas nagkabonding kami ng workmates ko actually kasi same same kami ng sentiments regarding this pandemic.” (We bonded more with my colleagues because we share the same sentiments). SN02 mentioned about teamwork, SS26 “Mas givalue namo ang teamwork and mas gaan ang trabaho if magtinabangay.” (We value teamwork more because it makes out work easier). She also added, SS27 “Mas mofocus ta sa positive kaysa negative.” (We focus more on the positive than the negative). SN04 stated about doing activities together with the colleagues who live with her, SS50 “Sa flat naman, mas nagkaroon kami ng time magbonding kasi most of the time nasa flat lang talaga kami kapag walang duty.” (In our flat, we bonded more because we spend more time together during our days off). SN07 also shared the same sentiments about doing activities with his flatmates, SS12 “Aw duwa mig video games sa flat.” (We play video games in the flat). SN 05 said, SS75 “Kita ra sad juy magsinabtanay ug magtinabangay.” (We understand and help each other). The ICU is a stressful work environment. Nurses are experiencing exposure to workplace stress, verbal and physical hostility, burn-out, moral distress, circadian rhythm disruption, and depression (Shaw, 2015). The stressful work environment leads to low-quality nursing care. Teamwork and collaboration prevent errors and promote healthy work environments (Shaw, 2015), which was also experienced by the key informants. Subtheme 2. Seeing Oneself This section discusses the realizations of the key informants, including being more appreciative and giving importance to life. SN02 stated that, SS29 “I learned to be more appreciative of what I have and what really matters.” SN04 verbalized, SS57 “Narealize ko na life is short, dapat itreasure natin ito.” (I realized that life is short and we should treasure it). SN05 shared the same opinion, SS78 “One, life is short.” SN08 mentioned about appreciation, SS134 “Ug nalearn sad diay nakog appreciate ang little things.” (I learned to appreciate the little things). According to a survey conducted by the National Research Group, roughly 90% of the respondents say that the COVID-19 pandemic “is a good time to reflect on what’s important to them” (Olin, 2020). The experiences of the OFW nurses made them realize the value of life that they have to cherish and appreciate. Discussions OFW nurses face a lot of challenges every day, even before this pandemic started. ICU nurses have to take care of critically ill patients and are required to be mentally, emotionally, and psychologically prepared every time they go to work. When the pandemic started, these OFW ICU nurses were being pulled out from their respective units and transferred to the COVID-19 ICU. New protocols were implemented, adjustments were made, relationships with the colleagues were stronger, and slowly, resilience was built with each other’s support. For the key informants, these situations are very difficult for them. Challenges during the pandemic discuss the problems faced by the OFWs nurses being far from their homes, the issues they encountered when they were transferred to the COVID-19 ICU, and the fear of the unknown. Even before the pandemic started, these nurses were already faced with the problems of adjusting to a different culture, language barrier, and homesickness. At present, they are faced with additional problems like being unable to go home because their leaves were canceled. One informant also mentioned about her wedding ceremony being postponed because of this. Aside from these personal modifications, there are also changes in the workplace settings. The key informants were then transferred to the COVID-19 ICU because the number of COVID-19 patients needing their care increased. They expressed their feeling of anxiety about being in the new unit and anxiety about contracting the disease. They also expressed the hassle of wearing many layers of PPE for long periods. Aside from this, they also mentioned about having a shortage of PPE. The major issues facing nurses in this situation are the critical scarcity of nurses, beds, and medical supplies, including personal protective equipment, as reviews indicate, psychological fluctuations and fears of infection among nursing staff (Al Thobaity & Alshammari, 2020). According to the key informants, the quality of care given to the COVID-19 ICU patients was not meeting the standards because they are spending less time inside the patient’s room to limit their exposure. As one informant has mentioned, they are not turning the patients to sides to release back pressure as often as the patients in the non-COVID-19 ICU. Furthermore, another challenge the COVID-19 ICU nurses were facing is the fear of the unknown. During the time of the interview, there is little information on the management of the disease. They also expressed the feeling of uncertainty about the future. An American Nurses Survey of more than 30,000 nurses reported that 87% of nurses are very or somewhat afraid to go to work, 58% are highly concerned about their personal safety, and 55% about caring for a COVID-19 patient or person suspected of having the virus (American Nurses Association, 2020). In addition, the difference in the care of patients in the COVID-19 ICU was also stated. Clustering of care is done to limit exposure. The nurses also verbalized to provide support to their patients, especially during these times. The importance of nursing as a profession was also realized by the nurses. They were reminded of their roles and responsibilities as a nurse and how noble the nursing profession is. Some expressed that they are just doing what they have to do because it is part of their job. With all of these, being adaptive to change helped these nurses to cope with the present situation. The new normal when going out includes the wearing of a mask every day and observing physical distancing. On their days off, they mostly stay at home. Adjustments have been made for the current situation. They expressed about staying connected with the family, and time spent communicating with them through video calls has increased. After how many months of being assigned in the COVID-19 ICU, they have already made necessary changes to adjust to the present situation. With the ongoing pandemic, it is important to protect one’s self. Measures to protect one’s health were done like taking a bath more than usual, having long hours of sleep and rest, and having a healthier lifestyle. The nurses also verbalized that they value health now more than ever. That this also helps building resiliency among them. Building resilience is possible with the presence of a support system. The presence of the nurse’s friends as their second family helped them a lot. Closer bonds with their colleagues and workmates were formed through teamwork and doing activities together at home. Having a more positive outlook also helped them during this pandemic. Furthermore, the nurses realized the value of life and how it should not be taken for granted. They also learned to be more appreciative of the little things they have. Lastly, the government and policymakers can possibly look into the situation of Filipino nurses in their country. They are currently anxious because they cannot take their leave or spend their vacation in the Philippines, even during their end of the contract periods. This factor adds up to their uncertainty abroad while they are practicing nursing in ICU amidst pandemics. According to Garcia et al. (2018), the Filipino culture is one of the main factors on why they have qualms in working away from their home. However, living here also means challenges in terms of compensation. Despite this, true-blooded Filipinos are willing to sacrifice for the family. The limitation of the study includes focusing only on ICU Filipino nurses. Future studies could explore other target populations. Furthermore, the protection of these nurses is highly important to be explored by policymakers, and Philippine Nurses Association, and other relevant agencies. Providing them with enough PPE could help lessen the stress they feel being assigned in the COVID-19 ICU. Although the nurses were able to adapt to the present changes, it is highly suggested to provide an avenue for them to voice their concerns and make them feel that support is there from the management. There was no mention from the interviews about any compensation or support done by the management. Conclusion Despite the existing challenges like cultural differences and homesickness faced by these OFW nurses and the new challenges they are faced with the pandemic today, they were still able to continue living and do what is expected of them. From the hassle of wearing the PPEs, shortage of PPE, and being transferred from one unit in the hospital to another, the OFW nurses were able to adapt to these changes. Up until now, the travel ban and cancellation of vacation leaves are still implemented. These nurses found ways to be connected with their families through frequent video calls through the internet. The nurses already got used to the routine, but the fear of getting infected by the virus is still there. Support from peers and a positive outlook were also helpful to build resilience. They also learned to value life more and be more appreciative. All of these imply that OFW ICU nurses are resilient as they did their duties professionally and that comprehensive support be provided to safeguard their wellbeing as they continue making their significant contributions out of moral and professional responsibility in taking care of the COVID-19 patients. Acknowledgment We thanked Cebu Normal University, College of Nursing, Philippines. Declaration of Conflicting Interest No Conflict of Interest. Funding None. Authors’ Contribution JMP is the lead author from the conceptualization, formulation, and finalization of the research paper. JCC contributed significantly to the conceptualization, formulation, critiquing, and completion of the research paper. All authors agreed with the final version of the article. Authors’ Biographies Jane Marnel Pogoy, RN is a Graduate Study Researcher of Cebu Normal University, Philippines. Jezyl C. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-139 10.33546/bnj.2446 Original Research Strategies and challenges in addressing ethical issues in the hospital context: A phenomenological study of nurse team leaders https://orcid.org/0000-0002-3305-8837 Nopita Wati Ni Made 1* https://orcid.org/0000-0002-5445-7861 Juanamasta I Gede 1 https://orcid.org/0000-0002-1933-0515 Thongsalab Jutharat 23 https://orcid.org/0000-0003-3608-1650 Yunibhand Jintana 2 1 Nursing Program, STIKes Wira Medika Bali, Indonesia 2 Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand 3 Boromarajonani College of Nursing, Surin, Thailand * Corresponding author: Ns. Ni Made Nopita Wati, S.Kep., M.Kep, Nursing Program, STIKes Wira Medika Bali Kecak No.9a, East Gatot Subroto, Denpasar, Bali 80239, Indonesia. Email: ners.pita@gmail.com Cite this article as: Nopita Wati, N. M., Juanamasta, I. G., Thongsalab, J., & Yunibhand, J. (2023). Strategies and challenges in addressing ethical issues in the hospital context: A phenomenological study of nurse team leaders. Belitung Nursing Journal, 9(2), 139-144. https://doi.org/10.33546/bnj.2446 18 4 2023 2023 9 2 139144 21 11 2022 04 1 2023 18 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Nurse team leaders encounter considerable ethical challenges that necessitate using effective strategies to overcome them. However, there is a lack of research exploring the experiences of nurse team leaders in Indonesia who face ethical dilemmas in their professional duties. Objective This study aimed to explore nurse team leaders’ experiences regarding strategies and challenges in dealing with ethical problems in hospital settings in Indonesia. Methods This qualitative study employed a hermeneutic phenomenology design. Online semi-structured interviews were conducted between November 2021 and February 2022 among 14 nurse team leaders selected using a snowball sampling from seven hospitals (three public and four private hospitals). Van Manen’s approach was used for data analysis. Results The strategies for overcoming ethical dilemmas included (i) seeking the facts, (ii) stepping back, (iii) considering support, and (iv) standing by patients. The challenges for the nurse team leaders in resolving ethical problems consisted of (i) seniority, (ii) trust issue, and (iii) lack of reflection and ethics training. Conclusion Nurse team leaders recognize their specific roles in the midst of ethical challenges and seek strategies to deal with them. However, a negative working environment might impact ethical behavior and compromise the provision of quality care. Therefore, it is imperative for hospital management to take note of these findings and address issues related to seniority by providing regular ethics training and group reflection sessions to maintain nurses' ethical knowledge in hospital practice. Such interventions can support nurse team leaders in resolving ethical dilemmas and provide a conducive environment for ethical decision-making, ultimately improving patient outcomes. ethics hospitals nurse administrators leadership team leader hermeneutic Indonesia ==== Body pmcBackground In 2021, Gallup’s annual poll revealed that nursing was voted the most ethical and honest profession (Saad, 2022). This achievement is largely attributed to the efforts of those in nursing leadership positions who are recognized for their actions and interventions aligned with their values and beliefs (Stanley & Stanley, 2018). Nurse leaders can be found at any healthcare organization level and in all clinical settings and hold various positions, including nurse team leader, first-line nurse manager, clinical nurse specialist, and nurse executive (Birkholz et al., 2022; Stanley & Stanley, 2018). However, nurse leaders’ roles face complex challenges (Sugianto et al., 2022), including ethical challenges in their daily practice, such as complaints, critical decision-making, patient and family demands, and conflicts between staff (Aitamaa et al., 2016), which require an excellent strategy to respond appropriately. Thus, ethical leadership is crucial, aligning nursing fundamentals with ethical nursing behavior and positively impacting clinical practice (Barkhordari-Sharifabad et al., 2018; Zhang et al., 2019). In the context of the inpatient department, nurse leaders experience considerable pressure, and ethical challenges in clinical practice are prevalent, such as inadequate ethical vocabulary, competing demands on nurse leaders, and concerns about young nurses' ethical awareness (Storaker et al., 2022). Nevertheless, ethical nursing leaders show professional insight and mentorship through empathic interactions, ethical behavior, and exalted manners (Barkhordari-Sharifabad et al., 2018). One specific type of nurse leader is the nurse team leader, who plays an essential role in managing and coordinating their team during working hours. However, there is a lack of research exploring their experiences overcoming ethical dilemmas, particularly in Indonesia. Therefore, this study aimed to fill this gap. Specifically, the study aimed to explore the experiences of nurse team leaders regarding challenges and strategies for resolving ethical problems in hospital settings. This study will contribute to the development of ethical leadership in nursing and inform future research on the role of nurse team leaders in promoting ethical nursing practice. Overview of Nursing Care Delivery Models in Indonesia In Indonesia, the nursing delivery model used in inpatient departments generally follows the person-centered care method (Juanamasta et al., 2021b). The patient-centered care method has three models: individual, team, and primary care (Parreira et al., 2021), and the model depends on the unit type and the number of beds. However, most hospitals in Indonesia use the team delivery model (Juanamasta et al., 2021a). Therefore, the role of the team leader is emphasized as they are responsible for decision-making during each shift, including complex, ethical, and interprofessional healthcare and patient issues (Arisanti et al., 2018). A hierarchical reporting model is applied when reporting problems (Figure 1). Staff nurses, also known as associate nurses or “Perawat Pelaksana” in Bahasa Indonesia, report to the nurse team leader or nurse shift coordinator, also known as “Ketua Tim” in Bahasa Indonesia. The nurse team leader then consults with the head nurse and continues to escalate the problem to upper management if it cannot be solved (Gunawan & Juanamasta, 2022). Figure 1 Typical team care delivery model structure Head nurses or head wards/units typically work only during the morning shift. Staff nurses can consult with them if there are any problems. Unfortunately, they are not present during the afternoon and night shifts, during which the nurse team leaders handle most issues. A previous study found that the afternoon and night shifts increase the number of miscarriages (Bonde et al., 2013). Therefore, the essential role of the nurse team leader in dealing with ethical challenges should be considered. Methods Study Design Hermeneutic phenomenology was used for this study to explore the experiences of nurse team leaders when dealing with ethical issues (Spence, 2017; Todres & Wheeler, 2001). The aim of phenomenology is to understand the human experience by interpreting the phenomena encountered daily. Specifically, Heidegger's philosophical approach is used in this study, which emphasizes that a person’s “being” in time shapes their interpretation of experiences. Heidegger's concept of Dasein, which refers to how humans live their lives, is essential in reflecting on the existence (Todres & Wheeler, 2001). Humans engage in inter-subjectivity, a subjective encounter with the objective elements of the world, to reflect on their existence, which is consistent with the concept of Dasein. This study's philosophical approach comes closer to one's life world and the setting of their regular contacts (Lamb et al., 2019), which is critical in understanding the experiences of nurse team leaders. Participants The respondents were selected from seven hospitals (three public and four private hospitals) in Indonesia. Specifically, the participants were nurse team leaders who met the inclusion criteria: clinical nurses currently working in an inpatient environment, having experience as a nurse team leader, and having reported at least one ethical case problem within 90 days prior to the start of the study (1 November 2021– 28 February 2022). Due to the limited information on nurse team leaders who had previously faced ethical issues, the participants were recruited using a snowball sampling technique. During the process, sixteen nurses refused to provide information for various reasons, such as discomfort with the topic, concern about its impact, feeling unsafe, and busy working conditions. Finally, 14 registered nurses (RNs) were included. The number of participants was decided when data reached saturation, or no new codes were extracted. It is noted that the researchers analyzed the data after each interview. Data Collection Interviews were conducted based on the nurse’s time and place. Online interviews were preferred using video conferencing tools like Zoom or Google Meet and social media platforms like WhatsApp, Line, and Messenger due to the COVID-19 pandemic (Gunawan et al., 2022). This study used Bahasa Indonesia for interviews, analysis, and interpretation. The lead author interviewed each participant for approximately an hour, mostly in the hospital’s conference room after their shifts were over. Semi-structured interview guideline was prepared, and the opening question was, “Please tell me about nursing ethical issues.” The interviews were dialogical, with a special focus on the strategies and challenges faced by the nurse team leaders to deal with ethical problems. Answers to the primary question guided the interviewer to ask other exploratory questions concerning the nurse team leader’s strategies and challenges to facing ethical dilemmas by asking, “Can you tell me more?” “Can you give an example?” The research team had four members: the lead investigator, one researcher, one research team member with managerial responsibilities or supervision of nurses, and one member directly tied to the study organization. The research team members used online meetings to track the study’s progress and conclusions. All members have experience in nursing research. No repeated interviews in this study, and it is noted that there was no relationship between researchers and participants that might influence the responses. Data Analysis The researchers utilized Van Manen’s approach (Van Manen, 2016) to analyze the data, which provides four levels of analysis that help to gain a more profound understanding of the significance of the living experience of the individuals being studied. These four levels of analysis include (1) identifying thematic aspects, (2) extracting thematic statements, (3) creating linguistic transformations, and (4) extracting thematic descriptions (Ritruechai et al., 2018). The transcripts of the interviews were read multiple times to gain a holistic comprehension of the information. All essential parts were marked up with codes. The initial coding was done by the first and second authors in Bahasa Indonesia, and then similar data were grouped into sub-themes and themes. The findings were translated into English by the first and second authors and then reviewed for accuracy by the third and fourth authors. Finally, the team discussed and agreed on the sub-themes and themes. Trustworthiness The researchers utilized specific rules to gain rigor and trustworthy criteria to ensure the study’s methodological soundness. Firstly, using a well-known method for phenomenological research (Van Manen, 1990) provided rigor. Additionally, evaluation methods of Guba and Lincoln (1989) were utilized, which included staying in touch with the participants for a long time and being honest about the study’s focus, in-depth data analysis, discussion of emerging themes with participants, and modification of themes based on participant input (Polit & Beck, 2017). These processes were documented in Excel files to ensure confirmability and dependability, which included participant descriptions in the final report to illustrate the applicability of the study’s findings. Furthermore, to ensure the credibility of the study, participants received a process summary and diagram, and member checks were conducted. In addition, qualitative research and nursing leadership experts were consulted throughout the study to improve accuracy. Finally, transferability was provided by explaining the study’s context, background, and stage in the introduction and choosing participants with the greatest possible variance. Ethical Considerations The Bali Institute of Technology and Health Research Ethics Committee (No. 04.0554/KEPITEKES-BALI/XI/2021) granted ethical approval for the study and data collection. Before participating, participants were provided with written and verbal information regarding the study’s purpose and methods. After agreeing to participate by signing the consent form and establishing a time and place for the interview, participants could withdraw at any point before data collection was concluded. Each interview was assigned a code instead of being identified by name or institution to ensure confidentiality and protect participants’ privacy. As a result, their identities and information were kept confidential. Results Of 14 participants, the majority of the participants were females (78.6%), aged 36-45 years (50%), and held a bachelor’s degree level in nursing (71.4%). In addition, most participants worked between 10 – 20 years (50%), eight (57.1%) worked in public hospitals, and six (42.9%) worked in private hospitals (Table 1). Table 1 Characteristics of participants Characteristics n % Sex Male 3 21.4 Female 11 78.6 Age Early adulthood (26-35 years) 3 21.4 Late adulthood (36-45 years) 7 50 Early old age (46-55 years) 4 28.6 Education Diploma in Nursing 4 28.6 Bachelor in Nursing 10 71.4 Working experience < 10 years 4 28.6 10-20 years 7 50 > 20 years 3 21.4 Hospital Public 8 57.1 Private 6 42.9 Aligned with the study objective, the findings of this study were grouped into strategies and challenges in facing ethical problems (Figure 2). Figure 2 Strategies and challenges in addressing ethical issues Strategies in Resolving Ethical Dilemmas Nurse team leaders have to use appropriate strategies when dealing with an ethical dilemma, especially when the problems involve patients. The techniques include seeking the facts, stepping back, considering support, and standing by patients. Seeking the fact. Nurses have to seek facts to solve the problem. First, the patient’s complaint has to be checked and rechecked to confirm the problem. Then, they need to check all nursing staff and other teams. The participants express this: “A caregiver complained about my member (nurse) that she (member) refused to answer and give information about everything when she injected the new chemical medicine to my son (caregiver’s son), and just said “don’t know” when I (caregiver) asked. At that time, I (Nurse) was head of the nursing team. So, I learned the truth from the caregiver, my member nurse, and other colleagues. It was found that the nurse was acting really badly.” (N 5) Stepping back. The nurse team leaders should be aware of their position. If a problem might become bigger, it is better to step back. They also need to remind their staff to do the same. The participants state this: “I (Nurse team leader) saw my member (Nurse) talk with a male family caregiver who was drunk. I walked and told my member to go back to the nurse station because the headward called to ask about her job.” (N 1) “I have a lot of bad experiences. Now, I understand, I have to consider our position before dealing with the problem.” (N 3) Considering support. Asking for another team’s support is crucial to give direction when deciding, particularly to follow up on patient treatment, because there are different situations among respondents. It is expressed by the participants: “Actually, at the hospital, there are procedures and policies regarding presenting a palliative team, but this condition or presenting a palliative team cannot be brought to us immediately.” (N 4) “There was a time I [team leader] was not so sure which way was correct, so my team and I decided to call the expert [Nurse who takes responsibility for the abortion policy of the province] to get support and information.” (N 13) Standing by the patient. Hospitals need to gain benefits to maintain their employees and keep the facilities. However, the nurse’s position is sometimes a dilemma between the patient’s condition and the workplace need. The participants stated: “An ethical situation arose when a patient had to discharge because they wanted to die at home. The breathing machine and oxygen tank were often not enough to lend because, if allowed, they borrowed to back home, and during that time, patients still survived. While in the hospital, there might have a case(s) with a greater need to use it. I [team leader] and the team have to decide what should be done to benefit all patients equally.” (N 2) “When I [team leader] was taking care of underprivileged patients who used BPJS [Indonesia Universal Health Coverage], my manager said that the patient should be referred to another hospital because the complicated and long procedure for claiming will harm the hospital. I’m in a dilemma with this condition. Unfortunately, I need to follow the instruction, but manage to help the patient first.” (N 6) Challenges in Addressing Ethical Issues Seniority. Senior has a big responsibility as a model, and junior brings new hopes because they are updated with the latest knowledge. However, there are two different perspectives between seniors and juniors, in which juniors feel the senior pressures at work, while seniors think that juniors are too confident. Juniors expressed this: “I want to report this to our nurse manager, but I am afraid that my seniors will get angry and complain.” (N 12) “I tried many times to remind teammate or other healthcare about following the standard, but many times I get trouble from the coordinator or above.” (N 8) Seniors stated this: “The senior nurses had the experience doing nursing so long and learned a lot about mistakes. I understand there are bad and good role models, but they can learn from us” (N 10) “New generation is so confident. They do not care even though seniors try to remind them.” (N 5) Trust issue. In dealing with ethical challenges, nurses must have excellent teamwork, which requires trust. However, in this study, the trust issue is the problem. The participants state this: “I’m here as a primary nurse [nurse team leader], I have a bigger responsibility, so when I’m going to delegate an activity to a colleague, it’s a little difficult because my colleagues feel they can’t handle it.” (N 7) “One time, when I was a staff nurse, after I injected the wrong medicine into patients, my team leader didn’t trust me to do injections when working with her. She will ask for checking many times, or she chose to do it herself even though she did not have the injecting assignment. That’s the lesson I learned when I become a team leader now” (N 5) Lack of reflection and ethics training. The participants stated that the past mistakes made by the nurses should be discussed in pre or post-conferences during the shifts or in a forum to avoid repeating mistakes in the future. This also should be supported by the hospital to provide nurses with ethics training to raise awareness. Participants stated this: “It will be beneficial for learning if the past mistakes can be discussed.” (N 6) “We rarely take part in the training. The hospital said there is no financial support for that. We are encouraged to take the training independently.” (N 2) “When there was a nurse who injected the wrong medicine, the head nurse instructed team leaders and staff nurses to observe her performance at all shifts. That nurse felt down, and she decided to resign. No reflection after that.” (N 1) “When the hospital committees solve the problems related to nursing errors or ethical mistakes, they do not spread the solution. Many nurses say they do not know. So, how can we deal with this problem which has persisted for many years?” (N 3) Discussion Nurse team leaders face significant challenges when dealing with problems in everyday situations, particularly when it comes to ethical dilemmas involving patients and their families. These dilemmas often arise due to various reasons, such as patient complaints, uncontrolled family conditions, or requests beyond the nurse’s competence (Rainer et al., 2018). To solve such problems, nurse team leaders need to gather facts, step back, consider support from other teams, and stand by their patients, according to our study. Unfortunately, some hospitals may make unethical decisions, highlighting the importance of ethical decision-making in nursing leadership. This finding is linked with two root elements of the ethical sensitivity concept: “being aware” and “responding and reacting to the needs of others,” both of which encompass ethical considerations (Bebeau et al., 1999). Furthermore, ethical sensitivity involves role and moral responsibility, leading to moral reasoning and decision-making, which guide ethical behavior (Lützen et al., 2006). The task of managing a team of nurses during a shift can be challenging. According to a previous study, nurse leaders struggle to address team members’ conflicts (Wittenberg et al., 2015). Senior nurses are responsible for serving as ethical role models for their junior counterparts, as one of the core competencies of all nurse leaders (Bowles et al., 2018). Nurses can develop and improve their ethical behavior by integrating role modeling, articulating expert practice, reflecting on practice, and providing feedback. However, delegating a significant responsibility to another person can be difficult, as it requires considering their ethical experience and understanding. Our findings show that while senior nurses and team leaders attempt to guide their junior counterparts, the younger nurses may be too confident to accept their advice, similar to a discussion in a previous study (Gunawan & Marzilli, 2022). In contrast, junior nurses may strive to address ethical issues to achieve professional competence and bring new perspectives based on the latest knowledge (Rennó et al., 2018). Despite appearing at odds, both generations share the same ethical goal of protecting patients’ rights. These nurses take an active role in handling challenging ethical problems as part of their professional duties. As such, they deserve support to enhance their learning and ethical competency development (Andersson et al., 2022). On the other hand, the working environment plays a significant role in shaping the leadership style of nurse leaders. A strict and oppressive environment can lead to nurse turnover, while a healthy and supportive environment can foster a culture of learning and growth (Bove & Scott, 2021; Juanamasta et al., 2021a). According to our study, it is crucial for nurse leaders to provide an environment of learning from their mistakes, group reflections, and cultural support. It is understandable that ethical dilemmas are common in nursing practice and can be recurrent issues for various reasons. However, nursing theory and practice evolve continuously, offering new solutions to address ethical problems. Therefore, organizations must support ethical education for nurse team leaders through seminars or workshops to enhance their knowledge and skills, especially when supporting new nurses (Andersson et al., 2022; Hemberg & Hemberg, 2020). A lack of support from the hospital can negatively affect the mindset of nurse leaders, leading to unethical decision-making, which can impact nurse and patient outcomes (Juanamasta et al., 2021a). Therefore, fostering an ethical learning environment is critical to promoting ethical behavior and improving patient care. Implications for Nursing Practice and Hospital Policy Ethical dilemmas cannot be stopped or avoided, and nurse team leaders have to approach them carefully. They need to consider the nurse’s position and reduce tension by remaining aware and calm. Unethical decisions can occur if they cannot adopt moral reasoning and understanding, leading to unclear nursing roles. The problem arises because of a conflict of interest between the patient and the workplace. Meanwhile, nurse team leaders should unite their team by training seniors as role models and encouraging knowledge-sharing and ethical experiences to establish a positive learning atmosphere. Additionally, the workplace environment is essential in motivating nurses to reflect and learn from ethical dilemma issues or study from mistakes. Finally, an interdisciplinary policy is necessary to avoid blaming individuals when facing ethical problems. Strengths and Limitations This study was the first in Indonesia to explore nurse team leaders’ experiences in dealing with ethical dilemmas, making it a valuable contribution. However, the findings could not be generalized, which require further research for confirmation. Conclusion Nurse team leaders have a significant responsibility to unite their teams, as a good team can bring good performance and reduce the gap between seniors and juniors. However, they face significant challenges in dealing with patients/families and team members. The strategies for solving the problem include seeking facts, stepping back, considering support, and standing by the patient. Additionally, the working environment and hospital support play an important role that affects the nurse team leader’s character in leading their team. Acknowledgment None. Declaration of Conflicting Interest The authors declare that there is no conflict of interest in this study. Funding None. Authors’ Contributions Study design: NMNW, IGJ, JT, JY; Data collection: NMNW; Data analysis: NMNW, IGJ, JT; Supervision: JY; Manuscript writing: IGJ, JT; Critical revisions for important intellectual content: NMNW, IGJ, JY, JT. All authors approved the final version of the article to be published and agreed to be accountable for each step of the study. Authors’ Biographies Ns. Ni Made Nopita Wati, S.Kep., M.Kep is a Nursing Lecturer at STIKes Wira Medika Bali, Indonesia. Her research interests are leadership and management, legal and ethics in nursing practice, and complementary and alternative medicine. Ns. I Gede Juanamasta, S.Kep., M.Kep is a Nursing Lecturer at STIKes Wira Medika Bali, Indonesia. His research interests are management, quality nursing care, and well-being. Jutharat Thongsalab, M.N.S, Dip. PMHN is a Senior Nurse Instructor at the Boromarajonani College of Nursing, Surin, Thailand, and a PhD student at the Faculty of Nursing, Chulalongkorn University, Thailand. Her research interests are mental health, community health, and family nursing. Assoc. Prof. Jintana Yunibhand, Dip. PMHN, Ph.D is an Associate Professor at the Faculty of Nursing, Chulalongkorn University, Thailand. Her research interests are mental health, community health nursing, smoking cessation, leadership and management. Data Availability The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-055 10.33546/bnj.1265 Letter to Editors Nursing ethics education in Brunei Darussalam – Where are we today? https://orcid.org/0000-0002-1348-9904 Zolkefli Yusrita * PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Brunei Darussalam Corresponding author: Assistant Professor Yusrita Zolkefli, PhD, PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link Gadong BE1410, Brunei Darussalam. Email: yusrita.zolkefli@ubd.edu.bn Cite this article as: Zolkefli, Y. (2021). Nursing ethics education in Brunei Darussalam – Where are we today? Belitung Nursing Journal, 7(1), 55-56. https://doi.org/10.33546/bnj.1265 22 2 2021 2021 7 1 5556 10 12 2020 11 1 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. ethics nursing Brunei Darussalam education bioethics informed consent confidentiality ==== Body pmcIn the recent years, Brunei Darussalam had witnessed a greater interest in setting out ethical guidelines and best practices, particularly when several professional documents such as the Code of Ethics for nurses were issued by the Nursing Board for Brunei (2010). This critical milestone of the Code suggested changes in the way the ethical dimension is perceived in nursing practice. A study on the ethical dimension of nursing practice indicates that Bruneian nurses are not entirely certain of the extent of their professional nursing ethical responsibility (Zolkefli, 2019). At the same time, the health authority urges nurses to assume more accountability and practise good patient care. However, this is only possible if nurses understand and appreciate the moral aspect of the profession. Amongst the earlier questions regarding revising the teaching and learning of nursing ethics is the issue of course content. Previously, the main subjects were related to bioethics – for example, brain death and organ transplantation – and such emphasis addressed only partial concepts in nursing ethics that were inadequate for preparing students to assess moral issues in nursing practice. Another challenge is related to making ethical judgements. Arguably, ethical judgements were least prioritised in Brunei, and this is evident in the fact that too much importance was attached to helping students make technical or clinical judgements. Instead of ethics, it was professional etiquette that received the most attention – though this has changed a lot in the past decade. Another issue is the fragmentation and gaps of courses related to the application of classroom learning in the clinical context. To ensure continuity in ethics learning, it was proposed that the nursing curriculum should include a language of ethics that would be employed during classroom and clinical training through activities such as the debate on ethics among students, nursing mentors and clinical teachers. It was also assumed that ongoing ethics conversations might help students become more ethically sensitive. In response to the identified gaps, in 2009, a more comprehensive and realistic nursing ethics course was developed, refined and introduced in the undergraduate nursing programme. 'Law and Ethics for Health Professionals' is a course offered to students in both nursing and midwifery and holds two flexible credits, including 14 weeks of teaching and learning. The course is designed to introduce an ethical dimension to nursing practice, and the expectation is that students will reflect on their personal and professional values in different ethical concerns. This course primarily includes educational components in which students learn concepts unique to nursing ethics such as confidentiality and truth-telling. Several years later, in 2016, class debates were employed to reinforce both students' critical thinking skills by analysing ethical issues and, most importantly, their active participation. Students' active participation in the teaching of ethics is an essential contributor to the promotion of the active learning process (Self & Baldwin Jr, 1994). The results have reinforced contemporary thought that adult learners do better with less guidance and more engagement. They revealed contrasting experiences in conventional classes for the nursing students and those in the modern form of teaching. Meanwhile, a 'legal café' learning style has been introduced recently, where students are divided into several groups and are expected to review and provide a PowerPoint presentation of pre-assigned landmark cases – such as Bolam, Bolitho and Canterbury – in a more laid-back learning style. Not only did students thoroughly enjoy the sessions, but it also proved to be useful in making them cognizant of the legal considerations and how ethical values are reflected in such cases. This exercise also highlighted critical legal–ethical relationships. It is worth noting that there is already a proposal to strengthen further the legal components by inviting legal officers from the Attorney General Chambers (implemented within the context of postgraduate ethics) and even attending an actual court hearing. All the essential elements of nursing ethics education were also covered within the course, including the use of professional documents, as mentioned earlier, which serve as national ethical standards and values. They set the expected conduct for the nursing and midwifery professions. This is particularly significant where elements of the Malay Islamic Monarchy's national philosophy are upheld and integrated into the documents, which teach Islamic values. Because of the globalisation of nursing education, Western ideals are being incorporated in the nursing curricula (Harding, 2013). Ethical values, such as informed consent are primarily based on Western theory, which focuses on individualist principles. The concept of individualism is prevalent in Western countries (Brougham & Haar, 2013), while the concept of collectivism reflects Bruneian culture. In response to this, the application of ethical theories based mainly on Western principles is adapted and modified following the values and traditions of the country. For example, there are several groups of people who strongly believe in God, whereby they trust and confidence in Allah (Twakkul) as a true treatment (Ibn Qayyim Al-Jawziyya, 1978). This can potentially prove challenging for health professionals to maintain the principle of respecting the autonomy of the patient when they decline to expose themselves to any physical treatment. Above all, it seems pertinent to remember that teaching ethics is about raising ethical expectation and standard in the nursing profession. Current approaches to nursing ethics education may lead to possibilities of new, modern and creative educational methods. Still, they require further unorthodox pedagogy if they are to bridging any existing educational gaps and meeting nursing education standards at all levels. This may include, for example, the use of artistic teaching strategies such as drama or therapeutic letter writing. In a nutshell, there is no doubt that professional engagement and a deep sense of duty from teachers' are essential. Still, classroom interventions alone can have only a partial effect in maintaining a robust ethical dialogue. Simultaneously, the current course on nursing ethics must include an ongoing discussion on ethics in clinical settings. Such visibility and emphasis on nursing ethics are highly welcomed and embraced in the profession of nursing. Declaration of Conflicting Interest The author declares no conflict of interest. Funding None. Author Biography Yusrita Zolkefli, PhD is An Assistant Professor at PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam and is also currently Chairperson for the Faculty Research Ethics Committee. ==== Refs References Brougham, D., & Haar, J. M. (2013). Collectivism, cultural identity and employee mental health: A study of New Zealand Māori. Social indicators research, 114 (3 ), 1143-1160. 10.1007/s11205-012-0194-6 Harding, T. (2013). Cultural safety: A vital element for nursing ethics. Nursing Praxis in New Zealand, 29 (1 ), 4-11. Ibn Qayyim al-Jawziyya. (1978). Tibi Nabawi. Cairo: Dar AlTurath. Nursing Board for Brunei. (2010). Code of Ethics for registered nurses and midwives in Brunei Darussalam. Brunei: Ministry of Health. Self, D. J., & Baldwin Jr, D. C. (1994). Moral reasoning in medicine. In J. R. Rest & D. Narváez (Eds.), Moral development in the professions: Psychology and applied ethics. (pp. 147-162). Hillsdale, NJ, US: Lawrence Erlbaum Associates, Inc. Zolkefli, Y. (2019). Negotiated ethical responsibility: Bruneian nurses’ ethical concerns in nursing practice. Nursing Ethics, 26 (7-8 ), 1992-2005. 10.1177/0969733018809797 30442065

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-145 10.33546/bnj.2482 Original Research Experiences of Infection Prevention and Control Nurses (IPCNs) in performing their roles and duties in the Indonesia Army Central Hospital: A qualitative descriptive study Dewi Laurentia 1 https://orcid.org/0000-0002-3548-1348 Hamid Achir Yani S. 1* Sekarsari Rita 2 1 Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia 2 Rumah Sakit Jantung dan Pembuluh Darah Harapan Kita, Jakarta, Indonesia * Corresponding author: Prof. Achir Yani S. Hamid, M.N, DNSc, Department of Mental Health Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia Jalan Prof. Dr. Bahder Djohan, Kampus UI Depok, West Java 16424, Indonesia. Email: achir@ui.ac.id Cite this article as: Dewi, L., Hamid, A. Y. S., & Sekarsari, R. (2023). Experiences of Infection Prevention and Control Nurses (IPCNs) in performing their roles and duties in the Indonesia Army Central Hospital: A qualitative descriptive study. Belitung Nursing Journal, 9(2), 145-151. https://doi.org/10.33546/bnj.2482 18 4 2023 2023 9 2 145151 08 12 2022 04 1 2023 13 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The Infection Prevention and Control Nurse (IPCN) is a professional nurse with a crucial role in promoting patient safety and service quality by preventing and controlling infections. However, little is known about their experiences regarding their roles and duties, particularly in Indonesia. Objective This study aimed to explore IPCNs’ experiences in performing their roles and responsibilities, including motivations and obstacles encountered, as well as organizational support while carrying out their jobs. Methods This research used a qualitative descriptive study design, collecting data through Focus Group Discussions (FGDs) with six purposively sampled participants in April 2021 at the Gatot Soebroto Army Central Hospital (RSPAD), Jakarta, Indonesia. Thematic analysis was used to analyze the data. Results Five themes were identified: 1) roles and duties of IPCNs, 2) conducive work environment, 3) constraints in carrying out tasks, 4) management support, and 5) hopes. Conclusion This study provides new insights into IPCN roles and duties that require collaboration and coordination with multiple professions, as well as management support to overcome obstacles that hinder fulfilling tasks and hopes of improving IPCN performance according to competency-based career paths to achieve patient safety, service quality, and job satisfaction. experiences Indonesia Infection Prevention and Control Nurse IPCN motivation roles and duties ==== Body pmcBackground In order to monitor and control infections in hospitals, a special nurse called the Infection Prevention and Control Nurse (IPCN) is employed. This nurse is part of the infection control professionals, also known as Infection Preventionists (IP). The IPCN plays a critical role in preventing Healthcare Associated Infections (HAIs), also known as nosocomial infections. These infections occur in patients during treatment in hospitals or other healthcare facilities and are not present during admission or incubation (World Health Organization, 2002). In addition to advocating for and implementing infection control practices (Freeman & Gray, 2013; Kalp et al., 2018; Liu et al., 2014), the IPCN brings a vision of discipline, reinforcement, responsibility, and high dedication. This vision serves as a constant driving force in preventing and controlling hospital infections (Assariparambil et al., 2021; Vassallo & Boston, 2019). Improving competence in controlling the risk of healthcare-related infections in hospitals has proven to be a challenge for IPCNs. This is due to the complex nature of Infection Prevention and Control (IPC), which involves various factors, such as environment, microbiology, pathology, human error, systems, and organizations (Freeman & Gray, 2013). Furthermore, IPCNs are required to think quickly and critically in response to rapid changes. Therefore, organizations are expected to support and encourage IPCNs to enhance their education, work experience, and performance based on their competencies (Gase et al., 2015). In an effort to maintain their competence, IPCNs are required to attend continuing education, develop new skills, and stay up-to-date with current infection control practices (World Health Organization, 2018). IPCNs possess expert skills and competencies that can help organizations increase staff engagement, productivity, and satisfaction. IPCNs can motivate staff to work more effectively, improve performance, create networks, and be proactive in improving services, making the staff feel valued (Aziz, 2016). IPCNs carry a heavy workload in implementing infection control programs, which is critical for patient and staff safety and service quality. During the COVID-19 pandemic, this responsibility is even more challenging as it requires strict infection control measures. IPCNs visit high-risk patients, monitor the implementation of infection control programs and Standard Operating Procedures (SOPs), audit isolation precautions, provide education to patients and staff, and investigate healthcare-associated infections (HAIs), as stated in the Regulation of Ministry of Health number 27 of 2017 (Ministry of Health, 2017). IPCNs functionally report to the Infection Prevention and Control Committee and professionally report to the Nursing Committee at the same level as senior managers. However, the healthcare industry is continuously changing, with an increase in infection cases leading to stress and potential burnout for IPCNs (Colindres et al., 2018). They face various challenges such as role conflicts, work overload, lack of personnel, institutional pressure, inadequate knowledge about infection control, and lack of support from nursing organizations, all of which increase the risk of turnover (Choi & Kim, 2020; Diño et al., 2022). A psychosocial work environment lacking appreciation and balanced rewards also reduces nurse adherence to preventing and controlling infections (Colindres et al., 2018). Unfortunately, IPCNs in Indonesia may still face these phenomena and issues with leadership support, facilities, infrastructure, and rewards. Therefore, this study aimed to explore IPCNs’ current experiences in performing their roles and duties in hospitals to recommend measures to improve their performance in preventing and controlling hospital infections. Methods Study Design This qualitative research applied a qualitative descriptive study design. Qualitative descriptive study is typically based on naturalistic inquiry, which involves studying a phenomenon in its natural state to the fullest extent possible within the research context. This means that study variables are not pre-selected, there is no manipulation of variables, and there is no prior commitment to any particular theoretical view of the phenomenon being studied (Lambert & Lambert, 2012). With this method, participants’ opinions or views about their experiences regarding their roles and duties in the hospital, the obstacles faced, organizational support, and IPCN’s expectations of their careers were explored and reported. Participants The study participants were all full-time IPCNs who served on the Infection Prevention and Control Committee. Six female participants were selected through purposive sampling, which ensured they had similar characteristics and work experience (aged 41-52 years with 3-12 years of work experience). None of the participants refused to participate or dropped out. The inclusion criteria required that participants work full-time at the hospital’s Infection Prevention and Control Committee, have a minimum of one year of work experience as an IPCN, and have basic/advanced/IPCN training certification. Data Collection Data were collected in April 2021 through a 120-minute Focus Group Discussion (FGD) at the Gatot Soebroto Army Central Hospital (RSPAD), Jakarta, Indonesia. FGD was used to explore specific issues to provide valuable information from groups of participants who interact with each other by expressing their thoughts, feelings, and experiences (Holloway & Galvin, 2010). The FGD was held in the Infection Prevention and Control Committee meeting room at the hospital. The data were audio recorded with the participants’ consent. The discussion began with the question, “What are your roles as an IPCN, and how do you perform these roles?” During the FGD, participants were also asked about their opinions regarding constraints, work environment, management support, and career development. The researchers validated all answers, observed non-verbal expressions, and asked probing questions to obtain meaningful words or views. Data Analysis The data were analyzed using thematic analysis of the FGD transcript, which looks at qualitative data analysis as a process that requires sequential steps to be followed, from the specific to the general (Creswell & Creswell, 2018). This process consisted of six steps: data preparation for transcription, reading of the entire data, detailed data analysis by coding the data, description of categories, definition of themes and interpretation of data, and preparation of a qualitative report. The transcript of the FGD was read, analyzed, and then described in keywords to be further discussed by the research team simultaneously to determine the categories and themes. Trustworthiness The researchers conducted member checking to ensure the validity of the search data. After obtaining the themes of the results of the data analysis, validation was carried out with all participants. All participants confirmed that they experienced the themes found based on the validation results. Next, the researchers carried out thick descriptions by writing down variations in participant characteristics to ensure that the results could be applied to a population with the same background. The researchers also conducted a peer audit with the research team to identify the accuracy of the research result in themes based on interview data. In order to enhance the study rigor, the research team conducted peer reviews at each stage, with all members participating. The team then cross-checked and validated the data to ensure that the findings were accurately allocated and matched to the relevant sub-themes and themes, reaching a consensus. Ethical Considerations Prior to participating in this study, all participants received information on the research objectives, procedures, duration of involvement, participant rights, and forms of participation and provided their consent by signing an informed consent form. Furthermore, this study underwent ethical review by the Research Ethics Committee of the University of Indonesia and was approved under number KET 214/UN2.F12.D1.2.1/PPM.00.02/2022. Results Characteristics of Participants The participants in this study were six full-time IPCNs in the IPC Committee, aged 41-52 years and with 3-12 years of work experience. One participant (17%) held a master’s degree in clinical epidemiology, while the other five (83%) had a bachelor’s degree in nursing. Each participant was assigned a code number (P1-P6). Table 1 presents the characteristics of the participants. Table 1 Characteristics of the participants Code Sex Age Education Length of Service P1 Female 43 Master’s Degree 12 years P2 Female 48 Bachelor of Nursing 5 years P3 Female 43 Bachelor of Nursing 4 years P4 Female 41 Bachelor of Nursing 4 years P5 Female 52 Bachelor of Nursing 4 years P6 Female 45 Bachelor of Nursing 3 years Thematic Findings Five themes were identified: 1) primary and secondary roles and duties during the COVID-19 pandemic, 2) conducive work environment, 3) constraints in carrying out tasks, 4) management support, and 5) hopes (Figure 1). Figure 1 Thematic findings Theme 1: Roles and duties of IPCNs Subtheme 1.1: Multiple roles as educator, role model, auditor and surveyor, clinical practitioner, motivator, investigator, and manager Of all participants, four IPCNs answered that they performed their role as educators. “… so, my role there is as an educator… providing education related to the SOPs.” (P3) “… disseminate policies and SOPs to the heads of installations, covering inpatient installation and outpatient installation, then to the department.” (P1) “… our roles as educators …” (P6) “… yes, for education … how to comply with health protocols …” (P2) Furthermore, two of the six participants mentioned that they became role models. “… IPCN as a role model, we continue to evaluate all activities, whether they are in accordance with the SOP or not …” (P1) “her role as a role model … how to maintain health protocols…” (P4) Four of the six participants responded that they had the roles of auditors and surveyors. “Our roles as auditors and surveyors on the wards enable us to detect extraordinary events …” (P1) “… I monitor … I evaluate how the PPE is used …” (P3) “… IPCN in this vaccination is monitoring, one of which is monitoring AEFI; this is the role of IPCN in vaccination activities.” (P4) “Monitoring and evaluation; how nurses adhere to audit bundles” (P6) In addition, four of the six participants stated they served as clinical practitioners. “… IPCN as a clinical practitioner … early detection of HAIs … monitoring symptoms, medical records, culture results … mastering diagnoses, signs, and symptoms …” (P1) “… postoperative patients who underwent surgery, how are the HAI bundles, how are the surgical bundles …, pre-, intra-, and post-surgery …” (P3) “Detection of ESBL or MRSA culture results …” (P4) “… patients with ventilator installed, how are their oral hygiene … catheter inserted … whether it is properly placed or not. Not on the floor.” (P5) Three of the six participants answered that they played a role as motivators. “… as a motivator to maintain the spirit of implementing health protocols.” (P2) “… yes, as Infection Control Nurses, our duty is to motivate …” (P3) “… we as motivators, Ma’am, … when our colleagues are feeling bored, having a meltdown due to exhaustion, the pandemic and isolation are at a high level, that …” (P5). Three of the six participants also acted as investigators. “So, the role of IPCN is to detect early outbreaks (extraordinary events) and infectious diseases such as diphtheria …” (P1) “… role in tracking …when there is a patient who has close contact with the patient.” (P5) “… As investigators, we also carry out the 3T, namely Tracking, Test, and Treatment, if there is a positive result.” (P6) Meanwhile, two of the six participants believed they performed the role of managers. “… as a manager through coordination with superiors …” (P1) “… as managers, Ma’am… we coordinate with relevant parties at the top levels and parallel levels …” (P2) Sub-theme 1.2: Duties according to applicable standards during the pandemic, including secondary ones All participants stated that their duty was to conduct surveys around the treatment wards. “Field monitoring, … whether … our colleagues comply with IPC [measures and standards] …, conduct initial investigations on HAIs, monitor … the implementation of bundles, …” (P1) “… around according to their respective areas” (P2) “We go around the treatment wards to do surveys, …” (P3) “We monitor … ward temperature and humidity.” (P4) “We do 5R supervision … related to HAIs.” (P5) “Ward infection control … audit bundles, … monitor ward cleanliness” (P6) Three of the six participants had a duty to establish policies and IPC SOPs. “We have to establish policies and SOPs so that our colleagues in this field do not follow all procedures in the hospital …” (P1) “… doing what is called additional job, that is SOP-making.” (P2) “… coordinating inpatient ward management policies with the heads of affairs, sub-divisions, or installations…” (P3) Two of the six participants carried out their duties in providing education. “… to educate patients in polyclinics about how they can prevent …, comply with health protocols” (P2) “… IPCN gives education to both patients and visitors or even internally to our colleagues …” (P4) Additionally, two of the six participants informed their duty of monitoring the Infection Control Risk Assessment (ICRA). “Monitoring ICRA … to develop work programs and … to assess the risk of infection” (P1) “… monitor ICRA …” (P6) Three of the six participants revealed the duties of making HAIs reports and recommendations. “Making HAIs reports, audits … and recommendations” (P1) “… Make a HAIs report, hand hygiene report, PPE, HD …” (P2) “We made a report of the officer’s needle piercing…” (P5) Furthermore, four participants stated they had additional duties to give vaccines and prepare COVID-19 reports. “… due to the pandemic, there is a special report on COVID-19” (P1) “… extra assignments, additional duties, vaccinations, and COVID-19 reports” (P2) “… reports on our employees infected with COVID-19 …” (P3) “… there is an additional duty as a vaccinator … as a PIC, report to the superiors” (P6) Theme 2: Conducive work environment Five participants reported a supportive work environment. “… our environment in this IPC Committee is warm and not problematic …” (P1) “As for the environment …. we are all fast respond” (P2) “… thank God … all of our colleagues here are loyal, Ma’am… willing to take the time, prove our outputs to everyone.” (P3) “… we do a lot for the good of everyone. That’s the principle, … so… pretty calm” (P4) “… enjoying the work … loving our work” (P6) Four of the six participants stated they were accepted and recognized in their work environment. “… we have involved the SOP, flow, zones, and PPE in the treatment ward” (P3) “… in the ward, has been a little accepting, and we’re involved” (P4) “We record the output data … we develop a policy … we can solve … a problem … that’s motivational” (P1) “We are selected people who have different knowledge … from our colleagues” (P6) Three participants believed that they worked in a challenging environment. “The environment is very dynamic …” (P5) “The demands are high from the superiors … the authority is high, and then … our colleagues … also never give up” (P1) “In the field of supervision, it is full of challenges. Because we are facing a lot of colleagues and characters … in the ward” (P6) Theme 3: Constraints in carrying out tasks Subtheme 3.1: Inadequate human resources Five of the six IPCNs revealed the constraints of inadequate IPCNs, overtime, and workload. “… lacking IPCNs, Ma’am.” (P3) “… sometimes we work overtime … on the other hand, sometimes those who are in the ward … think that we’re only taking data … and chatting” (P2) “Control Team … the pandemic … being a call-center staff for COVID-19 as well … taking care of the coordinator … taking care of the unit … (extra job)” (P1) “… during the pandemic, we also conduct tracking … becoming vaccine coordinator” (P4) “We have already been in the field too, writing … means of reporting that processes the data, we did that too.” (P6) Subtheme 3.2: Unclear career paths One participant revealed that the career path and competency test for IPCNs were equal to those of clinical nurses in the ward. “We are … still … adjusting … the level increase … and our careers are like nurses in the ward … Yes … our competency test … is still … the same as nurses in the ward” (P5) Theme 4: Management support Three of the six participants stated they received support in facilities and infrastructure. “For us personally during this pandemic, leaders also play a very important role in giving vitamins” (P4) “The leaders play a very important role in the administration of vitamins … snacks …” (P5) “… for the facility in the form of PPE and office stationery … equipped with Wi-Fi.” (P6) Three of the six participants also gained recognition and authority of work. “… give authority … support us from behind by providing backups” (P1) “… we started to feel that we are recognized as IPCN” (P2) “… equal welfare with the head of the ward …” (P3) Theme 5: Hopes Subtheme 5.1: Clear career paths Two of the six IPCNs expressed their hopes for the competency test for IPCNs. “… our career path is not the same as that of nurses in the ward … functionally, IPCNs’ duties and responsibilities still follow the clinical nurses.” (P1) “… yes, maybe in the future our career path is not the same as that of ward nurses … specifically for IPCNs themselves … What is their career path? … that is … our hopes are like that …” (P2) Meanwhile, four participants hoped for a career path based on competency improvement. “…our hope is that in the future our careers can develop, taken into account because of our leading role” (P3) “… able to develop … promotion … for example, we are IPCN … yes, but not only that. IPCNs have knowledge … our knowledge has levels” (P4) “… initial recruitment … what kind of increase … it can also be of the level … can also be with other awards … which already … over 10 years … how … those are what we hope for.” (P5) “Competency test according to management … we are independent as IPCN … that’s the point … specific according to IPCN hopes” (P6) Sub-theme 5.2: Improved welfare Two of the six participants expressed their hopes for an increase in IPCN remuneration. “… our hope … for welfare beyond the Head of the Ward …” (P3) “… and the benefits also increase … according to their role and duties” (P5) Furthermore, two of the six participants hoped for more IPCNs based on workload analysis. “… hope to increase the number of IPCNs per accreditation regulations, and nationally, 100 beds need one IPCN, whereas we have almost 800 bed or more … need two more IPCNs” (P1) “Actually, the crucial thing is the support of colleagues.” (P3) Discussion All participants in this study reported on the roles of IPCNs in the IPC Committee, which are performed and adopted as guidelines in their daily work. The most prominent roles are as educators, auditors, surveyors, and clinical practitioners. Every day, IPCNs facilitate health workers to socialize policies and SOPs, regularly conduct round-the-clock monitoring of treatment wards, and supervise IPCLNs to monitor clinical practices in implementing HAIs bundles. This is followed by their roles as investigators in detecting extraordinary events or tracking cases and motivators in implementing health protocols and encouraging health workers to comply with IPC standards and measures. In addition to these roles, some participants stated that they also serve as role models and managers. This is in line with a statement of Aziz (2016) that IPCNs have negotiation skills and abilities to provide education, become role models, carry out complex decision-making, and have leadership and management skills to motivate staff to improve performance, expand networks, and be proactive in improving services. In addition to their roles, all participants revealed their daily duties, the most notable of which was conducting surveys in treatment wards. Other duties widely carried out by IPCNs include establishing policies and SOPs, preparing HAIs reports, and making recommendations. Several participants also had a responsibility to monitor ICRA. During the pandemic, IPCNs have additional duties of providing vaccines and reporting on patients with COVID-19. This is in accordance with the results of a prior study by Popescu (2019), which stated that IPCN’s duties and responsibilities include supervision, investigation of infection-related cases, staff education and research, policy review, infection risk assessment, emergency preparedness, hospital infection reporting, and recommendation making. In addition, IPCNs have a vital role in communication, especially in high stress and anxiety about the COVID-19 pandemic, which increases the risk of transmission for nurses (West, 2021). Most of the participants expressed that there was leadership support for implementing their daily work. This is supported by the acceptance from the ward, as well as the openness and involvement of IPCNs in managing infection services in treatment wards, which can encourage confidence in performing their roles. This is consistent with a previous study by Reisinger et al. (2017), which found that competencies strengthened by environmental support will increase self-confidence and commitment to implement these competencies in standards of practice. All participants felt motivated after being given authority and the ability to solve problems and prove that their work benefited many people. In addition, they felt special with their distinct knowledge, which made them do good work and enjoy and love their work. Such support lifted their spirits, increasing their dedication and professional performance to improve service quality and job satisfaction. This is in line with Bernard et al. (2018), who proved that IPCN’s work motivation would increase the satisfaction of continuous innovation that encourages the improvement of organizational performance and goals. Well-maintained motivation would provide satisfaction for their achievements. Meanwhile, research conducted by Platace et al. (2020) identified that non-material factors have a greater influence on IPCN work motivation, such as a high sense of responsibility and concern for patients, colleagues, and their safety. Furthermore, the participants highlighted the constraints related to the lack of IPCN, the advancement of IPCN career paths, and the IPCN competency test, equated with that of nurses in the ward. As mentioned above, IPCN has different duties and responsibilities, as well as a broader scope of area and level of problems encountered. Therefore, insufficient IPCNs affect unbalanced, extra, or redundant work performance. This is in accordance with a prior study by Mugomeri (2018), which stated that human resource support greatly affects the effectiveness of IPCN performance, reducing unclear competencies and roles. This is also emphasized in the Regulation of the Minister of Health Number 27 of 2017 (Ministry of Health, 2017) on IPCN personnel standards, where one IPCN is in charge of 100 beds according to the level of needs and the risk of infection in the hospital. Regarding IPCN career paths, competency-based career development can be encouraged through a specific competency test done periodically to increase levels based on the competency domains specially formulated for IPCNs who work full-time (Billings et al., 2019). All participants stated that they received support from their superiors in carrying out their duties as IPCNs. Their superiors gave authority, support, backups, recognition, and welfare, as well as equip them with adequate facilities and infrastructure. This will provide IPCNs with comfort, eventually leading to job satisfaction and self-confidence. According to Yoon et al. (2016), human resources who play a role in the effective implementation of IPC programs need management support. Likewise, Mugomeri (2018) argued that the ineffectiveness of IPC organizations in controlling infections is influenced by ineffective organizational support. Concerning the IPCN’s hopes, all participants hope to advance the IPCN career path according to their roles and responsibilities, which can be developed by taking into account their prominent roles in preventing and controlling infections. They also expressed their hopes for recognition and appreciation that correspond to their work, length of service, and level, followed by increased IPCN welfare. This is aligned with a study by Knighton (2020), which argued that analyzing the incentive programs received along with the performance improvements described in career development in the form of financial support is necessary. Therefore, the criteria for awarding compensation are related to experience, education level, certification, and performance improvement according to their career path. In addition to financial support, competitive salary spurs career development and certification, lowering turnover rates. Likewise, Billings et al. (2019) clarify the roles and responsibilities of IPCNs and guide their career development, identify and design their career paths, and accurately reflect their roles and responsibilities in collaborating, communicating, and consulting with other parties in efforts to develop their competencies. Conclusion This study provides current insights into IPCN’s roles and duties that require collaboration and coordination with multi-professions, as well as management support to overcome barriers and challenges that hinder the fulfillment of responsibilities and hopes of improving IPCN performance following competency-based career paths to achieve patient safety, service quality, and job satisfaction. In addition, the findings may be served as basic information for future studies to measure IPCN roles and responsibilities and develop interventions to improve their skills and performances. Acknowledgment Our sincere gratitude goes to all Infection Prevention Control Nurses (IPCNs) of the Infection Control Committee of the Gatot Soebroto Army Central Hospital (RSPAD) who participated in this study. Declaration of Conflicting Interest The authors declare that there is no conflict of interest in this study. Funding None. Authors’ Contributions LDF conceptualized the study, reviewed the literature, collected and analyzed data, discussed findings, and drafted the manuscript. RS and ACH provided supervision and guidance and edited and prepared the manuscript for submission. All authors were accountable in each step of the study and approved the final version of the manuscript to be published. Authors’ Biographies Ns. Laurentia Dewi Fatmawati, M.Kep is a Doctoral Student in the Doctoral Nursing Program, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Achir Yani S. Hamid, M.N, DNSc is a Professor at the Department of Mental Health Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Dr. Rita Sekarsari, SKp., SpKV., MHSM is Head of Quality Assurance Committee of Rumah Sakit Jantung dan Pembuluh Darah Harapan Kita, Jakarta, Indonesia. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-176 10.33546/bnj.2480 Original Research Self-awareness as the key to successful adherence to antiretroviral therapy among people living with HIV in Indonesia: A grounded theory study https://orcid.org/0000-0001-9766-8880 Yona Sri 1* https://orcid.org/0000-0002-8093-5134 Edison Chiyar 1 https://orcid.org/0000-0002-3984-0336 Nursasi Astuti Yuni 2 https://orcid.org/0000-0002-9541-418X Ismail Rita 3 1 Department of Medical Surgical Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia 2 Department of Community Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia 3 Ministry of Health Republic of Indonesia, Poltekkes Kemenkes Jakarta III, Bekasi, West Java, Indonesia * Corresponding author: Sri Yona, S.Kp., M.N., Ph.D, Department of Medical Surgical Nursing, Faculty of Nursing, Universitas Indonesia Jalan Prof. Dr. Bahder Djohan, Kampus UI Depok, West Java 16424, Indonesia. Email: sriyona@ui.ac.id Cite this article as: Yona, S., Edison, C., Nursasi, A. Y., & Ismail, R. (2023). Self-awareness as the key to successful adherence to antiretroviral therapy among people living with HIV in Indonesia: A grounded theory study. Belitung Nursing Journal, 9(2), 176-183. https://doi.org/10.33546/bnj.2480 18 4 2023 2023 9 2 176183 10 12 2022 05 1 2023 17 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Adherence to antiretroviral therapy (ART) continues to pose a significant challenge for people living with HIV (PLWH). Non-adherence to ART can have far-reaching implications for patient well-being, particularly in increasing the risk of opportunistic infections when medication is not taken as prescribed. Objective This study aimed to develop a theoretical model that explains how PLWH in Indonesia adhere to their ART regimen and the strategies they follow to maintain adherence. Methods The study used a grounded theory approach. Data were collected through face-to-face in-depth interviews with 21 PLWH who had been taking ART for six months or more at a non-governmental organization (NGO) in Jakarta, Indonesia, between July 2019 and November 2019. Theoretical sampling was used, and the data analysis method of Corbin and Strauss was utilized, including open coding, axis coding, and selective coding. Results Three stages were identified as a process of adherence to the ART regimen: 1) initiating ART, 2) missing the connection, and 3) taking control. Self-awareness was identified as the central core theme describing the ART adherence process. Conclusion Having adequate self-awareness to take ART regularly is crucial to improving adherence to ART. Moreover, social support from one’s spouse and family members can help patients maintain adherence. Therefore, self-awareness and support systems should be included as components in nursing interventions when starting ART therapy. In addition, nurses can help identify potential support persons and provide information related to ART therapy. HIV infections antiretroviral agents adherence grounded theory Indonesia social support Directorate of Research and Community Engagement, University of Indonesia (Grant for novice researchers) ==== Body pmcBackground In 2021, it was estimated that approximately 38.4 million people globally were living with HIV, with 650,000 deaths attributed to HIV-related causes and 1.5 million new HIV infections (World Health Organization, 2021). In Indonesia, approximately 543,100 people were living with HIV by the end of 2022. Of these individuals, around 393,538 were aware of their HIV status, 160,249 people received therapy, and only 14% reported viral load suppression after taking ART for at least six months (Indonesian Ministry of Health, 2021). Adherence to ART is crucial for the quality of life in people living with HIV (Surur et al., 2017; Xu et al., 2017), but ART adherence remains a significant concern in Indonesia. Dropout rates from prescribed ART in Indonesia are high, with approximately 23% of those prescribed ART dropping out (Indonesian Ministry of Health, 2019). This situation can have severe negative impacts, such as an increased risk of opportunistic infection, drug resistance, and a poor quality of life (Weaver et al., 2014; Xu et al., 2017; Zhou et al., 2018). Adherence to ART is essential for optimal efficacy (Centers for Disease Control and Prevention, 2021), and non-adherence can lead to a susceptibility to opportunistic infection and a higher mortality rate (Castillo-Mancilla et al., 2021; Glass et al., 2015). Non-adherence to ART can also lead to the development of resistance to ART line one, necessitating a switch to ART lines two and three (Boyd et al., 2015; Rocheleau et al., 2018), which are more expensive (Farr et al., 2016). Several factors contribute to non-adherence to ART, such as a lack of knowledge about ART, non-disclosure of HIV status, low motivation arising from pill fatigue, forgetfulness, and worrying side effects (Martiana et al., 2019; Sefah et al., 2022; Shrestha et al., 2019). On the other hand, factors such as peer support and adequate family support can increase the level of ART adherence (Audi et al., 2021; Gabster et al., 2022; Sianturi & Dorothea, 2020). Other important factors, such as stigma, discrimination, and food insecurity, can also influence adherence to ART (Agnes & Songwathana, 2021; Shrestha et al., 2019). In Indonesia, several studies have examined adherence to ART among PLWH and the factors that influence compliance (Fahriati et al., 2021; Nurfalah et al., 2019; Sianturi & Dorothea, 2020). Most of these studies were quantitative and evaluated the correlation between ART adherence and knowledge, support system, and education level (Fahriati et al., 2021; Haryadi et al., 2020; Sianturi & Dorothea, 2020). Few qualitative studies have examined HIV in Indonesia, including the ART regimen (Agnes & Songwathana, 2021; Edison et al., 2021; Harison et al., 2020; Ismail et al., 2022; Mahathir et al., 2021; Nuraidah et al., 2022; Nurfalah et al., 2019). However, none of previous studies examined the process of ART adherence among PLWH. To understand the process of adherence to ART among people living with HIV in Indonesia, a qualitative methodology in the form of grounded theory was utilized in this study. This approach is sensitive to individual decision-making and the wider social context that impacts adherence. The study aimed to develop a theoretical model explaining how people living with HIV in Indonesia adhere to their ART regimen and their strategies to maintain their adherence. This study is expected to provide the basic data needed to develop nursing intervention programs that can help people living with HIV stay adherent to their medication. Methods Study Design This study utilized a grounded theory approach to identify explanatory constructs among the studied phenomena and the relationships among these constructs in order to build a substantive theory (Corbin & Strauss, 2008). The study aimed to develop a theoretical model that explains how people living with HIV in Indonesia adhere to their ART regimen. This approach provided a theoretical perspective for investigating how objects and other people are interpreted and how these processes of interpretation lead to behavior in specific situations (Glaser, 1998; Noble & Mitchell, 2016). Rich data were inductively derived from participant views, feelings, and actions related to adherence with ART. The Grounded Theory strongly emphasizes symbolic interaction, using symbols such as words, roles, and gestures to construct a reality that is seen as social interaction (Corbin & Strauss, 2008; Glaser, 2002). This approach was suitable for this study, which aimed to explore the process of adherence to ART among people living with HIV. This includes interactions among patients and their environment, such as healthcare providers, other people, and stigma. Participants A total of 21 volunteer participants were recruited and agreed to be interviewed. They were recruited from one of the non-governmental organizations in Jakarta in 2019, before the pandemic. Participants were recruited by posting flyers at the NGO office. The NGO staff explained the study to potential participants who met the inclusion criteria (e.g., had received ART for at least six months, were at least 17 years old, and had no cognitive disorders). Participants who met the inclusion criteria were invited by the NGO via telephone and hand-delivered letters. Interested participants then contacted the researchers by telephone. Once the potential participant agreed to participate, a time was set to meet, and they were informed about the study and asked to sign an informed consent form before the interview. All participants agreed to participate and signed an informed consent form before the interview. All participants were paid approximately US$5 or Rp. 50,000 for their participation. Audio recordings of all interviews were made digitally and transcribed verbatim by the researcher team and a transcription service. Data Collection Data for this study were collected from individual face-to-face in-depth interviews conducted between July 2019 and November 2019. The interviews were scheduled at a date and time each participant chose and lasted 45 minutes to 1.5 hours. In cases where further clarification was needed, an additional interview was conducted over the phone. All interviews were conducted in a private room at the NGO by the researcher team. The interview questions were developed by the research team, guided by a literature review and consultation with a professor in the faculty of nursing who has expertise in qualitative methods. All research team members had a nursing background, with three female researchers (SY, AYN, and RI) and one male researcher (CE). In addition, two researchers had PhD degrees (SY and RI), one had a doctoral degree (AYN), and one had a master’s degree (CE). The main interview question was, “Please tell me about your experience taking ART, and what strategies did you use to stay adherent to your medication?” Explanatory questions were asked during the interview, such as “What happened next?”, “What did you do then?”, and “How did you manage it?” based on the situation that the participants mentioned. Subsequent interviews were used to clarify and elaborate in more detail about their information during the interview. All interview transcriptions were open-coded line-by-line, with the actual information from the participants’ wording used as labeling codes. The researchers also made notes about participants’ behavior, expression, tone, and other details during the interviews. All interviews were audio-recorded with participants’ consent and transcribed using professional services. To ensure the accuracy of the data, the researchers compared the transcripts with the audio tape recording of all the interviews. Data collection was terminated when it was determined that theoretical saturation had occurred, meaning no new meaningful data were observed, and no new categorical properties or dimensions were identified. Data Analysis The grounded theory methodology proposed by Corbin and Strauss (2008) was used for data analysis. All data analysis was done manually by the research team. Data analysis was conducted simultaneously with data collection using open, axial, and selective coding methods. Initial coding was done through open coding, which involved identifying, labeling, and conceptualizing the phenomena experienced by the participants by reading all transcribed data, which was then categorized based on their similarity (Corbin & Strauss, 2008). Axial coding was used to search for answers to questions such as where, how, when, and with what. The categories were derived through open coding, and their relationship was examined through continuous comparison of the emerged codes and their meaning and concept. Selective coding involves identifying the main categories and their relationship between the concept and the initial framework of the theory. The researchers formulated a theory regarding the process of adherence among PLWH and a highly abstract core category in which to integrate the relationships among all categories found during data analysis. Trustworthiness/Rigor The application of four criteria for trustworthiness proposed by Lincoln and Guba (1985), namely credibility, dependability, confirmability, and transferability, demonstrated rigor in this study. To establish credibility, investigator triangulation was conducted where each research team member read all manuscripts, presented them during research meetings for discussion and comparison with previous data collection, and finalized analysis and coding. The summary finding, including quote results, was provided to three participants, and their opinions were sought. All three participants agreed with the results. The data source, coding, and categorization mechanism were disclosed to maintain dependability. Confirmability was maintained by emphasizing how the categories emerged and including direct quotations from all participants. Finally, transferability was achieved by providing rich contextual information about the situation during data collection. Ethical Considerations The study was approved by the Committee on Human Research of the Faculty of Nursing, University Indonesia (Ethical Number: SK-173/UN2.F12.D1.2.1/ETIK.FIK.2019). Before the interviews, all participants had signed the informed consent form. Furthermore, the research team ensured that all information obtained in this study would be used for analysis and publication only. All participants’ names were anonymous, and all data were kept confidential. Results In this study, a total of 21 respondents with a median age of 30 years participated. Among the participants, 57.2% were female, 57.7% had a senior high school education level. The duration of ART use among the participants ranged from 1 to 5 years. The majority of the participants were Muslim (90.4%) and employees (53.5%). Fourteen participants (66.6%) also have 1-2 children (Table 1). Table 1 Demographic characteristics of the participants (N = 21) Characteristics Number percentage Gender Male 9 42.8 Female 12 57.2 Age (years) 21-25 2 3.5 26-30 3 14.4 31-40 14 66.6 >40 2 3.5 Religion Islam 19 90.4 Christian 2 9.6 Education Elementary school 1 4.7 Junior high school 3 14.1 Senior high school 12 57.7 Senior vocational 2 9.4 Diploma/Bachelor’s degree 3 14.1 Occupation Employee 11 53.5 Self-employee 8 38 Housewife 2 8.5 Marital status Single 3 4.2 Married 12 57.1 Widow/widower 6 28.5 Number of children 0 (None) 6 28.5 1-2 14 66.6 >2 1 4.9 Duration of ART (years) 1-3 8 38 4-5 6 28.5 >5 7 32.5 The process of adhering or not adhering to ART is described as one’s self-awareness of ART, which has three phases: initiating ART, missing the connection, and taking control. Throughout this process, the participants applied several strategies, including how they dealt with stigma, in order to adhere to their ART. This study focused on developing a theoretical model to understand the process of adherence or non-adherence to ART for PLWH, and the model explains several categories, conditions, environments, and consequences (Figure 1). Figure 1 The theoretical model of adherence to ART Core Category: Self Awareness of ART The theoretical construct: Self-awareness was identified as the central core theme that integrated the previous categories Initiate ART, Missing the connection, and Taking control. This core theme, self-awareness, explains the ART adherence process among PLWH. Although participants realize that several factors may influence them to adhere to their ART, they know that self-awareness of taking ART regularly is the key to maintaining adherence. I understand that all people like me (living with HIV) already know that taking ART regularly is important for their health. But why are there still a lot of people who do not want to take their medication regularly? It is because the willingness to take ART does not come from them but from their doctor, nurse, or family. If you really want to take your ART regularly, you have to have high motivation from yourself, not from others. If you do, you can combat all obstacles you will face to maintain adherence to your ART [Participant 1] Phase 1: Initiating ART Phase 1 (Initiating ART) began when the participant recognized that non-adherence could lead to serious health problems. The problems of initiating ART included understanding the importance of ART and making the decision to begin ART treatment Understanding the importance of ART. At the same time that the participants discovered they were HIV positive, they received information about their health and ART treatment from their health practitioner. As a result, the participants generally understood that they needed to do something to improve and maintain their health. I need to stay healthy. That’s why I am here now, to see the doctor. The doctor prescribed me ART that I have to take for the rest of my life. [Participant 8] Making the decision to start ART. The participants received information about ART once they knew they were HIV positive. For example, one participant explained how they began ART. At the beginning of my HIV status, I was informed by the doctor to take ART. She said that these ARTs could help me stay healthy. Initially, my CD4 value was high, but she said I still needed to take ART. I was thinking, if I am taking ART, then it means that I will take ART for the rest of my life, but can I really take it regularly? [Participant 3] Phase 2: Missing the connection Missing the connection is described as a situation where the participant cannot take their ART regularly. Mostly, participants who missed the connection show less consistent behavior with their ART. Although they acknowledge the importance of ART, they do not take their medication. Forgetfulness was the commonly described reason by the participants for not taking their medication. Thus, this became their reason for non-adherence: Actually, the reason that I do not take my medication regularly is, yeah, I forget to take it, miss. As you know, I am a housewife with two children and am busy taking care of my children. So, in the morning, at 9:00 am, I am supposed to take ART, but because I am busy with my children, I forget to take it. Then I realize it is already noon, and I have not taken my medication in the morning. So, that’s what happened. [Participant 5] Marital problems were another reason that prevented a participant from taking their medication. I have a conflict with my husband. Once he knew that I had HIV, he easily got mad. He is always mad at me. Sometimes, he is angry without any reason. I was thinking that I wanted to complain by not taking my medication. He did not support me; he did not understand my situation. In this situation, why should I take my medication? No, I complained by not taking my medication. [Participant 6] The side effects of ART, such as nausea and vomiting, were identified by some participants as their reason for not taking their ART. One participant said: This ART always made me vomit all the time, so I stopped it. I do not want to take it anymore. [Participant 8] Another side effect was a change in skin color. One participant said: This ART had a bad side effect on my skin. As you can see, my skin is getting dark. See the skin of my hand. In the past, I had very light skin. However, since I started taking ART last year, my skin has become dark and is not glowing anymore. I then stopped taking my ART and asked my physician to change my ART. [Participant 11] Several external factors have been identified as the reason for non-adherence, such as the social stigma of HIV, financial problems, and no support from family. One participant mentioned one instance when she had to go out of town: I brought my medication, yeah, ART, because I have to take it every morning and afternoon. However, sometimes when I hung out with my friends, I was uncomfortable taking medicine. I thought it would be shameful if my friends knew that I was infected with HIV. So, they may not want to be my friend anymore. I don’t want to take that risk. So, I didn’t take the ART at the time. [Participant 2] Social facilitator The participant said they received social and emotional support from their family and community. For example, one participant said: My husband also reminds me when it is time to take my medicine before we sleep at night. He said to me, ‘Mom, do not forget to take your medication. [Participant 5] One participant said that all her family members know her HIV status and give her support in regularly taking her ART: My husband, sibling, my aunty, and all my big family, including my mom and father, know my HIV status. But they understood and accepted me and did not treat me differently. If we had family gatherings together, they would remind me to take my medication, If I forgot it. So, I can take it with no worry about my HIV status. [Participant 5] All the participants who have children described that having the responsibility of taking care of their children helped them with the self-discipline necessary to achieve adherence to the ART regimen. Most of the participants, particularly mothers who have children, said that children are a gift from God and that they are responsible for taking care of them. I have one child, a daughter, 10 years old. She is HIV-negative. I want to see her grow up, marry, and have a family. This is my responsibility as a mother. If it is not me, who else will take care of her? Therefore, I have to stay healthy and take my medicine regularly. I know that if I take my ART regularly, I will look like a normal person and not like a sick person. [Participant 9] Phase 3: Taking control The process of taking control describes the capabilities of participants to deal with their condition. Several categories in this phase include managing their condition and coping strategies. Managing their condition. In this phase, the participants tried to manage their bodies and were highly motivated to adhere to ART. Several factors influenced their motivation, such as wanting to stay healthy, having a bad experience with non-adherence to ART, and worrying about developing resistance to ART from non-adherence. I take my medication regularly. I realize that ART medication can make me look like a normal person as healthy person. So, I always motivate myself to take my medication to stay healthy. [Participant 3] ART adherence coping strategies. Several strategies were identified, such as using alarms, family support, and reminders from peer groups. For example, one participant shared her story about trying to match her medication schedule with her husband’s. I managed my schedule of taking medicine to be at the same time as my husband’s. In the beginning, my schedule was at 8:00 am. But eventually, I changed it to 6:00 am so that I could take medicine with my husband. [Participant 9] Another strategy to conceal their HIV status with ART was changing their ART bottle into a vitamin one. As one participant mentioned: I know that people in my workplace may recognize me as having HIV once they see my ART. However, I still need to take my medicine regularly. So, I tricked them by changing my ART bottle into a vitamin bottle. If people ask me what kind of drug I take, I will say I take vitamins. People will not know my HIV status because everybody takes vitamin daily. [Participant 10] Setting the alarm as a reminder was also mentioned by participants. I know that sometimes I forget to take my medication. So, I set my alarm using my cellphone twice a day. I usually set it early in the morning to 6:00 am and set it to 7:00 pm at night. This is just to remind me. As a housewife, I forget to take my medication because I am busy as a mother, such as when doing laundry and cooking. [Participant 6] Discussion To the best of our knowledge, this is the first study that develops a theoretical model for the process of adherence among people living with HIV (PLWH) in Indonesia. The core category, “self-awareness,” refers to how participants adhere to their antiretroviral therapy (ART). Our findings suggest that self-awareness is a process rather than an instant occurrence. The first step in enhancing our understanding of ART adherence is to pay attention to the initial phase, where patients receive information and start ART. In this phase, it is important to inquire about their perceptions and understanding of the importance of taking ART regularly, even before deciding to start ART. Several studies have demonstrated an association between poor adherence and a lack of knowledge (Martiana et al., 2019; Weaver et al., 2014). In our study, participants identified several conditions that can hinder an individual’s ability to adhere to treatment, such as forgetting to take medication, fear of stigma, lack of motivation, and ART side effects. We found that forgetting to take medication was the most common reason for non-adherence to ART. This unintentional reason is similar to what was found in previous studies as the main cause of poor adherence (Hadaye et al., 2020; Sefah et al., 2022). PLWH stigma is also cited as a factor that contributes to non-adherence. Several studies have highlighted that stigma is the major cause of a patient’s non-adherence (Camacho et al., 2020; Martiana et al., 2019; Rudolph et al., 2022; Shrestha et al., 2019; Stecher et al., 2023; Zeng et al., 2020). Stigma exists in Indonesia, particularly for women living with HIV, and it is the primary cause of non-adherence to ART (Ismail et al., 2022; Nurfalah et al., 2019; Yona et al., 2021). Internal factors, such as lack of motivation and forgetfulness, were also mentioned as barriers to ART adherence (Mugo et al., 2023; Sefah et al., 2022; Shrestha et al., 2019). A mixed-method study by Sefah et al. (2022) found that lower adherence to ART was associated with patients’ belief in herbal medicine and, from qualitative analysis, low motivation arising from pill fatigue, forgetfulness, frequent stock out of drugs, long waiting times, and worrying side-effects became barriers to ART adherence. Measures that can improve patient satisfaction with ART services and better assessment of adherence are included in strategies that ensure improved adherence and health facility-related activities. A side effect of ART that was also mentioned as a reason for non-adherence is physical changes, such as lipodystrophy and changes in skin color, which lead to depression due to poor body image. This outcome is similar to those of previous studies (Byrd et al., 2019; Hadaye et al., 2020; Zeng et al., 2020). Some participants also mentioned a lack of motivation to continue their medication due to boredom. This reason made it difficult for them to integrate their activities with their ART. However, although participants mentioned a lack of motivation, they also said that having a high self-awareness of ART is essential to deal with this problem. Taking control is the second step in broadening our understanding of the adherence process. Taking control refers to how individuals manage their condition and develop strategies to adhere to ART. In this study, participants employed multiple strategies to adhere to their medication, recognizing that adherence is essential for PLWH but needs to be tailored to each patient’s lifestyle. Patients who can incorporate treatment into their daily routines are more likely to be adherent. Several strategies were mentioned by participants, including using alarms, family support, and peer group pressure. Implementation of innovative methods is essential to ensure ART adherence. Some studies have highlighted the importance of PLWH involvement in the ART medication process, such as ART distribution, planning, and monitoring activities (Gabster et al., 2022; Goparaju et al., 2017). For example, a qualitative study by Gabster et al. (2022) in Panama found that structural barriers, such as difficult access to ART care due to travel costs, ART shortages, and uncooperative Western/Traditional medical systems, became barriers to ART adherence among PLWH in Panama. Likewise, PLWH receives their ART medications from a pharmacy or hospital in Indonesia, so it is difficult for them to become involved in the ART therapy process (Indonesian Ministry of Health, 2021). Social support from a spouse, such as taking care of children, facilitated medication adherence and retention of HIV care. This finding is consistent with research reported in other countries (King et al., 2021; Maragh-Bass et al., 2021; Mi et al., 2020; Oliveira et al., 2020). In addition, receiving love and support from family members, including spouses, can facilitate participants’ adherence to their medication (Mi et al., 2020). In previous studies, adequate support and a positive mindset have been shown to enhance ART adherence (King et al., 2021; Maragh-Bass et al., 2021; Oliveira et al., 2020). This finding is essential in Indonesian society, where the concept of family responsibility is highly valued. With this concept, the family will stay together through difficult times, including providing a support system for a sick family member (Sianturi & Dorothea, 2020). Finally, the research team identified the core category and theoretical construct, self-awareness, as the central theme that integrated the previous categories of initiating ART, missing the connection, and taking control. This construct explains the process of adherence among PLWH in Indonesia. The participants in this study realized that several factors could influence their adherence to ART, but their self-awareness of taking their medication regularly is the key to maintaining adherence. These findings highlight the importance of individual self-awareness and the mindfulness strategies that have been proven to enhance adherence to ART. As Kerrigan et al. (2018), self-awareness of ART is one of the mindfulness strategies proven to enhance adherence to ART (Sibinga et al., 2022). This method involves becoming aware of the conditions that cause or remove distortions or biases, leading to positive, healthy behaviors, including adherence to the medication regimen. Mindfulness is similar to the Buddhist concept of “Sati”, which means “memory,” and is closely related to “Sarati”, meaning “process.” It emphasizes a close and constant connection between being fully present, observing, sitting with, and accepting (Brown & Ryan, 2003). Thus, mindfulness focuses on memory and attention functions (Thera, 1962). The present study underscores the significance of individual self-awareness in achieving better adherence rates. Individuals who perceive their ART as necessary can develop several strategies to take their medication regularly. Several studies have also identified mindfulness training as one of the strategies that can help patients improve adherence to their medical treatment and decrease HIV viral load (Salmoirago-Blotcher & Carey, 2018; Sibinga et al., 2022). The study found that highly self-aware participants employed multiple strategies to continue adhering to their medication, such as adjusting their medication with ART. This finding is similar to a previous study that found geriatric patients adjusted their medication according to their daily activities (Dworakowska et al., 2019). The study also found that some participants dealt with stigma by changing the bottle of their ART to a bottle of vitamins, allowing them to take their medication without worrying about stigma. Implications for Nursing Practice and Healthcare Policy Our findings suggest that factors such as lack of motivation, ART side effects, and stigma can easily trigger nonadherence to ART. High self-awareness of the importance of taking ART is critical for staying adherent to the ART regimen. Moreover, frequent and ongoing social support is needed rather than focusing only on pill counts and viral load. Nurses can assist in identifying potential support persons and the kind of necessary information regarding ART therapy. For some PLWH, this information may include managing stigma while taking ART in public places. By encouraging PLWH to develop coping strategies for taking ART, they will remain adherent, regardless of the situation. Limitations Since this study used a retrospective perspective from participants, recall bias may occur. Additionally, this study was conducted before the COVID-19 pandemic and only represented the situation of participants before the pandemic. Furthermore, due to the methodology design, the study’s results may not generalize to the larger population since it was conducted only in Jakarta. Conclusion Self-awareness of the importance of adhering to ART was identified as the core factor that can describe the process of adherence or non-adherence to ART. Understanding the concept of ART and the importance of self-control in taking ART regularly is the most crucial factor for ART adherence. Acknowledgment The authors acknowledge all participants who joined this study. Declaration of Conflicting Interest The authors declared no potential conflicts of interest concerning the research, authorship, or publication of this article. Authors’ Contributions SY contributed to conceptualization, methodology, and data analysis. CE contributed to data collection and draft manuscript. AYN contributed to conceptualization and data collection. RI contributed to data analysis, discussion, and references. All authors were accountable in each step of the study and approved the final version of the article. Authors’ Biographies Sri Yona, S.Kp., M.N., Ph.D. is an Assistant Professor at the Department of Medical Surgical Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Ns. Chiyar Edison, S.Kep., M.Sc. is a Lecturer at the Department of Medical Surgical Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Dr. Astuti Yuni Nursasi, S.Kp., M.N. is an Assistant Professor at the Department of Community Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Rita Ismail, PhD, RN, MPH, MTD (HE) is an Assistant Professor at the Ministry of Health Republic of Indonesia, Poltekkes Kemenkes Jakarta III, Bekasi, Indonesia, 12120, West Java, Indonesia. Data Availability The datasets generated during and analyzed during the current study are not publicly available due to privacy issues of the participants (vulnerable population). Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Agnes, Y. L. N., & Songwathana, P. (2021). Understanding stigma and coping strategies among HIV-negative Muslim wives in serodiscordant relationships in a Javanese community, Indonesia. Belitung Nursing Journal, 7 (5 ), 409-417. 10.33546/bnj.1600 Audi, C., Jahanpour, O., Antelman, G., Guay, L., Rutaihwa, M., van de Ven, R., Woelk, G., & Baird, S. J. (2021). Facilitators and barriers to antiretroviral therapy adherence among HIV-positive adolescents living in Tanzania. BMC Public Health, 21 (1 ), 1-8. 10.1186/s12889-021-12323-1 33388037 Boyd, M. A., Moore, C. L., Molina, J.-M., Wood, R., Madero, J. S., Wolff, M., Ruxrungtham, K., Losso, M., Renjifo, B., & Teppler, H. (2015). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-219 10.33546/bnj.1494 Original Research DAHAGA: An Islamic spiritual mindfulness-based application to reduce depression among nursing students during the COVID-19 pandemic Dwidiyanti Meidiana 1* Munif Badrul 2 Santoso Agus 1 Rahmawati Ashri Maulida 3 Prasetya Rikhan Luhur 3 1 Department of Nursing, Diponegoro University, Semarang, Indonesia 2 Nursing Program, Institute of Health Sciences Banyuwangi, East Java, Indonesia 3 Master Program in Nursing, Diponegoro University, Semarang, Indonesia Corresponding author: Dr. Meidiana Dwidiyanti, S.Kp., MSc, Department of Nursing, Diponegoro University (UNDIP), Jl. Profesor Soedarto, SH, Tembalang, Semarang, Indonesia 50275. Phone/Fax: 08164891140. E-mail: meidiana@fk.undip.ac.id Cite this article as: Dwidiyanti, M., Munif, B., Santoso, A., Rahmawati, A. M., & Prasetya, R. L. (2021). DAHAGA: An Islamic spiritual mindfulness-based application to reduce depression among nursing students during the COVID-19 pandemic. Belitung Nursing Journal, 7(3), 219-226 https://doi.org/10.33546/bnj.1494 28 6 2021 2021 7 3 219226 26 4 2021 21 5 2021 26 6 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The COVID-19 pandemic significantly impacts students’ mental health. Most of them may experience depression. Due to restrictions and social distancing during the pandemic, counseling may not be applicable in detecting the problems. Therefore, an Islamic spiritual mindfulness-based application called DAHAGA is created in order to detect and reduce depression. It is believed that this innovative app could reduce mental health problems among students. Objective This study aimed to determine the effect of DAHAGA on reducing depression among nursing students during the COVID-19 pandemic in Indonesia. Methods This was a quasi-experimental study with a comparison group pretest/posttest design conducted from May to June 2020. Seventy students were selected using convenience sampling, of which 35 were assigned in an experimental group and a comparison group. The validated Indonesian Version-Beck Depression Inventory-II (BDI-II) was used for data collection. Paired t-test and independent t-test were used for data analysis. Results There was a significant effect of DAHAGA on depression (p < 0.001). The level of depression after intervention (mean 11.49, SD 4.49) was lower than it before the intervention (mean 17.20, SD 4.94). Additionally, there was a significant difference in depression level between the experimental and comparison groups after the intervention with a p-value of < 0.001. Conclusion The DAHAGA is proven effective in reducing depression. Therefore, this study offers a new and innovative app that fits with the COVID-19 pandemic to help Muslim students maintain their health status. The findings also support Islamic spiritual mindfulness as a part of nursing interventions among psychiatric nurses to deal with mental health problems, especially depression. COVID-19 mindfulness nursing students mental health depression Islam Indonesia ==== Body pmcThe outbreak of novel coronavirus diseases (COVID-19) was first reported at the end of 2019 in Wuhan, China (Manik et al., 2021). The virus has rapidly spread throughout the world. On 11 March 2020, the World Health Organization (WHO) declared the pandemic outbreak (WHO, 2020; Sadang & Palompon, 2021). Due to this pandemic, many universities in Indonesia are starting to implement distance teaching and learning activities or online lectures (Abidah et al., 2020). Even before the COVID-19 pandemic, research shows that many nursing students experience depression (Tung et al., 2018). Similarly, Njim et al. (2020) reported that the prevalence of depression among nursing students in two regions in Cameroon reached 69.57%, and 26.40% of these students experienced severe depression. However, Asia was the region with the highest prevalence of depression in nursing students (43.0%) (Tung et al., 2018). The majority of depression can be increased depending on stressors and environmental conditions (Acharya et al., 2018). There is no doubt that the pandemic exacerbates depression among students (Graupensperger et al., 2020). Multiple stressors in a pandemic situation contribute to the increased levels of depressive thoughts among students. A previous study found that 72.93% of students in Italian universities experienced depression during the COVID-19 pandemic (Villani et al., 2021). In Indonesia, 41.5% of nursing students experienced depression during the pandemic (Hasanah et al., 2020). Prolonged depression can affect students’ academic performance and clinical practice (Chernomas & Shapiro, 2013). Also, research showed that 59 and 87% of suicide victims suffered from severe depression, and up to 15% of them eventually die of suicide (Gonda et al., 2007). Hence, it is necessary to identify an appropriate approach to help nursing students deal with depression or its symptoms. Islamic spiritual mindfulness is one of the interventions that adopt an Islamic spiritual approach to deal with psychological problems and psychiatric disorders (Asiah et al., 2019). Mindfulness is practiced with a high level of awareness, believing that every problem an individual is facing comes from God (Allah), and it is only God (Allah) that has the power to overcome (Dwidiyanti et al., 2019; Munif et al., 2019). Previous studies have investigated the effect of Islamic spiritual mindfulness. It was found that it is effective on anxiety and depression among pregnant mothers in Iran (Aslami et al., 2015), drug adherence on patients with schizophrenia in Indonesia (Ardinata et al., 2019; Ardinata et al., 2021), the stress of family of patients with schizophrenia (Utama et al., 2020), depression level in older people at nursing homes (Arini et al., 2019), and depression among patients in a psychiatric hospital in Indonesia (Asiah et al., 2019). However, these studies only focused on depression for non-students and were conducted before the pandemic. The application of Islamic spiritual mindfulness and the detection of depression among students may not be adequate and limited during the COVID-19 pandemic due to the restriction and social distancing. In fact, most students are studying from home, and the teachers are unable to monitor. Therefore, the researchers in this study developed an innovative application called DAHAGA (Deteksi Sehat Bahagia/Happy Healthy Detection), an Islamic spiritual mindfulness app, to prevent or reduce depression among students. As the application has not yet been studied, this study aimed to determine the effect of DAHAGA on reducing depression among nursing students. This study would benefit mental health nursing services that aim to maintain optimal health and well-being and prevent psychological disorders. Inability to perform self-care or deal with impaired bodily functions related to mental and emotional distress is vital in mental health prevention practices, including avoiding depression and suicides (Videbeck, 2008). Nurses should be able to identify problems to prevent depression through innovations that facilitate the detection of disorders as early as possible, especially during the pandemic. Thus, DAHAGA would be the best fit to help nurses and nurse educators to develop an awareness of the problems faced by nursing students and identify depression levels to increase the ability to perform self-care. Overview of Islamic Spiritual Mindfulness The Islamic spiritual mindfulness is the combination of three concepts: mindfulness, spiritual, and Islam. Mindfulness is simply a state of mind, a process of keeping one’s mind in the present moment, on purpose, non-judgmentally, fully observe and accept what is experienced in life from a place of calm objectivity, and detached from potentially destructive thoughts and feelings (Creswell, 2017; Dwidiyanti et al., 2019; Munif et al., 2019). Spiritual means believing and connecting beyond the physical/material world to the soul and spirit state of existence (Dwidiyanti et al., 2019; Munif et al., 2019). Meditation and other relaxation techniques connect the two concepts, in which we pay attention to thoughts, feelings, and sensations at that moment without being overwhelmed or overly reactive while connecting to stronger spirits (Dwidiyanti et al., 2019; Munif et al., 2019). Mindfulness is found in various forms, in all religious and secular traditions, from East to West, and has roots in Buddhism, Hinduism, Judaism, Christianity, and Islam (Dwidiyanti et al., 2019; Munif et al., 2019). However, in this study, we focus only on the Islamic perspective. Islamic spiritual mindfulness refers to a spiritual state of an individual who is conscious of the awareness of God (Allah) over their soul, innermost thoughts/feelings, and actions (Dwidiyanti et al., 2019; Munif et al., 2019). In other words, it is comprehensive self-knowledge and self-awareness that Allah is always watching us at all times, which consequently will change our actions, feelings, thoughts, and inner states of being to be better. It can also be described as a mutual awareness, while we are of Allah, and Allah is aware of us (Mindful Muslim Life, 2021). Islamic spiritual mindfulness exercise consists of six steps (Dwidiyanti et al., 2019): (1) intention - generating a desire in the heart with full awareness according to needs prayed to Allah accompanied by the belief of Muroqobahtullah (the belief of feeling supervised by Allah), (2) self-evaluation - self-introspection by acknowledging shortcomings and accepting without judgment of oneself and generating a desire to correct mistakes, (3) body scan - realizing every mistake made and believing that Allah is Most Forgiving by fulfilling the conditions of repentance. The conditions for repentance are to create a sense of regret, stop and be determined not to repeat the sins that have been committed, and fulfill the rights of others who have been hurt, such as apologizing, (4) repentance - focusing on feeling the reactions of the heart and body, such as pounding, heat in the chest, heaviness in the neck, etc., and accept these reactions with complete acceptance and relaxation, (5) prayer - praying to God solemnly then blowing it into the palm and washing it on the organs of the body that feel hurt or pain, (6) surrender – giving (oneself) up to Allah with sincerity to get benefit and prevent harm, and (7) relaxation - holding the body that hurts or pain, take a deep breath, and then cough (Dwidiyanti et al., 2019). Methods Study Design This study used a quasi-experimental design with a comparison group pretest/posttest design. The study was conducted from May to June 2020. Participants The participants in this study are 148 bachelor nursing students (semesters one to eight) at the Faculty of Medicine, Diponegoro University, Indonesia. The number of participants in this study was calculated using G*Power 3.1 (Faul et al., 2009) with type of a priori power analysis for independent t-test, with Effect Size (ES) value of > 0.80 (Munif et al., 2019), power of 0.95, and error probability ratio of 0.05. The total samples needed were 70, with 35 assigned in an experimental group and a comparison group. Random sampling could not be used in this study because the students would be selected if they fit inclusion criteria, especially the students who experienced mild depression as indicated using Beck Depression Inventory-II (BDI-II), held Islamic religion, and agreed to participate. So, we conveniently examined the students one by one, and those who had depression were asked to join the study until the required samples in each group were fulfilled. Instrument The Beck Depression Inventory-II (BDI-II) (Beck et al., 1996) was used for data collection. The inventory consists of 21 questions. The Indonesian version of the BDI-II was available (Sorayah, 2018) and considered valid and reliable using a confirmatory factor analysis (CFA). Each answer is scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs used differ from the original: 0–13 (minimal depression), 14–19 (mild depression), 20–28 (moderate depression), 29–63 (severe depression) (Sorayah, 2018). Intervention The experimental group in this study was given spiritual training using DAHAGA. DAHAGA was an android-based application that contained mental health service packages that focus on Islamic spiritual mindfulness intervention. This application offers features that make it easier for individuals to self-detect depression they experienced. These features are developed based on the experts’ agreement through a series of workshop meetings. A patent for the DAHAGA app has also been granted by the Director General of Intellectual Property, Ministry of Law and Human Rights, Indonesia (Grant Number: EC00202114477). The following are the features of the “DAHAGA” application (Figure 1 and Table 1): Table 1 Difference in the level of depression among students in the intervention and comparison groups (N = 70) Group Depression Mean Difference p-valuea Pretest Posttest Mean±SD Mean±SD Experiment (n=35) 17.20±4.94 11.49±4.49 4.28 <0.001a Comparison (n=35) 16.49±4.11 16.34±4.92 1.80 0.861a p-value b 0.513b <0.001b a Paired t-test | b Independent t-test Figure 1 Homepage of DAHAGA App The explanation of each feature is described in the following. The Problem Feature (or Masalah) is a means to make it easier for someone to detect problems that they had with their closest people (family members, such as father, mother, brother, sister, husband, wife, and others), other people (e.g., neighbors, friends at home or work, and others), and the environment (Dwidiyanti et al., 2019). The problem databases in this feature were validated by the participants of the workshops organized three times, related to the environmental problems that were too broad and had to be more specific. The Bad Behavior Feature (or Perilaku Buruk) was developed based on a focus group discussion with 20 participants. They wrote any bad behaviors on their books which were then collected and analyzed. This feature contained 13 items of bad behaviors, which were validated by the participants of the workshops organized three times. These bad behaviors were used as a reference for independent health targets that should be carried out. The validation was related to the behaviors concerning ritual implementation, which need to be simplified and not too detailed. This feature is to identify how far the users can remember and admit (in a mindful state) previous bad behaviors they have done. The 13 items include (1) rarely have five times of prayer, (2) seldom read Qur’an, (3) rarely Dua (a prayer of invocation), (4) think negatively, (5) jealous, (6) arrogant, (7) Riya (show-off), (8) hurt others, (9) vindictive, (10) lie, (11) dirty talk, (12) immoral behavior, and (13) fornication (eye, mind, and physical). Self-Detection Feature (or Deteksi Diri) contains seven items of feelings currently expressed by participants, including angry, broken heart, sadness, cough, headache, and hard to breathe. These items were validated by the participants of workshops organized three times. After the data related to problems, bad behaviors, and self-detections were identified, the results were then used to identify factors causing depression. Validation was carried out using real pictures to determine the expression of the problems faced. Independent Health Target Feature (or Target Sehat Mandiri) contains ten items about independent health targets that participants planned to change for improvement. These items were validated by the participants of workshops organized three times. This feature serves as a solution that the participants would achieve after identifying problems, bad behavior, and self-detection. During the validation, several targets were removed as they were confusing and did not relate to the issues that the participants were experiencing. The ten items include (1) forgiving everyone who hurts or disappoints, (2) praying on time and in a congregation, (3) reading Qur’an every day, (4) drawing closer to Allah and always prays or participates in Islamic studies, (5) understanding yourself and others, (6) being more patient and sincere, (7) learning to smile, at least a day to twenty people you meet, (8) thinking positively, (9) always being grateful and realizing Allah’s grace, and (10) being more open-minded and not quickly getting angry. Pretest Feature is to detect depression before the intervention using the Beck Depression Inventory-II (BDI-II) (Beck et al., 1996; Sorayah, 2018). Pretest Feature is to detect depression after intervention using the Beck Depression Inventory-II (BDI-II) (Beck et al., 1996; Sorayah, 2018). Islamic Spiritual Mindfulness (or Latihan Mindfulness Spiritual Islam) contains a step-by-step tutorial / Standard Operating Procedure (SOP) on Islamic spiritual mindfulness that had been previously identified by the researchers. In the SOP, the individuals would be invited to consciously accept the bad behaviors that had been done and try to correct them through independent health targets that would be performed. This feature was packaged in an audio form that could be listened to by participants. This mindfulness exercise contained six steps: intention, self-evaluation, body scan, repentance, prayer, surrender, and relaxation. The steps are explained in the background (overview of Islamic spiritual mindfulness). The procedure can be done between 10 to 15 minutes. Information Feature (or Informasi Aplikasi) contains information related to the app, developers, and contents. The comparison group was given a book of Islamic spiritual mindfulness only (Dwidiyanti et al., 2019) (see Figure 3). There was no spiritual training provided; only after the whole process of study was completed, the researchers offered them the same treatments as done in the experimental group. Figure 2 Features of DAHAGA App Figure 3 Islamic spiritual mindfulness book cover Data Collection The data collection was performed using a website linked to the “DAHAGA” application for screening. The data were collected in a nursing college with the help of two research assistants. The researchers ensured that the research assistants had been given training for the procedures of the data collection. Their jobs were to facilitate the participants in filling out and using the “DAHAGA” application in the WhatsApp group. Each participant in the experimental group was asked to do a pretest before applying each feature of Islamic spiritual mindfulness in the app. The participants were asked to do the mindfulness exercise six times and then followed by a posttest. All data were recorded automatically in the app and could be accessed by the researchers and admin only. In the comparison group, the pretest and posttest were conducted online using Google Forms. The research assistants also helped them via WhatsApp. After practicing mindfulness according to the book, the participants were asked to do a posttest. Data Analysis Data were analyzed using descriptive statistics and bivariate analysis. As data were normally distributed, paired t-test and independent t-test were used to determine the effect of the intervention on depression in each group and compare its impact between the experiment and comparison groups. The significance level is set at 0.05. Ethical Consideration This study received ethical clearance from the Health Research Ethics Committee of the Department of Nursing, Faculty of Medicine, Diponegoro University, with a reference number of 99/EC/KEPK/D.Kep/IV/2020. The researchers also ensured that each student had signed a written informed consent prior to data collection. Each has a right to withdraw from the study at any time without penalty. Confidentiality of the data was also ensured. Results Seventy participants were able to join and no one withdrawn from the study. The majority of them were aged 18-22 years old and included in the category of early adulthood (Hurlock, 2009). The difference in depression levels among students can be seen in Table 1. Based on the results of the paired t-test as shown in Table 1, it could be concluded that there was a significant effect of DAHAGA on the level of depression in the experimental group, seen from a significant difference in the depression level before and after the intervention (p <0.001). In contrast, there was no significant difference in the level of depression in the comparison group before and after the intervention (p = 0.861). This result is also supported by the statistical result of the independent t-test, which revealed a significant difference in depression level between the experimental group and the comparison group after the intervention with a p-value of <0.001. This finding indicates that the Islamic spiritual mindfulness combined with other features in the innovative app effectively reduces depression levels among students. Discussion This study aimed to examine the effect of DAHAGA application on reducing depression among nursing students. The results revealed a significant effect of the app on depression level in the experimental group seen from the dependent t-test analysis and confirmed by the independent t-test analysis, which shows a significant difference in depression level after interventions between the experimental and comparison groups. However, the findings of this study support previous research (Asiah et al., 2019) that Islamic spiritual mindfulness intervention is effective not only for patients with depression who are admitted to a psychiatric hospital but also for nursing students, as indicated in our study. An innovative intervention created in this study using the DAHAGA application helps the students identify problems that they have or the environment quickly through the detection feature. However, identifying the problems is essential for the prevention of mental disorders (Videbeck, 2008). The app also helps detect the bad behavior and independent healthy target plans (Dwidiyanti et al., 2019), which consequently awareness among the students will be increased, and they could cope with their problems independently and prevent mental disorders, especially depression. Additionally, the app allows the researchers to monitor and help the condition of the students, which is considered the benefit of the app. In contrast, the use of the Islamic spiritual mindfulness book alone was not effective in reducing depression levels among students compared to app use, as indicated in this study. Notably, the DAHAGA application is helpful and practical, especially during the pandemic. Wei et al. (2020) said that the provision of integrated internet-based interventions effectively reduced symptoms of stress and depression related to COVID-19. In this study, the DAHAGA application provides eight features: (1) problem, (2) bad behavior, (3) early detection, (4) independent health target, (5) pretest, (6) posttest, (7) mindfulness exercises, and (8) information. The problem feature contains questions about the problems faced, while the bad behavior feature contains questions regarding the user’s experiences of the committed behavior. The early self-detection element consists of two forms of questions, namely, current feelings and physical conditions. The independent health target feature contains target choices/user expectations for independent health. The pretest and posttest feature includes questionnaires about depression that should be completed before and after mindfulness exercises. The mindfulness training feature contains mindfulness exercise guidelines that aim to help users consciously accept the committed bad behavior and try to correct it through independent health targets that have been planned earlier (Sadipun et al., 2018; Dwidiyanti et al., 2019; Munif et al., 2019). It is noteworthy that Islamic spiritual mindfulness is fully emphasized in the app. Islamic spiritual mindfulness is an exercise that aims to help individuals aware of their current condition or experience by involving the presence of God (Dwidiyanti et al., 2019). It is also believed that Islamic spiritual mindfulness is able to change behaviors and build positive interpersonal skills through intention and self-evaluation (Dwidiyanti et al., 2019). According to Yapko (2016), for the healing of depression, a patient should be taught about (1) the ability to make effective decisions, (2) effective coping or stress management skills, (3) skills to build and maintain positive relationships, (4) problem-solving skills, and (5) building a realistic and motivating future. Such abilities are taught at each stage of Islamic spiritual mindfulness. The stages of mindfulness include the intention and self-evaluation that describe the decisions made effectively concerning the behavior to be changed. As for coping, stress management in Islamic spiritual mindfulness is taught through seven steps: intention, self-evaluation, repentance, body scan, prayer, surrender, and relaxation (Dwidiyanti et al., 2019). Implications of this Study for Nursing Practice Several implications of this study include: First, the findings of this study provide evidence to support Islamic spiritual mindfulness as a part of nursing intervention among mental health nurses or psychiatric nurses to reduce depression in their practice; Second, this study offers a new and innovative app called DAHAGA, which fit with the COVID-19 condition today where the utilization of the technology is necessary; Third, the results of the study provide additional knowledge for nursing science, which the concepts of Islam, spiritual, and mindfulness merged in order to provide holistic nursing care, especially for the individuals who hold Islamic religion. Limitation of the Study We notice two limitations of the study. First, when installing the “DAHAGA” application, some participants experienced difficulties due to the device restrictions. As a result, there was a time difference in starting the mindfulness exercises using the application. Further study is recommended to encounter this issue, which the app could be used in any devices. Second, as the app specifically focuses on individuals who hold Islam; thus, it cannot be used in others. Conclusion There was a significant effect of using the DAHAGA-Islamic spiritual mindfulness-based app on reducing the students’ levels of depression. The app can be used to detect and treat depression among college students. Also, it can be utilized as a part of the intervention in nursing practice. The extended application of the app with non-students and non-Muslims is a necessity to validate the findings. Acknowledgment This work was supported by the Faculty of Medicine, Diponegoro University. We also thank the Department of Nursing, Diponegoro University, for allowing us to conduct this research. Declaration of Conflicting Interest The authors declared that they do not have a conflict of interest, either individuals or institutions. Funding This study received funding from the Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia. Authors’ Contribution All authors contributed equally to the drafting of the manuscript, revising the manuscript critically for important intellectual content, conception, and design of the study, acquisition of data, analysis, and/or interpretation of data. All authors approved the final version of the article. Data Availability Statement The research data could not be shared because they were saved by Diponegoro University’s server. We strictly followed the research ethics to ensure the confidentiality of the data. Authors’ Biographies Dr. Meidiana Dwidiyanti, S.Kp., MSc is a Lecturer of Mental Health Nursing in the Faculty of Medicine, Diponegoro University, Semarang, Indonesia. She is also the Head of the Postgraduate Nursing Program at the Nursing Department, Faculty of Medicine, Diponegoro University, Semarang, Indonesia. Ns. Badrul Munif, S.Kep., M.Kep is a Lecturer of Mental Health Nursing in Nursing Program, Institute of Health Sciences Banyuwangi, East Java, Indonesia. Agus Santoso, S.Kp., M.Kep is a Lecturer of Nursing Management and Leadership in the Faculty of Medicine, Diponegoro University, Semarang, Indonesia. He is also the Head of Degree Nursing Program at the Nursing Department, Faculty of Medicine, Diponegoro University, Semarang, Indonesia. Ns. Ashri Maulida Rahmawati, S.Kep.,M.Kep is a Student of Master Program in Nursing, Diponegoro University, Semarang, Indonesia. Ns. Rikhan Luhur Prasetya, S.Kep is a Student of Master Program in Nursing, Diponegoro University, Semarang, Indonesia. ==== Refs References Abidah, A., Hidaayatullaah, H. N., Simamora, R. M., Fehabutar, D., & Mutakinati, L. (2020). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-118 10.33546/bnj.2555 Original Research Factors influencing intention to plagiarize among nursing students in the Philippines https://orcid.org/0000-0001-6411-2755 Debuque Mary Bless G. https://orcid.org/0000-0002-2774-7281 Dofitas John Bernard A. https://orcid.org/0000-0001-6659-6909 Espia Dorothy Arlene Paz P. https://orcid.org/0000-0001-5961-7142 Ferrariz Trixie Camille R. https://orcid.org/0000-0001-5659-6905 Gargarita Francis John P. https://orcid.org/0000-0001-9107-3069 Oducado Ryan Michael F. * West Visayas State University, College of Nursing, Iloilo City, Philippines * Corresponding author: Prof. Ryan Michael F. Oducado, PhD, RN, West Visayas State University, College of Nursing, Iloilo City, Philippines, 5000. Email: rmoducado@wvsu.edu.ph Cite this article as: Debuque, M. B. G., Dofitas, J. B. A., Espia, D. A. P. P., Ferrariz, T. C. R., Gargarita, F. J. P., & Oducado, R. M. F. (2023). Factors influencing intention to plagiarize among nursing students in the Philippines. Belitung Nursing Journal, 9(2), 118-123. https://doi.org/10.33546/bnj.2555 18 4 2023 2023 9 2 118123 23 1 2023 22 2 2023 14 3 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Plagiarism is an ethical concern among students but is insufficiently discussed and acknowledged in some educational institutions. Determining what factors influence plagiarism can help the academic community manage its incidence. Objective This study determined the factors affecting the intention to plagiarize among Filipino nursing students. Methods Utilizing a cross-sectional research design, data were gathered from 304 nursing students last June 2021 using valid instruments administered online. Regression analysis identified influencing factors of intention to plagiarize. Results Findings indicated a generally low intention (M = 1.47, SD = 0.74) to plagiarize among nursing students. Internet literacy (B = -0.314, p <0.001), attitude (B = 0.257, p <0.001), moral obligation (B = -0.236, p <0.001), past behavior (B = 0.139, p <0.001), and subjective norm (B = -0.095, p = -0.001) influenced nursing students’ plagiarism intention. Conclusion Several interrelated factors play major roles in nursing students’ tendency to plagiarize. Creating an educational environment that does not favor the unethical practice of plagiarism is recommended for nursing schools. cross-sectional study intention moral obligations nursing plagiarism Philippines students ==== Body pmcBackground Plagiarism among students has remained a significant and central issue for institutions of higher learning (Malik et al., 2021). With the advent of technology and the massive availability of information online, plagiarism remains a rampant issue, especially among students. Plagiarism is defined as the “copying (or using) of others’ work that (accidentally or otherwise) deceives a third party about the authorship (or ownership) of the work” (Uzun & Kilis, 2020; Yeo, 2007). It is an offense against scholarly works’ strict standards of originality, and according to the Philippine Department of Justice (2012), it is the “deliberate and knowing presentation of another person’s original ideas or creative expressions as one’s own.” Unfortunately, in educational institutions, plagiarism is insufficiently acknowledged and discussed (Carnero et al., 2017), with little emphasis on avoiding it and its corresponding consequences, which cause students to intentionally and unintentionally plagiarize (Jereb et al., 2018). With the rise of COVID-19, schools and universities have temporarily shifted to online instruction (Oducado & Soriano, 2021). Educators are concerned that online education and the availability of cyber information may breed academic dishonesty and further increase the risk of practicing plagiarism (Oducado, 2020). Technological advancement in educational practices increases the concern of academic misconduct as technology offers convenient ways for students to easily pass information and plagiarize (Abusafia et al., 2018; Eret & Ok, 2014). Educators commonly use assignments and essays to assess and evaluate learning, making the students dependent on the information on the internet. With this, students may pass on requirements with contents lifted from the internet, making citing sources completely necessary. Plagiarism, an act of academic dishonesty, is an ethical issue in nursing education (Carter et al., 2019). Nursing educators correlate the act of dishonesty in plagiarism as a vehicle for future unethical actions in the profession (Allen et al., 2017). Honesty and ethical standards are hallmarks of the nursing profession; however, plagiarism endangers the reputation of nursing education to the academic and social community (Krueger, 2014). The concept of dishonesty by plagiarism in higher education must be eradicated as this behavior may be carried by students into nursing practice (Carter et al., 2019). Thus, plagiarism in nursing education should be given attention, as observing ethical practices ensures client safety in clinical settings (Birks et al., 2018). Nursing is a profession that highly values integrity and honesty. In fact, according to the 2020 Gallup report, nurses have been rated highest in honesty and ethics among other professionals for the past 18 years (Saad, 2020). While it is expected that there can only be a minor incidence of academic dishonesty among students in nursing schools, studies have shown otherwise. Studies from Australia (Birks et al., 2018), Malaysia (Abusafia et al., 2018), and Italy (Macale et al., 2017) reported nursing students engaging in acts of academic misconduct, with plagiarism reported as one of the common forms. In addition, Ismail (2018) conducted a study among 280 medical students and 120 nursing students in Iraq. He found that 54.3% of the sample practiced plagiarism, 34.8% were unaware of the practice of plagiarism, and only 28% were knowledgeable about its legal consequences. Prior studies highlighted the prevalence of plagiarism in academic circles. Thus, an urgent need to widen the knowledge and understanding regarding the nature of plagiarism is of paramount importance. However, plagiarism in nursing education in the Philippine setting has not been explored. There also have been some anecdotal observations of students failing to give proper attribution of someone else’s work and submitting academic requirements with contents lifted straight from the internet. And while plagiarism per se is not as serious as being considered a crime in the Philippines unless it amounts to copyright infringement (Philippine Department of Justice, 2012), it is still an ethical issue and an offense against academic integrity that requires prompt exploration and attention. Hence, this research was conducted to assess factors affecting the intention of plagiarism among Filipino nursing students. Exploring and identifying these factors will help confront and deal with this academic misconduct among students (Uzun & Kilis, 2020). Anchored on the Theory of Planned Behavior or TPB (Ajzen, 1991), this theory hypothesizes that behavioral intention, or in this study, the motivational factor or plan to plagiarize, is the immediate determinant of behavior. The TPB also assumes attitude, perceived control, and subjective norm as antecedents to behavioral intention (Ajzen, 1991). More recently, Uzun and Kilis (2020) extended the TPB framework and included additional variables such as past behavior, moral obligation, and Information and Communication Technologies literacy in studying the factors influencing plagiarism in universities. This extended theory of TPB was adopted in this study to explore the antecedents of plagiarism intention among undergraduate students in one government-funded nursing school in the Philippines. Methods Study Design This study adopted a quantitative research design using a cross-sectional approach. Participants/Samples All 417 undergraduate nursing students of one government-funded nursing school in the Philippines were invited to participate in an online survey, but only 73% of the total population, or 304 nursing students, responded. The sample adequacy was determined using G#x002A;Power 3.1 with a priori power analysis (Faul et al., 2009), suggesting 112 is the required sample size for multiple linear regression with eight independent variables, an effect size of 0.15, an alpha of 0.05, and 80% power. Instruments The data were gathered using nine questionnaires and a demographic profile section. The scales to assess attitude, subjective norm, computer, internet, and information literacy, moral obligation, past behavior, and intention to plagiarize were adopted from Uzun and Kilis (2020), while the items on the scale to assess perceived behavioral control were adapted from the work of Stone et al. (2010) and Verma and Chandra (2018). The respective authors granted permission to use the research instruments through email correspondence. Only the adapted tool was content validated by a nurse educator, nurse lawyer, and a licensed librarian and was pilot tested among 30 nursing students. The attitude was evaluated using four bipolar semantic differential items on a 7-point Likert scale. Negative attitude choices (unfavorable, harmful, foolish, bad) were given lower points, while positive attitude choices (favorable, beneficial, wise, good) were given higher points. A negative attitude means student nurses did not favor the concept of plagiarism. Subjective norm (3 items), moral obligation (3 items), and intention (3 items) were answerable by a 7-point Likert scale with responses ranging from “1 = strongly disagree” to “7 = strong agree.” Computer (5 items), internet (5 items), and information literacy (7 items) assessed the level of awareness and skills of nursing students in the use of the internet, information, and computer technology. All items were answerable by a 5-point Likert scale with choices ranging from “1 = strongly disagree” to “5 = strongly agree.” Past behavior (2 items) assessed the occurrence of plagiarism behavior in the past. The first item evaluated the degree of previous plagiarism occurrences, and the second item assessed the frequency of plagiarism behavior in the past. Participants were asked to respond to a 7-point Likert scale with choices ranging from “1 = very little” to “7 = a lot” for the first item and from “1 = never” to “7 = every time” for the second item. Perceived behavioral control (8 items) assessed the ease and difficulty perceived by nursing students in committing plagiarism. Items in this section asked participants to respond to a 5-point Likert Scale with choices ranging from “1 = strongly disagree” to “5 = strongly agree.” The following are the Cronbach’s alpha values of each scale based on the survey: attitude scale = 0.85, and subjective norm scale alpha = 0.56. perceived behavioral control = 0.83, computer literacy scale = 0.77, information literacy scale = 0.91, internet literacy scale = 0.76, moral obligation scale = 0.82, past behavior = 0.85, and intention scale = 0.91. The mean values for each major variable or construct in this study were computed. Data Collection Relevant permissions to conduct the study in June 2021 were secured from the Office of the Dean, the level chairpersons, and the Ethics Review Committee. Before the actual conduct, point persons from each year level were contacted by the researchers to assist in distributing the online questionnaire accessed via Google Forms. The researchers then provided full disclosure of necessary information regarding the nature and purpose of the study, emphasized voluntary participation and self-determination, and guaranteed students’ anonymity. Participants can accomplish the instruments within 15 to 20 minutes. Due to the platform it was given, a window of 2 weeks was given to nursing students to complete the questionnaire. After achieving the target response rate, the link to the instrument was closed two days later. The responses were monitored for completeness, consolidated, and organized. Data Analysis The SPSS version 26 software package was utilized for data analysis. Frequency, percentage, standard deviation, and mean were used to describe the data. Pearson’s r was employed to determine significant relationships, and step-wise multiple linear regression was used to identify significant influencing factors. The results were considered significant if the alpha level was equal to or below 0.05. Ethical Consideration The Unified Research Ethics Review Committee (WVSU.URE RC-2021.CONS_002) approved the study on 16 June 2021. Participants had to answer an electronic consent form that was given together with the online questionnaire accessible through Google Forms. Results Table 1 shows that the mean age of the participants is 20.31 (SD = 0.97). In terms of sex, 70.4% were females, and 29.6% were males. When grouped as to year level, 31.6% were from the first year, 34.9% from the second year, and 33.6% from the third year. Table 1 Profile of participants Variables f % M (SD) Age 20.31 (0.97) Sex Male 90 29.6 Female 213 70.4 Year level Level 1 96 31.6 Level 2 106 34.9 Level 3 102 33.6 Table 2 shows that nursing students obtained the following mean scores: attitude towards plagiarism (M = 1.56, SD = 0.76), perceived behavioral control (M = 3.22, SD = 0.87), subjective norm (M = 5.97, SD = 1.19), computer literacy (M = 4.41, SD = 0.63), internet literacy (M = 0.71, SD = 0.47), information literacy (M = 4.34, SD = 0.63), moral obligation (M = 6.44, SD = 0.78), past behavior (M = 3.20, SD = 1.32) and intention to plagiarize (M = 1.47, SD = 0.74). Table 2 Descriptive of major variables Variables M SD Attitude 1.56 0.76 Subjective norm 5.97 1.19 Perceived behavioral control 3.22 0.87 Internet literacy 4.71 0.47 Computer literacy 4.41 0.63 Information literacy 4.34 0.63 Moral obligation 6.44 0.78 Past behavior 3.20 1.32 Intention 1.47 0.74 Table 3 reveals that all variables showed a significant relationship toward intention to plagiarize. Attitude (r = 0.512, p <0.001), perceived behavioral control (r = 0.188, p = 0.001), subjective norm (r = -0.434, p <0.001), computer literacy (r = -0.186, p = 0.001), internet literacy (r = -0.262, p = <0.001), information literacy (r = -0.224, p <0.001), moral obligation (r = -0.558, p <0.001), past behavior (r = 0.474, p <0.001) were significantly correlated with intention to plagiarize. Table 3 Correlates of intention to plagiarize Variables Pearson’s r p-value Attitude 0.512 <0.001 Subjective norm -0.434 <0.001 Perceived behavioral control 0.188 0.001 Internet literacy -0.262 <0.001 Computer literacy -0.186 0.001 Information literacy -0.224 <0.001 Moral obligation -0.558 <0.001 Past behavior 0.474 <0.001 When all significant variables were entered in the regression model, internet literacy (B = -0.314, p <0.001), attitude (B = 0.257, p <0.001), moral obligation (B = -0.236, p <0.001), past behavior (B = 0.139, p <0.001), and subjective norm (B = -0.095, p = -0.001) were found significant factors accounting for 51% of the variation in intention to plagiarize among nursing students (Table 4). Table 4 Multiple linear regression of intention to plagiarize Model Unstandardized Coefficients t p-value B Std. Error (Constant) 4.195 0.474 8.858 <0.001 Internet literacy -0.314 0.065 -4.848 <0.001 Attitude 0.257 0.046 5.574 <0.001 Moral obligation -0.236 0.049 -4.786 <0.001 Past behavior 0.139 0.025 5.550 <0.001 Subjective norm -0.095 0.029 -3.330 0.001 R Square = 0.510, F = 62.054, p <0.001 Discussion The present study looked into the factors that affect the intention to plagiarize among nursing students. While prior research noted plagiarism as a common form of academic misconduct among nursing students (Abusafia et al., 2018; Birks et al., 2018; Macale et al., 2017), it is significant to note that nursing students in this current study had a low intention to plagiarize, which means they are less likely to commit plagiarism in the future. Similarly, Mirzaei-Alavijeh et al. (2021) reported that most medical students in Iran intend not to plagiarize in the future. In addition, the creation of software, such as Turnitin and Grammarly, to detect plagiarism has made it easier for faculty to detect nursing students’ intentions to plagiarize (Carter et al., 2019). It is also noteworthy that while the intention to plagiarize was low, there are still students in this study who reported committing plagiarism in the past. The result of this present study disclosed that past behavior of plagiarism influenced the intention to commit plagiarism in the future. The more frequently the student nurses acted in response to committing plagiarism in the past, the higher their intent to practice plagiarism in the future. Students are likely to continue participating in behavior if no other factor hinders them from doing such (Anaman & Agyei, 2021). Uzun and Kilis (2020) similarly found past behavior significantly correlated with plagiarizing intention. Nursing schools may also look into the factors that cause and contribute to the act of committing plagiarism, as the act of dishonesty in plagiarism can be a vehicle for future unethical actions (Allen et al., 2017). This study found that internet literacy influenced the intention to plagiarize. Surprisingly, the higher ability of students to operate Internet technologies, the lower their intention to practice plagiarism. In contrast, the study of Uzun and Kilis (2020) showed that internet literacy was not a significant factor. While there can be an increase in plagiarism tendency with the use of the internet, especially due to the advancement of technology (Abusafia et al., 2018; Eret & Ok, 2014), it may also be that for this study, nursing students gained more information about the negative consequences of plagiarism through the internet and are familiar of plagiarism detection software available that lowered their plans of committing plagiarism. It may also be that less technology and internet-savvy students might believe that plagiarism is a less severe offense than other internet-related offenses like hacking or digital piracy (Chan, 2015); hence students with lesser internet literacy are more likely to plagiarize. Some scholars are also still arguing that no empirical support demonstrates that the internet has accelerated or is a contributor to student plagiarism (Davies & Howard, 2016). Moral judgment has a significant influence on a student’s ethical behavior. Another variable found to influence plagiarism intention was a moral obligation. This means that the higher student nurses’ moral obligation to avoid plagiarism, the lower their intent to practice it. Similarly, Uzun and Kilis (2020) found a significant negative association between moral responsibility and the intention to plagiarize. The more an individual perceives that the act or plagiarism is morally incorrect, the lower the intent to act (Camara et al., 2017). That is, the higher the anticipated sense of guilt the person has, the lower the intention to commit plagiarism (Cronan et al., 2018). Likewise, the study of Natalia et al. (2015) revealed a significant correlation between moral disengagement and plagiarism, suggesting that the higher the moral disengagement, the higher the chances of plagiarism. The choice or decision to engage or not engage in a behavior is likely influenced by social norms (Camara et al., 2017). Consistent with prior research, external factors such as subjective norms influenced the intention to plagiarize among nursing students. This means that the higher the perceived social pressure placed upon the student nurses by their significant others not to commit plagiarism, the lower the intent of the student nurses to practice it. Yusliza et al. (2020) explained that subjective norms that do not promote plagiarism lessen the intent of committing the act. Moreover, according to Mirzaei-Alavijeh et al. (2021), subjective norms that encourage plagiarism tend to increase the intention and are one of the main factors associated to plagiarize among college students. The negative opinion of their significant others about plagiarism influenced students’ tendency to plagiarize, and this may have given rise to the student nurses’ unfavorable attitude toward plagiarism. This study found that attitude toward plagiarism significantly influenced the intention to plagiarize. Positive attitudes towards plagiarism increase the intention, and negative attitudes lower the intention to plagiarize. The study of Stone et al. (2010) presented that favorable attitudes towards academic misconduct are positively associated with committing that kind of behavior, and in this case, plagiarism. Similarly, Camara et al. (2017) disclosed that negative attitudes predict plagiarism intention. Also, the study of Uzun and Kilis (2020) revealed that favorable attitudes toward plagiarism increase the intention to plagiarize. Finally, the results of this study support the extended theory of TPB (Ajzen, 1991) to some extent, wherein variables such as attitude and subjective norm from the original theory were found to be significant predictors to plagiarize. The inclusion of other factors such as internet literacy, moral obligation, and past behavior were also found to predict the plagiarism intention of nursing students in this study. Studies conducted locally and abroad (Al Maskari et al., 2022; Ditching et al., 2020; Oducado et al., 2022; Secginli et al., 2021; Zhong et al., 2022) have similarly found the TPB a helpful framework in successfully explaining the behavioral intention of nursing students. Implications of the Study The study results provide implications concerning the factors that may influence students to commit plagiarism. Nursing educational institutions can tailor intervention strategies to mitigate future problems related to this academic misconduct by using the results of this study as a guiding framework and blueprint for creating an environment that does not promote plagiarism. Moreover, given that certain social factors affect students’ plagiarism intention, this research implies the necessity for nurse educators to be good role models of integrity and ethical behavior. Despite the low plans to plagiarize among students of this study, there is still a need to continuously reinforce to the minds of students that plagiarism is a highly unethical and unacceptable act. This is because the very simple act of dishonesty in plagiarism can be a vehicle for future unethical actions that may be carried out in professional nursing practice. Limitations of the Study Limitations were noted in this study. The cross-sectional study focused on a limited factor associated with the intention to plagiarize among undergraduate nursing students in the Philippines. Therefore, generalizations can only be made among nursing students included in the sample. Moreover, the study cannot infer causality between variables. And because of online survey questionnaires, self-report bias is another potential limitation. Conclusion The decision to commit plagiarism is a result of a variety of interrelated factors. This study highlights that internal (moral obligation) and external (subjective norm) variables may contribute to nursing students’ plans to commit unethical behavior, such as academic plagiarism. Identifying and recognizing these factors are essential to understand the nature of plagiarism better and further preventing or mitigating committing such behavior in the future. Cultivating a habit of properly attributing sources and creating an environment that does not support plagiarism or other forms of academic dishonesty is vital for nursing schools. Educational nursing institutions may need to reinforce stricter policies and guidelines against plagiarism to teach students the value of maintaining academic integrity. Acknowledgment We would like to thank all the nursing students who willingly participated in the study. Declaration of Conflicting Interest No conflict of interest to declare. Funding This research did not receive any specific grant from funding agencies. Authors’ Contributions All authors made a substantial contribution from conception to the finalization of this study and approved the version of the manuscript submitted. Authors’ Biographies Mary Bless G. Debuque, RN, is a Board Exam Topnotcher and a Newly Registered Nurse in the Philippines. John Bernard A. Dofitas, RN, is a Newly Registered Nurse in the Philippines. Dorothy Arlene Paz P. Espia, RN, is a Newly Registered Nurse in the Philippines. Trixie Camille R. Ferrariz, RN, is a Newly Registered Nurse in the Philippines. Francis John P. Gargarita, RN, is a Board Exam Topnotcher and a Newly Registered Nurse in the Philippines. Ryan Michael F. Oducado, PhD, RN, RM, LPT, RGC, is a Professor of the College of Nursing and the University Research Director of the West Visayas State University, Iloilo City, Philippines. Data Availability The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Abusafia, A. H., Roslan, N. S., Yusoff, D. M., & Nor, M. Z. M. (2018). Snapshot of academic dishonesty among Malaysian nursing students: A single university experience. Journal of Taibah University Medical Sciences, 13 (4 ), 370-376. 10.1016/j.jtumed.2018.04.003 31435349 Ajzen, I. (1991). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-057 10.33546/bnj.1250 Letter to Editors Diploma in Nursing or Bachelor of Science in Nursing: Contradictory issues among nurses in Bangladesh https://orcid.org/0000-0002-6905-0554 Rony Moustaq Karim Khan * College of Nursing, International University of Business Agriculture and Technology, Bangladesh Corresponding author: Moustaq Karim Khan Rony, College of Nursing, International University of Business Agriculture and Technology. 4 Embankment Drive Road, Off Dhaka-Ashulia Road, Sector-10, Uttara Model Town, Dhaka, Bangladesh 1230. Email: mkkrony@iubat.edu Cite this article as: Rony, M.K.K. (2021). Diploma in Nursing or Bachelor of Science in Nursing: Contradictory issues among nurses in Bangladesh. Belitung Nursing Journal, 7(1), 57-58. https://doi.org/10.33546/bnj.1250 22 2 2021 2021 7 1 5758 24 11 2020 04 1 2021 15 1 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. ==== Body pmcThe importance of nursing has been seen in the COVID-19 epidemic situation worldwide (Gunawan et al., 2020). This letter prompts discussion about contradictory issues among nurses in Bangladesh. Firstly, in our country, since 2008, the Diploma in Nursing Science and Midwifery course has been upgraded, and the Bachelor of Science in Nursing degree has just been started (Bangladesh Nursing and Midwifery Council, 2018). Nursing has been considered a second-class job since 2011 (Ministry of Health and Family, 2011). However, there is a disparity between diploma and graduate nurses in Bangladesh. Diploma nurses have more priority than graduate nurses. Diploma nurses have 90% of the seats allocated for government jobs. On the other hand, graduate nurses are allocated only 10% of seats despite being more qualified (Bangladesh Public Service Commission, 2020). This inequality is a contemporary issue in Bangladesh. That is why undergraduate nurses in Bangladesh have an uncertain future. New meritorious students are also confused about these courses. Where should they be admitted? Diploma in Nursing or Bachelor of Science in Nursing? Secondly, most nursing students graduated from private institutions every year. The ratio of nurses graduating from private and government institutions is 25: 8 (Bangladesh Nursing and Midwifery Council, 2020). There are approximately 71,369 registered nurses in Bangladesh (Bangladesh Nursing and Midwifery Council, 2020) and 14,686 nurses working in government (Ministry of Health and Family Welfare, 2020a). Although more than 70% of nurses work in the private sector, those who work in the private sector face limited seats in higher education than government-employed nurses. Only 3% of the total seats allocated in the Master of Science in Nursing (MSN) program are for privately employed nurses (Bangabandhu Sheikh Mujib Medical University, 2020). New graduate nurses are being deprived of their careers because of these limited opportunities. Thirdly, there are inequalities for graduate nurses and graduates from other departments. Graduate nurses are considered a second-class profession, but graduates of other departments are considered a first-class profession. So, nurses are feeling dissatisfied working for this less value (Morsheda et al., 2016). Bangladesh bears 76 percent of the deficit of nurses. The country needs another three lakh nurses (Siddiqui, 2020). According to the World Health Organization (WHO), at least three nurses must be hired against a physician (Imam, 2020). But there are 2.85 times more doctors than nurses in our country (Alam, 2019). Fourthly, in Bangladesh, nurses join as senior staff nurses and retire in the same position due to lack of promotion (Ministry of Health and Family Welfare, 2020b). Only senior staff nurse posts are available in Bangladesh, and some nurses are promoted to the position of Nursing Supervisor, Matron, Nursing Instructor. However, this process takes a long year of works. Fifthly, if nurses with a diploma course join the job before a postgraduate degree nurse, they will be promoted with experience without educational qualifications. The first joining nurse gets them promotion first whether they qualify or not; the only experience is evaluated. Academic qualifications are not considered. However, qualified nurses are needed to establish a nurse-patient interpersonal relationship. In conclusion, nurses are central to the health care setting. We need to welcome qualified nurses to improve the nurse-patient interpersonal relationship and provide equal facilities to higher education for those who are qualified. Otherwise, nurses will not be interested in pursuing higher education. Thus, every job field needs to provide equal opportunities for graduate nurses. Not only that, but a new post needs to be created for graduate nurses, educational qualifications also need to be considered for promotion to ensure the quality of care. The honor should also be given to the graduating nurses as first-class employees like other graduate departments in Bangladesh. It is because the satisfaction of nurses’ work has a positive relationship with patient outcomes and satisfaction. Otherwise, the quality of care will never be improved. Declaration of Conflicting Interest The author has no conflict of interest to declare. Funding This article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Biography Moustaq Karim Khan Rony is working as a Faculty member at the International University of Business Agriculture and Technology. Before joining the University, he was the first Bangladeshi Helicopter Emergency Medical Services Specialist / (HEMS Specialist) at Hazrat Shahjalal International Airport. He is also a Gerontologist. He studied Master in Gerontology and Geriatrics at the University of Dhaka. He is currently pursuing a Master's degree in Public Health (MPH) in public University at the School of Science and Technology, BOU. He holds a Bachelor of Science in Nursing degree from Shahjalal University of Science and Technology. His research interests in public health and the social sciences. ==== Refs References Alam, A. (2019). Patient, doctors, nurses ratio: Bangladesh lags far behind its neighbours. Retrieved from https://www.dhakatribune.com/health/2019/07/21/patient-doctors-nurses-ratio-bangladesh-lags-far-behind-its-neighbours Bangabandhu Sheikh Mujib Medical University. (2020). Academic. Retrieved from https://bsmmu.edu.bd/notice/341/result-of-master-of-science-in-nursing-msn-admission-test-july-2020 Bangladesh Nursing and Midwifery Council. (2018). Education program. Retrieved from http://bnmc.gov.bd/site/page/290b4ffa-49db-4d3a-bfc8-88c6a419bf0d/- Bangladesh Nursing and Midwifery Council. (2020). Last database. Retrieved from http://www.bnmc.gov.bd/site/page/de902a93-ad44-4252-bb1b-3ed54cd0b0a1/- Bangladesh Public Service Commission. (2020). Non-cadre examination. Retrieved from http://www.bpsc.gov.bd/site/view/psc_exam/Non-Cadre%20Examination/Non-Cadre-Examination Gunawan, J., Aungsuroch, Y., & Fisher, M. L. (2020). One year of the COVID-19 pandemic: Nursing research priorities for the new normal era. Belitung Nursing Journal, 6 (6 ), 187-189. 10.33546/bnj.1255 Imam, S. H. (2020). Shortage of medical technologists, logistics hampering fight against pandemic. Retrieved from https://thefinancialexpress.com.bd/health/shortage-of-medical-technologists-logistics-hampering-fight-against-pandemic-1588518220 Ministry of Health and Family. (2011). Upgradation to 2nd class of nurses. Retrieved from http://www.mohfw.gov.bd/index.php?searchword=2nd+class+nurses&ordering=&searchphrase=all&Itemid=115&option=com_search&lang=en Ministry of Health and Family Welfare. (2020a). Directorate of nursing services. Retrieved from http://www.mohfw.gov.bd/index.php?Itemid=115&id=52&lang=en&option=com_content&view=article#:~:text=Present%20scenario%20of%20Nursing%20in%20Bangladesh%3A%20Nursing%20Services%3A&text=At%20present%20there%20are%20approximately,are%20working%20in%20the%20Govt. Ministry of Health and Family Welfare. (2020b). Post Retirement Leave (PRL). Retrieved from http://www.mohfw.gov.bd/index.php?option=com_content&view=article&id=59%3Apost-retirement-leave-prl&catid=44%3Apost-retirement-leave-prl&lang=en Morsheda, H. U., Zaman, M. N. U., & Afroze, N. (2016). Assessment of job satisfaction among the senior staff nurses working at Sadar Hospital, Naogaon, Bangladesh. Asian Journal of Medical and Biological Research, 2 (4 ), 611-615. 10.3329/ajmbr.v2i4.31004 Siddiqui, K. (2020). Bangladesh suffers from 76 percent shortage of nurses. Retrieved from https://tbsnews.net/bangladesh/health/bangladesh-suffers-76-percent-shortage-nurses-76387

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-001 10.33546/bnj.1276 Original Research Stress, adversity quotient, and health behaviors of undergraduate students in a Thai university during COVID-19 outbreak https://orcid.org/0000-0002-4309-9608 Choompunuch Bovornpot 1 https://orcid.org/0000-0003-1797-1260 Suksatan Wanich 23* Sonsroem Jiraporn 1 Kutawan Siripong 1 In-udom Atittiya 1 1 Faculty of Education, Mahasarakham University, Mahasarakham, Thailand 2 Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand 3 Saint Louis University, Trudy Busch-Valentine School of Nursing, St. Louis, Missouri, USA Corresponding author: Wanich Suksatan, M.Sc., RN, Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy. 906 Kamphaeng Phet 6 Rd, Talat Bang Khen, Lak Si, Bangkok, 10210 Thailand. Email: wanich.suk@pccms.ac.th. Cell Phone: +66827550027 Cite this article as: Choompunuch, B., Suksatan, W., Sonsroem, J., Kutawan, S., & In-udom, A. (2021). Stress, adversity quotient, and health behaviors of undergraduate students in a Thai university during COVID-19 outbreak. Belitung Nursing Journal, 7(1), 1-7. https://doi.org/10.33546/bnj.1276 22 2 2021 2021 7 1 17 21 12 2020 19 1 2021 01 2 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background University students are an essential human resource for national development. Thus, it is important to study the stress, adversity quotient, and health behaviors of these students during the COVID-19 pandemic. Objective This study aimed to identify stress, adversity quotient, and health behaviors and examine the relationship between these factors in undergraduate students during the COVID-19 outbreak. Methods The current study was a quantitative study with a cross-sectional design conducted from 27 November to 10 December 2020. A total of 416 undergraduate students in a Thai university were selected using a convenience sampling technique. A questionnaire was used to collect the data on stress, adversity quotient, and health behaviors of undergraduate students during the COVID-19 outbreak. Data were analyzed using mean, standard deviation, and Pearson’s Product Moment Correlation Coefficient. Results This study indicated that stress was at a high level (3.54 ± .53; Mean ± SD), adversity quotient was at a high level (3.77 ± .63; Mean ± SD), and health behaviors were at a moderate level (3.06 ± .53; Mean ± SD). The current study also found that stress and adversity quotient were irrelevant. Stress and health behaviors were negatively correlated with a level of significance of .01 (r = -.31), and adversity quotient and health behaviors were positively correlated with a level of significance of .01 (r = .051). Conclusion It is suggested that healthcare providers, families, and professors should consider stress and adversity quotient in developing interventions to promote healthy behaviors in terms of physical and psychological factors in university students. stress adversity quotient health behaviors COVID-19 outbreak undergraduate students ==== Body pmcIn December 2019, the first cases of COVID-19 were found in the city of Wuhan, Hubei Province, China (Hou et al., 2020). Several researchers collected samples from patient’s airways and revealed the presence of a novel strain of coronavirus (Tan et al., 2020). The World Health Organization (2020a) announced that the novel coronavirus was considered a pandemic due to its rapid spread. In every region of the world, people infected with the new coronavirus first developed symptoms of fever and dry cough; after a week, the patient experiences shortness of breath. COVID-19 causes pneumonia and is accompanied by inflammation that may be severe and can lead to internal organ failure (World Health Organization, 2020a). As of June 2020, the COVID-19 patients had increased to more than 6.5 million people infected with the novel coronavirus worldwide, and there had been 380,000 deaths (World Health Organization, 2020b). Following this outbreak, people around the world have difficulty in living their lives. For example, COVID-19 causes stress, coping, problem-solving, isolation, loneliness, and depression (Amaral-Prado et al., 2020; Kong et al., 2020), which influence students’ health behaviors (Xiong et al., 2020). These psychological and emotional issues may affect their study patterns, graduation, and employment status in the future (Ministry of Public Health, 2020). Currently, universities in Thailand offer a wide range of Thai and international programs for Thai and overseas students, ranging from undergraduate, graduate studies and several short training courses. The COVID-19 pandemic is an important opportunity to manage education in the “new normal” way, a large conceptual shift that must be aligned and connected to the learning of students (Sahu, 2020). COVID-19 brings not only life crisis but also psychological stress - tension, anxiety, sadness, and fear - among the patients, students, and healthcare providers (Song, 2020). To deal with the COVID-19 crisis, Thailand is trying to reduce the pandemic (Din et al., 2020; Ketphan et al., 2020) by hand hygiene, personal and social distancing, wearing masks, early detection of COVID-19, and also the isolation of patients (Malathum & Malathum, 2020; Velavan & Meyer, 2020). Stress is a physical and psychological response that results from internal or external stimuli (Turner et al., 2020; Wu, Zhang, et al., 2020). It is associated with changes in body systems that affect a person’s mental health and behavior, such as palpitations, sweating, dry mouth, and shortness of breath (Impey et al., 2020; Yang et al., 2020). During the COVID-19 pandemic, it is inevitable that a person will be exposed to stress, which is a normal response to the situation of the COVID-19 crisis and can affect different people, including university students who are at risk of mental health problems (Sahu, 2020). University students are considered significant human resources for national development (Pacnoy et al., 2017; Suksatan, Ruamsook, et al., 2020). Students in health science curriculums will have future responsibilities for providing all aspects of care to patients - physically, mentally, emotionally, socially, and spiritually - in disease prevention and health promotion (Mullan et al., 2017; Suksatan, Choompunuch, et al., 2020). The students also have to collaborate and coordinate with professional colleagues from different professions (Bronstein et al., 2010; Mueanwaja et al., 2018). Therefore, it is the responsibility of higher education institutions to produce graduates with advanced academic and practical knowledge and enable them to become effective professionals in the future (Suksatan, Ruamsook, et al., 2020). University students report more significant health behaviors and mental health problems, including increased stress levels, than non-students (Savitsky et al., 2020). The COVID-19 outbreak might have serious consequences for university students who are experiencing significant disruptions in teaching and assessment during the mid-and final-semester exams of their studies. The students might graduate late because of the postponement of examinations. In addition, students will face the severe challenges of the global recession caused by the COVID-19 pandemic. For the above reasons, the study aimed to examine the stress, adversity quotient, and health behavior levels and examine the relationship between these factors influencing undergraduate students during the COVID-19 outbreak. Methods Study Design A cross-sectional study was conducted to examine the stress, adversity quotient, and health behaviors of undergraduate students during the COVID-19 outbreak in Thailand. Setting and Sample Undergraduate students were selected from Mahasarakham University in Thailand. The research was conducted in the first semester of the academic year. This study included undergraduate students aged more than 18 years old, both male and female, studying at the university and registered in the academic year 2020 of Mahasarakham University in Thailand. Exclusion criteria were students not willing to participate and could not speak or write in the Thai language. This study used the G*power program (Faul et al., 2007) to calculate the sample size. A total of 416 participants were selected from the target population using a convenience sampling technique. Instruments The questionnaire adapted from reviewing literature and the previous studies were classified into four parts as follows: The questionnaire on the student’s characteristics consisted of 4-item multiple choices and open-ended questions, developed by the researcher, including gender, academic year, currently studying faculties/ colleges, and average monthly income. The Coronavirus Stress for Undergraduate Students Scale (CSUSS) was developed by the researchers. The scale consisted of 15 items. Respondents indicate their choices on a 5-point scale from 1 = low to 5 = most. Total CSUSS scores can range from 15-75. Higher scores indicate higher stress. Cronbach’s alpha coefficient was .84 for the pilot study and .86 for the main study. The Coronavirus Adversity Quotient Scale (CAQS) was developed by the researchers. The scale consisted of 17 items. Participants indicate their choices on a 5-point scale from 1 = low to 5 = most. Total CAQS scores can range from 15-75. Higher scores indicate a higher adversity quotient. Cronbach’s alpha coefficient was .86 for the pilot study and .93 for the main study. The Health Behaviors Scale, developed by the Health Education Division (Health Education Division; Health Service Support Department (2013), consisted of 18 items. Participants indicate their choices on a 5-point scale from 1 = low to 5 = most. Total CAQS scores can range from 15-75. Higher scores indicate a higher adversity quotient. Cronbach’s alpha coefficient was .84 for the pilot study and .82 for the main study. Data Collection Data were collected during 27 November – 10 December 2020. We used a convenience sample of eligible undergraduate students who were willing to participate in the study. Participants were recruited in seven faculties/colleges and within the Mahasarakham University community by collecting the survey and recruitment statement to the students. The participants then signed a consent form, and each student spent around 15-20 minutes completing the self-report questionnaires. The principal investigator (PI) and co-principal investigator (Co-PI) checked all questionnaires, and if an incomplete questionnaire was found, the participant was asked to complete the questionnaire. However, respondents who were not willing to participate could withdraw anytime. Data Analysis Descriptive statistics or IBM® SPSS® version 21 were used to analyze the data and describe the demographic characteristics of the participants. Pearson’s Product Moment Correlation Coefficient was conducted to examine correlations of stress, adversity quotient, and health behavior during COVID-19 outbreak variables. Statistical significance was set at <.05. Ethical Considerations The present study was approved by the Ethical Committee from Mahasarakham University (IRB No. 297/2563) and the directors of seven faculties/colleges. Each participant received explanations about the study and had their rights protected throughout, including confidentiality and the right to refuse or withdraw from the study. The participants also received information sheets and signed a consent form. Results Characteristics of the Participants As shown in Table 1, the majority of the participants were female, 71.90% (n = 299), the largest percentage of participants were first-year undergraduate students (43.30%), and the majority of participants were the students in the College of Politics and Governance (25.20%). Most participants lived in the northeast region of Thailand (95.09%), and the majority of monthly household incomes were 330 – 500 US dollars (33.20%). The most common occupation of the custodians of participants was agriculturist (28.40%). Table 1 Characteristics of the participants (N = 416) Demographic characteristics N % Gender  Male 117 28.10  Female 299 71.90 Education level (Year)  First 180 43.30  Second 87 20.90  Thirty 64 15.40  Forth 76 18.30  Fifth 9 2.20 Faculty/College  Faculty of Education 79 19.00  Faculty of Tourism and Hotel Management 84 20.20  College of Politics and Governance 105 25.20  Faculty Architecture, Urban Design, and Creative Arts 38 9.10  Faculty of Informatics 75 18.00  Faculty of Public Health 25 6.00  Faculty of Nursing 10 2.40 Hometown (region)  Northeast 387 95.09  Central 14 3.44  South 3 .74  North 2 .49  Eastern 1 .25 Household monthly income (US dollar)  < 330 68 16.30  330 – 350 139 33.40  350 - 660 79 19.00  660 - 830 29 7.00  830 – 1,000 31 7.50  > 1,000 70 16.80 Custodian’s occupation  Civil servant 56 13.50  State employee 12 2.90  Businessperson / trade 91 21.90  Agriculturist 118 28.40  Employment 97 23.30  Unemployment 5 1.20  Other (e.g., prefer not to answer) 37 8.90 Descriptive Characteristics of the Study Variables Based on Table 2, the overall stress of the participants was at a high level (3.54 ± .53; Mean ± SD). Table 3 also showed that most undergraduate students during the COVID-19 outbreak experienced an adversity quotient at a high level (3.77 ± .63; Mean ± SD). Similarly, the participants showed high levels of each component of adversity quotient of undergraduate students such as control of obstacles or problems (3.64 ± .70; Mean ± SD), cause and responsibility (3.68 ± .63; Mean ± SD), impact side (3.97 ± .89; Mean ± SD), and durability (3.79 ± .92; Mean ± SD). Table 2 Descriptive statistics of stress level of undergraduate students (N = 416) Variable Mean SD Interpretation by mean Stress level 3.54 .53 High Overall stress level 3.54 .53 High Table 3 Descriptive statistics of adversity quotient of undergraduate students Variables Mean SD Interpretation by mean Control of obstacles or problems 3.64 .70 High Cause and responsibility 3.68 .63 High Impact side 3.97 .89 High Durability 3.79 .92 High Overall 3.77 .63 High Based on Table 4, it was found that overall health behavior was at a moderate level (3.06 ± .53; Mean ± SD). Similarly, the participants showed high levels of behavior of illness and medical treatment (2.91 ± .80; Mean ± SD), health-promoting behavior (3.51 ± .66; Mean ± SD), therapeutic behavior, and participatory behavior (3.21 ± .71; Mean ± SD). Table 4 Descriptive statistics of health behavior of undergraduate students (N = 416) Health Behavior Mean SD Interpretation by mean Illness and medical treatment behavior 2.91 .80 Moderate Health-promoting behavior 3.51 .66 High Therapeutic behavior 2.75 .74 Moderate Participatory behavior 3.21 .71 Moderate Overall 3.06 .53 Moderate Factors Explaining Health Behavior of Undergraduate Students Based on Table 5, stress (r = -.31), adversity quotient (r = .51) had statistically significant relationships with health behaviors (p < .001). However, stress had no significant relationship with the adversity quotient. Table 5 Correlation Between the Study Variable (N = 416) Variables Stress (r) Adversity quotient (r) Health behavior (r) Stress 1.00 - 0.02 - .31** Adversity quotient 1.00 .51** Health behavior 1.00 ** p-value = .01 Discussion This study aimed to examine stress, adversity quotient, and health behaviors and their relationship in undergraduate students during the COVID-19 outbreak. This study found that the overall stress of undergraduate students during the pandemic situation of COVID-19 was at a high level. The findings of this study reinforced previous reports that stress is a factor that negatively and directly correlated with health behavior in undergraduate students (Pellegrini et al., 2020; Wu, Xu, et al., 2020; Ye et al., 2020). In the current study, the participants showed a high-stress level. This result may indicate that students’ stress management and health behavior changed under the COVID-19 pandemic. Both Thai and foreign students from various areas have returned to the university. The students may be more prone to COVID-19 infection, stress, and paranoia that can lead to the epidemic or university life. In terms of organizing activities on campus, it is important to limit the number of students and to reduce overcrowded activities. Students experience stress from being in their home even after preventative measures have been taken. However, they are still worried about attending class or travel and the return of the outbreak in a second or third phase of infection. In addition, income loss, parental income impact, government assistance, and the unavailability of a vaccine were concerns and causes of stress (Carroll et al., 2020; Pietrobelli et al., 2020). The results of this study showed that the adversity quotient of undergraduate students was at a high level. The results are consistent with those of Kurniawan et al. (2020) found that the adversity quotient can contribute to forming a student’s career maturity (4.7%). Furthermore, this result is similar to previous studies reporting that the adversity quotient was positively associated with health behavior in undergraduate students (Shek, 2020; Siahna, 2020). Therefore, it is suggested that students were aware of the epidemic in other countries and had taken precautions such as preparing personal protective equipment, consumer products, and pharmaceutical products. Most universities in Thailand had sudden shutdowns to control the COVID-19 situation. Therefore, the university allowed students to return to their domicile and comply with government measures (Imsa-Ard, 2020). When students returned to their homeland, they could spend more time with their families and plan for their daily lives in terms of purchasing consumer products, consumption, and transportation (Loxton et al., 2020). In addition, in Thai society, assistance comes from every corner whenever there is a crisis. Laypersons create several charity boxes or “Pun Sook” in each community nationwide where people can put food, medicines, or other necessities. Anyone can get them without spending any cost (Malathum & Malathum, 2020). This study found that the level of health behavior in undergraduate students was at a moderate level. The findings of this study are similar to prior international studies, which reported that 36.5% of the participants had positive health behaviors that were associated with increased engagement such as exercise, sleep, of which 61% were most commonly attributed to more time being available and to stress relief (Knell et al., 2020). Indeed, the findings of this study are similar to several studies that were conducted on other populations and non-communicable diseases, which indicated a moderate level of health behavior (Ounprasertsuk et al., 2020; Suksatan & Ounprasertsuk, 2020). In addition, the adversity quotient refers to a state of serious and continued incumbrance, including the COVID-19 crisis. Several students, particularly undergrad students, encountered hardships at university or society (Tian & Fan, 2014). This study has several potential limitations. First, the sample size in the seven faculties/colleges was homogeneity of the sample, so the comparison among variables could be ambiguous. Second, participants were recruited and conducted at Mahasarakham University, which may have omitted relevant studies conducted in other universities and other countries. Finally, data collection was based on self-report questionnaires. There is the potential for response bias because the PI and Co-PIs were checking the questionnaires; thus, students might have felt pressured to answer the questions. However, the study also has some strengths. It was the first study in Thailand to study stress, adversity quotient, and health behaviors using performance tests and validated instruments with a large sample of undergraduate students. Furthermore, this study also provided factors associated with the health behaviors of undergraduate students during the COVID-19 pandemic in a Thai university. Future studies might also use the CSUS and CAQS instruments to maintain validity in measuring stress and adversity quotient toward health behaviors in general and is relatively reliable. Conclusion During COVID-19 and its global change, education has been significantly challenged by using online learning for students. The adjustment of students took into account significant factors such as stress, adversity quotient, and health behaviors to overcome barriers during the transition period; these effects have impacted schools around the world and have had some important results on undergraduate students living in Thailand during the COVID-19 outbreak. Interestingly, this study found that the overall stress of undergraduate students during the epidemic situation of COVID-19 was at a high level. It is recommended that nurses, healthcare providers, families, and professors consider these factors in developing interventions to promote healthy behaviors in terms of physical and psychological factors in university students. Acknowledgment We would like to thank the reviewers for their helpful comments and suggestions to improve our study. We also thank the Faculty of Education, Mahasarakham University, and the Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy for their support. Declaration of Conflicting Interest The authors declare no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution B.C. and W.S. drafted the article, conducted a review of the literature. J.S., S.K., and A.I. conducted the data and data analysis. B.C. and W.S contributed to the design and concept, reviewed and revised the manuscript. All authors agreed with the final version of the article. Author Biographies Bovornpot Choompunuch, M.Ed is a Lecturer at the Faculty of Education, Mahasarakham University, Mahasarakham, Thailand. Wanich Suksatan, M.Sc., RN is a Lecturer at the Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand and also a Ph.D. nursing student of the Saint Louis University, Trudy Busch-Valentine School of Nursing, St. Louis, Missouri, USA. Jiraporn Sonsroem, BSc. is an undergraduate student of the Faculty of Education, Mahasarakham University, Mahasarakham, Thailand. Siripong Kutawan, BSc. is an undergraduate student of the Faculty of Education, Mahasarakham University, Mahasarakham, Thailand. Atittiya In-udom, BSc. is an undergraduate student of the Faculty of Education, Mahasarakham University, Mahasarakham, Thailand. Data Availability Statement All data generated or analyzed during this study are included in this published article. The data sets of this study are not publicly available due to the information that could compromise the research participants’ privacy. ==== Refs References Amaral-Prado, H. M., Borghi, F., Mello, T. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-037 10.33546/bnj.1251 Original Research Experience of healthcare workers in combatting COVID-19 in Indonesia: A descriptive qualitative study https://orcid.org/0000-0002-6092-9992 Tosepu Ramadhan 1* https://orcid.org/0000-0001-6694-8679 Gunawan Joko 2 https://orcid.org/0000-0001-9844-6462 Effendy Devi Savitri 1 https://orcid.org/0000-0001-8266-5126 Rustam HN Muhammad 3 https://orcid.org/0000-0002-4264-3771 Muchtar Febriana 1 https://orcid.org/0000-0002-9743-6518 Sakka Ambo 1 https://orcid.org/0000-0003-2485-1179 Indriastuti Diah 4 1 Faculty of Public Health, University of Halu Oleo, Indonesia 2 Belitung Raya Foundation, East Belitung, Bangka Belitung, Indonesia 3 Faculty of Medicine, University of Halu Oleo, Indonesia 4 Sekolah Tinggi Ilmu Kesehatan Karya Kesehatan, Kendari, Indonesia Corresponding author: Dr. Ramadhan Tosepu, Faculty of Public Health, University of Halu Oleo, Southeast Sulawesi province, Indonesia, Jl.H.E.Mokodompit, Anduonohu. Email: ramadhan.tosepu@uho.ac.id Cite this article as: Tosepu, R., Gunawan, J., Effendy, D. S., Rustam, HN. M., Muchtar, F., Sakka, A., & Indriastuti, D. (2021). Experience of healthcare workers in combatting COVID-19 in Indonesia: A descriptive qualitative study. Belitung Nursing Journal, 7(1), 37-42. https://doi.org/10.33546/bnj.1251 22 2 2021 2021 7 1 3742 06 12 2020 04 1 2021 11 2 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The number of COVID-19 cases in Indonesia continues to rise. The roles and responsibilities of healthcare workers are crucial in the battle of the COVID-19. Objective This study aimed to explore the experience of healthcare workers in combatting COVID-19 in some parts of Indonesia. Methods This study employed a descriptive qualitative study design. Online semi-structured interviews were conducted in April 2020 among thirteen participants who were purposively selected. Data were analyzed using thematic analysis. Results Eight themes emerged from data, including lack of personal protective equipment, lack of referral hospitals and limited facilities, dealing with patients with unknown status, feeling worried about getting infected or being a source of viral transmission, being creative, too long shift and fatigue, being surrender to God, and government issues. Conclusion Findings of this study could be used as the input for the government, healthcare workers, and the general population in combatting COVID-19. COVID-19 healthcare workers Indonesia experience qualitative research delivery of healthcare ==== Body pmcCoronavirus Disease 2019, or called COVID-19, was first reported in Wuhan, China, on 31 December 2019, and it has spread across the world (World Health Organization, 2020). World Health Organization (WHO) has announced COVID-19 as a pandemic on 11 March 2020. As of 28 January 2021, 219 countries and areas were involved, with 101,433,090 confirmed cases, 2,184,120 confirmed deaths, and 73,320,448 recovered (Worldometer, 2021). In Indonesia, as of 28 January 2021, there are 10,242,298 confirmed cases, with 164,113 under care, 831,330 recovered, and 28,855 confirmed deaths (Ministry of Health, 2021). While COVID-19 is continuing to spread, each country and its communities must make efforts to prevent further transmission and reduce the outbreak's impacts (Tosepu, Effendy, & Ahmad, 2020). Many countries have decided to lockdown, but Indonesia might be doubtful to do the same considering many factors, including business and economics. As a consequence, Indonesia is still struggling with new cases every day. In responding to the outbreak, health professionals are at the first line, and they are sacrificing their lives and put them at risk of infection (Gunawan, Aungsuroch, et al., 2020; Tosepu, Effendy, Lestari, et al., 2020). It is undebatable that their works are significant to save people's lives, particularly for those with COVID-19. However, the capacity of hospitals and the number of health workers are not in line with the number of cases that continue to rise. They are demanded to work extra while people are recommended to stay at home (Gunawan, 2020; Ketphan et al., 2020). Given the importance of the roles of healthcare workers in the battle of COVID-19, this study aimed to explore how their experience in handling the cases, either with positive cases or suspected ones. There is no such study discussing this topic. Therefore, this study will provide the input and reference to decrease the incidence rate of COVID-19 and, importantly, to appreciate healthcare professionals' hard efforts in this battle. Methods Study Design This was a descriptive qualitative study conducted in April 2020. Participants The participants were purposively selected to explore more information regarding their experience in taking care of persons with positive COVID-19 or those still under control. The inclusion criteria of participants were all healthcare workers involved in the battle of COVID-19 in Indonesia. Data Collection The respondents were contacted through a short message service (SMS) and phone call. Once they accepted the invitation, an appointment was scheduled for an online interview. The online semi-structured interview was conducted using the Indonesian language by principal investigators for approximately 30-60 minutes. The question guideline was prepared prior to data collection. Data Analysis In this study, a thematic analysis was used for data analysis. Thematic analysis is a qualitative research method for identifying, analyzing, organizing, describing, and reporting themes found within a data set (Braun & Clarke, 2006). Thematic analysis is a useful method for examining the perspectives of different research participants, highlighting similarities and differences, and generating unanticipated insights (Braun & Clarke, 2006). Ethical Consideration The ethical approval of this study was obtained from the Research Ethics Committee, Indonesian Public Health Association (IPHA), with approval number: 115/KEPK-IAKMI/IV/2020. Prior to data collection, the researchers explained the objective and the procedures of the study to the participants. It is also described that this study was voluntarily, which the participants could withdraw from the study at any time without penalty. The researchers in this study confirmed that each respondent had obtained appropriate informed consent. The researchers also guaranteed their data confidentiality and ensured them that their information would be published anonymously. Trustworthiness To ensure the trustworthiness of this study, we discussed among researchers and experts to ensure that there was no bias in analyzing and developing the themes. All researchers were agreed with all findings. Member checking was also done to validate the results, as it is the most critical technique to establish credibility (Gunawan, 2015). Results Characteristics of the Participants Thirteen respondents were included in this study, which consisted of four medical doctors (30.7%), three nurses (23.1%), three public health practitioners (23.1%), one midwife (7.7%), one member of the surveillance team (7.7%), and one health analyst (7.7%). The average age was 36 years. The majority of the respondents were females (53.85%) than males (46.15%). The participants were working at East Luwu Regency South Sulawesi, Konawe Regency Southeast Sulawesi, and Papua. Of all participants, ten participants (76.9%) were married, and three participants (23.1) were single. Eight participants (61.5%) were working at hospitals, four participants (30.8%) were at public health centers, and one participant (7.7%) was at the Department of Health. Analytical Findings Eight themes emerged from the data. Each is explained in the following: Theme 1: Lack of Personal Protective Equipment (PPE) The majority of respondents agreed that there was a lack of personal protective equipment, especially facial masks, and protective clothing. This is explained in the following statements: PPE is still limited in our workplace (p3) We have a lack of PPE based on a standard to take care of patients with COVID-19 or those who are under evaluation (p9) Theme 2: Lack of referral hospitals and limited facilities Most respondents agreed that there is a limited number of referral hospitals appointed by the Government of Indonesia. In addition, the existing hospitals have limited infrastructures. This is explained in the following: Too limited referral hospitals appointed by the government to deal (p6) Referral hospitals exist, but with inadequate facilities. For example, in intensive care units, the beds and ventilators are limited (p5) In terms of infrastructure, we have not enough quality and quantity; for example, ventilators, intensive care units, and the number of health workers are also limited (p2) Theme 3: Dealing with patients with unknown status The majority of respondents said that they most likely dealt with unknown status, which put them at risk of infection. Besides, many patients did not tell the truth about their conditions, traveling histories, and previous contacts. The respondents said: In the emergency unit, many patients who come but have not yet found out whether they were positive or not, but they were positive eventually. Try to imagine our situation, and we were without PPE or less than the standard to serve these patients (p12) Once the patient has shown symptoms of COVID-19, which has been served by nurses, then an examination is carried out, and it turns out positive, which eventually nurses are contaminated and infected with COVID-19. Patients were most likely dishonest with health workers about traveling or from a pandemic area (red zone) because of fear of being said to be people under observation. They were also dishonest if they have a history of contact with patients with positive COVID-19 and the symptoms. One patient was also dishonest that he had been examined at another hospital and was positive but refused to be treated. Theme 4: Feeling worried about getting infected or being a source of viral transmission The majority of respondents felt worried due to the lack of protective equipment. They were also worried that they would bring the virus to their homes and infect the family. It is explained in the following: This is the dilemma of medical staff who is in direct contact with patients. We must be anxious that we may bring “gift” from the hospital to family at home (p2, p10) Concerned about the potential for this patient to transmit to others and themselves, worry about the patient's prognosis and the clarity of the patient's diagnosis because, in this place, the facilities are very minimal (p4) Worried to be infected (p8) Feeling worried because PPE is very limited (p9, p10, p11, p12) Theme 5: Being creative Due to a lack of PPE, healthcare workers are demanded to be creative. Some modified the masks, and some were wearing raincoats for their protection. It is explained in the following: We can modify it by using alternative PPE even though the protection strength is not as good as the standard PPE (p2) We still use a raincoat as a personal protector (p3, p8) Yes, we use the raincoat at the public health center when we meet patients (p7) Theme 6: Too long shift and fatigue Some respondents thought that their shift is too long due to the spread of the virus is very fast. The other said that they felt uncomfortable wearing the protective clothing for such a long time. The respondents said: An eight-hour shift is dangerous because, in the current situation, the risk of contracting COVID-19 is very high (p5, p10) During an outbreak, I think this 8-hour shift is dangerous because the transmission of COVID-19 is very fast, and we do not know who is infected (p7) Eight hours is too long; considering the discomfort when using PPE, it should be even shorter (p4) Nurses work hard because of the many patients they serve. They feel fatigued, finally, their immunity drops, and the possibility of contracting COVID-19, which then they need to have isolation with positive status and eventually died (p12) Theme 7: Being surrender to God As all health professionals are at risk of being infected, all agreed they remember God, pray, and give all things to the Creator. The respondents said: We just pray and zikr, remembering God that we will return one day (p1) We do our best, and everything cannot happen without the will of the Creator (p4) I am being surrendered to God; it is our job to save lives (p8) Theme 8: Government Issues All respondents had given the critics or inputs to the government related to the policy, massive test, PPE, and physical distancing. It is explained in the following: Underestimating the pandemic (p2) Too slow in deciding a policy (p2) The government cannot conduct massive tests to detect as many cases as possible for early treatment (p2) The government cannot meet the PPE needs of medical personnel (p2) The government has failed to control the prices of PPE that are sold at unreasonable prices (p2) The government failed to limit the visit of foreign nationals from the beginning before COVID-19 became a pandemic (p2) Our society seems to ignore the social/physical distancing (p2), so we all need to emphasize all elements of society to do physical distancing (all respondents) Discussion This study aimed to explore the experiences of healthcare workers in combatting COVID-19 in Indonesia. Eight themes emerged from the data, which were discussed in the following: The theme lack of PPE is related to the personal protection of healthcare workers, especially for medical doctors and nurses who provide direct care to the patients. This theme is in line with a study by Gunawan et al. (2021). However, personal protective equipment is very important to protect the mucosa - mouth, nose, and eyes from droplets and contaminated fluids. The hands are known to transmit pathogens to other parts of the body or other individuals. Hand hygiene and gloves are very important in protecting health workers and preventing transmission to others (Juthamanee, 2020). Face masks, protecting clothes, and headgear are also considered important to prevent transmission to healthcare workers (Tosepu, Gunawan, et al., 2020). The theme lack of referral hospitals and limited facilities indicates that the number of referral hospitals for COVID-19 is limited if seen from the increased number of positive cases every day. In addition, several hospitals appointed by the government to handle the COVID-19 outbreak are now in the public spotlight. Not because of the satisfying service, but because of inadequate facilities. Some government hospitals have isolation rooms with small capacity and close screening services. This is in line with Marison (2020) said that there were six patients with suspect COVID-19 in a small isolation room in a hospital. A distance of two meters, called the safe distance to prevent the spread of the virus, is not applied in this room. In fact, some patients ended up using a wheelchair and sleeping on the floor without getting a mattress. Under the theme dealing with patients with unknown status, it indicates two missing points: there is no rapid test at the regional hospitals to find out the initial status of the patients quickly, so it is too late to anticipate the transmission of the virus to medical personnel. Second, many patients were not honest about their history of travel to the red zone (infected area) and COVID-19 symptoms. As a result, many doctors and nurses died from COVID-19. This patient dishonesty is due to misunderstanding and stigma that have arisen in the community (Gunawan, Juthamanee, et al., 2020). The theme feeling worried about getting infected or being a source of viral transmission is understandable. Being health personnel who provides direct care to patients with COVID-19 requires caution, accuracy, focus, and always be vigilant. It is not impossible they can be infected and even transmit to others, especially families at home (Gunawan, Juthamanee, et al., 2020; Visagie, 2020). Worry is also closely related to the first and second themes, which are related to the lack of facilities. The theme being creative is the response to the lack of facilities in hospitals—many nurses, doctors, and other medical personnel use raincoats to protect them. Salute for creativity, but sad if thinking about the risks. Besides, the theme too long shift & fatigue indicates that doctors, nurses, and other medical personnel are also human beings who need rest to enhance their immunity (Gunawan, Aungsuroch, et al., 2020). Eight hours shift with many patients and a high level of focus and alertness requires extra energy. So that hospital managers need to increase the number of available staff or shorten the shift schedule to reduce the risk of COVID-19 transmission to medical staff. The theme being surrender to God indicates that the healthcare workers believe every human will die in due course. Treating patients with COVID-19 has many risks, but apart from that, we can only surrender to God and believe that God will always protect our family and us. Surrender does not mean weak, but rather a combination of effort and prayer for the best of humankind. It is considered one of the coping mechanisms among them. The theme government issues indicate the government's unpreparedness in dealing with the pandemic, making the people's anxiety and emotions begin to increase. The government policy in dealing with the spread of the COVID-19 pandemic has not successfully decreased the transmission rate. It is not only about the lack of facilities, but also about the inconsistency to make decisions to do a massive test, limit the entrance of foreigners, and maximize the prevention in the community. Besides, the Ministry of Health policy regulates the COVID-19 National Referral Laboratory can only issue examination results. This has made it difficult to identify and potentially hide the seriousness of the problem. Therefore, more disclosures were found to be infected with COVID-19 after the victim died. The government also needs to disclose information, including the location of infected patients and travel history, while still ensuring the protection of the personal data of patients. It is also necessary to ask the government to clarify the mechanism and effectiveness of mass tests and not impose their costs on the people. Apart from the role of the government, it also needs to be emphasized that battling COVID-19 also needs the part of the community, especially in implementing physical distancing, because a lot of our people seem to ignore it (Tosepu, Gunawan, et al., 2020). The implications of this study include the need for additional PPE for health professionals, especially for nurses and medical doctors who make direct contact with patients, and the addition of the appointment of referral hospitals with complete facilities. It is also necessary to increase the number of health workers immediately to reduce fatigue that puts them at risk. The sample in this study might not represent the whole context of healthcare workers in Indonesia, which only involved several health professions. The settings of the study were also not representing the whole Indonesian context. Therefore, further study is needed with a bigger and equal sample size and equal settings to generalize the findings among the healthcare workers. Conclusion Eight themes were emerged from this study related to the lack of PPE and infrastructure, psychosocial problems, creativity, fatigue, and the roles of the government in handling COVID-19 in Indonesia. The results of this study can be input to the government to be more active and decisive in making decisions and pay more attention to human life than other interests. Acknowledgments We acknowledge the participants who participated in this study. We also thank the Faculty of Public Health University of Halu Oleo, Faculty of Medicine University of Halu Oleo, and Sekolah Tinggi Ilmu Kesehatan Karya Kesehatan Kendari for the supports of this study. Declaration of Conflicting Interest The authors declare no conflicts of interest. Author Contribution Criteria Author Initials Made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; RT, JG, YA, DSE, MRHN, FM, AS, DI Involved in drafting the manuscript or revising it critically for important intellectual content; RT, JG, YA, DSE Given final approval of the version to be published. Each author should have participated sufficiently in work to take public responsibility for appropriate portions of the content; RT, JG, YA, DSE, MRHN, FM, AS, DI Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. RT, JG, YA, DSE, MRHN, FM, AS, DI Data Available Statement All data generated or analyzed during this study are included in this published article. Author Biographies Ramadhan Tosepu, SKM., M.Kes., Ph.D is Lecturer of the Public Health Faculty, Halu Oleo University, Indonesia. He also the Head of the Department of Public Health, Postgraduate Study of the Halu Oleo University, Indonesia. Joko Gunawan, S.Kep.Ners., Ph.D is Director of Belitung Raya Foundation, Bangka Belitung, Indonesia Devi Savitri Effendy, SKM., M.Kes., Ph.D. is a Lecturer at the Department of Public Nutrition, Halu Oleo University, Indonesia. She graduated Ph.D program from the Department of Tropical Nutrition & Food Science, Faculty of Tropical Medicine, Mahidol University, Thailand. Muhammad Rustam HN, MD, SpOT is a Lecturer at the Faculty of Medicine, Halu Oleo University. He is also a Clinician in the field of Orthopedics and Traumatology and a Clinical Supervisor at the Bahteramas Hospital. Febriana Muchtar, S.TP., M.Kes is a Lecturer at the Department of Public Nutrition, Halu Oleo University, Indonesia. She graduated from the Department of Public Nutrition at Hasanuddin University. Ambo Sakka, S.KM., MARS is Lecturer of Public Health Study Program, Faculty of Public Health, Halu Oleo University. He obtained his S.KM from Hasanuddin University Makassar in 2005, MARS from the University of Indonesia in 2010. He is a Quality Assurance Coordinator in the Faculty of Public Health from 2014 to 2019. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-78 10.33546/bnj.1359 Theory and Concept Development A Proposed Theory of Symptom Cluster Management https://orcid.org/0000-0002-9878-0492 Tabudlo Jerick B. * University of the Philippines Manila, College of Nursing, Philippines * Corresponding author: Jerick B. Tabudlo, MA, RN, University of the Philippines Manila, College of Nursing, Pedro Gil St. Ermita, Manila, 1000 Metro Manila, Philippines. Email: jbtabudlo@up.edu.ph Cite this article as: Tabudlo, J. B. (2021). A Proposed Theory of Symptom Cluster Management. Belitung Nursing Journal, 7(2), 78-87. https://doi.org/10.33546/bnj.1359 29 4 2021 2021 7 2 7887 11 2 2021 11 3 2021 13 4 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Symptom cluster management is in its early stages in many chronic and debilitating illnesses. The development of a proposed theory should be an initial step in advancing this area of interest. Objective This article presents the development of a Proposed Theory of Symptom Cluster Management. Methods The concept analysis, statement synthesis, and theory synthesis by Walker and Avant were used in the development of this proposed theory. A search from July to September 2020 for published empirical and theoretical articles was conducted in scientific databases, expanded on the web, and secondary references from identified articles. Results The Proposed Theory of Symptom Cluster Management is both a descriptive and explanatory theory. The defining characteristics of symptom cluster management include the basic and effectiveness components. Antecedents for symptom cluster management include socio-demographic characteristics, symptom cluster characteristics, individual clinical characteristics, individual illness factors, and situational factors or symptom experience. The consequences are clustered as personal-related, health-related, social-related outcomes, and existential outcomes. Measurement tools for the antecedents and outcomes in symptom cluster management and the analytical and statistical strategies were considered. Relational statements were also identified. Theoretical assertions were advanced. Conclusion The Proposed Theory of Symptom Cluster Management may provide a holistic approach because it integrates both the symptom cluster and management strategies. The concepts, statements including the complete representation of the proposed theory identified in this article, may provide cues to policymakers and clinical researchers towards the development of tailored interventions and programs. symptom cluster management strategies theory nursing ==== Body pmcIn nursing, symptom, along with the sufferings arising from it, had been a significant consideration for early nursing theorists such as Florence Nightingale (Nightingale, 1946). Symptom assessment and management are considered a hallmark of nursing practice (Corwin et al., 2014). Generally, the symptom is a result of perceptions of an abnormal multidimensional state (Wilson & Cleary, 1995) of the individual experiencing it. It is subjective in nature that often affects the bio-psychosocial functioning, sensations, and cognition (Humphreys et al., 2014). The definition of symptom suggests that the emotional, cognitive dimensions (Kilbourne et al., 2001) and the interpretation of symptom are part of the symptom experience. In addition, the symptom may also exist concurrently with other symptoms known as symptom clusters. In the development of a framework for symptom cluster management, the concept of symptom cluster should be taken into context. Symptoms have research and policy implications (Rutledge & Mcguire, 2004) because often it what brings a patient to the health care system and an indicator of a developing illness (Humphreys et al., 2014). A symptom cluster offers an innovative way to assess and manage symptoms (Kim et al., 2005), and the occurrence of symptom clusters may direct the choice of management strategies. The purpose of this article is to present a proposed theory of symptom cluster management for chronic and debilitating illnesses. There are a few conceptual models and theories that capture the idea of a symptom cluster or multiplicity of symptoms. These are the Theory of Symptom Management (Humphreys et al., 2014), Symptom Experience (Armstrong, 2003), the Theory of Unpleasant Symptoms (Lenz et al., 1997), and the Symptom Experience in Time (Henly et al., 2003). Some of the identified gaps in the current models are the inclusion of underlying mechanisms (Humphreys et al., 2014; Miaskowski et al., 2007) and the vital elements in the description of a symptom cluster (Barsevick et al., 2006). Although these models have been successfully applied and tested, they may be short in terms of considering the factors to management strategies specific to symptom clusters. This may result in reductionism instead of a holistic approach. Although concurrent symptoms are frequently reported in clinical practice, the management of symptom clusters has not reflected this reality. Methods The proposed theory for symptom cluster management was developed using the concept analysis, statement synthesis, and theory synthesis by Walker and Avant (2004). A search from July to September 2020 for empirical and theoretical articles using the words “symptom” and “symptom cluster” combined with “management” or “strategies” was conducted. Scientific databases such as Scopus, CINAHL, Science Direct, JSTOR, and Ovid were queried for any related articles. The search was also expanded using the web and secondary references from the identified articles. Articles that reflect the keywords and their derivative terms are read in terms of the context of the abstract. Concept Analysis In the development of the concept of symptom cluster management, the seven-step approach of concept analysis by Walker and Avant (2004) was utilized. However, because the purpose of this article is to present a theory, the author omitted the step in identifying a model case, a borderline case, and a contrary case. In this regard, the six steps were followed, which include: 1) Selecting a concept; 2) Determining the aims or purposes of analysis; 3) Identifying all the uses of the concept that can be discovered; 4) Determining the defining attributes; 5) Identifying antecedents and consequences and; 6) Defining the empirical referents. Statement Synthesis In the statement development, the literary method of statement synthesis was used. The literary method aims to pull together statements from available research. This method of statement synthesis forms its base from available research and/or empirical evidence. There are two strategies for a statement synthesis: 1) Make the meaning of the concepts included in a statement to a more universal and; 2) Expand the borders to include a broader and variety of situations (Walker & Avant, 2004). Theory Synthesis The theory development follows the theory synthesis. It has three steps which include specifying the focal concept/s, reviewing the literature, and constructing an integrated representation (Walker & Avant, 2004). In the initial step, the identified focal concept for the theory is symptom cluster management. The second step involves combining the relational statements to form a logical theory. In the last step, based on the identified concepts and relationships, an integrated representation of the Proposed Theory of Symptom Cluster Management was created. The illustration is provided in Figure 1. Figure 1 Proposed Theory of Symptom Cluster Management Discussion The Proposed Theory of Symptom Cluster Management is both a descriptive and explanatory theory in terms of function. In terms of the level of development, this proposed theory is considered a grand theory because the concepts used are abstract and global in perspective. Assumptions that guided this theory include: 1) Symptom clusters are two, three, or multiple symptoms that occur concurrently and; 2) Symptom clusters are symptoms that can be identified clinically and/or statistically. Theoretical assertions include: 1) Situational factors or symptom experience is a moderating variable to a symptom cluster occurrence that serves as a consideration to management strategies; 2) The effectiveness of symptom cluster management lies in considering both the basic and the effectiveness component. To provide a logical sequence in the development of this theory, the concept analysis, statement synthesis, and theory synthesis will be discussed. Concepts are building blocks of a phenomenon, while statements are relationships, associations, or clarification of a given concept/s. A theory is a logical representation of the concepts and statements of a phenomenon. A theory usually presents a new idea or new insight into the area of interest (Walker & Avant, 2004). Concept Analysis A symptom cluster, an assumption of this article, is either two, three, or multiple symptoms that occur concurrently. On the other hand, symptom management can be defined as efforts or strategies to eliminate, avert, delay or minimize the distress brought by the symptom experience (Humphreys et al., 2014). Combining these two terms, therefore, symptom cluster management includes strategies and/or efforts to avert, delay or minimize the overall symptom cluster experience. Based on analysis of literature, symptom cluster management has two components: 1) Basic Components and 2) Effectiveness Component. The former serves as the primary structure of a symptom cluster management strategy, while the latter serves as an indicator for the delivery, performance, or effectiveness of the management strategy. Basic components The basic components of symptom cluster management serve as the basic structure for a symptom cluster management strategy. It includes the purpose, type, nature, and composition of the management strategy. The purpose of symptom cluster management refers to the goal or what the management strategy is trying to achieve. It is geared towards the reduction of the frequency, minimizing the severity, relieving the stress (Portenoy et al., 1994), improving holistic outcomes and the quality of life. The type of symptom cluster management refers to the intentional or unintentional inputs of the healthcare provider, the nurse, and the patient or significant other. The types include clinical or nursing management, self-care management, and/or cognitive, behavioral, and environmental changes. Clinical/nursing management covers interventions (Brant et al., 2010) such as cognitive-behavioral interventions (Barsevick et al., 2006; Kwekkeboom et al., 2012), medical therapy (Humphreys et al., 2014), and interventions provided solely or in collaboration with the healthcare provider. Moreover, self-care management may include self-care strategies (Brant et al., 2010; Henly et al., 2003), complementary therapy, relaxation techniques, or any interventions carried out by the patient and family member (Humphreys et al., 2014). Cognitive, behavioral, or environmental change comes as an indirect result of a certain phenomenon (intentional or unintentional effort), for example, adherence to clinician influences (Brant et al., 2010), health-seeking behavior (Brant et al., 2010; Henly et al., 2003) and alteration of the hospital room, home, or work environment (Humphreys et al., 2014). The nature and composition of symptom cluster management refer to the level of evidence or number of management strategies needed. Symptom cluster management may come as tailored (Skelly et al., 2008), targeted, diverse (Humphreys et al., 2014), or multimodal interventions (Miaskowski et al., 2004). Effectiveness components The effectiveness component cluster refers to the aspects that may influence the delivery, performance, and effectiveness of a symptom cluster management strategy. These may include the desirability, dose, temporal dimension, and bio-behavioral mechanisms of symptom cluster management. It was noted that desirability (Donesky-Cuenco et al., 2009) or preference (Kwekkeboom et al., 2012) of the management strategy influence outcomes. In addition, the dosage of the intervention (Humphreys et al., 2014) and the setting of the intervention (Miaskowski et al., 2004), duration (Kwekkeboom et al., 2012) also influence the effectiveness of the symptom cluster management. The bio-behavioral mechanism and the temporal dimension are understood in relation to symptom cluster management. A symptom cluster may share common biologic mechanisms (Cleeland et al., 2003). Also, the symptom within a cluster may occur in different clusters (Albusoul et al., 2017; Barsevick et al., 2006), thus influencing the choice of symptom cluster management. Antecedents and Consequences Antecedents are occurrences or concepts that must take place prior to the occurrence of a certain concept, while the consequences are occurrences or concepts that happen or arise as a result of a given concept (Walker & Avant, 2004). Antecedents The antecedent considered for the concept of symptom cluster management is the very occurrence of a symptom cluster. In this regard, symptom clusters should arise before symptom cluster management occurs and is considered. To aid in the understanding of this section, Figure 1 is presented. The identified antecedents for symptom cluster management include socio-demographic characteristics, symptom cluster characteristics, clinical characteristics, individual illness factors, and situational factors or symptom experience. Socio-demographic characteristics refer to the sociological and demographical characteristics of the individual who develops and may develop symptom clusters. Sociological factors may include socio-economic status (Brant et al., 2010), employment status (Kim et al., 2012), a role, education, sexual preference (Brant et al., 2010), culture (Armstrong, 2003; Brant et al., 2010), and ethnicity (Kwekkeboom et al., 2012). While the demographic factors may include age, gender (Armstrong, 2003; Brant et al., 2010; Kim et al., 2012), marital status (Brant et al., 2010; Kim et al., 2012), and race, significantly associated with symptom cluster membership (Armstrong, 2003; Brant et al., 2010; Devon et al., 2017; Kim et al., 2012). Clinical Characteristics refer to the current physiological and psychological status or attributes of the individual with symptom cluster. The factors under this concept include the disease type and state (Armstrong, 2003; Brant et al., 2010; Kim et al., 2012), baseline physical performance status, symptom burden (Kim et al., 2012), types of treatments, co-morbid conditions (Brant et al., 2010; Kim et al., 2012) attitude, mental ability, mental illness and developmental stage (Brant et al., 2010). Individual Illness Factors refer to the previous individual experiences which may influence current symptom cluster experience and management. These may include surgery experience before baseline data (Kim et al., 2012), or past experiences (Brant et al., 2010), health knowledge, values, attitudes, a sense of coherence, self-efficacy, motivation, resiliency, a personal definition of wellness, substance abuse issues (Brant et al., 2010) and genetics (Miaskowski et al., 2007). Situational Factors or Symptom Experience is defined as the simultaneous reaction to include perception, evaluation, and response to an alteration in one’s feeling (Humphreys et al., 2014) that may be brought by the symptom cluster. Constructs in this concept include symptom assessment, symptom meaning (distress, impact, existential meaning), symptom appraisal (Brant et al., 2010), the perception of the symptoms, self-care strategies (Humphreys et al., 2014), response to self-care, symptom appraisal (Brant et al., 2010), and evaluation of the symptoms (Brant et al., 2010; Humphreys et al., 2014). Consequences The consequences of symptom cluster management strategies are collectively described as the symptom status outcome in the Theory of Symptom Management (Humphreys et al., 2014). In this paper, consequences or outcomes are clustered as personal-related, health-related, social-related outcomes, and existential outcomes. The consequences in personal-related outcomes may include self-care ability, quality of life, emotion (Brant et al., 2010; Humphreys et al., 2014), adjustment to illness or adaptive behaviors (Brant et al., 2010), functional status, the quality of life (Dodd et al., 2001; Miaskowski et al., 2004) and alteration in mood (Miaskowski et al., 2004). For health-related outcomes, these may include better physical, mental functioning (Humphreys et al., 2014), morbidity (Brant et al., 2010; Humphreys et al., 2014), mortality (Brant et al., 2010; Humphreys et al., 2014; Miaskowski et al., 2004), disease progression (Miaskowski et al., 2004), cognitive factors (Brant et al., 2010), function or functional performance (Armstrong, 2003; Brant et al., 2010; Humphreys et al., 2014; Kim et al., 2012; Lenz et al., 1997), and cognition (Brant et al., 2010; Lenz et al., 1997). Concurrent symptoms or symptom clusters have been used as outcomes themselves (Given et al., 2001). Moreover, in terms of social-related outcomes, these may include outcomes that affect functioning, productivity, and health costs (Humphreys et al., 2014). In addition, self-care costs (Brant et al., 2010), finance (Brant et al., 2010; Humphreys et al., 2014), mortality, and healthcare use (Cheville et al., 2011) were identified to be the outcomes of symptom cluster management. Interestingly symptom experience as a consideration to symptom cluster management may also impact existential concepts such as hope, hopelessness, and death thoughts (Henoch et al., 2009). Empirical Referents Defining empirical referent is the last step of concept analysis. These are measurements to determine the existence of identified concepts in concept analysis. Although there is no established tool to measure the properties of symptom cluster management, the following empirical referents below are valuable components in measuring the basic and effectiveness components of symptom cluster management because symptom cluster management is often measured in terms of the symptom cluster experience and other identified outcomes. This section will discuss the empirical referents for antecedents and consequences as well as analytical and statistical strategies. Empirical referents for antecedents In terms of measurement tools of the antecedents, socio-demographic characteristics can be measured using a demographic survey (Breland et al., 2015; Kwekkeboom et al., 2012; Uçeyler et al., 2007) either through self-report or medical records (Beddhu et al., 2000). In patients on dialysis, co-morbidity can be measured using the modified Charlson Comorbidity Index (CCI) (Beddhu et al., 2000). In terms of symptom cluster measurement, the most widely used is the M.D. Anderson Symptom Inventory (MDASI) is used in many studies (Cherwin, 2012) and has been validated in different languages such as Chinese and Filipino versions (Wang et al., 2006; Wang et al., 2004). It can also measure symptom interference using the symptom interference sub-scale (Cleeland et al., 2000). From this questionnaire, symptom concurrence can be measured (Kwekkeboom et al., 2012). Furthermore, other questionnaires to measure symptom include the Edmonton Symptom Assessment Scale (Cheung et al., 2009), the Memorial Symptom Assessment Scale (MSAS) (Molassiotis et al., 2010), the Symptom Distress Scale (SDS) (Henoch et al., 2009), the Functional Assessment of Cancer Therapy–Anemia Scale (FACT-An) (Jarden et al., 2009) and the Medical Research Council Dyspnea Scale (Breland et al., 2015). In HIV, symptoms are measured using HIV Symptom Index (HIVSI) (Zuniga et al., 2017), HIV (SSC-HIV) (Holzemer et al., 1999), its revised version, the SSC-HIV (Holzemer et al., 2001), Memorial Symptom Assessment Schedule (Namisango et al., 2015), HIV Symptom Experience Assessment Scale (HIV-SEAS), HIV Symptom Manageability Scale (HIV-SMS) (Vincenzi et al., 2009), and Symptom Assessment Scale-Short Form (MSAS-SF) (Moens et al., 2015). In emphysema, the University of California, San Diego, Shortness of Breath Questionnaire (SOBQ) can be used to measure dyspnea (Park & Larson, 2014). In osteoarthritis, the Western Ontario McMaster University Osteoarthritis Index (WOMACTM)–physical function sub-scale is used to measure functional status (Jenkins & Mccoy, 2015). Empirical referents for consequences Measures for symptom outcomes to measure the onset of symptom and experience is the PTDIQ (perception, timing, distress, intensity, and quality) (Henly et al., 2003). Symptom severity of lung cancer is measured using the Physical Symptom Experience tool (Gift et al., 2004). In terms of fatigue, the level of distress is measured by the General Fatigue Scale (Schwartz & Meek, 1999), physical fatigue using Lee Fatigue Scale (LFS) (Lee et al., 1991), or the Brief Fatigue Inventory (Mendoza et al., 1999). Sleep disturbance or insomnia is measured using the Pittsburgh Sleep Quality Index (Buysse et al., 1989) and General Sleep Disturbance Scale (GSDS) (Miaskowski & Lee, 1999). Pain can be measured using the Brief Pain Inventory (Daut et al., 1983). Depressive symptoms can be assessed using the Center for Epidemiological Studies-Depression (CES-D) scale (Carpenter et al., 1998). Moreover, in a broader perspective, QOL is measured using the Functional Assessment of Cancer Therapy Scale (FACT) (Paice, 2004). HRQOL in patients with kidney disease using the KDQOL-S (Hays et al., 1994) and Short Form Health Survey Instrument Version 2 (SF-36 v2) form (Ware et al., 1994). Adherence may also help in the impact evaluation of an intervention on aspects of both symptom experience and symptom outcomes (Humphreys et al., 2014). Concurrent symptoms themselves have been used as predictors of patient outcomes (Given et al., 2001). In HIV, the Karnofsky Performance Scale is used to determine the level of functioning ability (Namisango et al., 2015). Symptom experience can be measured using the HIV Symptom Experience Assessment Scale (HIV-SEAS) and the HIV Symptom Manageability Scale (HIV-SMS) (Vincenzi et al., 2009). Analytical and Statistical Strategies In terms of analytical and statistical strategies, cluster analysis is among the technique that forms homogeneous groups within complex among patients (Hermens et al., 2015). Exploratory factor analysis is another method that successfully clustered symptoms (Lee & Jeon, 2015; Taylor et al., 1998). In addition, symptom clusters were identified using latent class analysis (Dirksen et al., 2016), principal component analysis (Zuniga et al., 2017), principal component analysis with varimax rotation (Amro et al., 2014; Sarna & Brecht, 1997), principal component analysis with oblique rotation (Chen & Tseng, 2006) or the principal axis factor analysis technique with oblimin rotation (Fan et al., 2007). Further, the analytical strategy is the agglomerative hierarchical method with linking average to identify the clusters (Walsh & Rybicki, 2006), hierarchical cluster analysis in the exploratory secondary analysis (Bender et al., 2005), hierarchical cluster analysis with squared Euclidean distances using Ward’s clustering methods based on symptom occurrence (Namisango et al., 2015), hierarchical cluster analysis using Ward’s method applying squared Euclidean Distance (Moens et al., 2015). Multilevel modeling was also used to test for alterations over time in HIV-related symptom clusters (Cook et al., 2011) or secondary analysis from previous data sets (Bender et al., 2005; Cook et al., 2011). In osteoarthritis, hierarchical and k -means cluster analyses were used to determine symptom clusters (Jenkins & Mccoy, 2015) and binary exploratory factor analysis with varimax rotation (Bender et al., 2008). Proposed Theory of Symptom Cluster Management This section presents the statement and theory development using the literary method of statement synthesis and theory synthesis. Statement synthesis forms its base from available research and/or empirical evidence. Consequently, the theory synthesis outlined by Walker and Avant (2004) consists of three steps: 1) Specifying the focal concept/s; 2) reviewing the literature, and; 3) constructing an integrated representation (Walker & Avant, 2004). The final phase of this article is a presentation of an integrated representation of the theory located in Figure 1. Statement Synthesis Relational statements among antecedents vice versa In a study of fatigue and depression symptom clusters in HIV, the demographic and environmental characteristics show to influence symptom experiences (Voss et al., 2007). In a study of persons with mild to moderate traumatic brain injury, there is also a variation of symptoms frequency post-injury by age and gender compared to the positive, significant relationship with symptoms and severity and time since injury (Bay & Bergman, 2006). It was also shown that the frequency of symptoms might influence health-seeking behavior (Humphreys et al., 2014). In addition, in the context of HIV, disease progression reported symptoms increased over time on two of six SSC-HIV symptom clusters (Cook et al., 2011). In heart failure, patients at 75 years and older have significantly less symptom impact compared to the younger age groups, which suggests that age is an important consideration in the assessment of symptom clusters (Jurgens et al., 2009). Moreover, there are significant levels of depressive symptoms associated with uremic, neuromuscular, and skin clusters in patients on dialysis (Amro et al., 2014). These symptom clusters were initially identified in patients on incident dialysis (Thong et al., 2009). Female patients were likely to have severe symptoms than their male counterparts in the ‘energy insufficiency and pain’ cluster (Lee & Jeon, 2015). There are also significant associations between a number of demographic and clinical characteristics and Beck Depression Inventory scores (Amro et al., 2014). Interestingly, symptoms clustered differently in a sample of a dual diagnosis HIV and diabetes compared to a sample of previous PLWH patients (Zuniga et al., 2017). Female patients were more likely to experience cluster 1 symptoms in HIV (Namisango et al., 2015). Relational statements between the symptom cluster management and other concepts vice versa Management strategies such as changing the environment to improve sleep worked best for parents with low socioeconomic status (Lee & Gay, 2011). Gender-based differences were also found to influence the symptom management strategies (Zimmerman et al., 2011). In addition, the person, health/illness, and environment domains may influence symptom management strategies and ability in heart failure patients (Suwanno et al., 2009). The recognition of a distinct phenotype may also have a role in the modulation of “sickness behavior” in oncology patients and their family caregivers (Illi et al., 2012). Further, the dose and timing of the intervention, frequency and severity of the symptoms, and location of the intervention strategy may also influence the management strategies (Humphreys et al., 2014). Relational statements between the situational factors or symptom experience and other concepts Findings from a study suggest a large amount of inter-individual variability of symptom experience in patients on renal dialysis (Killingworth & Van Den Akker, 1996). Woman’s symptom experience may also vary by age, reproductive status, genetic risk (Humphreys et al., 2014). In addition, environmental factors such as perceived stress influenced the symptom experience among menopausal women (Nosek et al., 2010). In the same way that there is also inter-individual variability in terms of symptom experience that result in a genetically and biologically determined response in patients with cancer (Kelly et al., 2016). Relational statements between the consequences and other concepts vice versa In cancer, the presence of low levels of symptoms in the “all low” group reported had higher Karnofsky Performance Status scores (Miaskowski et al., 2006). It was also hypothesized that advanced disease, poorer functional status, and pain would yield higher scores on the sickness symptom cluster (Chen & Tseng, 2006). In osteoarthritis, there were also significant mean differences in both quality-of-life scores and Western Ontario McMaster University Osteoarthritis Index functional status scores based on the two symptom clusters (Jenkins & Mccoy, 2015). Furthermore, those who reported depression and anxiety had a poorer quality of life (Utne et al., 2010). There is also a bidirectional relationship between adherence and the symptom experience, symptom management, and symptom outcomes (Donesky et al., 2011). A study in patients undergoing hematopoietic stem cell transplantation found significantly lower symptom severity scores over time in the intervention group compared with the control group for four of the five clusters except for the affective symptom cluster (gastrointestinal, cognitive, functional/pain, and mucositis) (Jarden et al., 2009). In terms of symptom cluster, the score is significantly lower in patients provided with the psycho-educational intervention (PEI) than in those who received the standard care (Chan et al., 2011). In cancer, severity ratings of pain, fatigue, and sleep disturbance were significantly lowered in the intervention group (patient-controlled cognitive-behavioral) compared to the baseline severity prior to the intervention (Kwekkeboom et al., 2012). Demiralp et al. (2010) also reported significant improvements in fatigue and sleep quality among women with early breast cancer in the intervention group (patients assigned to progressive muscle relaxation). Theory Synthesis In this section, the author will lay down the integrated representation of the theory using theory synthesis as the method. Following the three steps of theory synthesis mentioned above, the focal concept of this proposed theory is symptom cluster management. In order to characterize the concept of symptom cluster management, the concept analysis method by Walker and Avant (2004) was used. The concept analysis yields the two components of symptom cluster management: 1) The basic component and; 2) the effectiveness component. The antecedents identified for symptom cluster management are considered in relation to the occurrence of the symptom cluster. Thus, the antecedents identified for symptom cluster management are:1) Socio-demographic characteristics; 2) clinical characteristics; 3) individual illness characteristics, and; 4) situational factors or symptom experience. The consequences of this theory are clustered as personal-related, health-related, social-related, and existential outcomes. They are identified because they are direct outcomes of symptom cluster management. Moreover, to identify the related factors and their relationships, the statement synthesis and in-depth analysis formed the bases of relationships. The socio-demographic characteristics and clinical characteristics have bidirectional relationships. Both antecedents have unidirectional relationships with situational factors or symptom experience and individual illness characteristics. Situational factors or symptom experience and individual illness characteristics have bidirectional relationships; both antecedents have unidirectional relationships with symptom clusters. As noted in Figure 1, situational factors or symptom experience serve as moderating variable to a symptom cluster. It means that it affects the overall perception, interpretation, or meaning of a symptom; in the same way that it affects the perception, interpretation, or meaning of symptom clusters. Finally, symptom cluster, the management strategies, and outcomes have each bidirectional relationship. The success of a symptom cluster management strategy lies in consideration of the basic components, which include the purpose, type, nature, and composition, and the effectiveness components that include the desirability, dose, temporal dimension, and bio-behavioral aspect. Conclusion The Proposed Theory of Symptom Cluster Management may provide a holistic approach to understanding both the symptom clusters on one hand and management strategies on the other. The defining characteristics of symptom cluster management which include purpose, type, nature, composition, desirability, dose, temporal dimension, and bio-behavioral aspect, may provide cues for policymakers and clinical researchers towards the development of tailored interventions and programs. This proposed theory then allows the integration of symptom clusters and their management strategies in one framework. It should pave the way for further expansion and exploration of this elusive concept of symptom cluster management. Lastly, although scholars are not in unison in terms of symptom cluster definition, the common ground in further understanding symptom cluster management should be highlighted. Although this proposed theory is recommended to be tested further, nurses can utilize this proposed theory by looking into the antecedents and consequences of an effective symptom cluster management strategy. Nurses taking care of patients with symptom clusters may also be guided in terms of the factors affecting symptom clusters. The outcomes clustered as personal-related, health-related, social-related outcomes, and existential outcomes, may also provide insights to nurses in planning and evaluating nursing interventions to patients who experience symptom clusters. Further, this proposed theory is both a descriptive and explanatory theory in terms. It functions to explain the properties of symptom cluster management, and at the same time, its relationships with other concepts. It is also considered a grand theory because the concepts are abstract and global in perspective. This proposed theory should be tested empirically across cultures and diseases. Although there is not a common definition of a symptom cluster at this moment, one assumption is that symptom clusters are symptoms that may be two, three, or multiple symptoms that occur concurrently. In addition, whether they are clinically or statistically related, the need to develop a proposed theory for symptom cluster management should be given greater value at this time as patients with symptom clusters also experience negative health outcomes and poor quality of life. Acknowledgment The author would like to acknowledge Dr. Lourdes Marie S. Tejero of the University of the Philippines Manila, College of Nursing, for her support, motivation, and valuable insights in writing this article. Declaration of Conflicting Interest The author has declared no conflict of interest. Funding The author of this manuscript receives no financial support from people or organizations in writing this article. Author’s Contribution The author solely conducted this article from conception, design, producing the initial draft, revisions up to the final version of the article. The author agrees to be accountable for all aspects of this work. Author Biography Jerick B. Tabudlo, MA, RN is a Doctor of Philosophy in Nursing Student at the College of Nursing, University of the Philippines, Manila, Philippines. ==== Refs References Albusoul, R. M., Berger, A. M., Gay, C. L., Janson, S. L., & Lee, K. A. (2017). Symptom clusters change over time in women receiving adjuvant chemotherapy for breast cancer. Journal of Pain and Symptom Management, 53 (5 ), 880-886. 10.1016/j.jpainsymman.2016.12.332 28062343 Amro, A., Waldum, B., Dammen, T., Miaskowski, C., & Os, I. (2014). Symptom clusters in patients on dialysis and their association with quality-of-life outcomes. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-260 10.33546/bnj.1500 Letter to Editors Reflections on International Nurses Day: Current status, issues, and the future of nursing in Indonesia https://orcid.org/0000-0002-8248-367X Betriana Feni 1 https://orcid.org/0000-0002-2847-1862 Tanioka Tetsuya 2* https://orcid.org/0000-0002-2952-6538 Locsin Rozzano C. 34 https://orcid.org/0000-0001-9089-8616 Nelwati 5 1 Graduate School of Health Sciences, Tokushima University, Tokushima, Japan 2 Department of Nursing Outcome Management, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan 3 Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan 4 Florida Atlantic University, Boca Raton, FL 33431, USA 5 Faculty of Nursing, Universitas Andalas, Padang, Indonesia Corresponding author: Tetsuya Tanioka, RN, PhD, FAAN, Professor, Department of Nursing Outcome Management, Institute of Biomedical Sciences Tokushima University, Graduate School, 18–15 Kuramoto-cho 3, Tokushima, 770–8509, Japan. Phone, and Fax +81-88-633-9021. E-mail: tanioka.tetsuya@tokushima-u.ac.jp Cite this article as: Betriana, F., Tanioka, T., Locsin, R. C., & Nelwati. (2021). Reflections on International Nurses Day: Current status, issues, and the future of nursing in Indonesia. Belitung Nursing Journal, 7(3), 260-261. https://doi.org/10.33546/bnj.1500 28 6 2021 2021 7 3 260261 24 4 2021 10 5 2021 11 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. International Nurses Day COVID-19 professional practice delivery of healthcare nursing Indonesia ==== Body pmcDear Editors, May 12 is celebrated as International Nurses Day and as the birthday of Florence Nightingale, the founder of Modern Nursing (International Council of Nurses, 2021). For nurses around the world, this is a momentous occasion reflecting on the state of nursing and how nurses are advancing the profession. Highlighted by the International Council of Nurses are three issues; COVID-19 infections and deaths among nurses and other healthcare workers; stress and burnout in the nursing profession; and nurse shortage and retention (International Council of Nurses, 2021). Regarding issues affecting the discipline and professional practice of nursing, nurses in Indonesia are austerely experiencing these issues because of the pandemic; of practicing professional nursing; and conducting research and enhancing nursing education. First, with the COVID-19 pandemic, nursing practice has become more challenging. The invisible disease agent has caused untimely deaths of many healthcare professionals, making nursing practice much harder (Chatterjee & Kagwe, 2020) and less attractive as a profession. As of March 2021, the Indonesian National Nurses Association reported that more than 15,000 nurses were infected with COVID-19 and 274 have passed away (Guritno, 2021). Improvements in regulations related to COVID-19 management in hospitals and other healthcare institutions were imposed, such as increasing supplies of personal protective equipment (PPE) and prioritizing benefits for healthcare workers regarding staffing, including the nurses. This prioritized frontline healthcare workers, including nurses, to receive vaccinations against COVID-19 (COVID-19 Handling Acceleration Force, 2021). Appreciations for nurses’ dedication to their professional practice during the pandemic were many, but still not significant enough, as nurses continue to risk their lives ― sometimes losing their lives ― in order to save their patients’ lives and the lives of other co-workers. This appreciation points to the realization that nurses and their practice deserve political and social actions for their valuable work, supporting a deserved salary raise (Gunawan, 2020). While the risks to nurses’ lives on the front lines is evident, the global society must finally realize the professional mandate that frontline nurses are soldiers-at-war, whose lives are valuable, therefore need protection by all costs from being uselessly exposed to an invisible organism and become patients themselves (Chatterjee & Kagwe, 2020). Second, in Indonesia, there are various classifications of nurses based on education. The Indonesian Nursing Law No. 38 the Year 2014 described categories of nursing education into vocational education, academic education, and professional education. Vocational education is a three-year program, while the academic program prepares nurses for a baccalaureate degree in nursing, Masters in Nursing, and Doctor of Nursing. With an academic degree, professional nursing education qualifies nurses through internships in the nursing professional (Ners) and nursing specialty program (Government of Indonesia, 2014). Despite the variety of educational levels and the limited number of graduate school programs, nursing education in Indonesia is steadily improving. With only 11 Professors of Nursing, there are now two Doctoral Programs in Nursing: a doctoral program at the University of Indonesia and the other at the Faculty of Nursing, Universitas Airlangga (Casman et al., 2020). Nevertheless, transforming the discipline to advance the professional practice of nursing requires more interdisciplinary collaboration, especially with expert nurse researchers from the international arena. Third, the regulations from the Indonesian Ministry of Higher Education require faculty members in academic positions to publish scholarly articles (Ministry of Research and Technology of the Republic of Indonesia, 2017), and for university students to also publish their final projects, theses, and dissertations in key scientific journals as a requirement for graduation (Ministry of Education and Culture, 2012). These requirements are clear evidence affirming the flourishing of nursing research and knowledge dissemination in Indonesia. Today, the requirement for enhancing scholarly articles authored by Indonesian nurses and nurse educators in international journals has increased manifold, instigating the establishment of more rigorous nursing journals. However, even with the increasing processes for knowledge dissemination as evidenced by the number of publications, journals indexed in reputable national and international indices are still few. As of March 2021, only three nursing journals were indexed in reputable international databases, such as Scopus, Web of Science, and EBSCO. These journals are Belitung Nursing Journal, Nurse Media Journal of Nursing, and Nursing Journal of Indonesia (Jurnal Keperawatan Indonesia). While this letter briefly highlights three current conditions as the basic informational needs of nursing practice, education, and research, focused attention on education, practice, and policies influencing scholarly nursing endeavors in Indonesia requires more recognition and appreciation. Editors, researchers, and practitioners of nursing need to be influential and establish nursing science journals in order to disseminate ground-breaking and important nursing work. With the nursing academe, further progress and recognition of nursing as a discipline of knowledge and a practice profession will materialize. Reflecting on the future of Indonesian nurses during this momentous International Nurses Day leaves us to realize that, while professional nursing practice in Indonesia is advancing, more disciplinary and professional ‘homework’ is needed to move nursing as a valuable and integral health care practice. This consideration is a significant step towards growing Indonesian nursing to a level of professional practice that is integral to human health and well-being. Declaration of Conflicting Interest None to declare. Funding None. Authors’ Contribution Initial draft: FB, TT, RL. Writing and editing the manuscript: FB, TT, RL, N. All authors approved the manuscript before submission and the final version of the manuscript. Authors’ Biographies Feni Betriana, Ns, S. Kep, MNS is a PhD Student, Graduate School of Health Sciences, Tokushima University, Tokushima, Japan. Tetsuya Tanioka, RN, PhD, FAAN is a Professor of Nursing Outcome Management, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan. Rozzano C. Locsin, RN, PhD, FAAN is a Professor Emeritus in Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan, and Professor Emeritus in Florida Atlantic University, Boca Raton, FL 33431, USA. Nelwati, S. Kp, MN, PhD is an Associate Professor, Faculty of Nursing, Universitas Andalas, Padang, Indonesia. ==== Refs References Casman, C., Ahadi Pradana, A., Edianto, E., & Abdul Rahman, L. O. (2020). Kaleidoskop menuju seperempat abad pendidikan keperawatan di Indonesia [A kaleidoscope toward a quarter century of nursing education in Indonesia]. Jurnal Endurance, 5 (1 ), 115-125. 10.22216/jen.v5i1.4291 Chatterjee, S., & Kagwe, M. (2020). Health workers are the frontline soldiers against COVID-19. Let’s protect them. Retrieved from https://www.un.org/africarenewal/web-features/coronavirus/health-workers-are-frontline-soldiers-against-covid-19-let’s-protect-them COVID-19 Handling Acceleration Force. (2021). Peran penting perawat Indonesia dalam menangani pandemi [Important role of Indonesian nurses in handling the pandemic]. Retrieved from https://covid19.go.id/p/berita/peran-penting-perawat-indonesia-dalam-menangani-pandemi Government of Indonesia. (2014). Indonesian Nursing Law No 38 Year 2014. Retrieved from https://peraturan.bpk.go.id/Home/Details/38782/uu-no-38-tahun-2014. Gunawan, J. (2020). COVID-19: Praise is welcome, but nurses deserve a pay rise. Belitung Nursing Journal, 6 (5 ), 150-151. 10.33546/bnj.1217 Guritno, T. (2021). PPNI: Lebih dari 15.000 perawat terpapar COVID-19, 274 di antaranya meninggal [Indonesian National Nurses Association: More than 15,000 nurses infected by COVID-19, 274 of them died]. Retrieved from https://nasional.kompas.com/read/2021/03/18/13443301/ppni-lebih-dari-15000-perawat-terpapar-covid-19-274-di-antaranya-meninggal International Council of Nurses. (2021). International Nurses Day. Retrieved from https://www.icn.ch/what-we-do/campaigns/international-nurses-day Ministry of Education and Culture. (2012). Publications of scientific papers. Retrieved from http://luk.staff.ugm.ac.id/atur/SKDirjen152-E-T-2012KaryaIlmiah.pdf. Ministry of Research and Technology of the Republic of Indonesia. (2017). Technical instructions to regulation of the Ministry of Research, Technology, and Higher Education No 20 of 2017 concerning lecturer and professor professional honorarium. Retrieved from https://luk.staff.ugm.ac.id/atur/Permenristekdikti20-2017Juknis.pdf.

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-152 10.33546/bnj.2479 Original Research Understanding the experiences of caregivers of HIV-exposed children under five: A phenomenological inquiry https://orcid.org/0000-0002-3101-8153 Hayati Happy 1* https://orcid.org/0000-0003-4880-7439 Nurhaeni Nani 1 https://orcid.org/0000-0003-0659-1748 Wanda Dessie 1 https://orcid.org/0000-0001-8083-5443 Nuraidah 2 1 Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia 2 Rumah Sakit Penyakit Infeksi Sulianti Saroso, DKI Jakarta, Indonesia * Corresponding author: Ns. Happy Hayati, S.Kp., M.Kep., Sp.Kep.An, Department of Pediatric Nursing, Faculty of Nursing, Universitas Indonesia, Jl. Prof. Dr. Bahder Djohan, Kampus UI Depok, West Java 16424, Indonesia. Email: happy@ui.ac.id Cite this article as: Hayati, H., Nurhaeni, N., Wanda, D., & Nuraidah. (2023). Understanding the experiences of caregivers of HIV-exposed children under five: A phenomenological inquiry. Belitung Nursing Journal, 9(2), 152-158. https://doi.org/10.33546/bnj.2479 18 4 2023 2023 9 2 152158 08 12 2022 05 1 2023 04 3 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Children born to mothers with HIV require special care from the womb to the postnatal period, and caregivers involved in their care face several challenges. Objective This study aimed to explore caregivers’ experiences providing care for HIV-exposed children under five. Methods This study employed a phenomenological approach. Ten caregivers of HIV-exposed children living in Jakarta, Indonesia, were selected using snowball techniques. Online in-depth interviews were conducted to collect data from September 2021 to July 2022, and thematic analysis using Colaizzi’s method was performed for data analysis. Results The study involved ten caregivers (nine females and one male) aged between 23 and 42 years. Seven of them were mothers who tested HIV-positive, while one was an adoptive father, one was a mother’s sister, and one was an aunt of HIV-exposed children. The majority of them were housewives and had a low educational background. Three themes were generated: (i) disease-transmission foreboding, (ii) prejudice against mothers and children exposed to HIV, and (iii) seeking support. Conclusion Caring for HIV-exposed children poses emotional and physical challenges for caregivers, necessitating support from health professionals and peer groups. Nurses play essential roles in improving caregiver well-being and supporting optimal growth and development in HIV-exposed children under five by designing intervention programs. Furthermore, to enhance home-based HIV care in Indonesia, the government must implement social interventions that target families with limited resources. HIV caregivers child prejudice mothers fathers Indonesia Hibah Penelitian Dosen FIK UI, Faculty of Nursing Universitas IndonesiaNKB-01/UN2.F12.D/HKP.01.03/2021 ==== Body pmcBackground HIV/AIDS is now considered a chronic disease that can be managed with the new treatment of Highly Active Anti-Retroviral Therapy (HAART) for several more years. As a result, the life expectancy and quality of life for many affected individuals are increasing (Kalomo et al., 2017). The World Health Organization (WHO) has established a plan for achieving an AIDS-free generation through the 90-90-90 target code, but this goal has not yet been accomplished globally. The target aims for 90% of people living with HIV to know their status, 90% of those diagnosed with HIV to receive continuous ARV therapy, and 90% of those receiving ARV therapy to achieve viral suppression (Bajunirwe et al., 2018). Interventions such as improved cognition, volitional counseling, access to ARVs, and the cessation of stigma have been implemented, resulting in decreased infections and improved health for affected individuals (Breckenridge et al., 2019; Ma et al., 2019). However, there is little evidence to suggest that counseling and screening programs are successful in ensuring that all patients are aware of their HIV status, and even when individuals are diagnosed, few attend ARV treatment programs to suppress the virus’s progression as expected (Denison et al., 2020). In Indonesia, where HIV/AIDS prevalence is at its highest, visible social, economic, and political consequences have affected every household (Putta et al., 2022). The increase in HIV cases among housewives in several regions of Indonesia has resulted in a rise in the number of children exposed to HIV. HIV transmission in children is mainly due to vertical transmission during pregnancy, childbirth, and lactation (Muskat et al., 2016). A child born to an HIV-positive mother requires special care from the womb to the postnatal period. Regular ARV treatment during pregnancy and childbirth and other preventive measures are necessary to prevent HIV transmission from mother to child. The regular treatment effectively suppresses the virus’s growth until the viral load drops below 1000 copies (Landes et al., 2019). The lower the mother’s viral load, the lower the baby’s risk of contracting HIV from the mother. In one study on HIV-exposed infants’ characteristics, Chen et al. (2019) found poor growth among HIV-exposed Chinese infants, including those HIV-uninfected, compared to unexposed, uninfected infants. Rencken et al. (2022) explain that HIV-exposed babies have lower neurobehavioral functions, which affect their quality of life and ability to develop reciprocal relationships with primary caregivers. This condition may also impact later childhood development, behavior, and mental health. Therefore, infants affected by HIV should be closely monitored, and their autonomic stability, motor control, and social interaction functions should be assessed regularly. Data on cases of HIV-positive children are generally well-recorded as they relate to treatment needs. However, HIV-exposed children born to HIV-infected mothers who are not always HIV-positive are generally not explicitly documented. Caregivers play a crucial role in the lives of children exposed to HIV, whether they are parents, relatives, adoptive parents, or guardians. Providing guidance and incorporating strategies into their care is vital to mitigate possible long-term adverse effects on their development. In addition, good parenting is essential for children to develop properly. However, the challenges caregivers face can affect their ability to provide optimal care, and HIV-positive caregivers have been found to harm child outcomes (Sherr et al., 2016). Research has shown that children with HIV-positive caregivers or living in HIV-affected households have significantly worse outcomes than those in HIV-free homes. Caregivers significantly impact the child’s health status, and understanding the care of children exposed to HIV and caregivers’ health and psychosocial conditions indirectly affects the child’s health status. Nurses are part of the healthcare team involved in maintaining and improving the physical and mental health status of caregivers and children. Nursing care would be better if there is a good understanding of the situation and needs of caregivers and children exposed to HIV. Although studies on caregivers’ experiences caring for HIV-infected children have been conducted widely, research on caregivers’ experiences caring for HIV-exposed children in Indonesia is still limited. Therefore, further studies are necessary to identify programs that improve the well-being of caregivers and children exposed to HIV. Therefore, this study aimed to explore the experiences of caregivers caring for children under five exposed to HIV. Methods Study Design The study utilized a qualitative method with a descriptive phenomenology approach to understanding caregivers’ experiences caring for HIV-exposed children under five. Qualitative research prioritizes meaning and clarity over quantitative study (Davidsen, 2013; Paley, 2017). The phenomenological inquiry aims to elucidate the structure or essence of the lived experience of a phenomenon in the search for the unity of meaning, which is the identification of the essence of a phenomenon. It accurately describes the everyday lived experience (Rose et al., 1995; Streubert & Carpenter, 2011). The design of this study emphasizes the meanings of caregivers’ experiences in caring for children under the age of five. This study included individual and situational experiences and their coping mechanisms for caring for HIV-exposed children under the age of five. Participants The study participants were caregivers of HIV-exposed children living in the Jakarta area and its surroundings. The researcher recruited participants who met the criteria using snowball sampling techniques. Participant inclusion criteria were primary caregivers of children under five exposed to HIV who directly cared for children, such as the mother, adoptive father, mother’s sister, and aunt. They were able to communicate verbally and had been caring for children under five exposed to HIV for at least six months. The number of participants included in the sample was determined by how much information could be gathered. The data collection process was deemed complete when subsequent interviews did not generate any new information because the process had become repetitive. To determine saturation and the necessity to conclude interviews, they were reviewed concurrently and iteratively with data collection to determine whether they were complete. The themes that emerged from the initial analysis of the interviews were seen in variations and relationships with subsequent interviews until data saturation was reached. After interviewing the tenth caregiver, this study achieved data saturation. Data Collection The data collection for this study was conducted between September 2021 and July 2022. Due to COVID-19 and social distancing policies, data were collected online via Zoom meeting. At the initial stage of participant recruitment, the researcher communicated with PLHIV assistants in the Jakarta area and its surroundings. The researcher explained the study’s aim and inclusion criteria to the PLHIV assistants, who then contacted caregivers of HIV-exposed toddlers who met the criteria during clinic visits. The researcher then contacted interested caregivers, explained the study’s objectives, benefits, rights of participants, and data collection procedures in writing, and sent the information via a Google form link through the WhatsApp application. Participants who agreed to participate expressed their consent through the same Google form link. Subsequent participants were obtained based on recommendations from previous participants who met the inclusion criteria. In the next stage, the researcher agreed with the participants on a suitable time for the online interview. The interviews with all participants were conducted online for 40-60 minutes using the Zoom meeting mode. The research team conducted open-ended interviews following the guide and continued with in-depth interviews. Before the interviews, the researcher explained the process and asked for permission to record the interviews. All participants allowed the researcher to record the interviews. The researcher conducted the interviews in a private place using earmuffs and recorded the audio and visual aspects. Following the interviews, debriefing sessions were conducted to ensure that the session had not caused any harm to the participants before disengaging. Data Analysis The recorded interviews were listened to prior to verbatim transcription and then re-listened for better understanding. Two Bahasa language experts transcribed the Bahasa interviews back-to-back to maintain meaning before translating them into English. Biographical information was compiled and labeled in a Microsoft Word document. The transcribed interviews and biographical data were given recognizable file names, stored on a flash drive and personal computer (PC) with a password, and made exclusively available to the research team. During the data collection phase, the researchers manually analyzed the data using Colaizzi’s analysis of phenomenological interviews. The researchers followed the seven iterative phases of Colaizzi’s method (Colaizzi, 1978; Polit & Beck, 2004): 1) they listened to the audio of the interview, transcribed it, and read it several times to grasp the overall message’s meaning; 2) they extracted all significant statements from the transcripts and compiled a comprehensive list; 3) interpretations were derived from all the significant statements provided; 4) the developed meanings were arranged into themes or clusters; 5) the researchers integrated the themes to provide a comprehensive picture of caregivers’ experiences with HIV-positive children under five; 6) they made a decisive and unequivocal declaration regarding the comprehension of this phenomenon, considering the setting and context of the caregiver’s experience caring for HIV-positive children under the age of five. As a result, this became the inherent meaning; 7) the researchers communicated with all caregivers via WhatsApp to confirm the final analysis. The participants did not provide new data during validation. Instead, the researchers used quotations from participants to emphasize points throughout the presentation of the results, and they used code identities (P1-P10) to protect confidentiality and anonymity. Rigor To ensure quality and rigor, the researchers followed several steps based on Lincoln and Guba’s parameters, as outlined by Polit and Beck (2004). These steps included peer debriefing, bracketing of prior assumptions, an audit trail, and member checks for all participants. The researchers also explained the setting, participants’ characteristics, and transactions to achieve transferability. This process confirmed that the interview guide phrasing, ability to comprehend, reliability, and accuracy were sufficient to elicit appropriate responses for the phenomenon. Ethical Considerations This study was reviewed and approved by the Commission of Ethics of the Faculty of Nursing, Universitas Indonesia, with an ethics review passing the number of Ket-217/UN2.F12.D1.2.1/PPM.00.02/2021. The researchers initiated contact with all participants through an online chat platform and introduced themselves and the purpose of the study. After the participants understood the research, they expressed their approval to participate in the research through a Google form. Results Table 1 shows all ten caregivers who directly take care of children under the age of five. A total of 10 caregivers were involved in this study, comprising nine female caregivers and one male caregiver. Seven of them were mothers who were HIV positive, one was an adoptive father, one was the mother’s sister, and one was an aunt. The caregivers’ ages ranged from 23 to 42 years. The majority of them were housewives and had graduated from elementary, junior, and senior high schools. Table 1 Characteristics of the participants Code Gender Age Educational background Work Relationship with the child HIV status HIV status of the child P1 F 36 Diploma Private employee Mother Positive Negative P2 F 34 Senior high school Housewife Mother Positive Negative P3 F 42 Junior high school Private employee Mother Positive Negative P4 F 34 Elementary school Self-employed Mother Positive Positive (1) and negative (1) P5 F 32 Senior high school housewife Mother Positive Negative P6 M 39 Junior high school Laborer Adoptive father Unknown Positive P7 F 38 Senior high school Housewife Mother’s sister Negative Positive P8 F 32 Junior high school Housewife Mother Positive Positive (1) and negative (1) P9 F 32 Elementary school Housewife Aunt Negative Negative P10 F 23 Elementary school Housewife Mother Positive Negative Three themes were generated from the data: 1) disease-transmission foreboding, 2) prejudice against mothers and children exposed to HIV, and 3) seeking support. The coding tree can be seen in Figure 1. Figure 1 Coding tree Theme 1. Disease-transmission foreboding Nine out of ten participants expressed fear of disease transmission. The primary caregiver participants, namely mothers with HIV, were afraid of the risk of HIV transmission from mother to child through breast milk, so they decided not to breastfeed their babies. The participant stated this: “I was worried when I was pregnant. I was afraid my son would be infected and felt a little scared. I am a bit of a worrier… I am terrified that my son will be the same as his parents.” (P1) The mother (P1) was worried about the possibility of transferring the virus to her baby. Her worries affected her during pregnancy, childbirth, and after childbirth. She did not want her baby to suffer from the same disease as her mother. Another mother was worried about how she could give breast milk to her baby. “When I was pregnant with my third son, I already knew my status, so we consulted with a doctor before the birth… I can give breast milk, but I am afraid. Finally, I decided not to give breast milk, just formula milk.” (P8) The mother had consulted with health workers before the birth of her third child. Although the mother was allowed to breastfeed, she was afraid that the child would contract HIV due to breastfeeding, so she decided not to breastfeed and used formula milk instead. Other participants, namely caregivers other than mothers, were concerned about HIV transmission to other family members at home, especially when the child was sick or experiencing opportunistic infections such as diarrhea (P7) and tuberculosis (P6). However, unlike other participants, one participant (P9) stated that they were not afraid of HIV transmission because they already knew how HIV is transmitted and how to prevent transmission. Theme 2. Prejudice against mothers and children exposed to HIV The caregivers who participated in the study were either HIV-positive or HIV-negative. The majority of the participants experienced public stigma, particularly from their community or neighborhood. Participants generally kept their HIV status confidential due to the stigma surrounding HIV. They only disclosed their status to spouses, relatives, and health workers involved in their care. “Some people know, and some do not. I did not tell everyone; only my mother knows… just my mother.” (P4) The mother (P4) revealed that not all of her family members knew the HIV status of the father, mother, and son. “The only parent who knows the HIV status is her mother.” (P4) Stigma concerns also impacted caregivers’ healthcare choices (P3 and P8). “I do not go to the Posyandu. The problem is, isn’t it better to go to a specialist? There is still a stigma, and I am afraid of being questioned: why isn’t he allowed to receive the polio vaccine? (P3) The mother (P3) does not take her child to Posyandu, a community-based healthcare center for children under five in Indonesia, for immunizations. Instead, she prefers to take her child to a midwife who knows about her HIV status. The mothers are concerned that questions about their babies’ immunizations will arise due to the stigma in society. Another participant also preferred to visit her usual doctor (P8). “I am afraid to go to the clinic… I am afraid of discrimination or something. They do not understand… there are still people who stare and judge, so I go to my regular doctor.” (P8) The mother (P8) prefers to visit the doctor she usually consults because she fears discrimination from other health workers or clinics. Theme 3. Seeking support Whether HIV-positive or HIV-negative, the caregivers involved in this study actively sought help in various forms. This assistance included information and advice for child care from health workers, emotional support and information from people living with HIV-AIDS (PLWHA), peer support groups (or called “Kelompok Dukungan Sebaya [KDS]”), and access to health services for examining and treating children. Some of the participants’ expressions are as follows: “I am going to ask first, when (the child) wants to start eating… instead of looking for info on the internet, it is better for me to ask the health workers, which is for sure.” (P1) The mother (P1) seeks information and advice from health workers before giving complementary foods to her baby. Other participants sought information about HIV screening services for their babies. “I do not know how. My son does not have the HIV test yet. There is nothing free. Then they told me to do this and this, finally I got the number contact.” (P2) The mother (P2) seeks information from friends in KDS, a free HIV screening service for children over one-year-old. However, the examination requires a high cost, as not all Puskesmas have a free HIV testing service program for children (Early Infant Diagnosis / EID). Other participants, besides mothers (P6), expressed their experiences seeking help from non-governmental organizations (NGOs). “I am telling you a story. I am having trouble with the pampers. Because, one day, the defecation was eight times. The NGO officer said already, sir, be patient. I will try later. Finally, she came to my house and saw my daughter’s condition.” (P6) The caregiver (P6) had difficulty meeting the need for diapers when the child had long-lasting diarrhea, so he told the NGO officials about the problem. NGO officials then provided in-person assistance during visits to participants’ homes while examining the child’s condition. Almost all participants, whether maternal or non-maternal caregivers, sought help proactively, demonstrating the need for support in various aspects of caring for children exposed to HIV. Discussion This study’s objective was to explore caregivers' experiences caring for children under five exposed to HIV. The study’s findings yielded three themes: disease-transmission foreboding, prejudice against mothers and children exposed to HIV, and seeking support. Disease-transmission Foreboding HIV is a contagious disease that can spread through body fluids. Although antiretroviral (ARV) treatment can minimize the risk of mother-to-child HIV transmission, there is still a chance of transmission during pregnancy, childbirth, and breastfeeding. This fact causes many HIV-positive mothers to decide not to breastfeed their babies. The study discovered that most HIV-positive mothers who are caregivers to HIV-exposed children did not breastfeed their infants, even though they had a high CD4 count and an undetectable viral load. In this regard, Ogbo (2016) argued that HIV transmission from mother to child is a significant determinant of suboptimal infant feeding practices, such as non-exclusive breastfeeding, in most African communities with a high prevalence of HIV. Keakabetse et al. (2019) found that mothers’ fear of infecting their babies is one factor that influences infant feeding patterns in children exposed to HIV. Caregivers’ fears about HIV transmission through breastfeeding have led to HIV-exposed children being deprived of breast milk from birth to later stages, unlike children not exposed to HIV. In contrast, caregivers other than mothers in this study have generally been educated about HIV and know that the disease is not easily transmitted to others. This knowledge makes most caregivers less fearful of HIV transmission in their daily activities. However, caregivers are still concerned about disease and opportunistic infections, such as Tuberculosis. Cowgill et al. (2008) found that many families feared HIV transmission through blood contact, bathroom items, kisses/hugs, and food. Families overcame their fears by educating their children about how HIV is transmitted and setting rules or taking precautions to reduce the risk of HIV transmission in the household. HIV-infected parents are also worried about contracting opportunistic infections from sick children. Prejudice Against Mothers and Children Exposed to HIV In society, there is a prejudice against those with HIV, which causes people living with HIV and caregivers to feel anxious if their HIV status is known to others. In this study, the participants expressed their belief that HIV disease is stigmatized in society due to bad deeds and is viewed as a risk for transmission, leading to avoidance from people interacting with people living with HIV (PLWHA). In addition, some mothers participating in the study were concerned that their children would be ostracized if their HIV status was known. Therefore, the participants sought to keep their HIV status private, only disclosing it to healthcare providers and some or all of their family members. This desire for privacy makes caregivers selective in choosing health services for child care. For example, one participant preferred immunization services in midwifery practices rather than public health service facilities like Posyandu because they were concerned that questions would arise about the immunizations obtained by the children. Related to the results of this study, Muharman et al. (2019) found that older parents move from one place to another to hide their children’s infection status from other family members. This strategy of avoiding stigmatization does not affect health care even if their status is known in health care units. However, there is anxiety that the child will not receive their rights to education, social relationships, and other social support necessary for growth and development whenever the child’s HIV status is known. McHenry et al. (2017), in their research on HIV-infected nannies in Kenya, found that stigma is closely related to the loss of social and economic support but also includes internalized negative feelings about oneself. Participants identified the impact of treatment-related stigma, including non-compliance, the confidentiality of status to children or others, and increased mental health problems. The results of this study indicate that caregivers’ concerns about stigma and discrimination influence their choice of health services for the children they care for. For this reason, healthcare providers need to consider these caregiver concerns to ensure the fulfillment of the child’s health promotion needs. Seeking Support Children exposed to HIV require an early HIV test (EID) to determine their HIV status. Early examination is necessary to ensure that the child receives appropriate treatment. However, this study discovered that several participants encountered obstacles when attempting to obtain EID services. One of the issues is the lack of available tools at health facilities that prevent them from providing EID services. The cost of examinations is also a significant obstacle. The economic status of the participants in this study was a factor, as they all had incomes below the regional minimum wage. These obstacles are similar to those identified in a study by Ernawati et al. (2022), which explored the experience of treating a child with HIV. Themes found in their research include unfamiliarity with HIV disease when treating a child, loss of follow-up related to treatment, limitations for early diagnostic examination, and economic demands in caring for the child. Children who are exposed to HIV, particularly those who are infected, require intensive treatment due to the repeated infections they experience when their HIV status is unknown. These children need continuous treatment and additional care for any growth and developmental issues they may encounter. In this study, caregivers, other than the mothers, were unaware that the child was infected with HIV. As a result, the child experiences recurrent pain, a deteriorating condition, and delays in receiving antiretroviral (ARV) treatment. In addition, administrative issues, such as the absence of health insurance, contribute to delays in ARV treatment. Caregivers in this study sought assistance accessing healthcare services when the child required hospitalization, managed the child’s health insurance and communicated with healthcare providers while caring for the child at home. Nemathaga et al. (2017), in their study, found that caregivers of children receiving ARV therapy experience financial burdens due to transportation costs needed to comply with follow-up appointments and a lack of funds for necessary food and clothing. In addition to the child’s condition requiring special attention, caregivers of children exposed to HIV also need specific information for childcare. Caregivers cannot consult anyone freely, only certain people who already know the HIV status of the mother and child being cared for. In this study, caregivers sought information or consulted with health workers in hospitals or health centers who had previous contact with caregivers. They also sought emotional support from PLHIV companions and friends in peer support groups and worked closely with family members when caring for a child at home. Some participants expressed gratitude for receiving help and support from health workers, PLHIV, and peer support group assistants for child care at home. Our findings align with a study by Sofro and Hidayanti (2019) found that peer support groups can provide social, emotional, self-esteem, and network support, such as intensive communication, strong friendships, and genuine assistance with venture capital, business skills, and medical access. Thus, the combination of peer groups and health professionals plays an essential role in improving the health status of children exposed to HIV through information support, emotional support, and easy access to health services for caregivers and children. Implications to Nursing Practice and Healthcare Policy The findings of the study have two significant implications for intervention. Firstly, for informal home-based care for HIV to be a suitable option or alternative to facility-based services in Indonesia, the government needs to implement direct social intervention strategies for families of HIV patients with limited resources. The existing paradigm of facility-based treatment in the country, which primarily consists of medicine refills, counseling, and peer activities, should be modified to include the direct delivery of needs such as psychological assistance to vulnerable households. Secondly, women in Indonesia who are the primary caregivers for HIV patients require social support and intervention programs to assist them. Nursing practices can take an active role in designing intervention programs to improve caregiver well-being and support optimal growth and development in HIV-exposed children under five. Limitations Our study, which may be the first to investigate the essential attributes of caregivers living with HIV-exposed children under five in Indonesia, provides a starting point for improving their health status. However, due to stigma, individuals with HIV typically limit interactions and communication with family, PLHIV companions, and peers in the same community, which poses a challenge for researchers to obtain maximum variation. Conclusion This study concludes that caregivers of children exposed to HIV generally have disease-transmission foreboding, including HIV transmission from mother to child through breast milk, transmission of HIV to other family members, and opportunistic infectious diseases. In addition, caregivers of children exposed to HIV are concerned about prejudice against mothers and children exposed to HIV, which puts caregivers and children at risk of ill-treatment or discrimination from society. Caregivers of children exposed to HIV require informational assistance, emotional support, and easy access to health services for screening and treatment. Furthermore, most caregivers were female mothers, and the participation of men can indeed be dismissed, despite informal and formal caring seeming to be gendered in most Indonesian contexts. Encouraging the involvement of more males in providing care would be beneficial in gaining their perspectives. Acknowledgment The authors appreciate all the support of companions of people living with HIV and AIDS (PLWHA) and all the caregivers who participated in this study. Declaration of Conflicting Interest The authors declared no potential conflicts of interest concerning the research, authorship, or publication of this article. Authors’ Contributions HH conceived the idea, conducted data collection and analysis, and paper writing. NN and DW reviewed the results of the data analysis and the paper. In addition, N contributed to recruiting participants and reviewing the results of data analysis. All authors were accountable in each step of the study and agreed with the final version of the article to be published. Authors’ Biographies Ns. Happy Hayati, S.Kp., M.Kep., Sp.Kep.An is a Lecturer at the Department of Pediatric Nursing, Faculty of Nursing, Universitas Indonesia, Indonesia. Dr. Nani Nurhaeni, M.N is an Associate Professor at the Department of Pediatric Nursing, Faculty of Nursing, Universitas Indonesia, Indonesia. Dessie Wanda, S.Kp., M.N., Ph.D is an Associate Professor at the Department of Pediatric Nursing, Faculty of Nursing, Universitas Indonesia, Indonesia. Ns. Nuraidah, S.Kep., M.Kep., Sp.Kep.An is a Pediatric Nurse Specialist working at RSPI Sulianti Saroso, Indonesia. Data Availability The datasets generated during and analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-246 10.33546/bnj.1457 Perspective Common ethical dilemmas of family caregivers of palliative patients in Indonesia https://orcid.org/0000-0001-6609-6285 Kristanti Martina Sinta 1* https://orcid.org/0000-0002-1207-3456 Kusmaryanto 2 https://orcid.org/0000-0002-8823-229X Effendy Christantie 3 1 Department of Basic and Emergency Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia 2 Faculty of Philosophy – Divinity, Sanata Dharma University, Indonesia 3 Department of Medical Surgical Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia Corresponding author: Martina Sinta Kristanti, S.Kep, Ns, MN, PhD, Department of Basic and Emergency Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Gedung Ismangoen lt.2 Sekip Bulaksumur, Yogyakarta Indonesia 55281. Phone: +6281227811976. Email: sinta@ugm.ac.id Cite this article as: Kristanti, M. S., Kusmaryanto., & Effendy, C. (2021). Common ethical dilemmas of family caregivers of palliative patients in Indonesia. Belitung Nursing Journal, 7(3), 246-250. https://doi.org/10.33546/bnj.1457 28 6 2021 2021 7 3 246250 01 4 2021 01 5 2021 02 6 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Family caregivers, especially in Asian countries, have a profound role in caring for a sick family member. However, there are wide variations between the Asian and western world in terms of culture and facilities. Therefore, the problems and needs of family caregivers between those two regions may also be distinct, and it is important to explore and elaborate based on our empirical evidence. In Indonesia, motives and values in caregiving and religion become the wheel-power of the family caregivers in providing care. This affects action and consequences for caregivers. This paper attempts to elaborate on common ethical dilemmas that usually face by family caregivers in Indonesia. Unfortunately, family caregivers typically are not prepared to make those challenging decisions. Therefore, we recommend not only that family caregivers need to be involved in the caring process, but also their issues and ethical dilemmas should be assessed and addressed by health care professionals, especially nurses, who have the most frequent contact with patient and family caregiver. Asia caregivers religion health personnel caring ethics nursing Indonesia ==== Body pmcProlog Without a good understanding of what it is like to be overwhelmed by the experience of illness - one’s own or that of a loved one - how can the doctor or ethicist (or other health care professionals) appreciate the human situation the doctor must address?” (Dresser, 2011). This implies that understanding the lived experiences of patients and family caregivers is an essential key to take care of patients with a terminal illness. Accordingly, we would start this perspective essay by presenting three real cases. Case one Roy, 25 years old, a young man we interviewed in a chemotherapy clinic in Yogyakarta, Indonesia, was accompanying his mother, diagnosed with breast cancer. He took it hard when we asked what his life activity was. Finally, he said: ‘Well, I was a happy newly graduate entering my first day of work, but then mom called me almost every hour that day. She asked what time would I be home. That night I could not sleep. I thought it should be fine to postpone my life for 1-2 years to be her caregiver. My life can wait, but my mother’s treatment cannot. I then submitted a resignation letter at the end of that week.’ Case two Celine, 34 years old, who has been married for ten years, was looking forward to having a child of her own. She used to live in Singapore, but since last year, she moved back to Jakarta to take care of her mother, diagnosed with tongue cancer, and her father, a diagnosed Alzheimer's patient. Celine has an older sister who lives nearby; however, she said she was already too busy to take care of her own three kids. Therefore, it should be Celine who becomes their mom’s caregiver since Celine has no kids. Coming from a wealthy family, they set up a proper home care plan fully equipped with nurses and a visiting doctor. However, it has been three months since she could go anywhere. One time she went to the gym, but she received a phone call from her husband asking how she could leave their parents at home in that condition. She was then stuck at home, bored and depressed. Case three Maria, almost 50 years old, decided to be her sister’s caregiver, Anna, since five months ago. In doing so, she needed to leave her family and job in Kalimantan, Indonesia, which was such a tough decision to make. Anna, 36 years old, was diagnosed with breast cancer around three years ago. She has fought bravely, and now she suffered from constant pain and a large malignant wound on both of her breasts. She also suffered from anemia and needed to go to the hospital for a transfusion. Nevertheless, Anna is a cheerful lady with a bright personality. She knew exactly what is going on with her condition and was ready for the worst scenario. Her concern was only for her daughter, Lia (16 years old). Lia never knew who her father is since she was born. Since Lia goes to school and Anna was bound to bed rest, Maria’s heart was moved. Actually, Maria and Anna had such opposite characters; they had argued in many ways since they were little. Maria decided to be Anna’s caregiver because she could not be on her mother’s side during her last moment in life. This guiltiness haunted her for many years. She was expecting that by becoming one of Anna’s caregivers, her guiltiness would fade away. When we asked: “With whom would Lia stay with when something happens to Anna?” With her soft voice, she said that this is the most important topic, but she could not initiate it with Anna. She does not know how and when to start this discussion. These cases illustrate that caring for the loved ones (who are ill) affects the patients and may also change the family caregivers’ life. Accordingly, the World Health Organization (2010) defines palliative care as an approach to enhance not only the quality of life (QOL) of patients but also their family caregivers. This definition relates to the Indonesian situation where caring for the family member is considered part of Asian culture (Funk, Chappell, & Liu, 2013). This perspective paper aims to elaborate experiences of family caregivers in Indonesia and to identify some common ethical dilemmas in their palliative experiences. Family Caregivers The family caregiver has various definitions. The most common meaning refers to people who provide care to their loved ones with or without blood relations, including in-laws and neighbors (Kilic & Oz, 2019). This person may or may not live with the care recipient, but they provide care for at least 6 hours a day. However, the most common differentiation with the formal caregiver is that there is no financial compensation from the care recipient to this family caregiver. Family caregivers’ circumstances are varied between Western and Asian regions. In the Western world, independence (or lack of dependency) is highly appreciated. The government responds by providing various formal facilities such as long-term, hospice care, nursing homes, and many other institutions in order to maintain the individual sense of independence for people with chronic and terminal illnesses. On the other hand, in Asian countries, including in Indonesia, taking care of family members is part of the culture. In this setting, there are many important lessons that we have learned from generation to generation—taking care of our family, especially our parents, may be the only way we know how to appreciate life and our inheritance. In Javanese culture, for example, tabon is a term that refers to a child that is assigned to take care of a parent (Keasberry, 2001). According to this culture, tabon will be granted ownership of the house once the parents are passed away (Keasberry, 2001). In relation to financial compensation, some developed countries have various schemes. For example, in the Netherlands, people are able to self-assign a ‘mantelzorg’ (family caregiver in Dutch). They put this information on legal government documentation. When something happens to their health, this mantelzorg will provide direct care, including taking the patient to the hospital, facilitating their groceries, and other daily activities. The Dutch government offers a financial scheme to compensate for the time spent by the mantelzorg in providing this care. There is a limited amount of Euros per day that can be accessed by the mantelzorg and applied as an invoice (Alice, Inger, & Mirjam, 2019). Considering the wide variations in the Western and Asian cultures, this implies that we need be careful about directly or thoughtlessly adapting ideas or interventions from the Western countries to Asian ones. Cultures are a form of intergenerational heritage that actively shapes people’s lives, including the family caregiving condition. Since one of the most suitable policy types is supported by empirical evidence, research on family caregivers in Asia, including Indonesia, is essentially needed. Family Caregivers in Indonesia When one of the authors (MSK) started PhD study in 2015, funded by the Dutch government, evidence was limited concerning family caregivers in Indonesia. Fortunately, research on this topic has been growing progressively in the past five years. A study revealed that family caregivers have a profound role in patient care even during hospitalization (Effendy et al., 2015). This finding implied that family caregivers must have important tasks at home. They should be supported. They should be part of the care. The next question is, how can we provide the support and care that they need? This initiated me to start my first study by comparing the experiences of family caregivers of patients with cancer and patients with dementia. We found more similarities than differences in the problems in caregiving, actions of caregivers, and beliefs in caregiving. Some differences were also identified (Kristanti, Engels, Effendy, Utarini, & Vernooij-Dassen, 2018). Family caregivers of people with dementia revealed that direct contact with health care professionals was highly appreciated. People with dementia are usually cared for by either gerontologists or neurologists, then the communication and coordination can be much simpler. On the other hand, care for most patients with cancer is done by multi-disciplines, including oncologists, internists, surgeons, and many other parties, depending on their needs. This lack of simple, one-to-one involvement increases the risk for friction and miscommunication issues. However, family caregivers of people with dementia revealed that they sometimes felt a loss of connection with the patient even when the patient was still beside them. “She doesn’t know me anymore; she doesn’t know anyone anymore” [Husband]. Meanwhile, family caregivers of patients with cancer often described a stronger family cohesiveness. For example, one participant said that she (55 years old) had only talked to her older brother (57 years old), who lived in a different city once or twice a year since they were busy with their own life, family, and work. But since she has been looking after their mother, they keep in touch on a daily basis, sometimes just to ask how they are doing. As a result, they found a reconnection during this caregiving process (Kristanti et al., 2018). The next study then elaborates on the experiences of family caregivers of patients with cancer (Kristanti, Effendy, Utarini, Vernooij-Dassen, & Engels, 2019). Data were collected from three major cities in Indonesia: Jakarta, Surabaya, and Yogyakarta. Belief in caregiving is the core phenomenon (Kristanti et al., 2019). It is the wheel-power of caregivers. It consists of spiritual and religion, values, and motives in caregiving. This wheel-power influences the actions of family caregivers and the consequences they received. The more constructive their belief in caregiving, the better the consequences it impacted on them. Those with this spirit eventually found themselves as a better person and vice versa. Common Ethical Dilemmas These empirical data can help us reflect on ethical dilemmas that the family caregivers must face in the caregiving process or their relationships with patients and other family members. In general terminology, extensive medical literature used ethics, dilemma, and moral distress interchangeably (Yildiz, 2019). In the nursing profession, an ethical dilemma may be alleviated by utilizing a scientific ethic, that is, by placing people (or the care recipient) at the center and interacting with family members and their network, by considering their values, uniqueness, dignity, and inherent human rights (Yildiz, 2019). In the case of the family caregivers’ journey, based on our empirical data (Kristanti et al., 2019; Kristanti et al., 2018), one of the most frequent dilemmas was ‘hiding’. Family caregivers tend to hide their emotions and burdens in front of the patient. They thought that their feelings were not relevant and should stay hidden. They would pose a cheerful, brave, and tough face in front of the patient. Another hiding is about revealing diagnoses. When the patient is younger (below 50 years old), the doctor mostly revealed diagnoses directly. However, when the patient is older and maybe illiterate (unable to understand), the family caregiver is the first to receive the diagnosis. The doctor then would request the family to inform the patient, or in some cases, the family would ask the doctor and nurses not to reveal the diagnoses until the patient is ready. When the patient was not aware of their diagnoses, the condition became the most problematic situation for the family caregivers. One of the participants in our study revealed that once she broke the news of the diagnosis to her mother, it felt like ‘a mountain had been removed from her shoulders’ (Kristanti et al., 2019). The second ethical dilemma was the perception of voluntary vs. obligatory actions in the caregiving tasks. In many Western publications, Asian countries are framed negatively that caregiving is a mandatory action. Our study in Indonesia showed that we framed ‘this obligation’ in a positive way so that we see this as a chance to make some payback to our loved ones. It is described as ‘a chance in disguise’ or some opportunities and benefits while facing some challenges (Kristanti et al., 2019). The third dilemma was that most caregivers were the so-called ‘first-time players’ with no training (Dresser, 2011), meaning that they are ‘newbies’ (in caregiving role), and they may need time to grasp information, to have second or third opinions, to make (some immature) decisions and/or to change their decision. It is because nothing is harder than making decisions about treatment and caring, resulting in life and death consequences. Family caregivers also felt like living as a shadow. Their presence was mostly overlooked by healthcare professionals or other family members. While all the spotlight is on the patient, the family caregiver is also the one who needs to be taken care of. The decision-making process is another dilemma that we identified. Some caregivers need to decide to continue or stop treatment when the patient can no longer participate in this decision. The decision for resuscitation can be a life-long traumatic memory for them. The guilty feeling to stop the treatment can also become their burden of guilt for the rest of their life. In order to reduce unnecessary guilty feeling, British Medical Association reminds us to apply the ethical principles of ordinary and extraordinary. The obligation of healthcare workers is to provide ordinary care, while extraordinary care is not an obligation (British Medical Association, 2007). One is not obliged to use all resources to defend human life. Extraordinary care is a situation in which we have to say “enough” and not prolonging treatment or care. The last dilemma is the appreciation concerning the formal facilities. Some palliative care experts in Indonesia are still discussing if hospice care is suitable for our culture. Would we dare to let our loved ones stay in the hospital at the end of their life? Can we ignore what people say to us if we put our loved ones in a nursing home? or do we prefer to have them stay with peace in their familiar place: at home? What is the formal facility to support both patients and caregivers that suits our economic condition, social status, and culture? Ethical Considerations in Involving the Family As nurses, sometimes we need to decide to involve or not involve family caregivers as part of our caring team. Becoming part of the team means that we may have an equal number of tasks and responsibilities. One of the important tasks of healthcare workers (including nurses) is to foster autonomous decision-making of the patients or their proxy (Beauchamps & James, 2019). As healthcare workers, nurses have an ethical obligation to give all necessary information so that patients or their prox may make autonomous decisions. In many cases, the final decision is a shared-decision making between family caregivers and nurses. We may refer to the four prima facie principles in making the decision: respect for autonomy, beneficence, non-maleficence, and justice (Beauchamps & James, 2019). Principles of beneficence must take positive steps to help others, not merely refrain from harming them (nonmaleficence). It is an ethical obligation to do good for patients and their families, including family caregivers. Involving family caregivers in patient care will enhance the collaborative aspect. We then need to identify who is the daily ‘family caregiver’ and who is the ‘key person to make a decision for the patient’ because their roles are different. They can be the same person. But in Indonesia, this is not always the case. There are cases where the main decision-maker is living in another part of the world. They can be the one who is funding the treatment or the eldest ones in the family. Nurses need to identify this hierarchy so that they can speak the right topic to the right person. Non-maleficence relates to the previous principles. The principle of nonmaleficence obligates us to abstain from causing harm to others. This principle is identical to the famous maxim Primum non nocere: “Above all [or first] do no harm.” Although this principle does not appear in Hippocratic writings, it is regarded as a fundamental principle in the Hippocratic tradition. It was found that that the most dilemmatic problem in family caregivers is their unbounded tasks (Dresser, 2011). They do everything every time. In some cases, family caregivers of dementia passed away when the patient was still alive. Nurses should assist them in setting up targets and boundaries to maintain the family caregivers’ own QOL. The third prima facie is justice. Traditionally justice means that equals must be treated equally, and unequal must be treated unequally. This traditional definition is attributed to Beauchamps and James (2019) added an important notion, justice means fair, equitable, and appropriate treatment in light of what is due or owed to affected individuals and groups. This implies that services offered by nurses for caregivers should have the same quality and standard. We should provide the support that is systematic and structured. Intervention such as providing basic care training is effective to maintain the QOL of patients in terminal illness (Kristanti, Setiyarini, & Effendy, 2017). Also, interventions offered should not only be for the patient’s QOL but also maintain the caregivers’ well-being. The last principle is respect for autonomy. Respect for autonomy is to acknowledge patients’ right to hold views, make choices, and take actions based on their values and beliefs. It means that nurses or other healthcare workers have to respect the autonomous decision of patients. The opposite is true: the decision by a non-autonomous person should not be respected. Respecting the autonomous decision of patients means that nurses should obtain people’s agreement for any decision and any medical interventions relate to them, keep confidentiality and promises, and not deceive others (Gillon, 1994). This principle may relate to the decision-making process in palliative care. Knowing how challenging the decision-making process in palliative care could be, advanced care planning (ACP) should be implemented soon in Indonesia. ACP is a discussion between the doctor, patient, and family (and nurses) for planning the treatment and future decisions. The patient should be in good condition physically and psychologically following a procedure. The discussion during ACP may include if the patient accepts or refuses resuscitation when it is needed. ACP will make the treatment and next step in the process easier for everybody and prevent a traumatic event due to the obligation to provide a decision in a short moment for family caregivers. Implication for Nursing Practice Nurses are part of health care professionals who have the most frequent contact and interaction with patients and families. Therefore, nurses have an important task to observe patient's and family’s situations and needs. In addition, knowing some of the ethical dilemmas that may be faced by the family caregivers, nurses need to assess and provide sufficient support for them. Patients and families are one unit in caregiving. By providing care to the family caregivers, we support the patients in facing difficult moments in life due to their illness. Conclusion Family caregivers have profound roles in caregiving for patients with chronic and terminal illnesses. Some ethical dilemmas along the journey were identified as signposts. Accordingly, nurses can utilize the four primary ethical principles of caregiving to provide support for family caregivers and enhance the family caregivers’ sense of well-being. Declaration of Conflicting Interest None declared. Funding None. Authors’ Contributions MSK was responsible for initiating the concept, writing, and drafting and had the ownership of data. K and CE provided important intellectual content and contributed feedback while writing a manuscript draft. All authors have provided final approval and agreement to be accountable for all aspects of the work regarding content. Authors’ Biographies Martina Sinta Kristanti, S.Kep, Ns, MN, PhD is an Assistant Professor at the Department of Nursing, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada Yogyakarta. Her research interest is on family caregiving in palliative care. Dr. C.B Kusmaryanto is an Assistant Professor at the Faculty of Philosophy – Divinity, Sanata Dharma University, Indonesia. He has written several textbooks on Medical Ethics and Bioethics. Dr. Christantie Effendy, SKp, MKes is an Associate Professor at the Department of Medical Surgical, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada Yogyakarta. Her areas of interest are adult nursing, oncology, and palliative care. ==== Refs References Alice, d. B., Inger, P., & Mirjam, d. K. (2019). Werk en mantelzorg [Work and informal care]. Retrieved from https://www.scp.nl/publicaties/publicaties/2019/02/13/werk-en-mantelzorg Beauchamps, T. L., & James, F. C. (2019). Principles of biomedical ethics. Oxford: Oxford University Press. British Medical Association. (2007). Withholding and withdrawing life-prolonging medical treatment guidance for decision making. Oxford: Blackwell Publishing. Dresser, R. (2011). Bioethics and cancer: When the professional becomes personal. The Hastings Center Report, 41 (6 ), 14. 10.1002/j.1552-146X.2011.tb00152.x Effendy, C., Vernooij‐Dassen, M., Setiyarini, S., Kristanti, M. S., Tejawinata, S., Vissers, K., & Engels, Y. (2015). Family caregivers' involvement in caring for a hospitalized patient with cancer and their quality of life in a country with strong family bonds. Psycho‐Oncology, 24 (5 ), 585-591. 10.1002/pon.3701 25288447 Funk, L. M., Chappell, N. L., & Liu, G. (2013). Associations between filial responsibility and caregiver well-being: Are there differences by cultural group? Research on Aging, 35 (1 ), 78-95. 10.1177/0164027511422450 Gillon, R. (1994). Medical ethics: Four principles plus attention to scope. British Medical Journal, 309 (6948 ), 184. 10.1136/bmj.309.6948.184 8044100 Keasberry, I. N. (2001). Elder care and intergenerational relationships in rural Yogyakarta, Indonesia. Ageing & Society, 21 (5 ), 641-665. 10.1017/S0144686X01008431 Kilic, S. T., & Oz, F. (2019). Family caregivers’ involvement in caring with cancer and their quality of life. Asian Pacific Journal of Cancer Prevention: APJCP, 20 (6 ), 1735. 10.31557/APJCP.2019.20.6.1735 31244294 Kristanti, M. S., Effendy, C., Utarini, A., Vernooij-Dassen, M., & Engels, Y. (2019). The experience of family caregivers of patients with cancer in an Asian country: A grounded theory approach. Palliative Medicine, 33 (6 ), 676-684. 10.1177/0269216319833260 30916614 Kristanti, M. S., Engels, Y., Effendy, C., Utarini, A., & Vernooij-Dassen, M. (2018). Comparison of the lived experiences of family caregivers of patients with dementia and of patients with cancer in Indonesia. International Psychogeriatrics, 30 (6 ), 903-914. 10.1017/S1041610217001508 28870266 Kristanti, M. S., Setiyarini, S., & Effendy, C. (2017). Enhancing the quality of life for palliative care cancer patients in Indonesia through family caregivers: A pilot study of basic skills training. BMC Palliative Care, 16 (1 ), 1-7. 10.1186/s12904-016-0178-4 28077099 World Health Organization. (2010). WHO definition of palliative care. Retrieved from http://who.int/cancer/palliative/definition/en/ Yildiz, E. (2019). Ethics in nursing: A systematic review of the framework of evidence perspective. Nursing Ethics, 26 (4 ), 1128-1148. 10.1177/0969733017734412 29166840

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-125 10.33546/bnj.1259 Original Research Working alliance among mental health nurses in Indonesia: A comparative analysis of socio-demographic characteristics https://orcid.org/0000-0003-3380-9538 Yosep Iyus 1* https://orcid.org/0000-0001-6960-3692 Mediani Henny Suzana 1 https://orcid.org/0000-0002-1569-4098 Lindayani Linlin 2 1 Faculty of Nursing, Padjadjaran University, Indonesia 2 Sekolah Tinggi Ilmu Keperawatan PPNI Jawa Barat, Bandung, Indonesia * Corresponding author: Iyus Yosep, S.Kp., M.Si., M.Sc, PhD, Associate Professor, Mental Health Department, Faculty of Nursing, Padjadjaran University, Jl. Raya Bandung-Sumedang KM. 21, Hegarmanah, Jatinangor, Kabupaten Sumedang, West Java, 45363, Indonesia. Email: iyuskasep_07@yahoo.com Cite this article as: Yosep, I., Mediani, H. S., & Lindayani, L. (2021). Working alliance among mental health nurses in Indonesia: A comparative analysis of socio-demographic characteristics. Belitung Nursing Journal, 7(2), 125-130. https://doi.org/10.33546/bnj.1259 29 4 2021 2021 7 2 125130 07 12 2020 04 1 2021 31 3 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Working alliance between therapist and client in psychotherapy practice has become proven to compensate for a significant difference in various psychotherapy modalities. However, few studies have investigated the structure of alliance in the context of nurses working at mental health hospitals in Indonesia. Objective This study aimed to compare the working alliance of mental health nurses according to socio-demographic characteristics. Methods A cross-sectional research was performed at the Mental Health Hospital in West Java, Indonesia, as a referral hospital in Indonesia from May to December 2019. The inclusion criteria were nurses with a minimum of one year of working experience and a Diploma III certificate in nursing. Convenience sampling was used to recruit 120 nurses who agreed to join in this study. The working alliance was measured using Working Alliance Inventory-Short Revised-Therapist (WAI-SRT). Results The majority of the respondents were female (77.5%), holding a Diploma III degree in nursing (49.17%), having working experience ranged from 11 to 15 years (34.17%), and working at the chronic unit (32.5%). The mean score of the working alliance was 44.46 (SD = 11.32). The domain of agreement on goals had a higher mean score (17.65 ± 3.45), followed by the task domain (16.56 ± 5.81) and bond domain (22.10 ± 7.23). There was a significant difference in working alliance according to education level and working experience (p < 0.05), while no significant differences in terms of gender and working unit. Conclusion Mental health nurses with higher education levels and more vast working experience had higher working alliances. Thus, nurse managers and hospital policymakers should provide Continues Nursing Education (CNE), working alliance training, and therapeutic strategies for nurses to improve their working alliances. It is also essential to cooperate with nursing schools to include working alliances as learning objectives. working alliance mental health Indonesia psychiatric nursing hospitals demography ==== Body pmcWorking alliance between therapist and client has become proven in psychotherapy practice to compensate for a significant aspect of the difference in result throughout various modalities of psychotherapy (Norcross, 2011). The practitioner-client relationship is also seen as enormously crucial in mandatory care. To investigate the significance of this relationship, many studies have extended the principle of alliance to the area of compulsory care (Menger, 2018; Polaschek & Ross, 2010). In general terms, the working alliance contains numerous elements relevant to the patient-clinician partnership (Flückiger et al., 2018). There are two forms of therapeutic alliance: (1) the Type I alliance, which is characterized by the patient’s presumed support for him or her, and (2) the Type II, which consists of teamwork that includes both the patient and the therapist in resolving the patient’s difficulty and distress (Luborsky, 1994). In the meantime, the working alliance has three elements: (1) the connection between both the client and therapist, which would be likely to be characterized and experienced in matters of love, faith, respect for one another, and a sense of shared responsibility and vision of the task, (2) the consensus between both the client and therapist on the objectives of psychotherapy, and (3) the commitment between both the client and therapist on the goals of psychotherapy (Bordin, 1994). Alliance at general hospitals is different from that at mental hospitals. Alliance at psychiatric hospitals has unique characteristics, including the consumers requiring the nurse’s expertise in interpersonal relations and empathy (Reynolds & Scott, 1999). Nurses are needed to be prepared for unpredictable situations at mental hospitals (Happell et al., 2003). Similarly, Ward (2013) found that fear is “part of the job and part of the unpredictable nature of caring for people experiencing complex distortions in thinking and behavior.” Alliance at mental hospitals, there are three essential characteristics. First, alliance for mental hospital nurses requires adeptness to build an interpersonal relationship because the behavior of consumers is challenging to predict, such as how to communicate with people who are depressed, withdrawing themselves from others, committing suicide, threatening, and behaving aggressively (Del Piccolo & Goss, 2012). Second, there is an unpredictable situation for nurses at work, such as cooperating with patients when suddenly they become threatening because of hearing a voice or hallucination (Jacob & Holmes, 2011). Third, another characteristic is the presence of violent behavior that patients may likely do against nurses. However, although hospitals’ settings are different, the alliance is an essential part of nurses’ role as facilitators for patients to improve or as “facilitators for the patients to grow” (Hemsley et al., 2012). Many factors influence alliance at psychiatric hospitals, including environment or workplace climate (Green et al., 2014), professional nurse’s attitude, and patient’s condition (Zugai et al., 2015). Working environment may take the form of supporting room atmosphere, a clear program, and guarantee of spontaneity are significant components for patent’s alliance (Johansson & Eklund, 2006). A study at Canadian Medium-Security Forensic Psychiatric Facility concludes that nurses often distance themselves from ideal service under a particular condition. In contrast, nurse’s attitude has been a predictor in a successful relationship between patients and therapists at psychiatric hospitals (Jacob & Holmes, 2011). Research by Mcsherry et al. (2012) reported that behavior and attitude have a strong relation with successful alliance; for example, making positive comments about the client and greeting the client with a smile. Spiers and Wood (2010) concluded that building an alliance consisted of three non-linear overlapping phases: “establishing mutuality,” “finding the fit in reciprocal exchange,” and “activating the power of the client.” Those are important to prevent negative perception in a team when achieving a target because the three views will provide an in-depth understanding of the actual condition. However, few studies exploring comparing demographics characteristics with the working alliance in mental health hospitals. Thus it becomes clear that while the role of the working alliance in forming clinical outcomes is founded in the literature on psychotherapy, the work alliance has played an important role in other disciplines (Stagg et al., 2019). Understanding the working alliance of mental health nurses and compare it according to socio-demographic characteristics is important, as they offer critical insights into how health care professionals can influence the patient’s outcome. Insights gained from comparing working alliances of mental health nurses according to socio-demographic characteristics can also help create and evaluate related strategies for mental health nurses to strengthen working relationships. This study aimed to compare the working alliance of mental health nurses according to socio-demographic characteristics. Methods Study Design Cross-sectional research was conducted at the Mental Health Hospital in West Java, Indonesia, as a referral hospital in Indonesia from May to December 2019. Samples All the samples were recruited from all locations in the associated hospital. The inclusion criteria were nurses with a minimum of one year of working experience and a certificate of Diploma III in nursing. The nurses who took leave were not allowed. Convenience sampling was employed, with a total of 120 nurses agreed to join in this study. Measures The socio-demographic characteristics included gender (male versus female), level of education (Diploma III, Bachelor, and Master degree with Specialist), duration of work in years, and working units (polyclinic, acute room, chronic room, emergency room, drug addiction, and administration). The working alliance was measured using Working Alliance Inventory-Short Revised-Therapist (WAI-SRT) for nurses developed by Adam O. Horvath (http://wai.profhorvath.com/). The subscales of the working alliance are goal, task, and bond. This instrument consists of ten items with five Likert-scale from seldom (0) to always (5). A higher score indicates a higher working alliance. Then, the working alliance level was categorized into low and high; low if score less than overall mean score, high if the score higher than the overall mean score. This instrument has been forward-backward translated and adapted into Bahasa Indonesia. The process includes four steps: forward translation, expert panel back-translation, pre-testing and cognitive interviewing, and final version and documentation (World Health Organization, 2016). This process aimed to get final language versions of the Indonesia instrument and conceptually equivalent for each target country or culture. The Bahasa version of WAI-SRT was subject to a content test (content validity) by a mental health nursing expert (Head of Department of Mental Health Nursing Universitas Padjadjaran Indonesia). The Cronbach’s alpha in the current study was 0.947. Data Collection The data were collected using questionnaires containing items organized on the basis of variable indicators, which were distributed to the respondents to receive their responses to each item. The steps and the procedure must be compatible with the research questions. The approach used in this study involved the completion of questionnaires on experiences of sensitivity to violence and loyalty to the alliance. These tools took about five to ten minutes to complete. After completing the questionnaires, the participants could return them, and the researchers reviewed their completeness. Data Analysis The descriptive analysis and inferential statistics were performed where appropriate. The results or normality testing showed that working alliance was normally distributed based on the nonsignificant Kolmogorov–Smirnov test. The standard deviation (SD) of the mean was added for continuous data, while frequency and percentage were used for categorical variables. ANOVA and post hoc analysis with Turkey’s test adjustments were done to determine differences between demographic characteristics with overall and domain scores of working alliances. A confidence interval of 95 % was used. The p-value of less than 0.05 was considered significant. The data were recorded and analyzed using SPSS version 20. Ethical Consideration Ethical approval from the ethical committees of mental health hospitals in West Java was obtained prior to data collection (Approval number: 2399/UN6.L/LT/2016). Subsequently, the researcher requested data on nurses working in the hospital under review and told the head nurse of the qualifying requirements. Before completing the questionnaires, the detailed consent form was given to the nurses. Results The total number of respondents was 120 psychiatric nurses from mental hospitals in West Java Province, Indonesia. The majority of the respondents were female (77.5%) and holding a diploma III degree in nursing (49.17%). A few of them were master’s graduates (10%), and the working experience duration ranged from 11 to 15 years (34.17%). Nurses were working more in the chronic rooms (32.5%) (Table 1). Table 1 Socio-demographic of nurses by the level of working alliance (N = 120) Socio-Demographic Working Alliance Low (n = 55) High (n = 65) Gender  Male 12 (44.4) 15 (55.6)  Female 43 (46.2) 50 (53.8) Education Level  Diploma III 46 (78.0) 13 (22.0)  Bachelor 8 (16.3) 41 (83.7)  Master degree with Specialist 1 (8.3) 11 (91.7) Working Duration, Mean ±SD 15.56± 7.65 18.43± 8.73  Less than ten years 16 (61.5) 10 (38.5)  11-15 years 22 (53.7) 19 (46.3)  16-20 years 15 (46.9) 17 (53.1)  More than 20 years 2 (9.5) 19 (90.5) Working Unit  Polyclinic 4 (66.6) 2 (33.3)  Acute Room 13 (37.1) 22 (62.9)  Chronic Room 20 (51.3) 19 (48.7)  Emergency Room 12 (66.7) 6 (33.3)  Drug Addiction 4 (44.4) 5 (55.6)  Administration 2 (15.4) 11 (84.6) The mean score of the working alliance was 44.46 (SD = 11.32), with a minimum score was 30, and the maximum score was 50. For each subscale, agreement on goals had a higher, with a mean of 17.65 (SD=3.45), followed by task (16.56 ± 5.81) and bond (22.10 ± 7.23) (Table 2). Table 2 Detail Exploration of working alliance among mental health nurses in Indonesia (N = 120) Domain Mean ± SD Range Overall score 44.46 ± 11.32 30 – 50 Goal 17.65 ± 3.45 8 – 20 Task 16.56 ± 5.81 8 – 20 Bond 22.10 ± 7.23 15 – 25 Table 3 shows differences between socio-demographic characteristics with overall score and domain scores of working alliances. Findings showed a significant difference in the overall score of the working alliance and all subscales, including goal, task, and bond domains, according to the educational level (p < 0.05). Nurses with bachelor level had working alliance than those with master and diploma. In addition, there was a significant difference in working alliance according to working duration (p < 0. 05), in which nurses who worked 11 to 15 years had higher working alliance than those who worked for more than 16 years or less than ten years. There was no significant difference in working alliance according to gender and working division. Table 3 Differences in working alliance of mental health nurses by socio-demographic characteristics (N = 120) Overall Score Mean ± SD t/F (p-value) Goal Score Mean ± SD t/F (p-value) Task Score Mean ± SD t/F (p-value) Bond Score Mean ± SD t/F (p-value) Gender a 1.19 (0.281) 2.47 (0.410) 1.85 (0.535) 1.36 (0.120)  Male 43.91 ± 10.35 17.32 ± 3.84 16.73 ± 5.23 22.74 ± 7.23  Female 44.31 ± 09.42 18.57 ± 4.72 16.04 ± 5.81 23.12 ± 7.23 Education Level 5.32 (0.007) 4.49 (0.041) 4.12 (0.021) 3.79 (0.03)  Diploma III 42.21 ± 11.71 17.62 ± 3.84 14.61 ± 4.63 20.56 ± 5.76  Bachelor 46.82 ± 12.32b 19.04 ± 4.72b 17.24 ± 6.47b 25.78 ± 6.92b  Master degree with Specialist 43.16 ± 11.58 18.42 ± 4.72 15.11 ± 5.04 23.05 ± 7.35 Working Duration 5.49 (0.021) 5.63 (0.013) 5.58 (0.01) 6.18 (0.001)  Less than ten years 41.56 ± 11.71 16.91 ± 6.84 14.73 ± 6.53 20.56 ± 5.76  11-15 years 47.34 ± 12.32b 19.04 ± 7.49b 16.56 ± 7.90b 25.78 ± 6.92b  >16 years 45.78 ± 11.58 17.35 ± 5.31 14.53 ± 6.64 23.05 ± 7.35 Working Unit 1.98 (0.613) 2.01 (0.549) 1.73 (0.549) 1.76 (0.425)  Polyclinic 43.31 ± 11.75 16.56 ± 6.13 16.73 ± 5.23 23.60 ± 5.25  Acute Room 44.56 ± 10.32 18.53 ± 4.32 16.04 ± 5.81 22.71 ± 6.62  Chronic Room 43.71 ± 12.05 17.38 ± 5.47 16.04 ± 5.81 23.18 ± 7.14  Others 44.32 ± 11.42 17.45 ± 4.42 16.04 ± 5.81 24.73 ± 6.95 Note: astatistics test using independent t-test | bresults from post hoc with Turkey’s test Discussion This study found that the majority of nurses working at mental health hospital has a good working alliance. The importance of the partnership between nurses and patients with mental illness is becoming an important topic (Thurston, 2003). However, conflicting opinions and different conclusions have been stated by Rise and Steinsbekk (2015) that the relationship between patients and nurses reported no significant effects on patients outcome. This is because the workload of psychiatric nurses is very high, and the treatment of mentally ill patients varies in the general hospital (Khalaila & Cohen, 2016; Suro & Weisman De Mamani, 2013). On the contrary, Roche and Duffield (2010) found that, compared to nurses in general settings, nurses in mental health hospitals had scored higher in nurse-patient relationships, although the burden for engaging with patients was very high. Therefore, it is vital to establish the importance of the alliance between nurses and patients since the alliance has been confirmed to reduce the high burden of psychiatric nurses associated with complete patient dependency on nurses (Suro & Weisman De Mamani, 2013). There was a significant difference between education level and working alliance. The lower the education level, the lower the working alliance would be. Furthermore, with regard to the partnership in psychiatric hospitals, the standard of education is becoming an important cause. First, the mental hospital nurses’ alliance allows the nurses to develop interpersonal relationships with the clients, primarily to interact with individuals who are depressed, withdraw from others, commit suicide, attack, and behave aggressively (Del Piccolo & Goss, 2012). Second, there is a condition that is utterly uncertain for nurses, such as cooperating with patients when they are unexpectedly threatened by hearing a voice or hallucination (Jacob & Holmes, 2011). Another trait is the involvement of patients with aggressive behavior, which is likely to occur towards nurses. This situation involves a specific competence, in particular through education and training. Another view is that nurses are trained to face the various characteristics of mentally ill patients. Regardless of how difficult the experience is, it will continue to be professional (Trenoweth, 2003). The study concludes that nursing professionals have the expertise and the ability to assess patient abuse easily and intuitively. Caregivers can minimize the risk of abuse by being able to recognize circumstances and work as a team. Happell et al. (2003) show that nurses appear to leave or resign after abuse from the hospital. Furthermore, nurses in the acute room have been reported to be suffering from distress; they dispute with their families and want to leave their jobs (Daneault et al., 2006). In reality, trauma and violence exposures can adversely impact nurses and even hinder patient involvement. To cope with the burden, specific training and education in psychiatric hospitals are very important. The pressure is a concern not only at home for the family but also at the psychiatric institution for nurses (Ennis & Bunting, 2013). It leads to a rise in occupational distress for nurses (Khalaila & Cohen, 2016). That’s because the distinction is that patients with emotional and mental wellbeing suffer from a lack of productivity and capacity to help. This can be justified by the argument. This is exacerbated by the unique state of the mentally ill patient, such as hallucination, depression, self-isolation, suspicion, and risk to himself and the environment. In short, it can be said that a high level of education to promote a nurse’s alliance with the patient would reduce the strain on the nurse (Happell et al., 2003). Limitations of this study might include the low number of samples. Ideally, to generalize the findings and represent the national study, the samples should include all mental hospitals in all Indonesian provinces. Conclusion Our study revealed that the working alliance of mental health nurses in Indonesia was good, including the domains of agreement on goals, tasks, and bonds. The nurses with higher education and more ample working experience showed higher working alliances. Therefore, it is suggested to hospital policymakers and nurse managers to provide Continues Nursing Education (CNE), working alliance training, and therapeutic strategies for nurses, especially in unpredictable situations. It is also essential to cooperate with nursing schools to include working alliances as learning objectives. Acknowledgment The authors would like to acknowledge the support given by Padjadjaran University, and the authors also would like to thank all participants. Declaration of Conflicting Interest The authors declare no conflict of interest in this study. Funding This study was fully funded by Padjadjaran University, Indonesia. Authors’ Contribution IY and HS contributed equally to the conception and study design, data collection, data analysis, data interpretation, drafted and revised the manuscript. LL contributed to data collection, data analysis and interpretation, and critically drafted and revised the article. All authors agreed with the final version of the article. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Authors’ Biographies Iyus Yosep, S.Kp., M.Si., M.Sc, PhD is an Associate Professor at the Mental Health Department of the Faculty of Nursing, Padjadjaran University, Indonesia. Henny Suzana Mediani, S.Kp., M.Ng., PhD is an Associate Professor at the Pediatric Nursing Department of the Faculty of Nursing, Padjadjaran University, Indonesia. Linlin Lindayani, S.Kep., Ners., MSN, PhD is an Assistant Professor at the Medical Surgical Nursing Department of the Sekolah Tinggi Imu Keperawatan PPNI Jawa Barat, Indonesia. ==== Refs References Bordin, E. S. (1994). Theory and research on the therapeutic working alliance: New directions. In A. O. Horvath & L. S. Greenberg (Eds.), Wiley series on personality processes. The working alliance: Theory, research, and practice (pp. 13-37). New Jersey: John Wiley & Sons. Daneault, S., Lussier, V., Mongeau, S., Hudon, E., Paillé, P., Dion, D., & Yelle, L. (2006). Primum non nocere: Could the health care system contribute to suffering? 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-163 10.33546/bnj.1456 Theory and Concept Development The development of Spiritual Nursing Care Theory using deductive axiomatic approach https://orcid.org/0000-0002-8228-9930 Bangcola Ashley A. * Mindanao State University – Marawi City, Philippines Corresponding author: Dr. Ashley A. Bangcola, RN, MAN, DScN, Mindanao State University – Marawi City, Block. 446 Zone 10 Purok 24 Brgy, Maria Christina Iligan City, Philippines 9200. Mobile: +639-177-101-258. Email: ashley.bangcola@msumain.edu.ph Cite this article as: Bangcola, A. A. (2021). The development of Spiritual Nursing Care Theory using deductive axiomatic approach. Belitung Nursing Journal, 7(3), 163-170. https://doi.org/10.33546/bnj.1456 28 6 2021 2021 7 3 163170 20 3 2021 30 4 2021 21 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. The concepts of spirituality and spiritual well-being are not novel ideas as they have been subjects of scrutiny in several studies. However, there has yet to be a formalized framework of spiritual nursing in the Philippines despite its importance. Developing such a framework is significant, especially since holistic nursing believes in the relationships among body, mind, and spirit. Thus, the Spiritual Nursing Care theory was conceptualized, which states that every person has holistic needs, including spiritual needs that must be satisfied to attain spiritual well-being. It forwards that for the patient’s spiritual needs to be met, what is required is the triumvirate interconnection among the nurse, the external environment, and the spiritual nursing care which may be provided by the nurse as a healthcare provider and the significant others or family as part of the external environment. The theory has two propositions that were subjected to validation studies that either strengthened or repudiated the propositions presented: (1) the meaning of spirituality differs from person to person, and (2) the patient’s spiritual well-being is influenced by the nurse’s spiritual care competence, as well as the patient’s internal and external variables. Spiritual Nursing Care Theory spirituality holistic nursing health personnel Philippines ==== Body pmcSpirituality is an evolving concept that has significance in relation to bodily health. It is also considered an aspect of health. Gone are the days when spirituality was limited to the esoteric; it has now been deemed to have practical applications, such as in nursing care. There is extensive literature about the connection between spirituality and its influence on health and well-being (Puchalski, 2001; Koenig & Cohen, 2002; Chaves & Gil, 2015; Ebrahimi et al., 2017). Furthermore, strong spirituality has been linked to resilience (Koenig, 2012). Thus, it would be remiss not to incorporate the spiritual component in the practice of nursing care, which considers the holistic care of the person to be its goal. Yousefi and Abedi (2011), in their study, posit that real and complete healthcare can only be possible through sensitivity to the patient’s spiritual needs. The concept of spirituality has gained increasing interest from researchers. Although it has significance in the healthcare profession in general, the spiritual component is still most often associated with nursing care (Timmins & McSherry, 2012). History would show that even in the past or ancient forms of nursing, patient care was always holistic, including both spiritual and religious care. This may be because caring is an important component of nursing practice. Although some measure of care is to be expected in other forms of healthcare, it can be said that in nursing, the nurse takes a more active and invested role in their patient’s well-being as their task is not just to diagnose or dispense, but to provide holistic care. This is also an important factor to consider as to the rationale of developing a Spiritual Nursing Care Theory. Spiritual care is compatible with nursing care as patient care is more than just the medical aspect of nursing. The nurse has to meet not just the medical needs of the patient but all aspects which deal with the patient’s well-being. Not only is it demanded from nurses by nature of their profession, but studies would show that they are also well-suited for the task. In a study that compared how doctors and nurses provided emotional care, it was found that the respondent doctors would reassure their patients by continuing clinical care and explaining the curative nature of the treatment. Furthermore, they believed that they could not reassure patients if they discussed the latter’s fear with them. In contrast, nurses relied on psychological and social skills, often being open and discussing patients’ concerns with them, this being their way of providing reassurance and emotional support (Forsey et al., 2013). Furthermore, the majority of the international literature and studies have supported the increasing importance of spiritual care and recognize it as an important component of nursing care that is well-rounded and holistic (Koenig, 2012; Chaves & Gil, 2015; Ebrahimi et al., 2017). The concepts of spirituality, spiritual needs, and spiritual well-being have also been discussed and defined in various studies. Fisher defines spirituality as a “personal quest for understanding answers to ultimate questions about life, about the meaning and about relationships that are sacred or transcendent” (Fisher, 2011). Meanwhile, according to a study by Guerrero-Castaneda and Flores (2017) on spiritual nursing care as perceived by older persons, older people make use of spirituality and religiosity to find a sense of life amidst all of the radically developing circumstances brought about by advancing age. (Narayanasamy et al., 2004) identified specific spiritual needs of older persons, including religious beliefs and practices, absolution, seeking connectedness and comfort, and healing or looking for meaning and purpose. Spiritual Well-Being was defined as the “ability to experience and integrate meaning and purpose in life through a person's connectedness with self, others, their environment, or a power greater than oneself and the totality of circumstances that would lead a person to say that his life is going well” (Fisher, 2011). It can thus be inferred that studies generally agree that spirituality is a state of being of a person; however, there is still an evident lack of consistency in the definition of spirituality (Timmins et al., 2015). In addition, while there have been studies conducted to investigate the spiritual needs of aged persons in residential homes and those at the end of life stage in intensive care units (Erichsen & Büssing, 2013), there is unexplored potential in studying their spiritual well-being. According to the National Health Service Scotland (2009), all healthcare staff, caregivers, and families could provide spiritual care. However, there is also a significant lack of literature concerning the three-way relationship between the nurse, the patient, and his or her family as current studies on spiritual nursing care tend to be general and broad. In light of all of these, there seems to be a great need to address these huge gaps in nursing literature related to Spiritual Nursing Care. For these reasons, the researcher wanted to develop a Spiritual Nursing Care Theory. In this study, the author wanted to explore another perspective that considers the interconnection of the healthcare provider, specifically the nurse, the family, and the patient himself or herself. There has yet to be a formalized framework of Spiritual Nursing Care in the Philippines despite its importance. Developing such a framework is significant because compared to traditional forms of healthcare which make use of equipment and facilities that may not be available, spiritual nursing care requires only the competency of the healthcare provider, specifically the nurse, in giving spiritual care. As of now, spiritual needs are considered only a small component of the holistic needs of a person. However, the author argues that the concepts of spirituality, spiritual needs, and spiritual well-being, which have been studied in previous literature, can all be interconnected in one formal theoretical framework. One way of understanding spirituality is the perception of a person on the importance of or how strong his or her spiritual practices or beliefs make up a part of his life. Spiritual needs are specific needs that must be addressed by the healthcare provider, in this case, the nurse, so that the patient can attain meaningful well-being, or be more specific, spiritual well-being. When spiritual needs are satisfactorily addressed, spiritual well-being is achieved and contributes to holistic health care. The author posits that spiritual well-being is as important as physical, emotional, and mental health, which deserves due consideration. This paper was meant to explore the patient’s understanding and perception of the concept of spirituality, the influence of the cultural elements of the patient’s external environment on the practice of spiritual nursing care, as well as the competencies of the nurse in providing spiritual care, and its link to attaining spiritual well-being for the patient. The eventual aim of this paper was to develop a comprehensive, holistic, and spiritually inclusive nursing care framework, which values the importance of each stakeholder. This paper can be of help to patients, the family, nursing practitioners, scholars, learners, and curriculum planners who may decide to incorporate spiritual nursing care as a part of the curriculum and the nursing profession as a whole. It would serve to add to the minimal knowledge of spiritual nursing care within the Philippine context. Methods The theory proposed in this paper on spiritual nursing care was conceptualized through the deductive form of reasoning. Deductive reasoning is the systematic and logical process whereby a conclusion is reached based on the concurrence of multiple premises that are generally assumed to be true (Sternberg, 2009). According to Creswell and Plano Clark (2007), utilizing deductive reasoning by the researcher would involve the researcher working from the ‘top down’ starting with a theory to hypothesis and then to data to add to or contradict the theory. The deductive method is used to construct a deductive axiomatic system or theory. The essence of an axiomatic approach as used in the field of logic and mathematics is that a group of statements, called propositions, are derived through the use of deductive logic applied to another more fundamental set of statements serving as basic assumptions, also known as axioms. Axioms represent the foundation statements in a deductive system. Meanwhile, a concept is defined as representing views or descriptions of some aspect of the real world. A concept of something is not the same as the thing itself (Lambert, 1973). Finally, a theory is a set of logically related statements, including some law-like basic assumptions having testable implications, are an explanation and description of some concept. All theories are deductive systems. Kerlinger (1973) defines a theory as a set of interrelated constructs or concepts, propositions, as well as a systemic view of phenomena through specifying relations among variables with the objective of explaining and predicting such phenomena. Theories are those which knit together observations (Thompson, 2005). The Spiritual Nursing Care Theory was developed following a deductive axiomatic approach. Within the framework of nursing theories and models, the author also used an empirical quantitative approach in her theory generation (Jacox, 1974) in developing the Spiritual Nursing Care Theory. The researcher identified the phenomena that she wanted to investigate within her field of study, specified, then classified concepts used when describing these phenomena. A broad topic in the field of nursing was chosen, specifically in gerontology, which was of interest to the researcher and which had the potential for further study. The topic chosen was the role of spirituality in nursing care. The next step was to research and gather related literature on the selected topic. The researcher then developed propositions on how two or more concepts are related. To elaborate, by identifying patterns among the studies made by prominent scholars in the field, the researcher was able to single out statements that were generally accepted to be true (axioms) to serve as a starting point for deducing and inferring other truths which would be the building blocks of the theory (propositions). The researcher then linked propositions to each other in a systematic way to come up with the theory. Walker and Avant (1995) identified four levels of nursing theories, which include practice theories, mid-range theories, grand theory, and metatheory. The term ‘grand theory’ is an alternative term to ‘model’. In contrast to grand theories, which do not easily find an application and are furthermore broad and abstract, mid-range theories are more restricted in their focus. Mid-range theories are also abstract, but only moderately so. Moreover, they are composed of measurable variables. The Spiritual Nursing Care Theory developed is an example of a mid-range theory that specifies how the propositions, and the concepts of spirituality, spiritual needs, spiritual well-being, and spiritual nursing care are related to each other, but which propositions remain measurable. The Spiritual Nursing Care Theory may also easily be applied in actual nursing practice. The related literature in the succeeding discussion was gathered to formulate the premises to base the more specific propositions, which made up the foundation of the proposed theory on Spiritual Nursing Care. Results and Discussion Five axioms were generated after thoroughly reviewing the literature and studies and were used as a basis for generating the two propositions, which served as the framework for the development of the Spiritual Nursing Care Theory. The connection between spirituality and health has been the subject of study since time immemorial. In the past, and even until now, the caring for the body and the spirit was done by the same person acting as both therapist or counselor and religious leader (Fradelos et al., 2014). Spirituality is linked to the human spirit and is an important component of human existence (McKee & Chappel, 1992). Many people consider their spirituality and religion as a crucial part of their existence. Spirituality also serves as a source of support and contributes to people’s well-being, and helps them cope with everyday struggles (Purdy & Dupey, 2005). Health professionals also recognize the part spirituality plays in healthcare (Monareng, 2012). Monareng, in her study, goes on to state that it is the holistic perspective on human functioning and in nursing which demands that nurses take into account aspects of spirituality when they provide nursing care (Monareng, 2012). Studies exploring spirituality from a holistic approach revealed that patients use religious or spiritual beliefs and practices to cope with suffering such as illness and stress (Koenig, 2012). One of the findings from Koenig (2012) was that religious people tend to spend less time in the hospital. He then claims in his study that healthcare providers, including nurses, have an obligation to the patient to include the patient’s religious beliefs in their care and incorporate their faith (spirituality) in promoting healing. The nature of nursing is to care, and thus it would make sense for nurses to have a more direct hand in attending to the spiritual needs of patients. Various studies also show that people who are more spiritual have better adaptive capabilities. They tend to adapt more quickly to health complications compared to their counterparts, who are less spiritual (Strandberg et al., 2007). Levin et al. (1996) meanwhile explored connections between spiritual beliefs and practices and health. His findings are corroborated by studies that revealed the many ways spirituality can prevent illness and promote well-being, such as by positively impacting physical health, lessening the risk of disease, and influencing responsiveness to treatment (Baker et al., 2015). Holistic approaches in healthcare take into consideration all aspects of the individual, and his or her needs, including mental, social, and spiritual needs. Research regarding spirituality suggests that meeting patients’ spiritual needs has a positive contribution to their adaptation to illness and improving rehabilitation (Levin et al., 1996). Based on the literature mentioned above (Purdy & Dupey, 2005; Strandberg et al., 2007; Koenig, 2012; Baker et al., 2015), it can be said that every person has holistic needs, which may include spiritual needs (Axiom 1). As people grow older, some tend to contemplate more on matters of mortality and spirituality (Axiom 2). Researchers posit that the natural process of aging comes with it the consciousness that life will eventually end. This creates a context where older adults are more accepting of deepening their understanding of their mind, body, or spirit (Atchley, 1999). Spirituality is a complex and abstract subject with many perspectives. It is something that touches all people in different degrees. By sex, various studies have suggested that females are more spiritual than males. The same study revealed that people with higher educational attainment tend to be less spiritual than those who finished lower levels. Furthermore, this same study demonstrated that spirituality decreases as income levels increase. As for health status, some studies indicate that religiosity or spirituality appears to positively correlate with physical health (Ellison & Levin, 1998). While patients and their families have different understandings and degrees of spirituality, individual nurses also have different levels of spirituality. Nurses are primarily trained in the physical and nursing care of the patient; however, their levels of spirituality can also impinge positively on their care of the older person. Other studies have also shown how providing spiritual care is influenced by multiple factors, including the spirituality of the healthcare provider and their understanding of the spiritual practices of the patients (Schleder et al., 2013). A study by Kisvetrová et al. (2013) found that nurses living in a predominantly secular country would tend to see themselves as non‐religious and, as a consequence, therefore, believe that providing spiritual/religious care was not something they were likely to do. Thus, what the literature would show is that nurses are indeed aware of the concept of spiritual care or spiritual nursing; however, they may differ in their interpretation and how they administer such care because of their differing understandings of spirituality. Therefore, it helps to understand that people have different understanding and levels of spirituality (Axiom 3). Internal and external environment contributes to a person’s spirituality (Axiom 4). People can find meaning in life in different ways and through different avenues (Eckersley, 2005). People would often have many things which are important to them, such as their family, friends, career, hobbies, interests, and desires. All of these are avenues through which people can find meaning in life. People can also find spirituality in their connection with their nation or ethnic group since spirituality is one of the deepest forms of interconnection. There is a link between interconnectedness and physical well-being. For example, it was found that socially isolated people five times likelier to die compared to those who have strong ties with their family, friends, and or community (Berkman & Glass, 2000). In addition, empirical studies would show that health cannot be reduced to just an organic and natural objective process, but rather is connected to the experiences of individuals and groups, which are in turn related to the cultural characteristics of a society (Minayo, 2006). The literature affirms that healthcare practices vary depending on a person’s culture and that culture is the basis for their explanations for their suffering and illness, their search for meaning in these occurrences, treatment choices, and life reevaluation (Mello & Oliveira, 2013). In 1996, the World Health Organization (WHO), as well as the United Nations Educational, Scientific and Cultural Organization (UNESCO), recognized the importance and significance of cultural aspects in international health (Mello & Oliveira, 2013). The two international organizations stated that health care, which includes nursing care, and culture should be approached in a way that integrates the two from the perspective of benefiting individuals and countries (Mello & Oliveira, 2013). Based on the above literature, it can be seen how the internal and external environment of a person, both his socio-cultural and physical environment, can influence his spirituality. Holistic nursing care includes spiritual care (Axiom 5). Taylor (2002), as cited in Monareng (2012), defines ‘spiritual nursing care’ as those activities that facilitate and provide for a healthy balance between the bio-psychosocial and spiritual aspects of the person, and thus contributing to a sense of wholeness and overall well-being. To adequately address the concerns of their older patients, nurses must be knowledgeable of their patient’s spiritual needs, meet these needs and contribute to maintaining their patient’s positive spirituality. The concept of spirituality has gained researchers’ interest in recent years. Although spirituality is present in general healthcare literature, the spiritual component of healthcare is still mostly associated with nursing care (Timmins & McSherry, 2012). Even in the oldest forms of nursing, patient care was said to be holistic and included spiritual and religious care as well. During the Byzantine era, the patients in the hospitals received physical and spiritual care (Papathanasiou et al., 2013). In addition, theories of nursing recommend a holistic model for healthcare. It has already been substantiated that patient care cannot be and should not be one-dimensional but should be holistic and composed of all aspects such as the biological, psychological, social, and spiritual dimensions (Papathanasiou et al., 2013). Florence Nightingale, who can be said to be the founder of modern nursing, introduced important elements necessary for the healing process. Some examples included the environment, touch, light, scents, music, silent reflection, and even birds. Each of those elements helped the patient connect with others, with nature, and with the divine (Nightingale, 1860). Holistic care may be defined as a comprehensive model of caring and is the heart of nursing (Strandberg et al., 2007; Albaqawi et al., 2021). Holistic care is built upon the principle of holism which puts forward the idea that for people, the whole is greater than the sum of its parts. In addition, mind and spirit both affect the body (Tjale & Bruce, 2007). Holistic care then is that care that recognizes that the patient is a whole. Furthermore, it acknowledges that there is interdependence and interconnection between and among the patient’s biological, social, psychological, and spiritual dimensions. Holistic care, being a comprehensive model of caring, includes the following components – education, self-help, medication, complementary treatment, and communication (Morgan & Yoder, 2012). Holistic care is also applied in nursing. In the context of holistic nursing, the patient’s attitude, opinions, emotions, thoughts, and even culture and spiritual beliefs and practices are factored in the care plan and are considered essential to the recovery, happiness, satisfaction, and well-being of the patient (Selimen & Andsoy, 2011). From the axioms generated, the following ideas were put forward as propositions to form the backbone of the theory on Spiritual Nursing Care. The first proposition posited states that the meaning of spirituality differs from person to person (Proposition 1). The second proposition posited is that the patient’s spiritual well-being is influenced by the nurse’s spiritual competence as well as the patient’s internal and external variables (Proposition 2). Spiritual Nursing Care Theory The theory being proposed in this paper on Spiritual Nursing Care states that every person has holistic needs, which may include spiritual needs that must be satisfied for the person to attain spiritual well-being. The theory forwards that in order to achieve spiritual well-being and for the person’s spiritual needs to be satisfied, what is required is the triumvirate interconnection among the nurse, the external environment, and the spiritual nursing care which may be provided by the nurse as the healthcare provider and the significant others or family as part of the external environment. The Spiritual Nursing Care theory claims that spiritual needs are part and parcel of the totality of needs of the patient; it is not lesser than any other need. They should be considered and dealt with holistically and accorded great weight. The theory postulates that satisfaction of spiritual needs contributes to the overall well-being, as it may contribute to the improvement of the physical and emotional well-being of the patient (Bangcola, 2019). Thus, it is assumed that people who find themselves spiritually satisfied would have a more positive attitude towards healing, both emotionally and physically, and are therefore more responsive to healthcare interventions. The schematic diagram of the theoretical framework for this study was based on the work of the author, the Spiritual Nursing Care theory, which proposed that holistic care for patients is composed of three interlocking factors that contribute to the satisfaction of the patient’s spiritual needs to attain spiritual well-being: the external environment which includes the nurse as the healthcare provider, and which necessitates that he or she must have enough spiritual competency to provide spiritual nursing care; the culture of the patient’s family or significant others; and at the center is the spiritual nursing care itself. Figure 1 illustrates the Spiritual Nursing Care Framework, which involves the tripartite relationship between the nurse as the healthcare provider, the family as providers of support, and the patient having spiritual needs. Figure 1 Spiritual Nursing Care Framework The theoretical framework is composed of four components: (1) spiritual nursing care, (2) the nurse’s spiritual competency, (3) the cultural background of the patient, both as part of the external environment, and (4) the patient’s spiritual needs. The Spiritual Nursing Care theory proposes that patients have spiritual needs as part of their holistic needs. When these needs are satisfied, they will have a more positive attitude towards healing and thus are more responsive to healthcare interventions which may be manifested in their satisfaction with the spiritual nursing care provided by the nurse. The trust between the nurse and the patient will help in the nursing aspect by creating an atmosphere of rapport between the nurse and the patient, thereby making the patient support the decisions of the nurse when it comes to the spiritual aspects of nursing care. As illustrated in the above schematic diagram, there must be trust between the nurse and the family members of the patient also because they both act as a healthcare provider and support system for the patient. Furthermore, there must be trust since the nurse is expected to provide spiritual nursing care, which must be sensitive to the patient’s needs and the cultural background of the patient’s family. This, in turn, will help make the patient’s family trust that the spiritual nursing care provided by the nurse will redound to the benefit of the patient. On the part of the nurse, as a healthcare provider, he or she must have spiritual competency in order to address the spiritual needs of his or her patient adequately. Competence refers to a set of traits and characteristics which form the basis for optimal performance. In other words, spiritual competency then is that defined set of attitudes, knowledge, and skills in the domains of spirituality that every nurse should have to effectively and ethically practice nursing, regardless of whether or not they consider themselves spiritual or religious. There must be congruence between the nurse’s spiritual competency and the spiritual nursing care to be provided in order to satisfy the patient’s spiritual needs. As defined in nursing, culturally congruent practice is that application of evidence-based nursing, which is in line with the preferred cultural values and practices, beliefs, and worldview of patients (Marion et al., 2016). Therefore, the spiritually congruent practice would be nursing which is sensitive to the preferred spiritual or religious beliefs of the patient and his or her significant others. Meanwhile, spiritual competence is the process wherein nurses demonstrate congruent spiritual practice. In other words, the nurse needs to be spiritually competent in providing spiritual nursing care that is congruent with the patient’s spiritual needs. In whatever healthcare setting, the nurse is likely to have patients with culturally diverse beliefs and practices concerning their own health, wellness, and illnesses. This is where the interaction between the nurse and the external environment (socio-cultural) would also be essential. Not only must the nurse provide culturally sensitive spiritual nursing care, he or she must also provide spiritually congruent nursing care. There may be instances where the personal belief system of a nurse may not match those of his or her patient. In this instance, there may be a conundrum since the nurse may have difficulty relating to his or her patient, which in turn may hinder the nurse from providing adequate spiritual care. Hence, it is necessary for the nurse to interact with the external environment of the patient or his family to be more specific. This is because, in the family setting, most persons develop and form their values and belief systems as influenced by their socio-cultural background. Meanwhile, the family members may not be expected to have the same spiritual competence as the nurse as they are already in a unique position of being the primary and fundamental emotional support of the patient. What is required is that they be sensitive to the spiritual needs of the patient and assist them as much as they are able. They should also assist the nurse in understanding how best to satisfy the spiritual needs of the patient and handle any confusion the nurse may have as to specific cultural and religious practices, as the family members are likely to come from the same socio-cultural environment as the patient. It is only with the nurse’s spiritual care competence that is congruent with the nursing care provided and is sensitive to the cultural background of the patient’s family, which would complete the holistic spiritual nursing care provided to the patient. It is through this three-way symbiotic relationship that holistic spiritual nursing care may be perfected. If the nurse is able to provide optimum physical, pharmacological and spiritual assistance to the patient and the family environment delivers spiritual guidance, then the patient can attain positive health status within his given physical illness or bodily condition. Conclusion The essence of spiritual nursing care is the understanding that spirituality can mean different things to different people, especially considering the physical and socio-cultural environment. The Spiritual Nursing Care theoretical framework involves three groups: the patient, the nurse, and the family or significant others as part of the external environment. It is also composed of three components: the nurse’s spiritual care competence, the cultural elements of the external environment, and the spiritual nursing care, the intersection of which directly influence the satisfaction of the patient’s spiritual needs. The higher the spirituality or how much the patient believes himself to be faithful, the higher the impact the corresponding faithfulness of his significant others would impact him. In providing holistic nursing care that includes spiritual care, there must be congruence between the nurse’s spiritual competency as well as the spiritual nursing care provided to meet patients’ spiritual needs. In other words, the spirituality inclusive nursing care provided would be the practical application of the nurse’s spiritual competency, the former’s effectiveness in meeting the patient’s spiritual needs to attain spiritual well-being, being directly influenced by how competent the nurse may be. Acknowledgment I would like to acknowledge Ashyanna Alexine Bangcola for her valuable input and advice, without which I could not have completed this manuscript. Declaration of Conflicting Interest The author declares no conflict of interest in this study. Funding This research received no specific grant from any funding agency in the public, commercial, or non-profit sectors. Author Biography Dr. Ashley Ali Bangcola is a holder of a Doctor of Science in Nursing degree major in Gerontology Nursing from the Cebu Normal University in the Philippines. She graduated with a Master of Arts in Nursing major in Nursing Administration from the Mindanao State University in 2011. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-159 10.33546/bnj.2481 Original Research Retaining employment in the hospital setting: A descriptive phenomenological study of Indonesian nurses’ experiences https://orcid.org/0000-0002-3174-5932 Wardhani Utari Christya * https://orcid.org/0000-0003-4496-4795 Hariyati Rr. Tutik Sri Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia * Corresponding author: Ns. Utari Christya Wardhani, S.Kep., M.Kep, Faculty of Nursing, Universitas Indonesia Jl. Prof. Dr. Bahder Djohan, Kampus UI Depok, West Java 16424, Indonesia. Email: wardhaniutari@gmail.com Cite this article as: Wardhani, U. C., & Hariyati, R. T. S. (2023). Retaining employment in the hospital setting: A descriptive phenomenological study of Indonesian nurses’ experiences. Belitung Nursing Journal, 9(2), 159-164. https://doi.org/10.33546/bnj.2481 18 4 2023 2023 9 2 159164 08 12 2022 04 1 2023 05 3 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Losing competent nurses due to turnover can have adverse effects on healthcare administration, service delivery, and organizational dynamics. Frequent staff turnover can hinder optimal nursing practices, but some nurses remain committed. Therefore, understanding factors that foster sustained engagement and retention is crucial to create a retention strategy. Objective This study aimed to explore the current experience of Indonesian nurses who retain their jobs in the hospital setting. Methods A phenomenological design was employed in this study, with ten nurses selected using purposive sampling. Semi-structured interviews were used to gather data from a private hospital in Batam, Indonesia, between January and March 2022. A conventional content analysis was used to analyze the data. Results The participants had an average total work experience of 10.4 years and an average age of 35.6 years, ranging from 28 to 44 years. The majority of the participants were females, held bachelor’s degrees, and were married. Three main themes were developed in this study: solid teamwork, adequate compensation, and professional career development. Conclusion Retaining experienced nurses in hospitals is influenced by antecedents such as teamwork, pay, and career growth. These findings offer nursing and hospital managers insights into developing policies and strategies to improve hospital nursing retention programs in Indonesia and beyond. personnel turnover employment retention intent to stay nurses hospital Indonesia intent to leave ==== Body pmcBackground Retention and intention to stay or leave a job are commonly used to evaluate employment outcomes in the nursing industry, and one concept that falls under this category is turnover. Retention is defined as a nurse remaining in their position, including registered nurses who leave their current role but continue working for the same organization in a different capacity (Lee & Jang, 2020). Nurses comprise 60% of the world’s healthcare workforce and are responsible for providing around 90% of essential healthcare services, making them the largest group of healthcare workers worldwide (World Health Organization, 2020). However, recent research on nurse staffing trends suggests this is no longer the case (Seitovirta et al., 2017). The issue of how to retain nurses is still subject to debate, but the prevailing notion is that having enough nurses on staff will enhance patient safety and, consequently, increase nurse retention. Turnover can have negative effects on hospital organizations. This phenomenon has had a detrimental impact on the financing of human resources, as hospitals may lose competent employees, leading to disruptions in organizational, service delivery, and administrative functions (Labrague et al., 2020). For example, the turnover of nurses may require the employment of more trained and skilled nurses in their respective fields (Al Sabei et al., 2020; Labrague et al., 2018). Moreover, turnover can increase the financial costs of recruitment fees, overtime, and training programs for new employees. High turnover rates within organizational management can result in compromised patient safety, leading to serious medical errors, adverse patient incidents, mistakes, and poor quality of patient care (Belton, 2018; Hu et al., 2022). On the other hand, some experts argue that turnover can have a positive impact on organizations by improving efficiency. Turnover is needed to eliminate employees with the lowest performance (Labrague et al., 2020). However, turnover rates must be controlled to ensure that the organization benefits from the increased performance of new employees. Additionally, organizations typically spend more on turnover costs than on recruitment fees. However, to maintain stability, turnover should be monitored, as many of the employees who leave are competent and loyal (Dewi & Wulanyani, 2017). One way to address turnover is to identify the factors contributing to turnover intentions, allowing for preventive measures to be taken before making a decision to leave. In the United States, 23.7% of hospitals reported a vacancy rate above 10%, with the average nurse turnover rate increasing from 16.2% in 2016 to 18.2% in 2017 (NSI Nursing Solutions, 2020). A survey of 23,000 nurses working in surgical and medical healthcare settings across eleven European countries found that 33% of nurses intended to change their professions in the current year, while 9% were considering leaving the profession. The turnover rate for leaving the profession varied from 5% to 17% in ten countries (Loft & Jensen, 2020). Indonesia also faces challenges related to high nurse turnover rates, with an annual prevalence of approximately 27.3% (Fitriasari, 2020). Studies conducted in Surabaya have shown nurse turnover rates of 13.67%, 13.69%, and 16.91% from 2014 to 2016 (Asmara, 2018). Similarly, research conducted in Batam has reported nurse turnover rates in private hospitals of 15.4%, 14.3%, and 18.9% over the last three years (Christiani & Ilyas, 2018). High nurse turnover rates have been observed worldwide, and various factors have been identified as contributing to the problem. These factors include personal development, job satisfaction, organizational culture, commitment, interpersonal relationships, and promotion opportunities (Akgunduz & Eryilmaz, 2018; Al Sabei et al., 2020; Christopher et al., 2018; Gebregziabher et al., 2020; Labrague et al., 2018). In addition, stress, fatigue, and the work environment are internal and external factors associated with nurse turnover (Yu & Lee, 2018). Faraz (2017) has highlighted three contributing factors to nurse turnover: role ambiguity, self-confidence, and competence; personal attributes such as educational background, work experience, and supervision; and job satisfaction, including professional autonomy and quality of professional relationships, and interpersonal relationships. Despite extensive research on the factors contributing to nursing turnover, limited studies have been conducted on nurse turnover in hospital settings in Indonesia (Dewanto & Wardhani, 2018; Dewi et al., 2020; Lukman et al., 2020). In addition, the studies were mostly conducted before the COVID-19 pandemic, which provides a lack of understanding of nurse retention. As stated by Marzilli (2022), the nursing profession recognizes that it cannot revert to the pre-COVID-19 era, as the previous nursing practices have become obsolete, and it is now essential to design the future of nursing. Innovation necessitates creativity, leadership, optimism, foresight, and planning. Therefore, this study aimed to explore the current experiences of Indonesian nurses in retaining their jobs in order to create a new retention strategy in hospitals. Methods Study Design This study used a descriptive phenomenology design to explore nurses’ experiences who retain their jobs in hospitals. Using a descriptive phenomenological approach based on Husserl’s writings, it is possible to describe these meanings without the need for interpretation (Sundler et al., 2019). Participants The participants were selected based on specific criteria, including 1) nurses working in all hospital departments, 2) nurses with more than five years of experience, and 3) nurses who could articulate their experiences clearly. Purposive sampling was employed to identify nurses who were willing to share their opinions on the comfort of their workplace. The research team provided an explanation of the study’s objectives and methods to the nurses, who were then asked to participate. To promote the sharing of diverse experiences, the study employed a maximum variation sampling approach. This approach involved selecting participants based on their department, age, education level, marital status, and gender. Data Collection The study was conducted using semi-structured interviews in a private hospital in Batam, Indonesia, between January and March 2022. The primary questions for the interviews were: 1) What has kept you working in this hospital for more than five years? 2) Could you describe your pleasant and unpleasant experiences? 3) What suggestions do you have for improving nurses’ work in this hospital? In addition, the researchers probed the participants’ responses by asking follow-up questions such as “Could you explain more about this?” to explore their experiences further. Before the interviews began, participants were informed about the study’s objectives and confidentiality and signed a consent form. All interviews were recorded, and each interview lasted approximately 45 minutes. Data collection continued until saturation was reached, at which point no new topics emerged during the interviews. It is noted that the researchers had no prior relationship with the participants. Data Analysis The data analysis in this study utilized a conventional content analysis method (Creswell & Creswell, 2018; De Chesnay, 2015). To ensure the transcripts’ quality, the researchers double-checked them. First, the researchers conducted a verbatim transcription of the interviews and read through them repeatedly to fully comprehend the participants’ perspectives. Next, the researchers coded and categorized the data based on their similarities through comparisons and discussions, and the codes were grouped into more general categories. These categories were then compared and organized into themes. Finally, the study team discussed the codes and categories to ensure agreement and enhance rigor before finalizing them. Trustworthiness Data credibility was attained by implementing a suitable data collection strategy through a semi-structured interview guide. The data analysis was comprehensively described to ensure reliability, and the source material was appropriately cited. The interviews were individually coded by the researchers, who held meetings to review the initial findings and reach a consensus on the codes and themes. These meetings served to establish the conformability and consistency of the study. In addition, the study explained the background, participant selection, data collection, and analysis procedure to enhance the transferability of the findings. Ethical Considerations The study received ethical approval from the Universitas Indonesia ethics committee after undergoing an ethical review process (Ethical approval number: Ket-08/UN2.F12.D1.2.1/PPM.00.02/2022). The study considered four ethical principles: respect, autonomy, beneficence, non-maleficence, and justice. The researcher explained the objectives and the process clearly to the participants, and each participant signed an informed consent form before being enrolled in the study. Results Characteristics of Participants Ten nurses with an average total work length of 10.4 years and an average age of 35.6 years (with a minimum age of 28 years and a maximum of 44 years) participated in this study. The majority of the participants were female (n = 7), held bachelor’s degrees (n = 6), and were married (n = 8) (Table 1). Table 1 Participants’ characteristics ID Sex Age Work Length Education Marital Status Department P1 F 35 9 Bachelor Married Polyclinic P2 M 28 6 Diploma Unmarried Emergency P3 F 37 12 Bachelor Married Polyclinic P4 F 29 6 Diploma Unmarried Pediatric P5 M 40 14 Bachelor Married Intensive care P6 F 44 16 Bachelor Married Surgical P7 F 29 6 Diploma Married Polyclinic P8 F 33 7 Diploma Married Emergency P9 M 39 13 Bachelor Married Intensive care P10 F 42 15 Bachelor Married Pediatric F = Female | M = Male Thematic Findings The study identified three major themes: (1) good teamwork, (2) compensation, and (3) professional career development (Figure 1). Figure 1 Thematic findings of nurses’ job retention Theme 1: Solid teamwork This theme explores how teamwork can affect nurses’ job retention. During the interviews, all ten participants mentioned that a solid and responsible team is essential for retaining their jobs. The following are some of the participants’ statements about teamwork: “A solid and responsible team is essential.” (P1) “The teamwork in my hospital is outstanding.” (P2) “We support each other.” (P4) “The family system that applies to my teamwork makes the work atmosphere comfortable.” (P5) Several participants believed that having supportive colleagues can contribute to solid teamwork. Some participants shared the following: “The relationship between colleagues is excellent and fun, and the supervisors are unified and mutually supportive. These make a perfect team.” (P3) “The work environment is so far so good; the communication in my team is excellent.” (P8) “If someone is unable to attend, others are willing to replace the service shift.” (P2) Some participants think that supervisors who provide exemplary support lead to excellent teamwork. They shared the following: “Our supervisor does not pressure us as workers, but they create a comfortable working environment. It is suitable for motivating me to give the best in my team.” (P5) “My supervisor gives me feedback to improve my skills.” (P7) “We are not considered only as employees, but we feel like friends. Thus, the work environment is comfortable even though we have to go through the COVID-19 pandemic.” (P6) “The supervisor allowed me permission if there was an urgent situation.” (P1) Theme 2: Adequate compensation Nonetheless, the study participants also identified other factors that contribute to their job retention. The interviews revealed that adequate compensation is another essential factor that provides comfort. The following participants expressed this sentiment: “I am satisfied with my professional income, which includes salary, allowances, and insurance. I believe it is higher than in other hospitals in the area” (P2) “During the COVID-19 pandemic, we received specific incentives and facilities” (P3) “For instance, if I fall sick, I receive an allowance for both outpatient and inpatient care. We also have access to the health BPJS” (P4) “Here, we receive a bonus twice a year” (P2) Theme 3: Professional career development Professional career development is a significant factor that motivates nurses to continue their jobs. During the interviews, five participants emphasized how having a clear career path encourages them to remain in their positions. Some participants shared: “The nursing career path levels are well-explained” (P7) “The career path is clearly defined, starting from level 1A, then 1B, and so on” “We are categorized into several levels according to the career path” (P8) “Education also plays a crucial role in my career path here” (P6) “Since the career path guidelines exist, I am eager to follow and improve my career” (P9) “Position levels are determined based on the duration of work, education level, and performance, which will eventually lead to salary increments” (P10) Additionally, the participants shared information about the opportunities for professional development, such as: “I was given a chance to continue my bachelor’s degree and received financial support” (P6) “I attended professional training in the intensive care unit” (P9) “They provided us with opportunities for learning, such as training and formal education” (P3) Discussion The current study emphasizes the crucial elements for experienced nurses in retaining their intentions to stay in the hospital. Our findings suggest that the nurses’ decision to remain in their current roles is complex and influenced by multiple factors, including teamwork, compensation, and professional career development. Although no single factor could be identified across all participants, these themes were significant to many respondents. Our study also found that the prestige of the specialty or department’s classification did not affect nurses’ intention to stay. Despite having diverse expertise, the nurses shared similar experiences and perceptions, indicating that feelings of peace, security, and confidence were essential factors influencing their decision to remain. These feelings were associated with effective teamwork, adequate pay, and opportunities for professional career development. The main themes describing nurses’ experiences and perceptions of working in the hospital consist of various factors contributing to their retention. The themes highlighting good teamwork and adequate compensation can make nurses feel more comfortable in their workplace. Numerous studies have demonstrated that teamwork and rewards can impact a person’s decision to remain in their job. Good teamwork, in particular, is a significant factor that influences nurses to stay in the hospital. Conversely, a work environment that lacks support can negatively affect nurses’ intentions to remain in their positions (Yu & Lee, 2018). Additionally, nurses with positive expectations regarding their leaders’ and colleagues’ support and a manageable workload are more likely to continue in their careers. Thus, an effective leadership style is necessary, which includes supervisors’ reliability and ability to manage and motivate staff in the workplace (Sugianto et al., 2022; Suliman & Aljezawi, 2018). Moreover, the support of supervisors has a positive impact on the work environment and strengthens the team (Wang & Ahoto, 2022). Maintaining the nurse-patient relationship, nurse-nurse relationship, and nurse-doctor interaction is crucial for retaining nursing positions, as noted by Ramli et al. (2021). A strong sense of collegiality among nurses is a significant factor in their decision to remain in their current roles. As a result, most nurses consider their coworkers crucial to their decisions. Nursing staff who have good relationships with each other enjoy going to work, making teamwork an essential strategy in nursing care. Good teamwork is characterized by attributes such as communication and an environment that fosters support, while team size and individual attitudes also contribute to it. Communication is the most important aspect of teamwork, especially within the critical team in carrying out joint activities to improve nursing services. Adequate communication within the team is essential, meaning that the communicating colleagues must have the same understanding of the information conveyed. The processes of exchanging messages that produce clear feedback should also be considered (Brommelsiek et al., 2019). The interview results conclude that good teamwork can provide a comfortable work environment. In addition, material and non-material rewards serve as incentives for nurses to keep their jobs, recognizing their hard work and professionalism. The six primary rewards important to registered nurses (RNs) are monetary compensation and benefits, a balance between work and personal life, work content, professional growth, appreciation, and effective leadership. These rewards motivate nurses to perform their duties well and increase job satisfaction. Nurses dissatisfied with their pay are more likely to leave, and compensation was ranked higher than other rewards (Seitovirta et al., 2017). Furthermore, compensation is a crucial factor in retaining nurses in their jobs. Compensation can also be grouped into monetary and non-monetary incentives. Financial incentives include bonuses, personal supplementary compensation, pension benefits, performance-based pay schemes, company perks, and fringe benefits. Additionally, non-monetary incentives such as providing individual nurses with more control over their work and offering professional development opportunities can increase job satisfaction among nurses. By providing incentives, nurses can enhance their performance and resilience, resulting in improved quality of work and increased job satisfaction (Al Sabei et al., 2020; Labrague et al., 2018). A professional career path also influences the retention of nurses. The existence of a professional career path has been shown to impact the intention of nurses to leave their jobs. Career barriers and support greatly affect professional commitment. Therefore, reducing obstacles and increasing support can decrease nurses’ intentions to leave their profession. A professional career path can serve as a means of retaining nurses and motivating them to improve their work performance, thus enabling them to progress at every stage of their career (Chang et al., 2019; Diño et al., 2022). Four major factors have been identified as significant barriers to career development: lack of workplace support, inadequate prospects for clinical career development, excessive working hours, and restricted access to further education based on merit (Christopher et al., 2018; Gebregziabher et al., 2020). Career development involves planning and implementing a career path that places nurses at a level commensurate with their expertise and provides better opportunities based on their abilities and potential. Formal education is pursued through advanced studies to increase the level of education, while non-formal education is pursued through training, seminars, and workshops. The evidence-based results on career explanations demonstrate the main benefits of implementing career stages, enhancing professional development, improving performance, increasing job satisfaction, and fostering a work culture of recognition. These factors are related to the decision to remain in the hospital (Christopher et al., 2018; Gebregziabher et al., 2020). Providing opportunities for workforce growth within proper role frameworks is an effective tool to improve work satisfaction, organizational engagement, and, ultimately, the retention of nurses. It has been consistently found that work satisfaction is a significant and most influential indicator of nurses’ intentions to remain in their current positions and the nursing profession. Implications for Nursing Management and Hospital Policy The study results might not be novel, but these are based on the participants’ perspectives. There are several implications from this study: 1) From the study findings, developing and implementing effective teamwork strategies are necessary. Hospital and nurse managers should create policies that foster good teamwork among nurses and prioritize effective communication, mutual support, and collaboration among team members. The hospital should also invest in programs that promote team-building and encourage a sense of collegiality among staff; 2) The hospital should develop policies that provide nurses with adequate monetary compensation and non-monetary incentives to motivate them to perform their duties well; 3) The hospital should create policies that promote professional development opportunities for nurses. These policies should encourage formal and non-formal education opportunities, training, seminars, and workshops to enhance nurses’ skills and knowledge; 4) Nurse managers should advocate for policies that support the career development of nursing professionals and establish a clear career path; 5) The hospital should develop policies that provide support for nurses’ career development, reduce barriers to career progression, and increase access to further education based on merit. These policies should encourage a work culture of recognition, improve performance, and increase job satisfaction; 6) Nurse managers should monitor and address workplace factors that negatively impact nurse retention, such as excessive workload and inadequate support. Implementing these recommendations can help hospitals to retain experienced nurses, improve job satisfaction, and ultimately improve the quality of patient care. Limitations The study was only conducted in a private hospital, providing a partial understanding of nurses’ experiences. Therefore, future research could investigate government or public hospitals, which may offer distinct perspectives. Conclusion Based on the findings, the retention of experienced nurses in hospitals is influenced by multiple factors, including teamwork, compensation, professional career development, and a supportive work environment. Good teamwork, effective leadership, and collegiality among nurses can create a comfortable and supportive work environment that can positively impact nurses’ intentions to stay in their current roles. In addition, adequate monetary and non-monetary compensation is crucial in retaining nurses, along with opportunities for professional career development. Finally, the existence of a professional career path that places nurses at a level commensurate with their expertise and provides better opportunities can decrease nurses’ intentions to leave their profession. By addressing these factors, hospitals can create a positive work environment that supports nurses, resulting in improved quality of care and patient outcomes. Acknowledgment The authors appreciated all nurses who participated in this study. Declaration of Conflicting Interest There was no conflict of interest in this study. Funding None. Authors’ Contributions UCW conceived the idea, conducted data collection and analysis, and paper writing. RTSH reviewed the results of the data analysis and revised the paper. All authors were accountable in each phase of the study and approved the final version of the article to be published. Authors’ Biographies Ns. Utari Christya Wardhani, S.Kep., M.Kep is a Student in the Doctoral Nursing Program, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Dr. Rr. Tutik Sri Hariyati, S.Kp., MARS is a Professor at the Department of Basic Science and Fundamental Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Data Availability The datasets generated during and analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Akgunduz, Y., & Eryilmaz, G. (2018). Does turnover intention mediate the effects of job insecurity and co-worker support on social loafing? International Journal of Hospitality Management, 68 , 41-49. 10.1016/j.ijhm.2017.09.010 Al Sabei, S. D., Labrague, L. J., Miner Ross, A., Karkada, S., Albashayreh, A., Al Masroori, F., & Al Hashmi, N. (2020). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-031 10.33546/bnj.1294 Original Research Media use and behavioral disorders among Saudi Arabian children https://orcid.org/0000-0002-4064-2724 Alghamdi Salmah 1* Bawageeh Duaa 2 Alkhaibari Hessa 2 Almutairi Amwaj 2 Aljuhani Shoug 2 1 Maternity and Child Health Department, Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia 2 Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia Corresponding author: Dr. Salmah Alghamdi, Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia, P.O.BOX 4105, Zipcode 22254. Email: saalghamdi6@kau.edu.sa Cite this article as: Alghamdi, S., Bawageeh, D., Alkhaibari, H., Almutairi, A., & Aljuhani, S. (2021). Media use and behavioral disorders among Saudi Arabian children. Belitung Nursing Journal, 7(1), 31-36. https://doi.org/10.33546/bnj.1294 22 2 2021 2021 7 1 3136 23 12 2020 19 1 2021 05 2 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Despite children’s frequent use of electronic devices, there is a lack of evidence showing how such media use influences their behavior. Objective This study was to assess the relationship between media use and behavior among a sample of children aged three to 11 years. Methods This was a descriptive cross-sectional study. An electronic self-administered questionnaire was completed from January 2020 to March 2020 by a convenience sample of 234 parents with healthy children in the target age group. Descriptive statistics and One-Way Analysis of Variance (ANOVA) were used for data analysis. Results There was no significant difference in children's behavior according to the type of media [F(3, 230) = 1.673, p = 0.174]. In contrast, there was a significant difference in children's behavior according to hours per day of media use [F(4, 229) = 2.701, p = 0.031]. The most commonly used mobile device was the smartphone (n = 87, 37.2%). More than a quarter of the children spent three hours a day using media. Conclusions This study offers insight into associations between children’s frequent media use and their behavior. The results suggest that the significant factor associated with behavioral problems is not the type of media but the time spent using it. Nurses are encouraged to use these findings in developing educational programs that raise awareness among parents and children regarding the consequences of excessive media use. behavioral problem smartphone children media nursing Saudi Arabia ==== Body pmcCurrently, individuals of all ages use media extensively to find information and connect with others all over the world (Zupanic et al., 2019). In this context, the term media refers to smartphones, videogames, tablets, game consoles, televisions, and computers. While media use can be favorable within certain limits, there is a risk of overuse. Indeed, the time spent using electronic devices continues to increase along with the growth in the range of available technologies. Media use among children has become a growing concern. The American Academy of Pediatrics (2016) recommends that children between age two and five years use media for only one hour a day, and children between six to 10 years use it for only 1.5 hours per day. Despite this recommendation, in Australian households, children’s device use and internet access have risen from 72% in 2004–2005 to 97% in 2016–2017 (Reus & Mosley, 2018). Children’s media use also has become a concern in Saudi Arabia. With the growing affordability of mobile devices, research has shown that the average time Saudi Arabian children spend using mobile devices was about two hours and 42 minutes (Statista Research Department, 2020). Furthermore, the number of internet users in Saudi Arabia is growing steadily, from 21.54 million in 2015 to 30.2 million in 2019 (Statista Research Department, 2020). This number is expected to reach 35 million in 2023 (Statista Research Department, 2020). Moreover, according to the General Authority of Statistics, 92.51% of Saudi families and 23.44% of children between five and nine use the internet (Al-Solami, 2019). Such high media use among children can come at a cost. Studies have shown that children with more media usage have a higher body mass index (BMI), less physical activity, and diminished rest and sleep than children with lower media usage (Reus & Mosley, 2018). Media use also can influence children’s behavior. For example, children can become physically and verbally aggressive after excessive media use, sometimes imitating violent behaviors portrayed in mass media (Şengönül, 2017; Tanwar & Priyanka, 2016). The assessment of children’s behavior in this study comprises a wide range of mental and social disorders. They include depression, overanxious, separation anxiety, relational aggression, oppositional defiant, inattention, impulsivity, and social problems with peers. Unfortunately, there is a lack of evidence about the specific relationship between media use and behavioral disorders in Saudi Arabian children. Therefore, the current study focused on Saudi children aged three to 11 years. With portable digital devices (e.g., smartphones and tablets) becoming more available and affordable, the time children spend using them is increasing rapidly (American Academy of Pediatrics, 2013). In addition, with the significantly accelerated growth of video apps, learning packages, and instructional software for young children, incentives for children to use mobile devices have expanded, resulting in longer usage periods. Furthermore, mobile device manufacturers are targeting younger children. With this widespread increase in children’s access to and usage of digital mobile devices—which has become an integral part of their lives—parents and researchers need to examine the effects of portable electronic media use (Paudel et al., 2016). Therefore, the current study aimed to determine if there is a relationship between media use and changes in children’s behavior. Researchers have suggested that frequent mobile media usage among children can intensify social loneliness, detract from social contact with family and friends, exacerbate emotional/behavioral issues, and possibly worsen social deficits (e.g., inattention, hyperactivity, peer problems, and emotional symptoms (Hosokawa & Katsura, 2018; Poulain et al., 2018; Wu et al., 2017). Interestingly, other researchers found no correlation between device use and mental and behavioral problems in girls, while in boys, each hour spent playing video games was correlated with higher chances of exhibiting borderline/abnormal conduct problems and emotional issues (Mundy et al., 2017). Furthermore, increasing media use also has been shown to negatively affect sleep outcomes, resulting in more bedtime resistance, later bedtimes, and shorter sleep durations (Chindamo et al., 2019; Nathanson & Beyens, 2018; Wu et al., 2017). Moreover, longer TV watching periods have been linked to an increased likelihood of future self-regulation issues, while less television consumption is correlated with improved self-regulation (Cliff et al., 2018; Inoue et al., 2016). In contrast, one study showed that tablet usage contributed adversely to self-regulation only in children who slept less at night n(Nathanson & Beyens, 2018). Another study indicated that high levels of media consumption contribute to high BMIs and have a detrimental effect on athletic behaviors and motor abilities (Kaiser-Jovy et al., 2017). Finally, the aggressive behavior common in the media (especially in superhero programs) also can influence children's behaviors. A study showed that one year after pre-school children encountered superheroes via media, these children exhibited increased physical and emotional violence (Coyne et al., 2017). However, superhero engagement was not shown to be related to prosocial or defensive behaviors (Coyne et al., 2017). Methods Study Design This was a descriptive cross-sectional study. Participants G*Power was utilized to calculate the needed sample size for this study (Faul et al., 2009). A priori analysis was employed to estimate the sample size for one sample means. The input parameters (alpha 0.05, power 0.80, and medium effect size 0.5) resulted in a recommended sample size of 67. The study’s participants were a convenience sample of Saudi Arabian parents with healthy children between the ages of three to 11 years. The participants were the parents of children; thus, the ages of children who use media under the control and supervision of their parents were determined for the purpose of this study to be between three to 11 years. The study did not include individuals who were not parents or those with children under age three, over age 11, not exposed to media, or experiencing a medical problem. Instrument The data were collected through an electronic survey created in Google Forms and shared through social media from January 2020 to March 2020. The authors of this study developed the first and second parts of the questionnaires. The first part of the questionnaire consisted of 10 items about sociodemographic factors: parent gender, age, marital status, employment status, number of individuals living in the household, monthly income, and education level, as well as child gender, age, and education level. The second part included multiple-choice questions about the child’s media use (the type of media used and time spent using it). The last part consisted of items adopted from the parent version of the MacArthur Health and Behavior Questionnaire (HBQ) for middle childhood (Essex et al., 2002). The HBQ includes scales that assess children’s mental health symptoms, physical health, social and school functioning. For the purpose of this study, only 44 items of HBQ addressed children's’ behaviors with regard to mental health symptoms (depression, overanxious, separation anxiety, relational aggression, oppositional defiant, conduct problems, overt hostility, inattention, and impul-sivity) and social functioning (a social with peers and prosocial behavior) were included. The HBQ requires the participant to check on the statement that applies to the behavior. The statements were assessed on a 3-point scale ranging from 0 (never or not true) to 2 (very true). The questionnaire was translated from English to Arabic using the back translation method, and the translated Arabic questionnaire was pilot-tested with five parents to ensure the clarity of items. To establish content validity, five Arabic-speaker specialists, including two doctoral-prepared and three master-prepared nurses in the field of pediatric nursing, evaluated the translated version of the HBQ and the relevance of the items to the concept of health and behavior. The HBQ (44 items) in this study demonstrated good internal consistency reliability with a Cronbach’s alpha of 0.88. Data Analysis Data were analyzed using SPSS software. Descriptive statistics (e.g., mean, percentages, frequencies, and standard deviation) were used to describe the study variables. One-Way Analysis of Variance (ANOVA) was employed to assess differences in children’s behavior according to type and time of media use. The level of statistical significance for statistical analysis was at 0.05. Ethical Consideration Ethical approval was obtained from the Nursing Research Ethical Committee (NREC Serial No: Ref No 2B. 37). The study maintained participant confidentiality, and the parents’ identities were not evident in any reports, presentations, or publications. Electronic informed consent was obtained from all participants before starting the questionnaires. Results In total, 234 parents participated in the study. The majority of study participants (93.2%) were mothers between 30 and 50 years (78.2%). Most of the children (60.3%) were between five and ten years of age. Details on the other demographic variables are shown in Table 1. Table 1 Demographic variables of the study sample (N=234) Variables N % Parents Mother 218 93.2 Father 16 6.8 Participants’ age Less than 30 years 41 17.5 From 30 to 50 years 183 78.2 More than 50 years 9 3.8 Child’s age From 3 to 5 years 85 36.3 From 6 to 8 years 105 44.9 From 9 to 11 years 44 18.8 Sex of Child Male 107 45.7 Female 127 54.3 Marital status Married 226 96.6 Divorced 6 2.6 Widowed 2 0.9 Employment status Working full-time (35 hours per week) 80 34.2 Working part-time 28 12.0 Student 8 3.4 Not working 118 50.4 Household Less than five persons 125 53.4 From five to ten persons 107 45.7 More than ten persons 2 0.9 Household monthly income in Saudi Arabian Riyal (SAR) SAR 3000 or Less 21 9.0 SAR 3001–SAR 8000 73 31.2 SAR 8001–SAR 13000 67 28.6 More than SAR 13000 54 23.1 Don’t know 19 8.1 Educational level Below high school 16 6.8 High school 60 25.6 Some college 14 6.0 Bachelor’s degree 130 55.6 Master’s degree or higher 14 6.0 Child’s educational level Kindergarten 59 25.2 Grade 1 52 22.2 Grade 2 31 13.2 Grade 3 22 9.4 Grade 4 31 13.2 Not enrolled 39 16.7 As presented in Table 2, the results of One-way analysis of variance (ANOVA) revealed that there was no significant difference in children's behavior according to the type of media [F(3, 230) = 1.673, p = 0.174]. In contrast, there was a significant difference in children's behavior according to hours per day of media use as presented in Table 3 [F(4, 229) = 2.701, p = 0.031]. Table 2 One-way ANOVA of children behavior by type of media use Source Sum of Squares df Mean Square F p Between Groups 0.334 3 0.111 1.673 0.174 Within Groups 15.305 230 0.067 Total 15.639 233 Table 3 One-way ANOVA of children behavior by hours per day of media use Source Sum of Squares df Mean Square F p Between Groups 0.705 4 0.176 2.701 0.031* Within Groups 14.934 229 0.065 Total 15.639 233 * p < 0.05 The most common types of media used were smartphones (n = 87, 37.2%). The least used media device was the PlayStation (n = 19, 8.1%). Detailed information on the most common types of media used among children is presented in Table 4. Table 4 Most common types of media used among children Type of Media f % Tablet/iPad 68 29.1 Smartphone 87 37.2 PlayStation 19 8.1 Television 60 25.6 Total 234 100.0 The average of time spent on media use were reported, the results indicated that, of the 234 children, 20 (8.5%) spent less than 30 minutes per day, 53 spent 30 minutes to 1.5 hours (22.6%), 47 (20.1%) spent between 1.5 to 2 hours, 54 (23.1%) spent two to three hours, and 60 (25.6%) spent more than three hours (Table 5). Table 5 Average of time spent on media use by children Media Time f % Less than 30 minutes 20 8.5 30 minutes to 1.5 hours 53 22.6 1.5 to 2 hours 47 20.1 2 to 3 hours 54 23.1 More than 3 hours 60 25.6 Total 234 100.0 Discussion The purpose of this study was to identify relationships between media use and behavioral disorders among a sample of Saudi Arabian children between the ages of three to 11 years. The results indicated that over a quarter (25.6%) of the children in the sample spent more than three hours per day using mobile devices, which is far greater than the media limits recommended by the American Academy of Pediatrics (2016), one hour per day for two- to five-year-old and 1.5 hours per day for six- to ten-year-old. These results are concerning, as technology overuse can influence the growth of children and teenagers, as their brains are more sensitive to the effects of technology use and overuse than are adult brains (Johnson, 2020). Social media and electronic application use can also lead to psychological and physical difficulties (e.g., eyestrain, trouble concentrating on essential tasks, and poor academic achievement), which can lead to more serious health problems (Mustafaoğlu et al., 2018). The study results also indicated that the children used various devices, ranging from stationary (television and game consoles) to portable devices (tablets and smartphones). The smartphone was the most frequently used device used, possibly due to its size and accessibility. Furthermore, because smartphones can run educational applications, parents may offer them to their children to keep them occupied and quiet in certain situations. Moreover, our findings aligned with those of other studies indicating that three-quarters of children have their own smartphones, and almost all children use them (Kabali et al., 2015; Setiadi et al., 2019). Indeed, smartphone use can be positive or negative for children, depending on the type of programs used and how long they are used. The current study results showed no significant relationship between physical problems without a medical cause and the type of media used or the time spent using it. This finding contrasts with other study findings indicating that long periods spent viewing TV, laptops, iPads, mobile phones, and video games can contribute to fatigue (Boyd, 2020). Furthermore, the absence of body and eye movement associated with using such devices can cause headaches (Yle, 2014). The most important finding of the current study was the significant relationship between children’s time spent in media use and behavioral disorders. This finding corroborates prior studies relating behavioral issues to time spent using media (Poulain et al., 2018; Wu et al., 2017). Implications of the Study The finding that the time of media uses is significantly associated with children’s behavior brings a different perspective to the media use for education, communication, and entertainment. Indeed, parents need such crucial information before deciding how much media their children should be allowed to consume. Nurses and future researchers can utilize results from this study to regulate the use of media among children. Nurses are encouraged to develop educational programs to raise awareness among parents and children regarding the consequences of excessive media use. One obstacle to reducing children’s excessive media use is adult media overuse, which can set a bad example for children. The authors of the current study recommend that parents adhere to the media usage hours recommended by the American Academy of Pediatrics (2016). Furthermore, individuals obliged to use media for long periods should consider the American Academy of Ophthalmology’s 20-20-20 rule: for every 20 minutes of media use, shift your eyes and focus on an object at least 20 feet away, for at least 20 seconds (Boyd, 2020). To expand upon these findings, future nursing research may replicate this study using the complete HBQ to assess children’s physical health and school functioning in relation to media use. Furthermore, qualitative research could be conducted using interviews, observations, or focus groups to explore children’s behavior secondary to media use. Moreover, larger sample sizes are needed to improve the generalization of results. Further randomized controlled trials are needed to examine the feasibility of interventions that regulate media use among children. Limitations of the Study This study has some limitations. While using a cross-sectional design makes it possible to identify associations between media use and behavioral disorder, causality cannot be inferred. Next, these findings may not be generalizable due to the small sample size. Moreover, using an online questionnaire made it difficult for respondents to clarify some questions they may have found difficult to answer. Constructs of the HBQ in this study have not been confirmed by exploratory and confirmatory factor analysis. Conclusion This study offers insights into the associations between frequent media use and children’s behavior. While the type of media used does not seem to influence children’s behavior, the time spent using media correlates with behavior problems. Therefore, it is concluded that the more time a child spends using mobile devices, the more impact such use will have on their behaviors. Future nursing research is needed to examine the feasibility of programs that regulate media use among children Acknowledgment None. Declaration of Conflicting Interest The authors have no conflict of interest to declare. Funding This research received no specific grant from any funding agency. Authors’ Contributions SA was responsible for the conceptualization, methodology, validation, and data interpretation. DB, HA, AA, and SA were responsible for literature review, data collection, analysis, and data interpretation. All authors contributed equally in writing, reviewing, and editing this manuscript. Data Availability Statement The datasets generated or analyzed during the current study are available from the corresponding author on reasonable request. Authors Biographies Salmah Alghamdi, PhD, MSN, RN is an Assistant Professor in the Maternity and Child Health Department, Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia. Duaa Bawageeh, Hessa Alkhaibari, Amwaj Almutairi, and Shoug Aljuhani are undergraduate nursing students at the Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia. ==== Refs References Al-Solami, Z. (2019). 23% of Internet users in Saudi Arabia are under 9. Retrieved from https://saudigazette.com.sa/article/558595 American Academy of Pediatrics. (2013). Children, adolescents, and the media. Pediatrics, 132 , 958. 10.1542/peds.2013-2656 28448255 American Academy of Pediatrics. (2016). AAP announces new recommendations for children’s media use. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-132 10.33546/bnj.2510 Original Research A correlational study of breastfeeding duration among Saudi mothers: The role of self-efficacy, intention, and social support https://orcid.org/0000-0002-7556-0454 Al Naseeb Nourah. M 12 https://orcid.org/0000-0002-2163-290X Badr Hanan 1* https://orcid.org/0000-0002-4064-2724 Alghamdi Salmah 1 1 Maternity and Child Department, Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia 2 Armed Forces Hospital in Al-Hada, Saudi Arabia * Corresponding author: Dr. Hanan Abdullah Badr, PhD, MSN, RN, Maternity and Child Department, Faculty of Nursing, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Email: habadr@kau.edu.sa Cite this article as: Al Naseeb, N. M., Badr, H., & Alghamdi, S. (2023). A correlational study of breastfeeding duration among Saudi mothers: The role of self-efficacy, intention, and social support. Belitung Nursing Journal, 9(2), 132-138. https://doi.org/10.33546/bnj.2510 18 4 2023 2023 9 2 132138 17 12 2022 14 1 2023 20 3 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Breastfeeding is an essential source of nutrition for infants and offers numerous benefits for both the mother and child. Despite the consensus on its advantages, limited research in Saudi Arabia has explored the factors influencing breastfeeding duration. Objective This study aimed to examine the relationships between breastfeeding self-efficacy, intention, social support, and breastfeeding duration. Methods The study employed a correlational research design, and data were collected from three armed forces hospitals in Taif, Saudi Arabia, from December 2020 to February 2021. The samples comprised 356 conveniently selected breastfeeding mothers, assessed using the Breastfeeding Personal Efficacy Beliefs Inventory, Modified Infant Feeding Intention Scale, and Exclusive Breastfeeding Social Support Scale. Simple linear regressions were conducted for data analysis. Results Breastfeeding duration was divided into two groups. Group 1 consisted of mothers still breastfeeding at the time of data collection, while Group 2 comprised those who had discontinued breastfeeding. Of the total samples, 51.6% (n = 184) of mothers were classified under Group 1, while the remaining 48.4% (n = 172) were allocated to Group 2. Specifically, 78.3% of mothers had stopped breastfeeding by the time their infants were six months old, and 93.3% intended to introduce formula feeding at three months. In Group 1, the results revealed that self-efficacy (β = 0.625, p <0.001), intention (β = 0.643, p <0.001), and social support (β = 0.612, p <0.001) were positively associated with breastfeeding duration. Similarly, in Group 2, a strong positive correlation was observed between self-efficacy (β = 0.72, p <0.001), intention (β = 0.73, p <0.001), social support (β = 0.699, p <0.001), and breastfeeding duration. These three factors jointly explained 40% of the variance in breastfeeding duration in Group 1 (adjusted R2 = 0.4) and 50% in Group 2 (adjusted R2 = 0.5). Conclusion Breastfeeding intention was found to have a more significant impact on breastfeeding duration than self-efficacy and social support. These results can inform nurses and midwives in supporting breastfeeding mothers by providing them with the necessary information and increasing their awareness of breastfeeding-related factors. breastfeeding self-efficacy intention social support breastfeeding duration mothers Saudi Arabia nurses midwifery ==== Body pmcBackground Breastfeeding is described as a gift from a mother to her infant (Goebel, 2018), providing a substantial source of safe, complete, and appropriate infant food and promoting child survival and well-being effectively (UNICEF, 2018). In addition, breast milk provides adequate nutrients and minerals, boosts newborn immunity, improves cognitive and psychological development, and protects the child from developing diabetes mellitus (Nguyen et al., 2021; Sankaran, 2012). In 2018, a Spanish study found that healthcare costs were 400–500€ lower in exclusively breastfed (EBF) newborns compared to formula-fed newborns (Santacruz-Salas et al., 2019). Previous studies have also shown that breastfeeding lowers the risk of ovarian cancer by 30% and breast cancer by 5% (UNICEF, 2018). The World Health Organization (WHO) recommends that mothers should breastfeed their infants exclusively for the first six months, followed by complementary feeding with breast milk for up to 2 years (Goebel, 2018). The WHO has defined EBF as the practice of feeding an infant with breast milk only, with no other substances, including water, except for any medically necessary vitamins or mineral supplements, or drugs (Al-Nuaimi et al., 2017). Despite the widely accepted benefits of breastfeeding, there has been a noticeable decline in breastfeeding rates in both the Kingdom of Saudi Arabia (KSA) and globally (Al-Nuaimi et al., 2017). For example, recent studies conducted in the KSA between 2017 and 2019 revealed that while the rate of breastfeeding initiation was high in the previous decade, the duration of exclusive breastfeeding (EBF) was relatively short (Ahmed & Salih, 2019; Alyousefi et al., 2017; Hegazi et al., 2019; Raheel & Tharkar, 2018). For example, Raheel and Tharkar (2018) conducted a cross-sectional study in Riyadh and Dammam, which showed that 75% of participating mothers were able to initiate breastfeeding, but only 37% were able to continue for the recommended six months. In addition, Hegazi et al. (2019) reported that only 30.9% of mothers in the western region of Rabigh initiated breastfeeding, and only 27.6% of them continued to do so. Murad et al. (2021) conducted a phenomenological study investigating factors affecting breastfeeding practice in the KSA. The researchers found that social support, specifically from the mothers of postpartum women, was a key factor in initiating breastfeeding within the first 40 days of the postpartum period. In contrast, negative comments from others, such as “I feel so sad for your baby,” which mothers interpreted as suggesting that their baby was not receiving adequate nutrients from breastfeeding, discouraged continued breastfeeding after the postpartum period. Both maternal and infantile factors contribute to unsuccessful breastfeeding. Factors that can reduce breastfeeding duration include inadequate breast milk, maternal dissatisfaction, and psychological factors. In addition, maternal age, educational level, occupation, socioeconomic status, parity, and birth type are also correlated with breastfeeding duration. Infantile factors such as the newborn’s health status and age are essential to breastfeeding success (Awaliyah et al., 2019). To promote successful breastfeeding, early identification of mothers at risk of premature termination of breastfeeding is crucial (Kronborg & Foverskov, 2020). Healthcare professionals, including nurses, should address psychosocial factors such as maternal intention to breastfeed, self-efficacy, and social support to prevent early cessation of breastfeeding. These factors are modifiable, and healthcare professionals can leverage them to achieve positive breastfeeding outcomes. Breastfeeding self-efficacy (BFSE) is the most effective and modifiable factor associated with EBF duration (Brandão et al., 2018). According to Bandura’s social cognitive theory, self-efficacy is a dynamic cognitive process that assesses people’s beliefs and ability to conduct healthy behavior (Tuthill et al., 2016). Factors such as the husband’s support, society’s attitudes and understanding, and the role of health professionals in educating the mother can influence a mother’s intention to breastfeed and modify their breastfeeding goals (Al-Sagarat et al., 2017). The key to enduring social relationships is social support, which consists of four categories: (a) emotional support (such as love, care, trust, and empathy); (b) instrumental support (such as assistance and direct help for the person in need); (c) informational support (such as counseling, advice, and necessary information to solve problems); and (d) positive feedback. All forms of social support are essential to maintaining sustainable breastfeeding intention and self-efficacy, which will positively affect breastfeeding duration (Pujól von Seehausen et al., 2020). BFSE, either alone or in combination with other factors, is correlated with the duration of EBF in the antenatal and postnatal periods (Awaliyah et al., 2019; Chaves et al., 2019; Nilsson et al., 2020). In addition, other factors, including support resources (partner, family, and workplace), influence breastfeeding. These influences on breastfeeding intent affect breastfeeding duration and may lead to early breastfeeding cessation (Al-Sagarat et al., 2017; Asiodu et al., 2017; Marks & Yardley, 2004; Nelson et al., 2018; Wallenborn et al., 2017). Sufficient social support is essential for the success and duration of breastfeeding practices (Maleki-Saghooni et al., 2020; Rosuzeita et al., 2018; Van Dellen et al., 2019; Wallenborn et al., 2019). Unfortunately, few studies in the Kingdom of Saudi Arabia (KSA), particularly in Taif, have attempted to identify the factors affecting breastfeeding duration. Furthermore, no scholar has conducted investigations in Taif to determine the effect of BFSE, intention, and social support on breastfeeding duration. Therefore, our study aimed to examine the relationship among postpartum BFSE, intention, and social support on breastfeeding duration. Our research will provide the necessary information to mitigate possible early breastfeeding cessation and avoid adverse effects of early breastfeeding cessation on mothers and children. Our research will also expand scholarly knowledge on breastfeeding, bridge existing knowledge gaps, and reveal areas for further studies. Finally, our results will justify using evidence-based practice to improve breastfeeding duration. It is also noted that our study utilizes the social cognitive theory of Bandura (1977) to understand maternal BFSE. The conceptual framework of the study also employs Bandura’s theory of self-efficacy to improve breastfeeding duration, as described by Chan et al. (2016). The framework was adapted to investigate how social support and self-efficacy levels influence a mother’s intention to continue breastfeeding during the postpartum period until their child reaches two years of age. The study’s results could inform practice by identifying mothers at risk of early cessation of breastfeeding and introducing necessary interventions. Methods Study Design This study employed a descriptive correlational design conducted in Taif, Saudi Arabia. Data were collected from pediatric and well-baby clinics in three armed forces hospitals: Al-Hada Armed Forces Hospital, Prince Mansour Military Hospital for Community Medicine, and Prince Sultan Hospital. Participants/Samples Convenience sampling was used to select the study participants. The inclusion criteria of the samples were Saudi mothers who were at least 18 years old, had either recently practiced or discontinued breastfeeding, had a healthy child age two years or younger, and were residents of Taif. Exclusion criteria were mothers with illnesses that prevented them from breastfeeding, postpartum depression diagnoses, or babies with health problems that prevented the mother from breastfeeding. To determine the appropriate sample size, G*Power 3.1 was utilized. The suggested sample size was based on a slope H1 of 0.15, an α error of 0.05, and a power of 0.95, chosen to decrease the possibility of error (Cohen, 1992). A required group size of 472 was estimated after adding 10% to compensate for missing data. Instruments Our study utilized three scales and sociodemographic questions to gauge the variables. The sociodemographic questions encompassed (a) social information such as marital status, occupational status, educational status, maternal age, and monthly income; (b) reproductive history; and (c) breastfeeding history and duration. The duration of breastfeeding was categorized into two groups: Group 1 comprised mothers who were still breastfeeding their children at the time of data collection, and Group 2 comprised mothers who had ceased breastfeeding. The researchers obtained permission to use and translate all scales in the study. Breastfeeding Personal Efficacy Beliefs Inventory (BPEBI). The BPEBI scale assesses a mother’s confidence in all aspects of breastfeeding, including (a) managing the duration of breastfeeding, (b) receiving encouragement during the process, (c) managing breastfeeding in different environments, and (d) handling potential breastfeeding challenges (Cleveland & McCrone, 2005). The responses to the items are categorized into three levels, which are “cannot do,” “moderately certain I can,” and “certainly can do.” The scores on the scale range from 0% to 100%, and a higher score indicates greater self-efficacy (Tuthill et al., 2016). The scale was translated from English to Arabic using a back-translation technique to ensure cultural appropriateness. Additionally, a professor and three doctoral-nursing faculty experts in maternity and child health reviewed the translated scales to ensure their accuracy, adequacy, content, and face validity. Finally, the reliability of the scale was tested through a pilot study involving 50 mothers, and the Arabic version of the scale demonstrated appropriate levels of reliability and validity (Cronbach’s alpha = 0.78). Modified Infant Feeding Intention Scale (MIFIS). The MIFIS scale primarily focuses on exclusive breastfeeding, which involves no introduction of any fluids or food to the newborn before they reach six months of age. The scale comprises five questions assessing the mother’s intention to breastfeed exclusively. The mother responds to each question by selecting one of five options: very much agree, somewhat agree, unsure, somewhat disagree, and very much disagree (Al-Sagarat et al., 2017). The original infant feeding intention scale, developed by Nommsen-Rivers and Dewey (2009), aimed to estimate the intention to feed infants, particularly pregnant women’s intention to exclusively breastfeed (Tuthill et al., 2016). In a study involving Jordanian mothers, Al-Sagarat et al. (2017) translated and modified the MIFIS scale to make it suitable for the Arabic culture. The scale demonstrated acceptable reliability with a Cronbach’s alpha of 0.675. Exclusive Breast-Feeding Social Support (EBFSS). The EBFSS scale was used to measure the social support that a mother receives during breastfeeding. It comprised three primary domains: emotional support, informal support, and instrumental support (Boateng et al., 2018). The Hughes breastfeeding support scale, initially developed by Hughes (1984), inspired the scale’s origin to evaluate the various types of support given to lactating mothers. Boateng et al. (2018) modified the EBFSS scale, reducing it from 30 to 16 items, which were then validated with postpartum women. In addition, the scale was translated from English to Arabic using a back-translation technique to guarantee cultural suitability. Subsequently, the translated scales underwent review by a professor and three doctoral-nursing faculty experts in maternity and child health to ensure accuracy, adequacy, content validity, and face validity. Furthermore, a pilot study comprising 50 mothers was conducted, resulting in an appropriate level of validity and reliability (Cronbach’s alpha = 0.86). Data Collection Data were collected from December 2020 to February 2021 by the researchers on a daily basis from the female waiting areas of pediatric and well-baby clinics. The participants were invited to participate in the study, and informed consent was obtained before the primary researcher handed out the questionnaires. Before distribution, the primary researcher provided an overview of the study’s title, objectives, and eligibility criteria, along with ensuring participants of the confidentiality of their information, their right to withdraw from the research until data completion, and the low-risk nature of the study. Participants were also given the researcher’s contact information, including the telephone extension of the nursing office and the researcher’s organizational email address. Data Analysis Data were analyzed using Statistical Package for Social Sciences software, version 25. Descriptive statistics were calculated for the sample variables, including means, standard deviations, and frequencies. Simple linear regression (through the origin) was used to identify and describe the relationships between variables. This method was deemed more appropriate to achieve the research aim. Ethical Considerations The study received ethical approval from multiple sources, including the Nursing Research Ethics Committee at King Abdulaziz University in Jeddah (NREC Serial No: Ref No1M.20), the Research Ethics Committee of the Armed Forces Hospital Research Centre, and the Scientific Research Ethics Committee (REC.2020-492). Additionally, ethical security approval was obtained in Taif to access participants in three-armed forces hospitals. The participants were also provided informed consent, which they were required to sign before participating in the study. Results Characteristics of the Participants Out of all the participants, only 356 responses were included in the analysis due to missing data from 14 participants. More than half of the participants (n = 190, 53.4%) had one to three pregnancies, and 190 (53.4%) had one to three deliveries. Additionally, the mothers were asked about their previous experience with breastfeeding. Most (n = 300, 84.3%) had previous experience with breastfeeding, whereas some (n = 55, 15.4%) had never breastfed before. The detail can be seen in Table 1. Table 1 Participants’ characteristics (N = 356) Characteristics f % Age 19–25 years 49 13.8 26–31 years 107 30.2 32–38 years 136 38.4 39–45 years 62 17.5 Marital Status Married 354 99.4 Divorced 2 0.6 Occupational Status Employee 38 10.8 Housewife 298 84.4 Student 17 4.8 Monthly Income by Saudi Riyal More than 10,000 67 19.0 5,000–10,000 252 71.4 Less than 5,000 34 9.6 Education Level Elementary School 53 15.0 Intermediate School 37 10.5 High School 89 25.1 University or Higher 171 48.3 Other 4 1.1 Breastfeeding Duration To study the duration of breastfeeding, the participants were classified into two groups: Group 1 mothers were still breastfeeding their children at the time of data collection (M = 4.1, SD = 0.17), whereas Group 2 mothers had ceased to do so (M = 6.83, SD = 0.19). At the time of data collection, almost half of the participants were still breastfeeding (n = 184, 51.6%), whereas the rest (n = 172, 48.4%) had stopped breastfeeding, and two participants did not answer the question. Breastfeeding duration was measured in months (Table 2). Table 2 Breastfeeding duration Duration f (%) Mean SD Max Min Group 1 184 (51.6%) 4.1 months 0.17 23 months 3 days Group 2 172 (48.4%) 6.83 months 0.19 18 months 7 days BFSE, Intention, and Social Support Among Mothers Table 3 demonstrates that the data were normally distributed, with scale scores falling within the normal range of -3 to 3 for skewness and -8 to 8 for kurtosis. The total scores on the BPEBI ranged from 0% to 100%, with 100% representing the highest level of self-efficacy achievable (Rosuzeita et al., 2018). The overall BPEBI score was high (M = 66.20, SD = 6.79). Table 3 Breastfeeding self-efficacy, intention, and social support Scale Mean SD Skewness Kurtosis Max Min Range BPEBI 66.20 6.79 −0.75 0.50 79.0 40.0 39.0 MIFIS 11.69 3.23 0.19 −0.48 25.0 8.0 17.0 EBFSS 42.59 6.00 −1.41 1.48 48.0 20.0 28.0 The scores on the MIFIS scale ranged from 0 to 16, with 0 indicating no intention to breastfeed the newborn and 16 indicating the strongest intention to breastfeed. The average total score on the MIFIS scale was moderate (M = 11.69, SD ± 3.23). Most participants reported receiving sufficient social support (M = 42.59, SD = 6.00). The mean score for instrumental support was 7.74 (SD = 2.15, range = 3–9), indicating adequate instrumental support. The mean score for informational support was 13.29 (SD = 3.41, range = 5–15), also showing adequate informational support. The mean score on the emotional support scale was 21.58 (SD = 4.87, range = 8–24), indicating that the mean score on this scale was also adequate. Relationships Between Self-Efficacy, Intention, Social Support, and Breastfeeding Duration Relationships among variables in Group 1 All variables fulfilled the assumptions for linear regression, including normal distribution, linear relationships, and no multicollinearity. The results in Table 4 indicated a positive correlation between higher levels of BFSE, intention, social support, and longer breastfeeding duration. The adjusted R² value of 0.4 (p <0.001) suggests that the three independent variables accounted for 40% of the variation in breastfeeding duration. Furthermore, in Group 1 mothers, there was a moderate positive association between the intention to breastfeed and the duration of breastfeeding, indicating that mothers who breastfed their children beyond six months intended to have a longer breastfeeding duration. Table 4 Relationships between BFSE, intention, social support, and breastfeeding duration (Group 1) Independent Variables Standardized Coefficient Unstandardized Coefficients R2 Adjusted R2 SE t F p-value β B SE BFSE 0.63 0.07 0.01 0.4 0.4 5.6 10.3 104.4 <0.001 Intention 0.64 0.28 0.03 0.4 0.4 5.5 10.73 115.2 <0.001 Social Support 0.61 0.10 0.01 0.4 0.4 5.7 9.89 97.8 <0.001 Relationships among variables in Group 2 Linear regression assumptions, including normal distribution, linear relationships, and no multicollinearity, were met by all variables. Table 5 presents the results of simple linear regression, indicating a strong positive association between BFSE, intention, and social support with breastfeeding duration among mothers who stopped breastfeeding (Group 2). The adjusted R2 value for the three variables (0.5, p <0.001) suggests that these independent variables explained 50% of the variation in breastfeeding duration. Table 5 Relationships between BFSE, intention, social support, and breastfeeding duration (Group 2) Independent Variables Standardized Coefficient Unstandardized Coefficients R2 Adjusted R2 SE t F p-value β B SE BFSE 0.72 0.053 0.004 0.5 0.5 3.43 13.3 177.61 <0.001 Intention 0.73 0.21 0.02 0.5 0.5 3.38 13.64 186.09 <0.001 Social Support 0.69 0.10 0.01 0.5 0.5 3.53 12.54 157.3 <0.001 Discussions Our study found that longer breastfeeding duration was associated with higher self-efficacy, intention, and social support levels. Among these factors, the intention was found to have the strongest influence on breastfeeding duration, although self-efficacy and social support were found to enhance mothers’ intention for extended breastfeeding. It is worth noting that the BFSE levels among the breastfeeding mothers in our study were moderate, with a mean score of 66.20 (SD 6.799), which was lower than the scores reported in previous studies on Iranian mothers (M = 130.89, SD = 13.60; M = 138.7, SD = 11.93) (Maleki-Saghooni et al., 2020; Mirghafourvand et al., 2018). According to the BFSE theory, previous breastfeeding experience is a crucial factor in BFSE, with mothers with prior experience having higher levels of BFSE than those without experience (Chan et al., 2016). In this study, the majority of the participants had previous breastfeeding experience, and the quality of their prior experience influenced their BFSE (Chan et al., 2016). Furthermore, Nilsson et al. (2020) also found that negative previous breastfeeding experiences were associated with lower levels of BFSE. Additionally, our study aimed to assess mothers’ intentions regarding breastfeeding. The results showed that participants had moderate intentions to breastfeed, with a mean score of 11.69 out of 16 points on the MIFIS. More than half of the mothers planned to engage in EBF, higher than the rates observed in previous studies (Al-Sagarat et al., 2017; Asiodu et al., 2017). Asiodu et al. (2017) found that only half of the African American mothers in their study intended to engage in EBF, while Al-Sagarat et al. (2017) found that most Jordanian mothers did not intend to engage in EBF. The results of our study are in line with a cohort study conducted in Lebanon, which showed that 41% of mothers who intended to breastfeed for less than six months introduced formula feeding in the first month after birth, while only 27% of those who intended to breastfeed for more than six months did so (RR = 1.5, 95% CI 1.1–2.1, p <0.01) (Chan et al., 2016). Amir et al. (2019) suggested that mothers who introduced formula feeding before the age of 6 months did not do so because of their children’s needs but rather due to their own perceptions. Although this study did not examine mothers’ perceptions regarding breast milk, previous research indicates that mothers with insufficient breast milk prefer mixed breastfeeding as it provides their children with the necessary nutrients while allowing them to continue breastfeeding (Murray, 2022). Therefore, future studies could consider investigating mothers’ perceptions of breast milk during breastfeeding. The results of our study indicate that mothers received sufficient social support during breastfeeding (M = 42.59, SD = 6.00) as measured by the EBFSS scale, which assesses three dimensions of support: instrumental, informational, and emotional (Boateng et al., 2018). This finding is consistent with a study conducted in Iran in 2018, which also found high levels of social support among breastfeeding mothers (M = 67.36, SD = 5.52) (Maleki-Saghooni et al., 2020). It is possible that the high level of social support observed in our study and the previous study may be related to the fact that a majority of our participants (84.4%) were housewives, similar to the participants in the previous study (90.7%) ((Amir et al., 2019; Hamid et al., 2017). This suggests that working mothers may face challenges accessing social support for breastfeeding, as noted in previous studies (Amir et al., 2019; Hamid et al., 2017). Our study identified a moderate positive correlation between self-efficacy, intention, social support, and longer breastfeeding duration in Groups 1 and 2. In Group 1, the maternal intention was the strongest factor influencing longer breastfeeding duration, followed by self-efficacy and social support. Our findings are consistent with prior research that has linked these variables to longer breastfeeding periods (Goldbort et al., 2021; Granberg et al., 2020; Kronborg & Foverskov, 2020; Maleki-Saghooni et al., 2020; Wallenborn et al., 2019). In addition, Zarshenas et al. (2020) found that introducing formula feeding before the age of 6 months is associated with early discontinuation of breastfeeding. In addition, higher levels of self-efficacy have been associated with EBF and longer breastfeeding duration in prior research (Chan et al., 2016; Khresheh & Ahmed, 2018; Kronborg & Foverskov, 2020; Wallenborn et al., 2019). These findings suggest that mothers who do not intend to practice EBF and have low self-efficacy may be more likely to introduce formula feeding before the recommended six months of exclusive breastfeeding. Future research may explore the role of maternal perceptions regarding breast milk in relation to breastfeeding duration. Strengths and Limitations This study conducted in Taif is noteworthy for its examination of the relationships between BFSE, intention, social support, and breastfeeding duration. The findings demonstrate that the intention to breastfeed has the most significant influence on duration. Using data from three military hospitals in Taif enhances the generalizability of the study’s results. Additionally, the BFEPI and EBFSS scales used in this study were validated and translated into Arabic, increasing their relevance to the population studied. However, this study’s cross-sectional design, which assessed variables at a single time instead of over an extended period, is a limitation. Additionally, due to the recruitment process, many mothers were occupied with consoling their crying children after immunization, making it difficult to invite them to participate in the study. Implications of the Study The implications of our findings are significant. Our study highlights the crucial role of postnatal BFSE, social support, and maternal intentions in achieving positive breastfeeding outcomes. This information can be valuable to healthcare professionals, particularly nurses, midwives, or clinicians in postpartum wards, as they can use it to understand and evaluate mothers’ attitudes toward breastfeeding. Understanding the essential components of mothers’ confidence, intention, and social support can help practitioners ensure that all three variables remain high for as long as possible, thereby improving breastfeeding outcomes. Early interventions are vital in promoting longer breastfeeding duration and preventing breastfeeding cessation. All dimensions of social support are critical in achieving this goal. Nurses should provide breastfeeding mothers with the necessary information and improve their awareness of breastfeeding-related factors. It is essential to include information on breastfeeding mechanisms and positions and natural or mechanical pumping, especially for working mothers. Breastfeeding education should not be limited to the benefits of breastfeeding. Our study results provide insight into the influence of intention, self-efficacy, and social support on breastfeeding duration. However, further research is necessary to explore why Saudi mothers do not adhere to EBF and to identify additional strategies to support postpartum breastfeeding. In addition, longitudinal studies can be valuable in evaluating mothers’ intentions to breastfeed, starting from the antenatal period. Conclusion This study investigated the relationship between postpartum BFSE, intention, social support, and EBF duration. The results indicated that breastfeeding mothers had high levels of BFSE, moderate intention to practice EBF beyond the first month, and adequate social support. BFSE, intention, and social support were all positively associated with breastfeeding duration in Group 1 and Group 2. In addition, the study revealed that intention had a stronger influence on breastfeeding duration than BFSE and social support, but a combination of high maternal BFSE, adequate social support, and strong intentions was necessary for longer breastfeeding duration. Acknowledgment The researchers would like to extend their sincere gratitude to the research committee at Al-Hada Hospital as well as to Ms. Shatha, Dr. Najla Kamal, and Dr. Fahad AlAmri for their invaluable support in completing this work. Declaration of Conflicting Interest The authors declare no conflict of interest. Funding This research did not receive any specific grant from funding agencies. Authors’ Contributions All authors have made substantial contributions to the design, acquisition, analysis, and interpretation of the data in this work. They have also contributed to drafting and critically revising the manuscript for important intellectual content. All authors have given final approval of the version to be published and have agreed to be accountable for all aspects of the work. Authors’ Biographies Nourah. M Al Naseeb, MSN, RN, MID is a Master Student at the Maternity and Child Health Nursing Department, King Abdulaziz University, and a Registered Nurse at the Armed Forces Hospital in Al-Hada, Saudi Arabia. Dr. Hanan Abdullah Badr, PhD, MSN, RN, SANE, CKC is an Assistant Professor at the Maternity and Child Department, Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia. Dr. Salmah Awad Alghamdi, PhD, MSN, RN is a Vice Dean of Development and an Assistant Professor at the Maternity and Child Department, Faculty of Nursing, King Abdulaziz University, Jeddah, Saudi Arabia. Data Availability The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Ahmed, A. E., & Salih, O. A. (2019). Determinants of the early initiation of breastfeeding in the Kingdom of Saudi Arabia. International Breastfeeding Journal, 14 (1 ), 1-13. 10.1186/s13006-019-0207-z 30627208 Al-Nuaimi, N., Katende, G., & Arulappan, J. (2017). Breastfeeding trends and determinants: Implications and recommendations for gulf cooperation council countries. Sultan Qaboos University Medical Journal, 17 (2 ), e155-e161. https://doi.org/10.18295%2Fsqumj.2016.17.02.004 28690886 Al-Sagarat, A. Y., Yaghmour, G., & Moxham, L. (2017). Intentions and barriers toward breastfeeding among Jordanian mothers—A cross sectional descriptive study using quantitative method. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-086 10.33546/bnj.2382 Original Research: Methodology Paper Psychometric properties of Clinical Learning Environment Inventory and its association with Moroccan nursing students’ satisfaction: A PLS-SEM approach https://orcid.org/0000-0002-5897-4567 Saka Khadija 12 https://orcid.org/0000-0002-0523-1348 Amarouch Mohamed-Yassine 1 https://orcid.org/0000-0001-5433-0804 Ragala Mohamed El Amine 34 https://orcid.org/0000-0002-2996-8459 Btissame Zarrouq 34 https://orcid.org/0000-0001-6215-9226 Tahraoui Adel 5 https://orcid.org/0000-0002-2527-2518 El Achhab Youness 45 https://orcid.org/0000-0002-3137-4975 El-Hilaly Jaouad 15* 1 R.N.E Laboratory, Multidisciplinary Faculty of Taza, Sidi Mohamed Ben Abdellah University, Morocco 2 Institute of Nursing and Health Technology (ISPITS), Fez, Morocco 3 Teachers Training College (Ecole Normale Superieure), Department of Biology and Geology, Sidi Mohamed Ben Abdellah University, P. B 5206 Bensouda, 30030, Fez, Morocco 4 Laboratory of Epidemiology and Research in Health Sciences, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, 30070 Fez, KM, Morocco 5 Laboratory of Pedagogical and Didactic Engineering of Sciences and Mathematics, Regional Center of Education and Training (CRMEF) of Fez. Rue Koweit, P.B 49 Agdal, 30050 Fes, Morocco * Corresponding author: Prof. Jaouad El-Hilaly, PhD, R.N.E Laboratory, Multidisciplinary Faculty of Taza, Sidi Mohamed Ben Abdellah University, Marocco. Email: elhilaly.jaouad@gmail.com Cite this as: Saka, K., Amarouch, M. Y., Ragala, M. E. A., Btissame, Z., Tahraoui, A., Achhab, Y. E., & El-Hilaly, J. (2023). Psychometric properties of Clinical Learning Environment Inventory and its association with Moroccan nursing students’ satisfaction: A PLS-SEM approach. Belitung Nursing Journal, 9(1), 86-95. https://doi.org/10.33546/bnj.2382 12 2 2023 2023 9 1 8695 21 10 2022 18 11 2022 14 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The Clinical Learning Environment (CLE) is integral to pre-registration nursing curricula. Assessing the student’s perceptions of their CLE is essential to adjust clinical placement to trainees’ needs. Clinical Learning Environment Inventory (CLEI) appears to be widely used in measuring CLE, but no previous study has reported a full structural validity and its association with students’ satisfaction in the Moroccan context. Objectives This study investigated the psychometric properties of the CLEI and its subscales association with Moroccan nursing students’ satisfaction. Methods The research design was descriptive, cross-sectional, and conducted from March and June 2022 using convenience sampling in three nursing institutes of the Fez-Meknes region of Morocco. The selected sample involved Moroccan nursing students undertaking clinical practice. First, exploratory factor analysis (EFA) was used to determine the factor structure of the pilot sample (N = 143). The second sample (N = 206) was then used to confirm this structure using partial least squares structural equation modeling (PLS-SEM) confirmatory composite analysis (CCA). Finally, using a bootstrapping method, the significance of the structural path was evaluated. Results The CLEI scale depicted convergent validity (AVE = 0.56 - 0.71), discriminant validity, estimated by the square roots of AVE and bootstrapped HTMT confidence interval, and significant reliability (rhoC = 0.83 - 0.92). Using a bootstrapping approach, structural path significance displayed a substantial association between task orientation and students’ satisfaction (β = 0.29, p <0.001). This ascertains that nurse students need well-planned guidelines from their facilitators in clinical wards. Conclusions The CLEI instrument revealed adequate psychometric properties and supported its original structure. As a result, the instrument might be used to measure students’ perceptions of their CLE. Task orientation appeared to be the most important factor influencing the students’ satisfaction in CLE. CLE clinical learning environment PLS-SEM psychometrics satisfaction factor analysis Morocco nursing students ==== Body pmcBackground Nursing is a practical field, and as such, clinical practicum embodies a substantial part of the pre-registration nursing courses. Clinical experiences offer realistic prospects for students to gain skills in the actual context and help put theory into practice. Combining cognitive, psychomotor, and affective abilities with the capacity to come up with solutions in a real clinical context presents both achievements and challenges for students (Chan & Ip, 2007). Indeed, to shape nursing students’ skills and boost their self-confidence, a successful clinical education curriculum should focus on giving students a positive and practical learning experience. There are significant differences between classroom learning and clinical setting because students’ full grasp of theoretical nursing principles does not guarantee their translation into practice (Yazdankhahfard et al., 2020). Unlike organized classroom learning, clinical practice occurs in a dynamic complex social context, which requires high levels of resilience in addition to cognitive, psychomotor, and emotional skills (Chan, 2001). The quality of placement sites has raised suspicions about students’ learning outcomes, and many studies suggest that not all CLE are conducive to learning (Chan et al., 2018). Clinical learning quality depends on many factors, such as applying theory to practice, excellent mentoring, constructive feedback, student integration through effective interpersonal relationships, task orientation, professional leadership, outstanding mentoring, and positive criticism (Tuomikoski et al., 2020). Moreover, impaired interpersonal relationships, a lack of assistance, and challenging learning prospects are some negative experiences that students may undergo (Ten Hoeve et al., 2018). These experiences can vary from one clinical context to another, as clinical education planning may change according to the location or country (Antohe et al., 2016). The pre-registration nursing program in Morocco includes clinical instruction as a crucial component. Twelve public Higher Institutes of Nursing and Health Techniques (ISPITS) offer a 3-year Bachelor of Nursing. Students obtain the right to practice as registered Nurses after graduating from these institutes. However, as indeed other international nursing institutes, clinical education must be included in the curricula for at least 32 weeks (1,280 hours). Similarly, Moroccan nursing institutes consider the clinical practice a crucial part of students’ professional skills development. This recognition is justified by the overall proportion of credit hours allocated to the internship modules described in the nursing curricula. The amount of actual learning time varies according to nursing specialties (960 hours for family nurse practitioners to 1440 hours for polyvalent nurses). Students spend a significant amount of time in a clinical practicum before becoming staff nurses, where clinical educators help and gradually incorporate them into the nursing profession. The measurement of the CLE using a validated tool is crucial. Different approaches were used to assess CLE, such as case studies, interaction analysis, and students’ and teachers’ perceptions of the environment’s psychosocial qualities. The CLE assessment from the student’s perspective was adopted because it is cost-effective. Moroccan nursing institutes need efficient tools to assess students’ perceptions of CLE quality. However, there is still a massive lack of knowledge about the Moroccan CLE setting (ElIdrissi et al., 2022; Guejdad et al., 2022). The CLEI scale was developed from the CUCEI instrument (College and University Classroom Environment Inventory) after being modified for the unique hospital environment (Fraser, 2020). It consists of personalization, student involvement, task orientation, innovation, and individualization subscales. Each subscale is assessed by seven items. In addition, a sixth scale called “Student’s Satisfaction” was utilized by Chan (2002b) as a dependent variable. There are two versions of the CLEI scale, one actual and another preferred form. The two-form items are almost identical, with slight phrasing modifications. While the CLEI appears to be widely used, no previous study has reported a full structural validity of the CLEI scale combining both exploratory factor analysis and confirmatory factor analysis (Chan, 2001; Chan, 2002b, 2003; Chan & Ip, 2007; Ip & Chan, 2005; Midgley, 2006; Newton et al., 2010; Serena & Anna, 2009). This study examined the psychometric properties of the CLEI scale and its subscales association with Moroccan nursing students’ satisfaction. Therefore, in reference to Chan’s study (Chan, 2001), a research model was conceptualized (Figure 1), and five hypotheses were formulated as follows: Figure 1 Proposed research model H01: Personalization (PER) has a positive and significant impact on Students’ Satisfaction (SAT). H02: Involvement (INV) has a positive and significant impact on Students’ Satisfaction (SAT). H03: Task Orientation (ORI) has a positive and significant impact on Students’ Satisfaction (SAT). H04: Innovation (INO) has a positive and significant impact on Students’ Satisfaction (SAT). H05: Individualization (IND) has a positive and significant impact on Students’ Satisfaction (SAT). Methods Study Design A cross-sectional design was conducted between March and June 2022 to validate the CLEI scale and examine the relationships between its subscales and students’ satisfaction. Samples/Participants Moroccan undergraduates from three nursing institutes located in three cities (Fez, Meknes, and Taza) in the Fez-Meknes region of Morocco participated in this study. Inclusion criteria were that the participants be nursing students in one of the three-targeted Higher Institutes of Nursing and Health Techniques (ISPITS), be fourth and sixth-semester students, and complete a clinical internship in the semester during which the study took place. Exclusion criteria were students’ enrollment in the second semester during the study; because they had minimal clinical exposure. The ratio of cases to variables and the strength of the factor analysis results were used to estimate the sample size. The usual rule for the ratio of observations to variables is that there should be at least five times as many observations as variables. These ratios can be lowered if the EFA goal is to evaluate potential structural patterns. To complete the EFA, these recommendations were followed. On the other hand, the communality determines the significance of the variables in explaining each variable, which is relevant to the EFA strength. Accordingly, a sample size of 100 is enough if all the communalities are 0.70 or higher and there are at least three variables that have substantial loadings on each component; however, because the communalities in this study fall between 0.40 and 0.70, the sample size should be at least 200 (Hair et al., 2019). Overall, using convenience sampling, the 35‐item CLEI (version 1) was first piloted with 143 participants, then the modified 31-item CLEI instrument (version 2) was conducted on the second sample of 206 students. Measures Clinical Learning Environment Inventory (CLEI) scale The CLEI instrument was developed by Chan (2001). It consists of 35 items, with seven items for each subscale (Personalization, Student Involvement, Task Orientation, Innovation, and Individualization). The degree to which students choose their own studies and interests is measured by individualization. The ability of clinical educators to provide engaging learning experiences is reflected in innovation. Student involvement gauges how actively they participate in clinical activities. Individual student interactions with educators are highlighted by personalization. However, task orientation evaluates how well-organized the instructions for clinical activities are. The Actual and Preferred formats of the CLEI are available. The preferred form is made to gauge perceptions of the ideal clinical setting, whereas the actual form assesses perceptions of the actual clinical environment. The difference in the two forms’ items’ phrasing is very small. Items in the two forms depict a slight change of wording. With the authors’ express written consent, data gathering for this study used the “Actual” version. Students used a 4-point Likert scale with the options Strongly Agree, Agree, Disagree, and Strongly Disagree to respond to the CLEI scale. Negative items had their scores reversed such that they all pointed in the same direction. Student’s Satisfaction Scale In addition to the CLEI, a 7-item questionnaire called Student Satisfaction was also utilized (Chan, 2002b) to gauge how satisfied the students were with their clinical experiences. This scale was used to investigate the relationships between student results and the hospital learning environment. It was created as an outcome measure that indicates the level of student satisfaction. Demographic Characteristics section A demographics section representing the respondents’ characteristics was added to the questionnaire. Translation Process The CLEI scale and the students’ satisfaction scale were both translated back and forth between English and French (Sousa & Rojjanasrirat, 2011). First, two independent translators who are both competent in English and French translated the text into French. Then, the two versions were compared and adjusted to the Moroccan nursing practice. The first English version was then translated back into French by two separate translators without consulting the original English text. Comparison between the two back-translated versions and the original CLEI English version proved that both the precise meaning of the individual items and the agreement between the two versions had been preserved. Thirty-eight students pre-tested this CLEI version to ensure that it was clear. Following this, minor adjustments and edits were made without substantially changing the statements, resulting in the final French version of the CLEI scale. Data Collection Data were collected by distributing paper‐based cross-sectional questionnaires in the clinical areas. During their clinical internship, the students themselves filled out an anonymous questionnaire. Data collection was conducted during March and June 2022 in three nursing institutes located in three cities (Fez, Meknes, and Taza) in the Fez-Meknes region of Morocco. Data was collected by a PhD student in Nursing education, who is also a nurse educator, with the help of her colleagues working in the surveyed institutions. Data Analysis Statistical data analyses were performed on the RStudio software 2022.02.3 with packages “psych”, “FactoMineR”, “GPArotation”, “gtsummary”, and “SEMinR”. Exploratory Factor Analysis (EFA) was used to explore the CLEI factorial structure on the first sample (N = 143). Principal axis factoring (PAF) with an oblimin rotation was used as an extraction method. The items with low communalities, significant cross-loading, or unrepresentative loading were removed in a stepwise fashion, and the EFA was rerun after each step. The reliability was assessed by Cronbach’s alpha (CA) coefficient. After checking multivariate normality, the CCA was carried out on the second sample (N = 206) to validate the EFA results using PLS-SEM (Hair Jr et al., 2021). Collinearity, path significance, and effect size were measured for the structural model. The internal consistency and convergent validity were estimated by computing CR and AVE correspondently. When the outer loading value is between 0.4 and 0.7, the choice to keep, change or delete an item rests on item-outer loading, CR, and AVE values. Fornell Larcker criterion and Hetereotrait-Monotrait (HTMT) ratio were used to test the discriminant validity (Hair Jr et al., 2021). Then, a bootstrapping technique was performed to confirm the extent of HTMT confidence intervals (Mohd Dzin & Lay, 2021). Ethical Considerations The ethical consideration for this study has been secured. The study permission was also obtained from the heads of the surveyed nursing schools. In addition, before the questionnaires were distributed, informed consent was obtained from both the directors of the surveyed institutes and all participants. Results Sociodemographic Characteristics Three institutions from the Fez-Meknes region of Morocco participated in phases 1 and 2. There were 367 and 364 surveys returned during phase 1 and phase 2, respectively. One hundred forty-three valid survey responses were maintained in phase 1 versus 203 in phase 2 after data screening, cleaning, and eliminating invalid observations. The two samples showed comparable demographic traits. The average age was 20.7 ±1.2 and 20.8 ±1.2 for the first and second samples, correspondently. In addition, 97% of the participants in the first and second phases were Moroccan, and the female gender dominated the two samples (66% vs. 70%). Six nursing branches were surveyed in hospitals (57% vs. 77%) and dispensaries (23% vs. 43%) during the fourth (41-43%) and sixth semesters (51-52%). For both two samples, the polyvalent nurse’s branch (>50%) dominated the other specialties largely, and most of the participants were placed in hospitals (57% vs. 77%) (Table 1). Table 1 Participants’ sociodemographic characteristics Variable Phase 1, N = 143 Phase 2, N = 206 Student’s age 20.7 (1.2) 20.8 (1.2) Nationality Foreign 5 (3.5%) 7 (3.4%) Moroccan 138 (97%) 199 (97%) Gender Female 104 (73%) 136 (66%) Male 39 (27%) 70 (34%) Branch ¶ ARN 0 (0%) 20 (9.7%) CFHN 24 (17%) 41 (20%) MHN 19 (13%) 13 (6.3%) NM 2 (1.4%) 2 (1.0%) NN 19 (13%) 27 (13%) PN 79 (55%) 103 (50%) Location of higher nursing institutes* Fez 27 (19%) 76 (37%) Meknes 63 (44%) 80 (39%) Taza 53 (37%) 50 (24%) Semester 2nd Semester 12 (8.4%) 10 (4.9%) 4th Semester 58 (41%) 88 (43%) 6th Semester 73 (51%) 108 (52%) Clinical placement Community environment 61 (43%) 47 (23%) Hospital 82 (57%) 159 (77%) ¶ ARN, Anesthesia and resuscitation nurse; CFHN, Community Health, and Family Health Nurse; MHN, Mental Health Nurse; NM, Nurse Midwife; NN, Neonatal nurse; PN, polyvalent nurse * Fez, Meknes, and Taza are Moroccan cities Exploratory Factor Analysis Results First, before conducting EFA, the sampling adequacy (Kaiser– Meyer–Olkin test) and the factorability (Bartlett’s test) of the first sample were estimated. All KMO values for individual items were higher than 0.61, much beyond the permitted limit of 0.60, and the total KMO value was 0.82 (Yong & Pearce, 2013). Bartlett’s test of sphericity (χ2 = 2803.28, df = 465, p <0.000) showed that inter-item correlations were properly large to realize EFA (Taherdoost et al., 2022). A loading cutoff point of at least 0.40 was initially used. However, items INV14, IND6, IND18, and IND36 depicted communalities less than 0.40 and were thus dropped from the model. With the remaining 31 items, the final five-factor model explained 59% of the overall variation. The five constructs were Personalization (7 items), Involvement (6 items), Task Orientation (7 items), Innovation (7 items), and Individualization (4 items) with eigenvalues of 4.96, 4.15, 3.78, 3.58, and 1.81, correspondently (Table 2). Table 2 Exploratory factor analysis of the CLEI scale (Moroccan version) Factor/item Factor loading Eigenvalue Variance explained (%) Cronbach’s alpha Goodness of fit¶ Personalization 4.96 16 0.94 χ2/df = 1.31 PER1 0.85 RMSEA = 0.04 PER7 0.80 TLI = 0.92 PER13 0.83 PER19 0.82 PER25 0.82 PER31 0.85 PER37 0.85 Involvement 4.15 13.4 0.89 INV2 0.75 INV8 0.82 INV20 0.85 INV26 0.70 INV32 0.80 INV38 0.65 Task orientation 3.80 12.2 0.89 ORI4 0.79 ORI10 0.68 ORI16 0.73 ORI22 0.66 ORI28 0.82 ORI34 0.72 ORI40 0.68 Innovation 3.58 11.6 0.91 INO5 0.74 INO11 0.81 INO17 0.73 INO23 0.80 INO29 0.75 INO35 0.60 INO41 0.87 Individualization 1.81 5.8 0.74 IND12 0.63 IND24 0.70 IND30 0.60 IND42 0.70 ¶ Chi-square goodness-of-fit statistic/degree of freedom (χ2/df) (should be less than 3), root mean square error of approximation (RMSEA) (should be less than 0.05), Tucker Lewis Index (TLI) (should be less than 0.90) The constructs’ loadings oscillated from 0.60 to 0.87, demonstrating that all items appropriately measure their respective factors. All factors were highly reliable and well-defined by their items (CA = 0.74 - 0.94). The goodness-of-fit metrics were very satisfactory when using the fit threshold values (χ2/df = 1.31, RMSEA = 0.04, TLI = 0.92) (Finch, 2020). Partial Least-Squares Structural Equation Modeling Measurement model: Construct reliability and convergent validity The construct reliability, convergent validity, and discriminant validity were computed from the measurement model (Hair et al., 2019). We, therefore, analyzed the individual loads (λ) with their respective latent variables (λ ≥ 0.7 is accepted). CCA maintained five factors and discarded two items with lower loading values (INV20 = 0.34 and INO41 = 0.52). The construct reliability was estimated by the outer loading and CR values, while the convergent validity was assessed by the AVE values (Table 3 and Figure 2). Figure 2 PLS estimates for measurement model and structural model Every indicator below 0.7 crossed the 0.4 level, with ORI22 having the lowest value at 0.61. Whether to keep or delete an item depends on the high outer loadings of the other items and their impact on CR and AVE values when the outer loading is between 0.4 and 0.7 (Manfrin et al., 2019). The reliability coefficient for each of the constructs exhibits sufficient internal consistency of the measures since the CR coefficients for each construct were above 0.70 cutoffs (rhoC= 0.83-0.92). Concerning the convergent validity, the AVE values (0.56 - 0.71) demonstrated that the five constructs had reached the least benchmark of 0.50. As shown in Table 3, √AVE for each latent variable was higher than all factors matrix correlations, and the highest HTMT value was 0.27 (IND, SAT), below the maximum level of acceptable for HTMT levels. Moreover, the value “1” was not present in the HTMT confidence interval, represented by the values in brackets (Table 4). This demonstrated that the scale being employed had strong discriminant validity (Hair Jr et al., 2020). Table 3 Construct validity and reliability of PLS-SEM of CLEI Factor/item Factors loading Cronbach’s alpha Composite reliability (rhoC) AVE Personalization PER1 0.87 0.93 0.92 0.71 PER7 0.78 PER13 0.77 PER19 0.89 PER25 0.76 PER31 0.90 PER37 0.90 Involvement INV2 0.80 0.89 0.91 0.62 INV8 0.82 INV20 0.89 INV26 0.77 INV32 0.86 Task orientation ORI4 0.87 0.89 0.90 0.60 ORI10 0.77 ORI16 0.74 ORI22 0.61 ORI28 0.80 ORI34 0.78 ORI40 0.79 Innovation INO5 0.83 0.91 0.88 0.63 INO11 0.86 INO17 0.68 INO23 0.83 INO29 0.82 INO35 0.72 Individualization IND12 0.79 0.75 0.83 0.56 IND24 0.70 IND30 0.81 IND42 0.69 Satisfaction SAT3 0.89 0.92 0.90 0.70 SAT9 0.87 SAT15 0.77 SAT21 0.84 SAT27 0.67 SAT33 0.88 SAT39 0.85 Table 4 Discriminant validity coefficients Factor Fornell–Larcker test Heterotrait–monotrait ratio (HTMT) [2.5% - 97.5% CI] F1 F2 F3 F4 F5 F6 F1 F2 F3 F4 F5 PER 0.84 INV 0.16 0.82 0.22 [0.11, 0.33] ORI 0.12 -0.05 0.77 0.16 [0.12, 0.23] 0.14 [0.08, 0.22] INO 0.22 -0.17 -0.15 0.79 0.25 [0.12, 0.40] 0.22 [0.11, 0.35] 0.16 [0.11, 0.30] IND 0.06 0.02 0.18 -0.06 0.75 0.11 [0.10, 0.23] 0.17 [ 0.10, 0.25] 0.23 [0.13, 0.38] 0.19 [0.13, 0.27] SAT -0.10 -0.16 0.28 -0.12 -0.04 0.83 0.10 [ 0.08, 0.22] 0.17 [ 0.10, 0.30] 0.28 [0.17, 0.40] 0.13 [0.08, 0.24] 0.12 [0.07, 0.22] Structural Model Assessment All VIF values are lower than five, which ascertained the absence of a multicollinearity effect among CLEI factors (Table 5). The structural model was tested using a resample of 1000 bootstrap samples (Streukens & Leroi-Werelds, 2016). The standardized beta, t-test, p-value, and F square were estimated using the bootstrapping technique, specifying the hypotheses’ results. The direct effects of all the independent variables (PER, INV, ORI, INO, and IND) were considered while determining the impact of various constructs on the dependent variable (student satisfaction). Task orientation showed the greatest direct influence on student satisfaction (β = 0.29, t = 4.94, f2 = 0.10), followed by involvement with a weak negative significant effect (β = -0.14, t = -1.96, f2 = 0.02). Thus, task orientation might be the most important element influencing the students’ satisfaction in CLE. The beta value of 0.29 suggests a 29% variation in nurse students’ satisfaction explained by the ORI subscale. Meanwhile, PER, INV, INO, and IND showed no significant relationship with students’ satisfaction (f2 = 0.01). This gives support for the H01, H02, H04, and H05 hypotheses but fails to support the H03 hypothesis. Table 5 Path coefficients and hypothesis testing Hypotheses β 2.5% - 97.5% CI t-value p-value f2 Effect size VIF H01 PER→SAT -0.09 -0.28, 0.21 -0.70 0.24 0.01 No effect 1.13 H02 INV→SAT -0.14 -0.27, 0.00 -1.96 0.03* 0.02 No effect 1.10 H03 ORI→SAT 0.29 0.17, 0.40 4.94 0.001*** 0.10 Small 1.07 H04 INO→SAT -0.10 -0.27, 0.25 -0.65 0.26 0.01 No effect 1.14 H05 IND→SAT -0.09 -0.25, 0.13 -0.88 0.19 0.01 No effect 1.03 Discussion The CLEI reliability was examined using CA and CR, which were computed from EFA and PLS-SEM models. The convergent validity was examined using cross-loadings and AVE, while the discriminant validity was tested by the Fornell-Larcker and Heterotrait-Monotrait tests. All the subscales indicated acceptable CA values, ranging from 0.74 to 0.94, in agreement with previous studies (Chan, 2001, 2002a). The CR of the scale, estimated by computing rhoC, revealed that all the values lie above the standard value of 0.7, which reflects good reliability. Moreover, the levels of internal consistency are higher than those found in a previous study (Woo & Li, 2020). Of note, none of these previous studies, including those of Chan (2002b), has examined the factorial dimensions of the CLE scale using SEM techniques. In addition, very few studies reported factorial analysis of the CLEI scale, but surprisingly they computed CA from factors loadings as a test of reliability (Ergezen et al., 2022; Hudacek et al., 2019). However, contrary to CR, the CA coefficient does not take into consideration the varying factor loadings of the items. Thus, it is no longer warranted to rely solely on CA as a reliability indicator (McNeish, 2018). The main purpose of this study was to validate the CLEI scale in the Moroccan context following Chan’s scale structure, which considered the satisfaction scale the dependent variable (Chan, 2002a). Then, the five-factor scale was extracted through EFA and validated using a PLS-SEM approach because of the non-normal distribution and the sample size (Hair Jr et al., 2021). Interestingly, the results showed that a PLS-SEM using CCA generated the best model fit in terms of factor loadings for this version of the CLEI scale. The scale’s developing structural model was then verified using a Bootstrapping analysis approach. The current scale version showed good structural model fit characteristics and convergent and discriminant validity. However, Chan’s study (Chan, 2003) assesses the scale validity using only items and factor correlations. However, these first-generation methods are criticized due to the assumption that every variable is observable, error-free, and has a simple model structure (Hair et al., 2019). Associations between the satisfaction subscale and the CLEI-five subscales were investigated using PLS-SEM path analysis. The associations were not significant between students’ perceptions of personalization, innovation, and individualization, and their level of satisfaction, while there was a slightly and strongly significant association, respectively, for involvement and task orientation. Nevertheless, students who placed high importance on task orientation in their clinical environment reported much higher student satisfaction (β = 0.29, p <0.001). These results are partly in agreement with those of Chan (2002b), reporting that students who gave task orientation, involvement, individualization, and innovation a high priority in their clinical placement experienced significantly higher satisfaction levels (β = 0.17-0.37). The latter demonstrated that student satisfaction is significantly greater in students who highly valued task orientation, involvement, individualization, and innovation in their clinical placement (β values ranged from 0.17 to 0.37). Whereas, and in congruence with our findings, they showed the highest standardized path coefficient of direct effect from Task Orientation to students’ satisfaction (β = 0.37, p <0.001). This ascertains that nurse students put more emphasis on the importance of task orientation, which reflects the extent to which guidelines for clinical activities are well planned. Several studies on this topic confirmed that many nursing students found clinical experiences to be anxiety-inducing and frequently felt exposed to these settings due, in part, to the lack of clear instructions given to students (Kushnir et al., 2014). Therefore, clinical educators must examine how vulnerable nursing students are on the clinical wards as a potential means of lowering their anxiety (Chan, 2002a). On the other hand, and in agreement with a previous study (Henderson et al., 2012), no association had been demonstrated between innovation and student satisfaction. This pleads in favor of possible students’ disinclination towards innovation, which may indicate that educators adopt a teacher-centered approach rather than a student-centered approach (Abualhaija, 2019). In addition, these findings are in dissonance with those of Chan (2002b) concerning other construct associations. This could be attributed to the caveats that underlie the first-generation multivariate methods used by previous studies, including multiple regression analysis. The latter assumes a simple model structure involving one layer of dependent and independent variables that can only be estimated piecewise rather than simultaneously with SEM, which could, subsequently, distort the quality of the result (Sarstedt et al., 2020). Additionally, since students’ perceptions may fluctuate depending on the unique traits of each country, various factorial designs might reveal cultural variations through different settings. For instance, Moroccan students might be less sensitive to authorities compared to European people (Ciavolino et al., 2022; Mohammadi et al., 2020). This might explain why Moroccan students did not place much emphasis on the personalization dimension when compared to previous studies (Chan, 2001). But this does not exclude the positive impact of interpersonal relationships between clinical ward participants on the students’ outcomes (Ergezen et al., 2022). Limitations The study was carried out in one Moroccan region with a sample size that did not include all the wards’ students. This limits its generalizability across the country’s subpopulations. In addition, the participants were enrolled in diverse clinical settings from three different areas, which vary broadly in terms of infrastructure and the quality of supervision. So, combining these differences in one sample could bias the results because some had especially positive experiences, compared to perhaps negative ones for others. Moreover, it seems necessary to investigate both CLEI scale forms (actual and preferred versions) to effectively address students’ expectations. Implications of the Study CLEI was specifically developed to define the learning environment constructs. With an emphasis on individualization, innovation, involvement, personalization, and task orientation, this conceptual model investigated the predictability of students’ cognitive and attitude outcomes. The main purpose of this work was the investigation of the CLEI-scale validation in the Moroccan context following Chan’s scale structure and the relationships between students’ satisfaction and each CLEI construct. Indeed, the scale was validated, and the students’ satisfaction seems to be more impacted by the task orientation subscale than other subscales. This study raises the question of the pedagogical skills of nurse educators in CLE. These aspects were not explored in this work but should be investigated further by a qualitative study. Therefore, the implications of our findings are multifold. First, a Moroccan version of the CLEI Scale has been psychometrically investigated for further extensive use in Morocco. This is of paramount importance because the studied scale could fill a complete lack of valid instruments to gauge the CLE in Moroccan wards. Second, this widely used scale has been thoroughly explored for the first time by the PLS-SEM techniques, which sheds new light on the psychometric characteristics of Chan’s conceptual model. Conclusion The results of this study reflect the prior work of Chan (2001) in terms of the psychometric properties of the CLEI scale. Task orientation was found to be strongly connected with students’ levels of satisfaction following their clinical placement. Consequently, the students showing high expectations for task orientation demonstrated a highly positive perception of their clinical placement outcome. Contrary to other cultural backgrounds, personalization, involvement, innovation, and individualization subscales showed insignificant direct effects on the students’ satisfaction in the Moroccan context. Therefore, it is of paramount importance that clinical educators tailor their instructions to the students’ needs to enhance learning and reduce anxiety in clinical settings. Overall, this study is the first to use SEM techniques to validate the CLEI instrument in Moroccan clinical wards. Furthermore, because this short CLEI version is a rapid, accurate, and reliable tool for evaluating CLE, nursing facilitators may use it to assess student outcomes and improve clinical supervision. Acknowledgment We are grateful to all the students, tutors, and administrators who participated voluntarily in the study. We also thank all the health professionals working in hospitals and dispensaries who helped us recruit participants for our research. Declaration of Conflicting Interest The authors reported no potential conflict of interest. Funding None. Authors’ Contributions KS has contributed to data acquisition, data analysis, and manuscript drafting. MYA analyzed data, wrote, and revised the manuscript. MEAR has contributed to the acquisition, analysis, conceptualization, and editing of the work. ZB has conceptualized, designed, reviewed, and edited the manuscript. AT analyzed data and reviewed and edited the manuscript. YEA analyzed, reviewed, and edited the manuscript. JEH has contributed to the conceptualization, design, statistics, and writing of the manuscript. All authors agreed with the final version of the article to be published. Authors’ Biographies Khadija Saka is a PhD student at the Higher Institute of Nursing Professions and Technical Health, Fez, Morocco. She is also a nurse educator and trainer at the same institute. Mohamed-Yassine Amarouch, PhD is an Associate Professor in the Polydisciplinary Faculty, Taza, SMBA University. His research interests lie in cardiology and nursing education. Mohamed El Amine Ragala, PhD is an Assistant Professor at Teachers Training College and an Associate Researcher in the Laboratory of Epidemiology, Faculty of Medicine and Pharmacy, Fez, Morocco. He is also a Lecturer in the School of Nursing. His main research interests lie in therapeutic education. Zarrouq Btissame, PhD is an Associate Professor at Teachers Training College and Faculty of Medicine and Pharmacy, Fez. She is also a Lecturer at the school of nursing in Fez city. Her main research interests lie in epidemiology and Psychometrics. Adel Tahraoui, PhD is an Associate Professor at Teachers’ College Training. He is also a Lecturer of Pharmacology at the Faculty of Science. His research interests lie in pharmacology and education. Youness El Achhab, PhD is an Associate Professor at Teachers’ College Training. He is a member of the Laboratory of Epidemiology in the Faculty of Medicine and Pharmacy, Fez. His main research interests lie in epidemiology and education. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-179 10.33546/bnj.1424 Original Research Influence of self-esteem, psychological empowerment, and empowering leader behaviors on assertive behaviors of staff nurses https://orcid.org/0000-0001-9107-3069 Oducado Ryan Michael F. * West Visayas State University, College of Nursing, Iloilo City, Philippines Corresponding author: Dr. Ryan Michael F. Oducado, West Visayas State University, College of Nursing, La Paz, Iloilo City, Philippines, 5000. Email: rmoducado@wvsu.edu.ph Cite this article as: Oducado, R. M. F. (2021). Influence of self-esteem, psychological empowerment, and empowering leader behaviors on assertive behaviors of staff nurses. Belitung Nursing Journal, 7(3),179-185. https://doi.org/10.33546/bnj.1424 28 6 2021 2021 7 3 179185 15 3 2021 16 4 2021 03 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Being assertive is essential skill nurses need to learn and develop. While many studies exist on nurses’ assertiveness, there is limited research on the factors associated with Filipino nurses’ assertive behaviors. Objective This study examined the correlation of self-esteem, psychological empowerment, and leader empowering behaviors on staff nurses’ assertiveness in the workplace. Methods This cross-sectional study conducted in 2019 involved 223 staff nurses working in two tertiary hospitals in the Philippines. Data were gathered using four validated self-reported scales: self-esteem scale, psychological empowerment scale, leader empowering behavior questionnaire, and workplace assertive behavior questionnaire. Correlational analysis using Pearson’s r was performed to test the relationship between the key variables. Results The composite scores for the self-esteem, psychological empowerment, empowering leader behaviors, and workplace assertiveness were 32.06 (SD = 3.65), 4.22 (SD = 0.43), 3.86 (SD = 0.51) and 3.61 (SD = 0.55), respectively. Self-esteem (r = 0.216; p = 0.001), psychological empowerment (r = 0.455, p = 0.000), and empowering leader behaviors (r = 0.269; p = 0.000) were significantly correlated with staff nurses’ assertiveness in the workplace. Conclusion Self-esteem, nurse leadership behaviors, and empowerment play vital roles in staff nurses’ assertiveness. Understanding the factors influencing nurses’ assertiveness is important, and looking into these variables can be beneficial for nursing management when developing strategies to build nurses’ assertiveness. Thus, it is vital to focus on helping nurses nurture healthy self-esteem and initiate empowering conditions at work to aid nurses in setting healthy boundaries and supporting assertive behaviors at work. assertiveness leadership nurses self-concept workplace Philippines ==== Body pmcAssertiveness is the ability to express your ideas, interests, thoughts, feelings, beliefs, and needs freely, clearly, confidently, and honestly, without denying or violating others’ rights (Alberti & Emmons, 2008; Oducado, 2021). Assertiveness is an important skill that nurses must learn to acquire and need to develop (Oducado, 2021; Yoshinaga et al., 2018). With the advancements and developments in healthcare, nurses are expected to exhibit assertiveness to work with other health care professionals effectively, thereby impacting positively patient safety and outcome (Okuyama et al., 2014a). Being the largest workforce in the hospital settings, nurses are uniquely positioned to speak up for changes in the care plan of their patients if they see it deemed necessary (Hall, 2016). In other words, nurses need to speak up or call the attention of the healthcare team member when they see a problem with regards to patient care, when standard processes are not followed, or when improper practices are observed. However, being assertive and speaking up can be challenging for nurses, and that silence still prevails in many nursing situations (Okuyama et al., 2014b; Rainer, 2015; Schwappach & Richard, 2018). The importance of assertiveness in nursing cannot be overemphasized. Firstly, assertiveness is necessary for establishing a trusting nurse and patient relationship and communicating effectively with patients and members of the health team (Larijani et al., 2017; Mushtaq, 2018). Assertiveness is required for openness to speak up, is instrumental in ensuring patient safety, and is integral to professional accountability (Nacioglu, 2016; Reid & Bromiley, 2012). Additionally, nurses are ethically, morally, and legally bound to question an inappropriate or incorrect doctor’s order and speak up to protect patient’s rights and safety (Rainer, 2015; Reuter & Fitzsimons, 2013). Patient advocacy is an important nursing responsibility (Gerber, 2018). Nurses have the critical role as patient advocates, serving as voices of their patients (Palatnik, 2016). The State Practice Acts in other countries like the United States of America mandate that nurses act as patient advocates (Gerber, 2018). The Code of Ethics of Filipino Registered Nurses explicitly states that nurses should take appropriate steps to safeguard the rights and privileges of their patients (Board of Nursing of the Philippines, 2004). Being assertive means nurses are defending and safeguarding the rights of their patients. Nurses have to be assertive enough to preserve their rights as well as the rights of their clients (Mushtaq, 2018). Lastly, assertiveness is a means which can be used to combat negative and stressful situations like mobbing, conflict situations, to communicate better, and to enhance empowerment (Asi Karakas & Okanli, 2015; Deltsidou, 2009). Given the importance of assertiveness in nursing, identifying variables that influence or promote assertiveness is therefore necessary. Some prior studies conducted elsewhere studied the factors affecting assertiveness among nursing students (Ibrahim, 2011; Larijani et al., 2017). Other scholars investigated the effectiveness of assertiveness training on nurses (Asi Karakas & Okanli, 2015; Kanade, 2018; Nakamura et al., 2017; Shimizu et al., 2004; Yoshinaga et al., 2018) and nursing students (Omura et al., 2019). Variables such as self-esteem (Binuja, 2020; Maheshwari & Gill, 2015; Shrestha, 2019) and psychological empowerment (Azizi et al., 2020; Bostanabad et al., 2018; Ibrahim, 2011) were found to be associated with assertiveness. However, for most studies, these variables were correlated with general assertiveness and not specifically with workplace assertiveness of nurses. Studies have also shown that leadership, managerial, and administrative support influenced speaking-up and voicing behaviors (Darawad et al., 2020; Lee et al., 2021; Okuyama et al., 2014a; Wong et al., 2010), but the role of leader empowering behaviors on assertiveness has not been investigated. Besides, the studies earlier cited were conducted in other countries and not in the context of Filipino nurses. Although there has been growing research on nurses’ assertiveness abroad, there is a scarcity of published research looking into the factors associated with nurses’ assertiveness in a generally collectivist culture like the Philippines. In general, the Filipino culture and their Asian counterparts are predisposed to be conformist, collective, and group-oriented instead of individualistic and assertive (Niikura, 1999). Assertiveness is frowned upon as it can be suggestive of pride, and some Filipino traits work against it. Alongside this backdrop, this study was conducted to determine the influence of self-esteem, psychological empowerment, and empowering leader behaviors on staff nurses’ workplace assertiveness. Methods Research Design A cross-sectional study design was adopted. Sample and Setting The participants were registered nurses with staff nurse positions (N = 403) from two randomly selected tertiary hospitals in the Western Visayas part of the Philippines. Tertiary or teaching and training hospitals were chosen since these hospitals had a greater number of nurses compared to other hospital levels. The Slovin’s formula n = N/(1+Ne2) cited in Almeda et al. (2010) was used to compute the sample size yielding the desired sample size of 201. Also, priori power analysis using G*Power 3.1 software suggested that a sample size of 84 staff nurses would already be sufficient to achieve a statistical power of 0.80 in bivariate correlation analysis with 0.05 alpha and 0.30 medium effect size (Faul et al., 2009). However, to enhance the geographical diversity per hospital unit or department, the researcher included more than the desired sample size. A total of 230 questionnaires were randomly distributed and administered to staff nurses; 223 responded, obtaining a response rate of 97%. This study only involved staff nurses. Nurses occupying supervisory positions, trainees, volunteers, over 65 years old and employed in other hospitals were excluded from the study. Instruments Data were gathered using four validated self-reported scales used among nurses in studies conducted in other countries. The authors of the scales granted permission to use the instruments in the current study through email correspondence. Self-esteem Scale (SES) (Rosenberg, 1965). The 10-item SES was used to measure nurses’ global self-worth. Nurses were asked to rate each item using a 4-point scale (1 = strongly disagree to 4 = strongly disagree). The SES had a fairly acceptable internal consistency of 0.75 in nursing samples (McMullen & Resnick, 2013) and 0.77 among Filipino youths and adolescents (Reyes et al., 2017). Psychological Empowerment Scale (PES) (Spreitzer, 1995). This 12-item scale with four subscales (meaning, competence, self-determination, and impact) was used to measure nurses’ psychological empowerment. All items were answerable in a 5-point Likert scale format (1 = strongly disagree to 6 = strongly agree). Studies conducted among nurses reported fairly high Cronbach’s alpha values of 0.80 and above (Shapira Lishchinsky & Benoliel, 2019; Uner & Turan, 2010). Leader Empowering Behavior Questionnaire (LEBQ) (Konczak et al., 2000). This scale was administered to measure staff nurses’ perception of the empowering behaviors of their leader. The LEBQ by Konczak et al. (2000) originally consisted of 17 items, but Bester et al. (2015) recently added two items. The 19-item version of the scale was utilized in this study, consisting of six subscales: accountability for outcomes, self-directed decision-making, information sharing, skills development, delegation of authority, and coaching for innovative performance. Nurses responded using a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree). The LEBQ was previously pilot-tested among Filipino nurses (Oducado, 2019). Konczak et al. (2000) reported reliability coefficients that range between 0.82 and 0.88. Workplace Assertive Behavior Questionnaire (WABQ) (Timmins & McCabe, 2005a, 2005b). This scale was utilized to assess nurses’ assertiveness in the workplace. The participants were asked to indicate how often they use the eight assertive behaviors towards their nursing colleagues or co-staff nurses, the nursing management (head nurses or supervisors), and the medical personnel (doctors or physicians). Nurses were asked to answer using a 5-point Likert scale (1 = never to 5 = always). Timmins and McCabe (2005a, 2005b) stated an acceptable internal consistency (α = 0.88) of items within the questionnaire. For all the scales in this study, higher scores indicate a higher level of self-esteem, psychological empowerment, leader empowering behaviors, and assertiveness in the workplace. The personal characteristics of nurses were also collected. To make sure that the result of this study will be culturally sensitive and to increase its scientific accuracy, the instruments were subjected to face and content validation and pilot testing. Seven local experts with master’s or doctoral degrees and relevant experience and training in nursing, management, and psychology evaluated the items in the instruments to be relevant, clear, and culturally appropriate. A survey instrument validation rating scale was used in the validation of instruments (Oducado, 2020). Pilot testing was done among 30 nursing staff in another hospital. Preliminary reliability testing and actual survey revealed acceptable to high internal consistency values of SES (α = 0.87, α = 0.71), PES (α = 0.88, α = 0.88), LEBQ (α = 0.91, α = 0.89) and WABQ (α = 0.95, α = 0.92). Five participants during the pilot test were interviewed to share their comments about the instruments. No further changes were made to the instruments as per the acceptable result of pilot testing. Data Collection The survey was conducted between June to July of 2019. Before actual data gathering, administrative clearance to conduct the study was obtained from the Hospital Director through the Director of Nursing. In coordination with the Nursing Service Office, the researcher and trained data gatherers distributed the survey instruments inside a sealed envelope to staff nurses either before they go on duty or after shift. Staff nurses were briefly oriented regarding the purpose of the study, were allowed to ask questions, and were given the opportunity to refuse to join the study. The participants were asked to answer the forms at their most convenient time and place and were asked to return them sealed to the researcher or data gathers to ensure confidentiality of responses. The researcher allocated sufficient days for data collection to allow the adequate representation of staff nurses despite shifting schedules of staff nurses, and the participants were given ample time to answer the survey. During retrieval, the completeness of data entry was checked. Data Analysis After data checking and cleaning, the responses were encoded and computer-processed via the IBM Statistical Package for the Social Sciences (SPSS) software version 23. Frequency (n), percentage (%), mean (M), and standard deviation (SD) were used to quantify and describe the data. Kolmogorov-Smirnov (p = 0.20) and Shapiro-Wilk (p = 0.31) indicated that data do not significantly deviate from normal distribution. The Pearson’s r correlation coefficient was used to determine the relationship between the key variables of the study. The correlation coefficient was interpreted following the work of Schober et al. (2018): + 0.90-1.00 = very strong positive (negative) correlation, + 0.70-0.89 = strong positive (negative) correlation, + 0.40-0.69 = moderate positive (negative) correlation, + 0.10-0.39 = weak positive (negative) correlation, and + 0.00 to 0.10 = negligible positive (negative) correlation. A p-value equal to or less than 0.05 was considered the level of acceptable significance. Ethical Consideration The study was reviewed and approved by the Ethics Committee of the West Visayas State University. A written informed consent form was obtained from all participants. No personal identifiers were collected to protect the anonymity of the participants and the confidentiality of the data. This report is part of a larger study exploring Filipino nurses’ assertiveness. Results Table 1 shows that the mean age was 32.34 years (SD = 8.14), and the average number of years of nursing work experience was 7.36 years (SD = 6.41). The majority were female (n = 153, 68.6%) and Bachelor’s degree holders (n = 150, 67.3%). There was an almost equal number of participants from public (n = 113, 50.7%) and private (n = 110, 49.3%) hospitals. There were 126 (56.5%) staff nurses assigned in specialty areas and 97 (43.5%) in medical and surgical units. Overall, the composite scores of the key variables in this study were above midpoint (Table 2). The composite score of nurses’ self-esteem was 32.06 (SD = 3.65), whereas the composite scores of the measures of psychological empowerment and leader empowering behaviors were 4.22 (SD = 0.43) and 3.86 (SD = 0.51), respectively. Assertiveness in the workplace had a composite score of 3.61 (SD = 0.55). The correlation between variables is presented in Table 3. There was a positive, weak, significant correlation between nurses’ level of self-esteem (r = 0.216; p = 0.001) and assertiveness and staff nurses’ perception of the empowering behaviors of their leaders (r = 0.269; p = 0.000) and assertiveness. Moreover, statistical analysis revealed a positive, moderate, significant correlation between psychological empowerment (r = 0.455, p = 0.000) and assertiveness in the workplace. Table 1 Profile of staff nurses Profile Categories M SD n % Age 32.34 8.14 Years of experience 7.36 6.41 Sex Male 70 31.4 Female 153 68.6 Education Bachelor’s degree 150 67.3 Bachelor’s degree with Master’s units 73 32.7 Type of hospital Public 113 50.7 Private 110 49.3 Hospital unit Specialty Areas 126 56.5 Medical and Surgical 97 43.5 Table 2 Description of the key variables Scales/Subscales M SD Self-esteem 32.06 3.65 Psychological Empowerment 4.22 0.43  Meaning 4.51 0.50  Competence 4.26 0.52  Self-determination 4.13 0.52  Impact 3.97 0.58 Leader Empowering Behaviors 3.86 0.51  Accountability for outcomes 4.07 0.63  Self-directed decision-making 3.89 0.69  Information sharing 3.88 0.66  Skills development 3.87 0.73  Delegation of authority 3.85 0.58  Coaching for innovative performance 3.62 0.72 Assertiveness in the Workplace 3.61 0.55  Toward nursing colleagues 3.78 0.55  Toward medical personnel 3.65 0.65  Toward management personnel 3.40 0.68 Table 3 Correlation of independent variables to assertiveness Independent variables Pearson’s correlation (r) p-value Self-esteem 0.216 0.001* Psychological Empowerment 0.455 0.000*  Competence 0.434 0.000*  Impact 0.412 0.000*  Self-determination 0.351 0.000*  Meaning 0.272 0.000* Leader Empowering Behaviors 0.269 0.000*  Accountability for outcomes 0.355 0.000*  Delegation of authority 0.262 0.000*  Self-directed decision-making 0.200 0.003*  Information sharing 0.192 0.004*  Coaching for innovative performance 0.173 0.010*  Skills development 0.111 0.098 Discussion The present study looked into the influence of self-esteem, psychological empowerment, and leader empowering behaviors on nurses’ workplace assertive behaviors. This study demonstrated that self-esteem had a positive, weak, yet significant correlation with nurses’ workplace assertiveness. Healthy self-esteem is important to learning to be assertive, or being assertive can lead to high levels of self-esteem. Healthy self-esteem represents a critical asset or necessary quality in developing assertiveness (Darjan et al., 2020). It can be difficult for nurses to assert themselves when nurses have low self-esteem. Those with low self-esteem are likely to encounter problems defending their opinions or making decisions for themselves (Darjan et al., 2020). Studies among Japanese and Indian nurses found that nurses’ self-esteem improved after assertiveness training (Kanade, 2018; Shimizu et al., 2004). Similarly, a significant positive correlation between assertive behavior and self-esteem was reported in a study conducted in India among nurses (Binuja, 2020; Maheshwari & Gill, 2015) and in Nepal among nursing students (Shrestha, 2019). This study proposes that efforts should be made to improve and to achieve healthy and balanced self-esteem among nurses to better communicate and assert themselves in the workplace. This study also found that psychological empowerment was significantly related to assertiveness in the workplace with a moderate positive correlation. Results of the current study also indicated a significant correlation between all the components of psychological empowerment and workplace assertiveness. This finding indicates that a higher level of psychological empowerment, such as giving nurses the authority to make decisions and enhancing their competence, results in higher levels of assertiveness. This finding is relatively consistent with that of the study of Azizi et al. (2020) and Ibrahim (2011). The authors found a significant positive relationship between psychological empowerment and assertiveness with samples of midwifery and nursing students in Iran and nursing students in Egypt. A similar finding was reported among Iranian neonatal nurses (Bostanabad et al., 2018). The result of this study suggests the importance of empowering nurses for them to act more assertively. Accordingly, it is necessary to pay attention to improving nurses’ competence, independence, and autonomy, likewise creating better opportunities for nurses to appreciate the impact and value of their work for them to exhibit assertiveness. Finally, it was shown in this study that there was a positive, weak, but significant relationship between leader empowering behaviors and workplace assertiveness of staff nurses. It has been disclosed that managerial and organizational support enables nurses to become more assertive, empowered, and speak up against unsafe practices, and the process of becoming assertive or learning to speak up tends to be influenced by the management’s approach toward nurses (Darawad et al., 2020). Garon (2012) likewise discovered that the strongest theme for nurses to speak up was related to a climate of openness that is generally created by the leaders (managers and administration). The role of a supportive working culture in facilitating nurses’ ability and willingness to voice concerns was also noted in another study (Mansour et al., 2020). Correspondingly, the study of Wong et al. (2010) revealed that authentic leadership influenced nurses’ trust in their manager, which predicted voicing behavior. Review studies similarly noted that hospital administrative support and attitude of leaders or superiors were actors influencing health care professionals and nurses’ speaking-up behavior for patient safety (Lee et al., 2021; Okuyama et al., 2014a). The finding of this current study indicates the valuable role of nurse leaders and managers in supporting nurses to exhibit assertive behaviors. Nurses tend or are likely to assert themselves when assertive behavior is supported in the workplace. It is, therefore, vital for the nursing management to set up empowering conditions at work, such as increasing nurses’ accountability, autonomy, and self-directed decision-making to support nurses’ assertive behaviors. In the process of becoming more assertive, managerial and organizational support should also be in place to grant nurses the necessary power, autonomy, and access to resources to exercise assertive behaviors (Darawad et al., 2020). Some shortcomings were encountered in this study that could be addressed by future scholars. This research was limited among nursing staff in two tertiary hospitals. Caution is recommended when results of the present study are extrapolated with all Filipino nurses and nurses working in other countries and other healthcare sectors. It might be useful to replicate the study on a larger scale involving nurses from different countries. Another limitation is the study design (cross-sectional) has temporal limitations and cannot establish causality between the variables. The use of survey questionnaires is subjected to self-reported bias. Validating self-reported data through method triangulation may be conducted in future studies. There may also be other factors influencing nurses’ assertiveness, such as personality and emotional intelligence not included in this analysis. Nevertheless, this research has contributed to a better understanding of the factors influencing nurses’ assertiveness in the workplace. Conclusion This research highlighted that higher levels of self-esteem, psychological empowerment, and empowering behaviors of the leader result in higher workplace assertiveness among nursing staff. Nurse leadership behaviors and empowerment play vital roles in staff nurses’ assertiveness. The results suggest that empowered nurses are assertive nurses. Also, helping nurses nurture healthy self-esteem and improve their confidence can potentially lead to better assertive behaviors in the workplace and assist nurses in setting and maintaining healthy boundaries. Nurses’ evaluation of themselves and empowering conditions significantly contribute to nurses’ assertiveness or their chosen method of communicating with others in social interactions. Understanding and looking into these factors can help the nursing management develop strategies to build and improve nurses’ assertiveness. Interventions and necessary platforms aimed at enhancing nurses’ self-worth should be initiated. At the same time, efforts must be directed towards fostering greater empowerment at the individual and organizational levels to promote assertiveness in the workplace. Acknowledgment The author would like to thank the Hospital Administration and Nursing Directors for allowing the researcher to conduct the study and all the staff nurses who participated in the study. The author would also like to express his gratitude to Dr. Hilda C. Montaño for her guidance in the completion of this study. Lastly, the author wishes to acknowledge the Philippine Commission on Higher Education for the support awarded to the researcher. Declaration of Conflicting Interest The author has no conflict of interest to declare. Funding This research received funding from the West Visayas State University – University Research and Development Center. Author Contribution The author made a substantial contribution from the conception, finalization, and writing of the final version of this article. Author Biography Ryan Michael F. Oducado, PhD, RN, RM, LPT is an Assistant Professor at West Visayas State University, College of Nursing, Iloilo City, Philippines. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-235 10.33546/bnj.1332 Original Research Psychometric properties of Quality-of-Life Index for Vietnamese women with breast cancer three weeks postmastectomy https://orcid.org/0000-0002-7055-1540 Xuan Ha Thi Nhu 1* https://orcid.org/0000-0001-6638-2863 Thanasilp Sureeporn 2 1 Faculty of Nursing and Medical Technology, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam 2 Faculty of Nursing Chulalongkorn University, Bangkok, Thailand Corresponding author: Dr. Ha Thi Nhu Xuan, PhD, APN, RN, Faculty of Nursing and Medical Technology, University of Medicine and Pharmacy at Ho Chi Minh City, 217 Hong Bang street, District 5, Ho Chi Minh City, Vietnam. Mobile: +84 356435986. Email xuanha@ump.edu.vn Cite this article as: Xuan, H . T . N., & Thanasilp, S. (2021). Psychometric properties of Quality-of-Life Index for Vietnamese women with breast cancer three weeks postmastectomy. Belitung Nursing Journal, 7(3), 235-245. https://doi.org/10.33546/bnj.1332 28 6 2021 2021 7 3 235245 01 2 2021 02 3 2021 10 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The patient’s quality of life immediately after mastectomy usually receives less attention than the quality of life after three months, six months, or a year. It is because the focus is mainly on surgical complications. Many instruments measure the quality of life from three months onwards. Still, the quality-of-life instruments right after postmastectomy are not yet verified. Objective This paper aimed to test the reliability and validity of the Quality-of-Life Index Vietnamese version (QOLI-V) in Vietnamese women with breast cancer three weeks postmastectomy. Methods The descriptive cross-sectional study was designed to analyze the psychometric properties of a Vietnamese version of the modified Quality of Life Index. The modified process was conducted after granting permission from the original authors. The content validity of the modified index was examined by five experts. Brislin’s model was used for the translation process. The 26-item QOLI-V was tested in 265 patients with breast cancer stage II three weeks postmastectomy who expected to have a poorer quality of life score. The reliability of the index was measured using Cronbach's alpha. The construct validity was examined using confirmatory factor analysis (CFA). Result The content validity index results showed that the lowest I-CVI was .80 and the highest was 1.00. S-CVI/Ave was 0.95, and S-CVI/UA was 0.76. The Cronbach's alpha of QOLI-V was .84, which was considered acceptable. Most of the 26 items featured the correct item-total correlation of .30 to .60. There were only two items correlated with the total scale at .18, and the item with the lowest correlation (.06) was deleted from the item set. The CFA of model 1 with 26 items was not an ideal fit with the data, with Chi-Square/df = 2.15, CFI = .815, GFI = .853, TLI = .792, RMSEA = .066. After deleted an item #general quality of life, and the CFA of model 2 was conducted on the 25-item index. The final result indicated the improvement of the model fit, with Chi-Square/df =2.26, CFI = .852, GFI = .814, TLI = .790, RMSEA = .069. Conclusion The 25-item QOLI-V version is considered valid and reliable to measure the quality of life of Vietnamese women with breast cancer three weeks postmastectomy. Nurses and midwives could use this instrument to measure the quality of life of the patients, and the patients could use it for self-assessment. quality of life mastectomy factor analysis psychometrics nursing Vietnam ==== Body pmcPatients with breast cancer feel considerable uncertainty when diagnosed with a life-threatening (or terminal) illness. Later on, patients facing the treatment process realize these are events they could not foresee and are therefore wholly unprepared. From systematic reviews, the stage from mastectomy one month to initial chemotherapy represented a transition time of poor adjustment and decreased quality of life (Paraskevi, 2012). However, most of the studies focus on describing and providing support for quality of life as much as three months, six months, or over one year postmastectomy, but ignoring the immediate poor quality of life for the patients in the hours, days, and weeks after their mastectomy during the transition from hospital to home (Razdan et al., 2016). According to previous studies, it has been shown that decreased quality of life after surgery may predict early treatment discontinuation in patients with breast cancer (King et al., 2000; Richardson et al., 2007). The later poor quality of life will lead to reoccurrence, metastatic, or even death among this group (Coates et al., 2000; Mols et al., 2005). Thus, poor quality of life in patients with breast cancer postmastectomy exists as an urgent problem and requires effective interventions to reduce it. In addition to introducing a measure for the concept of quality-of-life postmastectomy, a reliable and valid scale must necessarily be established. Definition of Quality of Life of Patients Postmastectomy Quality of life (QOL) is the primary goal that most people attain during their daily life. Since this concept has been recognized, QOL is not separate from health because it is considered as the person’s sense of well-being that stems from the satisfaction and dissatisfaction with aspects of life (Ferrans, 1990) or functional capacity, symptoms (physical and psychological) and perceptions of health (Mccorkle et al., 1989). The quality of life in the nursing context is related to a specific illness, and it can be considered similar meaning with health-related quality of life. A concept analysis of nursing, based on the guiding theory of Peplau’s, Rogers’, Leininger’s, King’s, and Parse, is defined as a contextual, intangible, subjective perception of one’s lived experience (Plummer & Molzahn, 2009). Cella (1994) identified four dimensions of quality of life in the context of cancer that encompasses physical well-being, functional well-being, emotional well-being, and social well-being. The concept of Cella (1994) and its four significant domains of quality of life help investigate the concept multi-dimensionally. Besides, (Padilla & Grant, 1985) describe the quality of life as five dimensions: physical well-being, social concerns, body image concerns, psychological well-being, and diagnosis/treatment response. In breast cancer, the concept of QOL describes the impact of breast cancer on the domains of physical, social, psychological well-being, and spiritual well-being (Ferrell et al., 1998). Receiving a mastectomy also raises concerns about body image, uncertainty in the situation of illness, surgical symptoms, lacking nursing care or social support, and poor patient-physician communication impacting the patient’s quality of life (Denieffe et al., 2014; Mandelblatt et al., 2003; Wronska et al., 2007). Thus, in patients with breast cancer postmastectomy, the concept of quality of life should be more specific, clearly describing the situation, which occurs among this group. That is why the definition of QOL defined by Padilla and Grant (1985) as physical well-being, social concerns, body image concerns, psychological well-being, and diagnosis/treatment response remains the most suitable application for QOL postmastectomy. Following Padilla and Grant (1985), physical well-being can be considered a strength, fatigue, ability to work, current health, and perceived usefulness. Psychological well-being implies happiness, satisfaction, fun, general QOL, pleasure in eating and sleep. The body image concerns mean the ability to look at the changes in one’s body, the tendency to worry, and the ability to adjust and live with body changes. The social concerns focus on social rejection, social contact, or the need for privacy. Diagnosis/treatment response relates to surgical treatment symptoms, which are defined as the ability to have sufficient sexual activity, nutrition, weight, pain, and severity of pain, nausea, and vomiting (Padilla & Grant, 1985). In postmastectomy patients, the attributes of physical, psychological, and social concerns of QOL might be the same as other cancers; however, the defining attributes of body image and treatment response might differ. The body image in breast cancer patient postmastectomy relates to the ability to look at the changes of the body, worry over scarring, perceived femininity, and how easy it is to live with anybody changes (Barolia, 2008; Denford et al., 2011; Fobair et al., 2006; Lindwall & Bergbom, 2009; Toriy et al., 2013). The treatment response of mastectomy patients focuses on symptoms around the hand and shoulder such as the ability to raise the hand, any swelling of the arm, the sensitivity of the breast incision, sufficient nutrition, weight, as well as the severity and frequency of pain (Champion et al., 2014; Janz et al., 2007; Taghian et al., 2014). Operationally, the concept of quality of life on postmastectomy patients is defined as the perception of life experienced based on five domains: physical well-being, psychological well-being, body image concerns, social concerns, and treatment responses. Defining attributes of QOL consist of physical well-being (strength, fatigue, ability to work, current health and perceived usefulness), psychological well-being (happiness, satisfaction, fun/hobbies, eating pleasure and sleep), body image concern (look at the body, scare of scarring, perceived femininity, ability to live with losing a breast, the worry of future living without a breast), social concerns (family, friends or healthcare giver staff contact, social rejection, and privacy needs and treatment responses (ability raising the hand, swelling of the arm, sensitive of destroying breast, nutrition sufficient, weight, severity, and frequency of pain) Existing Instruments Most of the effective existing instruments measuring the quality of life for patients with breast cancer are all well-known instruments that have been used to examine QOL in many stages of breast cancer (Perry et al., 2007). Among those, FACT-B and EORTC-BR23 are specific for patients during chemotherapy treatment. QOL-BR23 focuses on physical function, whereas FACT-B emphasizes emotional well-being (Nguyen et al., 2015). EORTC-QLQ30 and SLDS-BC or QOLI are suitable for QOL in general. Interestingly, the QOLI of Padilla and Grant (1985) is based on the concept of QOL across a range of cancers in women, though sharing similar circumstances to breast cancer patients, such as cervical cancer, colorectal cancer, and hysteric cancer post-surgery. The original QOLI of Padilla and Grant (1985) identifies 14 factors and has been validated in many studies measuring QOL; hence it has proven validity and reliability (Rukholm et al., 1998). Over time, the QOLI has been modified for colostomy patients by adding nine items focusing on some aspects of symptoms post-surgery. The dimensions of QOLI would seem to be closest to the definition of quality-of-life postmastectomy with five domains of physical well-being, psychological well-being, social concerns, body image concerns, and treatment/diagnosis response. The length of 23 items with self-administer base on the visual line for the most concern in the past four weeks. Summarily, with the same aspects of colostomy and mastectomy on colorectal and breast cancer patients, the QOLI of Padilla and Grant (1985) covers most aspects of the operational definition of quality of life postmastectomy. Thus, this instrument will be selected to test the psychometric properties in the breast cancer population postmastectomy. The summary of the comparison of the tools measuring QOL is presented in Table 1. Table 1 Summary of existing instruments measuring QOL for patients with breast cancer Name & Authors Purpose Domains Scale Duration Items Type Reliability Validity European Organization for Research and Treatment of Cancer QOL Breast Cancer-Specific Version (EORTC QLQ-BR23) (Sprangers et al., 1996) QOL in the breast cancer population at various stages and with patients with differing modalities 5 (Therapy side effects; arm symptoms; breast symptoms; body image; sexual functioning) Four-point Likert scale ranging from 1 (Not at all) to 4 (Very much) Past week 23 Self-report (10 minutes) Reliabilities ranged from .70 to .91 Discriminant validity of mutually exclusive groups based on their initial performance status scores produced medium to large effect sizes ranging from .43 to 1.1 European Organization for Research and Treatment of Cancer QOL Cancer-Specific Version (EORTC QLQ-C30) (Aaronson et al., 1993) QOL in the general cancer population 9 (Physical; role, cognitive; emotional; social; fatigue; pain; nausea and vomiting; global health status and quality of life) Four-point Likert scale ranging from 1 (Not at all) to 4 (Very much); 1 (Very poor) to 4 (Excellent) Past week 30 Self-administered (Under 10 minutes) Reliabilities ranged from .69 to .90. (Carlsson & Hamrin, 1996) Test-retest reliabilities ranged from .63 to .87 (Hjermstad et al., 1995) The correlation coefficient between the QLQ-C30 and the Profile of Mood States (POMS) was .56 (Mclachlan et al., 1998). Functional Assessment of Cancer Therapy – Breast Symptom Index (FACT-B) (Brady et al., 1997) Specific to breast cancer patients 6 (Physical well-being; social/family well-being; emotional well-being; functional well-being; relationship with doctors; additional concerns) Five points Likert scale ranging from 0 (Not at all) to 4 (Very much) Past week 37 Self-report or interviewer-administered (estimated 25 minutes) Internal consistency was .90 Spearman correlations between FBSI and FACT ranged from .34 to .84 Functional Living Index – Cancer (FLIC) (Morrow et al., 1992) Assess the effect that cancer treatment and symptoms on functional ability in all areas of life 5(Physical functioning; mental functioning; social functioning; general health/well-being; gastrointestinal symptoms) Answer questions by placing a vertical line at the point in the best present point Past two weeks; Past month; Today 22 Self-administered (Under 10 minutes) Reliability ranged from .64 to .87 (Morrow et al., 1992) Correlation coefficients between FLIC and SF-36 ranged from .50 to .62 (Wilson et al., 2005). Life Satisfaction Questionnaire (LSQ) (Carlsson & Hamrin, 1996) Measure one’s general sense of satisfaction with life as it relates to school, relationships, leisure time, religious practices, and overall health for women with breast cancer 6 (Quality of family relation; physical symptoms; socioeconomic situation; quality of daily activities; sickness impact; and quality of close friend relation) Seven points Likert scale ranging from 1 (very much) to 7 (Not at all) Past week 32 Self-report (estimated 20 minutes) Reliabilities ranged from .62 to .92 Correlation coefficients between LSQ and EORTC QLQ-C30 were -.68 to .54 Medical Outcome Short Form Health Survey (SF-36) (Ware et al., 1993) Developed to assess health-related QOL 8 (Physical functioning; role limitations due to physical health; role limitations due to emotional problems; energy/fatigue; emotional well-being; social functioning; bodily pain; health) Scaled using various scales Unspecified 36 Self-administered (5 minutes) Reliability ranged from .74 to .98 (Hays et al., 1995) Correlation coefficients between the SF-36 and the General Health Questionnaire (GHQ-29) were -.35 to =.61 (correlations are negative because the two scales run in opposite directions) (Failde & Ramos, 2000) Quality of Life Index (QL-Index) (Spitzer et al., 1981) Assess health outcomes of those with cancer and other chronic diseases 5 (Activity; daily living; health; support; outlook) Three points Likert Scale Past two weeks 5 Interviewer administered or self-administered (Under 10 minutes) Internal consistency of .78 Correlation coefficients ranged from .40 to .63 (32) Satisfaction with Life Domains Scale for Breast Cancer (SLDS-BC) (Spagnola et al., 2003) Developed for satisfaction with life among breast cancer patients 5 (Social functioning; appearance; physical functioning; communication with medical providers; spirituality) Seven points Likert-type scale ranging from 1 (A “delighted” face) to 7 (A “very unhappy” face Unspecified 32 Self-report (estimated 20 minutes) Reliabilities ranged from .90 to .93 Correlation coefficient between SLDS-BC and FACT-B was .59 World Health Organization Quality of Life – Brief Version (WHOQOL-BREF) (Whoqol Group, 1998) Designed to examine domain level profiles assessing the quality of life 4 (Physical health; psychological; social relationships environment) Five points Likert scale with varying anchors Past two weeks 26 Self-administered (estimated 15-20 minutes) Reliability ranged from .66 to .84. Similar alphas have been shown for test-retest reliability ranging from .66 to .87 Correlation coefficients between the WHOQOL-BREF and SF-36 ranged from .36 to .78 (Da Silva Lima et al., 2005) Quality of Life Index (Padilla & Grant, 1985) Examine the quality of life of colostomy patients 4 (Physical concerns, psychological concern, social concern, body image concerns, treatments, and responses 10 points analog scale. Patients placing a vertical line at the point in the best present point Past one month 23 Self-administered 10 minutes Reliability Ranged from .65 to .85 Methods Study Design The descriptive cross-sectional study was designed to analyze the psychometric properties of a Vietnamese version of the modified Quality of Life Index (QOLI-V) on patients three weeks postmastectomy. The modified process was conducted by researchers after granting permission, acceptance, and consultation of the original authors. Sample and Setting The population of this study was the patients three weeks postmastectomy at the Breast Surgical Oncology Ward in the Oncology Hospital in Ho Chi Minh City, South of Vietnam. Convenient sampling was used to select the respondents. The inclusion criteria of the respondents were aged 30-60, could read and write Vietnamese, no other diseases, and normal surgical recovery process at seven days. The literature suggests the estimated sample size of CFA should not be less than 200 to avoid violating the thumb rule of “too few degrees of freedom” (Hair et al., 2010). Other assumptions requested that the sample was > 200 for the theoretical model or ≥ 300 for the population model for CFA in physical health care. A systematic review also proposed that the number of subjects should be equal to the number of items multiplied by 10 in the nursing field (Watson & Thompson, 2006). It is estimated that 265 patients were included to test the psychometric properties of QOLI_V, with 26 items modified from QOLI (Padilla & Grant, 1985) combined with the five domains. Instrument Validation The demographic form and the modified quality of life index Vietnamese version (QOLI-V) were used to collect data in this study. The demographic form was developed by the researchers asking about the characteristics of the respondents, such as age, marital status, occupation, education, income, and mastectomy type. The QOLI_V was a 26-item questionnaire composed of five domains: physical well-being, psychological well-being, social concerns, body image concerns, and treatment response. Data were indicated by marking an X on the visual line equal from 0 to 10 score. Scores were presented as numeric rating scales. QOL was calculated by the sum of the scores divided by the sum of items with a low score indicating a low QOL. The original QOLI with 23 items retained with five domains. In reference to the concept of QOL in a mastectomy group, four items related to the symptoms of patients with breast cancer postmastectomy, including swollen arms, the ability to raise hands, the sensitivity of breast incision was added to the section on treatment response and perceived femininity was added to the section on body image concerns. Then the 27-item QOLI was sent to five experts for testing its content validity index following the recommendation of Polit et al. (2007): two surgeons with ten years of experience in the mastectomy process, two Ph.D. nursing lecturers, and one head nurse in the Breast Surgical Department. The results showed that the lowest I-CVI was .80 and the highest was 1.00; S-CVI/Ave was .95, and S-CVI/UA was .76, which implied good validity for this instrument (Osanloo & Grant, 2016; Polit et al., 2007). The CVI testing of 5 experts confirmed that for 26 items, most of all item was rated from 3 (relevant) to 4 (very relevant). The sum agreements of each item related to the quality-of-life postmastectomy were calculated. The result confirmed that most of the items correlated well with the quality-of-life postmastectomy, except the item of sufficient sexual satisfaction (.40). Experts rated this item with a lower score of relevancy and recommended researchers consider the meaning of this item on Vietnamese culture. Instrument Translation The 26 item-modified QOLI was translated into Vietnamese using Brislin’s model. It was translated from English into Vietnamese and back-translated by two different bilingual experts at the Language Center, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam. Two translated versions were reviewed by a Vietnamese nurse responsible for teaching English to nursing students in the university, identifying ambiguous words and confirming the symmetry. The Quality-of-Life Index Vietnamese version (QOLI-V) was then assessed for its intelligibility in the Vietnamese context and culture with 5 cases of patients in the Surgical Oncology Ward. The piloting of QOLI-V also showed that most patients skipped the question asking about sufficient sexual satisfaction after mastectomy. When researchers discussed the reason with patients, the answer was that mastectomy treatment was terrifying and tiring. They and their partner did not want to have sex, or it was of no meaning in the postmastectomy period. Based on the Vietnamese culture, women often feel shame and become uncomfortable when asked about sexual activities, or they could not express the meaning of sexual satisfaction. In the stage of three weeks postmastectomy, sufficient sexual satisfaction was felt completely irrelevant to ask because patients were usually concerned with other aspects of their life than sexual satisfaction. Therefore, this item was deleted from the questionnaire. Ethical Consideration This study was approved by the Board of Ethical in Biomedical Research at the University of Medicine and Pharmacy and the Research Ethical Board of Oncology Hospital. This study was an instrument development part of the Dissertation project for PhD education in the Faculty of Nursing, Chulalongkorn University, Thailand. After IRB approval, the researchers met patients and presented the objectives, procedures to collect data, and approximate length of time for data collection at the Surgical Oncological Ward. Patients who matched the inclusion criteria and wished to volunteer signed the consent form to prove that they agreed to answer the whole questionnaire. Data Analysis The input data were checked for errors before entering the analysis tests. The data were analyzed for the assumption of normal distribution and descriptive demographic data and reliability of the measurement by the SPSS program version 16.0. Then the confirmatory factor analysis was conducted by using the AMOS version 20.0. The process of conducting the CFA conducted by following standardized recommendations: (a) Initial data analysis to identify any problem of missing data or input errors, (b) Fix one-factor loading on each sub-construct to a specific value as equal to 1, (c) Factor loading higher .5 to .7, (d) Construct reliability .6 was accepted, (e) Standardize residual accepted (from 2.5 to 4.0), (f) Not using modification indices to adjust the model fit (Hair et al., 2010). Results Characteristics of the Respondents The demographic data of the respondents showed that most of them were in middle age (47%). Many of the women were married and living together as a family (78.9%). However, the respondents had low education (primary and secondary school, 60.5%), and income from the main family members was still low (<3 million and/month, 51.7%). The majority of the respondents were housewives (42.3%), farmers, or doing small business at home (19.6%). Only one-third of them were office workers or executives; 64.5% of the respondents received radical mastectomy (see Table 2). Table 2 Characteristics of participants (N = 265) Characteristic f % Age  39 60 22.6  40-49 125 47.2  50-59 80 30.2 Marital status  Married 209 78.9  Widowed 29 10.9  Divorced 12 4.6  Singled 15 5.7 Education  Primary school 75 28.3  Secondary school 84 31.7  High school 63 23.8  University or higher 43 16.2 Occupation  Housework 112 42.3  Small business 52 19.6  Worker 57 21.5  Officer 31 11.7  Retire 13 4.9 Monthly income (VND)  < 3 million 137 51.7  3-5 million 107 40.4  5-10 million 21 8.0 Mastectomy type  Simple 94 35.5  Radical 171 64.5 Reliability of the QOLI-V The reliability of the revised translation version, 26-item QOLI-V, was tested for its reliability with 265 Vietnamese patients three weeks postmastectomy. Cronbach's alpha of QOLI-V was .84, which was considered acceptable for the modified instrument (Polit & Beck, 2003). Most of the 26 items featured the correct item-total correlation .3 to .6. There were only two items correlated with the total scale at .18. Regarding the last item, "general quality of life," the total correlation was only .06, and Cronbach's alpha increased when it was deleted. Thus, it was considered that this item should be deleted from the item set or not (see Table 3). Table 3 Item correlation of Quality-of-Life Index Vietnamese Version Items Scale Mean if Item Deleted Corrected Item-Total Correlation Cronbach's Alpha if Item Deleted Strength 172.82 .525 .832 Tired 171.63 .209 .841 Sleep 172.22 .469 .833 Weight 171.22 .185 .842 Appetite 171.96 .557 .829 Food amount 171.71 .521 .831 Daily work 173.94 .514 .831 Current health 172.82 .603 .827 Fun 173.26 .393 .836 Useful 171.99 .552 .829 Happiness 171.36 .556 .830 Worry of future 171.32 .236 .841 Life satisfaction 171.97 .525 .830 Pain 172.06 .284 .839 Frequency of pain 171.77 .396 .836 Arm swollen 170.28 .284 .839 Raise hand 171.82 .165 .842 Breast sensitive 171.53 .291 .839 Adjust easy 171.66 .374 .836 Scare of scar 171.50 .360 .837 Femininity 171.98 .288 .839 Difficult to look body 171.68 .329 .838 Meeting 172.22 .355 .838 Reject 170.26 .367 .837 Private 171.99 .318 .840 General quality of life 171.98 .060 .847 Construct Validity - Confirmatory Factors Analysis The construct validity of the instrument was tested using the confirmatory factor analysis (CFA). The model validity is assessed based on exact test fit, with Chi-Square/df <2.0 is considered good and <5.0 is acceptable, Root Mean Square Error of Approximation (RMSEA ≤ .08), Standardized Root Mean Square Residual (SRMR ≤ .05), Comparative Fit Index (CFI ≥ .90) (Hair et al., 2010). The researchers also used other evidence to concern the appropriate model fit. The initial model 1 was drawn up in the AMOS graphic program and run CFA with the data set. The first analysis showed that with 26 items based on the construct of 5 dimensions, model 1 was not an ideal fit with the data. The findings in detail were reported as Chi-Square/df 623/289 = 2.15, CFI =.815, RMSEA =.066. The model was presented in (Figure 1). Figure 1 CFA Model 1 Note: PS: Psychological well-being | Phys: Physical well-being | Tr: Treatment responses| BI: Body image concerns| SO: Social concerns For most items, the standardized estimation (factor loading) was from .50 to .66. There is no estimation indicated the cross-loading factor. However, there were three items that the general quality of life, weight, and breast incision sensitivity were lower than .50, with the standardized regression weight estimated as .045, .48, .48, respectively. The residual estimation of 26 items ranked from 1.1 to 3.8 was acceptable based on the standardization rule. However, the residual estimate of e6 (general quality of life) exceeded the accepted level with the result at 4.2. The construct reliability of the measurement was high and exceeded the level of .6. As for the modification indices, the general quality of life item is considered the cross-loading item. The regression weight of these items was adjusted for the par change in every item or latent variable of the model. Therefore, this item was considered for deletion from the model. Following the empirical evidence of the CFA in model 1, the general quality of life was deleted, and the CFA of model 2 was conducted. The findings showed that the model fit improved, with the criteria Chi-Square/df =2.269, CFI=.814, and RMSEA=.069. The construct reliability of the Psychological dimension was improved after deleted one item. The model was presented in Figure 2. Figure 2 CFA Model 2 Note: PS: Psychological well-being | Phys: Physical well-being | Tr: Treatment responses BI: Body image concerns| SO: Social concerns Discussion Following Hair et al. (2010) to assess the model validity, we need the key value of Chi-Square/df, CFI, and RMSEA and other evidence to concern the appropriate model fit. Firstly, the confirmed factor analysis showed that the model of quality of life was acceptable as consistent with the concept. Although the Chi-square value was .00 (< .05) implied that the model might not fit. However, the Chi-square value may be influenced by the number of samples. In this study, 265 cases were higher than 250, as referenced (Boateng et al., 2018). When we considered the Chi-Square/df in both models, the result was 2.15-2.26, less than 3 acceptable occasionally (Hair et al., 2010). The CFI, GFI, TLI of these models was over 8 compared to the standard of >.9 (Hair et al., 2010). Although it was not a perfect fit, the model was considered good for measuring the quality of life. Regarding RMSEA, both models were acceptable, with RMSEA were .06 (< .08) suggested the adaptable criteria for model fit. Secondly, from model 1 to model 2, there was a slight decrease of CFI, GFI, TLI with increased Chi-Square/df. RMSEA increase proved that the deleted item " general quality of life" was not contributed to the quality of life or considered redundant. Therefore, this item was deleted from the model. Thirdly, although model 2 was not also highly fit with the result of Chi-Square/df =2.269, CFI=.814, and RMSEA=.069. The researcher did not try to rerun the model because this model was consistently based on CVI, Cronbach’s alpha, and experts from a clinical view. Therefore, deleted more items did not help improve the model but ruin the construct of the quality of life in patients with breast cancer. This study proposed the model for concept quality of life three weeks postmastectomy. The original model has been modified with four items and deleted two items through the process of developing the scale. The final 25-item QOLI should be tested in another group of patients with breast cancer in the early stage of treatment to conclude the validity and reliability of this scale. In addition, the construct of social concerns needs to be adjusted by adding the new constraints for increasing the decrease of freedom set up the tau-equivalent between each construct in the model following the suggestion of (Hair et al., 2010). The modification indices also suggested a high correlation between the appetite and food amount that may imply the redundancy of the item. This model should be considered for testing on a larger sample size to satisfy the assumption of the test and not violate the thumb rule of few degrees of freedom. Conclusion The findings of this study provided good reliability and validity of the QOLI-V among postmastectomy patients. The QOLI-V consisted of 25 items with five dimensions: physical well-being, psychological well-being, social concerns, body image concerns, and treatment response. Nurses and midwives can use this instrument to measure the quality of life of the patients with breast cancer postmastectomy, and the patients could use it for self-assessment. Acknowledgments The first author would like to send the gratefulness to her supervisor from Chulalongkorn University, who had supported her in the studying process during the PhD program. Declaration of Conflicting Interest There is no conflict of interest in this study. Funding This study was funded by the 90th Anniversary of Chulalongkorn University Scholarship, Chulalongkorn University, Thailand. Authors’ Contribution HTNX designed the study, collected data, analyzed the data, wrote and revised the manuscript. ST designed the study, wrote and revised the manuscript. All authors contributed and agreed with the final version of the manuscript. Authors’ Biographies Dr. Ha Thi Nhu Xuan, PhD, ANP, RN is a Vice Head of Nursing Department, Faculty of Nursing and Medical Technology, University of Medicine and Pharmacy (UMP) at Ho Chi Minh City, Vietnam. She manages and contributes to updating the curriculum training for Bachelor and Master program of Nursing at UMP. She has experiences doing research in adult nursing care, nursing education, leadership and management. Assoc. Prof. Sureeporn Thanasilp, DNP, MSN, RN is A Former Dean and Lecturer at the Faculty of Nursing, Chulalongkorn University. She is an expert in cancer nursing caring and contributes many articles for nursing science. Data Availability Statement The datasets of this study are available from the corresponding author on reasonable request. The final instrument is available in appendix. Appendix The Quality-of-Life Index for patients with breast cancer three weeks postmastectomy Modified from Quality-of-Life Index of Padilla and Grant (1985) Instructions: Please read each question and place an “X” on the line that most closely measures how you feel during the past weeks. The line level is measured from “Not at all” to “Completely/Extremely”, with the score from 1 to 10. Please answer every question. ==== Refs References Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., … de Haes, J. C. J. M. (1993). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-096 10.33546/bnj.2470 Perspective Let’s put mental health problems and related issues appropriately in social media: A voice of psychiatric nurses https://orcid.org/0000-0002-9569-8784 Saputra Fauzan 12 https://orcid.org/0000-0001-9169-0542 Uthis Penpaktr 1* https://orcid.org/0000-0002-9978-7979 Sukratul Sunisa 1 1 Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand 2 Faculty of Health, Technology, and Science, University of Bumi Persada, Lhokseumawe, Aceh, Indonesia * Corresponding author: Assoc. Prof. Dr. Penpaktr Uthis, Faculty of Nursing, Chulalongkorn University Boromarajonani Srisatapat Building, Rama1 Rd, Floor 11, Patumwan, Bangkok 10330, Thailand. Email: penpaktr.u@chula.ac.th Cite this article as: Saputra, F., Uthis, P., & Sukratul, S. (2023). Let’s put mental health problems and related issues appropriately in social media: A voice of psychiatric nurses. Belitung Nursing Journal, 9(1), 96-99. https://doi.org/10.33546/bnj.2470 12 2 2023 2023 9 1 9699 05 12 2022 16 1 2023 28 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Social media is one convenient way to express ourselves. Much information is offered; most is difficult to filter and can be consumed by anyone, anywhere, anytime. However, sometimes it crosses the boundaries of someone else’s life or privacy, especially when discussing sensitive issues, such as mental health problems. There are a lot of discussions about whether bringing the personal experiences of people with mental health problems to the public domain can potentially increase the community’s attitudes toward them or not. Still, one thing is for sure, this kind of content has caught public attention by having more viewers. Unfortunately, it potentially brings other consequences for people with mental health problems, such as stigmatization, discrimination, and sadfishing. Therefore, this paper aims to provide the viewpoints of psychiatric nurses regarding how to address mental health-related issues and appropriately put content about mental health problems on social media. psychiatric nursing privacy public sector mental health issues stereotyping stigmatization ==== Body pmcPerspective The world is entering a new direction. The development and advances in information technology allow us to access anything that occurs in any part of the world. In other words, we can easily get information from any source because information exchange happens quickly (Prasetyo, 2022). Unfortunately, the changes that are currently occurring may sometimes violate someone’s privacy rights, especially the information obtained on social media. Whereas the available information on social media is not necessarily true, it is difficult to hold it accountable. However, many people still use the information from social media as a reference because it is convenient and accessible (Oducado et al., 2019). In this case, many people may seem ignorant and do not care whether the information they get from social media is accurate or a hoax. As long as the obtained data is relevant and under their desires and expectations, they can easily share it on their social media platforms. Like in the market, the goods will be available if there is a demand. Social media as a market provides tremendously needed information that drives many people to provide them. Moreover, many reports show that social media users worldwide have increased drastically. Current reports indicated that the number of people using social media was growing by over 4.26 billion in 2021, and it was projected to reach almost six billion in 2027 (Dixon, 2022). This number may be projected based on the addition of the population in the world. But it is possible that everyone with access to a cell phone, regardless of age, tends to access social media. Interestingly, another report revealed that social media users in Indonesia reached 191.4 million in January (68.9%), an increase of 21 million compared to last year (Kemp, 2022). This number can also be biased as Indonesia is one of the world's most populous countries, so the number of social media users surpasses other countries. But, taking Indonesia as an example may be interesting because it is included as one of the developing countries with a high population growth in Southeast Asia (ONeill, 2022). So, it is undeniable the number of social media users will be increased over the years, as well as social media platforms. Indeed, there are so many social media platforms where people spend most of their time. But, the reports mentioned that Facebook, YouTube, Instagram, and TikTok are the most popular social media sites for showing explicit content that viewers may find intriguing (Dixon, 2022; Kemp, 2022). Based on the types of platforms, people will usually be provided with photos and videos, which triggers many content creators to compete with each other to produce more attractive images and videos. Some content creators develop ideas to generate a specific theme, but others do not follow some particular pattern. Often, other content creators steal others' opinions or just copy and repost them on their platforms. Literally, various types of social media content could increase the number of viewers across all platforms (Koshy, 2022). First of all is educational content. Most of this type of content provides information about education, for example, how to succeed at school, get a scholarship, experience studying abroad, or even make and publish a paper. The next type of social media content is inspirational content which relates to how to inspire others by showing good experiences, attention, caring, and helpful actions. This content is one of the most popular and searchable content because people tend to look nicer to another person, especially deprived people. Another type of content is interactive content, which provides interaction with the viewers by giving them chances to ask questions and answer quizzes. Celebrities, public figures, and influencers offer most of this content. Then, connecting content targets specific audiences with particular interests by posting something related to popular hobbies, such as sports, movies, or music. Furthermore, the other type of social media content is promotional content. The mostly content creator will provide much information to increase the added value of something by giving facts, benefits, etc. Subsequently, newsworthy content provides factual information by offering links to famous news websites to ensure its validity and truthfulness. People tend to refer to this type of content to ensure that the data is valid and trustworthy. Finally, the last type of content that gets attention from the viewers is entertaining content. This type of social media content provides something for fun and to be amused by posting funny videos, jokes, memes, puzzles, etc. No less important, content creators will find ways to make watchable content by following the desires and trends of the community. In other words, they will make videos based on their last-highest number of viewers. This includes mental health problems-related content. Therefore, this paper aims to provide the perspectives of psychiatric nurses regarding mental health-related issues in social media, including how to put content about mental health problems on social media appropriately. Admittedly, content about mental health problems looks like two sides of a coin. On one side, it can increase negative perspectives regarding people with mental health problems, as they are frequently portrayed as insane that look shabby and unkempt. As a result, they are easy to be discriminated against and stigmatized in their community. On the other side, if they are portrayed better, the public perception may be changed. For example, those who take medication regularly will lead to fewer symptoms, and those with a successful life with controllable symptoms and supportive families. Interestingly, Betton et al. (2015) mentioned that putting personal experiences in the public eye could minimize discrimination and stigmatization towards people with severe mental health problems. Therefore, it will depend on how people with mental health problems are portrayed on social media platforms. But the content is not only about delivering the messages to the public. In fact, content creators may have their own intentions. In addition, as one of the most searchable and watchable impressions on social media platforms, inspirational content about people with mental health problems caught most people's attention, for example, Indonesian YouTube viewers (Ariska & Syaefudin, 2021). They revealed that one popular YouTube channel, which focuses only on people with mental health problems, has almost five million subscribers, nearly 50 million views per month, and earns almost 200,000 USD per month. This specific content has become popular in Indonesia because people with mental health problems are still perceived as a weak and vulnerable group that needs to be fully supported in daily activities (Hanifah et al., 2021; Purnama et al., 2016). Therefore, most videos will depict people with mental health problems in deplorable conditions, useless, helpless, and powerless. It is part of the show to appeal to people, and sympathy can be conveyed as a form of concern without realizing that content creators may see it differently. However, it is questionable whether the content creators genuinely care about people with mental health problems or just want to get compensated by YouTube, given that they reveal several details about their private lives with dramatic taglines, such as “bathing and dressing them to like models.” Unfortunately, the majority of the videos did not blur the faces of those who appeared uncomfortable participating in the assigned activities. Therefore, it becomes a question of whether they truly want to engage with the content or are not allowed to say “No.” One ethical question that needs to be answered and investigated is, “Do content creators inform them or their families before recording?” In addition, the hyper-exploitation of people with mental health problems on social media platforms has another significant impact, for example, stigma, discrimination, or even sadfishing. The California Mental Health Services Authority (2014) mentioned apparent differences between stigma and discrimination among people with mental health problems. Stigma reflects their attitudes and beliefs that lead those to have feelings of rejection, avoidance, and fear as they think they are different from others. There are three kinds of stigma: public stigma, self-stigma, and institutional stigma (Borenstein, 2020; California Mental Health Services Authority, 2014). Firstly, self-stigma refers to negative attitudes and beliefs regarding their own condition. Secondly, public stigma refers to negative attitudes and beliefs of the community regarding people with mental health problems who perceive them as a dangerous group and have a higher risk for violence. Lastly, institutional stigma refers to negative attitudes and beliefs of organizations or governments by using stigmatized terms such as “schizophrenic persons” or other limitations in their policies, whether intentionally or unintentionally. Unfortunately, stigmatization among people with mental health problems becomes an unfinished task, especially when they have poor appearances (Saputra, 2016). Currently, the over-exploitation of people with mental health problems on social media platforms may increase their risk of having the stigma (Robinson et al., 2019). Let’s take a look one by one. First, on self-stigma, they will perceive themselves like content creators portray them as people with lack the capacity and ability to take care of their own. This perception will be internalized and make them believe they are incompetent. If this situation continues, they will keep this perception, and their self-stigma will remain or even increase. On public stigma, the public who watch content about incapacity and helplessness of people with mental health problems will perceive that they always need to be helped to take care of themselves, without knowing that sufficient support and empowerment are better than providing them with total help permanently. As a human, they need to be empowered and do many things in their lives on their own because it will increase their self-esteem. How about institutional stigma? Unluckily, the government and private organizations exposed to this particular content may perceive them the same as the public perception. Therefore, they may develop impartial policies unfavorable to people with mental health problems. They may also limit the opportunities for people with mental health problems to work in their company. That leads them to discrimination. Discrimination reflects behavioral forms regarding the stigma, where people with mental health problems tend to receive unequal treatment, especially for their rights and opportunities (Borenstein, 2020; California Mental Health Services Authority, 2014). Therefore, it will be easier for them to get marginalized to access their civil rights, for example, higher educational level, higher paid salary employment, or even participation in elections. In addition, the content about people with mental health problems that spread on social media platforms may also increase discrimination towards them. For example, they may perceive that they do not need to go to schools or universities, work, or do other daily activities due to their conditions. Actually, it needs to be emphasized that the perception is wrong. They needed to be fairly given opportunities to access those civil rights like others. Besides stigmatization and discrimination, the other impact of social media content about people with mental health problems is sadfishing. In a simpler way, sadfishing can be defined as posting someone’s emotional and dramatic personal content to get attention or sympathy from the viewers (Rutledge, 2021). As mentioned earlier, content creators tend to show that people with mental health problems are unable to take care of themselves. So, they like to deliver that message all over again and display it in their videos to make them look nice or care about that issue. Most of the time, the content creators will try to find people with mental health problems in terrible conditions, offer them bathing, dressing, and feeding, and turn them into “good-looking people.” They seem friendly and kind, but they reinforce the perspective that someone has to look terrible to experience mental health problems. In fact, many people with severe mental health problems have normal appearances like others. Moreover, people with mental health problems with minimal dependence and recovery look like ordinary people so they can study and work as usual (Safitri, 2011). Therefore, content creators should consider many important issues before making videos. One crucial initial issue that content creators should notice is to ensure that people with mental health problems should be put as the subject and not the object of the videos. It means that content creators should have to determine that they have already received permission from people with mental health problems and their families before taking a shot. The content creators should blur their faces if they want to participate in the videos but do not want to be fully exposed. Subsequently, the videos’ objectives must be clear first, so both know exactly how the videos will be made. It will also determine the involvement of certain persons to support the whole story of the videos. After that, it will be better if they discuss the concept of the videos and how the narration will be made to describe them. Any input from people with mental health problems and or their families should take into consideration by content creators. Furthermore, after every shot is finished, the video should be watched together, and the content creators have to ensure that everyone agrees to put it for the result of the video. After the editing process, the video’s final version should be watched together once more to convince that the agreement is achieved and everyone is satisfied with the video. But, it is noted that the messages in the videos have to be efficiently delivered and digested by the targeted audiences or viewers with misinterpretation. The content creators should pay attention to those steps to confirm that people with mental health problems become subjects rather than objects of the videos. The ethical concern is also already achieved by following those mentioned steps. The copyright issue is the other important issue that content creators should notice regarding the inspirational content of people with mental health problems. As content creators raise an issue about the lives of people with mental health problems, they need to have rewards for their agreement to participate in the videos. It will be better if the content creators talk about this issue before taking the videos, so they and their families know what they will get from their participation. That is how the content creators appreciate people with mental health problems and their families. It will also protect the content creators from being sued over the published videos. Even less, money is one sensitive issue that should be appropriately treated. Another critical issue is sustainability concern, where content creators should ensure that their goodwill is sustainable for a long time by involving healthcare providers, especially psychiatric nurses and community nurses. They have standardized nursing care for people with mental health problems in the community, so their information will benefit the content creators. Usually, psychiatric nurses in the community will provide people with mental health problems with structured methods, starting from mental health screening, conducting a full nursing assessment, establishing a nursing diagnosis, developing nursing intervention, delivering nursing implementation, and undertaking nursing evaluation (Kudless & White, 2007). So, it will be better if the content creators follow the program already planned for people with mental health problems. By doing so, the benefits can be achieved not only by the content creators, by earning more money from popular videos, but also for people with mental health problems and their families, by receiving standardized care that will achieve therapeutic outcomes, as well as psychiatric nurses, by having content creators to be involved in the program and spreading the video via their social media platforms. So, conclusively, content creators may play their part in articulating care for people with mental health problems in the community. However, they still need to pay attention to ethical and sustainability issues. In the end part of the discussion, as psychiatric nurses, we may say that content creators have an essential role in supporting successful medication regimens for people with mental health problems in the community. As the number of relapses among people with mental health problems is so prevalent because of taking medication irregularly, the content creators can be involved in the campaign about medication adherence among that population. We have to agree that successful medication initially comes from two aspects, the internal motivation of the patients and supportive family members. They should be supported to have a motivation for recovery because the strong belief in recovery that came from them will direct them to follow the nursing care and treatment advice. But, if they hesitate and believe they will not recover, it will become more difficult to ask them to take medication. Therefore, the empowerment of people with mental health problems by putting them as subjects of the content creators’ videos will help them appreciate themselves and be more powerful in controlling their lives. The content creators also can help people with mental health problems by triggering them to become supportive families. As stated above, in the very first process of video making, the content creators will welcome the involvement of the families. This will also help their families empower themselves. They may want to contribute more to caring for their family members with mental health problems. They even can learn how to provide support during the process by learning from the involved psychiatric nurses in the community. Unconsciously, the content creators act as facilitators to mediate the participation of family members in patients’ treatments and nursing care. So, showing those two strong messages in the videos will change the public perspectives. In addition, the content creators should have a video that displays the differences between patients who take and do not take medication regularly that drive from their own motivation to be recovered, including how the differences if they have supportive family members that always remind them to take medication regularly until it becomes a habitual activity. In conclusion, content creators may change the public perspective regarding mental health issues in the community if they realize their essential roles and expose the messages appropriately on their social media platforms. That is how content creators properly put mental health problem-related issues in social media. Hence, their content not only provides them with benefits but also positively contributes to people with mental health problems and fights stigmatization and discrimination. Acknowledgment The authors acknowledge the Faculty of Nursing, Chulalongkorn University, for the support. Declaration of Conflicting Interest The authors declare that there is no conflict of interest. Funding Graduate Scholarship Program for ASEAN and Non-ASEAN Countries, Chulalongkorn University, Thailand. Recipient: Fauzan Saputra. Author’s Contribution The authors contributed equally to this manuscript. Author’s Biography Fauzan Saputra, S.Kep, Ners, MNS is a Lecturer at the Faculty of Health, Technology, and Science, University of Bumi Persada, Lhokseumawe, Aceh, Indonesia. He is also a PhD nursing student at the Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand. Dr. Penpaktr Uthis is an Associate Professor at the Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand. Dr. Sunisa Sukratul is an Assistant Professor at the Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand. Ethical Consideration Not applicable. Data Availability Not applicable. ==== Refs References Ariska, Y., & Syaefudin, R. (2021). Komodifikasi ODGJ pada kanal Youtube dalam perspektif ekonomi politik di media baru [Commodification of ODGJ on Youtube channel in a political economy perspective in new media]. Jurnal Ilmu Komunikasi, 8 (1 ), 65-76. Betton, V., Borschmann, R., Docherty, M., Coleman, S., Brown, M., & Henderson, C. (2015). The role of social media in reducing stigma and discrimination. The British Journal of Psychiatry, 206 (6 ), 443-444. 10.1192/bjp.bp.114.152835 26034176 Borenstein, J. (2020). Stigma, prejudice and discrimination against people with mental illness. https://www.psychiatry.org/patients-families/stigma-and-discrimination California Mental Health Services Authority. (2014). Definition of stigma and discrimination. http://www.pwdf.org/wp-content/uploads/2014/05/DefinitionsOfStigmaAndDiscrimination.pdf Dixon, S. (2022). Number of global social network users 2018-2027. https://www.statista.com/statistics/278414/number-of-worldwide-social-network-users/ Hanifah, H., Asti, A. D., & Sumarsih, T. (2021). Stigma masyarakat dan konsep diri keluarga terhadap orang dengan gangguan jiwa (ODGJ) [Community stigma and family self-concept towards people with mental disorders]. Proceeding of The 13th University Research Colloqium Sekolah Tinggi Ilmu Kesehatan Muhammadiyah Klaten, Klaten. Kemp, S. (2022). Digital 2022: Indonesia. https://datareportal.com/reports/digital-2022-indonesia Koshy, V. (2022). Seven types of social media content to create to wow your fans. https://nealschaffer.com/types-social-media-content/ Kudless, M. W., & White, J. H. (2007). Competencies and roles of community mental health nurses. Journal of Psychosocial Nursing and Mental Health Services, 45 (5 ), 36-44. 10.3928/02793695-20070501-08 17526329 Oducado, R. M., Sales, M. R., Magarzo, A. J. P., Panes, P. M. A., & Lapastora, J. T. P. (2019). Perceptions and attitude on using social media responsibly: Toward social media literacy in nursing education. Belitung Nursing Journal, 5 (3 ), 116-122. 10.33546/bnj.789 ONeill, A. (2022). Indonesia: Population growth from 2011 to 2021. https://www.statista.com/statistics/319176/population-growth-in-indonesia/ Prasetyo, Y. A. (2022). Digital competence: What makes nurses a ‘big gun’ in the future health industry. Belitung Nursing Journal, 8 (5 ), 462-463. 10.33546/bnj.2165 Purnama, G., Yani, D. I., & Sutini, T. (2016). Gambaran stigma masyarakat terhadap klien gangguan jiwa di RW 09 Desa Cileles Sumedang [An overview of the community's stigma against clients with mental disorders at RW 09 Desa Cileles Sumedang]. Jurnal Pendidikan Keperawatan Indonesia, 2 (1 ), 29-37. 10.17509/jpki.v2i1.2850 Robinson, P., Turk, D., Jilka, S., & Cella, M. (2019). Measuring attitudes towards mental health using social media: Investigating stigma and trivialisation. Social Psychiatry and Psychiatric Epidemiology, 54 , 51-58. 10.1007/s00127-018-1571-5 30069754 Rutledge, P. B. (2021). Sadfishing: Attention-getting or genuine calls for help? Psychology Today. https://www.psychologytoday.com/us/blog/positively-media/202102/sadfishing-attention-getting-or-genuine-calls-for-help Safitri, D. (2011). Menderita skizofrenia tapi tetap bekerja [Suffering from schizophrenia but still works]. BBC News Indonesia. https://www.bbc.com/indonesia/laporan_khusus/2011/10/111004_mental4 Saputra, F. (2016). Poor appearance as a never ending stigmatization for people with severe mental health problems. Belitung Nursing Journal, 2 (2 ), 19-21. 10.33546/bnj.9

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-001 10.33546/bnj.2551 Editorial Exploring the future of nursing: Insights from the ChatGPT model https://orcid.org/0000-0001-6694-8679 Gunawan Joko * Belitung Raya Foundation, Manggar, East Belitung, Bangka Belitung, Indonesia * Corresponding author: Joko Gunawan, S.Kep. Ners, PhD, Belitung Raya Foundation - Desa Padang, Manggar, East Belitung, Bangka Belitung, Indonesia 33512. Email: jokogunawan@belitungraya.org Cite this article as: Gunawan, J. (2023). Exploring the future of nursing: Insights form ChatGPT model. Belitung Nursing Journal, 9(1), 1-5. https://doi.org/10.33546/bnj.2551 12 2 2023 2023 9 1 15 19 1 2023 20 1 2023 20 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. This editorial aims to provide a comprehensive overview of the future of nursing through the lens of the ChatGPT model, a state-of-the-art language processing artificial intelligence (AI) developed by OpenAI. The edited chat transcripts with ChatGPT may offer key trends and developments in nursing, such as the increasing use of technology and digital tools, the integration of AI, and the use of robotics in patient care, as well as insights into the implications of these changes for nurses, patients, and the healthcare system as a whole. However, the future of nursing is continuously evolving. Therefore, nurses need to keep abreast of the latest developments and adapt to them while remaining committed to providing quality care. ChatGPT OpenAI artificial intelligence future of nursing robotics state-of-the-art language processing ==== Body pmcIntroduction ChatGPT (Generative Pre-training Transformer), a chatbot launched by OpenAI on 30 November 2022 (OpenAI, 2022), has gained widespread popularity. The model is considered one of the most advanced language generation models available to the public and is used to generate text for a wide range of applications. It was trained on a diverse set of internet text and is able to render text in various styles and formats, including human-like conversation, poetry, and news articles (O'Connor, 2022; OpenAI, 2022). However, the impressive ability of ChatGPT has raised the question of whether we have reached a point in technology's evolution where an AI-driven chatbot can write, or assist in writing, an article on the “Future of Nursing.” This editorial presents the edited transcript of chats with ChatGPT Jan 9 Version on 18 January 2023. The Chats Joko Gunawan (JG): Provide an introduction to ChatGPT. Explain that this article was written by ChatGPT in response to prompts from JG. ChatGPT: ChatGPT is a large language model developed by OpenAI. It has been trained on a diverse range of internet text and can generate human-like responses to a variety of prompts. This article was written by ChatGPT in response to prompts provided by JG. It is important to note that the information provided by ChatGPT may be limited by its knowledge cutoff and may not be entirely accurate or up-to-date. JG: Tell me what nursing is ChatGPT: Nursing is a healthcare profession dedicated to providing care to individuals, families, and communities in order to help them achieve, maintain, or regain optimal health and high quality of life. Nurses assess patient needs, develop and implement nursing care plans, and evaluate patient outcomes. They also collaborate with other healthcare professionals to provide comprehensive care. Nurses may work in a variety of settings, such as hospitals, clinics, nursing homes, and schools. They may also specialize in specific areas of healthcare, such as pediatrics, oncology, or critical care. Nurses play a vital role in promoting health and well-being, preventing illness and injury, and managing chronic conditions. JG: Summarize the history of nursing ChatGPT: The history of nursing can be traced back to ancient times when religious orders and individuals provided care for the sick. In the 19th century, Florence Nightingale, a British nurse, established the first professional nursing school and developed modern nursing principles (Matthews et al., 2020). Her emphasis on cleanliness, organization and proper nutrition in hospitals helped reduce patient mortality rates. During the Civil War in the United States, nurses such as Clara Barton and Dorothea Dix played a significant role in the organization and provision of nursing care for soldiers (Woodward, 1991). This led to the formation of the United States Army Nurse Corps, which helped establish nursing as a respected profession. In the late 19th and early 20th centuries, nursing education shifted from apprenticeships to formal educational programs, and the scope of practice expanded to include public health and community-based care. In the mid-20th century, nursing continued to evolve with the introduction of advanced technology and new areas of specialization, such as pediatrics, gerontology, and psychiatric nursing. The nursing profession also became more diverse, with an increasing number of men and minorities entering the field. Today, nursing continues to adapt to changing healthcare needs and advancements in technology. Nurses are key members of healthcare teams and play an essential role in patient care and outcomes. JG: Speculate the future of nursing ChatGPT: The future of nursing is likely to involve a continued emphasis on preventative care and patient-centered care. With the aging population and increasing rates of chronic conditions, there will likely be a greater need for nurses who specialize in gerontology and chronic disease management. In addition, nursing practice is likely to become more technology-driven, with the use of electronic health records, telehealth, and other digital tools becoming more prevalent. This will enable nurses to access patient information more easily and provide care remotely, which can improve access to healthcare for patients in remote or underserved areas. This is in line with Marzilli (2022) in discussing the future of nursing. There may also be an increased focus on nursing education, with a greater emphasis on evidence-based practice and interprofessional collaboration. This will help ensure that nurses have the knowledge and skills necessary to provide safe and effective care in an ever-changing healthcare environment. In addition, the nursing profession will probably continue to become more diverse, with an increasing number of men and minorities entering the field. This will provide patients with more culturally competent and sensitive care. Overall, the future of nursing is likely to see a greater emphasis on “preventative care,” “technology integration,” and “interprofessional collaboration,” with the goal of improving patient outcomes and promoting the health and well-being of the population (see Figure 1). Figure 1 Six depictions of the ‘‘Future of Nursing’’ as envisioned by the AI-powered DALL-E 2 image generator (OpenAI) (https://openai.com/dall-e-2/) JG: Speculate the future of nursing on preventative care ChatGPT: In the future, nursing is likely to play an even greater role in preventative care as healthcare systems shift towards a more proactive, population-based approach. Nurses will likely be involved in identifying and addressing health risks in the community, such as providing health education and screenings for chronic conditions such as diabetes and hypertension. Nurses will also be instrumental in promoting healthy lifestyles and behaviors, such as encouraging physical activity, healthy eating, and smoking cessation. They may also be involved in providing care for patients with mental health conditions, such as depression and anxiety, which can be risk factors for chronic diseases. Telehealth, telenursing, and telemedicine technology will probably be used more frequently to provide remote care, enabling nurses to monitor patients with chronic conditions, provide education and support, and adjust treatment plans as needed (Gunawan et al., 2022). This will help improve access to healthcare for patients in remote or underserved areas. The use of big data and analytics will also be important in preventative care, as nurses will be able to identify trends and patterns in health data that can help identify and target populations at high risk of certain conditions, helping to prevent the onset of the condition. Overall, the future of nursing in preventative care is likely to see a greater emphasis on “community-based care,” “technology integration,” and “evidence-based practice,” with the goal of improving the health and well-being of the population. JG: Speculate the future of nursing on technology integration ChatGPT: In the future, nursing is likely to become increasingly technology-driven as technology continues to advance and become more integrated into healthcare delivery. Nurses will likely use electronic health records (EHRs) more frequently, which will enable them to access patient information more easily, provide more accurate and up-to-date care, and collaborate more effectively with other members of the healthcare team. In addition, Telehealth and telemedicine technology will probably become more prevalent, enabling nurses to provide remote care and monitor patients with chronic conditions, such as diabetes and hypertension. This will improve access to healthcare for patients in remote or underserved areas and allow for more efficient care coordination. Nurses will also be able to use wearable technology, such as smartwatches and fitness trackers, to monitor patients' vital signs and activity levels, and provide real-time feedback and support. Robotics, artificial intelligence, and machine learning will also be integrated more into nursing, for example, in tasks such as triage, patient monitoring, and medical diagnosis. These technologies will allow nurses to perform more complex procedures, such as administering medication and will help improve efficiency and accuracy in care delivery. Overall, the future of nursing in technology integration is likely to see a greater emphasis on the use of digital tools and technologies, with the goal of improving patient outcomes, increasing efficiency, and reducing errors in care delivery. JG: Speculate the future of artificial intelligence in nursing ChatGPT: The future of artificial intelligence (AI) in nursing is likely to involve the integration of AI-powered tools and technologies into various aspects of nursing practice, such as patient diagnosis, treatment planning, and care delivery. AI-powered diagnostic tools, such as computer-aided diagnosis (CAD) systems, will probably be used more frequently in nursing practice, enabling nurses to make more accurate and efficient diagnoses and provide more timely treatment. These systems can process large amounts of data from multiple sources, such as images, lab results, and patient history, and can identify patterns and anomalies that might be missed by human practitioners. AI-powered treatment planning tools will also become more prevalent, helping nurses to develop personalized care plans for patients based on their individual needs, preferences, and medical history. These tools can also help nurses to monitor the progress of patients over time, adjust treatment plans as needed, and identify potential complications. AI-powered care delivery tools, such as robotic assistants and virtual nurses, will also become more common in nursing practice, helping nurses to perform routine tasks more efficiently and allowing them to spend more time with patients. These technologies can assist with tasks such as administering medication, monitoring vital signs and providing patient education. AI-powered decision support systems will also be used more frequently in nursing practice, helping nurses make more informed patient care decisions by providing real-time access to evidence-based guidelines and best practices. Overall, the future of AI in nursing is likely to involve the integration of AI-powered tools and technologies into various aspects of nursing practice, with the goal of improving patient outcomes, increasing efficiency, and reducing errors in care delivery. JG: Speculate the future of robotics in nursing ChatGPT: In the future, robotics technology is likely to become more prevalent in nursing practice as healthcare systems look for ways to improve efficiency and patient outcomes. One potential application of robotics in nursing is the use of robotic assistants to perform routine tasks such as administering medication, monitoring vital signs, and providing patient education. These robots could be programmed to carry out specific tasks, such as taking vital signs and could be remotely controlled by a nurse. This could free up nurses' time to spend more time with patients and focus on more complex care. Betriana et al. (2022) and Tanioka et al. (2021) provide examples of the communication between Pepper robots with patients. Another potential application of robotics in nursing is the use of telepresence robots, which allow nurses to remotely monitor patients, provide education and support, and adjust treatment plans as needed. This could improve access to healthcare for patients in remote or underserved areas. Robotics technology could also be used to perform more complex procedures such as wound care, IV insertion, and other procedures that require dexterity and precision. Additionally, robots could be used to assist with patient lifting and transferring, helping to reduce the risk of injuries to nurses and patients. Overall, the future of robotics in nursing is likely to involve the integration of robotic assistants and telepresence robots into nursing practice, with the goal of improving patient outcomes, increasing efficiency, and reducing errors in care delivery. JG: Will robots replace nurses in the future? ChatGPT: It is unlikely that robots will completely replace nurses in the future. While robots and other forms of automation can help improve efficiency and reduce errors in care delivery, nurses play an important role in providing patient-centered care, which is difficult to replicate with technology. This is in line with Aungsuroch and Gunawan (2019) emphasizing that, despite the prevalence of technology and robotics in this rapidly changing era, nurses, with their unique personal and caring skills, will not be replaced by technology. Robots can assist nurses in performing routine tasks, such as administering medication, monitoring vital signs, and providing patient education, but they cannot replace the emotional and social support that nurses provide to patients. Nurses also play a key role in patient assessment, treatment planning, and care coordination, which are critical components of care delivery. Furthermore, nurses are also responsible for educating patients and providing emotional and psychological support, which machines and robots can't replace. Instead, it is more likely that robots will augment the work of nurses by performing routine tasks, allowing nurses to focus on more complex care and spend more time with patients. This will enable nurses to provide better and more efficient care to patients. Overall, while robots and other forms of automation can help improve efficiency and reduce errors in care delivery, nurses will continue to play an important role in providing patient-centered care in the future. JG: Speculate the future of nursing on inter-professional collaboration ChatGPT: In the future, nursing is likely to involve even greater collaboration with other healthcare professionals, as healthcare systems focus on interprofessional teams to provide comprehensive and coordinated care. Nurses will likely work closely with physicians, physician assistants, and other healthcare providers to develop and implement patient care plans and share information and insights to improve patient outcomes. Nurses will also be working with other non-healthcare professionals, such as social workers, case managers, and community health workers, to provide a holistic approach to patient care, addressing not only the medical needs but also the social and economic determinants of health. Education and training for interprofessional collaboration will be emphasized more in nursing programs, preparing future nurses to effectively communicate and collaborate with other healthcare professionals and to understand and appreciate the unique contributions and perspectives of each profession. Telehealth and telemedicine technology will also enable nurses to collaborate more effectively with other healthcare providers, regardless of location, and to provide more coordinated care for patients. Overall, the future of nursing in interprofessional collaboration is likely to see a greater emphasis on teamwork, communication, and shared decision-making, with the goal of improving patient outcomes and enhancing the efficiency of care delivery. JG: Speculate the future of nurse image ChatGPT: It is possible that the nurse image could change in the future as nursing practice and technology continue to evolve. One possibility is that the traditional white uniform will be replaced by more functional and comfortable clothing, such as scrubs or other forms of protective clothing. This could be driven by the increasing use of technology and digital tools in nursing practice, which may require nurses to move around and use their hands more frequently. Another possibility is that the nurse image will become more diverse, reflecting the increasing diversity within the nursing profession. This could include more male nurses, as well as nurses from different cultural and ethnic backgrounds, wearing different types of clothing that reflect their cultural identity. The use of personal protective equipment (PPE) may become more common in the future, as nurses may be required to work in situations where infection control is a concern. This may include the use of gowns, gloves, goggles, and face shields. In addition, the use of technology such as augmented reality (AR) and virtual reality (VR) may also change the nurse’s image, as nurses may be seen wearing AR/VR headsets or other types of technology that enable them to access patient information and other resources more easily. Overall, the nurse image of the future is likely to be shaped by advances in technology, changes in healthcare delivery models, and increasing diversity within the nursing profession. JG: Is a nurse an assistant to a medical doctor? ChatGPT: A nurse is not an assistant of a medical doctor. Rather, nurses are healthcare professionals who work collaboratively with physicians and other healthcare providers to provide comprehensive and coordinated care for patients. Nurses have their own scope of practice and education and are responsible for administering medication, monitoring patients' vital signs, performing routine diagnostic tests, and providing patient education. They also play a key role in patient assessment, treatment planning, and care coordination. In some cases, nurses may work under the direct supervision of a physician, but in other cases, they may work independently or as part of a healthcare team. Nurses also have different levels of education and training. Nurses usually have a diploma, associate's degree, or bachelor's degree in nursing, while medical doctors have a medical degree (MD or DO) and have completed a medical residency. In summary, nurses are independent healthcare professionals who work collaboratively with physicians and other healthcare providers to provide comprehensive care for patients. They have a different scope of practice, education, and level of autonomy compared to medical doctors. JG: Speculate the future of male nurses ChatGPT: In the future, it is likely that the number of male nurses will continue to increase. Historically, nursing has been a female-dominated profession, but over the last few decades, the number of men entering the field has been growing. This trend is likely to continue as more men become aware of the opportunities and rewards of a career in nursing (Gunawan, 2018). One factor that may contribute to the increased presence of male nurses in the future is the growing demand for healthcare services. As the population ages and the prevalence of chronic conditions increases, there will be a greater need for healthcare professionals, including nurses. This will create more opportunities for men to enter the profession. Another factor that may contribute to the increased presence of male nurses in the future is the changing perceptions of the nursing profession. Historically, nursing has been seen as a “female“ profession, but this perception is changing as more men enter the field and as the public becomes more aware of the valuable contributions that male nurses make to the healthcare system. The education system will probably continue to support the increasing presence of men in nursing by offering more male-focused recruitment campaigns and more flexible schedules and options for men to pursue a career in nursing. Overall, the future of male nurses is likely to involve an increased presence in the profession, driven by growing demand for healthcare services, changing perceptions of the nursing profession, and a more supportive education system. JG: Thank you for answering my questions ChatGPT: You're welcome! I'm glad I could help. If you have any other questions, feel free to ask. Conclusion In summary, the future of nursing is a dynamic and rapidly evolving field that is driven by new technologies and changes in healthcare delivery models. Key trends shaping this future include the growing use of technology, digital tools, and artificial intelligence, as well as the incorporation of robotics in patient care. These advancements offer numerous benefits to the healthcare system and patients but also present new challenges and opportunities. The ChatGPT model may provide valuable perspectives on the impacts of these changes on nurses, patients, and the healthcare system holistically. However, it is essential to keep in mind that while technology and robots can aid nurses in completing routine tasks, they cannot replace the personal and emotional support that nurses provide to patients and the vital role that nurses play in patient assessment, treatment planning, and care coordination. As a result, the future of nursing is likely to involve integrating technology and robots into nursing practice to improve patient outcomes, increase efficiency, and reduce errors in care delivery. For nurses, it is crucial to stay informed and adapt to new technologies and developments in the field; this not only benefits the patients but also enhances the nurses' skills and knowledge, making their work easier and more efficient. Acknowledgment The author personally acknowledges OpenAI for creating such an advanced chatbot. Declaration of Conflicting Interest None. Funding None. Author’s Contribution This editorial was generated using OpenAI's ChatGPT language model. It is important to note that the responses provided by the model are generated based on the data it was trained on, and any errors or inaccuracies in the reactions are not the responsibility of OpenAI. JG provided the prompts to guide ChatGPT in generating the texts and added citations/references in line with the contents/texts. Author’s Biography Joko Gunawan, S.Kep.Ners, PhD is Managing Editor of Belitung Nursing Journal. Ethical Consideration Not applicable. Data Availability Not applicable. ==== Refs References Aungsuroch, Y., & Gunawan, J. (2019). Viewpoint: Nurses preparation in the era of the fourth industrial revolution. Belitung Nursing Journal, 5 , 1-2. 10.33546/bnj.744 Betriana, F., Tanioka, R., Yokotani, T., Matsumoto, K., Zhao, Y., Osaka, K., Miyagawa, M., Kai, Y., Schoenhofer, S., Locsin, R. C., & Tanioka, T. (2022). Characteristics of interactive communication between Pepper robot, patients with schizophrenia, and healthy persons. Belitung Nursing Journal, 8 (2 ), 176-184. 10.33546/bnj.1998 Gunawan, J. (2018). There is nothing wrong with being a male nurse. Nursing Science Quarterly, 31 (3 ), 309-309. 10.1177/0894318418774870 29916330 Gunawan, J., Marzilli, C., & Aungsuroch, Y. (2022). Sustaining e-caring leadership in a post-pandemic world. Belitung Nursing Journal, 8 (1 ), 1-3. 10.33546/bnj.2039 Marzilli, C. (2022). Creating the future of nursing in the post-pandemic world. Belitung Nursing Journal, 8 (3 ), 185-186. 10.33546/bnj.2186 Matthews, J. H., Whitehead, P. B., Ward, C., Kyner, M., & Crowder, T. (2020). Florence Nightingale: Visionary for the role of clinical nurse specialist. Online Journal of Issues in Nursing, 25 (2 ). 10.3912/OJIN.Vol25No02Man01 O'Connor, S. (2022). Open artificial intelligence platforms in nursing education: Tools for academic progress or abuse? Nurse Education in Practice, 66 , 103537-103537. 10.1016/j.nepr.2022.103537 OpenAI. (2022). ChatGPT: Optimizing language models for dialogue. https://openai.com/blog/chatgpt/ Tanioka, T., Betriana, F., Yokotani, T., Osaka, K., Locsin, R. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-251 10.33546/bnj.1480 Case Study Developmental assessment and early intervention for children with developmental delays: A case study in South Australia https://orcid.org/0000-0001-9416-8813 Mardiyanti 1* Case Amanda 2 1 Department of Pediatric Nursing, School of Nursing, Faculty of Health Science, Islamic State University UIN Syarif Hidayatullah Jakarta, Indonesia 2 College of Nursing and Health Sciences, Flinders University, Adelaide, Australia Corresponding author: Ns. Mardiyanti, MKep., MDS, Faculty of Health Science, Islamic State University UIN Syarif Hidayatullah Jakarta. Jl. Kertamukti no.5 Ciputat, Tangerang Selatan, Banten, Indonesia. Phone: +62217401925. Email: mardiyanti@uinjkt.ac.id Cite this article as: Mardiyanti, & Case A. (2021). Developmental assessment and early intervention for children with developmental delays: A case study in South Australia. Belitung Nursing Journal, 7(3), 251-259. https://doi.org/10.33546/bnj.1480 28 6 2021 2021 7 3 251259 14 4 2021 12 5 2021 10 6 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Child development monitoring and screening have been mandated as a national health service worldwide, including Indonesia; however, a recent study found that Indonesian community health nurses experienced difficulties detecting and stimulating a child suspected of a developmental delay. Objective To explore and provide an example of how Australian community health nurses, along with other professionals, contribute to a Universal child and family health service (UCFHS), a similar programme name in Indonesia is child developmental stimulating, detecting monitoring and early intervention programme or SDIDTK. Case study This is a case study of a young Australian boy (4 years old) whom the mother reported that her son has unclear speech and he was not speaking as much as other children at his age. The researcher, as a nurse, delivered the child developmental assessment and play skills assessment and found that the child has subtle developmental gaps and was at risk for developmental delay. Several goal setting and programming ideas have been developed to meet the child developmental milestones. These include goals in fine motor skills, communication, problem-solving and personal-social skills which have been regarded as early intervention for the child. Together with the therapy from a Speech Pathologist, these goal settings and programming ideas have been collaborated with the kindergarten teachers and the family as well as the UCFHS nurses as part of the child developmental monitoring programme. Conclusion Developmental delays can be detected through developmental and play assessments and can be followed by developmental stimulation and early intervention programme by developing goal settings and programming ideas around the delays or gaps in play or development. child development nurses Indonesia early intervention play assessment ==== Body pmcChild development monitoring and screening have been mandated as a national health service worldwide, including in Indonesia. Examples of the service are Child Find and Oregon Healthy Start in the US; Universal Child and Family Health Service (UCFHS) in Australia, and Stimulasi, Deteksi Intervensi Dini Tumbuh Kembang (SDIDTK, stands for growth and developmental assessment, stimulation and early intervention) in Indonesia (Australian Health Ministers' Advisery Council, 2011; Macy et al., 2014; Ministry of Health of Indonesia, 2021). Indonesian Ministry of Health has regulated SDIDTK’s Law number 66 by 2014 (Ministry of Health of Indonesia, 2021). This means that child developmental screening, stimulation, and early intervention should be provided regularly in Indonesian community health centres (Puskesmas). However, a recent study found that Indonesian community health nurses experienced difficulties detecting and implementing early intervention of a child suspected of a developmental delay (Mardiyanti et al., 2020). Meanwhile, other countries have delivered the programme successfully and may become an example for Indonesian health professionals, especially nurses. This article provides an example of how a child suspected of developmental delays has been screened, assessed, stimulated and intervened earlier so that the delay can be minimised or corrected before the child enters the primary school where the delays may become problems. Australian Context The Australian education system provides primary, secondary and tertiary education. Primary education starts from the foundation level (kindergarten or preschool from age 3.5 to 5 years) through year 6 or 7 (Department of Foreign Affairs and Trade, n.d.). Kindergarten or preschool are part of early childhood education which responsible for providing care and supervision for young children, preparing them for school, and ensuring that the children are able to effectively participate in subsequent learning opportunities (Department of Foreign Affairs and Trade, n.d.). This case study took place in South Australia kindergarten. Case Presentation Evan (not his real name), a 50-month-old male, was born prematurely on March 2010 at 36-week of gestation, with his birth weight of 3600 grams. During his first week of life, he experienced jaundice. He was breast-fed and formula-fed during the first 6-month of life because of reduced breast milk supply, then ceased breastfeeding completely at around 6-months. No feeding difficulties were reported during the infant period or at his current age. Physically, his weight and height are appropriate for his age, and he also looks taller than other children at his age. The only concern that his mother and teacher reported was his unclear speech. Dribbling sometimes occurs involuntarily during his speech. Mom reported a speech delay of 6-months, as diagnosed and assessed by the speech pathologist. In March 2013 (aged 3), Evan’s mother had referred him to a speech pathologist due to unclear speech as he was not speaking as much as other children at his age. Evan was assessed using the Diagnostic Evaluation of Articulation and Phonology (DEAP) (Dodd et al., 2006). It was found that his speech is relatively clear at the single word level, but when he tries to sequence sounds to say longer words and put words together, the clarity of his speech diminishes and becomes very difficult to understand. For example, he said: “hou” for a house, “sli” for slide and “muni” for “monkey”. Dribbling and low oral muscle tone result in difficulty to precisely make and sequence the tiny movements necessary for connected speech (Rosemary & Usha, 2021). The speech pathologist reported that poor motor control in his mouth and motor planning component becomes the issue to his imprecise speech. There were no other issues in developmental skills at the time, as she found Evan’s play, attention and social skills, and receptive language were appropriate to age. Evan will become a successful verbal communicator if he has regular exercise on speech motor tasks, such as teaching precise movements for different speech sounds and sequencing sounds together to form words and sentences. In addition, she also recommended referring Evan to Ear, Nose and Throat (ENT) specialist to find out any structural issue which may impact his oral motor skills. The Speech Pathologist advised having a hearing test with an audiologist to find any hearing issues that may be impacting his processing of speech sounds. She also advised the mother to include Evan in the Early Entry Preschool Programme where he attended in July 2013 until now, in one of the well-known Adelaide Kindergartens. The kindergarten principal said that she had made a referral to the Department of Education and Child Development to get support service, but to date, there has been no response. The family paid for private therapy as a result. After following all the recommendations from the speech pathologist, it concluded that he had not had any issue with hearing or structure disorder in his mouth. Currently, one teacher participates regularly in teaching different speech sounds as suggested by the speech pathologist. Since February’14, the focus has been on the speech of words ending with n, ch, f and c/k. Evan shows many improvements in his speech, as reported by the teacher and his mother. During observation in the kindergarten, it was noted the teachers and his best friend (Nivedh) relatively understand what Evan’s says, but it is likely difficult for other friends or adults who are unfamiliar with him. During free play, he pretended to be a spiderman with Nivedh excitedly. He can show others something that interested him, imitates others, join in a group if requested, seek adult assistance, and respond to questions. He also plays like others either inside (craft, puzzle, draw, and storytelling) or outside (climb the rungs, swing and slide). However, his unclear speech made the play assessment to some point hard for the assessor. For example, his verbalisation about the play scenario is hard to understand. In addition, the mother reported that he does not have any friends at home because there is no other child his age nearby. He usually plays with his little sister (Asley, 15-month-old) and his mother, who was not working at that time. Since starting Kindergarten, Evan was not attending other settings for early childhood programme, such as child care. Methods Structured observation has been performed two times; once at the kindergarten class and playground, and secondly observation at the child home. Informal interviews were also performed with the mother and the kindergarten teacher. 1. Child developmental assessment Evan’s developmental skills have been assessed using the Australian Developmental Screening Checklist (ADSC), Age and Stage Questionnaire (ASQ-3™) and Play skills checklist (Heidemann & Hewitt, 2010). ADSC is a professional-completed checklist developed by (Burdon., 1994), whereas ASQ-3™ is a parent-completed checklist developed by Squires et al. (2009). The play skills checklist is adapted from Heidemann and Hewitt (2010) and is an observational tool. The use of these tools combines both points of view (parents and professionals), which may differ in how they judge the child’s ability. ASQ-3™ has been recommended widely in English-speaking countries because of its sensitivity and specificity (85% and 86%, respectively) (Mackrides & Ryherd, 2011). Many studies recommend ASQ as a standardised screening tool to be used during well-child visits in any clinical settings either in urban or rural settings (Hamilton, 2006; Rydz et al., 2006; Rybski & Wilder, 2008; Burns et al., 2009; King et al., 2010; Guevara et al., 2013). The ASQ-3™ also utilised by the Child and Family Health Service (CaFHS) in the Adelaide region, which will subsequently be used if families or child health nurses are concerned about the child’s development (Arrowsmith, May 28, 2014). Evan’s ASQ-3™ results have been reviewed by Arrowsmith (May 28, 2014) from one local CaFHS in the Adelaide region. She suggested some sources and materials for developing Evan’s stimulating programme. Play assessments are often taken in screening children, as play is the central occupation for children (Lynch & Moore, 2016). Play is complex and may reveal many things about the child’s development relative to others, including developmental status and functional skills (Casby, 2003) and cognitive ability (Fink et al., 2012). 2. Observation The observation records can be seen in Table 1. Table 1 Observation records Date: 12/5/2014 Child’s name & Age: Evan (49 month) Time: 09.15 Setting: Morning session in kindergarten Who is present: one group (23 children), one teacher (leader), and four facilitators Observer: Yanti Background info: every morning, the one starts with a group session, singing, checking, and greeting each other’s (±20 minutes). Other involved: one parent whose daughter was unwell. Time Observation 09.15 T/ asking all students to come to the playroom for the group morning session. E/ follow the instruction and sit down at the front corner closed to his best friend Nivedh. T/ greeting and student too, T/ asked all students to greet all teachers using other languages such as Spanish, French, Chinese, Vietnamese, and Indonesian. Some students follow the greetings; some were not. E/ does too. T/ then asked about the weather today, some students answered correctly, and some were quiet. E/ tried to give his opinion by raising his hand, but the T/ did not look at him as he sat down at the corner. Finally, he said something, but it was not clear. When another student gave a comment to the T/, Nivedh laughed and E/ laughed excitedly, T/ reminded them that there was not something funny, and they stopped laughing. 09.35 Small group session (Reading story/storytelling) One facilitator with four students (two boys and two girls) sat down in the corner. F/ asked which book they wanted to read. The boys argued as they wanted to read different books, but finally, E/ agreed with his friend and chose to read his book later. F/ read a book about Charlie and Lola with the title “I like tomato” in front of the students. The boys actively questioned and answered with the F/, and the other two girls’ students were very quiet. E/ sat beside the F/, which was not a good position as he needed his head to keep turn right to see the book. While being suggested to move, E/ was still in the same position. During the conversation, sometimes F/ understood what E/ said, sometimes not. It was noticed that E/ saliva sometimes splashed while he was talking. E/ looked frequently opened his mouth during storytelling. He pointed to specific pictures frequently and said some words such as “to..a..too” for “tomato”; “..at..is..nge” for “eat fish finger” etc. He asked for a specific picture in the book, and F/ explained it and replied with a question and E/ answered it correctly. It was noticed that his mouth sometimes kept open with the tongue coming out a little bit. 09.50 Fruit time. E/ walked and grabbed his lunch book. Opened the bag’s zipper with his left hand. He took the apple and brought it to the T/ asked for help to cut it and brought it back to the previous place where he left his bag. Together with Nivedh, he enjoyed his apple. I noticed again that E/ could not control his saliva while eating. Date: 13/5/14 Child’s name and age: Evan (49 months) Time: 09.40 Setting: Kindy’s office Who is present: One teacher (S) and Evan Observer: Yanti Background info: every Tuesday (once a week), S stimulated E with a words card, asked E to mention the word and arranged it in the same group with other words with the letter ends with Ch, N, F and C/K. The programme has started on 26 February 2014. The cards consist of a picture of a word and its letters. Time Observation 09.40 E/ came to the office room in the kindy as the T/ asked him to do so. E/ sat down in a chair, and S/ asked him to sit on the floor because it was for the observer. E/ asked why the observer came to the office, and S explained it simply, and E/ asked again, but the observer could not understand what he’s talking about. S looked to understand what E/ said, and she explained and then shifted the focus to the activity. S started the intervention by explaining about talking at the right speed. She explained using a picture of three types of speed talking: slow (snail), just right and too fast (running people). She asked E/ to speak at the right speed. E/ looked at the cards and answered every question. S asked E/ to classify the card based on its sound. There were four groups for words ending with the sound n—ch—f—c/k. Examples of the word card are: Bee-Bean-Beach-Beak Win-witch-whiff-weck Lee-lean-leech-leak Tif-teen-teak-teach S asked E/ to sound the words correctly, and E/ did it sometimes clear and sometimes unclear. E/ looked excited with these games, and he tried to sound the words and to put them in the correct group. Sometimes he kept busy on where to put the cards to the correct group and not follow S instruction; he sometimes asked “where to put this on?” and S kept remain E/ to sound it correctly and said, “you know where to put don’t you” E/ looked enjoy if S looked a bit disturbed with his questions. S looked patient and asked E/ to “click them out” every time he finished grouping the cards. There was one word, “tea”, which did not fit with those four groups, and E/ noticed that correctly. The second games started. S asked E/ to close his eyes while she hid some words. After finished, S asked E/ to open his eyes. S asked E/ to find all the words and to pronounce them correctly. E/ could find most of the words, and when he looked difficult to find, S gave some clue of where the word was. S sometimes reminded E/ to speak just at the right speed if she could not understand what E/ said. T/: Teacher S/: teacher responsible for Evan language therapy E/: Evan F/: Facilitator Results from the developmental assessment A summary of Evan developmental skills can be seen in Table 2. Table 2 Summary of Evan developmental skills from ADSC and ASQ-3 No Domain ADSC ASQ-3™ 1. Communication Evan is able to name particular objects, join in songs/nursery rhymes, identify “same/different”, ask WH-questions, respond appro-priately to questions, and understand or verbalise physical needs. Apparently, his language skills are around the age of 44-49 month. An overall score is 45, which is above the cut-off (30.72). Evan is able to answer common questions and act to three commands without pointing or repeating (give me the pen, open the book and stand up). Sometimes, he is able to name at least three items for common questions, such as “tell me the names of some animals”. Sometimes, he is able to mention the ending of words (-s, -ed, -ing: such as I see two cats, I kicked the ball, I am playing) and uses all of the words in a sentence (“a”, “the”, “am”, “is” and “are”). 2. Fine motor Evan is able to pincer grasp, holds a pencil in hand, not a fist, draws horizontal and vertical lines, turns doorknob to open the door, cut paper with scissors, and draw a circle. Apparently, his fine motor skills are around the age of 44-49 month. An overall score is 35, above cut-off (15.81) but close to grey areas. He is able to draw three shapes and a picture of people with at least three features (head, eyes, arms, legs). Sometimes he is able to put together a 5 to 7-pieces puzzle, cut a piece of paper using a scissor or unbutton one or more buttons of his clothes. However, he has not yet drawn or colour in within line. 3. Gross motor Evan is able to jump forwards: feet together, hops on foot: on the spot, balances on 1 foot for a few seconds, can sit on the floor cross-legged, walks a straight line. Apparently, his gross motor skills are around the age of 50-55 months. An overall score is 60, which is above the cut-off (32.78). Evan is able to catch a ball, climb, throw a ball, hop up and down, jump forward and stand on one foot for 5 seconds, which are appropriate to his age. 4. Problem solving/cognitive Evan is able to tell the name of a friend or playmate, maintain interest or involvement for few minutes, refers to own gender accurately, understands 2: picks two objects, tries to count and understands 3: picks three objects. Apparently, his cognitive skills are around the age of 44-49 months An overall score is 50, which is above the cut-off (31.30). He is able to repeat three numbers in order without repeating the request, distinguish items by their size, name five different colours, and count items. Sometimes he understands the concept of “under”, “between” and “middle” and does pretend play. 5. Personal-social Evan is able to ask for help if needed, can tell his own first name, can wash and dry hands, recognise the gender of his friend Nivedh and himself, is able to go to the toilet by himself, sometimes joins in play with others. Evan is around 44 months development in this area. An overall score is 45, which is above the cut-off (26.60). He is able to serve himself, wash his hands, and brush all his teeth without any help. Sometimes he is able to mention the names of two or more playmates and recognises his identity, such as his first and last name, age and sex. 6. Overall Evan has strengths in the area of Gross Motor and is just under age appropriate for most other areas. There are some impacts of communication difficulties in his social and communication skills. There are also some slight delays in fine motor development. No problems in hearing, vision, behaviour and medical problems in the last several months. Evan’s mum worries about two things: “not talks like other children at his age” and “Others do not understand most of what your child says”. Since under speech therapy last year, Evan’s speech now shows many improvements. Play assessment checklist Based on the play checklist, which looked at areas of social play, communication, pretence and problem solving, Evan does pretend play by using imaginary objects and uses verbal declaration approximation (“I am a Spiderman”). During observation, he enjoys and interacts with Nivedh, and they play together as they are Spiderman and others are the bad people. He enjoys playing in a group if an adult requests it. He is able to show others an interesting object by pointing, bringing the object or express verbally, and engaging in the activities for several minutes or until the activity finishes. He is able to negotiate with a peer about which book should be read during the storytelling group, although then he accepted the adult suggestion without arguing. There are some difficulties in his communication during a play episode, verbalising about the play scenario to his play partner, and being understood. He also tends to play with one (the same) play partner. However, due to parents’ permission, the observation settings only happened in the kindergarten. Therefore, there is a need to observe the child’s play skills in his house, where he spends most of his time. Analysis Overall, Evan’s developmental level is relatively appropriate for his age. He still has many opportunities to improve the “sometimes” skills into his “routine” skills to help him reach his full potential. Evan’s mother and the teachers are very good sources in shaping his development. During observation, the mother is very active in questioning and clarifying Evan’s progress with the teachers. The teachers also persistently delivered the activity suggested by the speech therapist. It is believed that at the end of the kindergarten programme, Evan will be more than ready for his next primary school. When looking at each domain in the checklist, more focus should be taken on the fine motor area, communication, problem-solving and personal-social. This means that more activities in these areas should be supported and created. His dislike to colour in should be addressed. In addition, given his unclear speech, this may lessen his motivation to participate in play with others or lessen his social interaction later when others respond unexpectedly or when he realises that his speech is different from other children. This can be seen during observation in the kindergarten; Evan spent his time mostly play with Nivedh and not with other children, though he is an active person and show excellent enthusiasm during group sessions and story-telling. He tries to participate and connect with others, but sometimes others do not respond to him due to his unclear speech. Therefore, we need to develop strategies not only for building his articulation speech but also for encouraging him to interact with other children. Moreover, support should also be provided to help him achieve the kindergarten’s learning outcomes so that he can build a strong sense of identity, feel connected and contribute to the world, a strong sense of well-being, feel confident, independent and involved learner as well as an active communicator (Pasaneda Kindergarten, 2012). Perhaps providing a positive experience will help him construct his strong identity, confidence and independence. Goals setting Goal setting aims to provide assistance for Evan and his family to optimise his child development. The goals have been created based on Evan’s developmental level and his emerging skills that need to be strengthened to achieve his full potential. Please see Table 3 (Goals for Evan) and Table 4 (Goals and activities for the families). Table 3 Goals for Evan Fine Motor Goals Goal 1. Evan will colour a picture in a colouring book mostly within the lines minimally three times a week in his time at home by July 30. Goal 2. Evan will unbutton one or more buttons while undressing his clothes every time he comes back from school or playing with a cloth buttoning strip by June 30. Goal 3. Using a child-safe scissor, Evan cuts papers in half on a more or less straight line 3 times a week at home by June 30. Goal 4. Using a minimum five-to seven-piece interlocking puzzle, Evan puts them together correctly three times a week by June 30. Communication Goals Goal 7. (Collaboration with the intervention from Speech therapy). Then requested to sound the words provided, 50 % of Evan’s speech sounds are correct and clear by July 31. Problem-Solving Goals Goal 8. When requested, Evan pretends to play with one different/new child partner (not Nivedh or his little sister) in the playground or during kindergarten free play minimally once a week by July 30 (collaboration with the teachers). Goal 9. When requested to participate in socio-dramatic play, Evan can play with two or three children and interact with each other in the kindergarten play sessions 50% by July 31. (Collaboration with the teachers). Personal-Social Goals Goal 10. When asked by his mum after finish his school session, Evan mentions the names of two or more playmates (not including his little sister) by July 31. Table 4 Goals and activities for the families No Goals Items Activities Description 1. Evan family will look for and use the services from one of the local CaFHS in Adelaide by June 30 (e.g., Kid’s health and child developmental monitoring pro-gramme). Explain the CaFHS services in South Australia that family may gain benefits. Provide the website address (www.cyh.com) or the CaFHS local address and contact number close to their area (Edwardstown CaFHS; 2 Vurness Avenue 5039, Call number 1300 733 606 between 9 am and 4.30 pm, Monday to Friday to make an appointment). Explain that Evan needs an-ongoing services from CAFHS to monitor his development closely (e.g., using ASQ-3™ developmental monitoring until 60-month-old), including the early childhood intervention programme and parenting support. 2. Evan family will look for and use the services at Forbes children’s centre for Early Childhood Development and Parenting by June 30. Explain the Forbes Children’s Centre services that the family may gain benefits, such as: Sessional preschool for children for five sessions a week in the year prior to starting school. Long daycare child care for Evan or Asley. So, the mother will be helped in raising the children. Many programmes will benefit the family, such as Dad engagement, developmental play sessions, Saturday playgroup, Family service coordinator, Circle of Security, Premier’s be active challenge, Mums of toddler group). 3. Evan’s family will read to Evan every day. Offer article to the family about the risk for reading problems in children with speech sound disorders (Anthony et al., 2011). The Forbes Children’s Centre also creates a programme, Let’s Read, to support families reading with their children. Motivate the family to create a reading programme every twice a week at home. Programming Ideas Programming ideas aim to achieve those goals that are created based on Evan’s emerging skills and the availability of resources. Play is extremely important for children’s learning. It is regarded as an activity that helps develop the child’s cognition, communication, socialisation, sensory-motor functions, problem solving and self-awareness (Canadian Association of Occupational Therapist, 1996 cited in Stagnitti, 2004). The activities should be integrated into the child’s immediate interests and ongoing activities, although he might avoid these (e.g. colour in) (Johnson-Martin et al., 2004). The strategy could be to rearrange the environment (e.g. remove the materials the child persists in using for a period during the day and offer other activities) or to become more directed (e.g. “We need to spend some time colour in first, and then you can play with trampoline”). One activity can be used for some or all domains of development; for example, storytelling in a group of children may involve cognitive, fine motor, gross motor, communication and social skills (Table 5). Table 5 Activities for Evan Goals Activities Description Fine motor’s goals Colour in games Provide “Spiderman colouring books” and colour pencils. Ask him to colour in. If he does not show interest, he will be attracted by modelling first and saying, “I am busy with Spiderman”. Alternatively, guide his hand and later let him do it independently. Encourage him by stating, “can you cover all the white?” and “try and stay inside the lines.” Unbutton games Ask him to unbutton his cloth or another cloth strip from the dressing vest or doll, which has large, medium and small buttons. If he does not know how to approach this task, slowly demonstrate for him. Then try to assist him physically. He should hold and lightly pull the cloth next to the hole with one hand, grasp the button and push it through the hole with the other hand. Adapted from “The Carolina Curriculum for Pre-schoolers with Special Needs” (Johnson-Martin et al., 2004) Cut and draw games Place a piece of paper and the safety scissors in front of the child. Draw a line from the left to the right side of the paper. Ask him to cut the paper in half or to cut all of the ways across the paper. Give him verbal cues if needed (e.g., “follow the line”). Or use tape by placing it on either side of the line to encourage the child to stay on the line. If he is able to do this, expand the games by cutting a circle, square or pictures that he made and coloured in. It may be helpful to trace around the outline of the picture with a marker before cutting it out. Encourage the child to stay on the line and not cut into a picture. Select pictures easily to cut, then stick them into a paper board. Ask him to put his name and date on it. At the end of June, the families can know how far his progress is. Adapted from “The Carolina Curriculum for Preschoolers with Special Needs” (Johnson-Martin et al., 2004) Puzzles Choose a puzzle that has minimally 5 to 7-pieces. Encourage him to finish the puzzle. If he cannot do it, try to work together or one-by-one or backchain - do all but the last one and ask him to add the last piece. Next time do two last pieces, etc. Communication 3-related items games Choose three pictures from common categories (fruit, school items, food), then write the name of the picture on a piece of paper, place it close to the picture. Ask him to answer your question: “things that we eat”, “things in the school”, “things that are yellow”. Encourage the child to choose three pictures and bring them together with the name. If he is able to do this, expand the games by only stating the name of the item. Encourage him to be familiar with the letters. Encourage him to verbalise the name correctly. Model the correct articulation of the words, then ask him to sound them out. Identifying the sound of words Use the word cards from speech therapy or download the new one from www.busybugkits.com.au/freebiesarticulation/. Choose the letter of words that Evan needs to practice. Expand the games to “hungry for K’s”. Tell him and other children in a group that they are on a special diet and can only eat things that start with the /K/ sound. Ask them to put the things into their lunch box (e.g., carrots, corn, cucumber, ketchup). To make it more complex, add other objects that start with /k/ but cannot be eaten (e.g., cards, cat, key, cow). Alternatively, put some words that do not have any /k/ sound. Count to see how much they can put in their lunch box. Adapted from www.phonologicalawareness.org/#!phoneme/cr2d Problem-solving Spiderman shopping Ask Evan to play “Spiderman shopping”. Creates the situation like a shop. Evan becomes a Spiderman (provide Spiderman costume), and his friend pretends to be a clerk. Provide pictures as a cue to prompt, and ask Evan to buy things that start with the letter /f/. Encourage both of them to interact with each other. Spiderman Sick Ask Evan to play “Spiderman sick” and go to a clinic and meet customer service, doctors, pharmacists, and other people who need help. Discussion Evan, who has speech delays, shows much improvement in his communication since he started the Early Entry programme in kindergarten and several session therapies since last year from the Speech Pathologist. Evan will be more than ready for his next school journey if he and his family join many community-based programmes and do a lot of activities, as suggested above. Some articles show that Subtle Developmental Problems (SDPs) and Speech sound disorders are at high risk of academic failure, social-emotional disturbance and behaviour problems (Glascoe, 1999; Williams & Holmes, 2004; Anthony et al., 2011). These may be due to poor motor control and motor planning inadequacy that require much more intensive developmental stimulation. This stimulation may be hard to do if the family does not have enough resources and must deal with other demands such as work and other siblings. Therefore, it is important to refer all children with high risks of developmental delays to an early intervention programme, although they have not yet any diagnosis. It also important as well for CaFHS to monitor the child development closely and support the family. Parent’s willingness should also be supported so that they can participate in the programmes fully. The case in this report might become a good sample where the child may show delays in the communication skills that may not intervene earlier if parents had not sought help from the speech therapist. Early detection of the developmental problem may allow an early intervention programme to reach children’s full potential, academic success, independence, and confidence. Nursing Implications Nurses in the community health centres may be inspired by this case study and use the information for developing nursing care for children suspected of a developmental delay or subtle development. Evan’s goals may also be used for developing nursing outcomes, and Evan’s and family activities used for developing nursing interventions. The developmental screenings (either ADSC or ASQ-3™) showed Evan’s development was normal, although the mother’s concerns about Evan’s speech problem, therefore play skills assessment may be beneficial in finding which areas of development are specifically at risk of delay. Therefore it is recommended to use play skills assessment, such as the Pretend Play Enjoyment Developmental Checklist (Stagnitti, 2017) combined with developmental screening tools such as Kuesioner Praskrining Perkembangan (KPSP) in the SDIDTK programme. It is also suggested that policymakers train community health nurses for developmental assessment skills and play assessment skills to improve the quality of child universal health service in Indonesia. Limitations of this Study There are several limitations to this study. Firstly, this is a single case study, and further studies would need to include more subjects. Secondly, ideally, child development skills and play skills should be assessed in three different areas (house, school and other public areas such as playground); however, this study only conducts observation in the school and public areas. And thirdly, this case study did not report on outcomes of the early intervention for the child, and further studies would do well to include both quantitative and qualitative outcome data. Conclusion Evan’s developmental skills and play are relatively appropriate for his age based on the tools applied, although ASQ-3™ picked up parental concerns that need to be referred into an early intervention programme, followed by monitoring his development closely. Parents are strongly recommended to raise any concerns about their child development and seek help from professionals. Parents’ concern and willingness should be encouraged for the success of the early intervention programme and the well-being of the child. Acknowledgment We thank Pasadena Kindergarten South Australia, the Faculty of Health Science UIN Syarif Hidayatullah Jakarta and Flinders University for their great supports. Also, special thanks to Evan’s mother for her openness and kindness. Declaration of Conflicting Interest The authors have no conflict of interest to declare. Funding This study was part of a major assignment in Master of Disability Studies. The author (Mardiyanti) had funding support from AAS (Australian Award Scholarship) and Islamic State University UIN Syarif Hidayatullah Jakarta, Indonesia. Authors’ Contribution All author contributes to the study’s conception and design. MM and MC conceptualized the study. MM performed data collection, MM dan MC drafted the original version of the manuscript. All author accepts the final manuscript. Authors’ Biographies Mardiyanti, RN., MKep., MDS is a Lecturer at the Nursing Programme of the Faculty of Health Science UIN Syarif Hidayatullah Jakarta, Indonesia. She is also an Alumni of Master of Disability Studies, Flinders University, Australia. Amanda (Mandy) Case, MOccTh(GradEntry) is an Associate Lecturer at the College of Nursing and Health Sciences, Flinders University, Australia. Her work with children with delays and disabilities as a Developmental Educator/Occupational Therapist spans over 30 years. Mandy has taught the Play and Early Intervention topic at Flinders University for the last ten years. Her particular interest is play in young children with delays and disabilities. ==== Refs References Anthony, J. L., Aghara, R. G., Dunkelberger, M. J., Anthony, T. I., Williams, J. M., & Zhang, Z. (2011). What factors place children with speech sound disorders at risk for reading problems? American Journal of Speech-Language Pathology, 20 (2 ), 146-160. 10.1044/1058-0360(2011/10-0053) 21478282 Arrowsmith (May 28, 2014). [Personal communication]. Australian Health Ministers' Advisery Council. (2011). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-227 10.33546/bnj.1409 Original Research “Accessibility”: A new narrative of healthcare services for people living with HIV in the capital city of Indonesia https://orcid.org/0000-0001-5648-2393 Mahathir 1* https://orcid.org/0000-0002-2193-2064 Wiarsih Wiwin 2 https://orcid.org/0000-0002-5644-7624 Permatasari Henny 2 1 Faculty of Nursing, Universitas Andalas, Indonesia 2 Faculty of Nursing, Universitas Indonesia, Indonesia Corresponding author: Ns. Mahathir, M.Kep., Sp.Kep.Kom, Faculty of Nursing, Universitas Andalas, Jl. Kampus Unand Limau Manis Fakultas Keperawatan Pauh Padang Sumatra Barat, Indonesia. Phone: +6281364474488. Email: mahathirmahat@nrs.unand.ac.id Cite this article as: Mahathir., Wiarsih, W., & Permatasari, H. (2021). “Accessibility”: A new narrative of healthcare services for people living with HIV in the capital city of Indonesia. Belitung Nursing Journal, 7(3), 227-234. https://doi.org/10.33546/bnj.1409 28 6 2021 2021 7 3 227234 13 3 2021 12 4 2021 22 6 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The progress of the fight against HIV is highlighted by significant change. HIV of the past is different from HIV of the present. Healthcare services have played an essential role in achieving the optimal goals needed to end the HIV epidemic. However, people living with HIV and those at risk of catching it (PLWH) often misunderstand the rapid growth of HIV healthcare service options. Objective This study aimed to explore the experiences of PLWH in the healthcare services featured in this study. Methods A qualitative phenomenological approach was used. Semi-structured interviews were conducted in 2017 with 12 PLWH who engaged with healthcare services in Jakarta, Indonesia, by using a purposive sampling technique. Semi-structured questions were asked which related to their experiences of using the services. Stevick Colaizzi Keen method was used to extract the thematic analysis of the study. Results The study developed four essential themes of PLWH healthcare use. They were accessibility, availability at all healthcare levels, comprehensiveness of service, and affordability. Conclusion Providing accessible healthcare services is considered essential by PLWH. It is also pivotal to helping people feel positive about the community-related healthcare services on offer. Nurse-led HIV services must maintain this progress by continuously evaluating the quality-of-service outcomes and promoting the accessibility of the services to the broader population. HIV infections health services patient acceptance of healthcare nursing Indonesia ==== Body pmcUnited Nations Sustainable Development Goals demand sufficient progress in ending the epidemic of AIDS and also achieving universal health coverage by providing qualified essential healthcare services (United Nations, 2016). It is vital to establish quality HIV services that offer people-centered, safe, acceptable, appropriate, effective, and efficient care for PLWH (World Health Organization, 2019a). PLWH should be engaged in a qualified diagnostic and treatment of healthcare services (World Health Organization, 2016) and must be treated with Antiretroviral Therapy (ART) (World Health Organization, 2020). In 2019, a total of 37.9 million people around the world was living with HIV and AIDS (US Department of Health & Human Services, 2020). Global efforts have been made to reduce this, although the progress is not sufficient. The number of people who have tested positive for HIV may be reducing globally, but this reduction is not significant enough, and prevention strategies and programs still need encouragement. There is a significant gap between actual achievement and the 2020 target. Whereas the target was to bring the number of deaths down to 500,000, it currently stands at 770,000. Furthermore, the target for the number of patients acquiring HIV was 500,000, but in 2018 1.7 million people became infected (World Health Organization, 2019b). This is why HIV prevention programs continue to be encouraged. Patient experience and satisfaction are important to achieve better health outcomes (Leon et al., 2019). It is notably well-known that better healthcare services for PLWH will improve patients retention with healthcare services, maintain patients' adherence to ART, and ultimately reduce the HIV viral load (Dang et al., 2013). Discontinuation of healthcare engagement and ART adherence will have adverse HIV consequences and increase a major public health problem (Pérez-Salgado et al., 2015; Anh & Thaweesit, 2019). ART non-adherence will contribute to the failure of the immune systems of PLWH. It will also lead to an opportunistic infection that threatens the quality of life, and in the worst-case, lead to mortality (Johnson et al., 2017). ART is the key to suppressing the viral load in the bloodstream, which is important to prevention strategies. It is well known that viral suppression will reduce the risk of passing the infection to others (Siedner & Triant, 2019). The dream of an HIV-free world is facing critical gaps and barriers, including the optimization of healthcare services. Healthcare services sometimes have the limitations of poor performance and unequal treatments (Keller et al., 2014). Program collaboration and service integration are now considered vital to health departments to ensure a comprehensive approach, but this requires inter-sectional understanding (Bernard et al., 2016). Stigma also adds challenge to improving the accessibility of healthcare. Stigma disparaging is the equal access of all to receive appropriate services at all levels and circumstances (Moradi et al., 2014). Within the ecological and policy factors influencing HIV healthcare engagement, the availability of surveillance, testing, prevention, medical and supportive services are crucial. Access within minimal distance, clinic culture, medical home, and the availability of appointments also lead to further and better performances and increased retention of services (Mugavero et al., 2011). Negative experiences between the healthcare providers and at-risk population sometimes detriments their relationship. The feeling of awkward interaction, irrelevant questions, blaming, pettiness, poor support, and confidentiality breaches were often experienced by patients during their treatments (Stutterheim et al., 2014). In 2018, Indonesia had a total of 640,000 PLWH; 38,000 among them had died from HIV and AIDS-related illnesses, 46.000 people were newly infected in that year. Only 51% of the suspected population knew their status, and 17% of them living with HIV were receiving treatment (UNAIDS, 2018). Obviously, the number is very far from the target and needs intensive attention to improve achievement. Jakarta and parts of West Java, as one of the megalopolis cities in Indonesia, endure significant numbers of PLWH. Jakarta and West Java are both included in the top five most popular provinces that contained people who live with HIV. In 2017, Jakarta itself had around 6,626 people who tested HIV positive (Ministry of Health of Indonesia, 2018). Indonesia’s response to the HIV epidemic is considered modest. The escalation of stakeholders’ contribution is urgent and includes the public health service (Mesquita et al., 2007). The accessibility of healthcare services has to overcome a number of barriers. Stigmatization among healthcare is often high (Risal et al., 2018). It is recognized as a predictor of discriminatory attitudes towards PLWH who engage in healthcare facilities (Harapan et al., 2013). Indonesia also experiences the policy and practice implementation disjunction that will initiate the discrimination of treatment and care (Fauk et al., 2019). As a result, PLWH encounters difficulties in engaging healthcare access; it is also hard for them to adapt to their chronic disease (Senyurek et al., 2021). Nurses play a major role in the eradication of HIV, providing optimal services starting from preventing transmission to promoting the health and well-being of PLWH (Gilks, 2019). Nurses achieve this by implementing friendly and approachable services within health services. Nurses make mutual collaborations with the population and ensure the continuity of care being provided. Nurses circulate the information about HIV healthcare services available to the people and seek to improve the quality and accessibility of these services. Advocating comprehensive delivery must be empowered by nurse-led HIV services to bring forth patient-centered care for PLWH (Rouleau et al., 2019). Services for the wider population and PLWH are now broad and advanced. It can be accessed on both a static basis and a mobile one. The look of healthcare services is changing hand in hand with the efforts to move forward. Implementation faces financial obstacles and the progressive needs of the population. This is regarded as the key to widening the outreach of healthcare services (Falkenberry et al., 2018). HIV service delivery is now shifting from one size fits for all approach. It will accommodate comprehensive delivery across the prevention and care continuum through differentiated care (UNAIDS, 2018). HIV care continuum of HIV has been recognized as a progression from serotesting, medical and healthcare engagement, ART treatment and adherence to the ultimate goal that is viral suppression (Kay et al., 2016). The rapid shifting and continual efforts shall be followed by progressive evaluation from all perspectives. This study aimed to evaluate the experiences of PLWH who engaged with HIV healthcare services in Jakarta, Indonesia. Methods Study Design This research used a qualitative phenomenological method. It describes the phenomena of progressive change within HIV healthcare services. Phenomenology is a type of qualitative research that focuses on the individual’s lived experiences within a specific phenomenon (Creswell, 2013). This method was used to interpret the experience of the HIV healthcare use from the service user’s perspective. This study explores the experiences of PLWH who used healthcare services in Jakarta, Indonesia. Appropriate conditions help lead towards the successful achievement of objectives (Smith, 2018). Participants Participants in the study were PLWH who used HIV healthcare services in Jakarta, Indonesia. Purposive sampling is very commonly used in qualitative research. Purposive sampling allows the qualitative researcher to choose the participants and their characteristics for the study. It is essential for phenomenological study to accommodate participants who have experienced the topic of the research question. Furthermore, it will ensure the quality of the information provided by the research participants. Therefore, the criteria of participants in this study were PLWH who have engaged with HIV healthcare services and willing to share their experiences. The number of participants was determined by reviewing available information and data saturation. Participants were recruited and selected through a designated HIV non-government organization around the city. This study evaluates the data collected from twelve participants. Saturation was achieved when no other bits of new information or issues emerged. Participants in this study were PLWH, who used HIV healthcare services, such as voluntary counseling, mother-to-child transmission programs, and methadone maintenance therapy clinics within hospitals, public health services, and prison clinics. Data Collection This study was conducted in two non-government organizations (NGOs) in Jakarta, Indonesia, which provide social support and engagement for PLWH during their life with the disease. Jakarta has 38 active NGOs and foundations in handling HIV/AIDS issues. The two NGOs provided the list of participants who matched the study inclusion criteria. The selection of participants for the research was based on the types of HIV healthcare services used by the PLWH, as it was expected to enrich the data collected. The researcher made an appointment with the participant before the interviews were conducted to develop emerging environmental situations and build trust. They then set the appointment to carry out the interviews. The study was conducted between July 2016 to January 2017. The study collated the data and information through semi-structured interviews. Two experts independently authenticated the interviews. All interviews were conducted by one person (MH). The other supervisors (WW and HPS) contributed to data analysis and validated the trustworthiness of the research. The interviews were conducted in the Indonesian language and then translated by MH to the English language after data analysis. The interviews were conducted by questioning the participants through trigger questions and follow-up questions based on the initial responses. The first question in the questionnaire was, “Could you please tell me how has your experience in using HIV healthcare services been so far?” Then, based on the participant’s answer, the interviewer asked a followed-up question such as “Would you please describe to me what do you mean by easily accessed?” or “What do you mean by it was different from what you have ever expected? Could you please elaborate on what more you expected?”. Other follow-up questions were asked until the data was confirmed and verified. The interviews lasted between 45-60 minutes. The oral data were recorded through secure tape-recording, and any non-verbal communication data observed were documented in field notes. Data were stored securely within a confidential folder on the computer. The recording results were then written as a transcript in verbatim form and combined with the results of the field notes. Data Analysis The stages of the data analysis process in this study used the Stevick Colaizzi Keen method (Speziale et al., 2011) by arranging the information of the interviews and transcribing the recordings into verbatim form. The data script was repetitively listened to and read to ensure the accuracy of significant information. Participant statements were marked to point out the important information relating to the objectives of the study. Finally, themes were formulated by identifying the important information, classifying it into data groups, and categorizing themes and sub-themes. Trustworthiness/Rigor The researchers ensured the trustworthiness of the data and results by comparing the results with other research and ensuring the participants provided trustworthy information. Environment familiarity was also confirmed by holding pre-interview meetings and advance contact with all participants. The researcher also discussed the results with fellow researchers and supervisors (WW and HPS) with upper-level degrees of education and expertise. The transferability of the data was conducted by ensuring that other groups of participants fully understood the research results. The findings have been read by PLWH, who were not participants in the study but still fit the inclusion criteria. This study also surveyed a variety of participants. The reliability of the data is dependent on the saturation of the participant’s information by preparing questions that provide accurate answers based on the topic or issue of the study. This study also used repeat questions with an expectation of the same response to clarify and maintain the trustworthiness of the information provided by the participants. Data and results were also presented back to the participants who were involved. The researchers then showed the principles of the results of the research documentation and findings to participants who engaged in the research. Ethical Considerations All activities within this research are strictly compliant with the relevant ethical guidelines and considerations. Ensuring that no one was at risk of harm or experiencing negative impacts from the research activities conducted was crucial. By providing autonomy, beneficence, non-maleficence, confidentiality, and justice, this study was committed to protecting the participants involved. This study was reviewed by the Universitas Indonesia Ethical Council Committee and declared as ethically feasible to be conducted with ethical clearance number 0272/UN2. F12.D/HKP.02.04/2015. Results Characteristics of the Participants There were 12 participants in this study who were PLWH that used healthcare services in Jakarta, Indonesia. The 12 participants participated voluntarily in semi-structured interviews conducted during the research process. All participants acknowledged their HIV-positive status, were open to being involved in the study, and cooperatively answered the questions during the interview. In addition, participants did not express objection or unwillingness to provide answers to any of the questions. The quoted text in this study was originally in Bahasa Indonesia and translated to English to fulfill journal requirements. The characteristic of the participants is displayed in Table 1 below. Table 1 Participants’ Characteristics Participant Code Age Education Year of Status Risk Population P1 29 High School 2005 PWID P2 30 Elementary 2006 PWID P3 31 Junior High 2008 Heterosexual Male P4 32 Junior High 2008 PWID P5 34 High School 2008 Prisoner P6 34 High School 2008 PWID P7 34 High School 2010 Prisoner P8 34 Bachelor 2010 Heterosexual Female P9 39 High School 2010 PWID P10 41 Bachelor 2014 PWID P11 22 High School 2016 MSM P12 31 Diploma 2016 MSM Note: PWID= People Who Inject Drugs | MSM=Men Who Have Sex with Men Themes The study developed four significant themes such as accessibility, availability at all healthcare levels, comprehensiveness of service, and affordability. Each theme is explained in the following. Theme 1: Accessibility Almost all participants stated that they had easy access to a healthcare facility. According to the participant's statement, the accessibility of the healthcare facility was determined by the proximity of the HIV healthcare facility and the transportation facilities to help them reach it. One of the participants stated that he had no complaints about the HIV healthcare facility. His statement is documented below: “Actually, there was no obstacle in order to reach out the facility, and the hospital was really nearby! The only problem I have is to provide a specific time to go. We didn't have to be worried; it is no big deal.” (P5) The other participant said the same thing; he said that the healthcare facilities are near his home. He also said that the facility could be reached while attending another activity. Along with fitting facial expressions, the participant stated the following: “No, the public health center where I ran for regularly healthcare services was really close by. I can reach the place while I was going somewhere else. But the waiting was still taking some time.” (P3) Participants said that easy access to healthcare facilities was linked to the availability of transportation that they could use. There were so many transport choices in order to reach the services. Following is the relevant participant's statement: "… the access was not too difficult for sure, it was easy! Lots of vehicles and public transportation to use." (P1) Theme 2: Available at all healthcare levels Six participants felt that the healthcare services are now available in all levels of healthcare facilities, from a primary level to a tertiary one. Participants recognized that the facilities are part of government efforts to broaden the range of available services. Two participants summarized their experience as the following: “It depends on me, where do I want to go, which hospital do I prefer. It’s completely up to me, even though I heard I could choose from the services in public health centers around me. There are so many facilities that I acknowledged, and I chose the hospital because I did not want to be recognized.” (P5) “Surprisingly, at first, I thought it only could be done at the hospital far from my house. But my peer navigator enlightened me it could also be done in the public health center near my house. It helps me a lot, you know.” (P12) Theme 3: Comprehensiveness of service Participants are fully aware of their risk behaviors. It pushed them to start engaging with the healthcare services. Participants get sufficient knowledge and information from the facility, then complete serostatus checking and obtain the test results before starting ART and other behavioral therapy all in one place. Most participants admitted that all of the services for HIV care they experienced were simply done in one place. One participant stated that he felt relieved because the processes were comprehensively all in one place and helped fulfill all needs. Fluently speaking with a heavy tone, the participant expressed the following: “I am fully satisfied with all of the services, which began with the registration., I can choose whatever name I want to respect my secrecy. They collected me with the others in a room and told us information related to HIV before asking us to express our feelings before getting the test. Some people were crying at the time, but I felt so comforted by the manner of the facilitators. I admired that. Then when I tested positive, they recommended me to start the ART. They looked after me when I disclosed my status. That was a big moment of my life, really.” (P11) The other participant felt the same thing with all the services provided by the healthcare facility. She experienced all the procedures she needed to in one place and only needed to think of her feelings at that time. With a calm tone and soft smile, she spoke as follows: “…then they brought me to VCT. I was interviewed by the nurse, and he told me about HIV. I also ran the test there. When I came back, the doctor announced the result; I am positive. They counseled me when I reacted and checked how I was feeling, and then we planned the ART. They allowed me to ask as many questions and discuss as many things as I wanted to.” (P8) Theme 4: Affordability Five participants stated that most of the HIV healthcare services they accessed were free of charge, but some specific services still cost them. For participants who had limited financial income, it sometimes increased their financial challenges. One participant said that the services cost him little but still caused a burden on his financial situation: “Most of the services were free; I don't pay that much, only for the administration. I guess it might be for doctor service only. When I don't have any money, sometimes this fee was uncomfortable and hard to take.” (P1) The other participant stated that the affordability was convenient. The funding system did not burden him because it was just a small amount to cover. Compared to what he was getting, he felt it was quite cheap. With a confident tone, he said as follows: “It was free, I guess, but there were some specific services for which I should pay, but that was okay; I think that was normal. At first, I thought it would be expensive, but it was mostly free. I feel grateful. (P10) Discussion The themes indicated that there is a significant growth in HIV services. Easy access to the facilities mirrors the success of the healthcare system to provide accessible and quality healthcare facilities for PLWH. A study of factors associated with access to HIV healthcare services stated that HIV-positive patients preferred the nearest place in order to more easily engage with services (Lubogo et al., 2015). Distance to care will determine the ART compliance among the PLWH. A study in Malawi found the ART retention increased, and the possibility of loss during follow-up decreased. The range of healthcare facilities on offer influenced PLWH’s decision to maintain engagement with healthcare. It also improved annual visits in ART enrollment. Distance to travel was recognized as an obstacle for PLWH (Bilinski et al., 2017). Further distance between the healthcare facility and the patient will increase the cost for PLWH, who had a lower socioeconomic status (World Health Organization et al., 2013). The distance to travel for the affected population in rural areas was also proven to increase transmission probability. Viral suppression is the key to slow HIV transmission. Viral load suppression will never be achieved if ART compliance could not be obtained. ART compliance requires routine access to reliable and available facilities. The need to travel farther will reduce the likelihood of ART enrollment (Smith et al., 2017). The longer the distance to healthcare facilities, the lower retention in care and viral suppression (Terzian et al., 2018). The longer distance is also regarded as a barrier for healthcare service use (Tafuma et al., 2018). The availability of healthcare services within all levels of healthcare facilities is considered an advantage. All-level facilities will broaden the range of healthcare services available to the population. Decentralization of HIV services and facilities will also expand the range that HIV services can reach. A study of decentralization of HIV healthcare services experienced by the rural communities in Canada concluded that the PLWH prefers the services to expand to all clinics and public health centers. It provides them with a friendly and well-known environment (Cunningham et al., 2014). It is also cost-effective and reduces threats (Kolawole et al., 2017). A study from Yogyakarta, Indonesia, mentioned that the availability of services keeps the process simple and is convenient to the healthcare environments. The transgender women in this study recognized the positive attitudes of the healthcare professionals and friendly social relationships on both sides (Fauk et al., 2019). Expanding ART services delivery helps to achieve the desired outcomes of HIV eradication in low and middle-income countries. The expansion of healthcare facilities increases the potential of retention and decreases the mortality rate (Haghighat et al., 2019). The expansion of primary healthcare facilities for HIV services is also associated with the reduction of loss in follow-up and fulfills the gap of incomprehensive healthcare services (Cunningham et al., 2014). Comprehensive care is not merely one type of essential service at a time. It covers all needs and is patient-centered, i.e., the provision of test results must be followed by emotional support. A primary setting has much more time to deliver good services, and this increases patient satisfaction. The satisfaction is also linked to the attitude from reception, waiting times, HIV education, and the comfortability of the service from healthcare professionals. Satisfaction of PLWH also varies with the extent of the facilities (Odeny et al., 2013). Delivering comprehensive healthcare services for the PLWH will optimize the healthcare continuum. It is well known that comprehensive health services will evidence the strengths of HIV healthcare services. The comprehensive services also increase patient enrolment and retention (Wroe et al., 2018). Comprehensive care also boosts the reduction of HIV transmission in the community. Healthcare services focus on prevention and education. The preventive service scale up the HIV negative and unknown status to check their serostatus (Subramanian et al., 2019). Comprehensive healthcare services for PLWH will optimize the coordination and communication between healthcare services. Comprehensive services will unify the strategies into efficient and effective actions (Watts et al., 2019). Comprehensive healthcare services lead to universal access to ART, improving patient-centered care, and scale up the baseline of HIV testing among the population at risk and PLWH (Havlir et al., 2019). The affordable cost of engaging healthcare services is helping PLWH to deal with their catastrophic life-changing condition. Low-cost access is believed to be the gateway to universal access for all of the population affected by HIV. Providing universal access will increase the impacts of HIV eradication efforts (Hill & Pozniak, 2016). Providing ART to all PLWH is mandatory for low and middle-income countries to achieve clinical prevention and programmatic benefit for all (Ford et al., 2018). The limitation of the study found some participants were not able to express the qualitative narration of their experience. It required the communication competency of semi-structured interviews. It was also found that there is no scoring system in validating the semi-structured questions. The importance of exploring more about HIV healthcare services literacy among PLWH is crucial. The implication of this study can be seen that PLWH get fairly easy access to HIV healthcare services in urban and metropolitan settings. In fact, the healthcare services are now reaching the primary level and easier to access with good links to public transport. Equitable distribution of health services in urban and big cities shall be implemented in suburban areas, especially in concentrated epidemics by the government and policymakers. This study showed that the role of nursing is crucial in circulating the information of the availability of services to those PLWH. Conclusion HIV healthcare services are growing stronger and continuing to progress. The old paradigm of HIV being nothing but a death sentence is fading away. Precise and accurate information is increasingly being provided to all sectors, communities, and individuals. Healthcare providers and HIV activists are recommended to promote and campaign about the new perspective of accessibility: reduced travel to facilities and less financial hardship from using HIV healthcare services, especially within urban cities. Acknowledgment Gratitude appreciation to Faculty of Nursing Universitas Andalas and Faculty of Nursing Universitas Indonesia for facilitating and supporting the research. Declaration of Conflicting Interest There is no conflict of interest in this study. Funding Self-funding. Authors’ Contribution MM contributed to developing the research, collecting and analyzing data, presenting results, and drafting the manuscript. WW and HP contributed to the study concept and design, data analysis, and manuscript development. All authors agreed with the final version of the article. Data Availability Statement All data generated or analyzed during this study are included in this published article. Authors’ Biographies Ns. Mahathir, M.Kep., Sp.Kep.Kom is a Junior Lecturer at the Faculty of Nursing, Universitas Andalas, Indonesia. He is currently focusing on community health nursing, HIV and adolescent health research. Wiwin Wiarsih, S.Kp., MN is an Assistant Professor at the Faculty of Nursing, Universitas Indonesia, Indonesia. She is currently active in community health nursing development in Indonesia. Dr. Henny Permata Sari, M.Kep., Sp.Kep.Kom is an Associate Professor at the Faculty of Nursing, Universitas Indonesia, Indonesia. She is currently making her research dedication in community health nursing and occupational health. ==== Refs References Anh, L. H. T., & Thaweesit, S. (2019). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-110 10.33546/bnj.2521 Original Research Barriers and facilitators to access mental health services among people with mental disorders in Indonesia: A qualitative study https://orcid.org/0000-0003-0330-685X Munira Lafi 1 https://orcid.org/0000-0003-0673-4497 Liamputtong Pranee 2 https://orcid.org/0000-0002-9959-8860 Viwattanakulvanid Pramon 1* 1 College of Public Health Sciences, Chulalongkorn University, Bangkok, Thailand 2 College of Health Sciences, VinUniversity, Vietnam * Corresponding author: Pramon Viwattanakulvanid, PhD, Assistant Professor College of Public Health Sciences, Chulalongkorn University Institute building 3 (10th – 11th floor), Chulalongkorn soi 62, Phyathai Rd Bangkok 10330 Thailand. Email: pramon.v@chula.ac.th Cite this article as: Munira, L., Liamputtong, P., & Viwattanakulvanid, P. (2023). Barriers and facilitators to access mental health services among people with mental disorders in Indonesia: A qualitative study. Belitung Nursing Journal, 9(2), 110-117. https://doi.org/10.33546/bnj.2521 18 4 2023 2023 9 2 110117 26 12 2022 23 1 2023 14 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The care and treatment management of people with mental health problems has become a prominent global concern in recent years that requires consistent attention. However, the literature suggests that only a small percentage of individuals with mental health problems in Indonesia receive the necessary mental health care. Therefore, it is crucial to explore this gap. Objective This study aimed to explore barriers and facilitators that affect access to mental health services among people with mental health disorders in Indonesia. Methods The study employed a qualitative descriptive design and focused on individuals with depression, anxiety, or bipolar disorder. Data were collected through in-depth interviews conducted via WhatsApp chat with 90 participants aged 18-32, who were purposively selected from Sumatra, Java, Kalimantan, and Papua Islands in Indonesia between January and June 2022. Thematic analysis was used to analyze the data. Results The barriers to accessing mental health services included: 1) uneasy access to mental healthcare facilities, 2) stigma, lack of social support, and delay in receiving proper treatment, and 3) expensive treatment costs without national health insurance membership. Importantly, the facilitators to access mental health services included: 1) national health insurance membership, 2) support from spouse, family, and closest friends and its association with mental health literacy, and 3) self-help. Conclusion The widespread distribution of mental health knowledge is recommended among healthcare providers, including public health practitioners and primary care nurses, to enhance their mental health literacy and competencies while rendering services to individuals with mental disorders. Additionally, efforts should be made to educate and promote awareness among caregivers and communities to reduce the stigma faced by those with mental disorders. access barriers mental health services depression stigma facilitators social support Indonesia ==== Body pmcBackground In recent years, the care and treatment management of people with mental health problems has become a significant global issue that requires continuous attention (World Health Organization, 2014). This issue has also raised concerns in Indonesia following an increase in the prevalence of mental health cases. The higher incidence of mental disorders in the country highlights the need for policies and attention from the government and society (Rahvy et al., 2020). However, despite efforts to improve the mental health system, Indonesia still needs further progress in this area (Economist Intelligence Unit, 2016). Two major challenges facing the mental health system in Indonesia are a limited number of mental health professionals and an insufficient financial budget for mental health care. These budgetary constraints make it challenging to provide even the most basic standard of mental health care in society (Irmansyah et al., 2009; Pols & Wibisono, 2017). According to the 2018 Indonesian National Health Survey (Riskesdas), the prevalence of depression among individuals aged over 15 years old was found to be 6.1%, with a staggering 91% of individuals with mental disorders in Indonesia not receiving treatment (Indonesian Ministry of Health, 2018). These findings suggest that mental health services in Indonesia may not be fully accessible to those in need. The Ministry of Health Republic Indonesia conducted this survey on the entire Indonesian population residing in thirty-seven provinces every five years (Indonesian Ministry of Health, 2018). Overview of Indonesia’s Mental Health System Health services in Indonesia use a decentralized system whose management is handed over to the respective regional governments. Local governments also have a role in planning and managing the mental health service system. Based on the applicable laws, every province in Indonesia is required to provide at least one mental health hospital (Putri et al., 2021). However, seven provinces have not established mental health hospitals (Suryaputri et al., 2022). The authors illustrated Indonesia’s mental health referral systems in Figure 1. The referral system is regulated by BPJS Kesehatan (National Health Insurance) system in Indonesia. The referral system starts at primary health care. Patients/caregivers with mental health problems are required to visit primary health care to consult with general practitioners/any health professionals available at sub-district levels. After that, patients/caregivers with mental health problems will receive a referral letter to access psychiatric care at the secondary and tertiary levels. Psychiatric care is available in secondary care and tertiary care. Secondary care levels provide treatment for psychiatric outpatients, and tertiary care levels provide treatment for psychiatric inpatients. BPJS-K covers monthly psychiatric treatment costs for outpatients and two-weeks mental health hospital stays for inpatients. Figure 1 Mental health referral systems in Indonesia (developed by the authors) The availability of mental health services is expected to improve access and minimize treatment gaps. However, previous studies in Indonesia have revealed some challenges to achieving the goal of reducing the mental health treatment gap, such as poor mental health literacy (Brooks et al., 2018), limited availabilities, and ineffective mental health services (Idaiani & Riyadi, 2018; Tasijawa et al., 2021), insufficient numbers of mental healthcare professionals (World Health Organization, 2018), and stigma received by people living with mental illnesses (Hartini et al., 2018). Previous qualitative studies in Indonesia found social challenges, such as health practitioners’ negative attitudes and family communication styles. The previous research suggested the need for the interprofessional collaborative practice among health practitioners as part of a strategy to provide good mental health services (Putri et al., 2021). This paper fills the gap in the literature by exploring a large number of users/outpatients/people living with mental disorders’ perspectives on their access to services. The objective of our study was to explore participants’ perceptions of barriers and facilitators that affected their access to mental health services in Indonesia. People with mental disorders in this paper are defined as outpatients in psychiatric units at public and private hospitals with depression, bipolar, and anxiety in remission. The study findings can provide information on their struggles to access mental health services in the digital era. It can benefit mental health program implementers in Indonesia, mental health practitioners, students, caregivers, and future researchers. Furthermore, by exploring the barrier and facilitator to accessing mental health services, we can understand how to improve the facilitator/support and reduce/remove the barrier to accessing mental health services. Theoretical Concepts of Access to Healthcare and Stigma This paper is situated within the access to health care and stigma concepts. Access to health care means having “the timely use of personal health services to achieve the best health outcomes” (Burke et al., 2010). Barriers are described as factors that prevent/obstruct a given phenomenon. Conversely, facilitators are factors that promote/facilitate/enable a given phenomenon (Pagoto et al., 2007). Stigma is defined as the negative labeling of a particular group of people. It shapes a negative image of mental disorders and people with mental disorders (Hayward & Bright, 1997). The stigma they received could prevent them from seeking help and treatment for their mental health conditions (Corrigan et al., 2005). Stigma against people with mental disorders is found not only limited to the general population but also among health professionals who work with people with mental disorders (Arboleda-Flórez & Sartorius, 2008; Jorm, 2000). Methods Study Design Qualitative research is crucial in exploring issues that are not well understood, as in the case of this study, as it allows researchers to gain insight into the perspectives of individuals living with mental disorders (Liamputtong, 2019). The researchers adopted a qualitative descriptive research design to explore the issues directly from the participants and in great depth without having to adhere to a particular methodological framework (Sandelowski, 2000). The paper was written in accordance with the consolidated criteria for reporting qualitative research (COREQ) checklist (Tong et al., 2007). Participants Study participants were purposively recruited from support groups and online platforms for people with mental health disorders. Participants had to be at least diagnosed with depression, anxiety, or bipolar with aged 18-32. Participants are required to take screening tests using BDI II (Beck Inventory Depression II) to measure their depression level (Beck et al., 1996). The researchers excluded participants who had severe depression levels, participants with psychotic symptoms, those who did not give any response exceeding two weeks after recruitment, and participants who sent a request to refuse an interview. This study had a total of 90 participants with mental disorders from several main islands in Indonesia, namely: Sumatra, Java, Kalimantan, and Papua Islands. Data Collection In this study, the researchers used WhatsApp and Google Forms as platforms for data collection (Liamputtong, 2019). All data collection process was conducted from January to June 2022. The study’s participants were young people aged 18-32 who used mobile phones and online apps for daily communication. All of the participants in this study used WhatsApp messenger. This chatting method provides convenience for researchers to eliminate challenges and improve time and cost efficiency when collecting data from multiple sites (Stieger & Göritz, 2006). This online platform method also provides time efficiency in data analysis compared with the traditional approach that uses audio recording and typing all audio records into word sheets (Liamputtong, 2019). In this study, the chatting method also allows the researcher and participants to make an appointment to chat and avoid the awkwardness between the researcher and participants that usually happens in face-to-face in-depth interviews. The use of emojis and stickers in WhatsApp chat also makes the chatting method data collection feel comfortable for both parties. The researchers gave the participants two choices for sharing their stories/feelings. The first is through WhatsApp chat; this platform usually was chosen by participants who did not have difficulties communicating their stories, feelings, and experiences with people they trust or with new people they perceived they could trust. The second one is through Google Forms. The researchers set all questions with long answers with probing questions. This platform usually was chosen by participants who had difficulties communicating their stories, feelings, and experiences one-on-one. In-depth interviews through WhatsApp Chat lasted 15-20 minutes, and chat archives were exported and downloaded for analysis. The researchers used the Bahasa Indonesia language for data collection. Following are two main questions the researchers asked participants during WhatsApp chat: 1) Could you please tell me your stories about your experiences accessing mental health services? 2) How do you feel and perceive those conditions/situations? The theoretical concepts of access to healthcare and stigma were used to prepare semi-structured questions. Data Analysis Thematic analysis (TA) was applied to the data to determine the significant themes pertinent to the research question. TA is a method for systematically identifying, organizing, and offering insight into patterns of meaning (themes) across a data set (Braun & Clarke, 2012). The data analysis process was done manually. For the first step, the chat archives were exported and downloaded for analysis for in-depth interviews through WhatsApp Chat. In addition, the response sheets were exported and downloaded for analysis for in-depth interviews through Google Forms. In the second step, the transcripts are translated into English for further analysis steps. In the third step, all transcripts were read and reread to find the similarities and patterns between participants’ responses. In the fourth step, Author 1 (LM) was in charge of coding the data and classifying all data into several themes. In the fifth step, the final themes were named and written as a complete summary after a comprehensive discussion with Author 2 (PL) and Author 3 (PV). Trustworthiness The trustworthiness was checked with the triangulation method, building rapport, probing, and working with an expert (Liamputtong, 2019). WhatsApp chat with participants was conducted at different times to enhance the data quality. Several techniques were undertaken to improve the trustworthiness of this study. First, building rapport with participants was conducted before the researchers started the in-depth interviews. Building rapport in this study was defined as the researchers were made a good bond/rapport with all participants. The aims of building rapport were: 1) to make participants feel comfortable sharing their feelings, 2) to make them feel comfortable communicating with us, 3) to make the data collection process run well, and 4) to achieve rich data with good quality. Making a good rapport before conducting the in-depth interview has a positive effect. Almost all participants felt comfortable writing their experiences, feelings, and perceptions in a long paragraph. Second, probing was done to help understand the participants’ responses in deeper and more specific meanings. The researchers asked participants to clarify, elaborate, or explain their responses. Research Team and Reflexivity The research team comprised one research student (first author LM) and two supervisors. WhatsApp chat data collection was conducted by the first author as the facilitator. Author 2 (PL) and Author 3 (PV) supervised the data collection and analysis process by giving suggestions to ensure good data quality is achieved. Author 1 (LM) is a female public health researcher health. She was a second-year Ph.D. candidate with ten years of qualitative research experience and three years of mixed-method research in some particular settings, such as urban, rural, and remote settings. Author 2 (PL) is a female social sciences researcher in behavioral sciences and medical anthropology. She is a professor with more than twenty years of experience in qualitative and mixed-method research. Author 3 (PV) is a male social sciences researcher in empowerment, patient satisfaction, aging, and biostatistics. He is an assistant professor in social sciences with more than fifteen years of experience in quantitative research and experimental studies. All authors have conducted cross-cultural research and are interested in understanding mental health issues in an underdeveloped nation. These three authors did not have a reciprocal relationship with the study participants. Therefore, it reduced the research bias resulting from peer relations. All authors interpreted the result and were responsible for manuscript writing and evaluation. Ethical Considerations Ethics approval was obtained from Chulalongkorn University’s Ethical Committee No. 205.1/64, COA No. 247/2021, before the study began in 2022. At the time of recruitment and interview, respondents provided informed written and verbal consent, which acknowledged their awareness of the study's purpose and potential benefits, their right to withdraw their response, and their right to remain anonymous. Additionally, respondents were informed that they could receive further recommendations if their condition required treatment. Results Characteristics of the Participants There were 90 participants aged 18 to 32 years, both men and women, single and married, in this study. They lived on several islands in Indonesia, such as Sumatra, Java, Kalimantan, and Papua, with various settings in rural, semi-urban, and urban areas. The majority of participants have financial problems and poor relationships with caregivers (Table 1). Table 1 General characteristics of participants (N = 90) Characteristics f % Age 18-24 years old 54 60.0 25-32 years old 36 40.0 Sex Male 8 8.9 Female 82 91.1 Marital status Single 72 80.0 Married 18 20.0 Education level < Bachelor’s Degree 41 45.6 ≥ Bachelor’s Degree 49 54.4 Working status Unemployment 51 56.7 Employment 39 43.3 Household income minimum average in each district varies from 122.10 USD to 312.5 USD Low income < 122.10 – 312.5 USD 58 64.4 Middle income ≥ 122.10 – 312.5 USD 32 35.6 *USD rate: 21 October 2022, 1 USD = 15,623 IDR Thematic Findings From people with mental disorders’ perspectives, this study found some barriers to accessing mental health services in Indonesia, such as geographical barriers, travel costs, stigma and lack of support, and expensive treatment costs. These barriers caused uneasy access to mental healthcare and delay in receiving treatment. On the other hand, this study also found some facilitators in accessing mental health services in Indonesia, such as national health insurance membership, received support, and self-help. The researchers illustrated the overall findings of barriers and facilitators to access mental health services in Indonesia, as shown in Figure 2. Figure 2 Barriers and facilitators to access mental health services in Indonesia Barriers to Accessing Mental Health Services The study’s findings revealed some barriers people with mental illnesses face in accessing mental health services in Indonesia. These findings were divided into several themes: 1) Uneasy access to mental healthcare facilities, 2) Stigma, lack of social support, and delay in receiving proper treatment, and 3) Expensive treatment costs without national health insurance membership. Theme 1. Uneasy access to mental healthcare facilities Access to available mental health care and clinicians in rural settings may require traveling long distances, making attending treatments more challenging (Graham et al., 2021). It costs more to provide services in rural areas for several reasons (Nicholson, 2008). Consistently to the study findings, some participants residing in rural areas in Indonesia had difficulty accessing mental health facilities due to 1) long-distance travel to mental health care and 2) how much money they had to spend to pay for roundtrip travel costs to the hospital. “A long-distance journey from my house because it (the psychiatric unit) only exists in large hospitals. The distance was 60 kilometers.” (Informant 7, male, living in a rural setting, unemployed) “Distance from home that is too far from the hospital. The distance to the hospital is almost 1.5 hours drive. The travel costs have burdened me.” (Informant 9, female, living in a rural setting, unemployed) In summary, mental health services in rural settings in Indonesia are inaccessible due to the lack of availability of mental health workers and geographical barriers. In addition, the long travel distance is also linked to a financial burden for people with mental disorders in accessing mental health care. Theme 2. Stigma, lack of social support, and delay in receiving a proper treatment The stigma against people with mental disorders also poses barriers to mental health service use (Kung, 2004). People with mental disorders are not seeking help because they fear others will react negatively to them (Barney et al., 2006). In this paper, all participants received stigma and negative labels. In addition, some participants received stigma from closest family such as parents, closest friends, neighbors, and health workers at primary health care. “If I went to the psychiatrist, they would say I am crazy.” (Informant 20, female, living in an urban setting, unemployed) “No one supports me because they/people perceive those psychiatric medicines are dangerous to consume.” (Informant 31, female, living in an urban setting, unemployed) “General practitioners in primary health care cannot believe that I am depressed.” (Informant 25, female, living in an urban setting, unemployed) “Many service providers still do not know about mental health. I was judged as people who was crazy when asking for a referral letter to the first health facility, as well as when treated to a large hospital; the service provider blasphemed and underestimated the depression complaints that I felt.” (Informant 42, living in an urban setting, unemployed) Some participants experienced several refusals from general practitioners in primary health care to refer them to psychiatric services in hospitals. As a result of the delay in treatment, their symptoms worsened, and suicide attempts or self-harm increased. “After two times rejected to get referral letters, finally, the general practitioner in primary health care gave me the referral letter after I came again with scars on my hand after self-harm. Should I die first, then they would believe that I am so depressed?” (Informant 47, female, living in an urban setting, unemployed) “For the first time I went to primary health care, they did not trust me when I said I was depressed. They said that I should bring my parents with me. But how, one reason I got depressed was because of my toxic family. Later, I came with my best friend, and my best friend told them that I was doing self-harm several times. Thank my best friend that I got a referral letter because of her.” (Informant 50, female, living in an urban setting, unemployed) This study’s finding is consistent with the previous study in Indonesia. It was found that the negative attitude of mental health workers toward patients led patients to delay or stop treatment (Putri et al., 2021). Therefore, general practitioners in primary health care need to respond quickly to the symptoms and give a referral letter to a psychiatrist for those who are needed. Theme 3. Expensive treatment costs without national health insurance membership Unmet needs for access to mental health care were greater for the poor, those with low incomes, or without insurance (Wang et al., 2005). Consistently, in Indonesia, patients are required to pay expensive psychiatric treatment costs if they do not have a national health insurance membership (BPJS Kesehatan). “A hefty cost for me to seek treatment without BPJS (national health insurance).” (Informant 14, male, living in a rural setting, unemployed) “For now, it seems like the cost because I do not have national health insurance (BPJS Kesehatan), and psychiatrist rates in the city are now quite expensive.” (Informant 19, male, living in an urban setting, unemployed) “I find it challenging to pay for mental health services costs. I cannot earn money because I am still in college. So, I also often feel tired and want to stop treatment because it is very expensive.” (Informant 22, living in an urban setting, unemployed) Thus, having national health insurance membership is crucial for people with mental disorders. National health insurance (BPJS Kesehatan) covers all treatment costs and includes various psychiatric medications. Facilitators to Accessing Mental Health Services The findings also revealed some facilitators that help people with mental disorders face accessing mental health services in Indonesia. The results were divided into 1) National health insurance membership, 2) Support from a spouse, family, and closest friends and its association with mental health literacy, and 3) Self-help. Theme 1. National health insurance membership Mental health remains a challenge for UHC globally. In Indonesia, there are several challenges to mental health services, such as stigma, the limited number of mental health professionals, the need for long-term treatment, and involvement with the health system and national health insurance (Agustina et al., 2019). However, being an active user of national health insurance (BPJS Kesehatan) was one of the factors that were considered very helpful for people with mental disorders to access mental health services. In addition, some participants expressed gratitude because being registered as active users helped them financially because they did not have to pay for their medical expenses. “I feel lucky I have BPJS Kesehatan (national health insurance), which covers mental health services.” (Informant 70, female, employed) “Thank God it has been made easier so far as I have BPJS Kesehatan. It is affordable.” (Informant 72, female, employed) Participants had to go through several referral stages, from primary health care to hospitals with psychiatric units. However, some participants managed to cope with this long process as long as they received free treatment. Theme 2. Support from a spouse, family, and closest friends and its association with mental health literacy Most young people feel more comfortable talking and sharing with close friends or family members when they are having problems, including mental health problems (Offer et al., 1991). In this study, some participants received positive support from their spouses, family, and best friends. This positive support gave people with mental disorders a sense of feeling safe, comfortable, and motivated to undergo psychiatric treatment. A sense of feeling safe was perceived by participants’ positive support that made them feel safe and comfortable in communicating their mental conditions and struggles to the closest people. Feeling safe was also perceived as they would not receive any gaslighting or stigma and are not labeled as “Weirdos” and embarrassed. A sense of security was also perceived as the participant’s closest acceptance of the survivor’s mental condition, so they had the motivation to undergo treatment in a mental health service. “I received support from my husband and children. It is enough for me.” (Informant 44, female, living in an urban setting, employed) “I have a very supportive environment, from my husband, family, the husband’s family, and my closest friends.” (Informant 63, female, living in an urban setting, unemployed) In this paper, support is one of the facilitators that bridge people with mental disorders to accessing mental health services. In addition, support is also considered an essential factor in reducing the treatment gap and stigma. Theme 3. Self-help Self-help is one of the empowering treatments. Self-help can also be considered one of the best factors in terms of efficacy for treating mild to moderate depression (Lovell et al., 2008; Morgan & Jorm, 2009). In this paper, some participants still regularly accessed mental health services even though they were stigmatized. Self-help is an internal factor that manifests as motivation to access public health services. Therefore, it was considered more important than external factors that prevent them from accessing mental health services. “I do not care about stigma either. The point is that I want to be stable and heal anyway.” (Informant 16, female, living in an urban setting, unemployed) “I do not care if I got stigmatized negatively because of consultation with a psychiatrist. I do not care because who feels the benefits of receiving treatment is myself.” (Informant 27, female, living in an urban setting, unemployed) This phenomenon could be described as a motivation that enhances and strengthens people with mental disorders to help themselves even though they receive stigma and negative labels. Discussion This study found that financial hardship was the most crucial barrier for people with mental disorders to access mental health services. Therefore, national health insurance (BPJS Kesehatan) was identified as one of the factors considered very helpful for people with mental disorders to access mental health services. These findings align with previous studies that suggested health insurance as one factor that can help to reduce treatment expenses (Berchick et al., 2019). Thus, having health insurance is associated with access to mental health services (Wang et al., 2005). However, many Indonesians are unaware of BPJS-K’s tiered referral system (Handayani et al., 2018), highlighting the need for collaboration between local government and health sectors to disseminate information and promote the benefits of having national health insurance. This study further revealed that most participants experienced stigma and discrimination, but a self-help attitude was deemed more important than external factors such as stigma and discrimination. These findings are consistent with a previous study on positive motivators for seeking mental health treatment, such as hope, desires for a better life, and personal resolve (Pieters & Heilemann, 2010). Individuals with good mental health literacy can recognize mental disorder symptoms and problems, seek help and information, and appreciate the importance of addressing mental health concerns. Conversely, individuals with inadequate mental health literacy tend not to comprehend the significance of mental health, which can also stigmatize those with mental disorders (Hurley et al., 2020; Tambling et al., 2021). The study identified a knowledge gap among primary healthcare workers regarding the appropriate timing for referring patients to psychiatric units. Additionally, not all primary healthcare workers have the necessary understanding and skills to treat individuals with mental disorders in a humane and empathetic manner. Therefore, training in Mental Health Gap Action Programme (mhGAP) (World Health Organization, 2008) is necessary for primary healthcare workers to address this knowledge gap and improve their competencies in providing mental health services. This study comprehensively explored the barriers and facilitators to accessing mental health services in Indonesia, with participants from multiple regions. Future research could focus on understanding societal perceptions of mental disorders and the underlying reasons for persisting stigma. Furthermore, developing appropriate mental health education programs based on local context could be beneficial. Finally, it is essential to note that this study did not examine the perspectives of elderly individuals with mental disorders who may not use smartphones or the viewpoints of caregivers. Conclusion This study highlights that there is still much work to be done to improve access to mental health services. Providing mental health education in schools, communities and through television broadcasts can help reduce stigma and increase mental health literacy. To address financial barriers, the public should be informed of the benefits of having national health insurance membership. Furthermore, this study provides insight into the perspectives of service users regarding the difficulties they face in accessing mental health services. This serves as a reminder for healthcare workers, including general practitioners, mental health nurses, public health practitioners, and psychiatrists, to approach their work with compassion and strive for better mental health outcomes. Mental health training is also essential for those working in mental health service delivery. The study recommends widespread dissemination of mental health knowledge to primary healthcare workers, such as public health practitioners and nurses, to enhance their mental health literacy and competencies in providing services to individuals with mental disorders. Acknowledgment The researchers would like to thank all participants and the College of Public Health Sciences, Chulalongkorn University. This paper is a part of the first authors’ (LM) dissertation research. She received full scholarships for her Ph.D. study, covering tuition fees and monthly living allowance for three years. She did not receive any research grants for the research and did not work for any institution during these thirty-six months. She continued from her Master’s Study to her Ph.D. Study immediately at the same university that provided her full scholarships. Declaration of Conflicting Interest There is no conflict of interest in this study. Funding None for the publication of this manuscript. Authors’ Contributions Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data [LM, PL, PV]; Drafting the manuscript [LM]; revising it critically for important intellectual content [PL, PV]; Final approval of the version to be published [LM, PL, PV]; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved [LM, PL, PV]. Authors’ Biographies Lafi Munira, MPH is a PhD candidate at the College of Public Health Sciences, Chulalongkorn University, Bangkok, Thailand. Pranee Liamputtong, PhD is a Professor at the College of Health Sciences, VinUniversity, Viet Nam. Pramon Viwattanakulvanid, PhD is an Assistant Professor at the College of Public Health Sciences, Chulalongkorn University, Bangkok, Thailand. Data Availability The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Agustina, R., Dartanto, T., Sitompul, R., Susiloretni, K. A., Achadi, E. L., Taher, A., Wirawan, F., Sungkar, S., Sudarmono, P., & Shankar, A. H. (2019). Universal health coverage in Indonesia: Concept, progress, and challenges. The Lancet, 393 (10166 ), 75-102. 10.1016/S0140-6736(18)31647-7 Arboleda-Flórez, J., & Sartorius, N. (2008). Understanding the stigma of mental illness: theory and interventions. New Jersey: John Wiley & Sons. Barney, L. J., Griffiths, K. M., Jorm, A. F., & Christensen, H. (2006). Stigma about depression and its impact on help-seeking intentions. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-141 10.33546/bnj.1449 Original Research Implementation of nursing case management to improve community access to care: A scoping review https://orcid.org/0000-0001-7570-7842 Putra Alenda Dwiadila Matra 1 https://orcid.org/0000-0002-3597-3924 Sandhi Ayyu 2* 1 Department of Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia 2 Department of Pediatrics and Maternity Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia Corresponding author: Ayyu Sandhi, RN, MSc, Department of Pediatrics and Maternity Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada Jalan Farmako Sekip Utara, Sleman, Yogyakarta 55281, Indonesia. Phone: +62-274-545674 | Fax: +62-274-631204. Email: ayyusandhi@ugm.ac.id Cite this article as: Putra, A. D. M., & Sandhi, A. (2021). Implementation of nursing case management to improve community access to care: A scoping review. Belitung Nursing Journal, 7(3), 141-150. https://doi.org/10.33546/bnj.1449 28 6 2021 2021 7 3 141150 25 3 2021 24 4 2021 02 6 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Case management is an approach used to help patients locate and manage health resources as well as to enhance effective communication among patients, families, and health systems. Nurses’ role as case managers has been proven effective in reducing healthcare costs among patients with chronic diseases. However, little is known about its implementation in improving access to care in community-based settings. Objectives This scoping review aimed to examine the components of nursing case management in improving access to care within community settings and to identify the issues of community-based nursing case management for future implications. Design This study was conducted following the framework of scoping review. Data Sources The authors systematically searched five electronic databases (CINAHL, PubMed, Science Direct, Scopus, and Google Scholar) for relevant studies published from January 2010 to February 2021. Only original studies involving nurses as one of the professions performing case management roles in the community-based settings, providing 'access to care' as the findings, were included. Review Methods The article screening was guided by a PRISMA flowchart. Extraction was performed on Google Sheet, and synthesis was conducted from the extraction result. Results A total of 19 studies were included. Five components of nursing case management to improve access to care were identified: 1) Bridging health systems into the community, 2) Providing the process of care, 3) Delivering individually-tailored health promotion and prevention, 4) Providing assistance in decision making, and 5) Providing holistic support. In addition, three issues of nursing case management were also identified: 1) Regulation ambiguity, 2) High caseloads, and 3) Lack of continuing case management training. Conclusion Care coordination and care planning were the most frequent components of nursing case management associated with access to care. These findings are substantial to improve nurses' ability in performing the nursing process as well as to intensify nurses’ advocacy competence for future implications. case management care manager nursing process health service accessibility health resources nurses’ role ==== Body pmcAccess to health care is still a persistent challenge in the healthcare system around the world. Since the Alma Ata Declaration of 1978, 134 countries and 67 international organizations have committed to eliminating the barriers to universal health coverage (UHC), thus providing accessible health services for all populations (Pan American Health Organization, 2019). One dimension indicating the UHC is the proportion of people covered by the health system. Based on the report from the World Bank and World Health Organization (WHO), half of the global population could not obtain basic health services due to poor access (WHO, 2017). Access to health care is defined as reaching a health care service, provider, or institution to utilize appropriate services in proportion to their need for care (Levesque et al., 2013). It comprises three distinct components: 1) being able to gain entry into the healthcare system; 2) being able to locate provided health care services; and 3) being able to communicate with trusted health care providers (Agency for Healthcare Research and Quality, 2020). The commitment to accelerate the UHC should be accompanied by efforts to strengthen community-based health care services and maintain appropriate healthcare financing systems. Case management is used as an approach to promote better coordination of health care services and enable broader access to all populations. This intervention helps optimization of available resources; enhances communication among health care providers, patients, and their families; and serves as patient advocates within the health care system (Fabbri et al., 2017). As the largest occupational group in the health sector (WHO, 2020), the nursing profession contributes to important roles in case management. Within nursing, a case manager is a nurse responsible for case finding, multidimensional assessment, care delivery, monitoring, and evaluation of health outcomes of a patient and their families (Bertuol et al., 2020). To deliver effective case management intervention, a nurse case manager should obtain clinical, managerial, and financial skills. In addition, not only should a nurse case manager be proficient in the health and well-being of individuals across the lifespan, but also adept in communication (with patients, families, and health care team) and the health care system (Fabbri et al., 2017). Currently, nurse case managers work in multiple settings from hospitals, home health services, or patient homes (Armold, 2019). It has been known as one strategy to reduce health care costs (van Voorst & Arnold, 2020). There was strong evidence of using case management to significantly reduce the patients’ hospital use and improve their quality of life (Joo & Liu, 2017; van Voorst & Arnold, 2020). For individuals with chronic illnesses transitioning between hospitals and their communities, case management is often cited as an effective intervention to improve access to health care services (Joo & Liu, 2017). According to the Commission for Case Management Certification (CCMC) in the United States, on average, two-thirds of nurse case managers work within community settings (Armold, 2019). However, the majority of evidence focused on improving patients' and families' quality of life, cost-effectiveness, and reduced hospital readmission rates. Information about community-based case management implementation in relation to its impact on access to health care is limited. This scoping review aimed to examine the components of nursing case management in improving access to care within community settings as well as the issues for future implications. Two research questions were formulated: 1) “What are the components of nursing case management interventions to necessarily improve access to health care?” and 2) “What are the issues faced by nursing professions in delivering case management interventions?” This study is expected to provide existing information on how nursing case management contributes to leaving no one behind in the health system. Methods As the topic of community-based case management’s impact on access to health care has not been comprehensively reviewed, this study employed a scoping approach to evidence synthesis from existing literature following the guidelines by Arksey and O'Malley (2005): 1) formulation of the research question(s), 2) identification of relevant studies, 3) study selection, 4) charting the data, and 5) collating, summarizing, and reporting the results. A scoping review does not usually apply critical appraisal for selected studies as it includes a wide spectrum of studies and aims to broadly sum up the research findings (Nam et al., 2015). Search Methods Five electronic databases (CINAHL, PubMed, Science Direct, Scopus, and Google Scholar) had been searched to retrieve relevant references. Keywords of ((community) AND ("case manage*")) AND (nurs*) AND (access) AND (care) were applied to identify original studies published between January 2010 and February 2021 with free full-text availability in English or Bahasa Indonesia. Eligibility Criteria References were included if those were original studies employing quantitative, qualitative, or mixed methods; involving nurses as one of the professions performing case management roles; providing “access to health care” as the main finding; and published in peer-reviewed journals. Conversely, studies were excluded if they did not describe case management intervention or roles of nurse case manager; only focused on other types of health workers (i.e., community health workers, traditional healers); and in the form of review, editorial, commentary, book, policy documents, or government document. Screening Initially, 505 references were identified, of which 35 were duplicates. Two authors then independently screened 470 studies by title and abstract. After screening by title and abstract, the full texts of 34 studies were assessed for eligibility. After screening the full text, 15 studies were excluded. Six studies employed study designs that did not fit into the inclusion criteria, five studies focused on other types of health workers, and four studies provided no explanation about community case managers. Nineteen studies were found to meet the aim of this scoping review (Figure 1). Figure 1 Flowchart of searching and screening strategy Data Extraction Narrative tables were used to chart, collate, and summarize selected studies. The data charting table was created to identify themes from research findings in accordance with the research questions and purpose (Tricco et al., 2016). The data extraction table was formulated to insert the following information from selected studies: author, publication date (year), sample, design, research objectives, and findings. Data Analysis Data analysis was conducted by two authors, who summarized the major findings from selected studies to draw themes and subthemes independently (Tricco et al., 2016). Next step, the authors merged the data analysis and performed joint analysis to determine the sub-themes of research questions. Results Search Results Table 1 presents the characteristics of selected studies after the final full-text assessment. The majority of studies are qualitative studies, while the remaining articles included quasi-experimental studies, analytical studies (cross-sectional, case study, and cohort study), mixed-method study, and a study utilizing grounded theory. Table 1 Characteristics of selected studies Categories Details Total % Design of studies Qualitative studies 10 52.6 Quasi-experimental 3 15.8 Analytical studies 4 21.1 Others 2 10.5 Year of publication 2010-2013 6 31.6 2014-2017 6 31.6 2018-2020 7 36.8 Analytical Findings As seen in Table 2, five components of nursing case management interventions to improve access to health care were deduced, namely: 1) bridging health systems into the community, 2) providing the process of care, 3) delivering individually-tailored health promotion and prevention, 4) providing assistance in decision making, and 5) providing holistic support. There were also three issues of nursing case management identified, namely: 1) regulation ambiguity, 2) high caseloads, and 3) lack of continuing case management training. Table 3 presents a detailed summary of the final studies selected. Table 2 Themes and subthemes derived from the selected studies Studies Components Issues Bridging health systems into community Providing the process of care Delivering individually-tailored health promotion and prevention Providing assistance in decision making Providing holistic support Regulation ambiguity High caseloads Lack of continuing case management training Balard et al. (2016) V V V V You et al. (2016) V V Williams et al. (2011) V Uittenbroek et al. (2018) V V V V V V Tønnessen et al. (2017) V V Setiawan and Dawson (2018) V V Setiawan et al. (2016) V V Manthorpe et al. (2012) V V V V Klein and Evans-Agnew (2019) V V V V Hudon et al. (2015) V V V V Hensley (2011) V V V V V Head et al. (2010) V V V V V V Gage et al. (2013) V Dhingra et al. (2016) V V V David et al. (2019) V V V V Cicutto et al. (2020) V V V Chapman et al. (2018) V V V V V Brown et al. (2011) V V V V V Borgès Da Silva et al. (2018) V V Table 3 Detailed summary of the final studies selected Study Sample Design Objectives Major findings Balard et al. (2016) France Elderly, caregivers, case managers Qualitative, opened-ended, and guided interviews To explore the users’ (elderly and their informal caregivers) and case managers’ first experiences of case management Case managers delivered care to clients and subsequently helped patients and their families engage with the health system, be familiarized with health information and administrative processes, and make decisions. Case managers were also seen to perform caring behavior such as responsive, helpful, present, and aware. You et al. (2016) Australia Case managers (with nursing, social work, Allied Health, and other backgrounds) Qualitative study, semi-structured interview To explore the perceptions about case managers’ role in establishing community aged care in Australia The study reported 16 essential roles of case manager (CM) in Australia for community aged care. However, CM felt that the roles of broker, mediator, and counselor were ambivalent. Moreover, they consistently agreed that gatekeeper and direct service provision were not the case manager roles. This study suggested that case managers coordinate care services and plans. Williams et al. (2011) United Kingdom Patients receiving or had recently received care by community matrons An inductive qualitative design using a semi-structured interview To explore patients' views and experiences of the community matrons' roles in one primary care provider organization The study showed that community matrons (CMs) assist the patients in the community to obtain easier and shorter coordination and communication with general physicians, including the referral to advanced health facilities. Uittenbroek et al. (2018) The Netherlands District nurses (nurses and social workers) A qualitative study of in-depth interview To explore how district nurses and social workers experience new professional roles as case managers within embrace a person-centered and integrated care service for community-living older adults The reflection of the case manager about providing case management was related to the central element of person-centered and integrated care, such as proactive and preventive care delivery that includes monitoring, self-management support, care coordination, and network collaboration. Case management followed the nursing process framework. District nurses focused more on healthcare and medical problems, while social workers focused more on psychosocial aspects. Tønnessen et al. (2017) Norway Group meetings with care managers (nurses, occupational therapists, physiotherapists, and social workers) Qualitative To investigate the conflicting expectations and ethical dilemmas and to discuss future clinical implications The study identified the responsibility of care managers in providing services to vulnerable populations. However, balancing between the task of care manager and health provider appears as a challenge. Setiawan and Dawson (2018) Indonesia Primary healthcare workers (nurse, midwives, kader - cadre) Interpretative qualitative methodology To report on the implementation of community case management (CCM) to reduce infant mortality in a rural district Nurses and midwives gained confidence and trust from the community because they were often the only ones who could administer medication in the village. CCM reportedly thrived the primary health care workers (PHCWs) clinical reasoning despite the confusion of their prescription role. Setiawan et al. (2016) Indonesia Mothers and health workers Qualitative To investigate the implementation of community case management (CCM) in the Kutai Timur district from the perspective of mothers who received care Treatment provision could be initiated by primary health care workers (PHCWs) in villages; therefore, it reduced delays in receiving medical help. Besides, participants were more likely to seek help from PHCWs than traditional birth attendants since PHCWs were employed in the village. Moreover, under the CCM scheme, families with sick babies were frequently visited by PHCW. Manthorpe et al. (2012) England Nurse case managers, older people, family carers Case study To understand the effects of nurse case manager (NCMS) working in primary care in the English national health service (NHS) from multiple perspectives and how this new role impacts social workers The opinions of older people receiving nurse case management revealed the value of high-intensity assistance to individuals with major health and social needs. Older people or their carers reported the improvement of continuity of care provision and psychosocial support. NCM supplemented social services by identifying unmet needs. Klein and Evans-Agnew (2019) United State of America School nurses Grounded theory To develop a theory describing the processes and actions for school case management targeting children with chronic conditions Nurses provided direct nursing care in several forms for children in the school. Hudon et al. (2015) Canada Patients and family members Descriptive, qualitative, in-depth interview To examine experience of patients and their family members with care integration as part of a primary care case manager (CM) intervention Easy access to the CM nurse facilitated communication. This also allowed closer follow-up when needed. The privileged access to CM nurses fostered better communication with their family physicians. Participants reported improved access to personalized information, communication, coordination, and decision-making assistance, as well as better healthcare transition. Hensley (2011) United States of America Case managers with nursing background and professionals from other disciplines Qualitative, focus group interview To explore the perceptions and experiences of community-based mental health case managers in the field of Medicare prescription drug benefits These managers saw themselves as an essential bridge in the process of medication utilization for their clients. Case managers allocated their time to talk with clients by phone and browse the Medicare websites, assisting the client in understanding the information and making decisions about Medicare benefits. Head et al. (2010) United States of America Users, nurses Quasi-experiment To integrate palliative care principles and practices into the daily routines of a Medicaid managed care provider Provision of palliative care case management included assessment of physical and psychosocial complications experienced by patients with serious illnesses, pharmaceutical interventions, identification of community resources to assist palliative care patients, and assistance in hospice referrals. Gage et al. (2013) England Elderly, nurses Case study 147 147To compare community matrons in holding case management roles for impact on service utilization and costs The roles of case management were varied among nurses. Meanwhile, community matrons were working more intensively on the elderly and those taking more medication than nurse case managers. Dhingra et al. (2016) United States of America Adult users Retrospective cohort study To evaluate a diverse population served by an interdisciplinary model of community-based specialist palliative care and the variation in service delivery over time and identify subgroups with distinct illness burden profiles Case managers played roles in conducting a comprehensive assessment (medical evaluation and mental health wellness of patients and their family), formulation of goals of care and advance care plans, evaluation of the need for home care, and evaluation of the need for care coordination and hospice eligibility. In delivering care, the duties were assigned to an interdisciplinary team including nurses, physicians, social workers, nurses who provided telephone support, and chaplains. Individuals who received more home visits and telephone calls had greater health improvement. David et al. (2019) Spain Nurses Literature review and qualitative approach including individual interviews To present and discuss the central aspects of the case manager nurse work process in three Spanish autonomous communities As case managers, nurses should understand the health-illness process as a result of a complex interaction of factors at various levels of life; perform care beyond individual needs because the scope is broad and include not only patients but also the caregivers; own the leadership, articulation and mediation skills. Cicutto et al. (2020) United States of America Users, caregivers, school nurses Quasi-experiment To describe the elements of asthma care program and its utilization by school nurses and school health teams in two urban school districts A school nurse provided case management and case coordination, including delivering care (asthma management, asthma control, and medication management) and providing asthma education to both clients and parents/guardians. Barriers in conducting case management, among others, are difficulty in making contact with carers, restricted access to health-care records outside school settings, and time limitations experienced by school health teams. Chapman et al. (2018) United States of America Public county-based mental health delivery system Mixed methods approach, including a semi-structured interview To describe how psychiatric mental health nurse practitioners (PMHNP) are made use of, determine obstacles to full access, and evaluate PMHNP's economic contribution to public health systems A PMHNP provided case management services, including formulating care plans (medication management, crisis stabilization, and crisis intervention), assisting clients in administrative issues, and performing promotive functions (empower clients to be aware of lifestyles that might cause disturbance in health). Brown et al. (2011) United States of America Adult users Quasi-experiment To explore the feasibility of adding a nurse case manager to diabetes self-management education to foster users' attendance and increase utilization of other available health care services Roles of a nurse case manager, among others, are: providing health education and consultation about diabetes self-management, assisting patients in coping with cultural and environmental barriers, assisting patients in locating and accessing health care facilities, as well as collaborating with health care teams. Individuals who had higher contacts with nurse case managers attended diabetes self-management education sessions more often. In addition, participants expressed preference of having face-to-face contact with the nurse case managers than by telephone. Borgès Da Silva et al. (2018) Canada Adult users, primary health care organizations Cross-sectional To evaluate patients’ experience of care in primary care as it pertained to the nursing role Patients experienced better access to primary health facilities as nurses acted as case managers and systematically followed patients. In addition, sharing care between nurses and general physicians could enhance primary care access. Bridging Health Systems Into Community Nurse case managers should be able to engage clients and their families in the health system. This was the most common role, as mentioned in the 16 studies. Nurse case managers are responsible for interpreting the information from the health system to clients and vice versa (Balard et al., 2016). In one case, a nurse case manager becomes the only health worker in the designated area; thus, it is important to obtain community trust (Setiawan & Dawson, 2018) so that initial treatment could be promptly delivered (Setiawan et al., 2016). Service provided towards clients and family members from the vulnerable population would eventually help reduce delays in receiving medical care (Setiawan et al., 2016; Tønnessen et al., 2017). To ensure the continuity of this role, a nurse case manager should possess strong collaboration skills with other health professions (Borgès Da Silva et al., 2018; Uittenbroek et al., 2018; Klein & Evans-Agnew, 2019). Shared care could be in the form of communicating with family physicians or arranging schedules with general physicians, referrals, or other community health resources (Hensley, 2011; Williams et al., 2011; Hudon et al., 2015; Klein & Evans-Agnew, 2019). Providing the Process of Care As many as 13 studies emphasize the importance of a nurse case manager in providing the process of care. The care process includes five essential steps: assessment, problem analysis, planning, implementation, and evaluation (Hudon et al., 2015; Klein & Evans-Agnew, 2019; Toney-Butler & Thayer, 2020). Following those steps, a nurse case manager should determine the formulation of a care plan to meet clients’ needs (Head et al., 2010; Brown et al., 2011; Manthorpe et al., 2012; Gage et al., 2013; Balard et al., 2016; Dhingra et al., 2016; Borgès Da Silva et al., 2018; Chapman et al., 2018; David et al., 2019; Cicutto et al., 2020). The care plan should be shifted from traditionally task-oriented to person-centered care (Uittenbroek et al., 2018) and involve family members to maintain the continuity of care. Delivering Individually-Tailored Health Promotion and Prevention Six studies reported that nurse case managers provided personalized health promotion and disease prevention along with case management itself. The development of personalized service plans helped the patients and families understand where they were leading (Hudon et al., 2015). Furthermore, it indicated that nurse case managers prepare different approaches to each patients’ condition so that the health information obtained would be completely in accordance with the patients’ needs. For example, Cicutto et al. (2020) presented that the nurse case managers catered face-to-face visits to teach asthma management (asthma control, inhaler utilization technique) for children diagnosed with asthma, and Brown et al. (2011) provided additional information besides regular diabetes self-management education sessions. Moreover, Uittenbroek et al. (2018) showed flexible and creative personalities were needed in terms of giving chronic care health education for the elderly into their daily routine. In general, a nurse case manager should perform promotive and preventive care to empower clients to be aware of lifestyle that might cause disturbance in health (Chapman et al., 2018; Uittenbroek et al., 2018); the goal is not only to improve patients’ understanding about one’s health but also to change their health-seeking behavior (Setiawan et al., 2016). Providing Assistance in Decision Making Five studies reported the nurse case manager’s role in assisting patients and their families in making decisions regarding the treatment and health status. Patients who had easy access to nurse case managers were reported to have better communication with health professions, better participation in the process of improving their health and well-being, and better healthcare transition (Hensley, 2011; Hudon et al., 2015). To be able to do that, a nurse case manager should own the leadership, articulation, and mediation skills (David et al., 2019). Providing Holistic Support Seven studies reported that the nurse case manager contributed to provide holistic support towards patients and their families. As mentioned in one study focusing on the elderly, patients, and their families emphasized that nurse case manager’s clinical expertise and psychological support contributed to the improvement of the continuum of care provided (Manthorpe et al., 2012). In another study, elderly and caregivers saw a case manager as a person to be “present”, “help others”, “respond to all the questions”, and to be “aware of everything”; thus, it is important for a case manager to show caring behaviors (Balard et al., 2016). A nurse case manager should also be aware of any cultural or environmental barriers that might hamper one’s health status (Brown et al., 2011). Issues of Nursing Case Management Three sub-themes of issues of nursing case management were identified. First, the regulation ambiguity issue was raised in terms of the roles and legal aspects. In one study conducted in Indonesia, the legal aspect for prescribing becomes an issue since nurses are not allowed to prescribe medication, yet sometimes they are the only health provider in the rural areas (Setiawan & Dawson, 2018). In Australia, they consistently agreed that gatekeeper and direct service provision were not the case manager roles. This study suggests that case managers should just coordinate care service and plan (You et al., 2016). In Norway, case managers often found that balancing their roles as a care-manager and a provider was a challenging task, also to set the limits between being private and professional and consider between patients’ needs and limited resources grant (Tønnessen et al., 2017). The second issue of nursing case management is about the high caseloads; as mentioned in one study, a nurse case manager should perform multiple roles, thus working overtime (Klein & Evans-Agnew, 2019). The third issue in nursing case management is the lack of continuing case management training. Experienced nurses should serve as expert role models and consultants to the case management staff and help to develop training curriculum for case managers (Head et al., 2010). It is also mentioned that the understanding and recognition of a nurse case manager might depend on one’s adequate training, although, so far, there is no consensual model of course or training for nurse case managers (David et al., 2019). Discussion This study provided evidence on components of community-based nursing case management and related issues within the last ten years. To the best of our knowledge, this is the first scoping review to describe the components and issues in the implementation of case management in improving community access to care. This study discovered that nurse case managers connect, coordinate, collaborate, and care for the patients/community with health care service providers through holistic and personalized care provision. Also, it revealed that most of the nursing case management models cater to specific targeted populations. For example, elderly (Manthorpe et al., 2012; Gage et al., 2013; Balard et al., 2016; You et al., 2016), patients with long-term illness (Hudon et al., 2015; Uittenbroek et al., 2018), palliative patients (Head et al., 2010; Dhingra et al., 2016), students/children (Setiawan et al., 2016; Setiawan & Dawson, 2018; Klein & Evans-Agnew, 2019; Cicutto et al., 2020) and people living with mental health problems (Chapman et al., 2018) are the populations reported as the beneficiaries in this study. In one study conducted in Norway, Tønnessen et al. (2017) displayed nurse case managers as health providers to serve diverse populations with varied health conditions. Nurse case managers also play the same role towards adults under certain primary health care, as presented in a Canadian study (Borgès Da Silva et al., 2018). This finding showed that nursing case management could be implemented in bridging a broad range of cases and ages to improve access to care in various populations. Another highlighted finding of this review was related to the issues that occurred during the implementation of nursing case management in the community settings. Case managers struggle with the ambiguity of the nurse case managers’ roles and deal with high caseloads as well as limited case management training. A study by Joo and Huber (2014), which reviewed nursing case management, also reported unclear and confusing roles for nurse case managers in the United States. Periodically nurse case managers wished to set clear boundaries, but due to the patient’s condition, nurse case managers were still required to provide direct care. It shows that the sense of caring remains a principle among nurse case managers. Advance training would be required for case managers to equip themselves in dealing with these issues (Machini et al., 2020; Muscat, 2020). This review found the implementations of community-based case management are different according to each country’s health care system requirements. Developed countries like Australia, Norway, and Spain clearly divided the roles and responsibilities between nurses and nurse case managers. Case managers are only expected to perform their natural roles of the case manager. On the other hand, several countries' nurse case managers are also counted on to provide direct care services to the community besides performing their role as case managers. For example, in England, nurses can hold their role as case managers while simultaneously working as practice nurses in the clinic (Iliffe et al., 2011), as district nurses providing visits towards housebound clients in the community (Challis et al., 2011), and as disease-specific nurses in either secondary care settings or the community (Whittingham & Pearce, 2011). Also, in Indonesia, nurse case managers could be the only health professional in the particular area, so one should be familiar with disease management and treatments. Differences in roles of nurse case managers among countries are seen as the result of different health system issues and challenges in each nation. There is a limitation to this scoping review. The terminology of community nursing management may vary among countries. As a result, it is plausible that several essential articles might not be included in this study. Therefore, future review studies should include more terminologies for the keywords in literature searching. Implications for Nursing Management and Health Policy In the era of UHC reform, many countries committed to provide accessible health services for all populations despite the consequences of high spending. This commitment should be accompanied by efforts in strengthening the community-based health care services. This study showed that nurse case managers improve the access of care for different populations in the community in both urban and rural areas. Besides, previous studies have provided evidence on the implementation of case management to reduce health care spending and the number of readmissions or rehospitalization (Joo, 2014; Duarte-Climents et al., 2019). This is the starting point for the government to incorporate the implementation of community-based nursing case management into the policy level. In addition, the government still has to consider the needs and challenges in determining which case management model is most suitable to the population. Conclusion Care coordination and care planning were the most components of nursing case management frequently associated with access to care. This scoping review showed that nurse case managers improve the access of care for different populations in the community, both urban and rural areas, besides reducing health care spending and the number of readmissions or rehospitalization. However, the initiation of implementation still has to consider the issues, needs, and challenges of each country in determining which case management model is most suitable to the population. Also, clear regulation and continuing training for case management should be provided by the authorities to reduce the occurrence of possible constraints during the implementation. Further research is needed to find a nursing case management model according to primary health care to accelerate achieving UHC and develop validated measurement tools to measure access to care based on the components of the community nursing case management model. Declaration of Conflicting Interest The authors have no conflict of interest to declare. Funding This study did not obtain any grant from a funding agency. Authors’ Contribution All authors contributed equally to the study conceptualization, methodology, article search, data analysis, writing, and editing of the manuscript. All authors approved the final version of the article. Authors’ Biographies Alenda Dwiadila Matra Putra, RN is an Assistant for Publication, Research, and Collaboration at the Department of Nursing, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Indonesia. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-043 10.33546/bnj.2406 Original Research Health practice among Muslim homebound older adults living in the Southern Thai community: An ethnographic study https://orcid.org/0000-0003-2979-5620 Songwathana Praneed * https://orcid.org/0000-0001-7031-8506 Chinnawong Tippamas https://orcid.org/0000-0002-4354-6439 Ngamwongwiwat Benjawan Faculty of Nursing, Prince of Songkla University, Hatyai, Songkhla, Thailand * Corresponding author: Assoc. Prof. Dr. Praneed Songwathana, Faculty of Nursing, Prince of Songkla University Hatyai, Songkhla, Thailand. Email: praneed.s@psu.ac.th Cite this article as: Songwathana, P., Chinnawong, T., & Ngamwongwiwat, B. (2023). Health practice among Muslim homebound older adults living in the Southern Thai community: An ethnographic study. Belitung Nursing Journal, 9(1), 43-53. https://doi.org/10.33546/bnj.2406 12 2 2023 2023 9 1 4353 01 11 2022 30 11 2022 08 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Age-friendly environment helps promote older people’s health practices and healthy aging. However, little is known about health practices among those living at home in a Thai Muslim community. Objective This study aimed to explore the health practices of Thai Muslim Homebound Older Adults (HOAs) in relation to their beliefs and experiences to maintain their holistic health. Methods An ethnographic study design was used. Purposive and snowball sampling methods were used to select 15 HOAs as key informants, among whom nine were living in an urban area, and six were living in a rural area. Data were collected using in-depth interviews, participant observation, and field notes. Data were analyzed using thematic analysis. Results Muslim HOAs performed their health practices culturally under the central theme of “Life and health are designated by God (Allah) for living with nature and comfort at their age.” The health practices consisted of four patterns: 1) Maintaining day-to-day functioning to stay independent, 2) Having a simple and comfortable life with support, 3) Performing religious activities as a priority of life for well-being, and 4) Managing symptoms to gain a balance and restore health. Conclusions Understanding health practice patterns among HOAs would help nurses, especially primary care professionals, to promote healthy aging and independent living. In addition, culturally sensitive nursing care may be required to maintain the healthy living of Muslim older adults in the long term. homebound older adult healthy aging culturally competent care Islam nurses Thailand ==== Body pmcBackground The increased number of older adults worldwide is causing a change in the structure of the population. In 2020, 13 percent of the world's population was aged over 60 years, with an increase of 3% per year, and the highest rank was in Asia since 2005 (United Nations, 2020). Thailand is among the highest ranks, where the older population accounts for 18 percent of the total population. Among this number, 21 percent are living with dependency conditions. Of these, 15% are homebound older adults (Foundation of Thai Gerontology Research and Development Institute, 2019). The World Health Organization (WHO) has urged a strategy for healthy aging and defined it as ‘the process of developing and maintaining the functional ability that enables well-being in older age’ (World Health Organization, 2017). This has necessitated the intervention to promote the health of older adults and prevent health problems related to aging, chronic illness, and the inability to perform daily activities. A previous study showed that many older people living at home face some physical health conditions that may deteriorate into bedridden (Husebø & Storm, 2014). In addition, the deterioration of the physical condition and chronic diseases is the leading cause of declining quality of life for older adults, particularly those who are homebound. Therefore, homebound older adults (HOAs) are classified as a significant group regarding the great need for care to slow or prevent the deterioration of their physical condition and who require a particular health service system in accordance with their health needs. Research suggests that developing an age-friendly environment is also necessary to promote health within and around living areas. Each older person is culturally different in lifestyle, including social structure (Gunawan & Huang, 2022); for example, the living characteristics and social conditions of urban and rural communities differ in terms of housing. The older people in a rural community often live together with their children in a community, helping each other in Thai culture and having traditions and beliefs that have been passed on from ancestors and from generation to generation. The older adults are valuable social capital and affect the minds of their children, and they have their own wisdom, while the urban community has a modular style of living. However, the living conditions may be in different patterns, such as many children leaving home for work outside, leaving the elders alone, or living with their spouse without support. Therefore, it affects the quality of life and mental state of all older adults (Foundation of Thai Gerontology Research and Development Institute, 2021). In addition, Thailand has prepared a 20-year National Strategic Plan (Public Health section), which focuses on people’s life span, from youth up until old age. Its goal is to enable older adults to take care of themselves in 'active and healthy aging' (Ministry of Public Health, 2016). If health or social professionals have a better recognition of older people and their way of life in a community, a more 'health in the older adults targeted approach’ could be applied to address health and social problems and the needs of senior citizens. These working methods should be culturally sensitive and effective (Leininger & McFarland, 2002). In regards to the Muslim healthcare culture, it is often consistent with religious principles at each stage of life as a way of life, especially in the mental and spiritual aspects of Muslims who have faith in God. Muslims regard the body as a gift from God. Therefore, when an individual is ill, the sickness needs to be healed (Suprayitno & Setiawan, 2021). The recovery from illness will depend on God's schedule because Muslims believe God ordains sickness to test that person’s strength (Mohmula, 2007). In addition, a healthy person must have a good relationship between man and God and between self and environment. Muslims then focus primarily on spiritual well-being, believing it leads to better overall well-being (Dwidiyanti et al., 2021). Many Thai Muslims believe that spirit is the power of life which acts as a goal in a person's daily life. Spiritual wellness is the power to hold the mind that creates motivation and hope, awareness of one's self-worth and self-confidence, leads to interactions with others and the environment, and brings life satisfaction (Chansangrat et al., 2014). Religious practices are often aligned with Muslim lifestyles to become cultural health care. The belief that actual health starts with a strong and stable spirit can create the power to make decisions for oneself and maintain one’s own independently without falling to emotional desires or material values. To achieve holistic health, the value of life and health must be firmly contained in the soul, not the value seen by others except the value guided by Allah (Iman), followed by the conversion of value into action (Amal), which is the composition of “Ibadah” (Lohwithee, 2020). Thus, the attempt to balance health and life in their cultural practice is essential among Thai Muslims and may increase as they age. In addition, being within their own ways of life and having the ability to perform their daily activities based on their belief and values could promote healthy and active aging of older adults. Older adults living at home may enjoy life and wish to continue life as long as possible, but there has been limited study on HOAs. A previous study in a southern Thai province showed that the Thai HOAs were able to take care of themselves at home despite some health limitations (Detthippornpong et al., 2022). Some perceived themselves as a healthy group and able to control their illness by performing self-care, sharing a positive view of life with others, and integrating their beliefs in folk with modern medicine to maintain health. Supportive family networks and Thai cultural beliefs on respecting older people in the community and participating in religious activities were identified as facilitating factors. More importantly, HOAs who are virtually isolated and may have limited mobility should be taken into consideration for appropriate strategies in providing services for health promotion. However, the previous study was limited to Thai Buddhists, which suggests a need to explore another ethnic group, such as the older Thai Muslim population. This study then focused on those Muslim homebound older adults living in a different sociocultural context from Thai Buddhists. This study aimed to explore cultural care practices related to the health and well-being of Thai Muslim homebound older adults. Conceptual Framework The concept of holistic health nursing (Dossey, 2016) and Leininger’s culture care diversity and universality theory (Leininger & McFarland, 2006) informed this study. According to this theory, the goal of nursing is to offer culturally congruent care for the benefit of people’s health and well-being. Leininger defines culture as a set of beliefs, values, norms, and lifeways shared and learned by a group of people. In her theory, a cultural group shares folk and professional care systems, which can be mediated by nursing care (Leininger & McFarland, 2006). Various cultural and social dimensions were described that can influence health in a cultural group, for example, technological, religious, or economic factors. The meanings of health and those dimensions present differences and similarities between cultures (Leininger & McFarland, 2002). Another concept of Leininger’s theory is caring, which is the essence of nursing. It involves understanding and knowing about people being cared for by helping them improve their human condition and health. Cultural care is usually embedded in the daily life of humans as individuals, family members, and communities. Since this study focuses on cultural care, ethnography is an appropriate approach to gaining cultural data of the participants (Leininger & McFarland, 2002). It allows nurses to take actions to preserve, accommodate, or repattern cultural care to improve their health. Based on this theory, the health practice among Thai Muslim HOA in Southern Thailand is influenced by cultural dimensions. Therefore, to provide culturally congruent care, nurses need to better understand those health practices, particularly from the views of folk or traditional care systems and the influencing religious beliefs, to better support their holistic health and well-being. This theoretical perspective guided the various methodological aspects of this study, such as sampling, data collection, and analysis. Methods Study Design This ethnographic research was used to explore cultural care among Muslim older adults at home in order to maintain holistic health. The rationale for using ethnography is that its root is in cultural anthropology. It is an approach to studying the culture of the virtual world and is concerned with learning about people by learning from people. The systemic inquiry and interpretivism paradigm allow the researchers to research human experiences and evaluate the purposeful acts of people in various situations to understand behavioral patterns and the meaning of these patterns in certain contexts (Spradley, 1979). COREQ (COnsolidated criteria for REporting Qualitative research) Checklist (Tong et al., 2007) was used to report the study. The study was conducted in two subdistricts (one in an urban and another from a rural area) in Songkhla province. The areas were selected based on the 2020 annual report of the Songkhla Public Health office, which reported them as having the highest number of Muslim older adults and where the Subdistrict Administrative Organization identified more cases who were partially dependent and were mainly living at home (Regional Medical Science Center 12 Songkhla, 2020). Participants In this study, homebound older adults were approached as key participants. To ensure that those participants could provide rich information and were willing to participate in this study, we used participant observation by visiting the primary health center in the study site and joining with the community nurses and health volunteers to gain access to information related to the health records of the older population. In addition, purposive and snowball sampling was used to ensure the HOA experiences in health practice. Fifteen key informants who met the selection criteria participated, including 1) a homebound older person, as defined based on the National Health Security Office: NHSO (2016), with a Barthel Index score between 5-11, 2) a Thai Muslim older person (age over 60) who was able to take care or move with ease by his or herself, mainly living at home, 3) being healthy according to their own perception although there was a current underlying chronic disease but no history of complications or hospital admission for at least one year, and 4) able to speak and understand the Thai language or southern Thai dialect. In addition, to obtain in-depth information, the associate informants (family members) who were well recognized or referred by the key informants were approached to explain and clarify the studied phenomenon. Data Collection Semi-structured interview guidelines were mainly used to capture in-depth data from key and associate informants. The team developed the interview guideline based on the literature review and Leininger’s transcultural care theory (Leininger & McFarland, 2002). The interview format was based on open-ended questions in the Thai language to encourage extended responses. The general questions about the lives of participants were usually used at the start of each interview, and then the meaning of health and care for themselves in everyday life situations were probed. For example, “What do you think about your health and what do you practice in daily life, and why do you do those activities? How are life and health perceived at your age?”. The associate participants were asked about the daily life and activities usually performed to support or maintain key informants’ health. Each of the interviews lasted 45-60 minutes. In addition, a group interview with Muslim health professionals took place at the local hospital to gain more knowledge about the health services offered to people at the study site. All instruments were allowed to be used after receiving permission from the authors of a previous study in a Thai Buddhist homebound group (Detthippornpong et al., 2022) and were modified for use among Thai Muslim older adults. The researchers and research assistants collected data after gaining entry into the community. The researcher contacted and coordinated with the nurses working at the two selected Sub-District Health Promoting Hospitals, which many healthy Thai Muslim HOAs attended, to explain the objective of the research project and the data collection process. The Muslim older adults living at home were listed based on the community database and health report, and then the participants were introduced by community/home health care nurses. Due to the pandemic, local research assistants in each area (healthcare workers with public health backgrounds) were trained in the qualitative approach and interview skills during the community survey. A skill-building workshop on ethnographic research with a pilot study was held at the community hospital, focusing on qualitative techniques such as focus group discussion, semi-structured interviews, participant observation, and content analysis. The informants were interviewed in their homes at least twice with the help of family members living with them or those referred by participants when some had difficulty explaining. The observation of the informants’ behaviors and activities in their daily lives during the interview was also conducted using diary/record forms. A personal diary, field notes, an audio tape recorder, and a camera were used in the field. The field notes were recorded according to the first author’s reflection during the interviews, including the general context. Data were collected between August 2021 and February 2022 through participant observation and semi-structured interviews until the data were saturated. In addition, a meeting was organized to present the progress of data collection and analysis with research assistants through the ZOOM (https://zoom.us) system and video conference for researchers to verify that the data were consistent with the research objectives. This enabled the data to be analyzed and issues that needed additional information to be explored. Although there was an outbreak of COVID-19 during the data collection period, each household was aware of and protected the older adults by keeping them at home and avoiding taking them to the doctor. In addition, mask-wearing, hand washing, and keeping their distance were strictly performed by both researchers and associate informants. Data Analysis Data analysis was performed parallel with data collection in Thai until the data were saturated. Then, thematic analysis was used to identify, analyze, and report patterns of health practices. Four steps in ethno-nursing data analysis were used (Leininger & McFarland, 2006). First, researchers initially transcribed in-depth verbatim interviews. The recorded tape and field notes were repeatedly listened to and read, including the text used several times to understand the context or words that appeared to ensure that all information was covered. Second, descriptors and components were identified, coded, and categorized after becoming familiar with the data set. For example, the daily dietary practice of eating steamed rice, soup, and a lot of fish, avoiding spicy food, and drinking honey with warm water, were grouped into a potential subtheme of eating a soft diet to improve digestive function. Similarly, other subthemes were searched, such as praying and reading the Qur'an to restore mind, body, and spiritual health. Third, the researchers analyzed patterns and contexts related to the cultural care and health practice of the participants. For example, eating a soft diet to improve digestive function was analyzed among eating patterns for good health, and it was generated to “consuming safe food in the adequate amount.” Lastly, the researcher synthesized the major pattern and summarized the findings. For example, the eating patterns for good health was generated with other related information to understand health practice in their way of life under the theme of “having a simple and comfortable life with support.” All processes in data analysis were prepared in Thai to maintain the context and meaning before being translated into English by the Thai-English translator, who was bilingual and understood both languages. To ensure rigor, the forward and backward translation was performed by the researchers who knew the field of research and acted as co-researchers. Trustworthiness Trustworthiness was provided by prolonged engagement in the field, maintaining field notes and a reflexive journal, peer debriefing, and a form of data triangulation based on Lincoln and Guba (1985). Data were collected through different methods and different groups of participants. The researchers visited HOAs and their families a few times, at least 2 hours each visit, in their natural settings. Rapport and trust with the informants were established before the visits, which were arranged at different times to gain various perspectives for the data. Field notes and a reflexive journal were maintained to describe the research process in detail and the researcher’s role. Each step of the research process was appraised and confirmed by the team to check the accuracy of coding in data analysis and to ensure the consistency of the inferences. Ethical Considerations The study was an ethnographic study approved by the Institutional Research Board Committee of the Faculty of Nursing, Prince of Songkla University (PSU IRB code 2021-LL-Nur011). The study objectives, research methods, and potential risks and benefits were described to the informants before the data collection. Permission from the informants for audio recording was obtained, and data were kept confidential on a personal laptop secured by a password. The participants were free and had time to decide whether to participate in the research. Verbal consent was used instead of written form due to vision and handwriting problems. During participation, if the participants wished to leave or withdraw from the research before the end of the action, it could be done without giving any reason. However, no one left the study. Results The findings were presented in two parts: 1) characteristics of the participants; 2) cultural care of health practice of Thai Muslim HOAs. Characteristics of the Participants The demographic characteristics of the 15 key informants (six males and nine females) are presented in Table 1. Nine older adults in urban areas and 6 six older adults in rural areas participated. Their age was between 60-94 years, and most had activities of daily living (ADL), although some remained working in the rubber plantations. All lived at home with at least one of their family members, and five of them lived with their wives. Most had at least one illness; the most common diseases were hypertension and diabetes. In this study, six daughters (Ma1, Pa2, Ma6, Ma7, MaT2, MaT6) participated in an interview to gain more information. Table 1 Characteristics of the participants ID Sex Age Marital status Education level Occupation Past illness (year) ADL score No of child Caregiver Ma 1 F 94 Widow Grade 2 Trade market Gastric ulcer with HT (1) 11 11 Son/Daughter/Nephew Pa 2 M 84 Married Grade 4 Rubber cutting/gardening DM & HT (10) Stroke (3) 11 4 Daughter/Son Ma 3 F 86 Widow Grade 2 Trade market Kyphosis and chronic anemia 5 5 Daughter/Son/Nephew Pa 4 M 73 Married Grade 4 tailor Stroke (4) and HT 11 2 Wife/Daughter/Son Ma 5 F 84 Widow none selling fish in the market DM & HT (5), MI (1) 11 13 Daughter/Nephew Ma 6 F 89 Widow Grade 4 Farming/ DM & HT (4) 8 8 Son/Daughter Ma 7 F 93 Widow none trade market No history of illness 10 4 Daughter/Nephew Ma 8 F 67 Widow Grade 4 Manager DM & Stroke (1) 11 4 Daughter Pa 9 M 76 Married Grade 4 General contracting, cattle raising Hemiparalysis & HT (10) BPH (5) and CA colon (1) 11 5 Wife Ma-T1 F 68 Married Grade 4 Rubber farmer HT (13) Stroke (8) 11 5 Daughter Ma-T2 F 82 Widow Grade 4 Rubber farmer HT (29) Herniated disc disease (12) 11 8 Daughter/Son Pa-T3 M 60 Married Grade 7 Rubber agent DM (10), CKD HT (4 months) 11 6 Wife/Daughter Pa-T4 M 67 Married Grade 4 Rubber farmer Gastritis (15) Stroke & Lipidema (1) Paraplegia (19) 5 6 Wife Pa-T5 M 76 Married None Rubber farmer DM & Lipidemia (16) Post-amputation of the right leg (3) 11 7 Wife/Daughter Ma-T6 F 85 Widow Grade 4 Rubber farmer HT & Lipedema (4) Stroke (1) 11 3 Daughter/Nephew Note: DM = Diabetes Mellitus, HT = Hypertension, CKD = Chronic Kidney Disease, BPH = Benign Prostatic Hypertrophy, MI = Myocardial Infarction Cultural Care of Health Practices among Thai Muslim HOAs In describing their health, the participants (HOAs) defined health as mostly related to their physical functioning and emotional and spiritual well-being. This definition included how these components affected their daily lives and health. Although physical health and medical issues were part of living, participants holistically viewed their health, more in terms of basic needs, close to nature in a simple and self-sufficient way. “Life and health are designated by Allah for living with nature and comfort at their age” were merged as the overall theme of the health practice experienced by participants, as shown in Figure 1. Their daily health practices consisted of four patterns: 1) maintaining day-to-day functioning to stay independent, 2) having a simple and comfortable life with support, 3) performing religious activities as a priority of life for well-being, and 4) managing symptoms to gain a balance and restore health. Figure 1 Cultural care of health practice of Muslim homebound older adults Pattern 1. Maintaining day-to-day functioning to stay independence In daily life, participants described the importance of maintaining independence, which they considered a primary source of staying strong in health. They valued the ability to support themselves without burdening others. The activity of daily living (ADL), such as eating, bathing, and dressing, were considered the essential individual ability that should be maintained. Some talked about their self-care ability by performing these activities as much as possible in and out of their home. Some participants performed regular exercise for their recovery from illness. Some could go out where they wanted (even with limitations) and enjoy their life when they felt they could do so by themselves. One participant who had just recovered from paralysis reported: Currently, I have stopped working because I'm old, and my children do not allow me to leave the house since falling last year. Now, I try to help myself as much as I can, picking up things, moving to the bathroom, and taking a shower when staying at home alone because I can't go anywhere. I try not to stand still but try to exercise, move my arms and legs, flicking legs, swinging arms, and kicking my legs daily. I sometimes use massage oil to loosen the stretched muscles. (Ma1) Another participant also demonstrated her body movement after she stopped working. I exercise regularly, sit still and kick my legs, turn my arms around, and flick my arms every morning-evening or when I have free time. In the past, I sold fish at the market, working hard, I worked hard every day. After I had diabetes, I stopped selling stuff and stayed home for the past five years. Always exercise to keep my body strong. (Ma5) In the rural area, some participants enjoyed working at their farm by lifting muscles exercises and taking the cows for a walk in the early morning and evening, as a field note and interview: I exercise every day after waking up. I do many of the same postures. I can't remember them all. There are body lifts, leg lifts, arms up, or taking the cows for a walk. There are about six positions that the nurse has taught me. Do each position and move 20 times. (PaT3) Pattern 2. Performing religious activities as a priority of life for the well-being Participants addressed the importance of religious activities by accepting the laws of God's circumstances and believing their life and health as a destiny originated by God. Natural health care linked to divine blessings was performed daily with some modern medicine as necessary to restore health. All participants accepted their body's limitations and viewed the Muslim spiritual practices as important to life, health and death. The belief is that praying and reciting the Quran enables individuals to balance their mind and body and gain spiritual well-being by achieving inner peace and wisdom and bringing good health. I pray five times and pray to God for good health. Reading Quran is necessary for all Muslims. I believe in the laws of God that giving birth, being old age, having sickness, and death are normal. I always relax my body, keeping no stress or worry about health problems. Every day I pray, sometimes recite the remembrance of God 1,000 times, and read Yaseen (Chapter one of the Qur'an). Every morning, it helps me remember things to do in a good mood. Many people say that I am a kind person, have never felt angry with anyone, and it helps to sleep better. (Ma1) During the illness, there is a period of stress, too much thinking, feeling angry, irritability, trouble, and self-inflicted. I have no strength at all after having a stroke. I need a great power from God to walk. Must be a great power, not a little power. Let's look at others to heal. We feel empowered by God. In the past, I couldn't sit and stand or help myself. I can solve it by praying for blessings from God for good health; I pray and Zikr Ullah (Remembrance of God) every morning and evening 300 times. I then feel better; my mood has improved. (Pa4) In addition, adhering to religious doctrines is the culture where older people are regarded as the most important in later life when compared to other ages. The belief is that practicing religious principles brings merit, and having a happy mind to gain happiness in this world and the next and for a long life. Practicing a good deed and being faithful to religion throughout life is considered essential to enhance the peacefulness of mind and happiness, as some participants reflected: Allah said that by doing Prue (whatever way), we could combine our minds with Allah. You can lie or sit down, can think about it. You can go in your heart, ask Allah, and you will feel comfortable. To hurt, to be sick, to have a fever, to die is the duty of Allah. Allah is in control of everything; I feel comfortable when thinking like this. Don't be afraid if it's time Allah takes you back. We are not capable of holding on to life. Allah takes everyone back and leaves no one behind. It depends on whether it's slow or fast. (PaT3) Moreover, the participants were concerned with having good hygiene habits consistent with religious teachings, such as eating quality and wholesome food and cleaning the body and clothes. The participants tended to place personal hygiene as a top priority by believing cleanliness is the most basic form of health, a part of Muslim's obligation and individual responsibility. As some participants described: After taking a bath and praying five times a day, use clean water to wash hands, mouth, face, nose, arms, head, ears, and legs. I have to keep my body clean even if I can't walk. If it is clean, it will make the body strong. During the nighttime, the child will help me take a bath. Now, I can do it by myself; I feel happy that I can take good self-care. (PaT5) Pattern 3. Having a simple and comfortable life with the support In everyday life, participants described their lives as simple and self-sufficient. They focused on consuming safe food in the adequate amount, getting enough sleep and, being careful of falling, keeping the mind relaxed as the following details: Consuming safe food in the adequate amount Most Muslim older adults living in their homes focused on eating natural food in moderation, not overeating. They often used a product from the local market and cooked for themselves rather than buying from outside. They focused on eating fresh food, avoiding sweet, oily, salty foods, and focusing more on eating fish and vegetables rather than meat. In addition, non-toxic food was obtained by growing vegetables in the kitchen or on farms themselves. Some used herbs and ate dietary supplements, and focused on drinking enough water. Food, we must eat things that are grown by ourselves. My favorite food is kaeng som (spicy curry), yellow curry. Sometimes my kids make a curry with their own chickens. After eating, I must eat one banana every time (Ma1) Food that makes me strong. I like to eat Tom Yum Snapper. My wife makes sea bass tom yum. The fish is a marine fish, not the farmed fish to cook; it must be fresh, 2-3 pieces per plate. Cooking still has some good flavor, do not eat salty, but eat plain flavor following a doctor’s advice. When I woke up and grabbed water, I drank two glasses of water every day because the body is dehydrated during the night, the blood becomes viscous, and it is not good for the brain. Drinking water helps for better blood circulation. This idea came from a conversation with a friend a long time ago, who is a Chinese doctor, who said that we had to drink six glasses of water after waking up, saying that one glass goes to the heart, another glass to the liver and the rest to the body and other organs, so I use it. (Pa4) In addition, more organic food and vegetables, which they can find around the house and grow for their own farms, were consumed. Some participants avoided eating too much dinner under the belief that it would harm the digestive system as a participant who had gastritis said: I eat vegetables that I grow myself in the backyard. There are eggplants, long beans, morning glory, Chinese cabbage, and some fruits such as grapefruit and papaya to treat myself; during dinner time try not to eat a lot and avoid excreting heavily. I do not want to call my children to come and help me at night. (Ma1) Getting enough sleep and be careful of falling Participants described the important daily life practice as getting enough sleep and being careful of falling when staying home alone. Although the participants had much time to sleep at home, none reported difficulty sleeping. As a participant said, they always find ways to manage and get enough sleep by doing some activities. I will not sleep too much. If I can't sleep, I will recite a prayer for blessings. (Ma3) In addition, some participants emphasized carelessness and the need to be careful of falling due to muscle weakness and having enough sleep. A participant who recovered from paralysis reflected that sleeping is essential as being safe when mobilized at home. When I get better, I can start walking on my own. I do not underestimate my risk wherever I walk, keep in mind, don't forget to walk with assistance or use a four-legged cane, and don't think about walking on your own. I also sleep well and nap in the afternoon because feeling sleepy can increase my risk of falling. I always reminded myself of the risk of falling due to muscle weakness; be careful not to fall again. I used to go to the bathroom, couldn't lift a cane and legs, almost fell down, and couldn't move forward. Since that day, I have been very careful. (Pa4) Keeping relax the mind with a simple life that does not make a burden to children Some informants tried to live a simple life so as not to cause trouble for children, especially those whose children have low incomes and must go out to work. They would not be offended, not complain, and stay for the children. One said that living a simple life would not increase the burden on the children. I tried to live and eat easily. I have breakfast, and my children bought only 10 baht of Khanom Krok (local dessert), and it's okay. One banana is enough to eat, a piece of fruit; I will not think much, never insulted children. I live for the children with love and cherish, and I think of Allah only to relax the mind. (Ma5) All participants try to find simple stress-relieving activities for themselves in order to find happiness in doing what they enjoy, relieving emotions and stress, such as watching a favorite TV program, talking to their children and neighbors, and making products from crops near the house for sale. A field note from observation also reflected the participant’s daily life. In the morning, I will take a seat in front of the house. When someone I know walks or rides passes by my house, I greet them. I like talking to other people; it is enough to relieve loneliness. I also like watching the TV; my favorite was the shows, the news, and advertisements for alternative medicines and dietary supplements. It can help relieve boredom; TV could be a friend. (MaT1) Men would go out and sit in the sun in front of the house every morning. Get around the sun outside, help me Bye Jai (a Thai word that means happy). It is more comfortable in the sun and feels warm rather than cold inside. When sitting in the sun, we would greet neighbors each other. This just makes me feel comfortable. (PaT 3) When feeling bored or in the evening, I talk to my children and grandchildren; sometimes, I go out to talk with other people, which helps relieve my loneliness. (PaT 5) Moreover, preparing for their death was also thought of in advance. Some people have planned for their possessions by managing the assets available to their children. They felt no worry because it brings unity among relatives as clear information. Some participants who had a plan for their inheritance felt relaxed as it would not cause a burden to their children in the future. As one participant said: The properties are divided equally and prepared for each child. That stuff has already been set up. Let's allocate the land to every child, 3-4 rai (acre) each, so that each child won't have a debate; I have no stress, no worries. (MaT2) Pattern 4. Managing symptoms to gain a balance and restore health The participants in this study usually enjoyed staying at home. Some who had symptoms related to chronic illness, such as pain in the knee, backache, and numbness from their condition, often used self-management to relieve symptoms with natural methods, and some used alternative healthcare methods, as detailed below. I usually drink honey every day, about one bottle/month, to help my appetite. By dissolving warm water with two tablespoons of honey, eat before breakfast - evening. And take some pills to reduce wind when having symptoms of nausea, as it helps the circulation of blood and wind; eat real honey obtained from the island. (Ma3) I sometimes use massage, herbal baths, and holy water to rub the area that is painful or weak. It is also a method that Muslim elders widely use, and it has been recognized that it works well. In the past, my grandmother used to be a masseuse to treat people (this is an additional occupation learned from a great-grandfather). I used it when I had aches and pains and tended to massage by myself by touching, squeezing, and ironing. Massage oil was used when having sprains. (Ma2) Moreover, most participants could take care of their health when their illness was not severe or could be controlled by using alternative medicine to treat and restore health, such as using herbal medicines, relaxation massage, or seeking a local healer, especially for neuromuscular symptoms. Some participants with limb weakness from ischemic stroke described how chiropractors did their rehabilitation to improve muscle strength. They also shared time and information about the methods to heal and restore the body by folk healers. I had a stroke and weak limbs. In the past, there was a masseuse in the village who came to give massages with assistance from a daughter. I was then able to eat and go to the bathroom by myself. Now my daughter is urged to rejuvenate herself every day by squeezing my arms and legs by herself. My legs gained more strength (MaT1) Some participants reflected the ability to treat their own minor ailments using first aid and herbs found in the community. The herb was often used partly because it is easy-to-get access, as one participant reflected: We use Plai oil that Yo (Khao) made to treat toothache, gum pain, and swollen gums. When we have pain, we apply it to the gums. It will not be inflamed. Put some oil on hands and rub it inside; it becomes hot, feels numb, and has no sensation. When we have symptoms such as abdominal pain, flatulence, and body aches, we put oil on it, and it will get better soon. (PaT4) In addition, most participants sought ways to keep the mood clear when staying at home, particularly during the COVID-19 pandemic. The activities such as relaxing the mind by praying, finding a stress-relieving activity, watching a favorite TV program, meeting neighbors on occasion During this period, you can only watch television to relieve stress. I love to watch boxing shows. In the past, when there was no COVID-19, I went to sit and talk with friends who used to work in Malay and were able to speak multilanguage, both Malay, Chinese, and Thai. It helps to encourage, relax, and reduce boredom. (PaT2) This year there is an epidemic. I don't go to the doctor. My children said it was difficult to go to the doctor. I have diabetes and heart disease. If I don't take medicine. I cannot walk a lot due to being tired. I must sit and rest. God has given us what we are going to be; we must accept it and pray and pray. God bless you so you can live and help yourself. I pray five times and pray to God for good health. When I still see it, I read the Qur'an and donate some stuff occasionally because we believe giving to others will make merit and create good health for ourselves. (Ma5) Discussion The findings showed that 15 HOAs who participated in this study living in either the urban or rural districts similarly described their health practice based on their cultural beliefs for maintaining holistic health even though they were living in different areas. Religious beliefs related to health are regarded as part of life which guide their health practice. The living conditions, way of life, and culture were integrated according to the traditional and traditional Islamic principles (Lillahkul & Supanakul, 2020). Some participants preferred to treat their ailments using alternative medicine such as massage, using oil to massage the painful area, eating herbs to prevent disease, and selecting dietary supplements under the belief that it helps to improve health more than using modern medicine treatment alone. So, their daily health practices were perceived and experienced as “life and health are designated by Allah for living with nature and comfort at their age,” consisting of four patterns (Figure 1). Their health practices were integrated as a way of life with family, religion, and community support. In maintaining day-to-day functioning to stay independent, participants in this study spent most of their time at home to take care of their body, mind, and spirit, integrated between Islam, medicine, and public health principles. The participants had a belief and lifestyle that strictly adhered to the religious principles and teachings of the Quran. Holistic health care and health-promoting behaviors of Muslim elders are therefore continually practiced together until they become part of their daily lives. Maintaining day-to-day functioning to stay independent is essential and linked to having a simple and comfortable life with support. In addition, the participants described personal relationships with friends or neighbors to maintain their social networks as necessary. Although they were at home, the social context and interactions with others influenced their lives positively and were described as essential. It means being able to see and interact with family members and friends daily. Their social context of being central to this view is shared with Garbaccio et al. (2018), who found that active older adults generally enjoy their life of one able to stay in a private home, enjoying relationships with family and friends as part of life. In addition, it was consistent with the previous study on older adults’ perception of health, who defined their health in more psychological and social components (Tkatch et al., 2017). By having a simple and comfortable life with support, participants took care of their physical, mental, social, and spiritual health together to stay healthy and happy, eating natural food, organic food, or local vegetables available locally and seasonally. Most of them ate freshly cooked food, soft diet, and ate in moderation. They addressed the important issues which could promote health and strength by not overeating, avoiding sugary, oily, and salty foods, and eating foods that were appropriate for the disease or foods grown on their farms. This practice accords with the commandments set forth in the Quran regarding the care of food consumed, such as eating enough food (not too much) to sustain life and strengthen the body and eating nutritious, clean, chemical-free food appropriate for each person's age and condition. The proper foods for older adults should be easily digestible because the stomach, intestines, liver, and kidneys begin to deteriorate, and they should not include very salty foods (Sutheravut & Nima, 2009). In addition, some participants took herbs, honey, and immune-boosting supplements to prevent disease by nourishing health according to beliefs that it helps to maintain physical health. This is consistent with the study by Panyathorn and Thajang (2020), who addressed the attitudes towards products and consumption of dietary supplements among older adults in a rural district that supplements were considered to give strength in life. The Quran also mentions honey as a cure for human ailments because honey contains nectar from all fruits (Lillahkul & Supanakul, 2020). The findings showed that having a simple and comfortable life was interrelated with performing religious activities as a life priority for well-being and managing symptoms to gain balance and restore health. Most participants who had illnesses often consumed foods, supplements, and alternative medicine to achieve balance and restore health, which was considered essential for healthy older adults. Using herbal massage oil to rub and massage the sprained area alone would help them relax at home. A similar pattern of drinking holy water has also been found in the study of local wisdom on the self-care of Muslims in the southern border provinces. Healing with holy water is a prevalent treatment among the locals, particularly Muslim folk healers. It is also a drug listed in the Quran and Hadith. However, it is a treatment in conjunction with modern medicine (Hemman, 2016). In addition, participants described their exercises for health according to religious principles, such as swinging arms, swinging legs, and walking regularly to help keep the body healthy, which was similar to Lillahkul and Supanakul (2018), who explored its activities among Thai Muslim older adults for health promotion. In our research, HOAs tended to do some exercises with a low intensity that did not focus on strengthening the heart and lungs. This may be partly due to the presence of physical limitations. As part of religious practice, the HOAs were concerned with good hygiene habits by using clean water to wash their four organs, namely the face, both hands and arms, head and feet, before praying and linked it with the belief that those who are physically unclean would not be able to practice certain religions. Cleanliness is also a part of the faith and is connected with their mental health. They were taught as an inner purification by clinging to one Allah, and having faith would make the soul pure, calm, energetic, and ready to worship God. As a result, those who maintain cleanliness would have good health (Sutheravut & Nima, 2009). In addition, some HOAs drank warm water and enough amount of water to meet their physical needs under the belief that it helped blood circulation and body excretion (AlAbdulwahab et al., 2013). In mental health care, all HOAs tried to keep their minds refreshed and relaxed by doing stress-relieving activities such as watching television and greeting their children and grandchildren. Meeting the neighbors occasionally would help them enjoy life based on the principle of satisfaction in the present life. The practice of religious doctrine in enhancing mental health and being satisfied with Allah's destiny was critical to good mental health. A person's dissatisfaction with their condition would make them unhappy partly because of unappreciated what Allah said (AlAbdulwahab et al., 2013). In contrast, all participants believed that Allah had given them living in their homes to have good human relations and have smiling faces with their children and neighbors. Therefore, they spent a simple life by not acting as a burden to their children. In addition, they were taught to consider the charity given to others and keep their own mental health care according to religious teachings. So, the participants relied on their religion as a mental relief by praying regularly and reading and listening to the Quran regularly. Prayer was one of the religious practices that helped relax the mind and created peace of mind by purifying the mind without any sin or bad thing. As Allah says, “The reward of performing five prayers and Friday prayers is that Allah will atone (cleanse)”, and “even prayer suppresses badness and evil” (Sutheravut & Nima, 2009). Greeting their neighbors occasionally and participating in religious activities at the mosque were usually performed in everyday life. Although some HOAs could not walk and suffer from chronic diseases, they would greet their neighbors from a distance. They were accompanied by children to religious activities at the mosque when needed. Most HOAs had families who lived either in their homes or surrounding, which allowed them to have close relationships with family members by meeting neighbors and participating in religious activities. Similar to a study by Roket et al. (2019), who focused on the health behaviors of older Muslim adults in Satun province, they received support and assistance from their family, relatives, and neighbors whenever they needed it. Spiritual health care was found for all participants who performed strictly religious practices. They had brought the religious doctrines outlined in the Quran as a way of life and took care of their spiritual health for a variety of vitality and spiritual health as peaceful life. They described its importance by praying five times a day, saying Zikrullah (Remembrance of Allah) after the praying, including asking du'a (blessings) to Allah for good health to accept the laws of God's circumstances. Some participants listened to religious teachings from Baba (Tho Chru) on YouTube and donated money for merit-making on some occasions. Faith in Allah is regarded as the heart of being a Muslim (Sutheravut & Nima, 2009). They all believed that following Allah would bring them good health, happiness, and peace of mind. Strong willpower in the face of illness gained a lot of merit in this and the next world, similar to the study by Lillahkul and Supanakul (2020). Some participants had the plan to manage their wealth for their children to relieve anxiety when departing with the allocation of the existing assets to the children. It was a preparation for a peaceful departure according to religious principles in the Quranic text (Mhadman, 2014). Therefore, spiritual health care was often performed at all stages of their life under the faith of religion. This was consistent with the previous analysis of Muslim older adults in Malaysia, highlighting that religiosity and well-being among older adults were interrelated and essential to life (Achour et al., 2019). Family support also facilitated the health of the HOAs living at home by having children as their primary caregivers. The children rotated to take care of various aspects such as doing daily activities, offering disease-appropriate diet, movement, excretion, and religious and ritual activities at the mosque. Islam has urged all Muslims to do good and show gratitude to their parents as a noble and essential duty. Therefore, it is obligatory (compulsory) for children to care for their parents to the best of their ability (Tohma et al., 2019). It is consistent with a study by Aree (2013), who found that the children of Muslim older in urban communities had religious beliefs regarding living with older adults as a wondrous thing. The longer the older adults lived, the better the family life for children was. The longevity allowed them to do good deeds more than others. In addition, some participants who received regular family care felt worthy and gained the power to continue living. Getting visits and encouragement from neighbors was associated with the health of the Muslim older adults living at home, particularly being visited at home by healthcare workers. This is consistent with previous studies (Detthippornpong et al., 2022; Phithakkumpol, 2004), which found that village health volunteers in the community often acted in the form of kinship and could easily reach the older adults and support the work of nurses following home visits. All participants received a pension from the government; some received a disability allowance, but most received money from their children, who provided for personal expenses. It is consistent with a study by Kuhirunyaratn et al. (2018), who found that family and community members supported the health promotion behaviors of older adults living in suburban communities. In this study, all participants had God as their spiritual dependency, which was regarded as an essential factor in promoting their good health. They strongly committed to and had faith in God and strictly performed their religious duties. Doing Du`a' (blessings) keeps them healthy always, raising their peace of mind with good emotional control and accepting everything that happens to them as a will of God. This is consistent with the previous study (Thiprat, 2008) that the older adults had a high level of religious beliefs related to health. When stressed or worried about illness, they prayed for help to calm their minds. Therefore, it can be concluded that the Muslim HOAs had faith in Allah and holistically viewed their health as “Life and health are designated by Allah for living with nature and comfort at their age.” Therefore, Allah is always in their heart of health practice. The overall theme derived from the four patterns suggested that Muslim HOAs in our study addressed health practice to pursue an independent life and maintain their health with the purpose of God and a given tradition and value of relationships and social networks for as long as possible. Although they did realize that life would change, it was thought of as nature and a return to God under the religious concept. The ability to lead a whole and balanced life close to family, friends, nature, and activities were necessary for their feelings of good health and well-being. Therefore, Muslim older adults living at home performed self-care through natural methods, similar to a previous study (Detthippornpong et al., 2022). Based on Leininger’s theory, health-related religious practice was the main method, and the practice was performed regularly by all HOAs under the belief that religious practice would help them maintain health and happiness (Leininger & R McFarland, 2002). Each participant used religion to lead their practice naturally based on a warm environment and integrated both folk and modern medicine. Various modalities for health care, such as traditional massage, oil massage, and herbal therapy following the Quran teaching, were used. Muslim prayer was believed to improve the physical function of all bodies and personal hygiene. In addition, their health practices were supported and influenced by their family, community health workers, and health volunteers, including their Allah as a spiritual retreat. In addition, the concept of holistic health nursing (Dossey, 2016) also supports the health practice of participants by understanding individual care and respecting and attending to a human being’s spiritual and faith-based needs as an integral part of promoting health and healing. Limitations Some limitations could be 1) the participants were recruited from small areas, which might influence the transferability to apply the findings in other areas, and 2) the COVID-19 pandemic might have influenced the relationship between researchers and the informants and could have influenced their response during data collection. Implications to Nursing Practice The four patterns of health practice among HOAs include 1) maintaining day-to-day functioning to stay independent, 2) having a simple and comfortable life with support, 3) performing religious activities as a priority of life for well-being, and 4) managing symptoms to gain a balance and restore health could be included in the education of nurses and primary health care workers to cultivate the cultural awareness and provide better services for older adults at home or in long-term care. In addition, interventions need to consider older people’s cultural sensitivity and family values to strengthen and promote holistic health among Thai Muslim HOAs. Conclusion The study provides a holistic picture of traditional health practice in a natural setting in the Thai Muslim community describing the daily health practice of homebound older adults to maintain their health at home. The findings showed that healthy, independent living, meaningful relationships with family, and following God were essential to all participants in maintaining holistic health. The results also suggest that healthcare services for homebound older people should be integrated with religion and the nature of health practice. Acknowledgment The authors acknowledge the informants for their time and contributions throughout this research. Acknowledgments also go to all health officers in the community health centers and community leaders who kindly assisted us in approaching participants. Declaration of Conflicting Interest The authors declare that there is no conflict of interest in this study. Funding The authors thank the Thailand National Research Institute for funding support. Authors’ Contributions All authors contributed to the final manuscript. PS designed the study and wrote and revised the manuscript. PS and BN collected and analyzed the data, wrote, and revised the manuscript. TC collected the data, wrote, and revised the manuscript. All authors were accountable for all stages of the research and agreed with the final version of the article. Authors’ Biographies Dr. Praneed Songwathana is an Associate Professor and a Director of the Research Center at the Faculty of Nursing, Prince Songkla University, Hat Yai, Thailand. She is interested in Trauma and Surgical Nursing, Transcultural Nursing, Continuing Care, and Qualitative Research. Dr. Tippamas Chinnawong is an Assistant Professor at the Faculty of Nursing, Prince of Songkla University, Hatyai, Songkhla, Thailand. Benjawan Ngamwongwiwat, RN., M.Sc is a PhD candidate at the Faculty of Nursing, Prince of Songkla University, Hatyai, Songkhla, Thailand. Data Availability The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request. ==== Refs References Achour, M., Ab Halim, A. B., Ali, A. R. H., Sa'ari, C. Z. B., & Al-Nahari, A. A. A. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-210 10.33546/bnj.1452 Original Research The effect of warm compresses on perineal tear and pain intensity during the second stage of labor: A randomized controlled trial Modoor Soumaya 12 https://orcid.org/0000-0001-7060-764X Fouly Howieda 13* https://orcid.org/0000-0001-9832-7527 Rawas Hawazen 1 1 College of Nursing, King Saud Bin Abdul-Aziz University for Health Sciences, Kingdom of Saudi Arabia 2 Maternity and Children Hospital, Makkah, Kingdom of Saudi Arabia 3 Faculty of Nursing, Assiut University, Egypt Corresponding author: Assist. Prof. Dr. Howieda Fouly, College of Nursing, King Saud bin Abdul-Aziz University for Health Sciences, King Abdul-Aziz Medical City, National Guard Health Affairs Mail Code 6565 | P.O.Box.9515 Jeddah, 21423 Kingdom of Saudi Arabia. Telephone: 966 22246666 Ext. 46243, Phone No: 966538472739 Email: foulyh@Ksau-hs.edu.sa | hoida.elfouly2@aun.edu.eg Cite this article as: Modoor, S., Fouly, H., & Rawas, H. (2021). The effect of warm compresses on perineal tear and pain intensity during the second stage of labor: A randomized controlled trial. Belitung Nursing Journal, 7(3), 210-218 https://doi.org/10.33546/bnj.1452 28 6 2021 2021 7 3 210218 24 3 2021 25 4 2021 26 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Warm compress is believed to reduce perineal tear occurrence and decrease pain intensity during the second stage of childbirth. Objective This study aimed to determine the effect of warm compresses on perineal tear and pain intensity during the second stage of labor. Methods A randomized controlled trial was conducted between 28 September 2018 to 30 October 2018 in King Khaled Hospital (KKH), affiliated with the Ministry of National Guard Hospital Affairs, King Abdul-Aziz Medical City Western Region, Saudi Arabia. According to eligibility criteria, the sample randomly recruited through lottery included 100 primigravida pregnant women, with 50 in each intervention and control group. Data were presented in the form of frequency and percentages, standard deviation, and mean. Chi-square test was used for data analysis, with p-value significance at ˂ 0.05. Results Sociodemographic data revealed no statistically significant difference in the age, education, occupation, and residence of both the control and experimental group. The perineum area’s pain intensity after birth showed a statistically significant difference between the intervention and the control groups (p = 0.001). The perineal tear was also significantly different between both groups (p = 0.001). Conclusion The applied warm compresses on the perineum area positively reduce second and third-degree perineal tear and pain intensity during the second stage of labor and after childbirth. Therefore, midwives and nurses are expected to actively provide effective planned in-service training programs regarding warm compresses' advantages in the second stage of labor and apply this procedure actively. pain pregnant women perineum midwifery hospitals laceration nursing Saudi Arabia ==== Body pmcBefore the 1930s, women gave birth to children in home settings assisted by traditional midwives. During this time, childbirth was a dangerous affair because many pregnant women and newborns lost their lives during or following childbirth (Corretti & Desai, 2018). However, during intrapartum, different intervention techniques can inhibit the risk, like the choice of instrument for operative vaginal delivery, maternal birthing position, perineal massage, application of warm compresses, episiotomy, and manual perineal support (MPS) (Gupta et al., 2017). Labor is the process through which a fetus is delivered after 24 weeks of gestation. Labor begins when uterine contractions become consistent and cervical effacement and distention increase (Wahyuni et al., 2017). The first stage of labor occurs in two phases: the latent stage, the time taken for the cervix to open to 3 centimeters, and the active phase, which is the time taken from 3 centimeters to the complete opening of the cervix. During this stage of labor, the main problem is the failure to progress, which diagnosed if there is less than 2 centimeters dilatation in 4 hours or decelerating progress in parous women. Labor that is slow from the beginning is known as dysfunctional labor, whereas having sudden complications in previously progressive labor is referred to as arrest (Collins et al., 2008). Causes of unsatisfactory progress include inefficient uterine activity, malpresentation, or a large baby. Our study's primary focus is that the second stage of labor encompasses the period between the full dilatation of the cervix and childbirth. The active part begins when the mother starts pushing using the abdominal muscles to “bear down.” Different positions may be used during this stage, such as standing, squatting, a supine position, or an all-fours pose (Pillitteri, 2010). On the other hand, the perineum may be complicated by the fetal head, expanding the anus as it comes down. Therefore, to support the perineum, a pad may be used to hold the perineum and shield the anus while the other hand conserves flexion, thereby regulating the head’s rite of passage, reducing perineal expansion, and minimizing tears (Geranmayeh et al., 2012). Delivery should occur within three hours of the second stage of labor in nulliparous women and two hours for multiparous women (Simkin et al., 2016). During childbirth in the second stage, women could have a perineal trauma to the genitalia. The first-degree tear occurs spontaneously in the perineal skin; the second‐degree tear consists of the perineal muscles and skin; the third‐degree tears include the anal sphincter complex, and the fourth-degree tears include anal sphincter complex and anal epithelium (Fernando et al., 2015). Moreover, trauma may also result from prolonged pressure on the perineal nerve area during more prolonged childbirth labor (Akbarzadeh et al., 2016). The two classifications of perineal trauma: spontaneous perineal trauma or tear and episiotomy (National Institute for Health and Care Excellence; Essa & Ismail, 2016). The midwives and nurses should only consider episiotomies in specific situations, such as complicated vaginal delivery, breech, forceps, shoulder dystocia, and ventouse deliveries. A midwife or a nurse may also choose to perform an episiotomy when there are symptoms of fetal distress or signs that massive perineal trauma may occur. The indications of extensive perineal trauma include numerous perineal tears and perineal buttonholing (Oladapo et al., 2018). Moreover, perineal tears usually happen in women following vaginal childbirth that exert undue pressure on the perineum. It is classified into four groups depending on the extent of tissue damage. First-degree tears affect the skin around the perineum only, whereas second-degree tears damage the perineum and muscles. An episiotomy is an example of a second-degree tear. Third-degree perineal tears, on the other hand, involve damage to the anal sphincter complex. The three forms of third-degree tears are 3a, 3b, and 3c. In 3a tears, less than half of the external anal sphincter is destroyed, whereas 3b tears involve the destruction of more than half of the same anatomical area. In 3c tears, the internal anal sphincter is wrecked. Fourth-degree tears entail the destruction of the perineum, including the anal sphincter complex (internal and external) and the anal or rectal epithelium (Goh et al., 2018). It appears that there is a relationship between the extent of perineal trauma and the effect on pain intensity. The highest reports of complaining due to perineal pain come from women who have third- or fourth-degree tears through the anal sphincter and rectal canal. Women with intact perineum have a low risk for infection, less blood loss, and less pain after childbirth. Most vaginal births are associated with tears or trauma in the perineal area (Aasheim et al., 2017). Midwives and nurses use various management techniques of the perineum, which play a significant role in reducing episiotomy and decreasing or minimizing perineal trauma. One of the most common is warm compresses (Moore & Moorhead, 2013). Furthermore, a randomized controlled study by Essa and Ismail (2016) reported that pain intensity declined after warm compresses measured by VAS among the study group, and a strong significant effect was noticed on decreasing the episiotomy rate. In general, it is due to the potential treatment effects, including vasodilation, increased blood flow, tissue extensibility, muscle relaxation, and pain (Akbarzadeh et al., 2016). Studies in various parts of the world involving warm compresses during second-stage labor in nulliparous and primiparous women reported that it reduces the intensity of perineal pain. These findings were reported by Ibrahim et al. (2017) in Egypt, Baba et al. (2016) in Japan, and Ali et al. (2004) in Pakistan, among other countries. However, many countries have not implemented significant beneficial practices. Instead, they uphold ineffective or deleterious practices. For example, routine procedures such as shaving of the pubic hair, episiotomy, seizures, electronic fetal monitoring, and intravenous (IV) infusion are commonly observed in some Saudi Arabia areas (Altaweli et al., 2014). The debate still occurs because some researchers recommended warm compresses (Essa & Ismail, 2016; Aasheim et al., 2017), while others found them to have limited or no benefits (Zare et al., 2014). The use of warm compresses to prevent or reduce the incidence and degree of perineal tear and pain is still controversial (Ibrahim et al., 2017). These contradictory results necessitate several studies to fill the gap in this respect. Therefore, this study aimed to determine the effect of warm compresses on perineal tear and pain intensity during the second stage of labor. Methods Study Design This study applied a randomized controlled trial, post-test only design. The investigator allocates participants to an experimental or control condition on a random basis. So, this study tested if the independent variable, warm compresses, affected the dependent variables: perineal outcome and pain intensity. Setting Our study was conducted between 28 September 2018 to 30 October 2018 in King Khaled Hospital (KKH), affiliated with the Ministry of National Guard Hospital Affairs, King Abdulaziz Medical City – Western Region, Saudi Arabia. It is a 600 bedded Joint Commission International (JCI) accredited Tertiary level Hospital. The setting area for this experimental study was conducted in the labor and delivery (L&D) unit, which has six beds for delivery, three beds for induction of labor, and one room for operation room (OR). The patient characteristic and information attained from best care (medical record and patient). Participants All the primiparous pregnant women during the second stage of labor participated randomly in this study. The inclusion criteria include age from 18-35 years old, primigravida, healthy pregnancy, singleton pregnancy, cephalic presentation, full-term, and no contraindication for vaginal delivery. The exclusion criteria were multiple pregnant women, complicated labor, the coexistence of any medical or obstetrical risk factors, and pregnant women deliver a cesarean section. The number of births in hospitals is estimated at 3000 births every year. The G*power software program (Faul et al., 2007) was used to calculate the sample size. The program allows sample size analyses and high-precision power. Besides, it computes the power values for sample size, effect size, and alpha levels. The aim was to achieve the power of 80% with effect size = 0.3, a err prob = 0.05, power (1-B err prob) = 0.80. The estimation was based on two tails a = 0.05. After calculation by G*Power, the sample size was 90 and added 10% for the dropped cases, with a total sample size of 100 primigravida pregnant women who met the inclusion criteria. The investigator applied a simple random technique (lottery) through the participants' allocation into an experimental group or control group on a random basis. Each participant assigned the experiment by letter (A) and control by letter (B). Then paper folded and mixed inside a box, and the investigator asked one of the nurses to pick a number from the box. Then the participant was allocated to either the experimental group or control group (Figure 1). To avoid bias, the investigator divided the rooms for the control or experimental groups based on the women’s choices of the closed envelope. The experimental group room was numbered with an odd number, like 1, 3, and the control group's room was numbered with an even number like 2, 4,….etc. Figure 1 Flow chart for the recruitment of the sample Instruments The instruments in this study consisted of 1) Sociodemographic Tool comprising socio-demographic characteristics including women's age and education level, occupation, previous admission to the hospital, reproductive history gestational weeks, number of prenatal care visits. The information is attained from medical records and patients; 2) Numeric Rating Scale (NRS) For Pain (Hawker et al., 2011). The investigator got permission to use the NRS tool for pain assessment. It ranged from zero pain to 10 severest pain in between the two extremity points equal distances measured 1cm as mild pain (1-2) moderate (3-4), severe (5-6), very severe (7-8), and severest pain (9-10). The NRS can be administered verbally or graphically for self-completion. The investigator asked the women to reveal a numeric value on the scale that best describes their pain degree scoring. The number that the women indicate to rate their pain intensity was recorded. The scores extend from 0–10; 3) Assessment Tool for Perineal Outcomes. It includes perineal outcome assessment questions in the form of an intact perineum, perineal tears degrees “first, second or third”, and episiotomy guided by the obstetrician diagnosis and previous studies (Farghaly et al., 2017; Lane et al., 2017). All tools were tested for content validity by a jury of four experts in woman health nursing and one from the biostatistics field from the College of Nursing, King Saud Bin Abdul-Aziz University. A previous study also tested the reliability of the tool (Ibrahim et al., 2017). In addition, the second stage and perineal outcome assessment questionnaire were evaluated using Cronbach's Alpha coefficient test. The instrument contained relatively similar items, indicated high reliability, with an internal consistency of 0.81. Before the primary data collection phase, the tools for the study were tested at National Guard in King Khaled Hospital, with ten patients. Those patients were not included in the main study. It took around one week to accomplish. The data were collected quickly with the interpretation of participant outcomes. Intervention The control group received routine hospital care during the second stage of labor, such as half-hourly monitoring and documenting the frequency of contractions, assessing the vital signs, and checking the frequency of micturition or catheterization to evacuate the bladder. In addition, a vaginal examination was done after abdominal palpation without warm compresses. The intervention group received routine hospital care in addition to the application of the warm compresses. First, the application of warm compresses was made through applying a sterile perineal pad (gauze) socked in warm water with a temperature range from 45C-59C measured by lotion thermometers, and the soaked each perineal pad was squeezed before being placed in the perineum area. Then the warm compresses are given continuously until bulging of the head (Figure 2). Figure 2 Flow chart of the procedure Data Collection The investigators collected data in the labor room between 23 August 2018 to 30 October 2018. The investigators directly observed, measured, and recorded the pain and perineal outcomes for both groups using the validated instruments. The participants were also asked to enumerate the severity of pain they have experienced after birth. A trained health member was assigned to assist the researcher in obtaining consent and interviewing the participants. Data Analysis SPSS program version 20 was used for statistical analysis. The variables are presented in the form of frequency and percentages, standard deviation, and mean. The Chi-square test was used to compete for categorical variables and test a significant difference between the study groups' outcome criteria. P-value was set at <0.05 for statistically significant criteria. Ethical Consideration Ethical approval in this study was obtained from the research unit committee at the College of Nursing, Jeddah, and from King Abdullah International Medical Research Center (KAIMRC) with approval number of IRBC/ 1711/18 on 27 September 2018. Prior to the study, each participant has signed informed consent. The investigators explained the nature of the study objectives and a clear explanation of data collection. Confidentiality was also ensured by explaining to the participants that all information was used only for research purposes and their identities were in the form of numbers, not names. In addition, the data collected could only be accessed by the investigators only. All participants also had the right to withdraw from the study at any time without penalty. Results Table 1 shows that the majority of the participants in this study aged between 23-26 years, 46% of the control group and 50% of the experimental group, respectively. The Chi-square test revealed no statistically significant difference in age between both groups (p = 0.918). In addition, more than half of them in both groups respectively graduated from university (55%), and there was no statistically significant difference in educational qualification (p = 0.864). The majority of the participants worked as housewives (75%) and lived in the urban areas (84%), and most of them had enough income per month (91%). There were no significant differences in occupation, current residence, and family income between the control and experimental groups (p > 0.05). It is noted that gestational age was similar because of the inclusion criteria of the participants (37-42) weeks, so it was not included in the table. Table 1 Sociodemographic characteristics for control and experimental groups for study participants Items Control n (%) Experiment n (%) Total N (%) p-value Age (year)  18-22 14 (28.0) 14 (28.0) 28 (28.0) 0.918  23-26 23 (46.0) 25 (50.0) 48 (48.0)  27-30 10 (20.0) 5 (10.0) 15 (15.0)  31-35 3 (6.0) 6 (12.0) 9 (9.0) Educational qualification  Primary school 3 (6.0) 3 (6.0) 6( 6.0) 0.864  High school 19 (38.0) 20 (40.0) 39 (39.0)  Collegiate education 28 (56.0) 27 (54.9) 55 (55.0) Occupation  Working 10 (20.0) 8 (16.0) 18 (18.0) 0.261  Housewives 38 (76.0) 37 (74.0) 75 (75.0)  Business 2 (4.0) 4 (8.0) 6 (6.0)  Any other specify (online business) 0 1 (2.0) 1 (1.0) Current residence  Urban 43(86.0) 41 (82.0) 84 (84.0) 0.622  Rural 7(14.0) 9 (18.0) 16 (16.0) Family income/month  More than enough 0 2 (4.0) 2( 2.0) 0.743  Just enough 47 (94.0) 44 (88.0) 91 (91.0)  Not enough 3 (6.0) 4 (8.0) 7 (7.0) Table 2 shows that 28% of the total participants' gestational age was between 38 - 39 weeks. However, 6% of gestational age was 37 weeks. Regarding pelvic training, most participants did not attend any antenatal care classes (91%), and more than two-thirds of participants registered for seven visits during the pregnancy period (70%). Table 2 Obstetrical history of study participants Items Control n (%) Experiment n (%) Total N (%) Mean Std. Deviation Week of gestation 37 weeks 2 (2.0) 4 (4.0) 6 (6.0) 39.1 1.136 38 weeks 11 (11.0) 17 (17.0) 28 (28.0) 39 weeks 16( 16.0) 12 (12.0) 28 (28.0) 40 weeks 13 (13.0) 12( 12.0) 25 (25.0) 41 weeks 8 (8.0) 5 (5.0) 13 (13.0) Did you receive pelvic training Yes 6 (6.0) 3 (3.0) 9 (9.0) 1.91 0.287 No 44 (44.0) 47 (47.0) 91 (91.0) Items Median IQR Number of antenatal care visits 7.00 7.00 Table 3 shows that two-fifth of the experimental group (40%) revealed lesser mild pain than the control group (52%). There was a statistically significant difference in mild pain in both groups (p = 0.001). In addition, more than half of the experimental group (52%) reported moderate pain than the control group (34%), and there was a statistically significant difference in moderate pain (p = 0.001). Also, a significant difference was found in severe pain (p = 0.001), which was higher in the control group (14%) than the experimental group (8%). There was no one having very severe or worst pain. Table 3 Comparing the degree of pain among experimental and control groups immediately after birth (N = 100) Pain after birth Control n (%) Experiment n (%) Total N (%) df Chi-square p-value Mild pain (1,2) 26 (52.0) 20 (40.0) 46 (46.0) 4 54.6 0.001 Moderate pain (3,4) 17 (34.0) 26 (52.0) 43 (43.0) 4 54.8 0.001 Severe pain (5,6) 7 (14.0) 4 (8.0) 11 (11.0) 1 34.1 0.001 Very severe (7,8) 0 (0.0) 0 (0.0) 0 (0.0) 0 Worst pain (9,10) 0 (0.0) 0 (0.0) 0 (0.0) 0 Table 4 shows that there were significant differences in perineal condition between the experiment and control groups (p = 0.001), which the percentage of intact perineum was higher in the experimental group (22%) than in the control group (10%). In addition, those in the control group had a higher number of episiotomy (24%) than the experiment group (18%), and the majority of the control group (66%) and the experimental group (60%) had a perineal tear. Table 4 Effect of warm compresses on the perineal outcome for the experimental and control group (N = 100) Perineal Condition Control n (%) Experiment n (%) Total N (%) Chi-square p-value Intact 5 (10) 11 (22) 16 (16) 50 0.001 Episiotomy 12 (24) 9 (18) 21 (21) 58 0.001 Tear 33 (66) 30 (60) 63 (63) 38 0.001 Table 5 shows a significant difference in the degree of perineal tear in both groups (p = 0.043). However, the experimental group had lower degrees of perineal tear in the first, second, third degree than the control group. Table 5 Comparison of degree perineal tear between the experimental versus control group (N = 100) Degree of Perineal Tear Control n (%) Experiment n (%) Total N (%) Chi-square p-value First degree 13 (31.7) 19 (61.3) 32 (44.4) 66.8 0.043 Second degree 24 (58.5) 10 (32.3) 34 (47.2) Third degree 4 (9.8) 2 (6.5) 6 (8.3) Fourth degree 0 (0.0) 0 (0.0) 0 (0.0) Discussion Perineal injuries during childbirth may affect our goal to maintain perineal preservation, especially among primiparous women. Therefore, interventions for reducing perineal trauma and perineal pain are desirable. Midwives and nurses widely advocate warm compresses to reduce perineal trauma and improve comfort during the second stage of labor (Aasheim et al., 2017). Our study aimed to assess the effect of warm compresses on the occurrence of perineal tears and pain intensity during the second stage of labor. The findings revealed that the follow-up measurement for pain intensity after birth in both the control and experimental groups with no statistically significant differences for pain score measurement at p = 0.175. These findings are supported by a study of Dahlen (2012) that examined pain intensity during the second stage of labor after warm packs. In this study, among women who received warm packs, their pain intensity score was less than those who received standard care. As such, women who had warm packs were significantly less likely to report lousy pain or the worst pain experienced at birth compared with women who received routine care without the application of warm packs. Also, our findings reported mild and moderate degrees of pain in the intervention group. Furthermore, Dahlen (2012) examined the concepts of comfort and pain, including warm compresses' positive effects on reducing pain, and fewer women reported that the warm compresses helped to numb their perineum area. It seems that the warm compresses helped women to deal with the stinging sensation experienced in the perineum during the second stage of labor, also described by midwives as the “ring of fire.” Being able to get comfortable is a significant predictor of feeling in control during labor and birth. Likewise, a study done by Ahmad and Turky (2010) found that pain scores were better for the women who used warm compresses compared to other women during the second stage at different points of time. This finding may reflect the benefit of using warm compresses through the second stage of labor. In addition, Akbarzadeh et al. (2016) reported that the warm compresses yielded significantly decreased pain during the second stage of labor by increasing blood flow to the damaged or inflamed area, which increased the elasticity of the collagen, which helps increase tissue flexibility and provide a good feeling and psychological convenience, which reduces the pain. In the same vein, warm compresses can relieve pain by enhancing blood circulation in the perineum (Ozgoli et al., 2016). Regarding perineal tears, the results in this study revealed that the experimental group was better than the control regarding the intactness of the perineum. However, the experimental group had fewer perineal tears than the control group. Interestingly, the experimental group had fewer participants who received an episiotomy after childbirth than the control group. Further, the effect of warm compresses on different degrees of perineal tears reflected a statistically significant difference between both control and experimental groups at p < 0.043, with better outcomes for the experimental group than the control group in reducing the third degree of laceration and maintaining perineal integrity Regarding stitches of the perineum, two previous randomized studies agreed with the current study indicated that warm compresses had no effects on the reduction of stitches in primiparous women, confirming the long-term effects of warm compresses (Dahlen, 2012). Likewise, Dahlen et al. (2009) support our findings, as no reduction was reported in perineal suturing after application of warm packs, and the trial was underpowered to assess third- and fourth-degree tear. Meanwhile, a study by Akbarzadeh et al. (2016) was not in line with our current research, reporting that a warm compress was effective in reducing the rate of episiotomy and the mean length of episiotomy incision, reducing pain intensity after childbirth and increasing the rate of an intact perineum, which indicates the significant effects of warm compresses on the reduction of lacerations and perineal trauma. Another study by Aasheim et al. (2017) also reported that midwives applied different techniques to decrease perineal trauma, genital trauma, episiotomy, pain intensity lubricant massage, and antenatal pelvic training. However, no studies declared the most effective method for reducing the laceration of the perineum during childbirth. Even though physiology literature has indicated that using a perineal pack during the second stage of labor leads to vasodilation, increased blood flow in the perineum area, increased relaxation, and increased muscle stretch, which was effective in pain transmission through reduction of nociceptive stimulation and improving comfort for pregnant women (Ozgoli et al., 2016). Dissimilar to Essa and Ismail (2016), which was not in line with the present study’s results, revealing a significant reduction in episiotomy and vaginal/ perineal tear among the study group (p < 0.000). This finding may reflect the benefit of applying warm compresses on the perineum during the second labor stage. In addition, Mohamed et al. (2011) found that using a warm compress in the perineum area during the expulsive period reduces the occurrence of perineal laceration. A study of Essa and Ismail (2016) has a dissimilarity with our study related to sample size, as theirs was more significant than the current study's. Besides, the perineal pad's material was different, as their study used a towel, but our study used a perineal pad made of gauze layers. Additionally, these findings boost the use of perineal warm compress by trained birth attendants, in line with the meta-analyses study by Aasheim et al. (2017), which found a significant effect of using warm compresses on third- and fourth-degree tears. In the present study, findings revealed that warm compresses' application showed a reduction in third- and fourth-degree tears, reducing second-stage perineal trauma in primiparous women. In the same vein, Aasheim et al. (2017) also found that warm compresses and massage may reduce severe perineal trauma and third- or fourth-degree tears. Hands‐off techniques may decrease the number of episiotomies, but it was not clear that they had a valuable effect on other perineal trauma. Many advantages occur from applying warm compresses that produce relaxation by reducing muscle spasms and reducing pain intensity during childbirth. This study reflects the benefit of using warm compresses to decrease the perineal trauma, which is evident by reducing the second and third-degree tear rate in the experimental group compared with the control group. Therefore, all governmental/educational hospitals should provide effective planned in-service training programs for maternity nurses regarding warm compresses' advantages during the second stage of labor. Further research is required to assess the effect of warm compresses on multiparous women relating to receiving the same benefit of comfortable and relief pain degree during the second stage of labor integrating with assessing woman's satisfaction regarding the use of warm perineal compresses during the second stage of labor. The limitation of the study might include: First, eligible participant criteria as primiparous women lead to difficulty collecting data within the determined time of data collection. Second, most participants showed satisfaction regarding warm compresses, but the satisfaction variable was not included in this study. Conclusion This study concluded that the application of warm compresses during the second stage of labor has better effects on perineal outcomes. In addition, it showed evidence of other benefits regarding the positive effect on reducing the second and third-degree of perineal tear and pain intensity to lower pain degrees within the experimental group. Therefore, the practice of applying warm perineal compresses in the second stage of labor is highly acceptable by mothers and midwives or nurses in helping to reduce perineal pain and increase comfort. Furthermore, the finding reveals that the experimental group that experienced intact perineum reducing tear and pain is better than the control group. Interestingly, the experimental group lesser episiotomies compared to the control group. Acknowledgment We acknowledge the maternity nurses at King Abdulaziz Medical City's labor and delivery department for cooperation during data collection. Declaration of Conflicting Interest The authors declare no conflict of interest in this study. Funding None. Author Contribution HF drafted the article and language editing. SM reviewed the literature and data collection. HF, HR, and SM contributed to study design and concept, critically reviewed and approved the final version of the manuscript. Author Biographies Soumaya Modoor, RN had a Master of Midwifery Nursing at the College of Nursing King Saud Bin Abdul-Aziz University for Health Sciences, Kingdom of Saudi Arabia. Currently, she is a Senior Midwife Specialist at the Maternity and Children Hospital, Makkah, Saudi Arabia. Howieda Fouly, PhD, RN is an Assistant Professor of Maternity Nursing, College of Nursing King, Saud Bin Abdul-Aziz University for Health Sciences, Kingdom of Saudi Arabia, and Associate professor, Faculty of Nursing, Assiut University, Egypt. Hawazen Rawas, PhD, RN is an Assistant Professor of Medical-Surgical Nursing, College of Nursing, King Saud Bin Abdul-Aziz University for Health Sciences, Kingdom of Saudi Arabia. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. ==== Refs References Aasheim, V., Nilsen, A. B. V., Reinar, L. M., & Lukasse, M. (2017). Perineal techniques during the second stage of labour for reducing perineal trauma. Cochrane Database of Systematic Reviews(6 ), CD006672. 10.1002/14651858.CD006672.pub3 28608597 Ahmad, E., & Turky, H. (2010). Effect of applying warm perineal packs during the second stage of labor on perineal pain among primiparous women. Al-Azhar Assiut Medical Journal, 8 (3 ), 1-26. Akbarzadeh, M., Vaziri, F., Farahmand, M., Masoudi, Z., Amooee, S., & Zare, N. (2016). The effect of warm compress bistage intervention on the rate of episiotomy, perineal trauma, and postpartum pain intensity in primiparous women with delayed Valsalva maneuver referring to the selected hospitals of Shiraz University of Medical Sciences in 2012-2013. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-192 10.33546/bnj.2324 Original Research: Methodology Paper Developing a blended learning curriculum using a digital notebook application for a surgical nursing practicum: The ADDIE model https://orcid.org/0000-0003-2326-9371 Kardosod Apichat * https://orcid.org/0000-0001-7071-0217 Rattanakanlaya Kanittha Noppakun Lalida https://orcid.org/0000-0002-8212-225X Meechamnan Chutima https://orcid.org/0000-0001-5886-7713 Indratula Rujadhorn https://orcid.org/0000-0003-2582-0921 Deechairum Sirinard Department of Surgical Nursing, Faculty of Nursing, Chiang Mai University, Chiang Mai, Thailand * Corresponding author: Apichat Kardosod, MNS, Faculty of Nursing, Chiang Mai University Chiang Mai, Thailand, 50200. Email: apichat.k@cmu.ac.th Cite this article as: Kardosod, A., Rattanakanlaya, K., Noppakun, L., Meechamnan, C., Indratula, R., & Deechairum, S. (2023). Developing a blended learning curriculum using a digital notebook application for a surgical nursing practicum: The ADDIE model. Belitung Nursing Journal, 9(2), 192-197. https://doi.org/10.33546/bnj.2324 18 4 2023 2023 9 2 192197 21 9 2022 19 10 2022 16 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The COVID-19 pandemic has presented challenges to nursing practice globally. However, utilizing digital notebook applications to support nursing student practices may be an effective tool for surgical nursing practicum. Objective This study aimed to design a blended learning curriculum for surgical nursing practicum, utilizing a digital notebook platform. Methods This study applied the Analysis, Design, Development, Implementation, and Evaluation (ADDIE) model to create a blended learning curriculum for surgical nursing practicum, employing the OneNote application platform. The study included three experts and 90 third-year nursing students who evaluated the model. The study was conducted from July 2021 to March 2022 at the Faculty of Nursing, Chiang Mai University, Thailand. Data were analyzed using descriptive statistics. Results The experts rated the model highly (Mean = 4.33, SD = 0.57). The satisfaction level of the students with the blended learning curriculum using a digital notebook application was also high (Mean = 4.88, SD = 0.31). Conclusion The blended learning curriculum using a digital notebook application for surgical nursing practicum was satisfactory for learners. The results from this research can be applied in online learning or incorporated into nursing clinical practicum curricula during and even post-pandemic. The study results may also serve as an example or a piece of basic information to further develop an advanced online platform for teaching learning, either in Thailand or globally. nursing students blended learning digital notebook application surgical nursing practicum problem-based learning COVID-19 ADDIE Thailand Classroom research grant from the Faculty of Nursing, Chiang Mai University, Thailand ==== Body pmcBackground The COVID-19 pandemic has had a significant global impact on education, with healthcare education being one of the areas severely affected (Tipon et al., 2022). In Thailand, the teaching and learning of surgical nursing suffered as COVID-19 restrictions prevented students from practicing in surgical wards with their instructors during their practicum (Thai Ministry of Public Health, 2021). In response to this challenge, a blended learning online format was designed to address immediate needs while maintaining the required quality of learning outcomes, with the ultimate goal of producing genuinely qualified nursing professionals who can effectively apply their learning when deployed in real clinical settings after graduation. Despite the rapid technological changes and developments, the design of a blended curriculum in the 21st century has been a faltering and often unsuccessful process. However, the COVID-19 pandemic compelled nursing educational institutions worldwide to transfer to novel technological solutions for educational service delivery, thereby galvanizing longstanding trends and requirements for updated learning formats appropriate for the 21st century (Syakur et al., 2020). In addition, due to lockdown and social distancing policies applied in most countries, instructors had to adjust and change curricula to be more flexible and accessible by reducing dependence on physical presence at certain times and places through the use of online formats. It is imperative that the curriculum promotes students' learning and self-development at their own pace and potential to maximize the achievement of learning outcomes (Adams et al., 2010; Thongkaew, 2020). Furthermore, this approach is suitable for the modern student as it utilizes computers and information technology in daily communication. Therefore, this study aimed to design a blended learning curriculum for a surgical nursing practicum using a digital notebook platform based on the ADDIE model. The results of the study will be beneficial not only during the pandemic but also in the future learning environment fulfilled by advanced technology. Context of Surgical Nursing Clinical Practicum This study was conducted at the Faculty of Nursing, Chiang Mai University (CMU), with the aim of providing students with clinical skills in surgical nursing. The curriculum focuses on developing students' clinical skills, including nursing processes and nursing care delivery to clients with chest, GI, urology, and orthopedic illnesses. In addition, it emphasizes basic and intermediate nursing skills, medication administration, communication, and critical thinking, as well as holistic nursing care for adults and older adults with acute and chronic health problems in various body systems receiving surgical treatment. In addition, the curriculum is designed to incorporate nursing ethics, cultural diversity issues, and evidence-based concepts concerning patients' rights and safety (Sattrapruek, 2017). The Faculty of Nursing CMU strongly believes that students’ most critical learning objective is to have academic knowledge and clinical skills in surgical nursing to care for patients effectively. Thus, curriculum development in the 21st century adopts the “active learner” concept to promote students' learning, incorporating innovative information technology skills, media literacy, and life and career skills (Sattrapruek, 2017). The curriculum uses active learning principles to develop ten skills, including critical thinking, collaboration, cross-cultural understanding, communication, computing, and self-motivated career enhancement, designed to meet the requirements of nursing in the 21st century (Kaewsaeng-on et al., 2021; Laohacharasang, 2018). The associated learning activities are designed to meet the learning objectives with a standard framework for learning knowledge and skills. In addition, the curriculum aims to produce quality students with good morals and ethics who can be good citizens of the world and promote socially responsible behavior (Kunaviktikul, 2015; Syakur et al., 2020). CMU strives to become one of the world's leading universities, seeking to teach students to be active learners, including self-directed and autonomous learning, and to incorporate advanced technologies to facilitate the learning process (Thanormchayathawat et al., 2016). Technological readiness and development are central to CMU's quality improvement strategy, which emphasizes promoting socially responsible students who are outstanding in development. Instructors are responsible for ensuring that the curriculum meets the objectives of producing quality students with good morals and ethics. The “smart CMU students” approach includes six categories, namely Smart IT, Smart English, Smart Character, Smart Health, Smart Brain, and Smart Heart, which aim to develop students' skills, promote critical thinking, and incorporate technology into their learning, resulting in a unique character as CMU graduates (Student Development Division of Chiangmai University, 2019). Ultimately, the curriculum aims to enhance the professional nurse’s image and provide teaching and counseling to service users, including patients, relatives, and the community, in the future. Designing a Blended Learning Curriculum: ADDIE Model The study utilized the ADDIE model, which was originally developed in 1975 by the Center for Educational Technology (CET) at Florida State University for a project of the US Army. The model was later adopted by all branches of the US Armed Forces (Hannum & Briggs, 1982; Nurbaeti et al., 2021) and provided a structured design method for learning programs. In the current study, using the OneNote application platform, the ADDIE model was applied to design the blended learning curriculum for the surgical nursing practicum. Analysis Phase In this phase, the learning problems were assessed using interview techniques with 32 third-year nursing students on their first block rotation, from July to August 2021, to explore strategies during the COVID-19 restrictions to enable continuity of education using technology solutions and online learning and to achieve nursing curriculum goals. All agreed that a blended curriculum should be designed. In addition, every learning application was checked, whether it was appropriate for blended learning. Designing Phase In this phase, the outline, description, and contents of the application are created. This phase was conducted for one month, from August to September 2021, to create learning strategies. OneNote application platform from Microsoft 365 was used to design the blended learning curriculum (Microsoft 365, n.d.; MS-ONE, 2015; Protalinski, 2015). Such methods have been found to be suitable for adoption and development by instructors to meet course (and learner) objectives (Grissom, 2017; Grussendorf, 2020). In addition, it can be used with many other systems and inputs, such as forms, documents, nursing progress notes, learning images, suggestions, video files, drawings, or pictures. When designing the surgical nursing practicum, instructors need to use different delivery methods so that students can learn surgical nursing effectively and be effectively trained to begin practice on actual wards (Grussendorf, 2020). Instructors can download OneNote as a platform using the CMU Microsoft network account. This platform will connect the instructors and students to learn, correct their work, and collaborate online and onsite. They can insert pictures, videos, and other learning activities so the students can see real images online, despite an inability to see the real cases on the ward (Bader et al., 2021). The instructors in this phase learned about the flow of the platform. In addition, video clips demonstrating nursing care procedures in surgical practice were also developed and collected, such as changing ICD containers, pin and wound site dressing, walking aid, neurovascular status assessment, and exercise in orthopedic patients. The video clip demonstrated the application's effectiveness in terms of use, appearance, and learning. Development Phase The learning format model and materials were developed in this phase from September to October 2021 based on the design phase. The learning materials are based on the old curriculum from the Faculty of Nursing CMU, including 1) the principles of holistic nursing practice for adults and elderly who have undergone surgical treatment; and 2) holistic nursing practice for adults and the elderly with an acute and chronic health problem in various body systems who received surgical treatment (Anthony et al., 2022; Topping et al., 2022). In addition, related literature on the materials and a learners’ satisfaction questionnaire were included in the app (Figure 1), with a summary of the usage of the app also provided for instructors and learners. Next, the curriculum orientation was done, and samples for try-out were prepared. Figure 1 Example of the digital notebook application platform using OneNote [https://shorturl.asia/KerYH] Implementation Phase In this phase, the first round of the learning curriculum was implemented from October 2021 to February 2022, with a total of 28 third-year nursing student participants. They were also interviewed to determine the effectiveness of the application platform and identify its weaknesses. However, the interview results revealed that virtual documents in OneNote were arranged in a sparse way, making it difficult to access documents for some nursing records that need to be completed, resulting in incomplete reporting of operations. Based on students’ feedback, we organized all virtual documentation on the platform into separate groups. In addition, we prioritized key documents, like the patient’s hospital chart, so that the students could learn and write realistically. Some modifications were made for the final program (second round) for use with 30 third-year students, which was calibrated to meet students’ learning needs during the COVID-19 lockdown restrictions. The results showed that the program was effective for use by learners. Evaluation Phase In this phase, expert and student feedback was sought in March 2022. However, to evaluate the program, a questionnaire was first developed. Questionnaire development The researchers developed the questionnaire from July to August 2021. Validity A questionnaire for experts about the blended learning curriculum application was developed based on two studies (Carman, 2002; Henrich & Sieber, 2009), and the questionnaire uses a 5-rating scale (1 “most inappropriate” to 5 “most appropriate”). The researcher invited three experts, who rated the perceived validity of the questionnaire using the formula of the Index of Item-Objective Congruence (IOC). A three-rating scale was used to measure validity: 1 (if the expert is sure that the item measures the attribute), 0 (if the expert is not sure that the item does measure or does not measure the attribute), and -1 (if the expert is sure that the item does not measure the attribute). The validity scores were analyzed using the formula of the Index of Item-Objective Congruence (IOC); if a question scores less than 0.5 for IOC, the researchers should delete the question and consider improving or changing the question before finalizing the questionnaire for use with the sample (Grove et al., 2012; Polit & Beck, 2009). The IOC validity score of each item of the study questionnaire was 1. The satisfaction questionnaire was developed based on the information from Adams et al. (2010), and the questionnaire uses a 5-rating scale (1, “not at all satisfied” to 5, “very satisfied”). The researchers invited three experts, who rated the perceived validity of the questionnaire using the formula of the Index of Item-Objective Congruence (IOC). When the IOC was less than 0.5, the researchers would delete the questions and consider improving or changing the question before finalizing the questionnaire for use with the sample. IOC resulted in 1 each of the items. Reliability The item content validity (I-CVI) of the questionnaire for experts about the blended learning curriculum application and satisfaction, the item content validity (I-CVI) was tested by three experts, who rated the nine-item satisfaction questionnaire covering learning content, learning activities, and knowledge evaluation. It uses a five-point rating scale, with a score ranging from “questions do not fit the operational definition” to “questions fit the operational definition”. The criteria for accepting the validity index was 1.00 (Polit & Beck, 2009), and the acceptable I-CVI was 1.00. When the index and I-CVI of the content met the criteria standards, the content was included in the blended learning curriculum. To measure reliability, we tried out six samples that characterized the similarity of the sample. Internal consistency was measured using Cronbach’s alpha coefficient, and the result of 0.72 indicate reliability. Evaluation of the program In this phase, expert and student feedback was sought in March 2022. Appropriateness The results of the development of the blended learning curriculum via digital notebooks were done by the three designated experts, who rated the content overview of the integrated learning curriculum via digital notebook as most appropriate for format and learning at the highest level (Mean = 4.33, SD = 0.57) using a 5-rating scale (1 “most inappropriate” to 5 most “appropriate”). However, more details of each item, including the results from different learning formats, blended learning, evidenced-based learning, learning via digital notebooks, types of learning formats, types of learning via videos, and types of blended learning in the big picture, are shown in Table 1. Table 1 Results of experts’ evaluation regarding blended learning curriculum via digital notebook (n = 3) Types of learning management Mean SD Level Types of blended learning 4.33 0.57 Most Types of learning management via evidence-based learning 4.33 0.57 Most Types of learning management via digital notebook 4.00 0.10 Most Types of designing learning platforms 4.33 0.57 Most Types of learning via videos 5.00 0.00 Most Types of learning via blended learning in a big picture 4.33 0.57 most Satisfaction A total of 90 students provided feedback. The results showed that the students’ total satisfaction level, using mean and standard deviation, was at the highest level of satisfaction (Mean = 4.88, SD = 0.31). The satisfaction for each category, content, learning activities, and knowledge were evaluated. The results are shown in Table 2. The contents items pertaining to the contents’ clarity, the difficulty of the content, usefulness in a real setting, and applicability to oneself. The learning activities included hands-on practice, clinical instructor suggestions, and student collaboration. Knowledge evaluation related to the appropriateness of the test before clinical practice and total satisfaction. Table 2 Participant satisfaction levels for blended digital learning curriculum via notebooks (n = 90) Evaluation Mean SD Level Learning content Clarity of the content Difficulty of the content Useful in a real setting Applicability to oneself 4.63 4.76 4.88 4.78 0.58 0.42 0.31 0.41 Most Most Most Most Learning activities Hands-on practice Suggestions from clinical instructors Collaboration among students 4.68 4.78 4.88 0.46 0.41 0.31 Most Most Most Knowledge evaluation Appropriateness of the test before clinical practice Total satisfaction 4.56 4.32 0.54 0.51 Most Most Overall satisfaction with blended digital learning curriculum via notebooks 4.88 0.31 Most Ethical Considerations This study was approved by the Ethics Committee, Faculty of Nursing, Chiang Mai University (EXP019-024). The researchers provided an explanation of the study objectives and participants' rights, emphasizing voluntary participation. To ensure confidentiality, the subjects' names were anonymized during the study, and the researchers were unaware of individuals' responses. Prior to participating in the study, participants signed an informed consent form. Discussion During the COVID-19 pandemic, a blended learning curriculum program was developed using a digital notebook application to enable nursing students to learn while adhering to social distancing requirements. This program aimed to enhance the students' knowledge of surgical nursing and clinical practice and prepare them to provide appropriate patient-nurse interaction when working with patients in natural settings. In addition, the compatibility of the platform with the learning format and the management of the surgical nursing course was ensured. Blended learning has been found to improve learning outcomes, as demonstrated by Tongnate (2014)’s study, which examined blended learning via a computer network with content that blended seamlessly, resulting in improved students' ability to expand their thinking at a deeper level. This type of learning can enhance learning in each topic and course and is particularly suitable for 21st-century learners. It is modern and effectively utilizes technology for learning, including pedagogically, to encourage learners to think, reason, or find solutions to problems while studying. As a result, learners can gain deeper insights into issues, become more willing to solve potential problems and apply new knowledge and skills in real-life situations. Furthermore, this format maximizes students' potential, as supported by a study by Roekmongkol (2017), which deployed blended learning in education courses and reported high achievement of self-learning outcomes, student-instructor interactions, practical group projects, and convenience in conducting class activities. In addition, learners are free to research and seek information until they completely understand the material and can repeat the lessons as needed. Overall, the use of blended learning in nursing education during the pandemic has been a valuable tool for enhancing learning outcomes and providing a modern and effective means of utilizing technology for learning purposes. On the other hand, in our study, the blended learning program received excellent satisfaction ratings, as evidenced by the overall average analysis results. The program allows students to solve problems autonomously and concentrate on learning more effectively, thereby increasing their motivation to acquire new knowledge and make self-inferences. These outcomes are attributable to blended learning management, which enables learners to recall and integrate previously acquired knowledge during their studies. The autonomous learning process involves analyzing and synthesizing information, resulting in a more enjoyable and satisfactory experience for the learners. This finding is consistent with a systematic review by Kaewsaeng-on et al. (2021), who reported that an online learning model, which emulated a real classroom, helped students acquire clinical practice skills similar to actual practice. The online format allowed students to learn from trial and error until they had mastered the necessary skills, thereby increasing their confidence in their abilities. In addition, the self-learning format promoted students' problem-solving skills and time management and reduced their study-related stress. The students expressed satisfaction with the course, indicating that the program helped them achieve their learning goals. Implications for Nursing and Midwifery Practice The emergence of advanced digital technology and e-learning solutions in recent years, coupled with the COVID-19 pandemic and lockdown experiences, has presented new opportunities and challenges for nursing education in the 21st century. As current and future learners are part of “generation Z,” they require more extensive use of technology in education services. Therefore, advanced digital solutions are increasingly crucial for successful teaching and learning (Prasetyo, 2022). The development of teaching and learning with the digital notebook platform can be applied with a design approach compatible with the prevailing context, culture, and teaching and learning requirements of Thailand and international nursing education. Limitations This study identified some limitations. Firstly, the use of a blended program via a digital notebook application was a new experience for the instructors who applied it for student learning, and some of the features (e.g., animations) were not used effectively. This issue has been addressed in planning for the next orientation, with contingencies for problem-solving to enable and facilitate effective use on the ground. Secondly, learning online during the COVID-19 pandemic revealed that some of the procedures that are not actual practices students only practice with video demonstration. This issue could be attributable to failures in communication with the clients and a loss of hand skills once they finish the course. Finally, due to the critical conditions of the COVID-19 pandemic, online learning and teaching were not supported by the full range of supporting equipment for use and video clip demonstrations. This was resolved on an ad hoc basis with education by doing, and the results were entirely satisfactory for both teachers and learners. Recommendations for Future Studies This blended learning curriculum via digital notebooks design can be implemented in teaching clinical practice for surgical nursing either in a 100% online format or hybrid form, alongside onsite instruction. It can also be applied during or even post-pandemic. Instructors can adjust the steps or improve them according to their ability and the progress and pace of the learners. Future research should explore students’ total learning scores as key performance indicators for the curriculum and identify barriers related to the blended learning curriculum via digital notebooks by qualitative investigations of user experiences. Various studies providing insights into the curriculums’ development and practical effectiveness from different angles can help identify diverse ways to optimize learning effectiveness. Instructors and researchers should explore other complementary or improved approaches, and blended learning curriculums themselves must be continually evaluated and revised in future studies that could compare different formats. Conclusion The findings of this study demonstrate that the blended learning curriculum utilizing digital notebooks in the surgical nursing practicum program elicited significant satisfaction among its users. In addition, the use of technology resources to enhance learning outcomes and the delivery of lectures with learning strategies were instrumental in supporting CMU learners in their educational endeavors. Specifically, the digital notebook application served as an innovative learning strategy that proved beneficial in providing effective learning experiences amidst the challenging circumstances posed by the pandemic or any conditions requiring online learning. However, further testing of the curriculum is needed for a better teaching and learning environment. Acknowledgment We would like to express our appreciation to the third-year nursing students who participated in this study. Additionally, this research would not have been possible without the Nursing CMU Publication Support Center (PSC) to revise and provide information for manuscript writing. Declaration of Conflicting Interest None declared. Authors’ Contributions AK, KR, and LN drafted the article and conducted a review for this study. CM, RI, and SD performed the data collection and analysis. AK and KR contributed to the design and concept of the study. AK wrote the manuscript in coordination with other authors and discussed improving the final versions of the submitted and published manuscript. All authors were accountable for each study step and approved publishing the final article. Authors’ Biographies Apichat Kardosod, MNS; Kanittha Rattanakanlaya, PhD; Lalida Noppakun, PhD; Chutima Meechamnan, PhD; Rujadhorn Indratula, PhD; and Sirinard Deechairum, MNS are Lecturers at the Surgical of Nursing Department, Faculty of Nursing, Chiang Mai University, Chiang Mai, Thailand. Data Availability Due to privacy and ethical concerns, neither the data nor the source of the data can be publicly made available from the corresponding author. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Adams, J. M., Hanesiak, R., Morgan, G., Owston, R., Lupshenyuk, D., & Mills, L. (2010). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-72 10.33546/bnj.1300 Theory and Concept Development The development of Need–Threat Internal Resiliency Theory in COVID-19 crisis utilizing deductive axiomatic approach https://orcid.org/0000-0003-4901-3016 Sadang Jonaid M. 1* https://orcid.org/0000-0002-0037-7567 Palompon Daisy R. 2 1 College of Health Sciences, Mindanao State University, Marawi City, 9700, Philippines 2 College of Nursing, Cebu Normal University, Cebu City, 6000, Philippines * Corresponding author: Asst. Prof. Jonaid M. Sadang, RN, RM, LPT, MAN, PhD h.c., 0653, Cabingan, Marawi City, 9700, Philippines, Mobile number: +639-123-795-594. Email: jonaidsadang@yahoo.com | jonaid.sadang@msumain.edu.ph Cite this article as: Sadang, J. M., & Palompon, D. R. (2021). The development of Need–Threat Internal Resiliency Theory in COVID-19 crisis utilizing deductive axiomatic approach. Belitung Nursing Journal, 7(2), 72-77. https://doi.org/10.33546/bnj.1300 29 4 2021 2021 7 2 7277 09 1 2021 04 2 2021 22 2 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Resiliency for older people represents the capacity to return to equilibrium when difficulties arise and was found as integral predictor of their health status. This study aims to develop a theory that attempts to explain the older adults’ resiliency perspectives during crisis and how it has affected their well-being and quality of life as population group. Deductive theory generation using axiomatic approach was adopted resulting to five axioms that served as basis for the generation of three propositions such as: (1) An older person’s health needs have tendencies to develop into a health threat, (2) when the threat is perceived, older persons developed a sense of internal control and adaptation to the changes it creates known as internal resiliency, and (3) internal resiliency can influence the quality of life in old age. The evolved theory suggests that in times of crisis (e.g., COVID-19 pandemic), health needs develop into a health threat that compels older persons to develop internal resiliency in order to preserve their integrity, wellbeing and quality of life. This study widens the nursing perspectives in addressing older persons’ resiliency by the unique condition at which older clients are placed affecting both the pathological nature of the illness as well as the preventive interventions which the society is forced to implement. COVID-19 need-threat internal resiliency older adults deductive axiomatic approach nursing ==== Body pmcMonths have passed since the declaration of Coronavirus Disease 2019 (COVID-19) as pandemic health emergency by the World Health Organization (WHO) (D’cruz & Banerjee, 2020; Sands et al., 2020), however the threat and impact of this virus still continues most especially among developing countries with unsophisticated healthcare system, including The Philippines. This crisis has created abrupt changes and difficulties in the daily activities and survival between populations particularly those marginalized groups, including older adults (Sands et al., 2020). The economic insecurities of most Filipino older adults increases their risk of inability to access both healthcare and other essential needs (Buenaventura et al., 2020; Lekamwasam & Lekamwasam, 2020). This pandemic crisis has created a unique threat on the context of older adults’ life resulting to increased uncertainty, fears related to contagion, illness and death, new stressors and reduces access to protective factors (Ferreira et al., 2020). Socialization is vital to promote successful ageing and well-being among older adults (Van Tilburg et al., 2020), however this was challenged with the implementation of social distancing and other health protocols in most areas to prevent the spread of this illness among communities in the absence of effective therapeutic management (Buenaventura et al., 2020). Most older adults were usually isolated in their respective residences resulting to minimal contact with their families and friends (Buenaventura et al., 2020). This increases the vulnerability of both physical and psychosocial burden among this population group (Parlapani et al., 2020). In effect, older adults have experienced depressive symptoms, loneliness, stress, anxiety, fear, decline physical abilities, cognitive problems, and disruption of sleeping habits during this pandemic time (D’cruz & Banerjee, 2020). Social and demographic factors were known to be essential aspects affecting resiliency during any crisis as results of exposures to uneven social vulnerabilities (Ferreira et al., 2020). Older adults usually rely on their family members, friends, community groups and volunteers to meet their daily basic needs (Parlapani et al., 2020). Most people during this pandemic relies more on others to sustain their needs amidst the threat this illness has brought, and this results to decreased perspective on ones’ resiliency as an individual (Ferreira et al., 2020). Literature has identified the importance of psychological, social support and connectedness as well as health behaviors as integral components of crisis resiliency (Sands et al., 2020). Resiliency is seen as a resource that enables older adults’ stable performance when it comes to both internal and external imbalance within their environment (Chen, 2020). Older adults are considered resilient when they do not succumb to adversity, but rather exhibit the capacity for successful adaptation (Fontes & Neri, 2015). However, the presence of threat and the need to sustain their needs in the midst of pandemic crisis have created uncertainty and have affected their internal resiliency to adapt with such environmental circumstances. In the process or recovering from this crisis, older adults’ resilience may lead to different outcome that deserves careful attention (Chen, 2020). Older adults having good resilience tend to achieve better health outcomes resulting to successful aging and longevity (Chen, 2020; Fontes & Neri, 2015). Theories concerning older adults’ resiliency and quality of life have long been established, however, in special situation such as pandemic crisis and how it has affected their internal resiliency was not looked into. Therefore, this theoretical paper aims to design a theory that explains the older adults’ internal resiliency perspectives during pandemic crisis and how it affects their well-being and quality of life in specific. The study of the older persons’ internal resiliency in addressing pandemic crisis such COVID19 provides a global contribution to the health and well-being of this special population who are known to have been greatly affected in this crisis. This provides a more in-depth understanding in the nursing care of older persons in this crisis focusing on their socio-psychological well-being. The nursing perspectives in addressing older persons’ resiliency is widened by the unique condition at which older clients are placed affecting both the pathological nature of the illness as well as the preventive interventions which the society is forced to implement. Methods Deductive approach of theory development was adopted in the conduct of this theoretical research that explains the occurrence of the phenomenon under consideration. This approach follows the path of logic most closely as its reasoning begins with a theory out of the existing literatures supporting the phenomenon under consideration and leads to a new hypothesis (Streubert & Carpenter, 2011). This theory development started with coming up with number of axioms on the interplay between the nature of older adults’ resiliency and well-being amidst pandemic crisis, COVID-19 based on the literature and studies to understand the said phenomena under investigation, and eventually leads to the analysis and interpretation of propositions supporting the theory on need and threat internal resiliency among older adults. Results and Discussion Five (5) axioms were derived out of the literature and studies used and reviewed as basis for generating the three (3) propositions which then served as framework for the formulation of this theory on older adults’ need – threat internal resiliency during pandemic crisis as presented on Table 1. Maslow’s theory on hierarchy of needs explains that individuals irrespective of their age seeks to satisfy progressively higher human needs of which each of these levels has relevance for age-related resiliency and well-being, including older adults (Thielke et al., 2012). However, the presence of threat and other environmental crisis usually limits their capacity to maintain equilibrium, thus increases their needs for care and support from the people around them (Abdi et al., 2019; D’cruz & Banerjee, 2020). Disequilibrium exists when individuals are exposed to stressors putting big burden both in their physical and psychosocial aspects as human beings (D’cruz & Banerjee, 2020), depriving their independence and human needs during this trying situation (Buenaventura et al., 2020). Therefore, human beings have needs that must be met (Axiom 1). Table 1 Propositional structures from axiomatic extractions Axioms Propositions Theory Axiom 1. Human beings have needs that must be met. Proposition 1. An older person’s health needs have tendencies to develop into a health threat (Axioms 1, 2 and 3). In times of crisis, health needs develop into a health threat that compels older persons to develop internal resiliency in order to preserve their integrity, wellbeing and quality of life (Need – Threat Internal Resiliency Theory). Axiom 2. Human health is dependent on internal and external conditions. Axiom 3. Crisis and the presence of threat create uncertainty. Proposition 2. When the threat is perceived, older persons developed a sense of internal control and adaptation to the changes it creates known as internal resiliency (Axioms 3 and 4). Axiom 4. Human beings have the capacity to cope or adjust. Axiom 5. Health is a requisite to quality of life. Proposition 3. Internal resiliency can influence the quality of life in old age (Axiom 4 and 5). Human health is dependent on internal and external conditions (Axiom 2). It is a dynamic biological mechanism that over time reflects accumulated structural and functional changes in an organism which are genetically-regulated process that is sensitive to environmental influences (Gobbens & Van Assen, 2018; Tomljenović, 2014). Human health is both biological and social beings (Tomljenović, 2014). These two factors serve as important concept in the maintenance of human health, including the quality of life and well-being of older adults (Zeng et al., 2010). Older adults functioning are products of the interplay between their internal and external environments (Tomljenović, 2014). This population group tends to be more sensitive with their physical and social surroundings and more vulnerable than other age groups with the negative effects of environmental degradation on human health and survival (Gobbens & Van Assen, 2018; Zeng et al., 2010). As people age, the presence of various medical conditions which includes multi-morbidity, disability and frailty create special needs, however a responsive environment could reduce the effect of these problems (Gobbens & Van Assen, 2018), resulting to active aging and remaining independent during old age (Schehl & Leukel, 2020; Zeng et al., 2010). Older adults are categorized as one of the most vulnerable age group during any crisis (Parlapani et al., 2020). It is often attributed with their age-related status including decrease physical state, presence of chronic medical condition and disabilities, decline cognitive abilities and the increased probability of developing psychosocial problems during this times (Parlapani et al., 2020; Wolf et al., 2020). These factors are known to cause uncertainty that often results to various health problems among older adults (Wolf et al., 2020). Due to unexpected nature of most crisis situations such as for example, pandemic health crisis (D’cruz & Banerjee, 2020), and the higher susceptibility to acquire medical conditions, older adults are often left uncertain affecting how they should perceive, interpret as well as respond to such situation on a cognitive, emotional and behavioral level (Parlapani et al., 2020; Wolf et al., 2020). Uncertainty of what is going to happen next often leads to worry, anxiety and even inability to function as individuals affecting ones’ capacity as human being (Grupe & Nitschke, 2013). It disrupts ones’ ability to prevent or mitigate the stressors negative impact (Nuevo et al., 2009). This often leads to anxiety which refers to ones’ persistent, strong and irrational fear of being exposed to certain situation such as during pandemic health crisis (Parlapani et al., 2020), and is prevalent among older adults than younger people (Nuevo et al., 2009). COVID-19, for example, has induced numbers of psychological symptoms including fear and anxiety among this population group due to illness uncertainty and the significant risk or threat it poses among this age group (D’cruz & Banerjee, 2020). In fact, recent literature has revealed the prevalence of older adults’ anxiety and fear has increased throughout this pandemic crisis (Buenaventura et al., 2020; Parlapani et al., 2020). Hence, crisis and the presence of threat create uncertainty (Axiom 3). Health is a multidimensional aspect comprising physical, biological, psychological, economic and social factors of an individual (Pereira et al., 2015). It is an essential major component of quality of life (QLF) especially among older adults (Pereira et al., 2015; Van Leeuwen et al., 2019). Al though, QLF is subjective in nature, it always depends on individuals’ internal and external environments and perceptions (Pereira et al., 2015). Individuals with meaningful interpretations of life, including the absence of diseases, threat and frailty (Pereira et al., 2015), tend to have better well-being most especially during later life; the old age (Chui, 2018). In times of crisis when older adult’s experiences health needs, they feel threatened because there is a need to preserve or establish one’s internal resiliency so that the older person could go back to the normal self or stand up from falling down. As such, an older person’s health needs have tendencies to develop into a health threat (Proposition 1). Human beings have the capacity to cope or adjust (Axiom 4). Each of us normally experiences crisis and stress at a different level on a daily basis of our lives due to the various changes within and outside of our environment (Buenaventura et al., 2020; Galiana et al., 2020). These changes often result to alterations of one’s stability which greatly affects individual’s well-being and quality of life, including older adults when adaptation or coping strategies is not enough. Coping is defined as individuals’ efforts which aim to manage certain specific demands when one’s resources are exceeded (Galiana et al., 2020). Individuals have their unique way of coping that helps them compensate or alleviate from stressful circumstances however this might be different for older persons as stressors also change with age (Ribeiro et al., 2017). In difficult situation, such as pandemic crisis, older adults’ health may worsen and even exacerbate leading to life-threatening problems as risk of complications grows. The vulnerabilities and specific needs in older age is becoming a serious challenge for survival and well-being. This problem may result to inability in accessing and sustaining the care they need during these times. As results, health need becomes a health threat and this threatens the older person, which is why a certain level of internal resilience is developed by the older person. Thus, when the threat is perceived, older persons developed a sense of internal control and adaptation to the changes it creates known as internal resiliency (Proposition 2). Well-being which includes the experience of life satisfaction, emotions, and the sense of purpose and meaning of life is closely linked with older adults’ health (Parlapani et al., 2020; Steptoe et al., 2015). Literature indicates that older adults’ quality of life is strongly affected by one’s state of health (Steptoe et al., 2015). Older person’s well-being has always been considered as essential indicator of successful adaptation during old age (Cho et al., 2011). In fact, studies suggest the state of well-being in old age may even be protective factor of health, reducing the possibility of developing chronic medical problems as well as promotes longevity and successful aging (Steptoe et al., 2015). Hence, health is a requisite to quality of life (Axiom 5). Successful aging does not merely rely only on clinical health status, but also on psychological and social resources of an individual most especially in times of crisis (Galiana et al., 2020). The importance of ones’ perceptions of health rather than the sole count of existing threats has been proven by literature as significant determinants of older adults’ quality of life and well-being. Hence, internal resiliency can influence the quality of life in old age (Proposition 3). Need – Threat Internal Resiliency Theory The effect of crisis, for example, COVID-19 pandemic (Lekamwasam & Lekamwasam, 2020) varies differently between population and the aftereffect may be more pronounced among vulnerable groups, including older adults (Gayer et al., 2020; Mukhtar, 2020). Older adults’ population is considered marginalized for various reasons which includes socio-demographic aspects such as age and living condition, the presence of chronic medical condition and co-morbidities as well as declined physical and immune function to fight against stressors (Lekamwasam & Lekamwasam, 2020), including emerging infections (Fontes et al., 2020). Due to the serious public health concern it poses among this group, older adults are often isolated and restricted from community (Gayer et al., 2020; Mukhtar, 2020). However, despite that social distancing and isolation could save lives of older people, this also increases their risk for some health issues, including loneliness, anxiety and other psychosocial problems due to social constraints resulting to ones’ inability to sustain internal resiliency in times of crisis (Fontes et al., 2020; Vahia et al., 2020). As results, older adults tend to experience lesser opportunities to be satisfied with their living and or experience happiness, resulting to poor quality of life and well-being (Parlapani et al., 2020). Recent studies have also noted reduced quality of life following social isolation among older people during crisis due to these preventive practices (Mukhtar, 2020; Vahia et al., 2020). Older adults have special needs that must be met during any crisis, these include but not limited to nutrition, physical activity, health care, communication, and socialization (Vahia et al., 2020). Positive social connections and relationships are fundamental for older adults’ well-being as social beings, and the loss of these connections could have profound effects both with physical and mental health of these individuals (Gayer et al., 2020). In addition, the restricted contact with people around them has resulted to loss of financial and social support of which is significant for older people in their daily living (Bidzan-Bluma et al., 2020). As such, in order to respond to changing environmental conditions, the presence of these known threats during any crisis (e.g. pandemic crisis) and the need to sustain their individual needs as human beings for survival increases their internal resilience as human beings for adaptation and survival. Therefore, this theory assumes that in times of crisis, health needs develop into a health threat that compels older persons to develop internal resiliency in order to preserve their integrity, wellbeing and quality of life (Need – Threat Internal Resiliency Theory) as illustrated on Figure 1. Figure 1 Schematic diagram of the Need – Threat Internal Resiliency Theory Conclusion Internal resiliency plays an important role among older people during crisis as threat and needs coexist during this unanticipated and dynamic situation. As such, when doing crisis planning and implementing intervention as well as preventive measures to curb the problem, older adult needs should be taken into careful consideration as these individuals may require more special attention and support compare with other population group. Hence, the outcome of this study has big implications for public health policy as well as in developing and implementing health services concerning older person during any disaster or pandemic crisis. The theory further provides a wider perspectives on how nurses takes care of older persons to develop resiliency in times of pandemic such as COVID19. Moreover, further studies must be conducted to validate the three proposition of this theory supporting its assumption between the relationship of health needs and threat as strong force that drives older adults’ development of internal resiliency in times of crisis. Acknowledgment The authors would like to acknowledge the support of their respective Universities, Mindanao State University - Marawi and Cebu Normal University. Declaration of Conflicting Interest The authors declare no conflict of interest in this study. Funding This research did not obtain any research funding from any agency. Authors’ Contribution JMS contributed to conceptualization, design, analysis and the rest of the content of the article. DRP contributed to conceptualization and analysis of this study. All authors agreed with the final version of the article. Authors’ Biographies Dr. Jonaid M. Sadang, RN, RM, LPT, MAN is an Assistant Professor IV & designated as College Secretary of the College of Health Sciences, Mindanao State University, Marawi, Philippines. Dr. Daisy R. Palompon, RN, MAN, DScN is a Professor 6 & designated as Vice President for Academic Affairs of Cebu Normal University, Cebu City, Philippines. ==== Refs References Abdi, S., Spann, A., Borilovic, J., de Witte, L., & Hawley, M. (2019). Understanding the care and support needs of older people: A scoping review and categorisation using the WHO international classification of functioning, disability and health framework (ICF). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-024 10.33546/bnj.1223 Original Research Relationship between hand hygiene behavior and Staphylococcus aureus colonization on cell phones of nurses in the intensive care unit https://orcid.org/0000-0002-4082-2792 Afridayani Meri 1* https://orcid.org/0000-0003-2291-1289 Prastiwi Yohana Ika 1 https://orcid.org/0000-0002-2810-4800 Aulawi Khudazi 2 https://orcid.org/0000-0002-5337-3252 Rahmat Ibrahim 3 https://orcid.org/0000-0002-4028-0751 Nirwati Hera 4 https://orcid.org/0000-0003-2370-8581 Haryani 2 1 Master Program in Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia 2 Department of Medical Surgical Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia 3 Department of Mental and Community Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia 4 Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia Corresponding author: Meri Afridayani, S.Kep., Ns, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada Jl. Farmako Sekip Utara No.55281, Senolowo, Sinduadi, Mlati, Sleman Regency, Yogyakarta Special Region, Indonesia. Telephone: (0274) 545674 Email: afridayanimeri@gmail.com Cite this article as: Afridayani, M., Prastiwi, Y. I., Aulawi, K., Rahmat, I., Nirwati, H., & Haryani. (2021). Relationship between hand hygiene behavior and Staphylococcus aureus colonization on cell phones of nurses in the intensive care unit. Belitung Nursing Journal, 7(1), 24-30. https://doi.org/10.33546/bnj.1223 22 2 2021 2021 7 1 2430 11 10 2020 10 11 2020 10 1 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Healthcare-Associated Infections (HAIs) are infections that often occur in hospitals with Staphylococcus aureus as the primary cause. Staphylococcus aureus is usually found on nurses' hands and easily transferred by contact. Cell phones can be a convenient medium for transmitting bacteria. Accordingly, hand washing is one of the effective ways to prevent the transmission of Staphylococcus aureus. Objective This study aimed to determine the relationship between hand hygiene behavior and the colonization of Staphylococcus aureus on cell phones of nurses in the intensive care unit of the academic hospital. Methods This was an observational study with a cross-sectional design conducted from December 2019 to January 2020. The observations of hand hygiene behaviors were performed on 37 nurses selected using total sampling. Colonization of bacteria on each nurses' cell phone was calculated by swabbing the cell phones' surface. Colony counting was done using the total plate count method. Spearman Rank test and Mann Whitney test were used for data analysis. Results The nurses' hand hygiene behavior was 46.06%. Staphylococcus aureus colonization was found on 18.2% of the nurses' cell phones. However, there was no significant relationship between the nurses' hand hygiene behavior and the colonization of Staphylococcus aureus on their cell phones. Conclusion The hand hygiene behavior of nurses was still low, and there was evidence of Staphylococcus aureus colonization on their cell phones. As there was no relationship between the nurses' hand hygiene behavior with the colonization of Staphylococcus aureus on the cell phones, further research is needed to determine if there is an increase or decrease in colonization before and after regular observations. cell phone healthcare-associated infections hand hygiene Staphylococcus aureus nurses ==== Body pmcHealthcare-Associated Infections (HAIs), or formerly known as nosocomial infections, are infections acquired by patients receiving treatment for a medical condition or surgery and considered adverse events that often occur during treatment (World Health Organization, 2011). HAIs are also a significant cause of morbidity and mortality (Agency for Healthcare Research and Quality, 2019). The occurrence of HAIs is more common in the middle and low-income countries, 5.7% and 19.1%, respectively, or three times higher than in high-income countries (Khan et al., 2017). HAIs in Southeast Asia accounted for approx-imately 75% of the incidence (World Health Organization, 2011). One of the most common causes of HAIs is Staphylococcus aureus, a gram-positive bacteria that often causes various infections; MRSA is one (Bröker et al., 2016). World Health Organization (2011) reported that 5-10% of hospitals' infections are caused by Staphylococcus aureus, and the incidence is increasing every year. This increase has occurred in almost all regions of the world. Asia is the region with the highest incidence of infection across the globe. Indonesia is one of the countries with an increased incidence of infection with Staphylococcus aureus in Southeast Asia, approximately 28% (Chen & Huang, 2014). The high incidence of this infection can be a mode of transmission, from patients to patients, patients to health workers, patients to medical equipment, health workers to visitors, and from health workers to other health workers and the environment (Khan et al., 2017; Price et al., 2017). Hand contact is the main transmission in its spreading mode (Levinson, 2010; Nazliansyah et al., 2016). Health care workers' hands play an important role in the transmission of HAIs, including nurses. Cell phone is considered a convenient transmission medium for HAIs (Kanayama et al., 2017; Pillet et al., 2016), as it is rarely cleaned and frequently touched during or after examining patients without washing (Pal et al., 2015). Therefore, hand hygiene is recommended to be the primary measure necessary to reduce HAIs. Hand hygiene is also a key indicator in the infection prevention and control assessment for medical personnel (World Health Organization, 2018), especially for nurses who most often meet patients and take action on patients 24 hours of admission to a hospital. Given the explanation above, the purpose of this study was to determine the relationship between nurses' hand hygiene behavior with the colonization of Staphylococcus aureus on their cell phones in the intensive care unit. Methods Study Design This study employed an observational design with a cross-sectional approach from December 2019 to January 2020. Sample The study population included nurses who worked at the intensive care unit of UGM Academic Hospital, Yogyakarta, Indonesia. The sample size was determined by total sampling. The inclusion criteria were a nurse who had a cell phone and always brought the cell phone to the intensive care unit. The exclusion criteria were a nurse who took extended leave, maternity leave or attended training or activities outside the hospital during the study. Total respondents were 38 nurses, but one respondent dropped out because of an injury in his right hand, so he could not perform proper hand hygiene. Instrument Nurses' hand hygiene behaviors were measured using the checklist sheets in the form of compliance behavior observations of hand hygiene following 'My five moments' approach adopted from Pittet et al. (2009), with the measurement results in the form of a percentage comparison between actions and opportunities. The five moments observed were 1) before touching a patient, 2) before clean/ aseptic procedure, 3) after body fluid exposure risk, 4) after touching a patient, and 5) after touching patient surroundings. Colonization of Staphylococcus aureus was observed by implanting cell phone surface swabs on Nutrient Agar and Staphylococcus Agar media. After incubation at 37oC for 18-24 hours, the number of colonies that grew was counted by the total plate count method. Identification of Staphylococcus aureus was conducted according to the Standard Operating Procedure in the Microbiology Laboratory of the Faculty of Medicine, Public Health and Nursing (FKKMK UGM) (Granato et al., 2019). Data Collection Observations were made by the researcher and assisted by a research assistant, namely a master nursing student who has gained knowledge and practice related to procedures in bacterial identification. An interobserver test was done using the Intraclass Correlation Coefficient (ICC) with a test result of 0.988, which indicated the acceptable reliability of the two observers. Observations were made on nurses who were implementing nursing care during their shift. In making observations, the researcher did not tell the respondent who was observed in one shift to avoid bias. Each respondent was observed three times with a random observation time (a full hour for each observation). Data Analysis Univariate analysis was conducted to determine the characteristics of the respondents using the average distribution and frequency, including name, age, gender, last education, length of service, occupation, frequency of cleaning cell phones, cleaning materials, and length of time having a cell phone. Bivariate analysis was conducted to determine the relationship between hand hygiene beha-vior and bacterial colonization on nurses' cell phones. As data were not normally distributed (p < 0.05), the Spearman rank test was used to examine the relationship between hand hygiene behavior and the amount of colonization of bacteria. To identify the relationship between hand hygiene behavior and the presence of bacterial colonization, the Mann Whitney test was used. Statistical analysis was performed using SPSS version 21 software (IBM Corp., Chicago). Ethical Consideration This research has received ethical approval from the Medical and Health Research Ethics Committee of FKKMK UGM on 25 October 2019 with the number KE/FK/1267/EC/2019. After the researcher clearly explained the study's objectives, the respondents voluntarily signed the informed consent form to participate in the study. The respondents had the right to refuse to participate without penalty. We ensured that participants were not affected by any consequences in their work. Results Characteristics of Respondents The majority of respondents were women (78.4%), and their average age was 29.6 years old, with the education level of registered nurses (64.9%) and the average length of work of 4 years. All of the respondents indicated they had never cleaned their mobile phones with agents such as alcohol (97.3%). Most respondents had their cell phones for over 12 months (81.1%) (Table 1). Table 1 Distribution of respondents’ characteristics (n = 37) Characteristics Average (Year) f % Age 29.6 Gender Men 8 21.6 Women 29 78.4 Education Associate Degree 13 35.1 B.N. + RN 24 64.9 Length of work 4.0 Never cleaned cell phones Yes 37 100.0 Material Alcohol 36 97.3 Non-alcohol 1 2.7 Length of having a cell phone 0-3 months 3 8.1 4-6 months 2 5.4 7-12 months 2 5.4 >12 months 30 81.1 Hand Hygiene and Bacterial Colonization The highest average of nurses' hand hygiene behavior occurred at the moment 4 (after contact with the patient), 56.66%; while the lowest average occurred at the moment 2 (before action aseptic), 20% to 80%. The average of overall moments of hand hygiene was 46.06%. In this study, the use of gloves was also observed when performing hand hygiene. The result of observation showed 34.13% did not use gloves properly (Figure 1). Figure 1 Average hand hygiene for nurses in the intensive care unit in 2020 (n = 37) Gram-positive bacteria colonization was found on 35 respondents' cell phones (94.6%), and 24 (64.9%) of them contained Staphylococcus spp. Among all respondents, seven cell phones (18.92%) had Staphylo-coccus aureus colonization (Table 2). Table 2 Colonization of bacteria on cell phones (n = 37) Average (CFU/ml) Max (CFU/ml) Min (CFU/ml) f % Bacterial colonization Gram-positive  Positive 35 94.6  Negative 2 5.4  Amount 507.84 15.000 0 Gram-negative  Positive 21 56.8  Negative 16 43.2  Amount 1927.57 70.000 0 Staphylococcus spp.  Positive 24 64.9  Negative 13 35.1  Amount 31.35 250 0 Staphylococcus aureus  Positive 7 18.92  Negative 30 81.08  Amount 5.41 100 0 The Relationship Between Hand Hygiene Behavior and Bacterial Colonization Table 3 shows statistically no significant correlation between the nurses' hand hygiene behavior with either the number of bacterial colonization and the presence of bacteria Staphylococcus spp. and Staphylococcus aureus (p>0.05). Table 3 Relationship of nurses' hand hygiene behavior with colonization of Staphylococcus spp. and Staphylococcus aureus bacteria on cell phones (n = 37) Hand hygiene p Bacterial colonization Presence and absence of bacteria  Staphylococcus spp. 0.353  Staphylococcus aureus 0.450 Number of bacteria  Staphylococcus spp. 0.221  Staphylococcus aureus 0.473 Discussion Figure 1 shows that the average compliance behavior of respondents with hand hygiene was 46.06%, which is considered low. This is in line with Stahmeyer et al. (2017) reported an average hand hygiene adherence of 42.6%, and Selim and Abaza (2015) reported adherence ranging from 37-42%. These reports are of great concern because hand hygiene is the main measure for reducing HAIs and is a critical indicator for assessing infection prevention and control (World Health Organization, 2018). Sickbert-Bennett et al. (2016) reported that a 10% increase in hand hygiene adherence was associated with a 6% decrease in HAIs. In this study, it was found that 34.13% of nurses did not use gloves according to the indication. The improper use of gloves may affect low adherence to hand hygiene. Health care workers or nurses often remove their gloves after a single contact. Still, the gloves will only be changed when all courses of action are completed or when they are very dirty and need to be replaced (Kuzu et al., 2005), or at a change of action at different moments of patient interaction (Picheansathian & Chotibang, 2015). This is not in accordance with the recommendations established by the WHO guidelines (World Health Organization, 2009). Hand hygiene behavior affected by the improper use of gloves was reported by Moghnieh et al. (2017). The caregivers did not feel they needed to wash their hands before using gloves because they thought gloves already protect them. Another aspect that indicates that the use of gloves was not appropriate is at the moment 2 (before aseptic action). The average percentage shows a low number (18.3%), in line with Picheansathian and Chotibang (2015). It is well known that wearing gloves does not prevent cross-infection. Therefore, strengthening education on the appropriate use of gloves indication should always be emphasized. The length of time doing hand hygiene also affects behavior. According to Stahmeyer et al. (2017), the time spent on hand hygiene is 8.3 minutes in the intensive care unit. If nurses fully comply with the recommendation, then 58.2 minutes will be spent on hand hygiene for each patient during the shift. The results of the surface swab of the cell phones showed that there were gram-positive bacteria (94.6%) and gram-negative bacteria (56.8%) on the nurses' cell phones. Colonization of Staphylococcus spp. was found on the cell phones of 24 respondents (64.9%) with an average number of bacteria, namely 31.35 CFU/m. A total of seven respondents (18.92%) had colonization of Staphylococcus aureus on their cell phones. These results are consistent with other studies showing that cell phone use in hospitals poses a risk of transmission of various bacteria, including pathogenic agents resistant to some drugs, such as Methicillin-Resistant Staphylococcus aureus (MRSA) (Curtis et al., 2018; Selim & Abaza, 2015). Cell phones can function as reservoirs for infection in health care settings (Kanayama et al., 2017; Smibert et al., 2018), with very high levels of contamination (Pal et al., 2015). The growth rate of pathogens or bacterial contamination is 40-100% on cell phones' surface, and the majority of these bacteria are potentially nosocomial pathogens that cause HAIs (Curtis et al., 2018). Staphylococcus aureus is drought tolerant and can survive and reproduce rapidly in warm environments such as cell phones (Trivedi et al., 2011). The bivariate analysis revealed no relationship between hand hygiene behavior and Staphylococcus aureus colonization on nurses' cell phones. Poor hand hygiene will affect bacterial colonization growth on cell phones that occurs due to contact with hands. However, it was seen that the good bacteria were present, or there was no growth of bacterial colonization on cell phones, which is equally low with the value of hand hygiene behavior of nurses (46.06%), especially at the moment 2 (20.80%). The compliance value of hand hygiene that must be met is that it must exceed 80% (Ministry of Health, 2018) to influence the number of bacterial colonization. Still, it has not impacted the presence of bacterial colonization, seeing that the value of bacterial colonization is low. Other factors can also affect the colonization of bacteria on cell phones, such as the possibility of contamination on cell phones obtained not directly from the patient or nurses' hands but obtained from the care environment where the cell phone is placed. The environment near or far from the patient can be a place for bacterial contamination (Wille et al., 2018). As for findings in the air, they are considered not a priority because these findings are less than direct contact with the environment or with patients and other health workers (Kozajda et al., 2019). In our study, there was no relationship between hand hygiene behavior and colonization. After doing five moments of hand hygiene, certainly, nurses did not directly hold their cell phones. Still, they did other activities in the care area, either to write on patient medical records or to fill in data on a computer. However, when nurses wanted to use their cell phones, they did not wash their hands. Besides, the hand hygiene moments 4 and 5 (after touching a patient and after touching the patient's environment) showed that the average values of compliance behavior were only 56.66% and 48.66%. The habit of the respondents, who often hold their cell phones before the swab, also affects the number of bacterial colonies. The more frequent use of cell phones will increase the number of bacterial colonization (Hagel et al., 2019). Another analysis that might result in no relationship between hand hygiene behavior and coloni-zation is related to hand hygiene measures. Besides being done at the right time, hand hygiene measures must also be done with the right steps. Doing hand hygiene with the proper techniques and materials will make hands free of potentially harmful contaminants and lower the risk of contaminating objects or other people (World Health Organization, 2009). Savolainen-Kopra et al. (2012) reported that washing hands with the correct techniques and materials would reduce the risk of contamination by 6.7%. Also, hands that are not dried or are not completely dry when finished washing their hands will increase the amount of bacterial contamination. Transmission of bacteria is more likely to occur from wet hands than dry hands (Huang et al., 2012). Generally, the number of bacteria on the palms is very large, namely 3.9x104 – 4.6x106 CFU/cm2 (Siegel et al., 2007), so it is possible to transfer to objects are touched by the hands. After washing hands, some bacteria on the palms remain (Pittet et al., 2009). Widodo et al. (2017) reported remain-ing around 55.2 CFU ml of bacteria after washing hands. Hand hygiene measures are more effective if the hands' skin is free from wounds and has natural nails cut short so that no bacteria will remain between the nails, which will reduce transmission (Pittet et al., 2009). The fingers and hands are the parts that most frequently touch the cell phone when in use, so it is essential to perform hand hygiene to prevent transmission of the bacteria. Staphylococcus spp. or Staphylococcus aureus is normal in humans, especially in the nasal and skin areas (Taylor & Unakal, 2018). One of the factors that can cause the spread of pathogens is hand contact, so hand hygiene is crucial. Therefore, it is advisable to keep washing hands even though they are not in contact with the phone or contact the patient (Lin et al., 2017). Besides, various other factors, such as the use of cover for mobile phones, can affect the colonization of bacteria on cell phones. The use of plastic as a wrapper for cell phones can reduce bacteria's growth by as much as 4.2 times (Manning et al., 2013). The use of cell phones together with colleagues can also affect contamination from bacteria, and it would be better if cell phones were not carried when conducting actions on patients (Bhoonderowa et al., 2014). Based on the results of this study, hospital management can improve nurses' understanding related to infection control, namely by socializing about the use of gloves as indicated, hand hygiene, and limited use of cell phones to prevent cross-transmission. This research can be used as a basis for carrying out nursing practice and a reason for routine hand washing before and after using cell phones. The findings of this study also increase understanding about indications of glove use and regular cleaning of cell phones with a cleaning period. The limitation of this study is that there was no examination of bacteria before the observation was carried out. So, it could not show whether there was a decrease or increase in bacterial colonization on cell phones due to hand hygiene. The colonization data were also taken immediately after three random observations, so the relationship of hand hygiene behavior might not be described accurately. Conclusion Nurses' hand hygiene behaviors at the intensive care unit were still low and could contribute to the colonization of Staphylococcus aureus on their cell phones. However, the results showed no relationship between the hand hygiene behavior and the colonization of Staphylococcus aureus on the cell phones of nurses. Further research is recommended to identify colonization before and after regular observations to determine whether there is any increase or decrease in colonization. Similar studies are also advised to conduct with larger sample size. Acknowledgment The researchers acknowledged the respondents, UGM Academic Hospital, and all those who contributed to this study. Declaration of Conflicting Interest The authors have no conflict of interest to declare. Funding None. Author Contributions All authors contributed to the research concept. M.A. was in charge of developing the research proposal, performing data collection, data management and analysis, and drafting the manuscript. Y.I.P. performing data collection, while K.A., I.R., H.N., and H, supervised the proposal development, and provide critical revisions and complete the text. All authors approved the final version of the article. Author Biographies Meri Afridayani, S.Kep., Ns is a Postgraduate Student of the Master Program in Nursing. Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Yohana Ika Prastiwi, S.Kep., Ns is a Postgraduate Student of the Master Program in Nursing. Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Khudazi Aulawi, BSN, MNSc, Ph.D is a Head of Department of Medical Surgical Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Dr. Ibrahim Rahmat, S.Kp., S.Pd., M.Kes is a Head of Department of Mental and Community Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Dr. dr. Hera Nirwati, M.Kes, Sp.MK is an Associate Professor of Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Haryani, S.Kp., M.Kes., Ph.D is an Assistant Professor of Department of Medical Surgical Nursing, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Data Availability Statement All data generated or analyzed during this study are included in this published article. ==== Refs References Agency for Healthcare Research and Quality. (2019). AHRQ's Healthcare-Associated Infections Program. Retrieved from https://www.ahrq.gov/hai/index.html Bhoonderowa, A., Gookool, S., & Biranjia-Hurdoyal, S. D. (2014). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-100 10.33546/bnj.2476 Original Research Effectiveness of neurobic exercise program on memory performance in community-dwelling older adults with mild cognitive impairment: A randomized controlled crossover trial https://orcid.org/0000-0001-5672-9704 Sanghuachang Wiyakarn 1 https://orcid.org/0000-0002-7078-4037 Hengudomsub Pornpat 1* https://orcid.org/0000-0002-4336-8572 Chaimongkol Nujjaree 1 https://orcid.org/0000-0002-8893-059X Kotchabhakdi Naiphinich 2 1 Faculty of Nursing, Burapha University, Chon Buri, Thailand 2 Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand * Corresponding author: Pornpat Hengudomsub, PhD, Department of Mental Health and Psychiatric Nursing, Faculty of Nursing, Burapha University, 169 Long-Hard Bangsaen Road, Amphur Muang, Chon Buri, 20131, Thailand. Email: pornpath@buu.ac.th Cite this article as: Sanghuachang, W., Hengudomsub, P., Chaimongkol, N., & Kotchabhakdi, N. (2023). Effectiveness of neurobic exercise program on memory performance in community-dwelling older adults with mild cognitive impairment: A randomized controlled crossover trial. Belitung Nursing Journal, 9(2), 100-109. https://doi.org/10.33546/bnj.2476 18 4 2023 2023 9 2 100109 08 12 2022 07 1 2023 23 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Mild cognitive impairment (MCI) is an early stage of cognitive decline in individuals who are still able to perform their activities of daily living. They are at increased risk of developing dementia. Improving and maintaining cognitive functions are essential goals for older people with MCI to delay or prevent the transition to dementia. Objective This study investigated the effect of the neurobic exercise program on memory performance among community-dwelling older adults with MCI. Methods A single-blind, randomized, controlled, two-period crossover design was used. Thirty-two older adults who met the study criteria were randomly assigned to one of two sequence groups, A (n =16) and B (n = 16). Group A received three weeks of neurobic exercise, followed by a three-week washout period, and then three weeks of the traditional brain exercise program. Group B received the treatments in the reverse order but otherwise in a similar manner. Two aspects of memory performance were evaluated: subjective memory and objective memory. Blinded evaluators measured the outcomes four times at baseline, post-intervention (week 3), follow-up stage (week 7), and the end of the study (week 9). Descriptive statistics, independent t-tests, and repeated measures ANOVA were employed for data analyses. Results For subjective memory, rmANOVA revealed a significant difference of within-subject (F1.437, 43.113 = 9.324, p <0.05) and interaction effect (time*group) (F1.437, 43.113 = 12.313, p <0.05) and also showed significant differences of within-subject (F1.794,53.811 = 28.931, p < .05) and interaction effect (time*group) (F1.794, 53.811 = 31.190, p <0.05) for objective memory. The study results revealed that the participants in both groups had significantly lower mean scores on the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), indicating better or improved subjective memory. They also had significantly higher mean scores on the Common Objects Memory Test (COMT) after receiving the neurobic exercise program, indicating improvement in cognitive performance. Conclusion The neurobic exercise intervention could improve subjective and objective memory among community-dwelling older adults with MCI more than those who received the traditional brain exercise program. Therefore, the neurobic exercise program can be used by nurses and multidisciplinary teams to enhance memory performance among older adults with MCI. Trial registration Thai Clinical Trials Registry (TCTR) 20210326003. crossover trial mild cognitive impairment neurobic exercise older adults single-blind method brain National Research Council of ThailandD002/2564 ==== Body pmcBackground The term “Mild Cognitive Impairment: MCI” is used to describe older people with demonstrable cognitive impairment who have not crossed the threshold for dementia (Lopez, 2013). It is characterized by a minor but observable decline in cognitive function and is considered a symptomatic stage before dementia (Zhang et al., 2016). Among older adults, MCI increases the risk of dementia, especially Alzheimer’s disease. In the US, it is an estimated 12% to 18% of people age 60 or older have MCI (Alzheimer's Association, 2022). In Thailand, approximately 71.4% of older people have been diagnosed with MCI (Griffiths et al., 2020). Also, dementia in older people will rise from 1.1 million in 2030 to 2.0 million by 2050 (Leethong-In et al., 2019). Dementia significantly impacts older adults, their families, and carers. It also challenges health professionals throughout the pathway of care. The alternative strategy for reducing the prevalence of dementia is to slow down its onset in older adults at risk for progression to dementia. While there is no exact cure for MCI and dementia nowadays, it is possible to slow down or prevent the progression from MCI to dementia. Evidence shows the potential benefit of cognitive intervention in older adults. The neurobic exercise concept was postulated by Katz and Rubin (1999). It is a form of brain exercise designed to help keep the brain healthy and active. This exercise is distinct from other types of brain exercises. It involves non-routine or unexpected experiences using various combinations of the five physical and emotional senses. Neurobic exercise help improves nerve impulses and the linkage between various brain data. Moreover, this exercise help stimulates neurons to produce neurotrophins that have chemical effects on nerve cell growth, improve nerve fiber branch and reduce nerve cell degeneration. As a result, neurobic exercise can stimulate other parts of the brain, help prevent the decline in memory performance, and maintain a continuing level of memory performance (Katz & Rubin, 1999). Previous studies have explored the potential benefit of neurobic exercise. Patani (2020) conducted a randomized clinical trial (RCT) among patients with stroke (N = 40). Participants in the neurobic exercise group had significantly improved cognitive function and quality of life four weeks after completing the intervention than the control group. In another randomized controlled trial with older adults undergoing major, noncardiac, non-neurological surgery (N = 268), after receiving the neurobic exercise intervention, patients showed a decreased incidence of delirium than the controls at seven days post-operation (Humeidan et al., 2021). In addition, in a non-randomized two-group posttest design among older adults with comorbidities (N = 60), the result showed that one month after the intervention, participants in the neurobic exercise group had lower depression scores than the control group (Raj et al., 2020). The evidence showed that nurses play a significant role in delivering such programs or activities for seniors with a wide range of cognitive declines, such as MCI and dementia (Tanglakmankhong, 2021). In Thailand, a few studies have been conducted on neurobic exercise with older persons during hospital admission and in the community. Kanthamalee and Sripankaew (2014) performed a single-group posttest design testing the effects of neurobic exercise with 22 female dementia patients. The results demonstrated memory improvement one month after the neurobic exercise intervention was completed. Nevertheless, this study did not include a control group and was limited to female participants and one cognitive function domain. The effects of a neurobic exercise program were examined by Napatpittayatorn et al. (2019) in 55 older persons with normal to MCI. The findings demonstrated that, at six months after the intervention’s completion, participants in the neurobic exercise group had better cognitive performance and serum Brain-Derived Neurotrophic Factor (BDNF) levels than those in the control group. Kansri et al. (2018) investigated the effects of neurobic exercise on depressive symptoms in 60 older persons with MCI. The finding shows that neurobic exercise programs significantly reduced depression among community-dwelling older persons with MCI. Kriengkaisakda and Chadcham (2012) developed a brain training program based on the neurobic exercise theory to target the short-term memory of patients with mild dementia (N = 34). The result indicated that the brain training program could improve short-term memory among these patients. Wongkhamchai and Pantong (2017) examined the efficiency of the neurobic exercise program in 120 patients with type 2 diabetes mellitus using a non-randomized two-group posttest methodology. The result showed that the experimental groups’ scores on short-term memory were significantly higher after training than the control groups at three months follow-ups. The results of all studies showed that memory performance in the elderly with MCI could be improved by neurobic exercise. However, rather than older adults with MCI, most previous research focused on healthy aging, the elderly with dementia, and older adults with chronic illnesses (Kanthamalee & Sripankaew, 2014; Kriengkaisakda & Chadcham, 2012; Wongkhamchai & Pantong, 2017). In addition, the activities focused on health education and only used each physical sense to stimulate the brain (Kansri et al., 2018; Kanthamalee & Sripankaew, 2014). Therefore, it could be illustrated that the literature on nursing interventions aimed at improving health outcomes in older adults, especially those with MCI, is limited and has methodological limitations. Another type of brain training, such as traditional brain exercise performed in the senior club affiliated with Saraburi Hospital in Thailand, was used to prevent or slow the progression of dementia among these members. The traditional brain exercise was a practice-based program derived from expert panels as a part of health promotion to prevent or slow the progression of dementia among older adults. Traditional brain exercise focuses on simple brain exercise and social activities. However, traditional brain exercise has certain limitations because the program has not been empirically verified to be effective and enhance the health outcomes of older adults with MCI. Therefore, the randomized, controlled, two-period crossover design was employed to examine the effectiveness of the neurobic exercise intervention among older adults living in the community. Memory performance, both objective and subjective memory, served as this study’s outcomes. The study was conducted concerning the COVID restriction. In addition, the risk of confounding effects was minimized because all interventions were delivered and measured on the same participants, and every participant received both treatments. The participants serve as their control. This study’s results would benefit not only older adults with MCI but also those who care for them, such as their families, nurses, and other relevant healthcare providers. The purpose of this study was to determine the effect of a neurobic exercise program on memory performance among older adults with MCI residing in the community. The specific aims of this study were: 1) To compare the mean differences of subjective and objective memory between the experimental and control groups and 2) To compare the mean differences of subjective and objective memory within the experimental and the control group. Methods Study Design This study employed a randomized controlled trial with a two-period crossover design (two 3-week intervention phases separated by a 3-week washout period). The study was conducted from June 2021 to November 2021. Group A (n = 16) received the neurobic exercise program for three weeks, followed by a three-week washout period, and then the traditional brain exercise program for three weeks. Group B (n = 16) received the treatments in the reverse order but otherwise in a similar manner (Figure 1). This study had three research assistants (RAs), including two research assistants who conducted the screenings and collected the outcome data (RA1-2), and another RA3 was running the traditional brain exercise program. Two Ras (RA1-2) who are registered nurses with at least two years of experience in geriatric care were selected from Saraburi Hospital. The researcher trained two Ras (RA1-2) to collect accurate and consistent data from both groups blindly by not knowing which group was the neurobic exercise program or the traditional brain exercise program. Another RA3, a registered nurse who works in the senior club, was trained to run the traditional brain exercise program. This study was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) checklist (Moher et al., 2010) (Figure 2). Figure 1 Research design Figure 2 Consort flow diagram showing the flow of participants through each stage of the randomized crossover trial Samples/Participants Older people were recruited from the senior club of Saraburi Hospital in Tambon Pak Phriao, Amphoe Muang of Saraburi province. Among 78 older adults were eligible to participate in this study. Among them, 13 participants did not meet the study inclusion criteria. Of these 78 older adults, 32 were randomly selected and consented to participate in this study. The inclusion criteria consisted of (1) males and females aged 60 years or older, (2) scored <24 on the Montreal Cognitive Assessment (MoCA), (3) scored >12 on the Modified Barthel ADL index (BAI), (4) have a Body Mass Index (BMI) score in the range 18.49-34.9 kg/m2, (5) no history of psychiatric disorders or neurological conditions; no hearing or visual impairment as diagnosed by a physician, (6) ability to write and read as well as communicate well, (7) willingness to participate in the study throughout the program. The exclusion criteria consisted of (1) severe complications or serious neurological or musculoskeletal conditions, (2) serious conditions from comorbidity that made the participant unable to participate in the intervention, and (3) older adults with a history of allergies to the food or flowers used in the activities. In this study, the G* Power analysis was used to calculate the sample size, with a power of 0.08, α = 0.05, and an effect size of 0.50, according to Napatpittayatorn et al. (2019). The results indicated that the study needed 24 participants. In order to adjust for any participants dropping out or data attrition, an additional 30 percent was added to the sample size for a total of 32 subjects in total. These 32 older adults were randomly assigned into groups A or B, n = 16 for each group, through drawing lots (Figure 2). Instruments Three instruments were used in this study. First, the demographic variables include age, gender, marital and living status, education level, occupation, and underlying diseases. Second, the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), translated into Thai by Senanarong et al. (2001), was used to measure subjective memory. This test measures the informant’s perception of the older person’s cognitive decline. Older adults are required to compare their performance today with their performance ten years ago. Informants were asked to indicate the change on a 16 items scale from 1 (much improved) to 5 (much worse). The cut-off scores were based on the total score divided by the number of questions (average item score range 1- 5). Lower scores indicated better subjective memory performance (1) A score below 3.00 indicates improvement, (2) 3.00 indicates no change, (3) 3.01 – 3.50 indicates a slight decline; (4) 3.51-4.00 indicates moderate decline; and (5) 4.01 – 5.00 indicates severe decline. The Cronbach’s alpha reliability score of IQCODE for this sample was 0.94. Third, a standardized Common Objects Memory Test (COMT) was used to measure objective memory. The COMT was designed to assess age-related memory impairments in individuals with various educational, language, and cultural backgrounds. The author and a bi-lingual researcher translated the COMT manual instructions into Thai using a translation and back-translation method (Brislin et al., 1973). The translation achieved 100% inter-rater agreement. The COMT (Thai version) was tested with five older adults to ensure familiarity with the common objects and the distracters. The total COMT scores were summed across these three steps, and the possible range was 0-90. Higher scores indicated better objective memory performance. The Cronbach’s alpha of the instrument was 0.80. Interventions Neurobic exercise program The researcher developed the neurobic exercise intervention by integrating the neurobic exercise concept (Katz & Rubin, 1999) and previous evidence-based research (Kanthamalee & Sripankaew, 2014; Napatpittayatorn et al., 2019). The content, process, and arrangement of the neurobic exercise program were validated by five experts in neurological and geriatric care. Further, the researcher tested the neurobic exercise intervention with 20 older adults for its feasibility and acceptability. The pilot study results showed the neurobic exercise intervention was feasible and acceptable among these older adults. The neurobic exercise program utilized diverse combinations of physical and emotional senses. The neurobic exercise program consisted of six sessions 1) Stimulation of visual sense through a tray game, 2) Stimulation of smell sense through the use of natural aroma, 3) Stimulation of hearing sense through listening and identifying nature sounds, 4) Stimulation of the sense of touch through the writing and guessing game and a puzzle box game, 5) Stimulation of taste sense by tasting fruit, food, and desserts, and 6) Integration of multi-senses stimulation; Application in daily usage. The researcher conducted the intervention twice a week for three consecutive weeks. Each session lasted approximately 60 minutes. The activities were done in a group to stimulate the participants’ brains and help them enjoy spending time with others. Additionally, five homework assignments were given that involved simple brain stimulation activities to activate the participant’s brains when they were on their own. Specifically, participants were trained to practice various activities beyond the daily routine. For example, changing the directions in going out and back home, or going to specific places such as temples, markets, etc., touching the differently shaped objects in their houses while closing their eyes and creating new cooking menus by listing all ingredients and calculating the cost. Traditional brain exercise program The traditional brain exercise program was a practice-based program derived from expert panels as a part of health promotion activities in preventing or slowing the progression of dementia among older people. It was implemented in the senior clubs affiliated with Saraburi Hospital in Thailand. Activities based on scientific evidence were employed to improve the cognitive function of older adults. The activities were conducted in small groups, approximately 3-4 persons per group, and focused on brain stimulation. This program consisted of six 60-minute sessions conducted twice weekly for three weeks. The activity schedule was the same period as the neurobic exercise program. The activities consisted of 1) Psychoeducation, “brain exercise to prevent dementia for the elderly”, 2) Drawing and coloring, 3) Paper folding, 4) Singing a song, 5) Photo hunting, and 6) Calculation games. Data Collection Two research assistants (RA1-2) collected data from all older adults with MCI in both groups four times at baseline, post-intervention (week 3), follow-up stage (week 7), and the end of the study (week 9). During the intervention and data collection process, no unintentional harm or program-related negative effects were found among the participants. Data Analysis All statistical analyses were conducted using IBM SPSS version 26.0. Descriptive statistics were used to describe the characteristics of the participants. Chi-square, Fisher’s exact test, and independent t-test were used to examine the differences in demographic characteristics between these two groups. Repeated measures ANOVA was used to compare the differences in mean scores of the outcomes between the two groups and within the group across the four measured periods. Ethical Considerations Ethical approval was obtained from the Research Ethics Committee of Burapha University (IRB3-011/2564) and the Ethical Committee of Saraburi Hospital (EC002/2564), the date of approval Jan 26, 2021. Each participant willingly signed a consent form after learning about the goal of the study, the processes involved, and their rights to confidentiality and withdrawal autonomy. Permission to use the instruments was granted by the original authors before data collection. Results Characteristics of the Participants The baseline demographic characteristics of the sample are presented in Table 1. There was no statistical significance between groups A and B in demographics at baseline. The mean MoCA score was 21.13 (SD = 2.01, range 16-23), the mean ADL score was 19.91 (SD = 0.29, range 19-20), and the mean BMI was 24.56 (SD= 3.61, range 16.01-34.52). The mean age of the participants was 67.53 years (SD = 4.43, range 60-78), 93.8% (n = 30) were female, 46.9 % (n = 15) were married, and 87.5% (n = 28) lived with family members at home. Of the 32 participants, 87.5% (n = 28) had primary education. 81.3% (n = 26) reported having other chronic illness conditions, including hypertension 68.8% (n = 22), dyslipidemia 46.9% (n = 15), diabetes 21.9% (n = 7), and heart disease 3.1% (n = 1) whereas 43.75% (n = 14) reported more than one condition. Table 1 Baseline demographic data of older adults with MCI Characteristics Group A (n = 16) Group B (n = 16) t/ X2/F p-value n % n % Age Range 60-74 60-78 -0.671a 0.507 Mean (SD) 67(3.46) 68.06 (5.29) Sex Male 1 6.3 1 6.3 0.000b 0.999 Female 15 93.8 15 93.8 Marriage status Single 3 18.8 4 25.0 0.210c 0.901 Married 8 50.0 7 43.8 Divorced/widowed 5 31.3 5 31.3 Living status Living alone 2 12.5 2 12.5 0.000b 0.999 Living with other 14 87.5 14 87.5 Education level Less than high school 14 87.5 14 87.5 0.000b 0.999 Completed high school 2 12.5 2 12.5 Occupation Not working 10 62.5 12 75.0 2.186b 0.624 Working 6 37.5 4 25.0 Income (Thai Baht/month) Range 600-10,000 600-10,000 -0.417a 0.679 Mean (SD) 1393.75 (2320.47) 1737.50 (2338.91) Chronic illness No 3 18.8 3 18.8 0.000b 0.999 Yes 13 81.3 13 81.3 a = t-test, b = Fisher’s exact test, c = Chi-square Crossover Analysis Identifying carryover effects between the two study periods was the primary objective of the analysis. The statistical analysis found no carryover effects for either outcome (IQCODE, p = 0.219 and COMT, p = 0.139). It demonstrated that there were no carryover effects and that the washout phase of three weeks was sufficient. After that, significant differences between the intervention effects of neurobic exercise and traditional brain exercise programs were evaluated. Subjective memory We performed repeated measures ANOVA to demonstrate differences between both groups. For subjective memory (IQCODE), rmANOVA revealed a significant difference of within-subject (F1.437, 43.113 = 9.324, p <0.05) and interaction effect (time*group) (F1.437, 43.113 = 12.313, p <0.05). The comparisons of mean scores measured at different time points found non-significant differences between subjects (F1,30 = 0.023, p >0.05). Then, a post hoc t-test was conducted. For this test, the significance level was adjusted by dividing it by the number of comparisons (0.05/4 (times of comparisons) = 0.0125; Bonferroni correction). Results showed a significant difference in week 9 between the two groups (p <0.0125). Details are presented in Figure 3. Figure 3 Comparisons of subjective memory (IQCODE) between groups at each time For within the group, when comparing each pair of times for Group A, pairwise comparisons of the mean differences of IQCODE revealed significant differences at baseline and week 3 (p <0.05). After a washout period, there were no significant differences in week 7 and week 9 (p >0.05). In group B, the mean differences of IQCODE revealed significant differences at baseline and week 3 (p <0.05). After a washout period, there were significant differences at week 7 and week 9 (p <0.05). Details are presented in Figure 4. Figure 4 Pairwise comparisons of mean differences of IQCODE in each group Objective memory For objective memory (COMT), rmANOVA revealed significant differences of within-subject (F1.794,53.811 = 28.931, p <0.05) and interaction effect (time*group) (F1.794, 53.811 = 31.190, p <0.05). The comparisons of mean scores measured at different time points found no significant difference between subjects (F1,30 = .518, p >0.05). Post hoc t-test showed a significant difference in week 3 between the two groups (p <0.0125). Details are presented in Figure 5. Figure 5 Comparisons of objective memory (COMT) between groups at each time In group A, when comparing each pair of times, pairwise comparisons of the mean differences of COMT revealed significant differences at baseline and week 3 (p <0.05). However, there were no significant differences in week 7 and week 9 (p >0.05) after a washout period. In group B, the mean differences of COMT showed no significant difference at baseline and week 3 (p >0.05). However, there were significant differences in COMT scores at 7 and week 9 (p <0.05). Details are presented in Figure 6. Figure 6 Pairwise comparisons of mean differences of IQCODE in each group Discussion This study aimed to evaluate the effects of a neurobic exercise program on memory performance in older individuals with MCI. We found that participants who received the neurobic exercise program had lower mean scores of the IQCODE and higher mean scores of the COMT than those in the traditional brain exercise program at post-intervention (week 3) and at the end of the study (week 9). Based on the neurobic exercise concepts proposed by Katz and Rubin (1999) and relevant research, these results could be explained by the fact that the neurobic exercise program was designed to enhance memory performance, both subjective and objective memory, in older adults with MCI. The researcher developed the neurobic exercise program by applying the fundamental components of neurobic exercise to strengthen and enhance the memory performance of the participants. In each session, the fundamental components and techniques of neurobic exercise were utilized to stimulate the brain. If the brain is stimulated by using a variety of physical sense combinations and deviates from a usual activity, the nerve impulses and connections between different neurons in the brain assist the brain in having a steady level of mental fitness, strength, and flexibility (Katz & Rubin, 1999; Scotts, 2013). Neurobic exercise stimulates neurons to secrete neurotrophins, which have a pharmacological effect on nerve cell proliferation, nerve fiber branching growth, and inhibition of nerve cell degeneration (Napatpittayatorn et al., 2019). In addition, Brain-derived neurotrophic factor (BDNF) is a part of neurotrophic factors. BDNF is found all over the brain, predominantly in the brain areas of the hippocampus, basal forebrain, and prefrontal cortex. These areas are essential for human learning, memory, and other cognitive functions. The BDNF is advantageous for both long-term memory and overall brain function. BDNF helps enhance memory storage and the number, size, and intricacy of dendritic spines (Miranda et al., 2019). BDNF levels are increased by physical activity, maintaining a healthy weight, and leading a mentally and socially engaged, but not unduly stressful, lifestyle. Evidence also demonstrated that neurobic exercise is an alternative method for increasing BDNF levels (Gao et al., 2022). Moreover, the current study shows that the neurobic exercise intervention can increase BDNF levels in older adults, indicating improved brain function (Napatpittayatorn et al., 2019). According to neurobic exercise, trying to do new things and breaking a routine activity would help strengthen nerve cell stimulation, whereas routine activities use the same brain pathways that could be brain deadening (Napatpittayatorn et al., 2019; Raj et al., 2020). Doing new things or having unexpected experiences help stimulate the production of neurotrophins, which chemically affect the growth of nerve cells and nerve fiber branches, reduce the degeneration of nerve cells, and increase blood flow to the brain. Moreover, emotional sensation stimulates the diencephalon, particularly the hypothalamus, which regulates emotion and encodes memory by laying down memory attention. Emotional sensation also stimulates the limbic system, contributing to memory formation by linking emotional states with memories of physical sensations (Kanthamalee & Sripankaew, 2014; Katz & Rubin, 1999). These results were consistent with previous research studies that showed neurobic exercise effectively enhanced memory function in the elders. In a study conducted by Kriengkaisakda and Chadcham (2012), patients with mild dementia who completed a neurobic exercise program significantly improved their short-term memory three months after completing the program. One month after completing the neurobic exercise intervention, Kanthamalee and Sripankaew (2014) found an improvement in memory among 22 females with dementia, as measured by the Mini-Mental State Examination (MMSE) score. At a 3-month follow-up, (Wongkhamchai & Pantong, 2017) found that patients with type 2 diabetes mellitus in the neurobic exercise intervention group had significantly enhanced short-term memory scores compared to the control group. According to Napatpittayatorn et al. (2019), the participants in the neurobic exercise intervention group showed significant improvement regarding cognitive function and serum brain-derived neurotrophic factor (BDNF) six months after completing the intervention completion than those in the control group. Moreover, Patani (2020) discovered that four weeks after completion of the neurobic exercise intervention, patients had significantly better cognitive function and quality of life than the controls. Therefore, previous research supports our findings that a neurobic exercise program can improve both subjective and objective memory in older adults with MCI. However, the results showed that objective memory (COMT) score slightly decreased in the washout period when the participants did not continue the activities to stimulate their brains. Therefore, promoting continuous activities by the older adults themselves to stimulate the brain should be conducted. The evidence showed that if the brain is being used continuously and appropriately stimulated, the brain will improve even with advanced age (Patani, 2020). This study differs from previous neurobic exercise studies, including activities that stimulate the brain through several senses. The activities presented the brain with non-routine or changed daily activities. These activities can enhance the memory retention of older people and delay the deterioration of the brain. This intervention utilized the five senses and added the emotional sense to each activity. The participants were also encouraged to perform non-routine daily activities. This help promotes continuous growth and strength of the nerve cells. The activities were conducted in small groups and the form of games. Some activities include competitions to encourage teamwork and physical activity among participants. Combining the emotional sense with the five senses will stimulate the hypothalamus, which regulates emotion and encodes memory. It also helps stimulate the limbic system, which contributes to memory formation by integrating the emotional states with stored memories of physical sensations (Kanthamalee & Sripankaew, 2014). Moreover, combining two or more senses could promote the operation of the memory-related regions of the brain, such as the frontal, parietal, temporal, occipital, diencephalon, and limbic systems. As a result, the function of the neural network, which is responsible for both short-term and long-term memory, is enhanced. At the end of the program, participants in both groups were asked to complete a seven-item Likert-type questionnaire to measure their level of satisfaction with the neurobic exercise and traditional brain training programs. The mean satisfaction scores for the neurobic and traditional brain exercise programs were 34.63 (SD = 0.50) and 33.94 (SD = 1.61), respectively. There were no statistically significant differences in satisfaction between the neurobic and traditional brain exercise programs (p >0.05). In response to open-ended questions, participants reported that all neurobic exercise program activities were appropriate for their age and health conditions. The program activities were beneficial and suited to their needs. Moreover, participants appreciated the neurobic exercise program because it is simple to practice independently and does not require any specialized equipment to activate the brain. Limitations of the Study This study was was only conducted at one senior club under the Saraburi Regional Hospital. These older adults at the senior club were more likely to be active and learn new things. In addition, this study was conducted from June 2021 to November 2021 due to the COVID restrictions. Thus, only participants with complete vaccinations were enrolled. Implications to Practice and Recommendations The results obtained from this study showed promising positive outcomes and benefits of neurobic exercise for community-dwelling older adults with MCI. For further research, it is recommended to examine the sustainable effects of the neurobic exercise intervention among older adults with MCI. Testing the long-term effects of increased memory function on life satisfaction, quality of life, healthy living, fall incidents, and hospitalization or emergency department visits are also recommended. In addition, future studies should investigate the neurobic exercise program in other settings and the impact of neurobic exercise on other cognitions apart from memory. Testing improvement in brain function, such as brain waves and images, is recommended if possible. Also, this neurobic exercise program provides recommendations and practices for older adults residing in the community. Early brain stimulation, such as neurobic exercise, may benefit older persons with early signs of MCI. In addition, involving family members or other members of the community in the game-based brain exercise could also help older adults keep enjoying and doing such activities. Conclusion The neurobic exercise program is a new alternative nursing intervention approach, which was found to be effective in enhancing significant memory performance among older adults with MCI who are living in the community. Applying available Thai herbs, aromas, and foods to stimulate the brain was useful. Moreover, the neurobic exercise program is easy for older adults to use to stimulate their brains. It can also help older people make small changes in daily life, transforming routines into mind-building exercises. The neurobic exercise program was found to be effective in reducing or delaying subjective memory decline and improving objective memory in community-dwelling older people with MCI. In addition, neurobic exercise requires no need to find a special time or place to do it because everyday life is a neurobic exercise. The development of the care system for promoting cognitive functions among community-dwelling older persons with MCI should be conducted. Nurses and multidisciplinary teams are recommended to employ the neurobic exercise program alongside other activities to enhance cognitive function among older adults with MCI. Acknowledgment This research and innovation activity were funded by the National Research Council of Thailand (NRCT). We appreciated the older adults who participated in this study. Declaration of Conflicting Interest The authors declared no potential conflicts of interest concerning the research, authorship, publication, and publication of this article. Authors’ Contributions WS and PH conceived the outline, wrote the introduction, literature review, method, procedure, data analysis, and conclusion, and reviewed the whole paper for cohesiveness. All other authors (NC and NK) contributed to the critical analysis of the content. Finally, all authors approved the final version to be published. Authors’ Biographies Wiyakarn Sanghuachang has a master’s degree in gerontology nursing from Chulalongkorn University, Thailand. She is currently a PhD Candidate in Nursing Science (International Program) at Burapha University, Thailand. Her research focuses on improving the quality of life of older adults with dementia and their families in rural communities. Pornpat Hengudomsub is an Associate Professor at the Department of Mental Health and Psychiatric Nursing at Burapha University, Thailand. She specializes in health psychology and aging. Nujjaree Chaimongkol is an Associate Professor at the Department of Pediatric Nursing at Burapha University. She is currently a Dean of the Graduate School of Burapha University, Thailand. Her research fields include health promotion, prevention, and Thailand’s health care system. Naiphinich Kotchabhakdi is an Associate Professor at Research Center for Neuroscience, the Institute of Molecular Biosciences, Mahidol University, Thailand. He is an expert in Neuroscience. Data Availability The datasets generated during or analyzed during the current study are not publicly available due to the subject confidential information but are available from the corresponding author on reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Alzheimer's Association. (2022). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-062 10.33546/bnj.2434 Original Research Relationships between illness perception, functional status, social support, and self-care behavior among Thai people at high risk of stroke: A cross-sectional study https://orcid.org/0000-0002-3892-3180 Maninet Surachai 1* Desaravinid Chalermchai 2 1 Faculty of Nursing Ubon Ratchathani University, Thailand 2 Medical Service Department, Bua Yai Hospital, Nakhonratchasima Health Provincial Office, Thailand * Corresponding author: Surachai Maninet, RN, PhD, Faculty of Nursing, Ubon Ratchathani University, 85 Sathon Mark Road, Mueang Sikai Subdistrict Warin Chamrap District Ubon Ratchathani Province, 34190, Thailand. Email: surachaimaninet@gmail.com Cite this article as: Maninet, S., & Desaravinid, C. (2023). Relationships between illness perception, functional status, social support, and self-care behavior among Thai people at high risk of stroke: A cross-sectional study. Belitung Nursing Journal, 9(1), 62-68. https://doi.org/10.33546/bnj.2434 12 2 2023 2023 9 1 6268 13 11 2022 13 12 2022 01 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background People at high risk of stroke reported having difficulty performing self-care behavior. Although the literature has identified various factors related to self-care behavior in this population; however, there is a lack of studies to conclude the associated antecedents of self-care behavior, particularly in Thailand. Objective This study aimed to examine the relationships between illness perception, functional status, social support, and self-care behavior among people at high risk of stroke. Methods A correlational cross-sectional study design was used. One hundred and seventy people at high risk of stroke were selected from ten health-promoting hospitals in the Northeast region of Thailand using multi-stage sampling. Data were gathered using self-report questionnaires, including the brief illness perception questionnaire, functional status scale, multidimensional scale of perceived social support, and self-care behavior questionnaire, from November 2021 to February 2022. Data were analyzed using mean, standard deviation, and Pearson’s product-moment correlation. Results One hundred percent of the participants completed the questionnaires. The participants had a moderate level of self-care behavior (M = 64.54, SD = 7.46). Social support and functional status had medium positive significant correlations with self-care behavior among people at high risk of stroke (r = 0.460 and r = 0.304, p <0.01), respectively. In contrast, illness perception had a small negative significant correlation with self-care behavior among people at high risk of stroke (r = -0.179, p <0.05). Conclusion Social support, functional status, and illness perception are essential factors of self-care behavior among people at high risk of stroke. The findings shed light that nurses and other healthcare professionals should promote self-care behavior in these people by enhancing them to maintain proper functioning, positive illness-related perception, and family members' involvement. However, further study is needed to determine a causal relationship between these factors with self-care behavior. functional status illness perception people at high risk of stroke social support self-care behavior Thailand ==== Body pmcBackground Globally, stroke is one of the serious chronic diseases that cause significant health burdens (Bhagavathy et al., 2022), and it is currently the second cause of death (Feigin et al., 2021). In 2021, the stroke incidence was 12.20 million cases (Feigin et al., 2021), while in Asian countries, the prevalence of stroke is also high; Thailand reported the highest stroke prevalence that occurred in up to 75 percent of adults and older adults (Chantkran et al., 2021). However, stroke consequently impacts many aspects of the health system, including individuals with stroke, family members, and health services (Yang et al., 2021). People at high risk of stroke are an individual who suffers from many risk factors. In addition, various modifiable risk factors force individuals to be at a high risk of stroke. For example, people diagnosed with chronic diseases such as hypertension, dyslipidemia, heart disease, or diabetes mellitus have an increased risk for stroke (Feigin et al., 2021; Setyopranoto et al., 2019). Furthermore, lifestyle factors, including unhealthy diet consumption, physical inactivity, being overweight, and smoking cessation, can increase the prevalence rate of stroke (Harshfield et al., 2021). Thus, to prevent this disease, enhancing self-care behavior among these people at risk of stroke is recommended (Riegel et al., 2017). However, information regarding self-care behavior and its related factors is limited. Self-care behavior, for people at high risk of stroke, is defined as performance that individuals start and perform on their own to maintain well-being, such as consuming healthy food, taking prescribed medication, doing exercise, reducing stress, and reducing tobacco and alcohol consumption. These behaviors might help an individual to be physically and mentally free from illness and live happily in society (Riegel et al., 2017). Unfortunately, existing literature found that people at risk of stroke had difficulty maintaining self-care behavior (Riandini et al., 2018). For example, hypertensive patients consumed a high-salt diet and performed less exercise (Wiriyatanakorn et al., 2021). In addition, patients with diabetes mellitus had a low level of taking medication based on the prescription by the physician (Jannoo & Khan, 2019). Consequently, inadequate self-care behavior significantly reduces the quality of life and increases the cost of treatment (Bairami et al., 2017). Regarding the theory of self-care, Orem (2001) believed that individual initiates to perform health activities to maintain their well-being. There are several factors influencing individuals’ self-care behavior. Some studies have reported the potential facilitating and impediment factors correlated with self-care behavior in patients living with chronic disease. For the facilitating factors, Park and Kim (2019) noted that social support was associated with self-care behavior among patients with hypertension. In addition, functional status was correlated with self-care behavior among patients with diabetes (Riandini et al., 2018). For the impediment factors, a previous study found that a high level of negative illness perception was correlated to poor self-care behavior to control glycemic levels (Ngetich et al., 2022). These postulate that people at high risk of stroke with better self-care behavior might be supported by good social support, functional status, and a positive perception of their illness. However, to our knowledge, studies examining these factors in people at high risk of stroke are limited, especially in Thailand. Furthermore, no study examined these variables using the theory of self-care as the theoretical framework. These barriers might impede nurses and other healthcare providers from understanding and developing specific nursing interventions that support self-care behavior among this population. Therefore, the objective of this study was to examine the relationships between illness perception, functional status, social support, and self-care behavior among Thai people at high risk of stroke. The findings from this study can be utilized as empirical evidence for healthcare providers, including nurses, to support the guideline of enhancing self-care behavior among people at high risk of stroke. Furthermore, understanding the relationships among these variables will enhance the knowledge for developing an effective nursing intervention to maintain and improve self-care behavior for people at high risk of stroke. Methods Study Design A correlational cross-sectional design was employed in this study. Samples/Participants The inclusion criteria of the samples/participants were those: (a) having been diagnosed with diabetes mellitus, hypertension, hyperlipidemia, or heart diseases, (b) being a high risk of stroke screening by the Thai Cardio-Vascular (CV) Risk score (Division of Non-Communicable Disease, 2015) which scored ≥20%, (c) aged 30 and older, (d) understanding the Thai language, and (e) were able and willing to provide informed consent. In addition, participants with a history of stroke were excluded from this study. To calculate the sample size of this study, the power analysis technique recommended by Cohen (1988) was utilized through the G*Power version 3.19.2 (Faul et al., 2007). In addition, data from a previous study were used to calculate the sample size, including the statistically significant level as 0.05, the power of the test as 0.25, and the effect size as 0.25 (Saleema et al., 2016). Therefore, the minimum sample size required for correlational analysis was 164. In addition, to consider a 10% attrition rate, 170 participants were needed for the study. Generally, people at risk of stroke living in a community across Thailand were screened using the Thai CV Risk score (Division of Non-Communicable Disease, 2015). Therefore, selecting one province would provide samples from a broad geographical region of Thailand. In this study, multi-stage sampling was used, which can be described as follow: One region was randomly selected from the six-regions system. As a result, the Northeast region of Thailand was chosen. Of the 20 provinces in the Northeast region, one province was randomly selected, which was Nakhon Ratchasima. Thirty-two subdistricts remain in Nakhon Ratchasima province. Ten subdistricts were randomly selected. One health-promoting hospital was randomly selected from each selected subdistrict. Thus, ten health-promoting hospitals were chosen to collect the data. Due to each health-promoting hospital having a different number of samples, the probability proportional to the size sampling method was employed (Lemeshow et al., 1990). This method helped the researchers to recruit participants in each setting. Each participant was selected in accordance with the inclusion criteria. Instruments Six instruments were used in this study: Demographic data form The demographic information form was developed by researchers. This form comprised two parts: the first part was a self-administered questionnaire concerned with personal information, including gender, age, monthly income, marital status, education level, and occupation. The second part of this form was investigated by the researchers to assess diagnosis, duration of illness, and body mass index. The Thai Cardiovascular (CV) Risk score This instrument was developed by the Division of Non-Communicable Disease (2015) and used for stroke risk screening. It consists of eight items: age, gender, waistline, height, smoking status, diabetes mellitus, systolic blood pressure, and cholesterol. The levels of risk of stroke were identified as low (score <10%), moderate (score 10% - <20%, high (score 20% - <30%), very high (score 30% - <40%), and dangerous (score ≥40%). Its validation was found in a study by Jinatongthai et al. (2021). In our study, the reliability of this instrument was tested, and it found that Cronbach’s alpha coefficient was 1.00. Brief illness perception questionnaire This instrument was developed by Broadbent et al. (2006). The Thai language version of Thepphawan et al. (2011) was used in this study. Each item represents one component of this instrument, including 1) timeline, 2) personal control, 3) treatment control, 4) consequences, 5) concerns, 6) identity, 7) illness comprehension, and 8) emotions. A Likert scale (0 to 10) was used, and the total score was calculated by summing all eight items. Possible scores ranged from 0 to 100. The higher the illness perception score, the more likely the individual viewed their illness as a threatening event and impacted their health. The instrument’s reliability has been tested in a previous study (Maninet et al., 2021), with a Cronbach’s alpha value of 0.93. In the current study, Cronbach’s alpha coefficient was also examined, with a value of 0.84. Functional status scale The researchers developed this instrument to investigate the ability of each person to perform usual activities regarding physical activities, working and role activities, and psychological activities. This scale consists of 20 items using a Likert scale ranging from 1 (none of the time) to 4 (all of the time). The possible total scores on the scale ranged from 0-80. The functional status levels were divided into three categories, including low (score = 0-26), moderate (score = 27-54), and high (score = 55-80). For the validity testing, Exploratory Factor Analysis (EFA) was conducted with a Promax rotation using Statistical Package for the Social Science (SPSS) for Windows version 22. One hundred respondents with similar characteristics to the current study’s samples were invited to answer the questionnaire. As a result, this 20-item structure was found to explain 62.56 percent of the variance in the pattern of relationships among the items. For the reliability testing, Cronbach’s alpha coefficient of this instrument was 0.76. Multidimensional scale of perceived social support This instrument was developed by Zimet et al. (1990) and is available in the Thai version translated by Wongpakaran et al. (2011). This instrument has three components, including family members (3 items), friends (3 items), and significant others (3 items). These 12 items were rated on a 7-point scale ranging from 1 (totally disagree) to 7 (totally agree). The possible total scores on the scale ranged from 12-84. For the interpretation of the total score, the higher scores on social support indicated a greater perception that individuals have received support from others. A previous study reported good reliability of this instrument (Maninet et al., 2021). In the current study, Cronbach’s alpha coefficient was 0.90. Self-care behavior scale This instrument was developed by the researchers to assess individual’ activities regarding stroke prevention. It consists of 25 items which separate into five dimensions, including performing exercise, consuming alcohol and tobacco, consuming healthy food, declining stress, and taking medications based on prescription. A Likert scale was used from 1 to 4. The possible scores ranged from 25-100. The levels of self-care behavior are divided into three categories: low (score = 25-50), moderate (score = 51-75), and high (score = 76-100). EFA was conducted to measure construct validity with a Promax rotation using SPSS version 22 for Windows. One hundred respondents who had similar characteristics to the samples in this study were included. The results showed that this 25-item structure was found to explain 68.72 percent of the variance in the pattern of relationships among the items. In addition, Cronbach’s alpha coefficient was used to measure reliability, with a value of 0.84. Data Collection Two research assistants (nurses in the study setting) who had an experience in research data collection were invited. They were trained in the data collection techniques and explained about the study design, objective of the study, and research questionnaire. It was ensured they all understood before gathering data. Prior to the main data collection, field testing was conducted to examine the psychometric properties of the instruments. After the instruments were considered valid and reliable, the data collection for the main study was done from November 2021 to February 2022. A letter asking permission to collect data was then sent to the directors of each selected setting. The researchers asked for cooperation from the directors of each health-promoting hospital to choose the participants who met the inclusion criteria. The questionnaires were read to each participant, and the researchers gave appropriate explanations. The participants answered the questionnaires in approximately 30 minutes. Next, the researchers examined the questionnaire to ensure the completeness of the data. Data Analysis The data were analyzed using the SPSS for Windows version 22. The distribution plots for each variable were investigated prior to the data analysis. Examination of the obtained normal probability plots indicated that the distribution met the normality assumption for all studied variables. To describe the characteristics of the participants, percentages, means, and standard deviations were used. Frequencies and percentages were utilized to analyze the categorical data. Pearson’s product-moment correlations were employed to investigate relationships between the independent and dependent variables of the study. A p-value was set at <0.05, considered statistically significant. The strength of the correlation coefficient was divided into small (r = 0.10 - 0.29), medium (r = 0.30 - 0.49), and large (r = 0.50 - 1.00) (Cohen, 1988). Ethical Considerations This study was approved by the committee of human research from the Nakhon Ratchasima public health provincial office (NRPH 036) on 31 May 2021. This study is a part of the research project “Factors related to self-care behavior among people at risk of stroke in Nakhon Ratchasima province.” The first phase was done from July to October 2021 among participants at low and moderate risk of stroke, and it has been published in a local journal in the Thai language (Desaravinid, 2022). This current study used another dataset of participants at high risk of stroke with different independent variables collected from November 2021 to February 2022. The reason for collecting data in two separate phases was that it took more time to assess people at high risk of stroke, and it was according to the appointment with the medical doctors. Therefore, it is ensured no overlapping of data and no study duplication. In this study, the researchers approached the selected participant individually once the potential participants were identified. The participants were invited to interview in a prepared and quiet room at the health-promoting hospital. Then researchers introduced themselves, established rapport, explained the objectives, what contributions the subject would make, and how the confidentiality or anonymity of information was given to the participants. After the participants had agreed to participate in the study, they were asked to sign a consent form. One hundred percent of the participants gave formal consent to be a part of this study. Results Characteristics of the Participants The findings revealed that over half of the participants were female (55.30%). The mean age of the participants was 58.56 years old (SD = 9.24), ranging from 35 - 86 years old. The average duration of illness was 8.16 (SD = 5.80) years, ranging from 1 to 25 years. The average systolic blood pressure was 123.35 mmHg (SD = 17.60), while the average diastolic blood pressure was 73.21 mmHg (SD = 9.92). The average body mass index was 18.74 kg/m2 (SD = 2.66) and ranged from 13.75 to 27.27 kg/m2. Table 1 illustrates the information on the demographic characteristics of the participants. Table 1 Characteristics of the participants (N = 170) Variables n % Marital status Married 135 79.40 Single 20 11.80 Divorced 15 8.80 Educational level Primary school 130 76.50 High school 26 15.20 Uneducated 12 7.10 Bachelor’s degree or above 2 1.20 Career Agriculturist 71 41.80 Company employee 45 26.40 Owned business 25 14.70 Unemployed 25 14.70 Government officer 4 2.40 Family member with a history of stroke No 162 95.30 Yes 8 4.70 History of tobacco use No 142 83.50 Yes 28 16.50 Diagnosis Diabetes mellitus 119 70.00 Hypertension + Diabetes mellitus 29 17.10 Hypertension 15 8.80 Heart diseases 4 2.40 Hyperlipidemia 3 1.70 Descriptive Statistics of the Studied Variables The findings revealed that the average score of illness perception was 54.31 (SD = 9.78), which indicated that the participants had a high level of threatening view regarding their illness. For functional status, the mean score was 54.87 (SD = 10.46), which presented that the participants had a moderate level of functional status. In addition, the participants in this study perceived that they had a moderate level of social support from others (M = 74.12, SD = 8.28). Finally, the average score for self-care behavior was 64.54 (SD = 7.46), representing that the participants had a moderate level of self-care behavior. Table 2 presents the summary findings of the major studied variables. Table 2 Descriptive statistics for the studied variables (N = 170) Variables Min Max M SD Sk Ku Illness perception 24 76 54.31 9.78 -0.35 0.18 Functional status 23 79 54.87 10.46 -0.15 0.06 Social support 36 84 74.12 8.28 -0.26 0.73 Self-care behavior 36 86 64.54 7.46 -0.82 0.37 Min = Minimum | Max = Maximum | M = Mean | SD = Standard deviation | Sk = Skewness | Ku = Kurtosis Relationships between Studied Variables and Self-care Behavior The relationships between the studied variables are shown in Table 3. This study found that social support and functional status had medium positive significant correlations with self-care behavior among people at high risk of stroke (r = 0.460 and r = 0.304, p <0.01), respectively. In contrast, illness perception had a small negative significant correlation to self-care behavior among people at high risk of stroke (r = -0.179, p <0.05). Table 3 Relationships between studied variables and self-care behavior (N = 170) Variables Illness perception Functional status Social support Self-care behavior Illness perception 1 Functional status -0.218** 1 Social support -0.146 0.032 1 Self-care behavior -0.179* 0.304** 0.460** 1 * Significant p <0.05 ** Significant p <0.01 Discussion According to our knowledge, this is the first study to examine the factors related to self-care behavior among Thai people at high risk of stroke, which can be considered the strength of the study. This study found that social support was positively associated with self-care behavior. This indicates that the participants who received support from social around would perform good self-care to prevent stroke. This might be because the participants in this study perceived that family members, healthcare providers, and other significant people could support them in maintaining proper self-care behavior. In addition, most of the participants were married (79.40%). This might be relevant to Thai cultural beliefs and values that family members, particularly couples, are the key to looking after any person suffering from a health problem. Thus, people may feel responsible for performing self-care. This is, however, similar to the finding of one study conducted in Thailand by Ruangchaithaweesuk et al. (2021), indicating that the more people at risk of stroke receive support from society, the better their prevention behavior. Furthermore, like other studies conducted overseas, social support was associated with self-care behavior among patients with chronic illnesses such as diabetes, hypertension, heart disease, and hyperlipidemia (Jo et al., 2020; Karimy et al., 2018). Besides, regarding the theory of self-care (Orem, 2001), this study also supports that the perception of having support from society facilitates a person to look after themselves and consequently have better self-care behavior to prevent stroke. Therefore, enhancing social support might help a person at high risk of stroke in terms of performing better self-care behavior. Functional status was another factor that found a positive correlation with self-care behavior among people at high risk of stroke. It indicates that the participants who could perform the usual activities independently might have a better intention to maintain self-care. Interestingly, the highest age of the participants in this study was 86 years old. This old age might also impact the level of self-care behavior of the participants as well as the individual’s functional status (Zhou et al., 2022). Therefore, this age group should be specially recognized when promoting self-care behavior. The result of this study is, however, relevant to a previous study indicating that patients with chronic disease who have moderate to high functional status reported increasing their interest in self-care, such as exercising and preparing healthy food (Riandini et al., 2018). In addition, the finding in this study supports the theory of self-care that individuals who can perform the physical, role, and emotional functioning would be able to continue the requirements for self-care (Orem, 2001). Our findings also show that illness perception is an impediment factor related to self-care behavior. This finding suggests that a higher negative perception of being at increased risk of stroke is associated with poorer self-care behavior. It can be explained by the fact that the participants in this study have been living with their chronic disease for many years, with an average of 8.16 years. This long duration of illness might force them to face a high level of perceived illness threat and perceive it as an additional burden. Similarly, a previous study conducted by Oconnell et al. (2020) reported that patients with chronic disease believe that their illness is the major cause of stroke. In addition, Ngetich et al. (2022) also found that patients with diabetes with a high score of illness perception reported poor self-care behavior to control glycemic levels. Also, patients with type 2 diabetes believed that being diagnosed with this disease affected their life and increased their level of stress (Ngetich et al., 2022). Thus, enhancing proper perception regarding illness and health problems would increase the individual’s self-care behavior. On the other hand, one study conducted in Indonesia also used the brief-illness perception questionnaire to assess illness perception among patients with uncontrolled hypertension (Pahria et al., 2022). They noted that illness perception was positively correlated with self-care behavior. This reflects that various cultural and socioenvironmental aspects may affect the patients’ illness perception, including different diagnosis types and complications. Therefore, a positive perception of the disease might inspire people at high risk of stroke to make the right decisions to perform proper self-care behavior. Limitations of the Study This study has several limitations. First, these findings represent the results from one province in Thailand. Therefore, our results were limited and could not be generalized to the entire population among people at high risk of stroke in Thailand. Second, the selected factors were based on the facilitator and impediment factors which could not explain the entire conceptual framework of the self-care theory. Finally, most of the participants were diagnosed with diabetes mellitus. Thus, other health conditions included in this study, such as hypertension, heart disease, and hyperlipidemia, might not be well represented. Implications for Nursing Practice and Recommendations for Future Research For nursing practice, social support has a positive relationship with self-care behavior among people at high risk of stroke. This implies that nurses should question individuals at each appointment regarding the availability of spouses, family members, friends, and significant others. Importantly, families should be allowed to involve in the interventions to support this population and thereby increase self-care behavior actively. Nurses should also assess the individual’s ability to maintain functional status alone. Patients should receive the instruction and strategies to perform usual activities in daily life, working, and psychological functioning to enhance self-care properly. Additionally, individuals with a negative perception regarding their illness should be given information about their disease, treatment options, symptoms, emotional coping strategies, and strategies to look after his/herself at home. Future research can be recommended to explore the predicting factors of self-care behavior among people at high risk of stroke, underpinning the theory of self-care. However, due to using a cross-sectional design in our study, the ability to infer causality was limited. Therefore, testing the causal relationship among these variables is recommended. In addition, interventions that enhance self-care behavior among people at high risk of stroke should be tailored. The components of the intervention should include enhancing family involvement, positive perception of disease, and the individual’s ability to maintain functional status. Conclusion Self-care behavior is vital to maintain well-being among people at high risk of stroke. This study found that the participants had a moderate level of self-care behavior. The factors correlated to self-care behavior among this population were social support, functional status, and illness perception. This study highlights that healthcare providers, including nurses, should assess and encourage people at high risk of stroke to maintain their self-care behavior. To achieve the goal, family members should be involved, and patients should have well functional status. In addition, the perception of disease should be informed to enhance the understanding of their disease and motivate them to maintain sustainable self-care behavior. However, a causal relationship among these factors should be conducted in future research. Acknowledgment The authors acknowledge healthcare providers from ten public health-promoting hospitals in Nakhonratchasima province for facilitating participant recruitment. Importantly, the authors are greatly thankful to all participants in this study. Declaration of Conflicting Interest The authors declare there is no conflict of interest. Funding None. Authors’ Contributions The first author conceptualized the research design, reviewed the literature, performed data analysis, drafted the article, and was involved in writing the manuscript. The second author performed the data collection and was involved in writing the manuscript. All authors were accountable for each study step and approved the submitted and published versions. Authors’ Biographies Surachai Maninet, RN, PhD is a Lecturer at the Faculty of Nursing, Ubon Ratchathani University, Thailand. Chalermchai Desaravinid, MD is a Doctor of Medicine at the Medical Service Department, Bua Yai Hospital, Nakhonratchasima Health Provincial Office, Thailand. Data Availability The datasets used for analysis are available from the corresponding author upon reasonable request. ==== Refs References Bairami, S., Fathi, Y., Mohammadinasab, S., Barati, M., & Mohammadi, Y. (2017). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-184 10.33546/bnj.2485 Original Research Nursing services as perceived by inmates in correctional facilities in Jakarta, Indonesia: A qualitative study https://orcid.org/0000-0002-2542-4155 Wilma 12* https://orcid.org/0000-0002-3548-1348 Hamid Achir Yani S. 1 https://orcid.org/0000-0002-1746-267X Handiyani Hanny 1 https://orcid.org/0000-0002-7250-6727 Darmawan Ede Surya 3 1 Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia 2 Faculty of Nursing and Midwifery, University of Megarezky, Makassar, Indonesia 3 Faculty of Public Health, Universitas Indonesia, Depok, West Java, Indonesia * Corresponding author: Wilma, S.Kep,Ners., M.Kep, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Jalan Prof. Dr. Bahder Djohan, Kampus UI Depok, West Java 16424, Indonesia | Faculty of Nursing and Midwifery, University of Megarezky Makassar, Antang Raya street, Makassar, South Sulawesi-90234, Indonesia. Email: wilma.ui2019@gmail.com Cite this article as: Wilma., Hamid, A. Y. S., Handiyani, H., & Darmawan, E. S. (2023). Nursing services as perceived by inmates in correctional facilities in Jakarta, Indonesia: A qualitative study. Belitung Nursing Journal, 9(2), 184-191. https://doi.org/10.33546/bnj.2485 18 4 2023 2023 9 2 184191 08 12 2022 05 1 2023 27 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Nursing services play a crucial role in addressing the healthcare needs of inmates in correctional facilities while upholding their human rights. However, delivering nursing services in this context is challenging. Unfortunately, there is a dearth of research on this topic in Indonesia. Objective This study aimed to explore the experiences of inmates in receiving nursing services in order to provide insights into professional nursing services in the correctional context in Indonesia. Methods A qualitative phenomenological approach was used in this study. Twenty inmates were selected purposively from four prisons, three jails, and one child penitentiary in Jakarta, Indonesia. Semi-structured in-depth interviews were conducted from August to October 2021, and thematic analysis was used to analyze the data. Results Five themes were generated: (1) conditions requiring nursing services, (2) types of nursing services received, (3) nurse competence, (4) barriers to receiving nursing services, and (5) expectations for nursing services in the future. Conclusion This study highlights the importance of nursing services in correctional facilities and the unique challenges that correctional nurses face in providing services professionally and ethically. Strategies to enhance nursing services, advance nurse competence, and reduce barriers to accessing care are needed to improve inmates’ health outcomes. nurses human rights prisons jails Indonesia competence Educational Fund Management Institution (LPDP), Ministry of Finance of the Republic of Indonesia2020032130371 ==== Body pmcBackground In accordance with the World Health Organization’s (WHO) declaration, health services provided to inmates should meet both quality and quantity standards equivalent to those offered to the general public (World Health Organization, 2014). Furthermore, the treatment of inmates should conform to the Standard Minimum Rules for The Treatment of Inmates, as approved by the United Nations (1995). The International Council of Nurses (ICN) confirmed the crucial role of nurses in supporting human rights and delivering care to inmates (International Council of Nurses (ICN), 1998). Care in prisons is guided by ethical principles and is conducted in partnership with health professionals and authorities. Correctional nurses advocate for safe and humane treatment, including dignity, respect, clean water, adequate food, and other daily necessities (International Council of Nurses (ICN), 1998). The American Nurses Association (ANA) emphasizes several vital roles for nurses in advocating for the rights of inmates, including the right to receive visits, quality health services, even for those in isolation, and the right to report verbal or physical abuse, among others (American Nurses Association (ANA), 2021). Additionally, nurses serve as educators to enhance inmates’ knowledge of health-related matters. Nurses also act as collaborators and facilitators to ensure that health services are of the highest quality. Nurses begin their primary role as care providers, counselors, and coordinators by conducting assessments and interviews with inmates, followed by planning for continuing care (American Nurses Association (ANA), 2021). Nurses also play a critical role in the initial examination of inmates, especially when some inmates attempt to conceal their medical history. In addition, nurses ensure continuity of care for inmates to prevent the recurrence of health issues and complications. Moreover, nurses serve as coordinators for health promotion in prisons, including developing appropriate nursing service models for inmates’ needs and the prison environment (Kelly et al., 2020; Overton et al., 2019; Rosalim, 2020). These essential roles of nurses underscore their significant involvement in safeguarding and fulfilling inmates’ health service requirements. The mission of correctional institutions in Indonesia is to ensure the respect, fulfillment, and protection of human rights, including the right to health for inmates. Indonesia has 525 correctional facilities, which consist of male, female, and child prisons and jails. The number of inmates reportedly reached 249,139, with a room capacity of only 135,704 (Direktorat Jenderal Pemasyarakatan (Ditjenpas), 2020). The increase in population over the last five years shows that the inmate population has increased by approximately 10% annually, but this is not in line with an increase in facility capacity. This situation creates barriers to fulfilling inmates’ human rights to quality health services. The size of the rooms for activities and rest, sanitation, and availability of water no longer meet health requirements, thus increasing the number of respiratory disorders and skin diseases. Acute respiratory infections and skin diseases are the two biggest diseases that inmates suffer. Diseases of the heart and blood vessels are the leading cause of death in inmates, followed by tuberculosis and HIV/AIDS. Inmates’ mental health-related quality of life is reported to be below 75% due to poor coping mechanisms, self-acceptance, and inability to adapt to the prison environment (Maghnina & Andriany, 2020; Putri et al., 2020; Sinaga et al., 2020b). In addition to physical and mental health problems, inmates experience psychosocial and spiritual issues. Inmates show emotional responses, including sadness, boredom, anxiety, confusion, annoyance, and anger (Sinaga et al., 2020b; Zainuri, 2019). The qualifications and number of health workers, which are no longer balanced with the number of inmates, also affect the limitations of health services. Overcapacity that occurs in correctional facilities in Jakarta reaches 87-303%. Each prison has one to ten nurses, meaning one nurse has to provide care for about two hundred inmates. This imbalance causes the inability of nurses to respond to all inmates’ physical, psychological, psychosocial, and spiritual health needs (Maghnina & Andriany, 2020; Putri et al., 2020; Sinaga et al., 2020b). Studies related to nursing services in correctional facilities in Indonesia have not been widely carried out. However, several studies have reported that inmates’ rights to quality health services, including comprehensive nursing services, have not been fulfilled. In addition, the psychological and psychosocial aspects of inmates might not have been adequately addressed (Barus & Sylvia Biafri, 2020; Hermansyah & Masitoh, 2020; Maghnina & Andriany, 2020; Putri et al., 2020; Raswandaru et al., 2021; Sinaga et al., 2020a; Zuhair, 2020). In 2018, the legal and human rights research and development agency of the Ministry of Law and Human Rights of the Republic of Indonesia conducted a study on health services for inmates in Indonesia. This study used a quantitative method for inmates and a qualitative method for leaders and health workers at each regional representative in Indonesia, including Jakarta. Health services were generally reviewed, and nursing services were not specifically described. The recommendations focused more on improving the quality of health service management (Riyanto et al., 2018). Nursing services in correctional facilities face different challenges than those in other health units. These challenges become barriers to providing professional nursing services due to clients’ unique characteristics, which are described as manipulative, lying, dangerous, and exhibiting terrible behavior (Riyanto et al., 2018). Types of inmate law violations that affect sentence terms also influence nursing care planning. The isolated environment and conflicts of interest between security and the provision of health services sometimes hinder decision-making regarding inmate healthcare. These things can trigger ethical dilemmas, moral distress, and disputes between professionalism and institutional interests. Providing caring as an essential essence in nursing services becomes harder to deliver in this context (Cloyes et al., 2017; Cukale Matos & Champion, 2022; Dhaliwal et al., 2021; Lazzari et al., 2020). With this phenomenon and the gap in the literature, our study aimed to explore the experience of inmates receiving nursing services in correctional facilities in Indonesia. Methods Study Design The study used descriptive phenomenology to explore and describe inmates’ experiences receiving nursing services. This method aims to produce a unified meaning from experience by directly exploring, analyzing, and describing phenomena without untested presuppositions. It allows the researcher to perceive the experience without compromising its richness, breadth, and depth (Afiyanti & Rachmawati, 2014). Participants/Informants The study included twenty inmates from correctional facilities in Jakarta, Indonesia, where approximately 18,000 inmates live (Direktorat Jenderal Pemasyarakatan (Ditjenpas), 2020). Participants were selected using purposive sampling with the criteria of having served a sentence of more than six months, being willing to participate, being cooperative, and being able to express their experiences and opinions. Correctional nurses assisted in identifying potential participants who met the inclusion criteria. The researcher observed the ability of prospective participants based on the criteria and obtained their approval to participate. Data Collection Recruitment of participants and data collection took place between August and October 2021, with permission obtained from the Head of the Ministry of Law and Human Rights regional office in Jakarta. The research objectives were explained to the heads of prisons and jails to gain access to data collection, and the head of the inmate’s healthcare division and correctional nurses helped identify potential participants. After the participant candidates were identified, an interview schedule was made, and ultimately, twenty inmates participated in the study. No inmates who met the inclusion criteria refused to participate. In-depth semi-structured interviews were conducted face-to-face to collect data. Each of the twenty participants was interviewed for 30-45 minutes, and only one interview was conducted for each participant. The interviewer double-checked the participant’s statements during the interview to ensure accuracy and clarity. The discussions took place in a calm and comfortable setting, either in the waiting room or consulting room of the prison/jail clinic, with only the participants and interviewers present. Non-verbal behaviors, special events, and thoughts derived from the interview were recorded by the interviewer (Guest et al., 2020). The researchers maximized the interviews to achieve data saturation, meaning no new themes emerged from the participants’ narratives, and the data became repetitive. The interview questions were developed after discussions with three senior researchers specializing in qualitative studies, nursing management, and services. The validity of the questions was tested through expert judgment to analyze and evaluate whether they measured the intended aspects. Three test interviews were conducted and analyzed to optimize the interviewer’s skills before the study interviews. The following guide questions were used: 1) Could you tell me about your experience of receiving nursing services here? 2) When do you need the help of a nurse? 3) What did the nurse do to help you in terms of physical health, psychological health, relationships with others (psychosocial), worship, and respect for the values of your beliefs (spirituality)? 4) Are there any obstacles to getting nursing services? 5) How do you perceive the ability of nurses to provide services (competence, communication, coordination)? 6) What are your expectations for nursing services in the future? Data Analysis Data were collected using a voice recorder, transcribed verbatim, and encoded using thematic analysis. Four researchers repeatedly read the interview transcripts to familiarize themselves with the data set and developed codes that were compared and agreed upon through a joint discussion. This process is crucial in providing an overview of the personal experience of the phenomenon under study. Next, the researcher records meaningful data items and produces codes in the next step. Significant statements and codes are collected and become themes. An inductive analysis is performed to derive common themes (Kiger & Varpio, 2020), which are then analyzed to ensure they have sufficient supporting data, similarity, coherence, and differentiation. Finally, the refined themes are defined and described to provide insight and understanding of the phenomenon. At the end of the data analysis process, the researcher writes the final analysis (Kiger & Varpio, 2020). Rigor The researchers made efforts to meet the criteria for credibility by building relationships with participants to obtain accurate information, understanding and exploring the sensitive language and behavior of their life experiences, allocating sufficient time to make them comfortable with situations, observing health service activities at the research site, and conducting member checking with the participants. The transferability criteria were met by taking samples according to the research topic through purposive sampling. The dependability criteria were met through intensive discussions with supervisors regarding data findings and analysis. Additionally, the confirmability criteria were met through related journals and peer review with expert researchers. Ethical Considerations The study was approved by the ethics board of the Faculty of Nursing, Universitas Indonesia, Indonesia. Participants were given an explanation about the study information and signed an informed consent form. Data were anonymized, protected, and will be destroyed after five years. The interviewer was a female nursing doctoral student, not a prison employee, which provided an advantage in conducting interviews because the participants did not feel a legal bond. Results Participants Characteristics Table 1 provides a description of the demographic characteristics of the study participants. The sample consisted of 20 individuals, including three inmates from a narcotics prison, four from men’s prisons, four from men’s jails, three from women’s prisons, three from women’s jails, and three from children’s correctional facilities. Table 1 Characteristics of participants Demographics n % Age (year) 16-25 26-45 >45 7 10 3 35 50 15 Gender Male Female 14 6 70 30 Educational background Junior High School Senior High School Bachelor 6 10 3 30 50 20 Year of becoming an inmate ≤ 1 2-5 >5 8 10 2 40 50 10 Thematic Findings During the data analysis phase, the researchers generated 271 codes related to nursing services after reading the interview transcripts multiple times. From these codes, five main themes were developed: 1) Conditions requiring nursing care, 2) Types of nursing service received, 3) Nurse competence, 4) Barriers to receiving nursing services, and 5) Expectations of nursing services in the future. Theme 1: Conditions requiring nursing care In this study, nursing services are perceived as special services that inmates can access when they experience urgent or severe health conditions that require invasive procedures or drug administration that must be monitored and reported. Nursing services are primarily for physical health services, not psychological or other health services. This theme emerged based on several categories: Handled by inmate volunteers (Tamping). Fourteen participants revealed that nursing services do not necessarily have to be provided by nurses as long as inmate volunteers, known as “tamping,” can handle the situation. In cases where nurses are unavailable, tamping takes care of the inmates. Examples of participant statements include: “I don’t need anything… for example, if I’m sick, I’m handled by the inmate volunteers, thank God” (Participant 2) “If injected, directly from the nurse” (Participant 7) “When we are sick… Tamping takes care of us… the nurse hasn’t” (Participant 9) “Sometimes when we are sick, the nurse hasn’t come yet. They (tamping) take care of us…” (Participant 19) Severe pain or showing no improvement. Eleven participants reported that they require nursing care when they are seriously ill and need further treatment. They also noted that severe pain or no improvement in their condition were factors that would prompt them to seek nursing care. Examples of their statements include: “How can I be normal like that, ma’am… I want to ask about that with the nurse.” (Participant 1) “I don’t need it… I’ve never been seriously ill.” (Participant 2) “Thank God I haven’t… I hope never.” (Participant 3) “For example, if I’m already seriously ill… I can’t stand the pain… then I need them.” (Participant 11) Need medication. Most participants reported that they require nursing care when they need medication for their condition. Some of their quotes include: “For example, if I haven’t taken my medicine…” (Participant 15) “At least if I need medicine…” (Participant 17) “It’s more like… getting treatment… if the nurse is here…” (Participant 20) Not to share problems or feelings. When asked about the need to communicate issues or feelings with nurses, most participants reported that it was not necessary or inappropriate. They stated that they prefer to keep personal matters to themselves or to share them with friends rather than discussing them with nurses. Some examples of their statements include: “At the moment, I don’t think I need to consult with a nurse… well, maybe it’s specifically for the former program…” (Participant 3) “Being sad is usually a personal matter… we can’t talk to the nurses, right…” (Participant 5) “Never talked to nurses…mostly to friends…any story…talked about many things.” (Participant 7) “When I get emotional with people…I don’t want to tell stories… I’m like this…because I don’t want to get involved in other matters…I also don’t like complaining to officers or nurses…” (Participant 15) Theme 2: Types of nursing service received Nursing services mainly involve the administration of medicines and providing health education. In cases of emergency and specific procedures, inmates receive treatment according to their health conditions. Nurses also conduct initial health assessments for new inmates. Administration of medication. Most of the participants revealed that, generally, the nurse’s job is to give medicine. According to most of the participants, nurses primarily administer medication. The quotes include: “When I asked the nurse for medicine, they promptly provided it to me” (Participant 1) “The nurse gave me medicine and explained how many times I needed to take it” (Participant 5) “They provide medication and explain what it is for and how many times it should be taken” (Participant 17) Health education and information services. Most of the participants reported that nurses provided them with advice on staying healthy and avoiding factors that cause diseases. The participants express this: “They explained to us… for example, like lack of sleep… if there are complaints of headaches… maybe from the way we sleep or other causes… they give us information, so we don’t get sick… they let us know.” (Participant 3) “If this is the cause, we’re told to take a bath… that’s all they say… keep clean… take care of your body condition, that’s what they said…” (Participant 8) “Well, ma’am… we were told to sunbathe diligently… bathe diligently… so to reduce itchiness, he said.” (Participant 12) Health assessment at first admission to prison/jail. According to eight participants, upon their admission to prison/jail, a health assessment was conducted by a nurse who inquired about their medical history. In some cases, specific medical tests were performed. The participants state this: “The nurses…when they came in, we were examined because there was a history of diabetes… so we were examined when we entered here.” (Participant 4) “When we were here, we were examined when we entered, and my illness was discovered… then quarantined… the nurse took the sputum… then examined… and it was finished.” (Participant 7) “During admission, the nurse screened, then took blood as well… and was asked about the history of the disease… that’s all.” (Participant 11) Emergency services and specific procedures. Thirteen participants disclosed that nurses perform emergency actions and particular procedures such as administrating tuberculosis medication, conducting special specimen examinations, and initial handling in emergencies. Some examples of their statements include: “It’s very helpful… just inject it, it’s very helpful.” (Participant 7) “The emergency unit is 24 hours… there is a nurse… there is a morning to night shift.” (Participant 11) “There was one person here who was infected, and we were immediately separated…then we were all examined…it was plugged into the nose…it was examined by a nurse…” (Participant 14) “If it’s already severe… we’ll be examined intensively… then given oxygen… and other equipment.” (Participant 15) Theme 3: Nurse competence The participants mostly described nurse competence in performing nursing services as responsive, friendly, and caring. In addition, they appreciated nurses who had a positive and supportive attitude towards inmates who experienced emergency medical conditions, considering it to be a good and much-needed attitude. Responsive and fast. Thirteen participants praised the nurses for being responsive and quick in handling emergencies. Their statements include “They can do everything… because while I’m here being treated… if I have a need… I ask the nurses directly for help… and they take action right away… handle it right away.” (Participant 1) “Like yesterday a friend was sick… they immediately responded… brought it straight away… not postponed.” (Participant 9) “The officers or nurse are quick if someone is sick… quickly run… come immediately…” (Participant 15) Friendly. Eleven participants appreciated the friendly behavior of the nurses, including their polite manner, soft speech, and smiling faces. The participants express this: “They are polite and friendly ma’am… It’s like I’m sick and talk to me gently…indirectly tell me well, ma’am.” (Participant 1) “They are kind, if we greet them, they smile back. The nurse greets us…be patient first… they smile cheaply too, the point is the nurses are nice.” (Participant 2) “In my opinion, so far it’s been good… communication is also good… they also like to tell those who are sick… reprimand them too… reprimand them properly for the benefit of the patient’s health as well… they rebuke that in a sense encouraging us to be healthy too.” (Participant 5) Caring. Ten participants felt that the nurses showed a caring attitude by expressing curiosity about their healthy development. The quotes include: “I don’t just come to get an injection… sometimes I’m asked how it’s progressing… so we don’t just come to inject.” (Participant 7) “When I come, he asks questions about our illness…” (Participant 8) “Okay…well…they are outgoing…often asking whether we are healthy or not.” (Participant 20) Theme 4: Barriers to receiving nursing services The barriers are mainly associated with waiting time and a lack of follow-up services. Have to wait/queue for quite a long time. Twelve participants reported waiting in long lines or waiting for nurses during their breaks, resulting in delayed services. “Because the clinic is really small… but if we queued… there could be 45 people.” (Participant 4) “Sometimes when the nurses are on a break, so we wait for them… it’s like that, right… unless it’s critical, we’ll be served…but if it’s just coughing, right…sometimes we’re eating, maybe wait” (Participant 5) “I often want to meet, but most people queue, so I don’t meet often…many queues” (Participant 10) No further treatment. Fourteen participants reported not receiving follow-up services after their initial treatment or drug administration, which only treated their symptoms. “About how to handle it… no one tells us, ma’am… every day we are given medicine… just medicine ma’am… There’s just no way how to do it including healing.” (Participant 1) “At least…oh okay…given pain medication…it can only be like that.” (Participant 15) “For me, I don’t think there are any problems… maybe pay more attention to the elderly… because there are more elderly people who have complaints here… the complaints of the elderly are like cholesterol, so just give them pain medication.” (Participant 20) Theme 5: Expectations of nursing services in the future Participants’ expectations of better nursing services are related to nurses’ professional attitudes and improved access to health services. Friendly and caring nurses. Eight participants expressed a desire for friendlier and more caring nurses. “As for the service here, if it can be further improved… so that it will be better… so that the inmates can be treated more happily…, especially to us, Ms. Well, if we can be nicer to her, maybe she can be nice to us.” (Participant 3) “Just pay more attention than yesterday… it’s better ma’am… just like usual… just pay more attention to us.” (Participant 12) “Responding to us sometimes… well, it’s just a headache, right… well, never mind… that’s all… because we are all inmates with limitations… right?” (Participant 19) Being more responsive. Eight participants revealed that the service would be good if the nurses were more responsive to the health conditions of the inmates. “Yes, it is much more responsive… if there are complaints, the response is faster…” (Participant 5) “What I want, well, just respond faster… I mean, the service is even faster… if someone is seriously ill, refer them immediately… if, for example, someone complains of a serious illness, they must be referred immediately.” (Participant 6) “Those who are still in the block sometimes don’t get treatment when they are sick… but they can go to the clinic every day.” (Participant 18) Better access to health services. Ten participants conveyed the need for better access to health services, including expanding health services in clinics and procuring medical equipment to support the needs of inmates. “If possible, the place can be repaired… the facilities will also be more complete.” (Participant 4) “Yes… make the treatment easy… just make it easy… we are sick like this.” (Participant 10) “Yes, add more treatment… if someone is itchy, allow them to seek treatment… don’t limit it to, for example, only 40 people a day… if residents come because they are sick, they must be attended to.” (Participant 11) “Those who hurt… like a pinched nerve… the spine is sore… keep going… waist… kneel… calcification… we have to go to the physio. There is a physio here… so we don’t just take oral medicine medication… taking medication will only reduce the pain.” (Participant 20) Discussion This study aimed to explore the experience of inmates receiving nursing services in correctional facilities in Indonesia. There were five themes emerged as the findings. The first theme suggests that the participants in the study perceived nursing services in correctional facilities as specialized services that inmates can access when they require urgent or intensive medical attention. This includes invasive procedures or medication administration that require close monitoring and reporting. Furthermore, nursing services primarily focus on physical health needs and do not extend to psychological or other forms of healthcare. Inmates seek nursing care only when their health condition is severe, causing significant pain and requiring medication. However, the participants did not think it was necessary to discuss personal issues or emotions with nurses, instead preferring to keep such matters to themselves or share them with peers. The nurse-client relationship in the context of nursing services in correctional institutions is quite complicated because nurses also act as security officers. As a result, the relationship that develops is between inmates and security officers rather than a nurse-client relationship. This situation creates reluctance, fear of exposure by officers, and fear that the nurse’s response may not be as expected (Dhaliwal & Hirst, 2016; Wong et al., 2018). In situations where the nursing staff is absent or the number of inmates is high, inmate volunteers, known as “tamping,” attend to the needs of their fellow inmates. The benefit of involving inmate volunteers is that they have close relationships with other inmates and live in detention rooms, making it easier to mobilize sick inmates to the clinic to receive nurse treatment. Inmate volunteers receive training to assist nurses in caring for ill inmates (Cloyes et al., 2016). The assistance provided includes monitoring and reporting sick inmates in detention rooms, mobilizing sick inmates to the clinic for initial treatment, helping distribute medicines to inmates as instructed by nurses, cleaning the clinic room and surroundings, assisting during the implementation of health education, measuring blood pressure, and helping fulfill personal hygiene of inmates who need to be treated at the clinic. However, nursing managers must ensure that the assistance provided by inmate volunteers complies with applicable regulations and specified limits. Inmate volunteers also need to receive training, guidance, and evaluation to maintain the quality of health services for inmates. Nursing assistance is crucial in correctional facilities. The second theme, “type of nursing service received,” reveals that nursing services in correctional facilities primarily involve administering medication and providing health education. The participants preferred drug therapy since it faster-reduced pain and other symptoms of their ailments. Many inmates only visit the clinic to obtain medicine and disregard other self-care practices that could prevent disease. Providing health education about alternative pain reduction methods is essential to change inmates’ mindsets about medication use. Nurses also carry out preventive and promotional efforts, such as instructing inmates to engage in physical activities and bathe in the morning sun. Furthermore, personal hygiene is continually emphasized, and male inmates complain about scabies affecting nearly everyone. In contrast, female inmates more often experience non-communicable diseases like hypertension, reproductive system disorders, and digestive disorders. Population density and differences in clean and healthy lifestyles between men and women seem to play a role in these occurrences. Since inmates can be less cooperative and less attentive (Caro, 2021), preventive efforts are mandatory. The provision of nursing services in correctional facilities is a critical aspect of primary prevention, which aims to promote health and enhance the knowledge and skills of inmates to perform self-care. Due to their low level of education and history of communicable and non-communicable diseases, educating inmates about recognizing disease symptoms and taking early preventive measures is crucial. In addition, the status of being an inmate can potentially lead to mental health problems influenced by self-acceptance, changes in role status, conflicts with other inmates and security officers, and the restricted correctional environment. To obtain accurate data upon admission, nurses conduct initial health assessments, asking about medical history and performing necessary medical tests. This stage is essential as a safety document and to sort out convicts with a history of infectious diseases or other illnesses. However, the nursing process that begins with assessment is not complete until the implementation and evaluation of nursing. In correctional facilities with limited resources, nurses must handle emergency services and some special procedures using the tools available at the prison or jail. As primary healthcare workers, nurses must possess important competencies such as handling emergencies, caring for clients with infectious diseases, and treating wounds to meet the health needs of inmates (Almost et al., 2020; American Nurses Association (ANA), 2021; Kelly et al., 2020; Overton et al., 2019). The theme of “nurse competence” highlights the importance of nurses being responsive, friendly, and caring when providing nursing services in the correctional context. The challenging nature of this environment requires nurses to deliver services with professionalism while also navigating ethical dilemmas and conflicts between security interests and the need for health services. To carry out their professional duties, correctional nurses must display ethical values and culturally sensitive practices (Choudhry et al., 2017; Dhaliwal & Hirst, 2016). In emergencies, the responsiveness of nurses is highly appreciated by inmates. The isolated conditions of the correctional facility and the time-consuming referral process can cause concern for inmates when experiencing health emergencies. Timely and effective responses from nurses provide a guarantee that inmates will receive the necessary care and will not be left alone or neglected. Furthermore, the friendliness of nurses creates a sense of comfort for inmates in obtaining health services, which are often limited due to constraints on space and time. Nurses’ friendly, including smiling and using a soft tone of voice, is an effective means of communication that can positively influence the health behavior of clients (Thakur & Sharma, 2021). Additionally, nurses’ concern for the latest developments in the client’s health indicates their commitment to caring for the inmate’s well-being, enhancing their dignity and value as individuals. The fourth theme, “barriers to receiving nursing services,” indicates that inmates face difficulties meeting with nurses due to long wait times and queues. Often, interactions with nurses are limited to receiving medication as there are many other inmates to attend to, especially in male prisons/jails. However, women in female prisons and jails tend to have no problems with service time. To reduce waiting times for services, there is a need for an adequate number of nursing staff with appropriate competence to meet the needs of the inmates. The lack of sufficient time availability also results in incomplete and unsustainable nursing services, focusing solely on administering medications instead of following the complete nursing process (Dhaliwal et al., 2021; Foster et al., 2013). The final theme reflects the participants’ expectations for better nursing services related to nurses’ professional attitudes and improved access to health services. Implications of the Study This study has several implications: 1) The study highlights the importance of having an adequate number of nursing staff to meet the healthcare needs of inmates in correctional facilities. This implies that healthcare policy should prioritize funding for staffing in correctional facilities to ensure adequate healthcare services are provided; 2) Nursing practice in correctional facilities should emphasize health promotion and disease prevention to enhance the knowledge and skills of inmates to perform self-care. This approach can potentially reduce the burden of communicable and non-communicable diseases in correctional facilities; 3) The study suggests that the waiting time for nursing services can be a significant barrier for inmates to receive healthcare services. Therefore, healthcare policy should prioritize reducing waiting times for services, ensuring that all inmates have equal access to healthcare services regardless of gender; 4) Correctional nurses face unique ethical dilemmas and conflicts between security interests and the need for health services. Therefore, it is essential to ensure that nursing practice is based on ethical values and culturally sensitive approaches to carry out their role as professional nurses in a challenging service context; and 5) Healthcare policy should prioritize strengthening nursing competencies through training and continuing education programs. Limitations Despite the researchers’ efforts to consider age and gender distribution, the study was limited by inclusion criteria that may have hindered some inmates from sharing their experiences. Additionally, conducting interviews in prison or jail clinics could potentially influence the participants’ willingness to express themselves openly, even without intervention. Therefore, conducting interviews in different regions in Indonesia is recommended to gain new insights and identify other factors that influence nursing services as perceived by inmates. Conclusion This study sheds light on the experiences and perceptions of inmates regarding nursing services in correctional facilities. The findings suggest that nursing services are essential for promoting primary prevention and enhancing the knowledge and skills of inmates to perform self-care. However, inmates face barriers to receiving nursing services, such as long wait times and insufficient resources. The study also highlights the importance of nurses’ competence, including their professionalism, responsiveness, friendliness, and cultural sensitivity in providing care to inmates. Therefore, this study recommends the need for improving nursing services in correctional facilities, addressing the barriers to care, and enhancing the competence of nurses through training and education. The study also underscores the importance of healthcare policy that prioritizes the health needs of inmates and provides adequate resources for nursing services in correctional facilities. Ultimately, improving nursing services can promote better health outcomes and contribute to the rehabilitation of inmates as they transition back to the community. Acknowledgment The authors are highly thankful to the inmates participating in this study and to the managers and nurses of nursing services from the Ministry of Law and Human Rights, Jakarta Region, for their support. Declaration of Conflicting Interest The authors declared no potential conflicts of interest concerning the research, authorship, or publication of this article. Authors’ Contributions All authors contributed equally to all stages of the study, including conceptualization, methodology, validation, analysis, and interpretation of the data, drafting and revising the manuscript. In addition, all authors have read and agreed to the published version of the manuscript. Authors’ Biographies Wilma, S.Kep,Ners., M.Kep is a Doctoral Student at the Faculty of Nursing, Universitas Indonesia, and a Lecturer at the Faculty of Nursing and Midwifery, University of Megarezky, Makassar, Indonesia. Achir Yani S. Hamid, M.N, DNSc is a Professor at the Department of Mental Health Nursing, Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia. Dr. Hanny Handiyani, S.Kp., M.Kep is a Lecturer at the Faculty of Nursing, Universitas Indonesia, Indonesia. Dr. Ede Surya Darmawan, SKM, MDM is a Lecturer at the Faculty of Public Health, Universitas Indonesia, Indonesia. Data Availability The datasets interpreted and analyzed during the study process are not made public but available from the corresponding author upon reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Afiyanti, Y., & Rachmawati, I. N. (2014). Metodologi penelitian kualitatif dalam riset keperawatan [Qualitative research methodology in nursing research]. Jakarta: Rajawali Pers. Almost, J., Gifford, W., Ogilvie, L., & Miller, C. (2020). The role of nursing leadership in ensuring a healthy workforce in corrections. Nursing Leadership (Toronto, Ont.), 33 (1 ), 59-70. 10.12927/cjnl.2020.26191 32437322 American Nurses Association (ANA). (2021). Correctional nursing: Scope and standards of practice (3rd ed.). USA: American Nurses Association. Barus, B. J. P., & Sylvia Biafri, V. (2020). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-034 10.33546/bnj.2432 Original Research The effect of the multimodal intervention on blood pressure in patients with first ischemic stroke: A randomized controlled trial https://orcid.org/0000-0001-8077-2171 Jullmusi Orapin https://orcid.org/0000-0003-3608-1650 Yunibhand Jintana * https://orcid.org/0000-0002-0117-5959 Jitpanya Chanokporn Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand * Corresponding author: Jintana Yunibhand, APN, PhD Associate Professor, Faculty of Nursing, Chulalongkorn University, Boromarajonani Srisatapat Building, Rama1 Rd, Floor 11 Patumwan, Bangkok 10330, Thailand. Email: yuni_jintana@hotmail.com Cite this article as: Jullmusi, O., Yunibhand, J., & Jitpanya, C. (2023). The effect of the multimodal intervention on blood pressure in patients with first ischemic stroke: A randomized controlled trial. Belitung Nursing Journal, 9(1), 34-42. https://doi.org/10.33546/bnj.2432 12 2 2023 2023 9 1 3442 13 11 2022 26 12 2022 28 12 2022 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Multimodal intervention is currently promoted to control blood pressure in patients with first ischemic stroke. However, a dearth of studies has examined the influence of the intervention among patients with ischemic stroke, particularly in Thailand. Objective This study aimed to determine the effect of the multimodal intervention on blood pressure in patients with first ischemic stroke. Methods A randomized controlled trial was conducted. Sixty participants were randomly selected from two tertiary hospitals in Thailand. Eligible participants were randomly assigned into an experimental group (n = 30) and a control group (n = 30). The experimental group was provided with the multimodal intervention, while the control group was given the usual care. Data were collected from May 2021 to October 2021 at baseline (pre-test), 4th week, 8th week, and 12th week using the demographic data form and sphygmomanometer. The data were analyzed using the Chi-square test, t-test, and repeated measure analysis of variance (ANOVA). Results The participants’ blood pressures after receiving the multimodal intervention were lower than those before receiving the multimodal intervention. Both systolic and diastolic blood pressure were statistically significantly decreased over time, starting from baseline to the 8th week and 12th week (p <0.001). In addition, the participants’ mean scores of systolic blood pressure (F (1, 58) = 4.059, p = 0.049) and diastolic blood pressure (F (1, 58) = 4.515, p = 0.038) were lower than the control group. Conclusion The multimodal intervention is effective in controlling blood pressure. Therefore, nurses should educate patients with ischemic stroke to manage systolic and diastolic blood pressure, facilitate the patient’s participation in the exercise program, and monitor the patients via telephone to continue blood pressure control. Trial Registry Thai Clinical Trials Registry (TCTR) identifier number 20210318001. ischemic stroke blood pressure multimodal intervention nurses Thailand ==== Body pmcBackground High blood pressure is the major risk factor for stroke disease. It is reported to be a leading contributor to long-term disability, functional status decline, decreased quality of life, and death (Bath et al., 2022). In the United States, over 795,000 people have a stroke, and approximately 610,000 are first strokes (Virani et al., 2020). About 87% of all strokes are ischemic strokes, where blood flow to the brain is blocked (Yousufuddin & Young, 2019). In Thailand, the prevalence of stroke was 4.00%, 3.80%, and 3.90% in 2014, 2015, and 2018, respectively (Chantkran et al., 2021). About 104,028 strokes, up to one-third of these affect people who have already had a stroke (Chantkran et al., 2021). Although using medication is considered effective in preventing recurrent stroke; however, worldwide studies have shown nearly half of patients diagnosed with stroke remain untreated, and over half of them being treated continue to have uncontrolled blood pressure (Oftedal et al., 2018; Pandian et al., 2018). For example, in Thailand, it was found that 41.60% of strokes in the Thai population cannot control their blood pressure (Areechokchai et al., 2017). In comparison, a community-based study found that the prevalence of uncontrol blood pressure in patients with stroke was about 54.40% (Meelab et al., 2019). In addition, a meta-analysis study found that 91% of patients with stroke who cannot control their blood pressure had recurrent strokes during the follow-up period. Of these, 86.80% were ischemic strokes, and 13.20% were intracerebral hemorrhages (Kitagawa et al., 2019). Therefore, blood pressure control is a cornerstone for preventing recurrent stroke especially ischemic stroke. The 2017 American College of Cardiology/ American Heart Association Blood Pressure Guideline recommended keeping blood pressure below 130/80 mmHg in ischemic stroke (Kim et al., 2020; Whelton et al., 2018). A meta-analysis study reported that intensive blood pressure control of less than 120/80 mm Hg reduced stroke recurrence compared with blood pressure control of less than 140/90 mm Hg (Kitagawa et al., 2019). Regarding the 2017 ACC/AHA BP Guideline, the cut point of well blood pressure control in patients with stroke in this study is less than 130/80 mmHg (Whelton et al., 2018). However, patients with ischemic stroke reported having difficulty controlling blood pressure due to several modifiable factors, including lack of knowledge, consuming unhealthy food, higher sodium intake, less exercise, tobacco use, excessive alcohol intake, lower potassium intake, lack of motivation to change behaviors (Benjamin et al., 2017) and lack of medical adherence (Hameed & Dasgupta, 2019; Williams et al., 2018). Thus, these modifiable factors should be managed to control blood pressure in these patients. Empirically, several interventions have been developed to control blood pressure in particular patients with ischemic stroke. The intervention studies have reported results of implementing both single and multiple components of the intervention to reduce blood pressure. For example, a meta-analysis showed that exercise interventions significantly reduced systolic and diastolic blood pressure among patients after stroke (Wang et al., 2019). Other studies found that taking a healthy diet, consuming low salt, exercising, and quitting smoking reduced blood pressure in patients with ischemic stroke (Chen et al., 2022; Wajngarten & Silva, 2019). In Thailand, a quasi-experimental study reported that patients who received information regarding food, exercise, and medication had proper systolic blood pressure control (Thongbupa et al., 2022). Another meta-analysis study found that patients with stroke who participated in the multimodal intervention had better blood pressure control (Bai et al., 2017). Therefore, developing a multimodal intervention should benefit patients with ischemic stroke who have difficulty controlling blood pressure. It is noted that the multimodal intervention is an integrated approach addressing multiple risk factors for patients with ischemic stroke to control blood pressure. This intervention combined three components, including health-related behaviors education, exercise, and telephone monitoring. It is possible that patients can improve their health when they receive specific knowledge and apply it to everyday practice to maintain well-being. Moreover, active exercise could reduce stimulation of the sympathetic nervous system and strengthen the blood vessels to lower blood pressure. This intervention has been implemented and reported good progress in blood pressure control among patients with ischemic stroke in other countries (Chen et al., 2022; Wajngarten & Silva, 2019). However, few studies have explored its effect among patients with ischemic stroke in Thailand. Thus, this study aimed to examine the effect of the multimodal intervention on blood pressure in patients with first ischemic stroke. Methods Study Design A randomized controlled trial was employed in this study. Consolidated Standards of Reporting Trials (CONSORT) Statement (Schulz et al., 2010) was used to report the study. Participants/Samples Adults diagnosed with first ischemic stroke and visiting the outpatient department to receive continuing care from Buddhachinaraj Hospital and Naresuan University Hospital were recruited into this study. The inclusion criteria were: 1) adult aged 45 years and over, 2) diagnosed with ischemic stroke, 3) severity of stroke in mild to moderate when completing the National Institute of Health Stroke Scale-Thai version (NIHSS-T) confirmed by a physician at stroke units, 4) ability to perform activities of daily living by themselves, 5) had a caregiver who supported them during exercise, and 6) had a telephone and line application. In addition, the participants were excluded if they had a severe disability, mental illness, disabling chronic diseases, or participated in another trial. The sample size was calculated using the G*power program. The effect size was estimated based on a previous study (Kirk et al., 2014) which had similar characteristics to the study, including 1) patients with minor stroke, 2) using the multiple components intervention, and 3) the measured outcome was blood pressure. For this study, the minimal sample size was 60, calculated based on the estimated effect size of 0.24, the power of the test of 0.95, the significance level of 0.05, and four repeated measurements. A cluster randomization technique was utilized to select the study settings in the 2nd public health region of Thailand. Since there were five provinces in this region, a simple random sampling technique was used to select one province. Consequently, Phitsanulok province was chosen. This study was conducted at two tertiary hospitals, which only have a stroke unit in Phitsanulok province. These hospitals utilized the clinical practice guidelines for ischemic stroke 2019 recommended by the Neurological Institute of Thailand. All patients who had a first-event stroke from May 2021 to July 2021 were screened. First, eligible participants were identified through active screening by a research assistant. Then, a systematic randomization technique was utilized to assign the participants into experimental and control groups. This systemic randomization was performed until it reached 30 participants in each group (Figure 1). Figure 1 Flowchart of the sampling procedure Instruments Four parts of instruments were used in this study, including: A demographic data form was developed by researchers to collect the general characteristics, including age, gender, education level, and marital status. The clinical characteristics included smoking, co-morbidity-related ischemic stroke, medication taking, and exercise. Barthel index score (Dajpratham et al., 2006) was used to assess the ability to perform activities of daily living. Items are rated in terms of whether individuals can perform activities independently (scored as 10), with some assistance (scored as 5), or are dependent (scored as 0). A total score was out of 100. The interpretation of mobility and self-care are as follows, a score of 0-19 suggests total dependence, 20-39 severe dependence, 40-59 moderate dependence, 60-79 slight dependence, and 80-100 independent. Inter-rater reliability for the mobility subscale was 0.85, and the self-care subscale was 0.86. The National Institute of Health Stroke Scale-Thai (NIHSS-T) version (Nilanont et al., 2010) was used to assess stroke severity. This instrument measures 15 neurological items. There are 3- or 4- point scales for each item, resulting in a total score of 0-42. It assesses consciousness, motor, perception, and cognition in patients with stroke. The scale interpretation consisted of four categories: very severe impairment (score ≥ 25), severe impairment (15–24), mild to moderate (5–14), and mild impairment (≤ 4). Inter-observer reliability of the total NIHSS-T score was 0.99. The Spearman rank correlation coefficient was 0.53. A sphygmomanometer was used to measure blood pressure. A calibrated automated device OMRON HBP-1300 was used by two research assistants. It had a proper-sized cuff and sitting position after 5 minutes of rest and 1 minute apart. The cut point of well-controlled blood pressure in patients with stroke is less than 130/80 mmHg (Whelton et al., 2018). Therefore, the average of the second and third measures was used. Measuring blood pressure was based on the Eight Joint National Committee (JNC 8) guidelines (James et al., 2014). It was calibrated once a year by Buddhachinaraj Hospital’s technicians. Interventions The multimodal intervention in this study was developed based on a literature review and selected studies with the highest effect size (Chiu et al., 2008; Kono et al., 2013; Moore et al., 2015; Wang et al., 2014). The components and activities of the multimodal intervention are explained in the following. The first component was the education component, developed to improve patients’ knowledge of appropriate behavior after the first ischemic stroke. The knowledge components included 1) eating a healthy diet, 2) limiting salt intake, 3) increasing physical activities, 4) quitting smoking and avoiding secondhand smoke, and 5) medication adherence. The first component was divided into four sessions. Each session was set one by one based on the patient’s characteristics and because the patients were admitted at different times. However, the participants received knowledge in one session per week, with a total of 4 weeks. The second component was the 12-week exercise component. This component was developed to train the exercise skills of the participants, which consists of 1) walking exercise 3 times/week (40-minute/session) and 2) resistance exercise 2 times/week (20-minute/session). The third component was telephone monitoring. This component instilled a positive attitude and a follow-up telephone for 20 minutes/time as strategies to improve adherence to interventions. Patients recorded health behaviors about eating, physical activity and exercise, smoking, and medication intake in self-monitor form every week. For each telephone follow-up, the researcher discussed the participants’ health behaviors, barriers-related behaviors, and approaches to address the barriers and gave some suggestions related to the participants’ needs. The telephone follow-up was done on week 8th and week 12th. This intervention was validated for content validity by five experts: 1) a physician (an expert in ischemic stroke), 2) a nurse instructor (an expert in ischemic stroke and behavior change), 3) a physical therapist (an expert in ischemic stroke and has experience in stroke rehabilitation), 4) a nutritionist (an expert in diet patients with ischemic stroke), and 5) an Advanced Practice Nurse (APN) (an expert in nursing care in patients with stroke). The revised program was tried out on five patients with first ischemic stroke with similar characteristics to the study population. Data Collection Data were collected from May 2021 to October 2021 by the researcher and two research assistants. The research assistants were nurses, and they were trained before data collection. The researcher's assistant asked the participants in both groups to measure baseline blood pressure before starting the intervention. Then the experimental group was given the multimodal intervention, while the control group was provided the usual care. The research assistants repeatedly measured the control and intervention groups’ blood pressure in the 4th week, 8th week, and 12th week, and the accurate measurement was based on the clinical practice guideline (Whelton et al., 2018). The researchers were concerned about the data collection during the COVID-19 pandemic and the protection of the participants and their family members. Thus, this study followed the announcement of the Phitsanulok Provincial Public Health office and taking D-M-H-T-T (Distancing, Mask wearing, Hand washing, Temperature check, and Thaichana application) precautions to prevent the spread of COVID-19. In addition, the researcher completed two COVID-19 vaccines in the first month of collecting data. The researcher tested ATK 2-3 days before contacting participants. During collecting data, no participants or their family members reported positive cases of COVID-19. Details of the data collection in each group are in the following. The experimental group The research assistants were asked to assess the demographic data. Baseline (week 0): The research assistants measured blood pressure following the guideline. The participants received the five education booklets for ischemic stroke patients and the self-monitoring form. Then, the participants were trained to perform walking exercises and resistance exercises by researchers. At this step, family members or caregivers observed and walked together with the participants to prevent injury and encourage them to exercise. The researchers provided the sphygmomanometers for these participants. Then, the researcher trained participants and family members to measure blood pressure following the guidelines (James et al., 2014). From 1st to 4th week: The researcher provided four education sessions (40 minutes per week). Each session was set at the stroke unit or their houses. The participants received knowledge in one session per week, with a total of four weeks. The sessions include 1) providing knowledge about eating a healthy diet for the first ischemic stroke patient (40 minutes at week 1st), 2) providing knowledge about limited salt intake (40 minutes at week 2nd), 3) providing knowledge about increasing physical activities and quit smoking and avoid secondhand (40 minutes at week 3rd), and 4) providing knowledge about medication (40 minutes at week 4th). In addition, participants performed exercises, and the family member or caregiver was closely observed during the participants walking at their house. At 4th week, the participants were measured blood pressure by the research assistants. From the 5th to the 12th week: The participants performed exercises and recorded their behavior data in self-monitoring form. The participants were measured blood pressure by the research assistants in the 8th week and 12th weeks. The researcher made a phone call to the participants to discuss and suggest their activities based on the procedure of the multimodal intervention in the 8th week and 12th weeks. The control group Baseline (week 0): The participants were asked to respond to demographic data. The research assistants measured the participants’ blood pressure. From 1st week to 12th week: in discharge planning, the participants received general and very brief information covering lifestyle modification in discharge plans from nurses in the stroke unit. Physicians provided medication and took blood exams at the neurological outpatient clinic when they had a follow-up. The researcher made an appointment and measured their blood pressure in the 4th week, 8th week, and 12th week. Data Analysis The data were analyzed using Statistical Package for the Social Sciences (SPSS) version 22.0 for Windows. The comparison of demographic characteristics between groups at baseline was examined using a t-test for continuous variables and Chi-square tests for categorical variables. To examine the effect of the intervention on blood pressure, repeated ANOVA was used to test the difference in mean scores at different points in time. All relevant assumptions were tested prior to the analysis process. Statistical significance was accepted for p-value <0.05. Ethical Considerations This study was approved by the Research Ethics Committee of Human Subjects of Chulalongkorn University (Reference COA No.046/2021) and the Research Ethics Committee of Human Subjects of Buddhachinaraj Hospital, Phitsanulok province, Thailand (Reference No.027/64). The study participants were asked to sign a consent form. The researchers provided information about study objectives, procedures, and rights, including the right to withdraw until data analysis was started without affecting their quality of service. The confidentiality and anonymity of participants were protected throughout the study. Results Characteristics of the Participants In the experimental group, the mean age of the participants was 60.70 years old (SD = 6.53), ranging from 48 to 70 years old. Most of the participants were males (93.33%), married (86.67%), and completed primary school (63.33%). In contrast, in the control group, the mean age of the participants was 62.93 years old (SD = 5.18), ranging from 52 to 71 years old. The majority of the control group were males (86.67%), married (83.34%), and completed primary school (73.33%). There were no statistically significant differences between the experimental and control groups regarding the characteristics, specifically gender, age, marital status, and education level (Table 1). Table 1 Demographic characteristics of the study participants at baseline (N = 60) Demographic characteristics Experimental group (n = 30) Control group (n = 30) χ 2 p-value n (%) n (%) Gender 0.74b 0.39 Male 28 (93.33) 26 (86.67) Female 2 (6.67) 4 (13.33) Age 0.54a 0.76 45-59 12 (40.00) 10 (33.33) 60-69 17 (56.67) 18 (60.00) 70-79 1 (3.33) 2 (6.67) Marital status 2.82a 0.24 Single 3 (10.00) 1 (3.33) Married 26 (86.67) 25 (83.34) Divorced/Widow 1 (3.33) 4 (13.33) Educational level 2.11a 0.55 Primary school 19 (63.33) 22 (73.33) Secondary school 8 (26.67) 5 (16.67) Certificate 1 (3.33) 0 (0.00) Bachelor 2 (6.67) 3 (10.00) a = Chi-Square b = Fisher’s Exact Test *p-value <0.05 Table 2 shows the clinical characteristics of the participants. For the experimental group, over half of the participants reported currently smoking (56.67%), and almost all of them did not do exercise (96.67%). Concerning co-morbidity, many were diagnosed with hypertension (70.00%). However, all participants (100%) used prescribed antiplatelet and anti-hyperlipidemic medications. Stroke severity was assessed using NIHSS-T, and the mean score was 1.27 (SD = 0.45). The capability of the participants to perform the activity of daily life was assessed using the Barthel index (BI), and it was found that the mean score was 97.33 (SD = 3.88), ranging from 96 to 100. Table 2 Clinical characteristics of participants (N = 60) Clinical characteristics Experimental group (n = 30) Control group (n = 30) χ 2 p-value n (%) n (%) Smoking 2.51a 0.29 Never smoked 3 (10.00) 7 (23.33) Smoked in the past 10 (33.33) 11 (36.67) Currently smoked 17 (56.67) 12 (40.00) Exercise 0.35b 0.55 No exercise 29 (96.67) 28 (93.33) Exercise 1 (3.33) 2 (6.67) Co-morbidity-related ischemic stroke 3.52a 0.62 No co-morbidity 9 (30.00) 4 (13.33) HT 4 (13.33) 4 (13.33) HT and DLP 8 (26.67) 13 (43.34) HT and DM 2 (6.67) 1 (3.33) HT, DLP, and DM 6 (20.00) 7 (23.34) HT, DLP, and HD 1 (3.33) 1 (3.33) Medication taking 8.66a 0.12 Anticoagulant drug 30 (100.00) 30 (100.00) Antihypertensive drug 20 (66.67) 26 (86.67) Antihyperlipidemic drug 30 (100.00) 30 (100.00) Diabetic drug 8 (26.67) 7 (23.34) Anti-hypouricemic drugs 1 (3.33) 1 (3.33) Alpha-adrenergic blocker 1 (3.33) 1 (3.33) NIHSS-T 0.32 b 0.57 Score 1 22 (73.33) 20 (66.67) Score 2 8 (26.67) 10 (33.33) BI score 6.04a 0.11 ≤85 0 (0.00) 2 (6.67) 86-90 5 (16.67) 2 (6.67) 91-95 6 (20.00) 12 (40.00) 96-100 19 (63.33) 14 (46.66) Abbreviations: HT=hypertension, DLP=dyslipidemia, DM=diabetes mellitus, BPH= benign prostate hyperplasia, HD=heart disease, NIHSS-T = the National Institute of Health Stroke Scale-Thai version, BI = Barthel index a = Chi-Square b = Fisher’s Exact Test *p-value <0.05 In comparison, nearly half of the study participants in the control group were currently smoked (40.00%), and most of them did not do exercise (93.33%). Concerning co-morbidity, many of the participants were diagnosed with hypertension (86.67%). All participants (100%) used prescribed antiplatelet and anti-hyperlipidemic medication. Stroke severity was assessed using the NIHSS-T, and the mean score was 1.33 (SD = 0.48). The mean score of the participants’ capability to perform daily life activities using the Barthel index (BI) was 96.33 (SD = 4.34), ranging from 96-100. It was noted that there were no statistically significant in terms of smoking status, co-morbidity, medication taking, the severity of the stroke, and capability of the participants to perform the activity of daily life between the experimental and control groups. Blood Pressure Level among Patients with First Ischemic Stroke Table 3 demonstrates the blood pressure level between the experimental and control groups at four points. In the experimental group, the mean systolic blood pressure score decreased more than the control group in the 8th week and 12th week (p = 0.003, p <0.001, respectively). In addition, the mean score of diastolic blood pressure in the experimental group decreased more than the control group in the 8th week and 12th week (p = 0.003, p <0.001, respectively). The mean score of systolic blood pressure and diastolic blood pressure decreased from the 8th week (Figure 2). Table 3 Level of blood pressure between the experimental and control groups at four points in time Time Experimental group (n = 30) Control group (n = 30) t p-value Mean SD Mean SD Baseline (week 0) SBP 142.87 10.57 141.90 9.98 0.387 0.702 DBP 89.67 7.16 87.93 7.18 0.919 0.366 4th week SBP 141.33 11.31 141.40 11.46 -0.022 0.983 DBP 88.27 7.41 88.73 7.63 -0.239 0.812 8th week SBP 135.97 9.56 144.10 8.83 -3.257 0.003* DBP 84.60 5.47 89.53 6.09 -3.279 0.003* 12th week SBP 131.90 8.59 142.93 7.76 -5.967 0.000* DBP 80.53 5.69 89.43 5.20 -6.940 0.000* SBP, Systolic blood pressure. DBP, Diastolic blood pressure * p-value <0.01 Figure 2 Mean score of systolic blood pressure and diastolic blood pressure between groups at 4 points in time Effect of the Multimodal Intervention on Blood Pressure Normality, sphericity, and homogeneity of variance were tested, and the assumptions of repeated measures ANOVA were not violated. The results showed that participants in the experimental group had statistically significantly different mean blood pressure scores between baseline, 4th week, 8th week, and 12th week (p <0.05). In contrast, the control group had no statistically significant difference in mean blood pressure scores (p >0.05). In addition, the participants in the experimental group who received the multimodal intervention had the average systolic blood pressure and diastolic blood pressure better than the participants in the control group who received usual care (F (1, 58) = 4.059, p = 0.049; F (1, 58) = 4.515, p = 0.038, respectively) (Table 4). Table 4 Effect of the multimodal intervention on blood pressure control (between time differences) Blood pressure Time Experimental group (n = 30) Control group (n = 30) F-test between group p-value Mean ± SD F-test within group Mean ± SD F-test within group Systolic blood pressure Baseline (week 0) 142.87 ± 10.57 44.121** 141.90 ± 9.98 1.214 4.059 0.049 4th week 141.33 ± 11.31 141.40 ± 11.46 8th week 135.97 ± 9.56 144.10 ± 8.83 12thweek 131.90 ± 8.59 142.93 ± 7.76 Diastolic blood pressure Baseline (week 0) 89.67 ± 7.16 54.214** 87.93 ± 7.18 0.948 4.515 0.038 4th week 88.27 ± 7.41 88.73 ± 7.63 8th week 84.60 ± 5.47 89.53 ± 6.09 12thweek 80.53 ± 5.69 89.43 ± 5.20 ** p-value <0.05 Due to the effects of time changed mean score of systolic and diastolic blood pressure in the experimental group, at least one pair was found. Thus, the analysis of the mean difference of each pair in each group using Post Hoc tests comparisons was needed. Table 5 presents the comparison of systolic blood pressure of the experimental group across four points of time. The results revealed that the mean systolic blood pressure score at baseline was higher than in the 4th week, 8th week, and 12th week, respectively. Systolic blood pressure was statistically decreased over time comparing between baseline, 8th week, and 12th week (p <0.001, p <0.001, p <0.001, respectively). The biggest difference was found in the 12th week compared to the baseline. Considering the mean difference in each pair over time, the systolic blood pressure started to decrease statistically significantly in the 8th week (p <0.001). The systolic blood pressure level tended to decrease from the 8th week to the 12th week. Table 5 Pairwise comparison of systolic blood pressure of the experimental group across four points in time (n = 30) Time to measure Mean Baseline 4th week 8th week 12th week Baseline 142.87 4th week 141.33 1.53 8th week 135.97 6.90* 5.37* 12th week 131.90 10.97* 9.43* 4.07* * p-value <0.001 A comparison of the diastolic blood pressure of the experimental group across four points of time is presented in Table 6. The results showed that the mean score of diastolic blood pressure at baseline was higher than the 4th week, 8th week, and 12th week, respectively. Diastolic blood pressure was statistically decreased over time comparing between baseline, 8th week, and 12th week (p <0.001, p <0.001, p <0.001, respectively). The biggest difference was found in the 12th week compared to the baseline. Considering the mean difference in each pair over time, the diastolic blood pressure started to decrease statistically significantly in the 8th week (p <0.001). The diastolic blood pressure level tended to decrease from the 8th to the 12th week. In addition, the 12th week was significantly lower than the 4th and 8th weeks, and the 8th week was significantly lower than the 12th week. Table 6 Pairwise comparison of diastolic blood pressure of the experimental group across four points of time (n = 30) Time to measure Mean Baseline 4th week 8th week 12th week Baseline 89.67 4th week 88.27 1.40 8th week 84.60 5.07* 3.67* 12th week 80.53 9.13* 7.73* 4.07* * p-value <0.001 Discussion The study showed that the multimodal intervention decreased systolic and diastolic blood pressure in patients with first ischemic stroke. In addition, the systolic and diastolic blood pressure of the participants in the experimental group was reduced in the 8th week and 12th week. These results are consistent with earlier studies that systolic and diastolic blood pressure is decreased in the 8th week or 12th week rather than at baseline (Kono et al., 2013). Moreover, systolic and diastolic blood pressure in the experimental group was significantly decreased than in the control group in the 8th week and 12th week. Regarding the results of this study, the multimodal intervention that consisted of various components, including education, exercise, and telephone monitoring, affected blood pressure control among patients with first ischemic stroke. This may be because giving education could optimize their engagement in learning experiences (Merriam & Bierema, 2014). In addition, adequate education, including eating healthy food, taking salt restriction, increasing physical activities, quitting smoking, and medication adherence, increase the level of knowledge and understanding of the patients to change risk behaviors for controlling blood pressure in patients with first ischemic stroke. Patients with ischemic stroke who performed regular exercise within 12 weeks resulted in better blood pressure control. This finding indicates that blood pressure can be controlled by enhancing physical activity, and it needs time to control it. This result is consistent with a previous study that continuous exercise lowers stimulation of the sympathetic nervous system, strengthens the blood vessels, increases muscle fat metabolism, and decreases fat in adipose tissue, which lowers cholesterol and builds muscles (Abou Elmagd, 2016). Moreover, utilize glucose without insulin to encourage the stabilization of plaque and beneficial vascular wall modifications for lowering blood pressure (Abou Elmagd, 2016). Exercise and skills of self-blood pressure monitoring gained their skill, enhanced their attitude, drove them to maintain behaviors, and avoided a further stroke. The combination of education and exercise intervention encourages patients with ischemic stroke to perform their risk behaviors change (eating healthy food and intake salt restriction, increasing physical activities and 12-week exercise, quitting smoking, and medication adherence) and gain their physiological change as regular exercise made patients’ hearts good function and could pump blood more efficiently. As a result, the force on patients’ arteries decreased, reducing patients’ blood pressure (Billinger et al., 2012). A lower sodium intake helps the body retain less salt and water. It also inhibits sodium chloride reabsorption in the distal convoluted tubule, which results in a reduction in extracellular fluid and a decrease in peripheral resistance to lowering blood pressure (Larsson et al., 2016), reducing saturated, trans fats and statin that helps decrease cholesterol (Lim & Choue, 2013). In addition, avoiding sweetened foods and diabetes drugs reduce blood glucose which affects to vessel wall (Lakkur & Judd, 2015). Quit smoking reduces atrial stiffness and improves endothelial cell function to lower blood pressure (Chadwick et al., 2015). However, evidence suggests that mixing education and exercise intervention does not always lead to controlling blood pressure. Because most patients cannot sustain their behaviors changing as daily activities. Telephone monitoring was used to empower and consult during the intervention. These strategies improved adherence to intervention (Flemming et al., 2013). It is the process of attending to one’s actions and recording the presence or absence of target behaviors (McBain et al., 2015). As a result, the patients have increased knowledge, skill, and empowerment in blood pressure control and avoiding further strokes (Ovaisi et al., 2011). The RCT design, which examined the effectiveness of a multimodal intervention, was one of the strengths of our study. It is a mixed education, exercise, and telephone monitoring intervention derived during the hospital to the community setting. Furthermore, the results of this study are consistent with previous research (Chiu et al., 2008; Flemming et al., 2013; Kono et al., 2013). However, the study might have various limitations. Firstly, the limitation of this study was the small sample size. Thus, a large number of participants is recommended for future studies, and comparing the results in many settings is necessary to confirm the rigorous procedures of the program. Secondly, the time for substantial change to control blood pressure was relatively short. Therefore, long-term research needs to be explored in future studies. However, the long-term outcomes should be evaluated, and concerned about the cost of intervention should be compared with the long-term effectiveness. It is noteworthy that our study found that most participants had family members who took care of and encouraged them to maintain the intervention activities. Thus, future studies should include family members in this program as social support. Lastly, there was a significant decrease in blood pressure in older adults (mean = 61.82 years, SD = 5.95). It is to observe the effect of the multimodal intervention in the young stroke compared with the adult age group. Implications for Nursing Practice The results of this study are relevant to nursing practice. Implementing the multimodal intervention by providing knowledge, enhancing exercise continuously, and telephone monitoring can control blood pressure in patients with first ischemic stroke. For example, patients with first ischemic stroke should be trained to measure their own blood pressure regularly. The nurses should encourage patients with first ischemic stroke to participate in the multimodal intervention, which helps them understand stroke and maintain a healthy lifestyle, such as exercising regularly, eating healthy food, and stopping smoking. In addition, nurses should monitor whether the patients with first ischemic stroke can follow these guidelines to control their blood pressure. During the follow-up period, nurses should evaluate the impacts of this intervention on blood pressure. Any issues and concerns during the program occurred should be discussed between nurses and patients. In addition, healthcare administrators should continuously organize key people who can manage and follow the patients for about three months. These key persons can then deliver the information to community nurses who can provide holistic care to monitor clinical outcomes such as blood pressure. Conclusion Our study shows that the components of the multimodal intervention, including educational sessions, exercise, and telephone monitoring enhance the ability of patients with first ischemic stroke to control their blood pressure over 12 weeks compared to those in the control group. These findings indicate that the intervention is effective and can be implemented for patients with first ischemic stroke in the outpatient department. However, other studies with a more extended follow-up period should be conducted to evaluate the impacts of this intervention on blood pressure among this population. Acknowledgment The authors thank all participants who willingly participated in the research activities. Declaration of Conflicting Interest All authors declared that there are no conflicts of interest. Funding The authors have no external funding for this study. Authors’ Contributions All authors contributed equally to the conception and design, acquisition of data, analysis, and interpretation of data. All were given final approval of the version to be submitted and any revised versions, as well as agreed to be accountable for all aspects of the work. Authors’ Biographies Orapin Jullmusi, RN is a PhD candidate at the Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand. Jintana Yunibhand, PhD, APN is an Associate Professor at the Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand. Chanokporn Jitpanya, PhD, RN is an Associate Professor at the Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand. Data Availability Due to privacy and ethical concerns, neither the data nor the source of the data can be made available. ==== Refs References Abou Elmagd, M. (2016). Benefits, need and importance of daily exercise. International Journal of Physical Education, Sports and Health, 3 (5 ), 22-27. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-118 10.33546/bnj.1308 Original Research Developing an android-based application for early detection of postpartum depression symptoms in Indonesia https://orcid.org/0000-0003-1477-2311 Nurbaeti Irma * https://orcid.org/0000-0001-8512-2514 Syafii Moch https://orcid.org/0000-0002-8805-3873 Lestari Kustati Budi Nursing Program, Faculty of Health Sciences, Universitas Islam Negeri Syarif Hidayatullah Jakarta, Indonesia * Corresponding author: Irma Nurbaeti, M.Kep., Ph.D, Faculty of Health Sciences Universitas Islam Negeri Syarif Hidayatullah Jakarta. Jl. Kertamukti No.5, Ciputat, Tangerang Selatan, Banten, Indonesia. Email: irma.nurbaeti@uinjkt.ac.id Cite this article as: Nurbaeti, I., Syafii, M., & Lestari, K. B. (2021). Developing an android-based application for early detection of postpartum depression symptoms in Indonesia. Belitung Nursing Journal, 7(2), 118-124. https://doi.org/10.33546/bnj.1308 29 4 2021 2021 7 2 118124 12 1 2021 12 2 2021 16 3 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Postpartum depression has become a mental health problem in Indonesia. Screening symptoms of postpartum depression as early as one month during the postpartum period is needed. A smartphone application is considered one of the fastest ways for screening. Objective To develop an android-based application to early detect the symptoms of postpartum depression and evaluate its effectiveness. Methods The smartphone application was developed using Analysis, Design, Development, Implementation, and Evaluation (ADDIE) instruction model. The survey design was carried out to evaluate the effectiveness of the application among 109 postpartum mothers selected using convenience sampling. Data were collected from August to October 2019 in South Tangerang, Indonesia. Results The evaluation showed that the application is mostly positive. The appearance of the application is adequate (92.67%), easy to download (89.90%), understandable (96.33%), easy to fill-in (94.50%), beneficial (96.33%), new (90.83%), and reflecting psychological conditions (90.83%). Conclusion The symptoms of postpartum depression can be measured by the android-based application. It is therefore recommended to Indonesian mothers use this app to detect postpartum depression symptoms early. This app also helps nurses and midwives to prevent depression among postpartum mothers. Also, the app can be imitated by other developers for non-Indonesian mothers. ADDIE model digital application android postpartum depression smartphone nursing Indonesia ==== Body pmcPostpartum depression is a serious mental disorder after childbirth, and it is considered a health problem in the community (O’Hara & McCabe, 2013). The World Health Organization (WHO) declared 2017 as the year of depression, and it is predicted in 2030 that depression will be the second leading cause of death after heart disease. Based on the population, postpartum mothers are the second contributor to depression after the adolescent population. This is likely because, in the postpartum period, an average mother is three times more likely to develop depression than other periods (WHO, 2017). Postpartum depression can be called a hidden disease and a silent killer because postpartum depression is not like other mental disorders, such as psychosis or bipolar disorder. Postpartum depression is often invisible, and people will recognize it as a disease if the mother has committed acts to injure herself or her baby, such as abandoning, throwing away, strangling, or killing (Field, 2010; Garthus-Niegel, Ayers, Martini, Von Soest, & Eberhard-Gran, 2017; Hanington, Ramchandani, & Stein, 2010). The prevalence of postpartum depression exists in the world. The rate of postpartum depression is between 10% to 40% in the United States of America and European countries (Fiala, Švancara, Klánová, & Kašpárek, 2017; Werner, Miller, Osborne, Kuzava, & Monk, 2015). Similarly, the prevalence in Asia’s countries is between 10% to 40% (Kawai et al., 2017; Yusuff, Tang, Binns, & Lee, 2015). Whilst, the prevalence of postpartum depression in Indonesia is between 15% - 28% (Idaiani & Basuki, 2012; Nurbaeti, Deoisres, & Hengudomsub, 2018). Although postpartum depression exists in the community, its symptoms are not detected early. Almost all the signs of depression begin after a month of postpartum (WHO, 2016). O’Hara and McCabe (2013) stated that the first six months after delivery might represent a high-risk time for postpartum depression. Primipara mothers also have significant symptoms of postpartum depression than multipara mothers at one month of the postpartum period (Qandil, Jabr, Wagler, & Collin, 2016). According to hospital regulation, a mother will have early discharge on the second day after normal delivery or the fifth day for mothers with cesarean section. A mother usually has a postpartum follow-up, generally on the seventh day, when asked for a checkup. Many mothers, after months, have become less notice of the depression symptoms, which may lead to severe depression, and the babies are at risk of harm. Screening for postpartum depression in the health service is not available yet nowadays. However, the role of health workers, including nurses, midwives, doctors, and psychologists, to provide a referral system for mothers diagnosed or screened with postpartum depression is very important. If the screening is performed as early as possible, counseling by trained health workers will be more effective in reducing the symptoms of depression. On the other hand, a stigma towards postpartum mothers with mental health problems in the community also exists. The stigma is related to mood and mental disorder, feelings of disgrace, embarrassment, afraid labeling, and less understanding or less support from family or relatives. In fact, stigmatization towards mothers who have a mental illness is well-known to impede help-seeking (Schmied et al., 2016). In Indonesia, few women are unlikely to seek help from anyone for mental and psychological issues after childbirth because of the stigmatization. Most likely, they seek from family and relatives. This is another challenge both for mothers and healthcare providers. Therefore, to cope with those problems, an android-based application was developed in this study, considering every mother in Indonesia has at least one smartphone today. This will help mothers to identify the depressive symptoms as early as possible. This study described the application development using Instruction Systems Design (ISD) or Analysis, Development, Design, Implementation, and Evaluation (ADDIE) Model and evaluated its effectiveness. Developing a smartphone application using the ADDIE model The instructional systems design (ISD) is a systematic method of developing education and training programs to improve performance (Battles, 2006). The ISD process involves five steps: analysis, development, design, implementation, and evaluation (ADDIE). The concept of ISD has been emerged since the early 1950s and firstly established in 1975. The ADDIE model had been created by the Center for Educational Technology (CET) at Florida State University. The first project of the ADDIE model was for the US Army and adapted by all the US Armed Forces (Hannum & Briggs, 1982). In this study, we developed an android-based application using the ADDIE model as the following: Analysis This step aims to analyze the system regarding its characteristics, importance, and limitations and formulate health workers’ needs of the system. We analyzed the application by doing an in-depth interview with nurses, medical doctors, and midwives who work in outpatient and inpatient units in hospitals in Tangerang Banten Province and Sukabumi West Java Province, Indonesia. The results indicated that most postpartum mothers often come late to the hospitals after the symptoms of depression become severe. For that reason, all agreed that they need an innovation using a smartphone application to detect the signs of postpartum depression since a smartphone has become a part of everyone’s life. Design In this step, the outline, description, and contents of the application are created (Hadi et al., 2017). We worked together closely with a software developer based on the results of the analysis step. The design related to pictures, flow, and the system used was discussed. The blue color in the initial logo display was chosen because depression refers to the word "blue," which illustrates the incidence of postpartum depression as a blue event for the mother and baby. We also searched the literature for finding instruments to measure postpartum depression and the effectiveness of the application in terms of ease of use, language, appearance, and benefits. Development We created the application based on the design step (Hadi et al., 2017). In this study, the app development was android based, with the name of tes depresi (depression test) or Initiative Maternal Screening Depression (IMSD) available in Google PlayStore (https://play.google.com/store/apps/details?id=uinjkt.tesdepresimaternal). The research team developed this app under Irma Nurbaeti’s name in 2019, and it is available only in the Indonesian language. No login is required for users. We provide the figures of the app for clarity. Cover page Figure 1 Cover of the application Characteristics of mother and child In this app, a mother is asked to provide their information about the mother’s picture, health personnel who recommended using the application (if any), socio-demographic characteristics, current obstetric condition, and current baby’s condition (See Figure 2). Figure 2 Characteristics of mother and child including name, address, date of birth, religion, level of education, working status, married status, number of children alive, number of children died and type of childbirth, current baby gender, and current newborn weight The Modified Edinburgh Postpartum Depression Scale (EPDS) – Indonesian version Figure 3 shows the instrument used to detect postpartum depression using the Modified Edinburgh Postpartum Depression Scale (EPDS). The EPDS was developed by Cox, Holden, and Sagovsky (1987), and we had granted permission to use the instrument in this application. The original developer stated that the EPDS is not a diagnostic tool; therefore, we describe that our app is a tool for screening signs and symptoms of postpartum depression, not a tool for medical diagnosis of postpartum depression. The Indonesia version of EPDS has already existed since 1998, first translated by Kusumadewi, Irawati, Elvira, and Wibisono (1998). Figure 3 Modified EPDS - 12 items Indonesia version In this study, we added two items, numbers 10 and 12, suitable for symptoms of postpartum depression in Indonesian mothers. So, the questionnaire consists of 12 items. The validity test of the modified instrument was applied using Spearmen rho, with the results ranged from 0.347 – 0.778. The reliability test was also conducted using internal consistency, with a Cronbach alpha of 0.78. This indicates that all 12 items of the modified EPDS were valid and reliable. Output The questionnaire uses a rating score (0-36), with normal/non-depressed category (0-12), mild to moderate depression (13-15), and severe depression category (16-36) (Bhusal, Bhandari, Chapagai, & Gavidia, 2016; Töreki et al., 2013; Underwood, Waldie, D’Souza, Peterson, & Morton, 2017). Based on the score, a follow-up recommendation was made. If there is no depression or normal, a mother is recommended to keep contact with a nurse or a midwife. If having mild or moderate depression, it is suggested to consult a Psychologist. If a mother has severe depression, she is advised to go to a Psychiatry in the nearest hospital near her place. The example of the output can be seen in Figure 4. Figure 4 Screening results and recommendation Implementation The implementation phase includes testing digital application prototypes to participants (Fajriya, Supriyana, Bahiyatun, & Widyawati, 2017; Kholifah, Supriyana, Bahiyatun, & Widyawati, 2017). In this study, the smartphone application was tested in postpartum mothers, and a survey design was carried out to evaluate the application. Of 123 postpartum mothers who had been contacted, 109 respondents were included using convenience sampling. The inclusion criteria of the mothers were (1) a woman giving birth with lived infant(s), (2) married status, (3) a mother who had no history of mental illness, (4) a mother who was not being treated for complications, (5) could read Bahasa Indonesia, (6) having a smartphone, and (7) agreed to participate in the study. The study setting was conducted at South Tangerang City, Banten Province, Indonesia, for two months, from the second week of August to the second week of October 2019. This application has been registered at PlayStore (Figure 1). Prior to data collection, the study was approved by the Ethical Committee, Faculty of Health Science, Universitas Islam Negeri Syarif Hidayatullah Jakarta, Indonesia, with approval number: Un.01/F.10/KP.01.1/KE. SP/07.08. 001/2019. The study permission was also obtained from the Head of District, Ministry of Health, South Tangerang District, Indonesia, in the study setting. The researchers and two research assistants did the data collection. The training was conducted to prepare the research assistants about the objective procedure of the study and how to operate the application. After getting a permission letter, the researchers or research assistants had contacted the hospitals, especially the Head of Maternal and Child Units, to identify eligible participants. Potential participants who met the inclusion criteria were invited to participate in the study. Each participant was asked to sign a written informed consent once they agreed to participate. They were also able to withdraw from the study without any penalty. Their identities were kept confidential. After the agreement, the researchers and research assistants visited each participant’s home. During data collection, the participants were asked to download the application and follow the procedure (filled in the questionnaire). Data collection in each participant approximately spent from 10 to 15 minutes. Evaluation In this step, the android-based application has been evaluated by 109 postpartum mothers using the questionnaire. Table 1 shows the characteristics of the participants, in which the level of education of the participants tended to be similar between the elementary, high school, and graduated school, 36.70%, 28.44, and 34.86%, respectively. More than half of the participants (63.30%) were housewives, and more than two-third (66.06%) had two children and more. Of all participants, 74.31% had a normal birth, and 55.05% had a baby girl at the recent childbirth. The participants’ ages ranged from 16 to 50 years old (mean 30.98, SD 6.18). Table 1 Characteristics of the participants (N=109) Characteristic Category n % Level of education Elementary school 40 36.70 High school 31 28.44 University 38 34.86 Working status Housewives 69 63.30 Working 40 36.70 Number of children One child 37 33.94 Two or more 72 66.06 Type of labor Normal 81 74.31 Cesarian 28 25.69 Baby gender Boy 49 44.95 Girl 60 55.05 Table 2 shows the results of the app evaluation. The app was considered very easy (55.96%) and easy (33.94%) to download. Almost all participants (94.50%) also responded quite easy to fill out the application, and most of them (96.33%) answered the language used in the application was easy to understand. The majority of the participants described the display or appearance of the application as very interesting (65.2%) and interesting (27.53%). While they also claimed that they never used a similar test before (90.83%). Most participants said it was useful (96.33%) and reflected their psychological condition (90.83%). Almost all respondents (97.25%) will recom-mend this application to others. Table 2 Evaluating of Application (N=109) Characteristic Category n % Easy to download the application Very easy 61 55.96 Easy 37 33.94 Remain difficult 6 5.50 Difficult 5 4.60 Easy to fill in the application Very easy 67 61.47 Easy 36 33.03 Remain difficult 1 0.90 Difficult 5 4.60 Language Very understandable 67 61.47 Understandable 38 34.86 Difficult to understand 4 3.67 Display of application Very interesting 71 65.14 Interesting 30 27.53 Less interesting 6 5.50 No-interesting at all 2 1.83 Previously used the similar application Yes 10 9.17 No 99 90.83 Beneficial Yes 105 96.33 No 4 3.67 Reflecting psychological conditions Yes 99 90.83 No 10 9.17 Recommended to others Yes 106 97.25 No 3 2.75 Implication for nursing and midwifery practice Several implications of this study for nursing and midwifery practice: First, the Android-based app developed in this study can be used by nurses and midwives in their practice, especially for postpartum care. The best time for screening postpartum depression is in the first month of postpartum (Nurbaeti et al., 2018). However, the gap persists, which the detection of postpartum depression among mothers still often missed due to the regulation of the hospitals in regards to the length of stay. So, the app can be used before, during, and after follow-up; or introduced during discharge planning. Second, considering the stigma that still exists in the Indonesian community towards mothers with depression and other mental health problems, the app is very useful for mothers for self-assessment of postpartum depression. Mostly the mothers do not want to come to hospitals to check their conditions due to the stigmatization. However, it is not the best solution; stop stigmatization among mothers is necessary to do. Third, the app should also be used in hospitals and public health centers in Indonesia. Many mothers often visit the public health centers first before going to the hospitals for follow-up. The app could be used in a routine postpartum program, especially in the early detection program in public health centers. Fourth, the app will help nurses and midwives explore and understand the mothers’ mental health based on the output category. At this point, the nurses and midwives may provide nursing and midwifery interventions to reduce the depression symptoms, and they should have the ability or improve their competency. Last, the app was easy to download and use, easy to fill-in, sound, new design, interesting, and reflected their current condition. Therefore, this study serves as an input or idea for non-Indonesian developers to help mothers detecting post-partum depression. Limitation of the study The application can be accessed only via android smartphone, not via i-phone or laptop/computer, which needs further development. The use of a descriptive survey might limit the evaluation of results of the effectiveness of the app. Therefore, further studies are required to measure the efficacy, accuracy, and conformity using experimental designs. Conclusion It can be concluded that screening for postpartum depression using the smartphone application was practical and easy to use by postpartum mothers to detect the symptoms of postpartum depression. This innovation could have a positive contribution to nursing and midwifery practice to help reducing depression among mothers. Supplementary Material Developing an android-based application for early detection of postpartum depression symptoms in Indonesia Click here for additional data file. Acknowledgment We thank the Faculty of Health Sciences Universitas Islam Negeri Syarif Hidayatullah Jakarta for granting ethical permission, the Health Officers in South Tangerang city who allowed to collect data, and the participants’ willingness to participate in this study. Declaration of Conflicting Interest There was no conflict of interest to declare. Funding This research was funded by Universitas Islam Negeri Syarif Hidayatullah Jakarta under the research grant scheme for collaborative research (Un.01/KPA/511/2019). Authors’ Contributions All authors contributed to the study’s conception and design. IN conceptualized the study. IN, KBL, and MS collected data. IN and MS performed data management and analyses. IN, KBL, and MS drafted the original version of the manuscript and provided critical revisions. All authors have approved the final manuscript. Authors’ Biographies Irma Nurbaeti, M.Kep.,Ph.D is a Lecturer at the Nursing Program of the Faculty of Health Scienc,e Universitas Islam Negeri Syarif Hidayatullah Jakarta, Indonesia. Moch Syafii, MM is a Lecturer at the Faculty of Health Science, Universitas Islam Negeri Syarif Hidayatullah Jakarta, Indonesia. Kustati Budi Lestari, M.Kep is a Lecturer at the Nursing Program of the Faculty of Health Science, Universitas Islam Negeri Syarif Hidayatullah Jakarta, Indonesia. Data Availability Statement The datasets generated during and/or analyzed during the current study are available in the supplementary file. ==== Refs References Battles, J. B. (2006). Improving patient safety by instructional systems design. BMJ Quality & Safety, 15 (suppl 1 ), i25-i29. 10.1136/qshc.2005.015917 Bhusal, B. R., Bhandari, N., Chapagai, M., & Gavidia, T. (2016). Validating the Edinburgh Postnatal Depression Scale as a screening tool for postpartum depression in Kathmandu, Nepal. International Journal of Mental Health Systems, 10 (1 ), 1-7. 10.1186/s13033-016-0102-6 26734070 Cox, J. L., Holden, J. M., & Sagovsky, R. (1987). Detection of postnatal depression: Development of the 10-item Edinburgh Postnatal Depression Scale. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-069 10.33546/bnj.2334 Original Research Social support and associated factors among family caregivers of older people in North-East Peninsular Malaysia https://orcid.org/0000-0001-6409-0947 Makhtar Aniawanis 1* Ab Ghani Nor Nadiya 2 https://orcid.org/0000-0002-0391-7493 Syed Elias Sharifah Munirah 1 https://orcid.org/0000-0001-7155-798X Mohamed Ludin Salizar 3 1 Department of Special Care Nursing, Kulliyyah of Nursing, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia 2 Hospital Kuala Krai, 1800 Kuala Krai, Kelantan, Malaysia 3 Department of Critical Care Nursing, Kulliyyah of Nursing, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia * Corresponding author: Aniawanis Makhtar, RN, PhD, Department of Special Care Nursing, Kulliyyah of Nursing, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia. Email: aniawanis@iium.edu.my Cite this article as: Makhtar, A., Ab Ghani, N. N., Syed Elias, S. M., & Mohamed Ludin, S. (2023). Social support and associated factors among family caregivers of older people in North-East Peninsular Malaysia. Belitung Nursing Journal, 9(1), 69-78. https://doi.org/10.33546/bnj.2334 12 2 2023 2023 9 1 6978 29 9 2022 27 10 2022 18 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background The negative health results associated with the family caregivers of older people can be alleviated with social support, which is considered a valuable resource. Hence, the factors contributing to social support need to be understood. Objective This study aimed to evaluate the social support associated with the family caregivers of older people. Methods A cross-sectional study was conducted among 231 family caregivers of older people conveniently selected from two districts in Kelantan, a state in the North-East Region of Peninsular Malaysia. Data were gathered between June to December 2021 using a Multidimensional Scale of Perceived Social Support (MSPSS) questionnaire. Descriptive statistics were used to summarize the data in frequencies and percentages. Independent t-test and one-way analysis of variance were used to examine correlations among variables. Results The mean scores of social support for family caregivers were significantly higher among their family (Mean ± SD; 5.44 ± 0.969) and other important people (5.25 ± 1.123) compared to their friends (4.84 ± 1.094). Caregivers’ gender and duration of caregiving were significant factors associated with social support (p <0.05). Conclusions The family caregivers received maximum support from their family and other important people, but they were less supported by their friends. This study also observed that the perceived social support of the caregivers of older people was affected by several factors, such as gender and duration of caregiving. This finding gives nurses and other healthcare workers the basic information they need to enhance nursing interventions and promote social support among those who care for older people, which can positively impact caregiving. caregivers social support older people demographic variables Malaysia nurses ==== Body pmcBackground By the year 2030, Malaysia’s older population will have increased by 15%, thereby increasing the needs of the aged population simultaneously (Nor & Ghazali, 2021). With increasing life expectancy and aging populations, the global prevalence of chronic diseases and the requirement for long-term care for people with comorbidities are rising. The National Health and Morbidity Survey (NHMS) 2019 conducted by the Ministry of Health (MOH) discovered that a total of 1.7 million adults, or 8.1% of Malaysia’s adult population, are prone to diabetes, high cholesterol, and hypertension, and these non-transmissible diseases usually required long-term care (Zhao et al., 2018), severe, and associated with decreased functional abilities (Yilmaz et al., 2012), and thereby increasing health care needs (Liu et al., 2013). In addition, older adults are more likely to have multimorbidity, which may increase the burden on their caregivers. In Malaysia, most older people live in communities and depend on their family members for caregiving. Family support is also essential in countries like Malaysia, where long-term care insurance and social security benefits are unavailable (Goh et al., 2013). Most aged patients in Malaysia rely on their family members for informal care (Ghazali et al., 2015). Very few Malaysian families can afford paid caregivers, whether trained or untrained (Goh et al., 2013). Furthermore, in Malaysia, the view is that family members should take responsibility for caring for the elderly as an expression of the cultural value of “filial piety” (Canda, 2013). They respect their older relatives with the most respect and honor, so taking care of them is a natural responsibility and a commitment to the people who care for them (Chappell & Funk, 2012). The cultural obligation to provide care for older people may prevent caregivers from seeking help outside the home. Caregivers play a great role in providing adequate care and needs for older people. However, being a caregiver is demanding, and the lives of caregivers and their families are often restricted. Family caregivers occasionally encounter some difficulties while caring for recipients. In Malaysia, Abu Bakar et al. (2014) highlighted the adverse effects of caregiving responsibilities on caregivers’ emotional, financial, social, and physical well-being. A study on long-term care for care recipients by Michalík and Valenta (2012) reported that caregivers experienced fatigue, depression, hopelessness, and an inability to enjoy leisure time. Concerning care provided to older people, the caregivers also need support. Social support refers to “family members, friends and others (neighbors and community members) who are available in times of need to give psychological, physical, financial or other support” (Amoah, 2019). The stress and burden of caregivers can be relieved by adequate social support from family and the community, which enables them to engage in social activities. Studies have reported that social support can positively influence family caregivers’ well-being (del-Pino-Casado et al., 2018; Díaz et al., 2019; Perkins & LaMartin, 2012). For instance, social support is one resource that may alleviate caregiving pressure among caregivers in Shanghai, China (Leung et al., 2020). However, a recent meta-analysis of 56 studies revealed a moderately negative relationship between social support and the caregivers’ subjective burden (r = - 0.36) (del-Pino-Casado et al., 2018). To enhance the effectiveness of interventions to improve the perceived social support of caregivers, it is arguably important to identify associated factors that contribute to caregiver social support. The demographic factors that affect social support are significant in caregivers of older people. A study on family caregivers in India revealed a significant positive relationship between perceived social support and good caregiver-patient association (Maheshwari Preksha & Kaur, 2016). Research conducted among caregivers of dementia patients found a positive correlation between social support provided and participants’ race and gender (Miller & Guo, 2000). In a study conducted in Spain, compared to male caregivers, female caregivers were found to perceive less social support (del Río Lozano et al., 2017). In this context, it is clear that social support is an essential factor affecting older people's caregiving. The perception of social support is also influenced by cultural factors. Cultural and religious norms in Malaysia create intense family relations and support systems, which serve as a crucial source of elderly care (Ahmad Ramli et al., 2022). Malaysia is widely known as a multicultural country, with the main ethnic groups consisting of the Malays, Chinese, and Indians (Lai & Tey, 2021). The multi-ethnic populations can provide insights into understanding demographic variables associated with social support for older caregivers in Malaysia. To date, no study has attempted to investigate the influence of caregivers’ demographic factors and the provision of social support. Meanwhile, the findings from other nations may not be applicable to the local population. Hence, the present study aims to evaluate the perceived social support among family caregivers of older people. This study examined the connection between social support and demographic factors, such as race, age (Yurtsever et al., 2013), gender, race, household income, occupation, underlying medical illness, assistance from others, association with older people (Maheshwari Preksha & Kaur, 2016), educational level (Thirumoorthy et al., 2016), years spent in caregiving (Munoz-Bermejo et al., 2020), caregivers’ present perceived health (Winahyu et al., 2015), caregiving for others (Ang & Malhotra, 2018), and caregiver training received (Boonyathee et al., 2021). More information is expected to be obtained from the study. This data can help health professionals to take into account key factors when planning interventions for family caregivers. Methods Study Design This study utilized a descriptive cross-sectional design by recruiting family caregivers from two districts: Kota Bharu and Pasir Mas in Kelantan, Malaysia. Kelantan is a state located in the North-East Region of Peninsular Malaysia. These two districts in Kelantan recorded the highest proportion of older people from urban to rural localities, which served as the justification for selecting both districts. Thus, it is expected that the rise in the number of older people has also increased the demand for caregiving in these districts. Samples/Participants The sample size was computed using the single population proportion formula (Naing et al., 2006). Sample size, N=Z2P(1−P)d2 Z = Z value (1.96 for 95% confidence level) P = proportion in population expressed as a decimal d = 0.05 In this study, the sample size was calculated to be 138 using Z= 1.96, P = 95.2% (Bassah et al., 2018), and d = 0.05. Considering the issues of missing data, potential dropouts, and unusable questionnaires, this study aimed for a sample size of 10%, which was more than 138. Finally, the total sample size was 152. In this study, participants were selected using convenience sampling through advertisements shared on social media platforms. Altogether 231 participants answered the survey. Five inclusion criteria were as follows: 1) being a primary family caregiver for an older person aged ≥ 60, 2) being responsible for the care of older people for at least six months, 3) aged ≥18 years old, 4) living in the same household as the older people, 5) not being paid for the care provided. The exclusion criteria included: 1) unable to read, speak and understand English or Malay. Instruments The study instrument was self-administered by the researcher. The first section covered demographic characteristics such as age, race, gender, marital status, job, education status, number of children, health status (record and type of medical illness), caregivers’ present perceived health, household income, relationship with older people, the total of years spent in caregiving, caregiving for others, assistance from others, and caregiver training records. Age was categorized into three-year groups (18–32 years, 33–45 years, and 45 years and above). Gender was grouped into male and female. Race was originally classified as Malay, China, Indian, and others (e.g., Malaysian Siamese). Unfortunately, no Chinese caregivers were willing to participate in this study. Marital status included single, married, divorced/separated, and widowed. The number of children was categorized into three-year groups (none, 1 – 3, and 4 and above). The occupation was grouped into six categories: full-time work, part-time work, retired, unemployed, student, and housewife. Education level was classified into primary, secondary, certificate/skill, and college/university. Underlying medical illness was assessed as yes or no. Firstly, the caregiver’s self-rated perceived health was categorized into “very good,” “good,” “fair,” and “poor” (Aman et al., 2020). However, no participants perceived themselves as “poor” in this study. Relationship with older people was grouped as a spouse, son/daughter, son-/daughter-in-law, siblings, and others (e.g., niece and grandchildren). Household income was categorized into three-year groups: <RM1000, RM1000 - RM4999, and >RM5000. The caregiving period was divided into four categories: <1 year, 1 - 5 years, 5 - 10 years, and >10 years. Assistance from others was asked with received or did not receive assistance. Finally, caregiving for others and receiving caregiver training were assessed by yes or no, respectively. Content validity for the demographic characteristics was obtained in terms of accuracy and appropriateness for the healthcare context in Malaysia. The content validity experts consisted of two gerontology nursing lecturers and two medical-surgical nursing lecturers, and no modifications were required. The second section examined participants’ social support. To assess the perceived social support from family, friends, and other important personalities, the Multi-dimensional Scale of Perceived Social Support (MSPSS) was utilized (Zimet et al., 1988). It has 12 items. Each item receives a 7-point rating (ranging from 1 to 7). The total scores ranged from 12 to 84, with the highest score indicating high social support. The scale’s alpha coefficient ranged from 0.85 to 0.91, indicating strong internal consistency (Zimet et al., 1988). The study utilized a validated Malay version with a Cronbach’s Alpha coefficient of 0.89, considered acceptable (Ng et al., 2010). The original developer approved the formal usage of this instrument via email before commencing the study. A high Cronbach’s Alpha coefficient of 0.95 was attained in this study. A questionnaire with Cronbach’s Alpha coefficient value of 0.70 or higher indicated that the questionnaire demonstrated satisfactory reliability (Nunnally & Bernstein, 1994). Data Collection Data were collected by a research assistant who was trained to conduct the study procedures so that the variability in the data collection method was minimized. The study was conducted between June to December 2021. Firstly, bulk emails were sent to the researchers through their social media contacts (WhatsApp). After that, other eligible participants also began to receive the messages. Those who wished to be involved in the study were directed to the researchers. Eligible participants have been briefed on the research objectives and given an information sheet containing the procedures and details of the study. Next, the participants were physically instructed to either circle or tick their most preferred options. Then, they were told to contact the researcher if they had any questions and to provide their own answers. The research assistant ensured that participants were not rushed, distracted, or talking with other people while filling out the questionnaire. The participants took about 15 to 20 minutes to complete the questionnaires. Data Analysis The caregivers and the perceived social support characteristics were reported using descriptive statistics. Frequencies and percentages were used to define the categorical data, while means and standard deviations represented the continuous variables. The normality test was achieved using a skewness and kurtosis value. For data to be considered normal, the value ranged from ‐2 to +2 of skewness and ‐7 to +7 of kurtosis (Byrne, 2010). A skewness and kurtosis value for MSPSS were 0.085 and - 0.186, respectively. Hence, this can be concluded that the data were normally distributed. The relationship between social support and demographic variables was assessed using independent t-tests and one-way analysis of variance (ANOVA) depending on the number of groups. A p-value of less than 0.05 was considered statistically significant. IBM SPSS Statistics was employed to examine all the gathered data (version 25). Ethical Considerations Ethical approval for this study was obtained from the International Islamic University Malaysia Research Ethics Committee (IREC) (reference number: IIUM/504/14/11/2/IREC 2021- 083) on 20 April 2021. The participants were approached with an information sheet, and informed consent was obtained before data were collected. The participants’ involvement in the study was voluntary, and their confidentiality was protected. In order to preserve participant privacy and anonymity, the researchers kept the data confidential. Therefore, identifiers like names or identity card numbers were not used in the questionnaires. Results Demographic Characteristics of Participants Table 1 summarizes the descriptive outcome of the participants and their demographic characteristics. This study involved 231 participants whose mean age was 39.2 ± 12.6 years. Most participants were females (74.0%), married (61.0%), and Malay (98.3%). The mean number of children was 2.48 ± 2.35. Over half of the participants had completed tertiary education (58%). Most of them worked full time while they provided care for older people (55.4%) with a monthly household income between RM1000 - RM4999 (49.4%). The family caregiver perceived their health as good (52%) and had no underlying medical illness (67.1%). The relationship between the caregivers and older people was parent-children, either son or daughter (61.5%). The years of caregiving ranged from 1-5 years (39.4%). Unfortunately, slightly over half of the caregivers did not receive assistance from others (53.2%), and a majority did not carry out caregiving for others (61%). Meanwhile, most did not receive any caregiver training (90.5%). Table 1 Demographic characteristics of the participants Variable f % Mean ± SD (Range) Age 18 – 32 years 79 34.2 33 – 45 years 72 31.2 46 years and above 80 34.6 Age in years (average) 39.24 ± 12.66 (18-75) Gender Male 60 26.0 Female 171 74.0 Race Malay 227 98.3 India 1 0.4 Others 3 1.3 Marital status Single 69 29.9 Married 141 61.0 Separated / Divorced 9 3.9 Widow / Widower 12 5.2 Number of children None 77 33.3 1 – 3 81 35.1 4 and above 73 31.6 Number of children (average) 2.48 ± 2.35 (0-10) Occupation Full-time work 128 55.4 Part-time work 18 7.8 Retired 8 3.5 Unemployed 7 3.0 Student 33 14.3 Housewife 37 16.0 Level of education Primary 5 2.2 Secondary 56 24.2 Certificate / Skill 36 15.6 College / University 134 58.0 Underlying medical illness Yes 76 32.9 No 155 67.1 If you have an illness, tick at the list of illnesses below Heart Disease 2 0.9 Cancer 3 1.3 High Cholesterol 12 5.2 Diabetes 25 10.8 Kidney Disease 0 0.0 Thyroid Disease 10 4.3 Inflammation of Joint 13 5.6 High Blood Pressure 36 15.6 Others 31 13.4 Current perceived health of the caregiver Very good 85 36.8 Good 122 52.8 Fair 24 10.4 Relationship with older people Spouse 15 6.5 Son/daughter 142 61.5 Son-/daughter-in-law 22 9.5 Siblings 6 2.6 Others 46 19.9 Household income <RM1000 86 37.2 RM1000 - RM4999 114 49.4 >RM5000 31 13.4 Years of caregiving Less than 1 year 29 12.6 1 - 5 years 91 39.4 5 - 10 years 44 19.0 More than 10 years 67 29.0 Assistance from others Received 108 46.8 Did not receive 123 53.2 Caregiving for others Yes 90 39.0 No 141 61.0 Received caregiver training Yes 22 9.5 No 209 90.5 Social Support Sources among Family Caregivers The caregivers were advised to receive social support from three main sources: family members, friends, and significant others. Table 2 shows the mean score of social support sources in detail. Resultantly, the family caregivers perceived the highest support from family and significant others (Mean = 5.44, SD = 0.969 and Mean = 5.25, SD = 1.123, respectively) but received less support from friends (Mean = 4.84, SD = 1.094). Regarding support from family, the item “I can talk about my problems with my family” recorded a mean of 5.26, which is considered low. Meanwhile, the item “My family is willing to help me make decisions” recorded the highest mean score (5.52). Table 2 Social support sources among family caregivers No Item 1 2 3 4 5 6 7 Mean SD Significant Others 1 There is a special person who is around when I am in need. 2 (0.9) 1 (0.4) 19 (8.2) 20 (8.7) 109 (47.2) 28 (12.1) 52 (22.5) 5.27 1.244 2 There is a special person with whom I can share joys and sorrows. 2 (0.9) 0 (0.0) 16 (6.9) 20 (8.7) 113 (48.9) 29 (12.6) 51 (22.1) 5.31 1.193 3 I have a special person who is a real source of comfort to me. 2 (0.9) 0 (0.0) 23 (10.0) 23 (10.0) 104 (45.0) 35 (15.2) 44 (19.0) 5.20 1.232 4 There is a special person in my life who cares about my feelings. 2 (0.9) 0 (0.0) 18 (7.8) 28 (12.1) 105 (45.5) 31 (13.4) 47 (20.3) 5.23 1.214 Overall 5.25 1.123 Family 1 My family really tries to help me. 0 (0.0) 0 (0.0) 12 (5.2) 11 (4.8) 111 (48.1) 41 (17.7) 56 (24.2) 5.51 1.071 2 I get the emotional help & support from my family. 0 (0.0) 0 (0.0) 12 (5.2) 13 (5.6) 110 (47.6) 44 (19.0) 52 (22.5) 5.48 1.063 3 I can talk about my problems with my family. 1 (0.4) 1 (0.4) 14 (6.1) 24 (10.4) 114 (49.4) 36 (15.6) 41 (17.7) 5.26 1.123 4 My family is willing to help me make decisions. 0 (0.0) 0 (0.0) 10 (4.3) 14 (6.1) 111 (48.1) 37 (16.0) 59 (25.5) 5.52 1.071 Overall 5.44 0.969 Friends 1 My friends really try to help me. 0 (0.0) 3 (1.3) 32 (13.9) 24 (10.4) 122 (52.8) 24 (10.4) 26 (11.3) 4.91 1.152 2 I can count on my friends when things go wrong. 1 (0.4) 14 (6.1) 20 (8.7) 32 (13.9) 122 (52.8) 18 (7.8) 24 (10.4) 4.77 1.245 3 I have friends with whom I can share my joys and sorrows. 0 (0.0) 3 (1.3) 20 (8.7) 29 (12.6) 125 (54.1) 27 (11.7) 27 (11.7) 5.01 1.085 4 I can talk about my problems with my friends. 3 (1.3) 4 (1.7) 28 (12.1) 33 (14.3) 112 (48.5) 25 (10.8) 26 (11.3) 4.84 1.238 Overall 4.84 1.094 Note: 1 = very strongly disagree, 2 = strongly disagree, 3 = disagree, 4 = Neutral, 5 = agree, 6 = strongly agree, 7 = very strongly agree As for receiving support from significant others, the item “there is a special person who I can share my joys and sorrows with” recorded the highest mean of 5.31. On the other hand, the item “I have a special person who gives me comfort” recorded the lowest mean of 5.20. Lastly, as for support from friends. The item “I have friends who I can share my joys and sorrows with” recorded the highest mean of 5.01, while the item “I can rely on my friends when things go wrong” recorded the lowest mean of 4.77. Relationships between Social Support and Demographic Variables There was a significant difference in social support and demographic characteristics (Table 3). The results revealed that social support was significantly different according to gender (p = 0.006). That is, males had statistically significantly higher mean social support scores compared to females. Also, the mean social support scores were statistically significantly different across study participants among the four levels of the duration of caregiving (p = 0.001). Tukey HSD post hoc test indicated a significant difference between the below 1-year caregiving group and the 1 - 5 years caregiving group (p = 0.045). Furthermore, a significant difference was observed between the below-1-year caregiving group and the over 10 years caregiving group (p = 0.000). This finding suggests that the individuals in the below 1-year caregiving and 1 - 5 years caregiving groups scored significantly lower mean social support scores than the over 10 years caregiving group. Table 3 Relationships between social support and demographic variables Variables Mean SD t/F p-value Age2 18 – 32 years 5.63 2.321 0.195 0.823 33 – 45 years 6.67 2.455 46 years and above 6.75 2.173 Gender1 Male 5.47 0.869 2.774 0.006* Female 5.10 0.905 Race1 Malay 5.19 0.909 0.835 0.404 India and others 4.80 1.510 Marital status2 Single 5.12 0.937 1.658 0.177 Married 5.27 0.851 Separated/Divorced 4.66 1.514 Widow/Widower 5.06 0.781 Number of children2 None 6.05 2.328 1.829 0.163 1 – 3 6.12 2.477 4 and above 6.89 2.196 Occupation2 Full-time work 5.30 0.911 1.082 0.371 Part-time work 5.16 0.971 Retired 4.71 1.137 Unemployed 5.24 0.568 Student 5.05 1.045 Housewife 5.07 0.713 Level of education2 Primary 5.60 1.450 0.609 0.609 Secondary 5.13 0.659 Certificate/Skill 5.30 1.158 College/University 5.17 0.907 Underlying medical illness1 Yes 5.04 1.080 -1.617 0.109 No 5.27 .806 Current perceived health of caregiver2 Very good 5.24 1.006 0.204 0.816 Good 5.17 0.848 Fair 5.14 0.881 Relationship with older people2 Spouse 5.34 1.272 0.821 0.513 Son/daughter 5.14 0.877 Son-/daughter-in-law 5.36 0.776 Siblings 5.67 1.033 Others 5.16 0.923 Household income2 <RM1000 5.15 0.825 1.093 0.337 RM1000 - RM4999 5.17 0.940 >RM5000 5.42 1.011 Duration of caregiving (years)2 Less than 1 year 4.68 0.803 6.098 0.001* 1 - 5 years 5.17 0.878 5 - 10 years 5.11 0.953 More than 10 years 5.50 0.865 Assistance from others1 Received 5.29 1.028 1.482 0.140 Did not receive 5.11 0.785 Caregiving for others1 Yes 5.25 0.927 0.756 0.451 No 5.16 0.899 Received caregiver training1 Yes 5.36 0.956 0.903 0.368 No 5.18 0.905 Note: India was grouped with others in light of the small number of participants 1 t-test for the independent group 2 ANOVA with Tukey HSD post hoc test * Significant at p <0.05 Finally, no significant difference was identified between social support and race; marital status; occupation; level of education; underlying medical illness; current perceived health of caregiver; relationship with older people; household income; assistance from others; caregiving for others; received caregiver training; age and the number of children. Discussion The study aimed to evaluate the factors associated with perceived social support among family caregivers of older people. According to the results, family caregivers were highly supported by their family members and significant others, but they received less support from friends. In addition, caregivers’ gender and duration of caregiving were significant factors associated with social support. Demographic Characteristics of Participants The current study involved a total of 231 caregivers for older people. The mean age of the participants was 39.24 years, manifesting a relatively young group of people taking care of their older people. The results showed that most of the participants were female (74%), consistent with the studies by Aman et al. (2020) and Vun et al. (2020). This is common in Malaysia, an Asian country where women are frequently responsible for caring for the young and the old while men do the earnings to support the family. The findings revealed that most of the caregivers were Malay (98.3%), which may be due to the study location, Kelantan state in Malaysia, with a high population of Malay (Department of Statistics Malaysia, 2020). Hence, it explains why Malay is the ethnicity with the highest percentage of participants. Traditionally, in Asia, children are responsible for caring for older people. In this study, most caregivers were either the sons or daughters of older individuals (61.5%), consistent with previous local studies (Ahmad Zubaidi et al., 2020; Ghazali et al., 2015). Nevertheless, this result is expected since Malaysian children have been bred to care for their aged or sick parents. As a result, adult children are always responsible for caring for their parents. Apart from that, most of the participants were married (61%), full-time workers (55.4%), and university graduates (58%). The results showed the potential conflict when caring for older people as they had other commitments to be fulfilled. The findings of the current study also showed that almost half (49.4%) of the participants had a monthly income between RM1000 - RM4999; just over half (52%) perceived their health as good; approximately two-thirds (67.1%) had no underlying medical illness; just over a third (39.4%) spent caregiving from 1-5 years; over a half (53.2%) did not receive any assistance; almost two-thirds (61%) did not do any caregiving for others, and a significant majority (90.5%) did not receive any caregiver training. These reports are similar to prior research on caregivers of older persons in Malaysia, reporting that the majority of caregivers receive a monthly income of RM 1000 to RM 4999 (Ahmad Zubaidi et al., 2020). The latter study also revealed that most caregivers were unqualified to care for older people, while one-third had no chronic medical condition (Ahmad Zubaidi et al., 2020). The majority of 166 caregivers had good health and had been providing care to older people for more than two years; however, most of them had assistance in caregiving (Ghazali et al., 2015), and the majority of the 128 caregivers did not receive any caregiver training (Tan et al., 2020). Social Support Sources among Family Caregivers Caregivers received maximum support from family and significant others but perceived less support from friends. This result is supported by several studies in which caregivers received less social support from friends and other social network members (Akosile et al., 2018; Haya et al., 2019; Yu et al., 2013). Similar to this study’s results, the caregivers reported that they perceived the support was mainly from family members. This is much expected, as most caregivers in Malaysia were children of older people. The studies mentioned above depicted that caregivers are expected to care for their parents, regardless of their income or any associated factors that may affect this caregiving responsibility. Contrasted to the western country, a lack of nursing homes in the respondents’ areas creates a heavier burden for family caregivers. Moreover, it is an abomination in Malaysia to send the elderly to nursing homes (Jantan & Hussin, 2015). As a result, caregivers are obliged to fully provide their parents with the support they require. According to the data on the caregivers’ characteristics, the caregivers in this study have had 1 – 5 years of experience in caregiving for older people. This experience has exposed the caregivers to a variety of stressors on a daily basis, training them to be responsive and provide the best response. Furthermore, the caregivers’ success in providing care and support for 1 – 5 years has fueled their desire to continue providing their older people with the best support to achieve the best health and quality of care. Furthermore, many people hold a cultural belief in the concept of filial piety, whereby children are expected to respond to the needs of their family by sacrificing their own interests physically, financially, and socially for the benefit of their parents (Kristanti et al., 2021). In many Asian countries, including Malaysia, children must take care of their parents, especially those suffering from chronic medical illnesses. Regarding filial piety and gaps in caregiving, Makhtar and Samsudin (2020) explored the association between loneliness and filial piety expectations among older people in Kuantan, Pahang. The study’s results showed that older people typically have very high expectations for their children’s filial piety. This can be interpreted that the older people in this study believed and expected that they should be well taken care of by their children and other family members. Filial piety is the behavior of respecting and affection to parents, carrying out responsibilities, supporting the family, paying debts, and making other sacrifices. Besides the concept of filial piety, the majority of the participants were Malays, who are Muslims. Therefore, accepting their role as caregivers and the challenges that come with it is consistent with the Islamic philosophy of faith in predestination (Qada Wa Qadar) (Abu Bakar et al., 2014). It urges Muslims to be content and happy even in the face of hardship and adversity. According to this teaching, Allah has predestined each person’s lifespan and happiness or unhappiness (Abu Bakar et al., 2014). Therefore, believers must accept the decision of their God. Relationships between Social Support and Demographic Variables A significant difference was detected between social support and two demographic variables: years of caregiving and years. According to the literature, male caregivers are less likely than female caregivers to accept help from friends, family, or community organizations. However, the results indicated that males received more social support than females from family and friends because of the broad diversity of the male caregivers’ networks. A possible explanation is that women work outdoors less often and are more likely to stay at home, which should not result in a “higher number of good friends.” Another possibility is that, in Asian society, women are typically regarded as natural caretakers born with caring traits and raised or nurtured to be caring, compared to men. Men, therefore, appear to find it easier to seek assistance from those in their close social circles, whether they be co-workers, friends, or neighbors. Additionally, they see this support as legitimate because they fill an unprepared role (Rodríguez-Madrid et al., 2019). There was a significant difference in caregivers’ years of caregiving on the social support scores, as caregivers whose caregiving of more than 10 years received higher social support than others whose caregiving was less than 1 year and between 1 - 5 years. This indicates that the caregivers received a higher amount of social support with a longer duration of caregiving. Indeed, most caregivers have become used to the caregiving duties incorporated into their daily activities. In addition, the caregivers received more social support from family and friends because of the broad diversity of the caregivers’ networks. Most caregivers in this study were daughters or sons of older people. As mentioned earlier, all cultures in the Malaysian population still adhere strictly to filial obligations and the societal norm that families should be given the duty of caring for older people who are in need of assistance (Aman et al., 2020). In contrast, no significant relationship was observed between social support and the gender of caregivers for older people. Additionally, the educational level of caregivers was not associated with social support in this study, contradicting the result from a cross-sectional study conducted in Bangalore (Thirumoorthy et al., 2016). This result is thought to be related to the fact that the majority of caregivers in this study graduated from college or university. Therefore, caregivers with higher education levels are likely to have been more active in participating in caregiving activities. In addition, they are more willing to learn new and appropriate caregiving knowledge and gain information about elderly care services. Thus, they were more aware of the available resources and knew how to use these resources to support their caregiving role. In addition, this study found no significant difference between social support and race, marital status, occupation, underlying medical illness, current perceived health of the caregiver, household income, assistance from others, caregiving for others, received caregiver training, age, and the number of children. This could be because the current study’s sample size is smaller than that of other research. Additionally, the homogeneity of the study participants’ backgrounds, including their marital status, occupation, and race, may have contributed to the study’s insignificant findings. Implications for Nursing Practice Family caregivers are often the primary caregivers for older adults, and they endure a huge responsibility. These caregivers have encountered challenges when performing various caregiving chores (Giovannetti et al., 2012). Adequate and sufficient support must be offered to older adults as well as to the people who care for them. Although the findings in this study indicated caregivers rated that they had received high support from family, this support may not fully help the caregivers deal with some crises in the caregiving of older people. Nurses are advised to assess the family’s community-based resources to provide a social network that may help alleviate the caregivers’ burden and challenges. The current study also explains the association of perceived social support with gender and duration of caregiving. With this information, nurses should be able to recognize potential risk factors for caregivers who do not receive adequate social support. Additionally, it will help in deciding when intervention might be required. Such an intervention should specifically focus on addressing caregiver stress, burden, and a lack of knowledge and skills in providing care for older persons. Thus, nurses must be aware of the significance of social support as a strategy and care plan that may be used to enhance the quality of life and reduce the burden on the caregiver. Limitations and Recommendations for Future Studies This study has some key limitations that might have affected the results. First, overall, the present findings are insufficient to make any causal inference since the study employed a cross-sectional design. Second, the COVID-19 outbreak may have influenced the result as changes in participants’ behaviors and lifestyles. Third, the sample size in this study might have a bias in the data collection process. It is due to the lack of cooperation from participants from other races. The final limitation was the use of convenience sampling, which limits the generalizability of the study and increases the risk of bias. Furthermore, using a qualitative research approach might produce more robust results and enable researchers to gain a broader knowledge of the caregivers’ emotions and experiences. Future research should expand the number of the sample to gain generalization by using the probability sampling method and increasing the number of settings to gain a better insight into family caregivers of older people. Conclusion In conclusion, family and significant persons rendered more support to the caregivers than support from friends. This study also observed that the perceived social support of the caregivers of older people was affected by several factors, such as gender and duration of caregiving. Therefore, the study’s conclusions may thus assist nurses and other healthcare professionals in better understanding the factors influencing social support. The reports from this study can provide solutions that would improve social support among caregivers of older people. Acknowledgment The authors would like to express our thanks to the caregivers who participated in this study by generously lending their time to complete this survey. Declaration of Conflicting Interest The authors declare that there is no conflict of interest regarding the publication of this paper. Funding This research was partly supported by IIUM (International Islamic University Malaysia) Flagship Research Initiative Grant Scheme (IRF19-009-0009). Authors’ Contributions All the authors have made a substantial contribution from conception to the finalization of this study. AM was involved in the conception of the study, data collection, design of the study, analysis, interpretation of data, and revising the article for important intellectual content. NNAG was involved in the conception of the study, the collection of data, the design of the study, and the analysis and interpretation of data. SMSE and SML were involved in revising the article for important intellectual content. All authors have read and agreed to the published version of the manuscript. Authors’ Biographies Aniawanis Makhtar, RN, PhD is an Assistant Professor at the Kulliyyah of Nursing, International Islamic University Kuantan, Pahang, Malaysia. Nor Nadiya Ab Ghani is a Master of Nursing student at the Kulliyyah of Nursing, International Islamic University Kuantan, Pahang, Malaysia. Sharifah Munirah Syed Elias, RN, PhD is an Assistant Professor at the Kulliyyah of Nursing, International Islamic University Kuantan, Pahang, Malaysia. Salizar Mohamed Ludin, RN, PhD is an Associate Professor at the Kulliyyah of Nursing, International Islamic University Kuantan, Pahang, Malaysia. Data Availability The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request. ==== Refs References Abu Bakar, S. H., Weatherley, R., Omar, N., Abdullah, F., & Mohamad Aun, N. S. (2014). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-203 10.33546/bnj.1405 Original Research Knowledge, attitude, and practice towards COVID-19 among student nurses in Manila, Philippines: A cross-sectional study Quisao Earl Zedrick S. 1 Tayaba Raven Rose R. 1 https://orcid.org/0000-0002-6349-5560 Soriano Gil P. 12* 1 College of Nursing, San Beda University, Manila, Philippines 2 Graduate School, Wesleyan University-Philippines, Nueva Ecija, Philippines Corresponding author: Gil P. Soriano, MHPEd, RN, College of Nursing, San Beda University 638 Mendiola St., San Miguel, Manila, Philippines. Email: gil.p.soriano@gmail.com Cite this article as: Quisao, E. Z. S., Tayaba, R. R. R., & Soriano, G. P. (2021). Knowledge, attitude, and practice towards COVID-19 among student nurses in Manila, Philippines: A cross-sectional study. Belitung Nursing Journal, 7(3), 203-209. https://doi.org/10.33546/bnj.1405 28 6 2021 2021 7 3 203209 07 3 2021 07 4 2021 15 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Assessing the current understanding of future health care workers about the COVID-19 is very important in order to identify gaps that affect their perceptions and responses, which they can integrate into the people in the community. Objective This study aimed to investigate the knowledge, attitude, and practice towards COVID-19 of student nurses in Manila, Philippines. Methods This study utilized a descriptive cross-sectional survey of 314 individuals from October 2020 to December 2020 to evaluate the association of different factors to knowledge, attitude, and practice towards COVID-19. Frequency, percentage, mean, standard deviation, t-test, and one-way ANOVA were used to analyze the data gathered. Results The survey revealed that the respondents have a mean knowledge score of 18.76 (SD = 1.64), a mean score for attitude of 26.58 (SD = 2.71) and a mean score for practice of 4.26 (SD = 0.93). A significant different were noted in terms of year level with level 3 having a higher mean score (M = 19.01, F = 2.696, p = 0.046) compared to other levels and type of school, with public university students having a higher level of knowledge (M = 18.97, t = 2.070, p = 0.039). In terms of attitude, females have higher mean scores (M = 26.85, t = -2.630, p = 0.009 and students from public university have higher scores (M = 2.81, t = -4.406, p = 0.000) than students from private university. For practice, a significant difference was noted in terms of year level, with level 3 students having a higher mean score (M = 4.42, F = 3.180, p = 0.024) compared to other year levels. Conclusion Filipino student nurses have a high level of knowledge about COVID-19 and are mainly optimistic about controlling the pandemic. Nevertheless, having constant reminder from the authorities and health care professionals are the solution to aid public knowledge and comprehension relating to COVID-19. COVID-19 nursing students knowledge attitude practice Philippines ==== Body pmcA new strain of flu-causing coronavirus has been spreading and affecting the lives of many. Reports showed that the first case was discovered in Wuhan, China, in December 2019, making Wuhan its place of origin (World Health Organization, 2020a). Formerly known to be 2019-nCoV, this new strain named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the illness coined as the Coronavirus disease 2019 (COVID-19) having mild symptoms of fever, dry cough, and tiredness to many severe symptoms of chest pain, shortness of breath or difficulty of breathing (World Health Organization, 2020b). Experts believe that the virus can easily be transmitted when susceptible hosts inhaled small droplets that contain the virus, which is expelled from an infected person’s nose or mouth through coughing, sneezing, or speaking. But as the experts continue to study more about this pathogen, it turns out that there are other ways how this is being transmitted (World Health Organization, 2020b). The virus began to spread rapidly, even having cases outside China, making the World Health Organization’s Director-General declaring the outbreak a Public Health Emergency of International Concern. It spreads so fast that it became a pandemic just more than a month after the previous declaration (World Health Organization, 2020a). As the virus continues to spread worldwide, the Philippines was not able to contain the virus outside its borders. On 30 January 2020, the Philippine Department of Health (DOH) recorded the first case of COVID-19 in the country with a Chinese national. On 7 March 2020, the first local transmission was reported (World Health Organization, 2020c). Precisely months have passed since the primary affirmed COVID-19 case was reported within the Philippines. The government executed numerous actions, including adherence to the guidelines and health protocols released by the WHO, contact tracing to immediately detect and isolate those who have close contacts with carriers, and strict community isolation in Metro Manila extending to Luzon as well as other parts of the country closing almost all establishments, such as shopping centers, hoping to contain the rapidly increasing cases within the bounds of the Philippines (World Health Organization, 2020d). But despite these numerous actions, the country’s situation seems to worsen as time goes by. Ten months after the first recorded case, the country has reported a total of 431,630 confirmed cases with total deaths of 8,392 (Elflain, 2020; Philippine Department of Health, 2020; World Health Organization, 2020e). This makes the Philippines the 2nd country in Southeast Asia with the most number of confirmed cases and ranks 27th globally (Elflain, 2020; Petterson et al., 2020; World Health Organization, 2020e). According to experts, a significant factor why COVID-19 cases persist to increase is due to faulty human behavior (Lee, 2020; Maragakis, 2020) and Filipinos are no exceptions. On 25 October 2020, Manila Bulletin released an article announcing that over 100,000 quarantine violators were arrested by the Philippine National Police (Chavez, 2020). This shows that the success of the efforts of the government depends on people’s adherence to preventive measures, which is affected by their knowledge, attitude, and practices. A study revealed that public knowledge is vital in response to outbreaks (University of Surrey, 2018), which means that public health educators are as crucial as other front liners, including student nurses. In the Philippines, the Bachelor of Science in Nursing (BSN) is a four-year program that includes general and professional courses. Professional courses are threaded from the first year through the fourth year, emphasizing the concepts with corresponding Related Learning Experience (RLE). The BSN curriculum includes an intensive nursing practicum designed to improve nursing skills further and ensure that the BSN program results expected of an entry-level nurse are met (Commission on Higher Education, 2017). As early as in their 2nd year in the BSN program, student nurses are taught how to educate people in the community. Assessing their current awareness and knowledge about this virus and its prevention can identify gaps that affect their perceptions and responses, which they can integrate into those people in the community. COVID-19 is a new strain of infectious virus that has had a catastrophic effect on every individual within the short time it was first detected. Thus far, only a few published articles evaluate the knowledge, attitude, and practice of nursing students towards COVID-19. The novelty of this virus, together with its precariousness and serious threats, made it hard for health professionals and authorities to plan strategic action to stop the spread of the virus. To the best of our knowledge, this is the first study to examine COVID-19 knowledge, attitude, and practice related sociodemographic characteristics among student nurses in the Philippines. Thus, this study aims to determine the knowledge, attitude, and practice towards COVID-19 among student nurses in Manila, Philippines. Methods Study Design This study utilized a descriptive cross-sectional survey to determine the level of knowledge, attitude, and practice towards COVID-19. Participants An online survey using the Likert scale was used to gather the necessary data for this study. Total enumeration of students from two Colleges of Nursing in Manila was included with a total of 314 student nurses. The inclusion criteria include: (1) nursing students studying in a college or a university, either public or private, in Metro Manila; (2) currently enrolled in the academic year 2020-2021; (3) have access to internet connection; (4) understands the English language; (5) and of legal age (18 years old and above) who can give informed consent. Measures This study utilized the questionnaire developed by Al-Hanawi et al. (2020) in order to measure the knowledge, attitude, and practice towards COVID-19 among nursing students. Respondents were asked about their knowledge using the 22-item Dichotomous questions where the questions were answered by yes or no with Cronbach’s alpha coefficient of 0.71. In terms of attitudes, respondents were asked to answer six attitudinal statements and scored as 1 = strongly disagree, 2 = disagree, 3 = undecided, 4 = agree, and 5 = strongly agree. It has a Cronbach’s alpha coefficient of 0.81. In the section of practice, respondents five practice statements to be answered by “yes” or “no” were asked, and a score of one was given for answers that denote a good practice, and a score of zero was given for answers that denoted bad practice. The total score ranged from zero to five, with high scores indicating better practices. The instrument was administered using the English language translation of Al-Hanawi et al. (2020). No translation was conducted since English is the medium of instruction in the BSN program in the Philippines. Data Collection This study involved the use of primary data collection using a self-administered questionnaire. Prior to data gathering, the researchers got approval from the College Dean through a letter of request to conduct this study. Permission to utilize the COVID-19 knowledge, attitude, and practice instrument was secured from the developer of the tool. Further, with the Dean’s approval and a clearance from the ethics board, the researchers then collected the data using Google Forms. Given the physical distancing measures and other restrictions implemented, data were collected online to avoid face-to-face interactions during the course of the collection from October 2020 to December 2020. Data Analysis This study used frequency, percentage, mean, standard deviation, independent t-test, and one-way ANOVA to analyzed the data gathered from the respondents. The Shapiro Wilk test indicated that the data were normally distributed. The alpha level of significance was set at 0.05. Ethical Considerations This study was conducted in accordance with the established ethical standards of conducting research with human participants. The researchers obtained ethical clearance from San Beda University – Research Ethics Board with Protocol Number 2020-040. It was made sure that respondents were informed regarding the study’s objectives, associated risks, and benefits of participation and encouraged to ask any questions regarding the study. Written consent was also secured when the respondents decided to participate. Results Table 1 shows the socio-demographic characteristics of the participants, which displays the mean knowledge score of 18.76 (SD = 1.64), the mean attitude score of 26.58 (SD = 2.71), and the mean practice score of 4.26 (SD = 0.93). Of the total individuals, 77 (24.5%) were males and 234 (74.5%) were females, aged between 18 and 31. More than half of them were enrolled in private schools totaling 177 (56.4%) individuals, and the majority came from Level 1 with 122 (38.9%). These participants were also categorized according to their family’s monthly income in Philippine peso (Php), with 112 (35.7%) in the less than Php 20,000 bracket, 59 (18.8%) in the Php 20,000-30,000 bracket, 29 (9.2%) in the Php 30,000-40,000 bracket, 26 (8.3%) in the Php 40,000-50,000 bracket, and 88 (28%) in the more than Php 50,000 bracket. The content of the next tables, Table 2-4, shows the participants' responses about knowledge, attitude, and practice towards COVID-19. Table 1 Characteristics of the Participants (N = 314) Variable Mean (SD) n (%)  Knowledge 18.76 (1.64)  Attitude 26.58 (2.71)  Practice 4.26 (0.93)  Age 19.80 (1.54) Gender  Male  Female 77 (24.5) 234 (74.5) Year Level  1st year  2nd year  3rd year  4th year 122 (38.9) 86 (27.4) 75 (23.9) 31 (9.9) Type of School  Public  Private 137 (43.6) 177 (56.4) Income  Less than Php20,000  Php20,000 to Php30,000  Php30,000 to Php40000  Php40,000 to Php50,000  More than Php50,000 112 (35.7) 59 (18.8) 29 (9.2) 26 (8.3) 88 (28) Table 2 Level of knowledge of the participants about COVID-19 Statements n (%) Correct Answer Incorrect Answer SARS-CoV-2 spreads from person to person within close distance of each other (approx. six feet) 281 (89.5) 33 (10.5) SARS-CoV-2 spread through respiratory droplets, which occur when infected people cough and sneeze 313 (99.7) 1 (0.3) SARS-CoV-2 can be contracted by touching a surface or object on which the virus is attached and then touching one’s mouth, nose, or, perhaps, eyes 312 (99.4) 2 (0.6) Close contact or eating wild animals causes COVID-19 145 (46.2) 145 (46.2) People infected with SARS-CoV-2 cannot transmit the virus to others when a fever is not present 282 (89.8) 32 (10.2) The main clinical symptoms of COVID-19 are fever, fatigue, dry cough, myalgia, and shortness of breath 305 (97.1) 9 (2.9) Unlike the common cold, congestion, runny nose, and sneezing are less common in people infected with SARS-CoV-2 139 (44.3) 175 (55.7) Antibiotics are an effective treatment for COVID-19 247 (78.7) 67 (21.3) Currently, there is no effective cure for COVID-19, but early symptomatic and supportive treatment can help most patients recover from the diseases 302 (96.2) 12 (3.8) Older adults and those with serious chronic illnesses, such as heart or lung disease and diabetes, are at increased risk of developing more serious complications from COVID-19 208 (98.1) 6 (1.9) Not all people with COVID-19 have severe cases. Only older adults with chronic illnesses tend to be more severe 234 (74.5) 80 (25.5) Pregnant women are more susceptible to infections than non-pregnant women 231 (73.6) 83 (26.4) Children do not appear to be at higher risk for COVID-19 than adults 136 (43.3) 178 (56.70) It is not necessary for children or young people to take precautionary measures to prevent SARS-CoV-2 transmission 252 (80.3) 62 (19.7) After being in a public place, after nose-blowing, coughing, or sneezing, people must wash their hands with soap and water or use a hand sanitizer containing at least 60% alcohol for at least 20 seconds 287 (91.4) 27 (8.6) People should avoid touching their eyes, nose, and mouth with unwashed hands 310 (98.7) 4 (1.3) Ordinary residents can wear general medical masks to prevent the SARS-CoV-2 infection 291 (92.7) 23 (7.3) People should only wear a mask if they are infected with the virus or if they are caring for someone with suspected SARS-CoV-2 infection 271 (86.3) 43 (13.7) Healthy food and drinking water increase the body’s immunity and resistance to COVID-19 307 (97.8) 7 (2.2) Isolation and treatment of people infected with the SARS-CoV-2 are effective ways to reduce the spread of the virus 313 (99.7) 1 (0.3) People in contact with someone infected with SARS-CoV-2 should be immediately quarantined, in an appropriate location, for a general observation period of 14 days 313 (99.7) 1 (0.3) To prevent transmission of SARS-CoV-2, people must avoid going to crowded places and avoid taking public transport 312 (99.4) 2 (0.6) Table 3 Level of the attitude of the participants about COVID-19 Statement n (%) Strongly Disagree Disagree Neutral Agree Strongly Agree It is important to keep my distance from others to avoid spreading SARS-CoV-2 0 0 0 11 (3.5) 303 (96.5) Washing hands is essential to protect myself from COVID-19 0 0 1 (0.3) 6 (1.9) 307 (97.8) To protect myself from COVID-19 exposure, I should stay home if I am sick unless I am receiving medical care 0 1 (0.3) 8 (2.5) 28 (8.9) 277 (88.2) COVID-19 will eventually be successfully controlled 7 (2.2) 28 (8.9) 88 (28) 76 (24.2) 115 (36.6) Philippines’ strict measures can help win the battle against COVID-19 28 (8.9) 33 (10.5) 87 (27.7) 65 (20.7) 101 (32.2) Compliance with the Department of Health precautions will prevent the spread of COVID-19 3 (1) 11 (3.5) 41 (13.1) 68 (21.7) 191 (60.8) Table 4 Practices of the participants about COVID-19 Statements n (%) Yes No Have you recently been to a social event involving a large number of people? 58 (18.5) 256 (81.5) Have you recently been to a crowded place? 105 (33.4) 209 (66.6) Have you recently avoided cultural behaviors, such as shaking hands? 265 (84.4) 49 (15.6) Have you been practicing social distancing? 306 (97.5) 8 (2.5) Recently, have you frequently washed your hands with soap and water, for at least 40 seconds, especially after going to a public place or after nose-blowing, coughing, or sneezing? 302 (96.2) 12 (3.8) Table 5 shows the comparison of the characteristics of the participants with the level of knowledge, attitude, and practice. In terms of knowledge, a significant difference noted in terms of year level, with 3rd year having a higher mean score (M = 19.01, F = 2.696, p = 0.046) compared to other levels and type of school, with public university students having a higher level of knowledge (M = 18.97, t = 2.070, p = 0.039) as compared to private university students. Table 5 Comparison of the characteristics of the participants and average of knowledge, attitude, and practice score Variable Knowledge score Attitude score Practice score Mean SD F/t p Mean SD F/t p Mean SD F/t p Gender  Male  Female 18.62 18.80 1.97 1.52 -0.732 0.406 25.94 26.85 3.21 2.44 -2.630 0.009* 4.11 4.31 1.03 0.89 -1.594 0.112 Year Level  1st year  2nd year  3rd year  4th year 18.62 18.95 19.01 18.16 1.65 1.51 1.42 2.22 2.696 *0.046 26.55 26.92 26.57 25.74 2.66 2.36 2.75 3.54 1.447 0.229 4.22 4.32 4.42 3.83 0.89 0.96 0.79 1.21 3.180 *0.024 Type of School  Public  Private 18.97 18.59 1.64 1.63 2.070 *0.039 25.83 27.15 2.81 2.49 -4.406 0.000* 4.22 4.29 0.94 0.93 -0.704 0.482 Income  Less than 20,000  20,000 to 30,000  30,000 to 40000  40,000 to 50,000  More than 50,000 18.74 18.58 18.51 19.11 18.89 1.52 1.91 2.31 1.42 1.38 0.780 0.539 27 26.63 26.45 26 26.21 2.52 2.78 3.39 3.12 2.48 1.396 0.235 4.33 4.25 3.89 4.23 4.31 0.96 0.88 1.05 0.91 0.89 1.327 0.260 * p-value is significant at 0.05 In terms of attitude, females have higher mean scores (M = 26.85, t = -2.630, p = 0.009 and students from public university have higher scores (M = 2.81, t = -4.406, p = 0.000) than students from private university. For practice, a significant difference was noted in terms of year level, with 3rd year students having a higher mean score (M = 4.42, F = 3.180, p = 0.024) compared to other year levels. Discussion The objective of the study is to determine the significance of assessing the level of knowledge, attitude, and practice to be measured can serve as a guide (Azlan et al., 2020). These circumstances stipulate the necessity of public adherence to preventive and control measures, which is influenced by their knowledge, attitudes, and practices (Al-Hanawi et al., 2020). The survey on 314 student nurses showed that the majority of the participants were aware of COVID-19 related knowledge, exhibit a positive attitude and dynamic practice throughout the outbreak showing the effect of massive public education campaigns, such as social media (Peng et al., 2020). Although this study shows that the participants were very much acquainted with the precautions, symptoms, and transmission of the virus, it also manifests that more than half of the participants were still convinced that having close contact or eating wild animals causes COVID-19. A total of 169 or 53.8% of the participants erroneously answered on this item. This exhibits that these participants still adhere to the claims that the virus came from bats that were ingested by people in a marketplace in Wuhan despite the fact that several reports are claiming that there may have animals that tested positive for this virus, but there is still no evidence to suggest that animals are capable of transmitting the infection to humans (Ohio State University, 2020; Centers for Disease Control and Prevention, 2021). Another significant error was 178 (56.7%) of the respondents believe that children are at higher risk for COVID-19 compared to adults who may be due to thinking that children have a weaker immune system, but experts believe that children are not at higher risk but is equally susceptible to the virus as adults do (Beusekom, 2020). Several factors were also incorporated to see if there would be any differences in the knowledge of participants. Among the characteristics of the respondents, the year level and the type of school appear to have a significant difference. The study revealed that third-year students have a higher mean score than other levels. This is different from other studies that show a higher level of knowledge in fourth and fifth-year students (Noreen et al., 2020). This reflects the effectiveness of the new nursing curriculum where the nursing subject for communicable diseases is now embedded in the third year, giving them more opportunities to have further information about such diseases at an earlier time. It also came to light that students from public schools have a higher mean score than students from private schools, congruent with other studies (Peng et al., 2020). This may be rooted in private schools’ inferiority in terms of numbers, including quantity and quality of students and teachers, as well as support from authorities (The World Bank, 2011). The result for assessment of the participants’ attitude exhibits notable data. Although almost all of them have a positive attitude in following measures to address the spreading of the virus, 39.2% of them think that the current situation will not be controlled anytime sooner. Nearly half of them (47.1%) also think that the country’s austere measures will not be able to control this pandemic. These outcomes show a remarkable number of individuals who are not assertive in the government’s movement and immediate response, including austere lockdowns, suspension of public transports, school classes, leisure activities, and implementation of a curfew in disparate cities. However, some of the participants have been pessimistic regarding this issue owing to the fact that people tend to experience negative emotions, such as panic and anxiety, throughout the time of the pandemic that could influence their attitude. Further, gender and the type of school were showed to have a significant difference. The results showed that women tend to be more optimistic and have a positive attitude towards this crisis which is also reflected in several studies (Noreen et al., 2020). Overall, the majority of the participants abides by the control and preventive measures that the health workers along with the authorities enacted. This showed beyond doubt the eagerness of the participants to adjust and undergo behavioral changes in the face of the COVID-19 pandemic. The participants espoused good and safe practice for the reason that the government’s palpable campaign towards the disease influenced the behavioral change of the individuals. Based on our knowledge, this is the first study conducted to analyze the knowledge, attitude, and practice related to COVID-19 among student nurses in the Philippines. For that reason, it offers valuable information about public health education and prevention in Philippine universities during the COVID-19 pandemic. Our findings show that most Filipino undergraduate students have a basic understanding of COVID-19, though their performance varies by school type and year level. There is a difference based on gender and type of school based on the attitude towards COVID-19. These findings indicate that gender, year level, and type of school can influence students' responses to the COVID-19 outbreak and acquisition of public health education, which should be brought to the attention of educators and health officials. These factors should also be considered when developing contingency plans or preparation for students in the event of potential public health emergencies. Conclusion The current study was able to lay out an extensive exploration concerning the knowledge, attitude, and practice of the student nurses in the Philippines towards COVID-19. Knowledge about COVID-19 is pondered to be the first step in overcoming infectious disease. In addition, being educated about its basic information, such as its transmission and causes, increased the possibility of people being mindful of the spread of communicable diseases. The outcome proves that Filipino student nurses have a justifiable level of knowledge in the said disease and are mainly optimistic in their perspective in controlling the pandemic. Nevertheless, having constant reminder from the authorities and health care professionals are the solution to aid public knowledge and comprehension relating to COVID-19. Acknowledgment The authors would like to express their sincerest gratitude to all the students who participated in the study. Declaration of Conflicting Interest The authors have no conflict of interest to disclose. Funding This research did not receive any specific grant from funding agencies. Author Contribution All the authors have made a substantial contribution from conception to the finalization of this study. EZQ was involved in the conception of the study, data collection, and revising the article for important intellectual content. RRT was involved in the conception of the study, the collection of data, and editing the article for important intellectual content. GPS was in charge of the conception and design of the study, analysis and interpretation of data, and revising the article for important intellectual content. All authors approved the final version of the article. Author Biographies Earl Zedrick S. Quisao and Raven Rose R. Tayaba are Bachelor of Science Nursing students at San Beda University, College of Nursing, Manila, Metro Manila, Philippines. Gil P. Soriano, MHPEd, RN is an Assistant Professor at San Beda University, College of Nursing, Manila, Metro Manila, Philippines, and at Wesleyan University Philippines, Graduate School, Cabanatuan City, Nueva Ecija, Philippines. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. ==== Refs References Al-Hanawi, M. K., Angawi, K., Alshareef, N., Qattan, A. M. N., Helmy, H. Z., Abudawood, Y., … Chirwa, G. C. (2020). Knowledge, attitude and practice toward COVID-19 among the public in the Kingdom of Saudi Arabia: A cross-sectional study. Frontiers in Public Health, 8 , 217. 10.3389/fpubh.2020.00217 32574300 Azlan, A. A., Hamzah, M. R., Sern, T. J., Ayub, S. H., & Mohamad, E. (2020). Public knowledge, attitudes and practices towards COVID-19: A cross-sectional study in Malaysia. Plos One, 15 (5 ), e0233668. 10.1371/journal.pone.0233668 32437434 Beusekom, M. V. (2020). Study: Kids, adults equally susceptible to in-home COVID-19 spread. https://www.cidrap.umn.edu/news-perspective/2020/12/study-kids-adults-equally-susceptible-home-covid-19-spread# Centers for Disease Control and Prevention. (2021). How to protect yourself and others. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html Chavez, C. (2020). 124,576 quarantine violators freed; 1,751 remain detained – DILG. https://mb.com.ph/2020/10/25/124576-quarantine-violators-freed-1751-remain-detained-dilg/ Commission on Higher Education. (2017). CHED Memorandum Order No. 15, Series of 2017. https://ched.gov.ph/wp-content/uploads/2017/10/CMO-15-s-2017.pdf Elflain, J. (2020). Number of coronavirus (COVID-19) cases worldwide as of November 30, 2020, by country. https://www.statista.com/statistics/1043366/novel-coronavirus-2019ncov-cases-worldwide-by-country/ Lee, B. Y. (2020). Why are Covid-19 cases increasing? Here are 7 reasons. https://www.forbes.com/sites/brucelee/2020/11/23/why-are-covid-19-coronavirus-cases-increasing-here-are-7-reasons/?sh=2f35e88d4aa8&fbclid=IwAR2HVe5JbKBSaNKLDee7e5vTXXbwPOoUB6NGketxUTziyD1SHf-w4o9xZQ Maragakis, L. L. (2020). Coronavirus second wave? Why cases increase. https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/first-and-second-waves-of-coronavirus Noreen, K., Rubab, Z.-e., Umar, M., Rehman, R., Baig, M., & Baig, F. (2020). Knowledge, attitudes, and practices against the growing threat of COVID-19 among medical students of Pakistan. Plos One, 15 (12 ), e0243696. 10.1371/journal.pone.0243696 33306712 Ohio State University. (2020). What you need to know about COVID-19 and pets and other animals. https://vet.osu.edu/about-us/news/covid-19-and-animals?fbclid=IwAR3NnIWHoRBC60e4LHqsMKwjzcvfLHuf_VPtqgVXEWTOmOowlaN2adRPnMw Peng, Y., Pei, C., Zheng, Y., Wang, J., Zhang, K., Zheng, Z., & Zhu, P. (2020). A cross-sectional survey of knowledge, attitude and practice associated with COVID-19 among undergraduate students in China. BMC Public Health, 20 (1 ), 1-8. 10.1186/s12889-020-09392-z 31898494 Petterson, H., Manley, B., & Hernandez, S. (2020). Tracking coronavirus’ global spread. https://edition.cnn.com/interactive/2020/health/coronavirus-maps-and-cases/ Philippine Department of Health. (2020). Covid-19 tracker. https://www.doh.gov.ph/covid19tracker The World Bank. (2011). Education service contracting. https://openknowledge.worldbank.org/bitstream/handle/10986/27406/611540WP0P10651e0Govt1s0ESC0Program.pdf?sequence=1&isAllowed=y&fbclid=IwAR0aawD2UXxEdNey7K9Gi4KqOepBOPXGGucz6hT4r6POUG2ngptI7JWDYPo University of Surrey. (2018). Increasing public awareness is vital in the fight against infectious diseases. https://www.sciencedaily.com/releases/2018/01/180129104653.htm World Health Organization. (2020a). Rolling updates on coronavirus disease. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen World Health Organization. (2020b). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-171 10.33546/bnj.1382 Original Research Barriers to exclusive breastfeeding: A cross-sectional study among mothers in Ho Chi Minh City, Vietnam https://orcid.org/0000-0003-4698-9275 Nguyen Nhan Thi * Do Huong Thi Pham Nhu Thi Van Faculty of Nursing and Medical Technology, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam Corresponding author: Dr. Nhan Thi Nguyen, Faculty of Nursing and Medical Technology, University of Medicine and Pharmacy at Ho Chi Minh City. 201 Nguyen Chi Thanh Street, Ward 12, District 5, Ho Chi Minh City, Vietnam. Mobile: (+84)907307358. Email: nguyennhan@ump.edu.vn | nguyennhan.ump@gmail.com Cite this article as: Nguyen, N. T., Do, H. T., & Pham, N. T. V. (2021). Barriers to exclusive breastfeeding: A cross-sectional study among mothers in Ho Chi Minh City, Vietnam. Belitung Nursing Journal, 7(3), 171-178. https://doi.org/10.33546/bnj.1382 28 6 2021 2021 7 3 171178 26 2 2021 23 3 2021 03 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Exclusive breastfeeding provides numerous benefits to the health of infants, mothers, economics, and the environment. However, during the exclusive breastfeeding period, the mothers face many barriers. Objective This study aimed to describe the perceived barrier of breastfeeding and compare its differences among mothers in Vietnam according to demographic and individual characteristics. Methods A cross-sectional study was conducted among 246 women in Ho Chi Minh City, Vietnam. Data were derived from the original survey using a self-administered questionnaire asking about the barriers of breastfeeding in three aspects: maternal, infant, and socio-environment. Descriptive statistics, Independent t-test, and ANOVA were used to describe the mothers’ characteristics and the breastfeeding barriers. Results The barrier from the infants was the most noticeable, followed by socio-environment and maternal barriers, respectively. Breastfeeding in public places (M = 2.93, SD = 0.92), baby’s illness (M = 2.74, SD = 0.99), and insufficient milk supply (M = 2.70, SD =0.99) were considered as major barriers to six-month exclusive breastfeeding among mothers in Ho Chi Minh City, Vietnam. Among the age groups, mothers who were more than 35 years old perceived had lower breastfeeding barriers than the younger mothers (F = 3.67, p = 0.03). Conclusion The investigation of the barriers against exclusive breastfeeding practice can help nurses and midwives develop breastfeeding promotion programs to promote exclusive breastfeeding rate for women in Vietnam. barrier exclusive breastfeeding perception mothers nurses midwives Vietnam The University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam ==== Body pmcBreastfeeding is the most efficacious feeding method for the child, especially the exclusive breastfeeding in the first six months of infant’s life provides irrefutable benefits for the infant’s health, mother’s health, economics, and the environment. To illustrate, a baby who receives only breast milk in the first six months of life is less mortality and morbidity of gastrointestinal infection diseases, pneumonia, asthma, or diarrhea compared to non-breastfed infants (Ballard & Morrow, 2013; Biks et al., 2015). Additionally, exclusive breastfeeding for infants in the first six months is also significantly associated with higher scores in the intelligence quotient test than those who have no exclusively breastfed (Tasnim, 2014). Regarding the mother’s health, exclusive breastfeeding significantly reduces breast cancer and ovarian cancer, and it postpones returning the menstrual period as a lactational amenorrhea method (Labbok, 2016; Victora et al., 2016). For economics, Walters et al. (2016) estimated the economic benefits of breastfeeding across seven countries in Southeast Asia; the results found that the health care treatment could be saved 300 million US dollars annually by reducing the incidence of diarrhea and pneumonia by providing adequate breastfeeding. Furthermore, breastfeeding is assumed as climate compatible because of the nature of breast milk, e.g., no need for heating, no need the refrigeration to store, and breast milk can be used at any time with the right temperature. Because of the advantages of breast milk, World Health Organization (WHO) recommends mothers worldwide exclusively breastfeed their infants during the first six months after birth (WHO, 2011). However, globally only 40% of infants aged 0-6 months are exclusively breastfed (WHO, 2017). In Vietnam, only 24% of infants are breastfeeding exclusively for the first six months despite the multiple breastfeeding promotion programs that have been launched by the government (UNICEF, 2016). During six-month exclusive breastfeeding, the mothers could face many challenges, barriers, or difficulties. The common barriers are the perception about insufficient breast milk, and breast milk does not provide all the necessary vitamins and supplements (Kim & Chapman, 2013; Nguyen et al., 2018; Xuan & Nguyen, 2018). Another barrier of exclusive breastfeeding is the mother’s perception about foods and other liquids more nutritious than breast milk; therefore, formula milk, water, and solid food are commonly introduced before six months of age (Lundberg & Thu, 2012). In addition, mothers also face the barrier to exclusive breastfeeding due to the need to return to work outside the home or the feeling of uncomfortable to breastfeed in public places, such as restaurants, workplaces, shopping centers, and public transport (Coomson & Aryeetey, 2018). Besides, physical breast problems, such as mastitis, breast engorgement, sore nipples, and cracked or inverted nipples, become the challenge for mothers who breastfeed their children exclusively for six months (Babakazo et al., 2015; Karkee et al., 2014). Additionally, each culture has its own belief when it comes to breastfeeding. Some of these are helpful to mothers and babies, while others could negatively impact a baby’s health. For example, there is a widespread belief among Vietnamese mothers that colostrum is dirty milk and should throw away (Dixon, 1992). Discarding colostrum is associated with higher odds of non-exclusive breastfeeding during six months (Tamiru et al., 2012). According to Health Promotion Model, perceived barriers to action are anticipated, imagined, or real blocks and costs of understanding a given behavior (Pender et al., 2011). In the context of exclusive breastfeeding, perceived barriers refer to perceptions about inconvenience, difficulty, or obstacles in performing exclusive breastfeeding to the babies; the higher the perceived barriers to breastfeeding, the less implementation of exclusive breastfeeding among them (Kim & Chapman, 2013). Few studies documented the barriers of exclusive breastfeeding in the Vietnam context (Kim & Chapman, 2013; Nguyen et al., 2018). These studies were conducted in the Northern and Middle of Vietnam, where they have different cultures from the Southern of Vietnam. Therefore, conducting research in identifying the barriers of exclusive breastfeeding practices among mothers in the Southern of Vietnam was important. The findings from this study give comprehensive pictures about barriers of exclusive breastfeeding for six months among mothers in Ho Chi Minh City, Vietnam. It also provides baseline information for future researches on the relevant topic. In addition, the findings can help nurses and midwives to manage the exclusive breastfeeding practice and develop appropriate intervention to minimize the perception of barriers among Vietnamese mothers; hence, promoting the rate of exclusive breastfeeding among infants in Vietnam. Methods Study Design This was a quantitative study with a cross-sectional design to identify breastfeeding barriers among mothers in Ho Chi Minh City, Vietnam. It relied on secondary data of the research on “Factors predicting six-month exclusive breastfeeding among mothers in Ho Chi Minh City, Vietnam”, conducted by Nguyen et al. (2021). The data were collected from three hospitals named University Medical Center, Hung Vuong hospital, and Tu Du hospital at Ho Chi Minh City, Vietnam. Sample Size and Sampling Method The population of the study was mothers who were having babies aged from six to nine months. The study inclusion criteria for mothers included a mother from 18 years old or older, having a baby from six to nine months, being able to communicate in the Vietnamese language. For infants, the criterion included a singleton baby with a gestational age of at least 37 weeks. The exclusion criteria for mothers were mothers with chronic disease or other diseases in which breastfeeding was not allowed by physicians. The exclusion criteria for infants were infants with congenital disabilities or admission to the hospital during the first six months. The sample size was calculated using Cochran’s formula (Cochran, 1977). The estimated proportion of exclusive breastfeeding in Vietnam was 20% (UNICEF, 2016), the error of precision was accepted at 5%, and the confidence interval of 95% was assumed. Therefore, the total sample size in the current study was 246 mothers. Instruments The samples of this study were drawn from the secondary data of the original research, which was mentioned previously. The original survey was conducted using a self-administered questionnaire for collecting data. The Perceived Barriers to Breastfeeding Scale was developed by the first author based on the literature review (Babakazo et al., 2015; Coomson & Aryeetey, 2018; Kim & Chapman, 2013) and the concept of perceived barriers to action from the Health Promotion Model (Pender et al., 2011) to measure mothers’ perceptions of factors which were considered as breastfeeding barriers. The content validity of the scale was tested with three breastfeeding experts, and the item-level content validity (I-CVI) index of this scale was 0.91. Originally, this scale was developed in English and translated into the Vietnamese language using the back-translation technique. The Perceived Barriers to Breastfeeding Scale consisted of 20 items that covered three aspects of breastfeeding barriers: maternal barriers (item 1-10), infant barriers (item 11-14), and socio-environment barrier (item 15-20). The maternal aspect reflects the negative attitude or belief of mothers about breastfeeding practice, the lack of breastfeeding technique or skills, lack of confidence, mother’s physical and psychological changes that would bar the exclusive breastfeeding practice. The infant aspect reflects the false belief of mothers about the benefits of breast milk for infants and infant’s physical and psychological conditions. The socio-environment aspect reflects the negative mothers’ perception of inadequate support from family and health care providers, working status, and the adverse effect of formula advertisement against the exclusive breastfeeding practice. The response scale to each item was scored from 1 (strongly disagree) to 4 (strongly agree). Therefore, the total scores were ranged from 20 to 80, which a higher score means a higher level of perceived breastfeeding barrier. The psychometric properties of the scale were tested with internal consistency reliability of the scale was 0.92. Data Collection Data were derived from the secondary data of the original research; hence, the detailed information of the data collection could be seen in the study of Nguyen et al. (2021). Data Analysis Data were coded and analyzed using SPSS (statistical package for the social sciences) software program version 18.0. Descriptive statistics were used to describe the participant characteristics, compute the mean and standard deviation of the Perceived Barriers to Breastfeeding Scale. Independent t-test, one-way ANOVA were used to determine the different means between mother’s characteristics and perceived barriers to breastfeeding. If a statistically significant difference was found when running ANOVA, a post hoc test was done to find a specific difference between the groups. Prior to performing the ANOVA, the assumptions were tested to ensure the accuracy of the findings and confirm no violation of statistical assumptions. Ethical Consideration The current study obtained approval for secondary use from the first author of the original survey with the agreement for using the data. Additionally, the Institutional Review Board (IRB) Committee from the University of Medicine and Pharmacy at Ho Chi Minh City (no.992/HĐĐĐ-ĐHYD) approved this study. Furthermore, this study also received the mothers’ agreement to participate in the study. Mothers were also informed that they had the right to withdraw from the research and were assured about confidentially of the obtained information. Results Participant’s Characteristics Among 246 mothers, 61.4% of them aged 26 to 35 years. Slightly half of the mothers achieved the high school or diploma educational levels (52.0%), got the normal delivery (53.7%), and were the primiparous mothers (52.0%). Perceived Barriers to Breastfeeding The average total score of perceived barriers to breastfeeding was 49.24 (SD = 14.57), which was ranged from 22 to 76. The score in each item was varied from 1 to 4, which a higher score means a higher level of perceived breastfeeding barrier. The details of each item were presented in Table 2. Table 1 Mothers’ characteristics by frequency and percentage (N =246) Individual Characteristics n % Mother’s age  < 25 years old 46 18.7  25 – 35 years old 151 61.4  > 35 years old 49 19.9 Mother’s education  Less than high school 62 25.2  High school or diploma 128 52.0  Bachelor or higher 56 22.8 Delivery method  Normal delivery 132 53.7  Cesarean section 114 46.3 Parity  Primiparous 128 52.0  Multiparous 118 48.0 Table 2 Descriptive statistics of perceived barriers to breastfeeding (N = 246) Do you think that the following items were barriers to your breastfeeding? M SD Maternal  1. Breastfeeding is an exhausting process 2.34 0.84  2. Breastfeeding interferes with my sleeping pattern 2.56 0.97  3. Breastfeeding in front of family members is an embarrassing process for me 2.42 0.99  4. Experiencing physical breast problem (for example, sore or cracked nipple, breast engorgement) discourages me from continuing breastfeeding 2.52 1.01  5. Lack of knowledge about breastfeeding technique results in my unsuccessful practice 2.69 0.99  6. Breastfeeding makes me feel nervous about my body changes (such as weight gain, saggy breast) 2.27 0.87  7. I haven’t enough skills to practice breastfeeding 2.45 0.92  8. My breastfeeding is not successful as expected due to insufficient breastmilk 2.70 0.99  9. Breastfeeding interferes with my daily life activities 2.31 0.83  10. During breastfeeding, I often have negative emotion (such as feeling anxious, agitated, angry, disgusted, or rageful) 2.04 0.90 Infant  11. Exclusive breastfeeding does not provide my baby with enough nutrition. 2.26 0.92  12. It is difficult for me to keep my baby latch on my breast 2.46 0.94  13. My baby’s irritating mood makes breastfeeding harder 2.60 0.97  14 My baby’s illness makes breastfeeding very hard 2.74 0.99 Socio-environment  15. Breastfeeding in public places is uncomfortable to me 2.93 0.92  16. Breastfeeding limits my social activities with others 2.43 0.83  17. Lack of support from family members makes my breastfeeding practice more difficult. 2.45 0.89  18. Return to work affects my breastfeeding adversely 2.43 0.79  19. Formula advertisement from TV, parent magazines, etc. makes me feel unsure of continuing breastfeeding 2.31 0.88  20. Lack of support from healthcare personnel makes my breastfeeding practice more difficult. 2.34 0.91 For the maternal aspect, the results revealed that the item “My breastfeeding is not successful as expected due to insufficient breastmilk” had the highest mean score (M = 2.70, SD = 0.99), followed by the item “Lack of knowledge about breastfeeding technique results in my unsuccessful practice” (M = 2.69, SD = 0.99). The item “During breastfeeding, I often have negative emotion (such as feeling anxious, agitated, angry, disgusted, or rageful)” had the lowest mean score (M = 2.04, SD = 0.90). For the infant aspect, the item “My baby’s illness makes breastfeeding very hard” was the highest mean score (M = 2.74, SD = 0.99), followed by the item “My baby’s irritating mood makes the breastfeeding harder” (M = 2.60, SD = 0.97), and the item “Exclusive breastfeeding does not provide my baby with enough nutrition” had the lowest mean score (M = 2.26, SD = 0.92). For the socio-environment aspect, the results showed that item “Breastfeeding in public places is uncomfortable to me” had the highest mean score (M = 2.93, SD = 0.92), followed by the item “Lack of support from family members makes my breastfeeding practice more difficult” (M = 2.45, SD = 0.89). The lowest mean score was the item “Formula advertisement from TV, parent magazines, etc., makes me feel unsure of continuing breastfeeding” (M = 2.31, SD = 0.88). One-way ANOVA test showed a statistically significant difference between the mother’s age and breastfeeding barriers score (F = 3.67, p = 0.03). The post hoc (LSD) test calculated the smallest significance between two means as if a test had been run on those two means (as opposed to all of the groups together in the case of Tukey’s test). This enabled us to make direct comparisons between two means from two individual groups. The post hoc (LSD) test revealed that the mothers who less than 25 years old and from 25 to 35 years old had higher breastfeeding barrier scores than those who greater than 35 years old (Table 3). Table 3 The difference in breastfeeding barriers scores and mothers’ characteristics (N =246) Variable n Breastfeeding barriers Post hoc M±SD t/F p Mother’s age 3.67 0.03*  < 25 years old 46 53.30±15.31 (1), (2) > (3)  25 – 35 years old 151 49.28±13.92  > 35 years old 49 45.29±15.03 Mother’s education 0.81 0.45  Less than high school 62 51.13±15.17  High school or diploma 128 48.94±14.44  Bachelor or higher 56 47.84±14.57 Delivery method -0.90 0.37  Normal delivery 132 48.46±14.86  Cesarean section 114 50.14±14.23 Parity 0.68 0.50  Primiparous 128 49.84±14.29  Multiparous 118 48.58±14.90 * p <0.05 t = t-test, F = ANOVA, post hoc (LSD) Discussion The mothers in the current study were young adults, and the majority of them were in the appropriate range of childbearing ages between 25 to 35 years old. Slightly more than half of them were new mothers. The mothers’ perception of breastfeeding barriers was at a moderate level. According to Health Promotion Model, perceived barriers mean the perception of an individual about the inconveniences or difficulties of an action (Pender et al., 2011). In a breastfeeding context, perceived barriers represent the perception of mothers about the difficulties, the inconveniences, the challenges that the mothers face during the breastfeeding period; the more perceived barriers to breastfeeding, the less breastfeeding for the babies (Al-Darweesh et al., 2016). The top barrier by the perception of Vietnamese mothers in the current study with the highest score (M = 2.93, SD = 0.92) was “breastfeeding in public places was uncomfortable to the mothers”. It seems to be a common barrier from the perceptions of Vietnamese mothers and mothers from other countries. Coomson and Aryeetey (2018) conducted mixed methods research to describe the breastfeeding experience in public among 300 women in Accra, Ghana; these women reported difficulties in breastfeeding baby in public places due to the feelings of shyness, embarrassment, discomfort to expose the breasts (Coomson & Aryeetey, 2018). According to the literature review, there are controversial views of breastfeeding in public places; some support this practice while others do not. The rejection or acceptance of breastfeeding in public places depends on the requisite social norms. For example, a study by Morris et al. (2016) in the United Kingdom revealed that breastfeeding in public places was inappropriate because breasts were viewed as sexual objects. Whereas people in China claimed to breastfeed in public was appropriate and did not violate social morality (Zhao et al., 2017). In Vietnamese culture, it is acceptable for mothers to breastfeed in public places with covered-up breasts to avoid the exposure of their breasts. Vietnamese mothers would find a discreet place to feed their baby to prevent discomforting others, guard against judgment, and protect themselves from males’ unwanted gaze. Once a mother feels inconvenient or uncomfortable about breastfeeding in public, she is less likely to breastfeed her baby in public, which, in turn, more likely to stop exclusive breastfeeding before six months. Similarly, a study by Scott et al. (2015) indicated that mothers in European countries who had a negative attitude toward breastfeeding in public places were nearly never breastfed their babies in public (AOR = 0.05, 95% CI [0.12, 0.50]). Those mothers were also more likely to cease breastfeeding earlier compared to the others. The second highest score was baby's illness and irritating mood (M = 2.74, SD = 0.99). These Vietnamese mothers identified this barrier as one of the most common. One can theorize that when a baby becomes ill, mothers feel uncertain about caring for him, including feeding. Simultaneously, the baby's mood and appetite are likely to be altered, and the common baby/mother interactions towards feeding (Paintal & Aguayo, 2016). The best thing as we know that she should continue breastfeeding a sick baby to help the baby shorten the length of the illness and quickly recovery because breast milk contains antibodies (Manning et al., 2013). However, it is not easy to breastfeed an ill, irritated baby. To illustrate, the baby has a cold and stuffy nose; when he suckles the breast, it can be frustrating the baby, and he is fussier at the breast since he cannot breathe during suckling. Sharmin et al. (2016) reported that 64.8% of mothers in Bangladesh did not give exclusive breastfeeding during the baby’s illness time. In the belief of Vietnamese people, breastfeeding is unnecessary for the sick baby since it is difficult to feed the baby during the baby’s illness. Not surprisingly, the infant’s illness is highly correlated to the inadequate practice of exclusive breastfeeding in Vietnam. The third-highest score of barriers of exclusive breastfeeding from Vietnamese mothers’ perception was the insufficient breast milk (M = 2.70, SD = 0.99). Interestingly, perception about insufficient milk seems to be a global barrier for exclusive breastfeeding among mothers worldwide. In a study by Osman et al. (2009), mothers in Lebanon perceived that they had insufficient breast milk because their babies still felt hunger and cried after feeding. Similarly, a study by Nasser et al. (2018) reported that 78% of the mothers in Qatar stopped giving exclusive breastfeeding for babies because they thought they did not have enough breast milk. A study in Vietnam reported that 60.9% of the mothers felt that their breast milk was not enough for the child and the child would be hungry; consequently, they considered stopping exclusive breastfeeding during the first six months (Nguyen et al., 2018). There are various reasons for insufficient milk supply, such as poor nutrition due to poor appetite of the mothers (Lou et al., 2014), poor sucking (Sharmin et al., 2016), not breastfeeding often enough, over anxiety, excessive fatigue, and lack of support and guidance from nurse-midwives (Sultana et al., 2013). However, insufficient milk is preventable; the finding implied the importance of educating, supporting, and coaching the mothers to overcome this barrier and successfully exclusive breastfeed for the first six months. A previous study confirmed that mothers having sufficient breast milk for the baby in the first six months were 24.89 times more likely to give exclusive breastfeeding than mothers with the perception of insufficient breast milk (Kim & Chapman, 2013). Next, lack of knowledge about breastfeeding techniques resulting in unsuccessful practice was a barrier by the view of Vietnamese mothers in the current study (M = 2.69, SD = 0.99). A study by Nasser et al. (2018) revealed that approximately 53% of the mothers stopped exclusive breastfeeding their babies between zero and six months due to not knowing how to breastfeed the babies appropriately. Likewise, Sharmin et al. (2016) reported that 92.3% of mothers in Bangladesh who were in the non-exclusive breastfeeding group using faulty breastfeeding techniques led to poor suckling and attachment. In Vietnam, the mothers with normal delivery will be discharged from the hospital after two to three days; with the short period, the mothers might not learn and absorb the breastfeeding techniques provided by the hospital. In fact, breastfeeding is a “learned skill”, more than instincts. Thus, it is difficult to be successful in the breastfeeding practice if the mothers have less knowledge and fewer skills about breastfeeding techniques. Mothers in the current study were new mothers who had no breastfeeding experience before, and that is why lack of techniques in breastfeeding was their concern as a barrier of breastfeeding. Therefore, the teaching about breastfeeding techniques for mothers during antennal care visits is suggested for the hospital policy. Last but not least, the fifth-highest score was the lack of support from family (M = 2.45, SD = .89). The Vietnamese mothers exposed this barrier as one of the most common. Researches have proved that family support played an essential role in the exclusive breastfeeding practice of mothers. For instance, a study by Yenti et al. (2018) revealed that mothers in Indonesia who got family support for breastfeeding were 2.67 times (95%CI [1.1, 6.4]) more likely to give exclusive breastfeeding than those who did not have. Likewise, another study in Yogyakarta, Indonesia, found that mothers who received family support were 2.86 times (95%CI [1.25, 6.58]) more likely to practice exclusive breastfeeding compared to those who did not (Ratnasari et al., 2017). Similarly, a study in Ethiopia reported that mothers who were supported by their husbands were 2.67 times (95%CI [1.04, 6.95]) more likely to breastfeed exclusively (Tewabe et al., 2016). Family plays a crucial role in breastfeeding practice; thus, receiving support from family was important during the breastfeeding period for the mothers. Not surprisingly, lack of support from family was perceived as one of the barriers of exclusive breastfeeding practice. The current study provides the picture of perceived barriers to breastfeeding among mothers in Ho Chi Minh City, Vietnam; it is a piece of the puzzle to complete the picture of breastfeeding in Vietnam. In addition, it gives some implications for nursing and midwifery practice as mothers perceived they had insufficient milk and breastfeeding techniques to feed their babies. Therefore, nurses and midwives need to be with them in the first hours and days after birth to build their confidence when breastfeeding the babies. Also, nurses and midwives can develop the nursing interventions, such as the enhancement breastfeeding self-efficacy programs for mothers and students to build and boost self-efficacy so that the mothers or future mothers can confidently practice reaching the six-month exclusive breastfeeding. The top barrier perceived by mothers in this study was uncomfortable when breastfeeding in public places. It implies that the policy needs to have room for breastfeeding in public places, such as hospitals, restaurants, parks, cinemas, etc. The data from this study were drawn from convenience sampling; thus, the representativeness of this study was limited. It evokes a recommendation for further research. A cluster random sampling method should be used to obtain a sample with the best representativeness for the entire population in Vietnam. Besides, for comparison with the current study, further research should be conducted with the mothers in rural areas or other regions of the country to capture a broader picture of perceived barriers to breastfeeding practice in Vietnam. Conclusion The failure of exclusive breastfeeding practice in the first six months was derived from the mothers’ perception of different barriers. These barriers come from the three main factors, including maternal, infant, and socio-environment factors. The embarrassment, insufficient milk, baby’s illness and irritating mood, lack of knowledge about breastfeeding techniques, and lack of support from family were the most perceived barriers. The investigations in this study help nurses, midwives, and healthcare providers identify the barriers that obstruct the exclusive breastfeeding practice; hence, the breastfeeding promotion program could be proposed and implemented to improve the exclusive breastfeeding practice. Acknowledgment We thanked the University of Medicine and Pharmacy for providing the fund for conducting this research. We also acknowledged the experts for their valuable time to evaluate the content of the questionnaire. Declaration of Conflicting Interests The authors declare that there is no conflict of interest in this study. Authors’ Contribution NTN made significant contributions to the literature review (review of theory which can be applied in the study, recommendation from WHO, policies of Vietnamese government about exclusive breastfeeding, current situation of exclusive breastfeeding in Vietnam), design of the study, data acquisition, analysis/interpretation of the study. HTD and NTVP made significant contributions to the literature review (review the benefits of exclusive breastfeeding, the barriers of breastfeeding in other countries and Vietnam), study design, data acquisition, interpretation of the study findings. All authors drafted the manuscript, revised it critically for important intellectual content, approved the final version of the paper, and agreed to its submission for publication. Authors’ Biographies Dr. Nhan Thi Nguyen is a Lecturer at the Midwifery Department, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam. Huong Thi Do, MEd is Dean of Midwifery Department, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam. Nhu Thi Van Pham, MPH is a Former Lecturer at the Midwifery Department, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. ==== Refs References Al-Darweesh, F., Al-Hendyani, R., Al-Shatti, K., Abdullah, A., Taqi, M., & Abbas, A. (2016). Knowledge, intention, practice, and perceived barriers of breastfeeding among married working women in Kuwait. International Journal of Community & Family Medicine, 1 (108 ), 1-6. 10.15344/2456-3498/2016/108 Babakazo, P., Donnen, P., Akilimali, P., Ali, N. M. M., & Okitolonda, E. (2015). Predictors of discontinuing exclusive breastfeeding before six months among mothers in Kinshasa: A prospective study. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-59 10.33546/bnj.1509 Editorial A year later: Life after the Year of the Nurse https://orcid.org/0000-0002-7831-2536 Marzilli Colleen * The University of Texas at Tyler, USA * Corresponding author: Colleen Marzilli, PhD, DNP, MBA, RN-BC, CCM, PHNA-BC, CNE, NEA-BC, FNAP, The University of Texas at Tyler, School of Nursing, 3900 University Blvd., Tyler, TX 75799, USA. Email: cmarzilli@uttyler.edu Cite this article as: Marzilli, C. (2021). A year later: Life after the Year of the Nurse. Belitung Nursing Journal, 7(2), 59-61. https://doi.org/10.33546/bnj.1509 29 4 2021 2021 7 2 5961 27 4 2021 28 4 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. nurse COVID-19 pandemic midwife burnout professional fatigue ==== Body pmcThe year 2020 should have been a year celebrating the remarkable contributions of nursing as a profession on society. The “International Year of the Nurse and the Midwife”, was so designated by the World Health Organization to honor the 200th anniversary of Florence Nightingale’s birth and highlight the important role of nurses in addressing healthcare needs globally. In light of the events of 202 and the global pandemic, the World Health Organization extended the International Year of the Nurse and the Midwife through their “Year of Health and Care Workers” campaign while global partners have extended the International Year of the Nurse and the Midwife 2020/2021 through different campaigns. What started as a year to celebrate the work of nurses in advancing and promoting health globally transformed into a dramatic showcase of the extremely hard work of nurses in fighting COVID-19. The recognition and spotlight on nurses shifted from focusing on a thriving profession advancing health to a strong profession poised to be at the bedside responding to a global threat. It seems fitting that in the International Year of the Nurse and the Midwife, the efforts of nurses were publicized across international news outlets. Some hailed nurses as heroes. The smiling faces of nurses to celebrate such a momentous year were replaced by images of nurses with masks with a look of care and compassion in their eyes, often behind goggles, fighting COVID-19. Nursing as a profession must examine the International Year of the Nurse and the Midwife in context with the global COVID-19 pandemic and reflect on the effects to the nursing profession. The perception of nurses across the globe is generally one of positive regard outside of the pandemic response. In fact, in the United States, nurses are known as the most trusted profession by an annual, Gallup poll (Saad, 2020). Nurses have been played by political and religious leaders across the world recognizing the importance that nurses play in society and in the pandemic response. During the pandemic response, nurses have been excluded from society and alienated out of fear that being around a nurse will expose community members to the virus. Nurses have experienced ridicule and shame. In markets and amongst the community, instead of people seeing a nurse and consulting the nurse for health advice, nurses are told to get away. Nurses have sacrificed for the community at the expense that they are shunned by the community. Even in families, nurses may elect to stay in a separate room or location from their family so as not to expose their family. Nurses are making a huge sacrifice, and they do this out of a sense of duty, commitment, responsibility, and a sense of loyalty to their patients, their profession, and the greater global good. There is an awareness in the global community that nurses and other healthcare workers are sacrificing for the good of the community, and there are several unique ways that communities have shown their appreciation. The Clap for Carers social movement originated in the United Kingdom by Annemarie Plas, to show support for those working in the National Health Service (NHS) received global attention as healthcare workers were recognized for approximately two months between March and May 2020. This movement garnered the support of many celebrities and politicians. Businesses, schools, and religious organizations have made different gestures to recognize the work of nurses and other healthcare workers. Some businesses have donated meals and treats to nurses while others have recognized the work of nurses through different public service announcements and campaigns to reinforce the valuable role nurses continue to play in the pandemic response. Praise continues for nurses and other healthcare workers (Gunawan, 2020). A challenge that nurses face now is that as the pandemic response has persisted for well over a year, the public support has waned. The morale boost that nurses received from the public support was an important source of strength for nurses, especially considering the negative response from some community members (Gunawan et al., 2020). With that morale boost dwindling, the overall morale has declined amongst much of the nursing profession. Combined with the stress of caring for COVID-19 patients without fully understanding the virus and the fatigue from such a prolonged fight against the virus, members of the nursing profession are reaching alarming levels of fatigue and burnout. Nurses everywhere are facing overwhelming responsibilities to provide care for increasingly sick patients. Nurses have always done a great deal with very little resources, and this increased workload is nothing new to nurses across the globe. However, with the novel COVID-19 pandemic, novel is the key. This virus has not been seen before, and while nurses are using the best tools they have to fight this malicious virus, there is an insurmountable burden that nurses are shouldering as they provide daily care for acutely ill patients with little known about the virus. While we continue to investigate the virus and treatment modalities that are effective in treating the virus, there is still a great unknown associated with the virus. This unknown creates a significant mental barrier and adds increased stress to nurses as they blindly fight the virus. Nurses have historically provided care in extremely difficult circumstances, and nurses are familiar with carrying the burden of care in a professional and gracious manner. Nurses render aid in traumas and disasters worldwide, and this is nothing new. From Florence Nightingale providing care to British and Turkish soldiers in the Crimean War to today where nurses aid in epidemiological responses, war, and in treating viruses like Ebola, nurses place themselves in suboptimal situations out of a sense of duty to provide care. However, what exacerbates the strain and burden to nurses with the COVID-19 pandemic is the unknown and uncertainty associated with this virus. In different parts of the globe there are different variants and different responses to the virus. Despite these challenges and the unknown, nurses are on the front lines to provide care with a smile and a will to make patients as comfortable as possible while suffering from the devastating disease. Fatigue and burnout are common problems in nursing. Even pre-COVID, nursing was a physically, mentally, and emotionally demanding job. Nurses provide care to patients when people are at their most vulnerable state, and in that vulnerability comes fear and a lack of control. Patients may displace their fear and feelings of lack of control on the nurse, and the patient’s family may also displace their fear and frustration on the nursing staff. Other healthcare team members experience stress and fatigue, and nursing often feels the effects of this stress as the healthcare team member at the bedside 24 hours a day, seven days a week. Nurses work long hours on their feet rushing from one patient to the next. Nurses are increasingly under intense pressure to discharge patients as soon as possible and make sure zero errors or mistakes are made. Short-staffing and patient over-crowding means nurses work increasingly longer hours each week, and there are few opportunities to rest and reset towards a healthier physical, mental, and emotional outlook. Since COVID, these factors are exacerbated, and fatigue and burnout has increased (Sasangohar et al., 2020). As a profession, nursing needs to understand the role they continue to play in fighting the COVID-19 pandemic. The role of the nurse is invaluable in fighting this deadly virus. The long hours and fear of the unknown will continue as we work to control this virus and overcome. However, the fear and burden must be reconciled with the value of the nurse. Concerns that nurses have about contracting COVID-19, just like those in the general public, and fear of infecting family members are real concerns when providing care to patients with COVID-19. Feelings of isolation when choosing to quarantine to project the public, patients, and colleagues, and feelings of sadness when caring for patients are not improving are all real barriers and challenges that nurses face (Alharbi et al., 2020). Even if the role of the nurse goes unnoticed, underappreciated, or forgotten, the nursing profession must recognize their collective strength in fighting the virus. We must remember that 2020 was the International Year of the Nurse and Midwife and that as we progress through 2021, this designation as 2021 as the Year of Health and Care Workers, remains a tribute to the hard work and dedication of the nursing profession. Nurses must continue to find ways to feel connected and engaged with their work so they reduce feelings of fatigue and burnout (Acob, 2020). Here are seven ways nurses can celebrate their hard work and dedication to the profession. These strategies celebrate the nursing profession and the collective strength of such an invaluable profession. First, remember a special patient. All nurses have a story of one patient that was extremely meaningful for their career. When fatigue and burnout are looming, nurses can recall that patient and reflect on the care they were able to provide. Nurses can identify what felt rewarding and what you learned from the experience. Nurses can think about the patients in their care now and identify how they can translate that memorable patient to what they are doing now. Second, celebrate small victories. Nurses have a demanding job with multiple competing tasks to complete of equal importance. At times, it can feel like the nurse is pulled in multiple directions at once. By celebrating small victories, such as helping a patient out of bed for the first time or assisting a family member with education they need to provide care to their loved one, nurses can remind themselves of the positive difference they have in their role as a nurse. Even small wins are worth celebrating. Third, take a break. It can be easier to talk about taking a break instead of taking an actual break. If it is not possible to take an actual break, the nurse can take a mental break. The nurse can recall something relaxing and that brings them joy. The nurse can pause their focus on their patients and visualize that thing that provides joy. This mental break is a strategy to help reduce some of the mental fatigue felt by nurses. Fourth, sleep. It goes without saying that sleep is restorative. Nurses work long hours and go home to complete housework, chores, and other responsibilities. All nurses have a life outside of work, and when work is done, those other responsibilities are priorities. Nurses often sacrifice their sleep to ensure that their work and home responsibilities are maintained. Insufficient sleep is a significant factor in fatigue and burnout, and this also depresses the immune system making nurses, just like every other human, more susceptible to illnesses like COVID-19. Nurses with too little sleep are more likely to make errors in patient care, and this adds to fatigue and burnout, too. It is ok for nurses to sleep and engage in that restorative practice. Sleep is important tool for nurses to fight fatigue and burnout and stay well while fighting COVID-19. Fifth, proper nutrition. Nurses need proper nutrition to maintain their strength at work and help fight fatigue and burnout. Proper nutrition helps nurses boost their immune system and provide the energy needed to care for patients. Nursing is physically demanding work, and proper nutrition is the fuel that provides the strength to engage in such a physically demanding profession. Proper nutrition is a key component of addressing fatigue and burnout. Sixth, do something that brings joy. While it may be difficult to find joy while working and providing care to patient, especially COVID-19 patients, it is important to do something that brings joy to the nurse outside of working hours. Perhaps the nurse enjoys reading, sewing, playing cards, watching television, or listening to music, whatever is a source of joy should be identified. Nurses should aim to do at least one thing that brings joy dally. During days where the nurse does not work, the nurse should aim to do at least three things that bring joy. Seventh, reconnect to the profession of nursing. While it may seem counter-intuitive to reconnect to the profession when nurses are feeling fatigue and the burnout associated with providing care to patients suffering from COVID-19, nurses should challenge themselves to connect to the profession. Nurses can identify what led them to nursing and what they have found to be rewarding about nursing as a profession. Nurses should reconnect to the historical roots of nursing and the 200-year history of nursing as a profession since Florence Nightingale. The nursing profession has a long history of providing care, and reconnecting to the nursing profession can be a good reminder that nurses are part of an invaluable profession with a legacy of providing much needed care. The International Year of the Nurse and the Midwife garnered attention and make history for the nursing profession, but not as originally intended. Nurses have sacrificed greatly, both professionally and personally, to provide the necessary care for COVID-19 patients. Nurses are invaluable member of the healthcare team, and despite the burnout, fatigue, public recognition, and social media campaigns to recognize nursing, nurses must capitalize on the 2020 International Year of the Nurse and the Midwife campaign and look forward to the 2021 Year of Health and Care Workers campaigns and focus on recognizing the value of nursing as a profession in society. Nurses face challenges daily, and burnout and fatigue are real. Nurses are encouraged to try seven recommendations to fight burnout and fatigue and celebrate being a member of such a profession as nursing. Declaration of Conflicting Interest The author declares no conflict of interest in this study. Funding This research did not obtain any research funding from any agency. Author Biography Colleen Marzilli, PhD, DNP, MBA, RN-BC, CCM, PHNA-BC, CNE, NEA-BC, FNAP is Associate Professor at the University of Texas at Tyler. She is also on the Editorial Advisory Board of Belitung Nursing Journal. ==== Refs References Acob, J. R. U. (2020). Appreciating positivity of COVID-19. Belitung Nursing Journal, 6 (6 ), 226-228. 10.33546/bnj.1214 Alharbi, J., Jackson, D., & Usher, K. (2020). The potential for COVID-19 to contribute to compassion fatigue in critical care nurses. Journal of Clinical Nursing, 29 (15-16 ), 2762-2764. 10.1111/jocn.15314 32344460 Gunawan, J. (2020). COVID-19: Praise is welcome, but nurses deserve a pay rise. Belitung Nursing Journal, 6 (5 ), 150-151. 10.33546/bnj.1217 Gunawan, J., Aungsuroch, Y., & Marzilli, C. (2020). ‘New Normal’ in Covid-19 era: A nursing perspective from Thailand. Journal of the American Medical Directors Association, 21 (10 ), 1514-1515. 10.1016/j.jamda.2020.07.021 32859516 Saad, L. (2020). U.S ethics ratings rise for medical workers and teachers. Gallup. Retrieved from https://news.gallup.com/poll/328136/ethics-ratings-rise-medical-workers-teachers.aspx Sasangohar, F., Jones, S. L., Masud, F. N., Vahidy, F. S., & Kash, B. A. (2020). Provider burnout and fatigue during the COVID-19 pandemic: Lessons learned from a high-volume intensive care unit. Anesthesia and Analgesia. 10.1213/ANE.0000000000004866

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-113 10.33546/bnj.1293 Original Research Nursing handover in the Indonesian hospital context: Structure, process, and barriers https://orcid.org/0000-0001-7614-632X Yetti Krisna * https://orcid.org/0000-0001-9068-6488 Dewi Nani Asna https://orcid.org/0000-0003-3156-7408 Wigiarti Sri Herni https://orcid.org/0000-0002-0429-3184 Warashati Dina Faculty of Nursing, Universitas Indonesia, Indonesia * Corresponding author: Dr. Krisna Yetti, S.Kp., M.App.Sc, Faculty of Nursing, Universitas Indonesia, Jl. Prof. DR. Sudjono D. Pusponegoro, Kukusan, Kecamatan Beji, Kota Depok, Jawa Barat 16425, Indonesia. E-mail: krisna@ui.ac.id Cite this article as: Yetti, K., Dewi, N. A., Wigiarti, S. H., & Warashati, D. (2021). Nursing handover in the Indonesian hospital context: Structure, process, and barriers. Belitung Nursing Journal, 7(2), 113-117. https://doi.org/10.33546/bnj.1293 29 4 2021 2021 7 2 113117 30 1 2021 22 2 2021 24 3 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Nursing handover is an essential part of nursing practice to safe patient care, which occurs among nurses between shifts for transferring professional responsibility and accountability. However, there is limited information about the implementation and evaluation of nursing handover in Indonesian hospitals. Objective This study aimed to describe the structures, processes, and barriers of the nursing handover in the Indonesian hospital context. Methods This study employed a case study design in five inpatient units, especially in the medical-surgical wards of a referral hospital in Indonesia. The study was conducted from August to November 2018. A total of 100 handovers and 76 nurses were included. Focus group discussions were conducted in head nurses, nurse team leaders, and registered nurses. Observations were implemented to capture the handover process, including the number of the nurses in and out and the content of the information covered situation, background, assessment, and recommendations (SBAR). Data were analyzed using content analysis and fishbone analysis. Results The nursing handover consisted of three phases: before, during, and after. The handover barriers were divided into manpower, material, money, method, environment, and machine. The content of handover varied according to nurses’ familiarity with the patients and their complexity. The nurses also actively participated during the handover process, although some nurses were absent in the handover time. About 75% of nurses had sufficient knowledge about the shift handover process using SBAR. The SBAR was adopted as a standard for handover, but no specific guideline or standard operating procedure. Conclusion The results of this study can be used as basic information to develop a guideline of nursing handover and supervision in the context of hospitals in Indonesia and beyond. case study clinical handover nursing handover patient handoff Indonesia hospital ==== Body pmcNursing handover plays a vital role in patient care continuity to ensure the quality of care and patients’ safety (Australian Commission on Safety and Quality in Healthcare, 2011). Handover is a routine process that usually occurs two to three times a day in most hospitals (Chaboyer et al., 2010; Mcmurray et al., 2011). It is designed for transferring care, including information about the patient’s condition, treatment plan, and intervention priority (Kilic et al., 2017). According to the national hospital accreditation standards in 2018, handover is one way to improve the patient’s safety. Thus, health care professionals need to increase effective communication. Joint Commission International (JCI) recommends developing and implementing handover processes among health care professionals (Hospital Accreditation Commission, 2017). However, on some occasions, due to the high workload, the handover process becomes a burden for nurses, which leads to the miscommunication of the patients’ care (Spooner et al., 2018). Therefore, effective communication is essential to provide accurate and complete information and avoid unexpected outcomes (Spooner et al., 2018). There are four critical indicators considered on an excellent handover process in many Indonesian hospitals: timeliness, communication patterns, SBAR (situation, background, assessment, recommendations), leadership, and documentation (Herawati et al., 2018; Tobiano et al., 2018). These four things are assessed every month and recapitulated by the nursing department for monitoring and evaluation. SBAR technique has helped nurses to interact in a centered and easy manner during the transition of treatment (Achrekar et al., 2016). This model of interaction has gained popularity in healthcare settings, especially among professionals like the nursing staff. It is a way to communicate easily with each other for health care professionals and allows for efficient sharing of important information. Using standardized SBAR for bedside change handover in nursing practice would improve communication between nurses and ensure patient safety (Achrekar et al., 2016). SBAR format allows for the quick, structured, and consistent stream of professional knowledge (Thomas et al., 2009). SBAR technique’s primary purpose is to improve interaction efficiency by standardizing the communication system. Although handover is a common issue, the information about implementation and evaluation is limited. Therefore, this study aimed to describe the structure, process, and barrier of nursing handover in the Indonesian hospital context. Methods Study Design This study employed a case study design in five inpatient units, especially in the medical-surgical wards of a referral hospital in Indonesia. The case study was chosen as an appropriate methodological approach to conduct an active investigation limited by place and time (Yin, 2003). In the case study, we asked questions about what, why, and how to analyze current, real-life situations with all their complexity (Kyburz-Graber, 2004). Participants The study was carried out on adults’ medical-surgical wards for neurological, oncology, and general surgical cases from August to November 2018. Each unit mainly consisted of four to six beds. A team and primary nursing were used as nursing care delivery models. Each unit has one team led by one head nurse, primary and associate nurses. This study participants were nurse managers, nursing staff, team leaders (those in charge of patient groups and nursing staff), and shift coordinators (who took overall responsibility for the ward operations). Data Collection This study used two data collection forms; observation and semi-structured focus group discussion (FGD). Due to reduced personnel during handover periods, we only included afternoon shift-to-shift handover, but the FGDs included all nursing staff, nurse team leaders, and nursing managers. We conducted observations guided by a data collection form. We recorded the handover process, including a number of the nurses in and out, the content of the information covered situation, background, assessment, and recommendations (SBAR) (Haig et al., 2006). When nurses asked questions or made statements about the current conditions in the handover process, they were deemed to be actively involved in the handover process. We were not considering passive participants if they only made insignificant comments like just say ‘OK’. Nurses were deemed not to be involved in the handover when there was no contact between nurses during the handover. The participants were selected using a purposive sampling that involved nursing staff, nursing managers, and nurses team leaders. The focus group discussion was divided into five groups (one group from each ward). Questions were about structure, process, and barriers related to the handover, such as “how do you prepare handover?”, “What do you do in the handover process?”, and continued until there was no more new information. Data Analysis Data were analyzed through iterative review by all the research team members, which recursively examined the interview data, searching for similarities in the views of respondents and across the six cases using constant comparison. Similar ideas were then organized into categories of structures and processes. Structures involved physical and institutional properties, procedures done, and the results achieved. Assessing the quality of the handover process was undertaken by appraising and linking structures and processes with outcomes, assuming that structures influence processes, affecting outcomes. A fishbone analysis including man, method, machine, material, money, and environment was used as a framework to obtain barriers of nursing during handover. Trustworthiness A different technique was used to ensure the trustworthiness of this study. Credibility was achieved through detailed group discussions. Reliability was gained through the separate analysis of the transcript by three co-authors. The team then confronted and discussed the findings before an agreement on code, category, sub-theme, and theme had been attained. Transferability was demonstrated using semi-structured FGD sessions to reflect differences in specific populations and the appropriate quotations collected. Ethical Consideration The studied hospital’s ethical committee has approved this study (No. DM 01.01 / VIII.2 / 1359/2019). Participants were informed that the collected information would be kept confidential. All participants were provided a written informed consent to participate in this study. They had the right to withdraw from the study at any time without giving reasons or any penalties. Results A total of 100 handovers process were observed in five wards, and 76 nurses were interviewed. The majority of interviewees were males, graduated with a bachelor degree with a professional program with age ranged from 25 to 55 years old. The majority of the participants had been working for more than two years. About 75% of nurses had sufficient knowledge about the shift handover process using situation, background, assessment, and recommendations (SBAR). The results from the observation focused on addressing the handover process. The handover occurred in the nurse’s station, and the one who started to transfer information was the outgoing staff. Oncoming staff is a leader to document all information and write it in an official book. While each nurse made their notes about patients’ condition and treatment plan. The handover structures were generally occurred between the team, not as a whole of ward handover. Situation, background, assessment, and recommendations (SBAR) were used in varying degrees of handover ranged from 55% to 85%. The nurses also actively participated during the handover process, although some nurses were absent in the handover time. The time for handover in the afternoon usually started from 14:00 to 15:00 West Indonesian Time (WIB), and the night shift began at 20:30 until 21:00, and in the morning shift started from 7:00 to 08:00 clock. Approximately four to five people were present at the handover process, including the team leader of the outgoing shift and all three team members of the oncoming shift. Figure 1 describes the handover process in the studied hospital. There were three stages in the handover process: before, during, and after. Before the handover, the off-going nurses in charge of providing direct care to patients were prepared some notes or documents to report. The unique thing is that they started the process by firstly praying according to each religion, and then, the head nurse opened and started the meeting. The first meeting discussed new importation or reminded something, such as hand hygiene technique or updated information related to nursing interventions. During the handover, the outgoing staff reports the patients’ current situation, treatment plan, and other issues. The content of handover varied according to nurses’ familiarity with the patients and their complexities. After the handover finished, the upcoming nurses discussed job allocation and prepared to do routine activities. Figure 1 Handover process The results of focus group discussion were used to explore the barriers that commonly happened during handover. Figure 2 illustrates the fishbone analysis used to describe the barriers divided into manpower, material, money, method, environment, and machine. From the viewpoint of the human resources, the barriers included adherence of nurses in the handover process, lack of mentoring from head nurses, and less participation. As stated by nurses in the FGD as follows: “… sometimes I was confused how to share the information because it’s a routine activity, and I know what I have to do even though I am an off-going nurse…” AND “…I listen to the information only from the outgoing nurses, especially the instruction from the medical doctor or others.” Figure 2 Fishbone diagram of nursing handover barriers From the material point, there was a guideline for supervision of handover. But the documentation using SBAR was not well implemented due to the items were not completely clear. The nurses state this in FGD: “…I know SBAR, sometimes I wrote completely, sometimes not, it depends on the available time…” AND “…I don’t know whether what I wrote in documentation is correct or not, or follow the correct SBAR guideline.” Furthermore, lack of reward and unsupported environment were the other barriers of nursing handover. Discussion Our study shows a complex nursing handover process that involved management policy, environmental, and human resources. We found that the majority of nurses had sufficient knowledge about SBAR. Although SBAR was recommended to use during handover, the comprehensive information and communication direction was unclear. SBAR is a rigid handover structure that could transfer information objectively in a standard format (Haig et al., 2006). Interestingly, although the nurses adopted SBAR, no updated guideline or standard operating procedure about the handover; therefore, it is essential to evaluate the implementation of the handover process using SBAR consistently. A previous study suggested that prioritizing transferred information is important to help oncoming nurses to get information quickly and minimize overload information and time-consuming during handover (Patterson, 2008). Also, less use of current technology was applied during handover. Consequently, the documentation process has become a burden due to the time-consuming to write a complete story of the patients. Policymakers may consider using technology to reduce the time for documentation. In this study, nurses showed active participation during the handover process, including making a decision, although some nurses were absent. One of the problems from the managerial aspect was less supervision to monitor the quality of the handover process. Empowerment is required in nursing care to perform nursing care to achieve nursing goals by considering patient safety, using critical thinking skills, and making effective communication (Pulvirenti et al., 2014). All nurses need to share the knowledge about a patient during the handover period and at the same time know that the others do know it. During handover, nurses’ empowerment is crucial because good empowerment can help achieve the hospital’s goal to provide excellent service (Laschinger et al., 2014). A study suggested that top management is expected to have involvement and commitment to improving and facilitating handover according to standards (Barker & Ganti, 1980). Continuous education for nurses regarding handover is imperative to update the new information and maintain the process comprehensively and correctly. Conclusion In conclusion, this case study provided the process and structure of handover and barriers that commonly happened during handover. This information can be used as basic information to develop or update guidelines or standard operating procedures of the handover for comprehensive implementation. Importantly, policymakers need to design an effective system and environment to overcome problems in the handover, such as using electronic documentation, providing a complete sheet as a guideline for handover, providing rewards and adequate supervision. The development of continuous education programs for nurses is also needed to update the handover information and maintain handover quality. Acknowledgment Thanks to all nurses who participated in this study. Declaration of Conflicting Interest All authors declare no conflict of interest. Funding This study was funded by the Department of Nursing, Universitas Indonesia, Indonesia. Authors’ Contribution KT, NAD, SHW, and DW contributed equally in data collection, data analysis, data interpretation, drafted article, and critically revised the article. All authors agreed with the final version of the manuscript. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Authors’ Biographies Dr. Krisna Yetti, S.Kp., M.App.Sc is a Lecturer at the Faculty of Nursing, Universitas Indonesia, Indonesia. Nani Asna Dewi, Sri Herni Wigiarti, and Dina Warashati are graduate students at the Faculty of Nursing, Universitas Indonesia, Indonesia. ==== Refs References Achrekar, M. S., Murthy, V., Kanan, S., Shetty, R., Nair, M., & Khattry, N. (2016). Introduction of situation, background, assessment, recommendation into nursing practice: A prospective study. Asia-Pacific Journal of Oncology Nursing, 3 (1 ), 45. 10.4103/2347-5625.178171 27981137 Australian Commission on Safety and Quality in Healthcare. (2011). External evaluation of the national clinical handover initiative pilot program. Sydney: Australian Commission on Safety and Quality in Healthcare. Barker, M., & Ganti, A. R. (1980). An in-depth study of the head nurse role. Supervisor Nurse, 11 (11 ), 16-21. Chaboyer, W., McMurray, A., & Wallis, M. (2010). Bedside nursing handover: A case study. International Journal of Nursing Practice, 16 (1 ), 27-34. 10.1111/j.1440-172X.2009.01809.x 20158545 Haig, K. M., Sutton, S., & Whittington, J. (2006). SBAR: A shared mental model for improving communication between clinicians. The Joint Commission Journal on Quality and Patient Safety, 32 (3 ), 167-175. 10.1016/S1553-7250(06)32022-3 16617948 Herawati, V. D., Nurmalia, D., Hartiti, T., & Dwiantoro, L. (2018). The effectiveness of coaching using sbar (situation, background, assessment, recommendation) communication tool on nursing shift handovers. Belitung Nursing Journal, 4 (2 ), 177-185. 10.33546/bnj.464 Hospital Accreditation Commission. (2017). National standard of hospital accreditation. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-050 10.33546/bnj.1254 Perspective Nurses’ roles in palliative care: An Islamic perspective https://orcid.org/0000-0003-4389-6137 Suprayitno Edy * https://orcid.org/0000-0003-3426-1826 Setiawan Iwan Department of Nursing, Faculty of Health Sciences, Universitas ‘Aisyiyah Yogyakarta, Indonesia Corresponding author: Edy Suprayitno, S.Kep., Ns., M.Kep, Universitas ‘Aisyiyah Yogyakarta, Jl. Siliwangi Jl. Ringroad Barat No.63, Area Sawah, Nogotirto, Kec. Gamping, Kabupaten Sleman, Daerah Istimewa Yogyakarta 55592, Indonesia. Email: edysuprayitno@unisayogya.ac.id Cite this article as: Suprayitno, E., & Setiawan, I. (2021). Nurses’ roles in palliative care: An Islamic perspective. Belitung Nursing Journal, 7(1), 50-54. https://doi.org/10.33546/bnj.1254 22 2 2021 2021 7 1 5054 05 12 2020 04 1 2021 08 2 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Palliative care is an important approach for nurses to improve the quality of life of patients holistically and mitigate suffering among the patients in critical condition and near to death. This article provides an Islamic perspective about nurses’ roles in palliative care, which can be applied worldwide, especially in Muslim-majority countries. Understanding Islamic beliefs will help nurses provide professional and culturally sensitive nursing care. In its principle, Islam always respects the process of life until death comes. So, the application of Islamic values in palliative care will make the patients accept their ill condition completely, keep being close to Allah SWT (God), and die peacefully. The concepts of illness, death, early action on the dead, and palliative care application in nursing are explained in this article to open up new ideas rather than provide definitive answers. We hope that this perspective will highlight healthcare policymakers the need to integrate Islamic values in nursing practice. Islam quality of life palliative spirituality grief nursing ==== Body pmcIslam views that humans are the perfect creatures (Al-Ghazali, 2007). However, Allah explains that humans will experience weak physical conditions (illness). It is cited in the Holy Qur’an (30:54), “It is Allah Who created you in a state of weakness; then after weakness, He gave you strength, then after strength, He made you weak and old. He creates what He pleases. He is All-Knowing, All-Powerful”. This verse gives a signal that humans were created weak (at birth) then become strong then turn gray (weak, old, or sick) which needs treatment”. Therefore, the role of palliative care is significant in Islam, as every human will be weak when they get old. Palliative care can be provided in various contexts, such as hospitals, outpatients, and home settings, and applied according to cultural beliefs. This article offers an Islamic perspective about nurses’ roles in palliative care, which can be used worldwide, especially in Muslim-majority countries. The total population of Muslims in the world in 2015 reached 1.9 billion (World Population Review, 2020), and by 2050 it is predicted that Islam will spread and grow faster than other religions in the world (Leong et al., 2016). World Health Organization (WHO) explains that palliative care is an approach to improving the patients’ life quality and their families in dealing with life-threatening diseases. It includes prevention and cure of suffering through early detection, assessment, and treatment of illness and other conditions, including biological, psychological, social, and spiritual conditions (World Palliative Care Alliance, 2014). In providing care to palliative patients, nurses must involve the patient’s awareness, faith, and belief (Dewiyuliana et al., 2019; Rassool, 2015). According to Muishout et al. (2018), all Muslim patients who experience palliative care always want a good death (or Husnul Khotimah) and get good care according to the expected standard. Understanding Islamic beliefs will help nurses provide professional and culturally sensitive nursing care. It might happen by implementing religion, family perceptions, health, illness, medicine, and privacy issues (Attum et al., 2018). Death or nearly death is a current issue in terminal patients (Zahedi et al., 2007). It cannot be denied that Muslim nurses’ role is crucial, especially in providing palliative nursing care. The Prophet Muhammad SAW said that Allah SWT would not bring down a disease other than to bring down the antidote, except one: old age/death. This is explained in the Hadith of Sahih Muslim (43). This article aims to open up new ideas rather than provide a definitive answer. Palliative Care Aspects Some aspects that must be considered in providing palliative nursing care, including (1) upholding ethical aspects of care (nonmaleficence, justice, autonomy, and beneficence), maintaining politeness and respect, patient environmental cleanliness, social aspects, prayer (praying or praying for), (2) conveying what is being experienced by the patient (being honest with the patient), (3) giving opioids and sedatives, (4) giving healthy diets, (5) preparing for death and mourning, (6) completing all patient’s affairs, and (7) increasing worship (Al-Shahri & Al-Khenaizan, 2005). The other aspects are prayer, medical care, freedom of religious practice, modesty, professional care, pain management, and mental problems coping (Boucher et al., 2017). When someone is nearly dead or in a critical condition, it is necessary to increase one’s closeness to God (in the form of worship) (Choong, 2015). Therefore, the interaction and trust between patients and nurses or other health workers should be enhanced (Al-Jahdali et al., 2013) to provide a positive end to life (Rosemond et al., 2017). In other words, palliative care should include bio-psycho-socio-spiritual aspects for families and patients (Hagan et al., 2018). According to Barolia (2008), the core category of caring is maintaining the balance of five dimensions (physical, ethical, moral, spiritual, and intellectual) of human beings through response, reflections, relationships, relatedness, and role modeling. Besides, nurses also need to coordinate with the team of professionals (interdisciplinary team) to achieve the goals (Al-Jahdali et al., 2013; Barolia, 2008; Choong, 2015; Labson et al., 2013) (Figure1). Figure 1 The relation of bio-psycho-socio-spiritual and nursing practice for palliative care adapted from Al-Jahdali et al. (2013); Barolia (2008); Choong (2015); Labson et al. (2013) According to Hagan et al. (2018), the roles of nurses in providing palliative nursing care include symptom/pain management, good communication, and advocacy to patients and families. Also, it is necessary to increase the spiritual aspect of the patients, which includes four aspects (Irajpour et al., 2018), including: (1) aspects of religiosity - religious rituals, religious values, and religious practices, (2) aspects of religious assistance - consultation about the meaning of life/death, help to achieve intellectual tendencies, improve communication with oneself and others, (3) aspects of psychology - instill calm in the patient, help patients to adapt, foster hope and enthusiasm, and empathy, and (4) supportive aspects - maintain the patient’s basic needs, homecare, create awareness and self-acceptance, and respect the patient. Illness in the Perspective of Islam Muslims must believe that all trials in life, including illness, are the tests for humans. Allah SWT has said in the Holy Qur’an (29:2), “Do people think that they will be let go merely by saying: “We believe, and that they will not be tested?”. The verse explains that everything that happens in life is a test for humans, including illness. Muslims firmly believe that humans will meet illness and death (must be patient and pray); thus, maintain respect for each other is essential while avoiding haram food (Rassool, 2015). Allah promises that the test to be faced will be according to His servant’s ability. Allah says in the Holy Qur’an (2:286) that Allah does not lay responsibility on anyone beyond his/her capacity. Besides, humans must be patient in dealing with illness (as a part of the tests). Believers, be steadfast, and vie in steadfastness, stand firm in their faith, and hold Allah in fear that they may attain real success, described in the Holy Qur’an (3:200). In addition, the interpretation of the Ministry of Religion of the Republic of Indonesia (1995) states that patience is carried out in various conditions, such as patience in carrying out God’s commands and prohibitions, struggling, and facing all kinds of trials and calamities. When facing a critical situation or experiencing difficulties, the patient’s welfare and care must be improved; friends and relatives are encouraged to visit. This is done as a tribute to the patient to provide comfort (Choong, 2015). Besides, it is also a way to remind of spirituality. If there is a spiritual problem, it will cause disturbances in various aspects of the patient’s life (Stacey, 2018). Therefore, we must realize and believe that whatever happens in this life is the provision of Allah. It is written in the Holy Qur’an (6:59), “He has the keys to the realm that lies beyond the reach of human perception; none knows them but Him. And He knows what is on the land and in the sea. There is no leaf which falls that He does not know about, and there is no grain in the darkness of the earth or anything green or dry which has not been recorded in a Clear Book (Lohmahfuz)”. A Death in Islam In the Holy Qur’an (29:57), it is stated that every soul will die, then to Us, you will all be returned. Since the beginning, Muslims have been invited to realize that one day they will die. The hope is that every Muslim will be ready to die in peace and draw closer to Allah. All Muslims should always expect Allah’s forgiveness and mercy (Al-Shahri & Al-Khenaizan, 2005). Islam views death not as the end of life but, afterward, humans will be raised again in another life (or hereafter) (Asadi-Lari et al., 2008). To achieve readiness in facing death, patients need to get comfort from nursing care services to reduce anxiety and depression (Nuraini et al., 2018). Allah SWT has confirmed in the Holy Qur’an (13:28), “Those who believe and whose hearts find comfort in the remembrance of Allah; surely, do hearts find comfort.” Believers will have a peaceful heart because they always remember Allah. There will be no anxiety and fear or worry because people who always remember Allah will continue to do good things, and they will feel happy with the goodness they do (Goffar, 2004). When a person’s condition gets worse, and he/she fears that he/she will die, several things need to be done as follows. Having good prejudice to Allah. “And when he is nearing his death, let him have a good prejudice to Allah.” It is based on the Hadith of Jabir and Anas: “He heard the Prophet say before his death: Do not all of you die, except having good prejudice (Huznudzan) to Allah.” This is explained in the Hadith of Sahih Muslim (2877). Leaving a will before death. If a person is seriously ill or feels that death is coming, Islam leads to leaving a will with the living. This is based on the word of Allah in the Holy Qur’an (2:180), “It is prescribed that when death approaches any of you—if they leave something of value—a will should be made in favor of parents and immediate family with fairness. This is an obligation on those who are mindful of Allah.” Talqin (leading to pronounce). Unlike the general practice, the Muhammadiyah Tarjih Council determines the talqin as in the decision; “You should guide him to say to the person who is going to die by saying the sentence La-ila-ha illallah (There is no God but Allah).” It is based on the Hadith of Abu Sa’id: “From the Prophet SAW, he said: Guide to say to those who will die by saying La-ila-ha illallah.” This is explained in the Hadith of Sahih Muslim (916). Facing the Qibla. It is according to the Hadith of Abu Qatada. When Bara’ bin Ma’rur had a will to come to Kaaba and face the Qibla, the Prophet SAW said, “He matches his fitra (original disposition).” Early Actions on the Dead After a severe illness that cannot be helped and then dies, several things need to be done immediately by the relatives and people who are still alive. Those include: Closing their eyes and praying for them. This is explained in the Hadith of Ummi Salamah, “Rasulullah Peace Be Upon Him (PUBH) came to Abi Salamah (when he died) and his eyes were open, so he closed them.” Then the Prophet PUBH said, “Certainly the spirit, if released, is followed by the eye.” He also said to the people, “Do not pray for yourself, except for good, because actually, the angel agrees with what you say.” Then he said again, “O Allah, forgive Abu Salamah, uphold his rank as high as the degree of those who are righteous, open it and give change after he dies.” This is explained in the Hadith of Sahih Muslim (1524). Covering them with good cloth. This is described in the Hadith of Aisyah RA, “That when Rasulullah PUBH died, he was devoured with a hibarah cloth (a type of patterned Yemeni cloth).” Paying off their debt. One of the things that need to be done when someone dies is to pay off the debt concerned immediately. This is based on the Hadith of Abu Hurairah, in which the Prophet PUBH said, “The life of a Mu’min depends on his debt until he is repaid.” Taking care of the body. After someone is declared to be dead, the body must be treated immediately. This is based on the Hadith of Ali, in which Rasulullah PUBH said, “Three cases, O Ali, must not be postponed, including prayer when the time comes, the body when it is clearly said to be dead, and a woman who does not have a husband if she finds her soul mate” (Al-Albani, 2014). Spreading the death news. When someone dies, the next action is to immediately spread the word to relatives, friends, and Muslims. This is based on the Hadith of Bukhari Muslim, in which Rasulullah PUBH was told about the man who swept the mosque died and buried that night. He said, “Don’t you want to tell me?” Discussion Generally, the nurse’s treatment in providing care covers several aspects: giving their respects to the patient, being ready, being realistic, having empathy and care, sensitivity, empowering the patients, and discipline (Ciemins et al., 2015). The applications of Islamic values in the nursing practice include: (1) nursing care performed by professional nurses with good skills and behavior in taking care of dying patients (Muishout et al., 2018), (2) providing opportunities for patients to rest and gather with the family, (3) reminding about the greatness of Allah (God), happiness, and good rewards, (4) giving the patient religious therapy by reciting the Holy Qur’an, (5) discussing the hope towards Allah (God), (6) encouraging the patient to pray, (7) encouraging them to have a good deed and worship, (8) giving them a chance to deliver the last hope of the patients (relation between nurse and patient) (Haugan, 2014), (9) actions before death - reminding patients that an illness is not a punishment from Allah and should be faced as a test, doing thahara for Muslim who cannot do the ablution (according to Islamic law, it is the act of purifying oneself from ritual uncleanness or even impurity or najis until someone fulfills the requirements to perform certain actions to worship Allah). If there is no possibility of living, the medical team may do Do Not Resuscitate (DNR). Suicide is not the way the Muslims die; it is not allowed. Giving additional nutrition could be done as long as it is good and not harming the patient (explained in the Holy Qur’an 2:168). Lead the patients to recite Laa-ilaaha illallah during their dying situation, and (10) actions after the death, such as closing patients’ eyes and covering the corpse with the shroud. Grieving or mourning for a long time is not allowed; organ donation may be possible with family permission and an agreement not to be traded (Shuriye, 2011). Also, the cremation of the corpse is not allowed (Leong et al., 2016). Given the importance of the Islamic values in nursing practice, there are challenges in its application, such as the policy and system that may not support the integration of Islamic values to nursing practice. The policy most likely focuses on reducing the pain or other symptoms, reflecting a low spiritual aspect in nursing practice. In addition, there are still limited guidelines for the provision of spiritual care. Besides, although the concept of Islam in palliative care is not new among Muslim nurses; however, they may not perform it well. Palliative care requires high competence of nurses, especially in cultural competence and communication. Islam is often viewed at different levels of understanding and practice; thus, the communication skills of nurses should be improved for better care. Training in palliative care among nurses should be conducted regularly. Conclusion Islamic value provides a comprehensive approach in palliative care. Nurses are expected to apply this value in their practice to serve the patient as a whole person, rather than just someone with a health condition. It is also hoped that the health policymakers pay attention to the roles of Islamic values and integrate them in nursing practice, especially in palliative nursing care. Declaration of Conflicting Interest The authors declare that there is no conflict of interest. Funding This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contribution ES conceptualized, analyzed, and drafted the manuscript. IS critically reviewed and discussed the manuscript. All authors agreed with the final version of the article. Author Biographies Edy Suprayitno, S.Kep., Ns., M.Kep is a Lecturer at the Department of Nursing, Faculty of Health Sciences, Universitas’ Aisyiyah Yogyakarta, Indonesia. Iwan Setiawan, M.S.I is a Lecturer at the Department of Nursing, Faculty of Health Sciences, Universitas ’Aisyiyah Yogyakarta, Indonesia. ==== Refs References Al-Albani, M. N. (2014). Mukhtashar Shahih Bukhari (3rd ed.). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-124 10.33546/bnj.2484 Original Research Exploring the tuberculosis medication program in Indonesia as perceived by patients and their families: A qualitative study https://orcid.org/0000-0002-0662-3933 Ritonga Imelda Liana 12 https://orcid.org/0000-0002-4930-9928 Setyowati Setyowati 2 https://orcid.org/0000-0002-1746-267X Handiyani Hanny 2 https://orcid.org/0000-0002-3984-0336 Nursasi Astuty Yuni 2 1 Nursing Program, Universitas Imelda Medan, Indonesia 2 Faculty of Nursing, Universitas Indonesia, Depok, West Java, Indonesia * Corresponding author: Dra. Setyowati, S.Kp., M.App.Sc., PhD Professor, Faculty of Nursing, Universitas Indonesia, Jalan Prof. Dr. Bahder Djohan, Kampus UI Depok, West Java 16424, Indonesia. Email: wati123@ui.ac.id Cite this article as: Ritonga, I. L., Setyowati, S., Handiyani, H., & Nursasi, A. Y. (2023). Exploring the tuberculosis medication program in Indonesia as perceived by patients and their families: A qualitative study. Belitung Nursing Journal, 9(2), 124-131. https://doi.org/10.33546/bnj.2484 18 4 2023 2023 9 2 124131 08 12 2022 05 1 2023 27 2 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Tuberculosis (TB) remains a significant public health challenge in Indonesia, with the country experiencing one of the highest numbers of lost cases in TB management. Therefore, there is a need to identify the underlying reasons for this problem. Objective This study aimed to explore the experiences of TB-diagnosed patients and their families during the time of diagnosis and while undergoing the TB medication program. Methods This study employed a qualitative descriptive-interpretive approach. The study was conducted in government community health centers (CHC) from May 2022 to July 2022. A total of 22 participants, consisting of 12 TB-diagnosed patients and ten family members, were included in the study. Data were collected through focus group discussions and analyzed thematically. Results Five themes were developed: (1) Delay in tuberculosis diagnosis, (2) Delay in starting TB treatment, (3) High willingness of patients and their families to recover, (4) Understanding that TB is an infectious disease, and (5) Factors affecting patient recovery. Conclusion The study findings might contribute to the National TB elimination program. It is recommended that all health workers practicing in the community should be involved in the TB program to improve its management. Collaboration between multiple sectors in the community can also provide an advantage in solving TB problems by increasing new case detection. Additionally, it is suggested that all nurses working with TB patients establish rapport with health cadres and patients’ families to enhance medication adherence in patients. Indonesia tuberculosis nurses focus groups communicable diseases Universitas Imelda Medan, Indonesia ==== Body pmcBackground The burden of tuberculosis (TB) in Indonesia remains a challenge despite several TB control strategies implemented by the Indonesian government (Erawati & Andriany, 2022). In 2015, the World Health Organization (WHO) proposed The End TB Strategy and the Sustainable Development Goals to eradicate the global TB epidemic by 2030 (United Nations Development Programme, 2015). Indonesia, in response, drafted the Ministry of Health regulation number 67 in 2016 to guide TB medication control, which recommended the Direct Observed Treatment Strategy (DOTS) for health facilities (Indonesia Ministry of Health, 2016). Nevertheless, only government community health centers are required to have a DOTS team. In contrast, private primary care centers are only advised to be involved and can offer services to the appointed TB case manager in their district or province health office. Despite the efforts of the Indonesian government to implement various TB control strategies, the recorded data in 2019 indicates that Indonesia is among the seven countries with the highest number of lost TB cases (World Health Organization, 2019). These cases are mostly unreported or undiagnosed, and a high loss in case data correlates with the continuous widespread of TB cases with increased severity. Care-seeking patterns and diagnostic delays among TB patients are among the determinants contributing to the high number of lost cases. Most Indonesians initially seek care from private primary care centers with limited diagnostic tools, TB treatment supplies, and inadequate healthcare workers’ capacity to manage new cases (Sunjaya et al., 2022). Private primary care centers also tend to have less information regarding care methods and the required quality of TB care (Arini et al., 2022). Private primary care centers are crucial in supporting Indonesia’s healthcare system, as half of the research sample in a study by Surya et al. (2017) preferred private primary care centers for their health needs, and almost half of the participants did not understand TB symptoms, leading to a delay in seeking help for up to 14 days. This finding is essential in understanding the health-seeking patterns and the private primary care centers’ involvement in the nation’s TB control program, explaining the high risk of lost TB cases. However, the problem requires further exploration to identify solutions. Previous studies have suggested the concept of switching the focus from patient-centered care to community-centered care to increase surveillance and bridge various sectors in the community to solve obstacles in TB management (Biermann et al., 2019; Odone et al., 2018). The concept emphasizes the need to consider the difficulties patients and their families face in following and completing the program and to improve their awareness of their social, economic, cultural, and environmental conditions. The limited involvement of private primary care centers, incompetence, lack of willingness to follow the TB national program healthcare workers, and healthcare-seeking patterns by Indonesian citizens require inspection. Understanding the obstacles from the patients’ and their families’ points of view may help healthcare workers in providing a resolution. Nurses, as one of the professions in the DOTS team, have high contact with patients and informal workers (cadres) and are responsible for entering data into the information system and collaborating with the vertical team in the district or province. The unique roles and autonomy of nurses are suitable for building good relationships with groups and communities (Blanco-Fraile et al., 2022) and treating people equally with respect to their differences (Oblitas et al., 2010). This research aimed to explore the experiences of TB-diagnosed patients and their families during the time of diagnosis and while undergoing the TB medication program. The study aimed to understand the patients’ journey in obtaining a diagnosis of TB, following and completing their medication, as well as to provide insight into the obstacles experienced by these patients throughout the entire process. By exploring the experiences of the patients and their families through qualitative interpretative research, the researchers seek to understand the problems that prevent early diagnosis and medication and provide insight into the weakness in the healthcare system for the TB program. To our knowledge, no similar studies were conducted until February 2023, when this article was drafted. Methods Study Design This study employed a qualitative descriptive-interpretive approach (Thorne, 2016) to explore the experiences of TB patients and their families during diagnosis and medication programs. The study was conducted in government community health centers (CHC) in East Medan District, Indonesia, from May 2022 to July 2022. Participants The participants in this study were selected through purposive sampling from a population of patients and their closest family members who were currently undergoing TB medication under the care of government CHCs. The researchers collaborated with TB managers to collect participants, who were invited by health cadres. Patients included in the study were those undergoing a TB medication program for at least two weeks and were in stable condition, along with one of their closest family members. The exclusion criteria were patients still unstable and taking medication for less than two weeks. In addition, the researchers worked with health cadres to ensure that the patients were in stable condition and that transportation was prepared in case of emergency. The study included a total of 22 participants, consisting of 12 TB-diagnosed patients and ten family members. Data Collection The data for this study were collected through two focus group discussions (FGDs) conducted in a private room provided by the researcher to ensure privacy for the patients and their families. The first FGD was conducted on May 24, 2022, with seven participants: four TB-diagnosed patients and three family members. After the first FGD, the researcher found that more data were required and held a second FGD on July 15, 2022, with 15 participants, including eight TB-diagnosed patients and seven family members. The FGDs were steered using open-ended questions and a guideline for discussion and conducted in Bahasa Indonesia. The researcher believed using FGDs was appropriate to understand the process, as it stimulated participants to explain real and more detailed experiences. The first researcher was in charge of both sessions of FGDs. Initiation questions used for data collection included: (1) How did the patient end up being diagnosed with TB, (2) How the patients acquired access to medications, (4) How patients followed their medications program, and (5) Who became their support system throughout the medication program. These questions were developed concerning the need for data confirmation. After the second FGD, data were considered saturated, and no new information could be collected. Data Analysis The first researcher, who had a health education and career background and was pursuing a doctoral degree in nursing during the study, made meticulous verbatim transcriptions of the audio recordings. The transcripts were then returned to the participants for verification and correction to ensure accuracy. The data were analyzed using thematic content analysis (Braun & Clarke, 2006). The analysis involved manual reading, coding, identifying categories, and generating themes. The transcripts were scrutinized repeatedly to detect emerging trends and recurring concepts. Codes were assigned to segments of text, and similar codes were grouped to form categories, which were then organized into themes. The first author (ILR) did the coding while the rest of the team (SS, HH, and AYZ) reviewed the appropriateness of the coding, categories, and themes. The researchers jointly analyzed the findings, discussed the results, and resolved any discrepancies. They also examined the themes and sub-themes and their relevance to the research question. There was no significant dispute during the analysis, and the researchers agreed upon all themes. Trustworthiness/Rigor The data credibility was ensured during the FGDs, and participants were given sufficient time to express their opinions and share experiences without strict time limitations. The first researcher (ILR) facilitated the discussion using open-ended questions and confirming information when necessary. Participants were also encouraged to give feedback and clarify any misunderstandings within the group. The FGDs were recorded to avoid the loss of any data. To maintain trustworthiness, confirmation, and audit trails were conducted. ILR confirmed the transcript with the participants to clarify the written words. Next, ILR, HH, and AYZ reviewed and discussed the data to develop codes, categories, themes, and sub-themes from the transcription. Finally, the second researcher audited the transcription, coding, categories, themes, and sub-themes to ensure accuracy. Ethical Considerations Ethical approval was obtained from the appropriate body and local government before the study was conducted. The Ethics Committee of the Nursing Faculty of Universitas Indonesia granted ethical clearance with identity number KET-157/UN2.F12.D1.2.1/PPM.00.02/2022. Prior to data collection, the first researcher (ILR) introduced herself and explained the study’s objectives and data collection process to the participants. The TB officers and health cadres were with the participants throughout the process to assist them with any issues. Informed consent was obtained before data collection. The informed consent contained information about the research’s background and purpose, the participants’ roles, the data that would be collected, the privacy of the participants’ identity and provided information and the research results’ usefulness for improving the national TB program. Results The study included 22 participants, comprising 12 TB-diagnosed patients and ten family members. Gender was equally represented in both groups. Among the TB-diagnosed patients, the highest percentage of participants fell in the productive age group of 20-50 years old (58.3%), followed by the pre-older-adults to the older-adults age group of 50-70 years old (33.3%). One participant was in the teenage age group, aged 13 years old (8.3%). For the family members, the majority were in the pre-elderly to the elderly age group of 50-70 years old (70%), followed by the productive age group of 20-50 years old (20%). One participant was in the teenage age group (10%). To facilitate identification throughout the paper, the researcher used symbols; “K” represented TB-diagnosed patients while “KK” represented family members, as stated in Table 1. The patients and families were assigned numbers based on their arrival time, and the researchers made notes of their identities. All patient and family comments were analyzed as a single piece of data. Table 1 The participants’ demographic characteristics No Participants Years Gender 1. K1 28 years Man 2. K2 13 years Adolescent girl 3. K3 32 years Woman 4. K4 32 years Man 5. K5 56 years Woman 6. K6 62 years Man 7. K7 48 years Woman 8. K8 63 years Man 9. K9 68 years Man 10. K10 22 years Woman 11. K11 23 years Woman 12. K12 28 years Man 13. KK1 61 years Man 14. KK2 70 years Man 15. KK3 31 years Woman 16. KK4 19 years Woman 17. KK5 56 years Woman 18. KK6 67 years Man 19. KK7 47 years Woman 20. KK8 63 years Woman 21. KK9 57 years Man 22. KK10 61 years Man Note: K = Patient; KK= Patient’s closest family The research findings resulted in the development of five themes. The themes were as follows: (1) Delay in tuberculosis diagnosis, (2) Delay in starting TB treatment, (3) High willingness of patients and their families to recover, (4) Understanding that TB is an infectious disease, and (5) factors affecting patient recovery (Figure 1). Figure 1 Thematic findings Theme 1: Delay in Tuberculosis Diagnosis Subtheme 1.1: Community’s lack of knowledge of TB symptoms Three out of 22 participants mentioned the community’s lack of knowledge of TB symptoms, as follows: “When I first started coughing, I did not know that it was TB, so I went to the clinic and got better, but then I started coughing again around a month later, got better again, and then for some reason, I got sick again here (points at an area near the chest). So I was rushed to the hospital, and that was when they told me I had TB” (K8). “At the time, I was coughing continuously, but I just thought it was normal” (K1). “The coughing did not stop until I was coughing out blood. I thought it was my tonsillitis, but it turned out the coughing became more severe, so my sibling brought me to UPT Paru” (K3). It was found that coughing was the initial symptom presented by the patients. Patients would present this symptom to the pharmacy or clinics (PPCs) to seek medication. As there were no proper diagnoses, and the patients were just sent home with cough suppressants, patients tended to be diagnosed at a later date when the disease had developed further and the patients were in a poorer condition. Subtheme 1.2: The primary healthcare centers’ lack of knowledge of TB symptoms One participant mentions this: “Blood came out, but they said it was because of … turns out it was … and then we brought them to the hospital, and they were given this medication. After they took medicine, we got sent home, but over time they lost a lot of weight, and for five days, they felt feverish, so I brought them back to PH hospital. That was when we knew it was the lungs.” (KK2) Healthcare workers (HCWs) are expected to be appropriately trained and aware of early TB symptoms, and a delay in proper diagnosis should not occur. However, the study found that HCWs’ insufficient understanding of TB symptoms remains a weakness in TB recognition. In addition, limited knowledge of TB among patients and their families and the lack of appropriate education by HCWs further contribute to barriers during acceptance of the diagnosis. Subtheme 1.3: TB diagnosis occurred after patients experienced severe symptoms in the hospital or government community health services center This was mentioned by six out of 22 participants as follows: “At first, I was coughing, then brought to the clinic. In the clinic, they told us to do a sputum check in the government community health services center, and that’s it” (KK10). “So it’s like this, this is my in-law, so they live in the house but had to go here and there to get help because the coughing didn’t stop” (KK1). “Until my condition was so bad, I didn’t eat. One month, I didn’t eat rice, and at the end, I couldn’t even walk, couldn’t do anything. That was when my brother brought me to the hospital, Hospital H” (K12). “Yes, like that too, we just bought medicine for the past six years, and it became worse, so I brought them to the government primary healthcare services center. In the house, I couldn’t do anything. S would know” (KK9). “The coughing did not stop until I was coughing out blood. I thought it was my tonsillitis, but it turns out the coughing became more severe, so my sibling brought me to UPT P” (K3). “They got treatment inpatient at hospital A. They took him from the social affair district office, and they treated them in hospital A. There they got treatment for two weeks, then died.” (KK2) Patients and their families shared similar experiences during the time of their diagnosis. Unfortunately, most participants were diagnosed with TB only when the patients presented with bloody cough or malnutrition, at which stage they required hospitalization, blood transfusion, and nutritional support. The delay in confirming the diagnosis was due to the HCWs’ lack of understanding of TB symptoms and the importance of starting and completing medication, especially in their initial encounter with patients in PPCs. Theme 2: Delay in Starting TB Treatment Subtheme 2.1: Time is required to wait for laboratory results Two out of 22 participants mentioned the following: “Around two weeks before that, I did the lab check, then two weeks after I did another lab check” (K2) (when asked how long the patient had to wait to get the patient’s lab results) “Sputum check” (K9) (when asked about the reason the patient had to wait a week to get their medication) The delay in obtaining laboratory results is due to the overwhelming number of patients and inadequate testing facilities. The recommended laboratory test for TB diagnosis is the molecular test, which requires specific equipment called TCM (Tes cepat molekuler). The advantage of using TCM over conventional methods is its ability to produce faster results. However, our study found that the TCM available in this study setting can only run 50 tests per day. In addition, these facilities are also expected to handle samples collected from all health service units in the area. The mismatch between equipment availability and patient demand leads to delayed laboratory results, with an average of three days required to obtain results. Subtheme 2.2: The health center providing medication is different from the one that made the diagnosis Three out of 22 participants mentioned the following: “Alhamdulillah, after we were treated here (in a big hospital), they referred us back to the government primary health services center to get the medicine until now” (KK11) “Went back to the government primary health care services center, continuing up until now” (K5) (patient was referred from the hospital to the government primary health care services center to get their medication) “After all, they did not give me the medicine, I did not know the name of the medicine, but then I brought them back to the government primary health care services center to meet that guy” (K2) Patients do not immediately receive medication after receiving the laboratory result. Based on the national program’s system, these patients need to be referred to the health service units close to their homes. The responsibility for referrals falls on the health service unit where patients first register. These units would then conduct referrals according to the national regulations, in which patients diagnosed with primary TB are referred to a CHC, while patients diagnosed with co-morbidities or multi-drug resistant (MDR) TB are directed to a hospital. Theme 3: High Willingness of Patients and Their Families to Recover Subtheme 3.1: Patients understand the need to complete their medication as instructed by healthcare workers This was mentioned by four out of 22 participants, as follows: “Yes, because if we stop, then we would have to start again from the beginning, so like it or not, we need to continue taking medicine even though it’s hard.” (KK5) “The red medicine that I drink always gives me a headache and makes me want to vomit, but like it or not, I have to take it until I complete.” (K3) (Nodding, smiling) “From the doctor in that hospital, they said don’t stop taking medicine because if I do, I would need to start over from the beginning.” (K1) “Hospital P, when I was diagnosed with TB first, the doctor there explained that I need to take medicine, don’t stop because if I stop even for a day, I need to start over from the beginning.” (K4) The participants exhibited a high level of willingness in patients and their families to recover once they were confirmed with TB and had started medication. Subtheme 3.2: Family and cadre support help strengthen patients in their recovery This was stated by five out of 22 participants, as follows: “My weight was 40kg and didn’t increase after I started consuming the medicine, supported by A (sibling). Before that, I already felt hopeless, but there were people that supported me. Since A helped guide me, alhamdulillah, I am now healthy. Now I am supporting my child too.” (K3) “Alhamdulillah, I am a very fussy person. Medication needs to be taken at the right time. If we agree to take it at 6 in the morning, then it has to be done at 6 in the morning, and until now, they are getting healthier and gaining weight.” (KK10) “That is right because every day I ask them if they have taken medicine or not. Every morning, I check on them about the medication.” (KK8) “There are also times when taking medicine in the morning, they need to have very hot water. If not, it makes them sick in the stomach.” (K6) “By drinking a lot of warm water, it helps the medicine go down smoother.” (K5) Patients felt much support from their families and cadre in completing their medication. Cadre and their family also showed positive efforts to help the patient. Subtheme 3.3: Positive efforts are made by patients and their families to support recovery Two participants stated this: “Yeah, if it is difficult for them to take it, I grind the medicine. For me, because I want to be cured, I have to take medicine. I have to be cured. If I leave the medicine, I will have to start again from the beginning. So for me, I need to swallow it.” (K1) “I always drink natural goat milk. My mom always makes me ginger, red ginger water, buys fruits to make juice that I drink frequently, but I never eat fish.” (K12) Although feeling discomfort from the medication’s side effects, they continuously attempted different methods to overcome these so that they could continue consuming the medicine. Additionally, the patients and their families correctly understood the importance of continuing their medication to recover and protect people in their community. Theme 4: Understanding that TB is an Infectious Disease Subtheme 4.1: TB is infectious to other members of the family A participant expressed this: “Akbar’s brother, the one that passed away, did not seek treatment at all until his lungs swelled up. He got infected from his dad when he was one year and six months old.” (KK2) Patients realized that they were a risky source of infection to others, especially their beloved families. Subtheme 4.2: TB needs to be cured so that it does not harm others Two participants stated this: “There is a history of parents having TB.” (K4) “The suggestion is exactly like what this guy has mentioned, in which this sickness can harm other people, even loads of other people, so we have to get cured.” (K3) This adequate understanding of the risk of TB is a positive factor in pushing patients and their families to conduct screening for other members and contributes to early diagnosis. This also ensures patients follow through with their medication regimen. Theme 5: Factors Affecting Patient Recovery Subtheme 5.1: Patient’s pre-existing co-morbidities or experiencing TB relapse Two participants expressed this: “At first, it was just TB, but during my checkup at the lung hospital, they also checked my heart and blood sugar. It turns out my blood sugar was around 400.” (K3) “I’ve known about my TB for six years now. I know it affects my lungs, but I stopped taking the medication, so it came back. I went to the government primary healthcare center and got admitted to the hospital. It’s all my fault because I stopped taking medicine.” (KK9) The researchers discovered that several severity factors complicated TB, including the existence of co-morbidities and relapse in patients with incomplete therapy. Subtheme 5.2: Financial constraints This is mentioned by two out of 22 participants: “Yes, sometimes we want to buy vitamins, but we cannot afford them because of our economic condition. Even for this disease, they need a certain kind of milk and vitamins. Before taking medicine, they need to take vitamins first.” (K4) “We cannot afford additional food. Our job now is driving a pedicab.” (KK9) The main inhibiting factors identified were the economic constraints patients and their families face in providing good nutrition, especially for patients with poor financial status. Discussion The first theme indicated the delay in TB diagnosis due to insufficient knowledge of primary care clinicians (PPCs) to conduct TB screening and lack of awareness of TB symptoms. Therefore, Burman et al. (2019) suggest that all health workers practicing in a community should be trained in TB screening, medication provision, and counseling to participate in TB surveillance and ensure medication adherence actively. Furthermore, informal health workers should also be trained to assist in screening and supporting TB programs. Similar recommendations were made by Khachadourian et al. (2020) and Wroe et al. (2021), who advocate for the involvement of all HCWs in a TB program to facilitate the early detection of cases. As mentioned, low new case detection rates are another challenge facing TB programs besides patient non-adherence to medication. Therefore, inadequate knowledge and awareness of TB by HCWs is one reason for this problem, which may be attributed to the current TB management system. TB programs are typically managed by DOTS teams appointed by provincial or district health officers, and not all health service units are involved. Government-managed community health centers (CHCs) constitute the majority of the involved health service units, with only a small number of private units participating. As a result, HCWs involved in DOTS programs have a better understanding of TB detection and treatment. However, those not involved miss out on this opportunity, which may explain their inadequate understanding of the disease. Nurses comprise the largest portion of HCWs and have the most contact with patients (Oblitas et al., 2010). According to Rumsey et al. (2022), nurses constitute two-thirds of the healthcare workforce, making their active involvement in policy development regarding universal health coverage (UHC) crucial. Therefore, providing training for all HCWs, particularly nurses, in the early detection of TB and ensuring they have the proper knowledge is proposed as a strategy to increase TB case detection. The second theme, “delay in starting TB treatment,” indicated that there are weaknesses in the availability of laboratory facilities and the regulations regarding TB patients’ referral system, which results in delays in diagnosis and the initiation of medication regimens. Reza et al. (2020) recommended increasing TB screening in the community using GenXpert (TCM) and allowing patients to begin their medication immediately after diagnosis confirmation. The usage of TCM is beneficial as they require less time and are more sensitive. However, during the study period, the researchers found that TCM was only available in the research setting with a limited capacity of testing 50 samples per day, leading to delays in laboratory result confirmation. Furthermore, even after receiving their laboratory results, patients must be referred to a health service unit based on their address, which increases the risk of lost TB cases if patients fail to present themselves at the appointed place. This complication further acts as a barrier in patients starting medication regimens on the same day as diagnosis, as Reza et al. (2020) recommended. Fulfilling balanced laboratory test equipment is quite challenging to resolve due to requiring additional resources. Foster et al. (2022) conducted a scoping review on the effects of counseling on patients with suspected TB infection and found that having continued contact with suspected patients positively impacts TB case finding. By counseling TB suspects on the signs and symptoms to be aware of, they better understand when to return for further investigation. This concept helps patients to identify notable TB signs and symptoms and continue to be cautious of them. With this proper understanding, patients can promptly act and present themselves to HCWs when necessary. This strategy could be critical in tracking TB suspects who failed to be diagnosed (or had a delay in laboratory testing). The referral system for medication supply also contributes to medication delays. Ampomah et al. (2021) recommended integrating facilities to increase the quality of services. All health facilities should organize to support one another, which would push referral cases. There is an opportunity for the involvement of PPC units to provide screening for suspected cases and later refer cases to facilities that can conduct laboratory tests and medication. Referrals should also consider patients’ preferences to ease medication and support continued follow-ups. By having this integration between facilities, patients would be able to receive swift diagnoses and appropriate medication. The third theme demonstrated that patients and their families had good adherence to the TB program once the diagnosis was confirmed. This finding contrasted with studies from Adrian et al. (2020) and Falzon et al. (2011), which showed a low success rate of TB medication programs due to patients discontinuing their medication and the development of multi-drug resistance (MDR) resulting from low adherence to their medication regimen. Next, our study found that patients and families were willing to ensure recovery and understood the importance of continuing their medication to prevent the transmission of infection to others. Therefore, nurses who work closely with TB patients and informal workers should utilize these findings to build good relationships with patients’ families and cadres in the community to support the success of patients and the TB program. The researchers identified that the root of the problem lay in receiving confirmation of diagnosis and delayed commencement of medication, resulting in severe impacts on the patient’s close contact. Unclear information and delayed medication initiation were identified as problems that impacted patients and had adverse effects on others who had contact with the patient, leading to the spread of TB. This problem stemmed from improper education and information from the first contact healthcare workers (HCWs). Patients and their families often received inadequate information due to the HCWs’ oblivious behavior and inappropriate explanation. Stigma and feelings of shame also played a role in patients’ difficulty accepting the diagnosis of TB, leading to delayed acceptance and medication. Blanco-Fraile et al. (2022) identified the autonomy role of nurses in community practice to provide education to patients and their families, building their ability to be good educators in the first contact. Khachadourian et al. (2020) found that home visit-based DOTs significantly improved patients’ knowledge and reduced their depression and stigma. Therefore, continued explanation through home visits could improve patients’ knowledge and help them reduce depression and stigma. Turimumahoro et al. (2022) studied the advantage of mobile health (m-health) in increasing the service quality and communication between patients and health workers, and the study found that m-health significantly improved service quality and communication. The researchers recommended increasing the involvement of PPCs and HCWs in the TB program and applying information technology to assist and enhance integration. The use of a mobile application could integrate other facilities, including health officers, informal health workers, and other sectors, and provide increased infrastructural support for home-based services. Despite the potential cost, the benefit of this application development should be considered. This finding strongly emphasizes the need for all HCWs, especially nurses, to have good knowledge about TB and increase their sensitivity to early symptoms. Introducing TB programs to all HCWs and enhancing their involvement are good strategies based on this research. Most participants had contact with HCWs at the beginning of their symptoms but were not confirmed earlier with TB. Given the prevalence of TB in Indonesia, all HCWs should always consider TB a diagnosis for patients who present with continuous coughing or drastic loss of body weight. Based on the findings of this research, medication adherence should no longer be considered the main issue in TB programs. This is because participants felt they had adequate support from informal health workers and that medication was readily available. Informal health workers, such as health cadres, were found to play a significant role in providing support, such as positive motivation for patients and their families. This was also evident from the findings of Bello et al. (2017). Furthermore, Louwagie et al. (2022) also agreed on involving family and community support to help maintain patients’ adherence. Their findings are supported in this study. Once patients and their families understood the diagnosis, they willingly sought the medication and followed instructions from PHC officers and informal health workers. In the last theme, the researchers found several inhibiting factors, including existing health co-morbidities and economic constraints, that must be addressed. TB with other co-morbidities is associated with higher severity levels. Therefore, HCWs should be aware of these co-morbid conditions during first contact with the patient. The economic constraint is a complicated issue that impacts the general situation in Indonesia. This problem would require comprehensive treatment from multiple sectors. Limitations As this study only employed a qualitative descriptive design with small samples, the finding might not represent the whole context in Indonesia. Further studies are needed to confirm the results. Conclusion The current study has identified issues with the TB National Program, specifically a delay in diagnosis and medication for the majority of participants. Weaknesses in this process included inadequate PPC services, limited capacity of laboratory test centers, and a complicated referral system for medicine. However, the most significant problem was the lack of ability for HCWs to conduct TB screening. This weakness HCWs in the community to diagnose TB within a short period relates to the lack of TB screening. In addition, the study found that HCWs in the community who were not involved in the DOTS team lacked knowledge of how to detect TB. To address these issues, it is recommended to involve all health workers practicing in the community in the TB program. Furthermore, a collaboration between multiple sectors in the community can provide an advantage in solving TB problems by increasing new case detection. Additionally, it is recommended that all nurses working with TB patients establish rapport with health cadres and patients’ families to enhance medication adherence in patients. These recommendations aim to contribute to the success of the National TB elimination program. Acknowledgment The authors express their appreciation to the tuberculosis control case manager of PHC East Medan District, all informal health workers in PHC East Medan District, and the Faculty of Nursing at Universitas Indonesia and Universitas Imelda Medan for their support in conducting this study. Declaration of Conflicting Interest None. Authors’ Contributions ILR contributed substantially to the study's conception and design, data collection, data analysis, interpretation of data, and manuscript writing. SS contributed to drafting the work, revising it critically for important intellectual content, data analysis, and manuscript writing. HH and AYS revised the work critically for important academic content. All authors were accountable at each study step and approved the article’s final version for publication. Authors’ Biographies Dr. dr. Imelda Liana Ritonga, SKp., M.Pd., MN is a Lecturer at the Nursing Program, Universitas Imelda Medan, Indonesia, and a Doctoral student at the Faculty of Nursing, Universitas Indonesia, Indonesia. Prof. Dra. Setyowati, S.Kp., M.App.Sc., PhD is a Lecturer at the Faculty of Nursing, Universitas Indonesia, Indonesia. Dr. Hanny Handiyani, S.Kp., M.Kep is a Lecturer at the Faculty of Nursing, Universitas Indonesia, Indonesia. Dr. Astuti Yuni Nursasi, S.Kp., MN is a Lecturer at the Faculty of Nursing, Universitas Indonesia, Indonesia. Data Availability The datasets interpreted and analyzed during the study process are not made public but available from the corresponding author upon reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Adrian, M. M., Purnomo, E. P., & Agustiyara, A. (2020). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-025 10.33546/bnj.2408 Original Research The roles and competencies of welfare commissioners supporting children with developmental disorders and their families expected by Japan’s public health nurses https://orcid.org/0000-0003-2693-9799 Kawai Chihiro 1* https://orcid.org/0000-0001-9157-2984 Yokotani Tomoya 2 https://orcid.org/0000-0002-8248-367X Betriana Feni 3 https://orcid.org/0000-0002-0740-2104 Ito Hirokazu 4 https://orcid.org/0000-0001-9904-2339 Yasuhara Yuko 4 https://orcid.org/0000-0002-2847-1862 Tanioka Tetsuya 4 Mori Kenji 4 1 Awa City Hall, Tokushima, Japan 2 Faculty of Wakayama Health Care Sciences, Department of Nursing, Takarazuka University of Medical and Health Care, Wakayama, Japan 3 Faculty of Nursing, Prince of Songkla University, Hat Yai, Thailand 4 Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan * Corresponding author: Chihiro Kawai, RN, PHN, MSN, PhD (c), Awa City Hall, 201-1, Aza Furuta, Kirihata, Ichiba Town, Awa City, Tokushima 771-1695, Japan. Email: chihiro.2339@gmail.com Cite this article as: Kawai, C., Yokotani, T., Betriana, F., Ito, H., Yasuhara, Y., Tanioka, T., & Mori, K. (2023). The roles and competencies of welfare commissioners supporting children with developmental disorders and their families expected by Japan’s public health nurses. Belitung Nursing Journal, 9(1), 25-33. https://doi.org/10.33546/bnj.2408 12 2 2023 2023 9 1 2533 02 11 2022 02 12 2022 27 12 2022 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Public Health Nurses (PHNs) collaborate with community volunteer welfare commissioners to support children with developmental disorders and their families lead a life without isolation. Objective This study aims to clarify the roles and competencies that PHNs expect of welfare commissioners in supporting children with developmental disorders and their families. Methods An online survey was administered through Survey Monkey© to 220 PHNs working in Japanese municipalities using an independently developed questionnaire regarding the roles and competencies of welfare commissioners supporting children with developmental disorders and their families expected by PHNs. Exploratory Factor Analysis (EFA) was performed to simplify the data structure and enhance understanding. The reliability of the scale was confirmed using Cronbach’s α. Differences due to PHN attributes (e.g., experience collaborating with welfare commissioners) were analyzed using Welch’s t-test. This study was conducted between April and September 2021. Results The highest scoring items were, for the role, “a welfare commissioner’s role is to pass on accurate information to their successor,” and for competencies, “a necessary competency for a welfare commissioner is to protect the information about children with developmental disorders, and their families learned during one’s work.” The EFA results revealed a two-factor structure for role items: Factor 1, “Supporting children with developmental disorders and their families and preventing abuse,” and Factor 2, “Connecting to social resources.” Competency items were also found to have a two-factor structure: Factor 1, “Understanding the position of children with developmental disorders and their families and connecting with local residents,” and Factor 2, “Understanding developmental disorders and supporting them based on assessment.” A comparison of the attributes of PHNs showed no significant differences. Conclusion PHNs feel welfare commissioners should pass on the information and protect confidentiality when supporting children with developmental disorders and their families. Furthermore, PHNs expect welfare commissioners to connect children with developmental disorders and their families to the community, prevent abuse, and provide support based on assessment. PHNs had the same expectations regarding the roles and competencies of welfare commissioners regardless of their own attributes. welfare commissioner role competencies children with developmental disorders public health nurse Japan ==== Body pmcBackground Population aging and declining birth rates (Statistical Bureau of Japan, 2020), urbanization, depopulation, and changing family structures have led to diverse values and lifestyles that have gradually weakened the foundation for mutual support in the community. Community functions in which community residents support one another have also declined, reducing the well-being of the residents (Yabutani & Yamada, 2021). During the transition to a nuclear family structure and deteriorating ties with one’s neighbors and community, there is inadequate support for raising children, and they have felt anxiety about child-rearing (Honda & Kita, 2022; Ministry of Health Labour and Welfare, n.d.a.). In Japan, the transition to a nuclear family, marriage, and child-rearing was believed to reflect individual freedom, causing people to experience anxiety and burden under Japanese people’s inflexible attitude and a corporate culture that prioritizes work over family (Ministry of Health Labour and Welfare, 1997). This condition affects support for disabled children. In particular, parents of children with developmental disorders are reported to experience higher child-rearing stress (Giannotti et al., 2021; Gillespie-Smith et al., 2021), and they have a higher risk of abuse (McDonnell et al., 2019) than parents of children with typical development. The role of rescuing these children is increasingly important, but currently, the system is not fully functioning (Okuyama, 2006). It is vital to help households and reduce the stress of parenting for parents of children with developmental and other disabilities (Porter & Loveland, 2019). It is urgent to protect children with developmental disabilities who live in the community from abuse with the support of welfare commissioners. Japan has a unique system for this purpose, centering on “welfare commissioners” delegated by the Minister of Health, Labour, and Welfare. A welfare commissioner is a community volunteer who promotes social welfare. Welfare commissioners serve a three-year term and do not receive their salaries. The selection criteria are threefold: an understanding of and passion for social welfare, nomination as someone with a thorough knowledge of the existing circumstances in the community, and delegation by the Minister of Health, Labour, and Welfare. As of March 31, 2018, 232,041 welfare commissioners were delegated and actively serving (Ministry of Health Labour and Welfare, n.d.b.). The activities of a welfare commissioner include loving the community, building relationships of mutual trust, and keeping an eye on the community based on their connections therein (Hayashida & Nakao, 2020). The role of a welfare commissioner is to always be there for the people in the community, to offer consultations, and to provide necessary assistance. Welfare commissioners are also tasked with consultation and support regarding child-rearing anxieties or concerns during pregnancy, with the goal of allowing the children in the community to grow carefree and in good health (Ministry of Health Labour and Welfare, n.d.b.). Japan enacted the Act on Support for Persons with Developmental Disabilities in 2004. This law aims to detect developmental disorders early, provide support for development, and provide seamless assistance to people with developmental disorders. This leads to mutual respect for the personalities and individuality of all citizens without division based on disability status (Ministry of Health Labour and Welfare, n.d.c.). Japan’s public health nurses are responsible for supporting all community members, regardless of age or illness, to extend healthy life expectancy and reduce health disparities. Collaboration between public health nurses (PHNs) and welfare commissioners is essential for maintaining the health of community members and providing them with daily support. Furthermore, PHNs and welfare commissioners must work together to create a cooperative child-raising environment that affords neighbors and communities the opportunity to interact and increase community commitment (Arimoto & Tadaka, 2021). Thus, the current situation in Japan demands highly skilled welfare commissioners capable of providing the necessary support under various conditions. Recent research has included studies on raising children with developmental disorders and the need for community support (Kang-Yi et al., 2018; Lim et al., 2016; Masi et al., 2021; McConnell et al., 2008; Ueda et al., 2021). In Japan, research on welfare commissioners has examined support methods that enable them to continue serving (Saito & Morita, 2020). About 5.6% of the activities of community welfare committee members involve consultation and support for persons (and children) with disabilities. Matters related to children accounted for 20%, and cases related to the elderly were by far the most common (Ministry of Health Labour and Welfare, n.d.d.). However, there has been no research on the relationship between welfare commissioners and disabled children. Moreover, there have been no studies on welfare commissioners from the perspective of PHNs or on how welfare commissioners think about their own roles or competencies. Therefore, it is critical to clarify the abilities that PHNs expect from welfare commissioners at this time to lead to improved support for children with disabilities by welfare commissioners. This study aims to clarify the roles and competencies that PHNs expect of welfare commissioners in supporting children with developmental disorders and their families. Methods Study Design This study employed a web-based cross-sectional research design. In this study, “roles” refers to the duties allocated to welfare commissioners that are expected by PHNs. “Competencies” are defined as the ability to execute the duties of a welfare commissioner as expected by PHNs. Participants The participants were 300 PHNs affiliated with 134 municipalities. Participants were chosen based on the following criteria: 1) a licensed PHN and currently employed as a PHN, 2) affiliated with a municipality in Japan, and 3) consent to participate in the online survey. Participants were excluded if they failed to satisfy these three criteria. A statistical power analysis was conducted to estimate the sample size. In this study, the criterion set by Cohen (1988) was used, and the effect size was calculated using G*Power version 3.1.9.7 (Faul et al., 2007). For this study, the necessary sample size for an unpaired t-test was calculated to be n = 210, with an effect size of 0.5, α value of 0.05, and statistical power of 0.95. There were 220 subjects; therefore, the sample size for this study was considered appropriate. The level of statistical significance was set at p < 0.05. Questionnaires Participants’ characteristics included the PHNs’ gender, age, years of experience, experience working with children with developmental disorders and their families, the experience of collaborating with welfare commissioners in working with children with developmental disorders and their families, understanding the work of a welfare commissioner, and understanding the necessity of collaboration with welfare commissioners. To help developing the questionnaire questions for the survey to be conducted as a secondary study, interviews lasting 30–60 min were conducted based on the developed interview guide with nine PHNs participants who had been involved with welfare commissioners with experience in supporting children with developmental disorders and families. The interviews consisted of the following: What do you want welfare commissioners to be like for children with developmental disorders and their families in your community? What would be the participants’ ideal welfare commissioners? The participants’ experience of engaging with welfare commissioners. The role of the welfare commissioner in enabling children with developmental disorders and their families to live in the community. Competencies required of welfare commissioners. Participants’ characteristics. Interviewee participants were excluded from the survey respondents. The qualitative inductive analysis identified eight categories: system, environment, education, character/personality, role performance competency, community ties, perception of welfare commissioners, and initiative. The final version of the questionnaire was confirmed to have adequate content validity from the codes based on the categories (15 roles and 16 competency items). Responses were collected using a seven-point Likert scale. Data Collection This study was conducted using an online survey platform (Survey Monkey©) from April to September 2021. This study used a convenience sampling method to recruit participants. Our research group sent a letter or email, including a written explanation of the survey for participants and a URL to the survey tool (Survey Monkey©), to the supervisors of affiliated organizations that consented to participate in the study. Data Analysis Descriptive statistics were calculated to elucidate PHNs’ age (in years old), years of experience as a registered PHN, experience working with children with developmental disorders and their families, the experience of collaborating with welfare commissioners to work with children with developmental disorders and their families, and understanding of the work of a welfare commissioner. The following steps were performed to analyze the data. First, the frequency (n) and percentage (%) were calculated to show the demographic characteristics of the study subjects. Subsequently, the mean, standard deviation (SD), and 95% confidence interval (CI) were calculated to assess floor and ceiling effects. Content validity assessed individual questions on a test and asked experts whether each targeted the characteristics that the scale was designed to cover. Seven researchers systematically determined whether each item contributed appropriately and ensured no aspect was overlooked. To determine whether the data were suitable for exploratory factor analysis (EFA), Bartlett’s sphericity tests were applied (p < 0.0001), and the sampling adequacy was measured with the Kaiser-Meyer-Olkin (KMO) index. Additionally, anti-image correlations and communalities were assessed for each item. Next, the construct validity of the scale was assessed with EFA using equamax rotation, and the maximum likelihood method was performed for the roles and competencies scales. Cronbach’s alpha was calculated to evaluate the reliability of the scale. For between-group comparisons, Welch’s t-test (t-test) was performed to compare PHNs with and without experience working with children with developmental disorders and their families regarding their experience of collaborating with welfare commissioners in working with children with developmental disorders and their families and whether they understand the work of a welfare commissioner. Data analysis was performed using SPSS statistical software version 27 (IBM Corp.) and R (version 3.6.2, R Foundation for Statistical Computing, Vienna, Austria). Ethical Considerations Ethical approval was obtained from the Ethics Review Committee of Tokushima University Hospital (Approval Number: 3604-1, December 21, 2020). Informed consent was obtained from all participants. Participation was voluntary, and the participants could quit until data collection was complete, with no penalty if they decided to quit. Results Characteristics of Public Health Nurses Table 1 shows the participant characteristics. Questionnaire responses were requested from 300 PHNs working in the municipalities, and 220 responses with no missing data were used for analysis (valid response rate: 73.40%). Most participants were women (96.80%) with nine or fewer years of experience as registered PHNs (39.50%). Table 1 Participants’ characteristics Items (N = 220) N (%) Gender Male 7 (3.20) Female 213 (96.80) Age (years old) 29 or younger 49 (22.27) 30–39 54 (24.55) 40–49 57 (25.91) Over 50 60 (27.27) Length of experience as a registered public health nurse (years) 9 or less 87 (39.50) 10–19 42 (19.09) 20–29 60 (27.27) 30–39 31 (14.09) Experience involving children with developmental disorders and their families Yes 168 (76.36) No 52 (23.64) Experience related to welfare commissioners and children with developmental disorders and their families Yes 72 (32.73) No 148 (67.27) Understanding the work of welfare commissioners Yes 188 (85.50) No 32 (14.55) Necessity of cooperation with the welfare commissioners Yes 219 (99.00) No 1 (1.00) In addition, most participants (76.36%) had experience working directly with children with developmental disorders and their families, whereas 32.73% had experienced collaborating with welfare commissioners in working with such families. A total of 85.50% of the respondents understood the work of a welfare commissioner, and 99% stated that it is necessary to collaborate with welfare commissioners when supporting children with developmental disorders. Factor Analysis of the Questionnaire Responses Table 2 shows the mean, standard deviation, and 95% CI for the responses to the 31 items of the questionnaire. Among the items related to roles, QR11 (a welfare commissioner’s role is to pass on accurate information to their successor) had the highest mean value (5.62 ± 0.95, 95% CI [5.50, 5.75]). For items related to competencies, QC11 (a necessary competency for a welfare commissioner is to protect the information about children with developmental disorders and their families learned during one’s work) had the highest mean value (6.29 ± 0.97, 95% CI [6.16, 6.41]). However, a ceiling effect was observed for QC11; therefore, the item was excluded before EFA. QC13 (a necessary competency for a welfare commissioner is to be able to teach the families of children with developmental disorders how to interact with a child with a developmental disorder) had the lowest mean value (3.12 ± 1.28, 95% CI [2.95, 3.29]). Floor effects were not observed. Table 2 Questionnaire answer results Question number and items (N = 220) Mean SD 95% CI LL UL Welfare commissioner’s role QR1 A welfare commissioner’s role is to watch over children with developmental disorders and their families. 4.52 1.04 4.38 4.66 QR2 A welfare commissioner’s role is to acquire the necessary knowledge and skills to support children with developmental disorders and their families. 3.86 1.13 3.71 4.01 QR3 A welfare commissioner’s role is to educate the local residents under their jurisdiction to support children with developmental disorders and their families. 4.16 1.17 4.00 4.31 QR4 A welfare commissioner’s role is to stand and respond to the position of children with developmental disorders and their families. 4.48 1.18 4.32 4.63 QR5 A welfare commissioner’s role is to introduce child-rearing salons and places of interaction in the area under their jurisdiction to children with developmental disorders and their families. 4.53 1.03 4.40 4.67 QR6 A welfare commissioner’s role is to guide local government consultation counters (welfare counters at city and town/village offices) and services toward children with developmental disorders and their families. 4.90 1.08 4.75 5.04 QR7 A welfare commissioner’s role is to provide mental support for children with developmental disorders and their families. 4.06 1.14 3.91 4.21 QR8 A welfare commissioner’s role is to continue to be involved with children with developmental disorders and their families. 4.13 1.11 3.98 4.27 QR9 A welfare commissioner’s role is to find children with developmental disorders and their families in need of assistance in their area of jurisdiction. 4.02 1.22 3.86 4.18 QR10 A welfare commissioner’s role is to create a system that can support children with developmental disorders and their families in the area under their jurisdiction. 3.77 1.23 3.61 3.93 QR11 A welfare commissioner’s role is to pass on accurate information to their successor 5.62 0.95 5.50 5.75 QR12 A welfare commissioner’s role is to connect children with developmental disorders and their families to specialized institutions when necessary. 4.28 1.45 4.08 4.47 QR13 A welfare commissioner’s role is to cooperate with public health nurses belonging to the administration (including accompanying visits and consultations). 4.88 1.11 4.73 5.03 QR14 A welfare commissioner’s role is to detect the abuse of children with developmental disorders at an early stage. 4.95 1.07 4.81 5.10 QR15 A welfare commissioner’s role is to prevent the abuse of children with developmental disorders and their families. 4.45 1.10 4.30 4.59 Welfare commissioner’s competence QC1 A necessary competency for a welfare commissioner is to understand the characteristics of developmental disorders. 4.62 1.08 4.48 4.76 QC2 A necessary competency for a welfare commissioner is to be able to sympathize with the problems of children with developmental disorders and their families. 5.15 0.92 5.02 5.27 QC3 A necessary competency for a welfare commissioner is to be able to listen to the stories of children with developmental disorders and their families. 5.33 0.96 5.20 5.46 QC4 A necessary competency for a welfare commissioner is to understand the needs of children with developmental disorders and their families. 4.88 0.91 4.76 5.00 QC5 A necessary competency for a welfare commissioner is to be able to notice the problems of children with developmental disorders and their families. 4.66 1.05 4.52 4.80 QC6 A necessary competency for a welfare commissioner is to be able to assess the problems of children with developmental disorders and their families. 3.81 1.14 3.66 3.96 QC7 A necessary competency for a welfare commissioner is to be able to provide information on developmental support services to children with developmental disorders and their families. 4.40 1.08 4.25 4.54 QC8 A necessary competency for a welfare commissioner is to be able to notice changes in children with developmental disorders and their families. 4.99 0.95 4.86 5.11 QC9 A necessary competency for a welfare commissioner is to connect children with developmental disorders and their families to local residents. 4.67 1.05 4.53 4.81 QC10 A necessary competency for a welfare commissioner is to build a relationship of trust with children with developmental disorders and their families. 5.12 0.97 4.99 5.25 QC11 A necessary competency for a welfare commissioner is to protect the information about children with developmental disorders and their families learned during one’s work 6.29 0.97 6.16 6.41 QC12 A necessary competency for a welfare commissioner is to understand how to support children with developmental disorders. 4.71 1.08 4.57 4.85 QC13 A necessary competency for a welfare commissioner is to be able to teach the families of children with developmental disorders how to interact with a child with a developmental disorder 3.12 1.28 2.95 3.29 QC14 A necessary competency for a welfare commissioner is to understand the type and content of abuse of children with developmental disorders and their families. 4.58 1.18 4.42 4.73 QC15 A necessary competency for a welfare commissioner is to be able to contact a public health nurse immediately if there is a suspicion of the abuse of a child with a developmental disorder. 5.73 1.05 5.59 5.87 QC16 A necessary competency for a welfare commissioner is to be able to support the families of abusive children with developmental disorders. 4.11 1.11 3.97 4.26 SD: standard deviation; CI: confidence interval; QR: questions related to a welfare commissioner’s roles; QC: questions related to a welfare commissioner’s competencies. Likert scale measurements (7 levels), level of agreement: 1 = Strongly disagree, 2 = Disagree, 3 = Somewhat disagree, 4 = Neither agree nor disagree, 5 = Somewhat agree, 6 = Agree, 7 = Strongly agree Table 3 shows the results of the EFA for PHNs’ expectations of the roles of welfare commissioners. For role items, the KMO was 0.86, Bartlett’s test was 918.35 (p < 0.0001), and the anti-image correlation ranged from 0.79 to 0.92. The item communalities ranged from 0.32 to 0.63, with a mean communality of 0.50. In the equamax rotation with the maximum likelihood method, two eigenvalues were greater than 1. As a result of the EFA of the 15 items related to a welfare commissioner’s role, five items were eliminated due to low factor loadings (QR1, QR4, QR9, QR11, and QR13), revealing a two-factor and 10-item structure. Table 3 Exploratory factor analysis of the role of welfare commissioners expected by PHNs: Role questionnaire items Question number and Items (N = 220) Factor loadings Role dimension (Total items’ Cronbach’ s alpha = 0.87) F1 F2 Factor 1: Supporting children with developmental disorders and their families and preventing abuse (Cronbach’s alpha = 0.86) QR7 A welfare commissioner’s role is to provide mental support for children with developmental disorders and their families. 0.73 0.23 QR2 A welfare commissioner’s role is to acquire the necessary knowledge and skills to support children with developmental disorders and their families. 0.71 0.26 QR10 A welfare commissioner’s role is to create a system that can support children with developmental disorders and their families in the area under their jurisdiction. 0.70 0.21 QR8 A welfare commissioner’s role is to continue to be involved with children with developmental disorders and their families. 0.70 0.19 QR15 A welfare commissioner’s role is to prevent the abuse of children with developmental disorders and their families. 0.53 0.36 QR3 A welfare commissioner’s role is to educate the local residents under their jurisdiction to support children with developmental disorders and their families. 0.53 0.38 QR14 A welfare commissioner’s role is to detect the abuse of children with developmental disorders at an early stage. 0.45 0.34 Factor 2: Connecting to social resources (Cronbach’s alpha = 0.74) QR5 A welfare commissioner’s role is to introduce child-rearing salons and places of interaction in the area under their jurisdiction to children with developmental disorders and their families. 0.23 0.76 QR6 A welfare commissioner’s role is to guide local government consultation counters (welfare counters at city and town/village offices) and services toward children with developmental disorders and their families. 0.18 0.71 QR12 A welfare commissioner’s role is to connect children with developmental disorders and their families to specialized institutions when necessary. 0.33 0.55 Rotation sums of squared loading Fixed value 4.74 1.19 Proportion ratio (%) 30.10 19.70 Cumulative contribution ratio (%) 30.10 49.80 Note. N = 220. The extraction method was the maximum likelihood method with an equamax orthomax rotation. Factor loadings above 0.40 are in bold. The measure used from the questionnaire “The roles and competencies of welfare commissioners supporting children with developmental disorders and their families expected by PHNs: Role dimension.” F1 = Factor 1, F2 = Factor 2. Factor 1 of the roles of a welfare commissioner comprised seven items and was named “supporting children with developmental disorders and their families and preventing abuse” (RF1). Factor 2 included three items and was named “connecting to social resources” (RF2). Cronbach’s α coefficient was 0.87 for the overall scale, 0.86 for RF1, and 0.74 for RF2. Table 4 shows the results of the EFA for nurses’ expectations regarding the competencies of welfare commissioners. For competency items, the KMO was 0.86, Bartlett’s test was 1021.13 (p < 0.0001), and the anti-image correlation ranged from 0.78 to 0.91. Item communalities ranged from 0.36 to 0.81, with a mean communality of 0.53. In the equamax rotation with the maximum likelihood method, two eigenvalues are greater than 1. As a result of the EFA of the 15 items related to a welfare commissioner’s competencies, five items were eliminated because of low factor loadings (QC4, QC12, QC13, QC14, and QC15), revealing a two-factor, ten-item structure. Factor 1 of the competencies of a welfare commissioner comprised six items and was named “understanding the perspective of children with developmental disorders and their families and connecting them with community members” (CF1). Factor 2 comprised four items and was named “understanding developmental disorders and providing support based on assessment” (CF2). Cronbach’s α coefficient was 0.88 for the overall scale, 0.85 for CF1, and 0.81 for CF2. Table 4 Exploratory factor analysis of the competencies of welfare commissioners expected by PHNs: Competency questionnaire items Question number and Items (N = 220) Factor loadings Competence dimension (Total items Cronbach’s alpha = 0.88) F1 F2 Factor 1: Understanding the perspective of children with developmental disorders and their families and connecting them with community members (Cronbach’s alpha = 0.85) QC3 A necessary competency for a welfare commissioner is to be able to notice the problems of children with developmental disorders and their families. 0.89 0.14 QC2 A necessary competency for a welfare commissioner is to understand the needs of children with developmental disorders and their families. 0.78 0.29 QC10 A necessary competency for a welfare commissioner is to build a relationship of trust with children with developmental disorders and their families. 0.69 0.24 QC8 A necessary competency for a welfare commissioner is to be able to notice changes in children with developmental disorders and their families. 0.51 0.31 QC1 A necessary competency for a welfare commissioner is to understand the characteristics of developmental disorders. 0.49 0.35 QC9 A necessary competency for a welfare commissioner is to connect children with developmental disorders and their families to local residents. 0.48 0.37 Factor 2: Understanding developmental disorders and providing support based on assessment (Cronbach’s alpha = 0.81) QC6 A necessary competency for a welfare commissioner is to be able to assess the problems of children with developmental disorders and their families. 0.15 0.88 QC5 A necessary competency for a welfare commissioner is to be able to notice the problems of children with developmental disorders and their families. 0.36 0.64 QC16 A necessary competency for a welfare commissioner is to be able to support the families of abusive children with developmental disorders. 0.23 0.62 QC7 A necessary competency for a welfare commissioner is to be able to provide information on developmental support services to children with developmental disorders and their families. 0.32 0.59 Rotation sums of squared loading Fixed value 4.88 1.27 Proportion ratio (%) 29.10 24.40 Cumulative contribution ratio (%) 29.10 53.40 Note. N = 220. The extraction method was the maximum likelihood method with an equamax orthomax rotation. Factor loadings above 0.40 are in bold. The measure used from the questionnaire “The roles and competencies of welfare commissioners supporting children with developmental disorders and their families expected by PHNs: Competence dimension.” F1 = Factor 1, F2 = Factor 2. Effect of Differences in PHNs’ Characteristics on Questionnaire Results Table 5 compares the mean scores for each factor of the roles and competencies of welfare commissioners in supporting children with developmental disorders and their families expected by PHNs between PHNs with and without experience collaborating with welfare commissioners in working with children with developmental disorders and their families, experience working with children with developmental disorders and their families, and understanding the work of a welfare commissioner. There were no significant differences in the mean scores for each factor. Table 5 Comparison of public health nurses’ involvement with and understanding of welfare commissioners Experience involving children with developmental disorders and their families Yes (n = 168) No (n = 52) t p Mean SD Mean SD RF Total score 42.95 8.23 43.52 6.86 −0.50 0.62 RF1 Supporting children with developmental disorders and their families and preventing abuse 4.20 0.87 4.20 0.75 −0.04 0.97 RF2 Connecting to social resources 4.53 1.03 4.71 0.78 −1.34 0.18 CF Total score 46.83 7.45 46.90 6.30 −0.07 0.95 CF1 Understanding the position of children with developmental disorders and their families and connecting with local residents 5.00 0.77 4.91 0.66 0.78 0.44 CF2 Understanding developmental disorders and supporting children with developmental disorders based on assessment 4.21 0.91 4.36 0.76 −1.16 0.25 Experience related to welfare commissioners and children with developmental disorders and their families Yes (n = 72) No (n = 148) t p Mean SD Mean SD RF Total score 43.40 9.04 42.93 7.34 0.39 0.70 RF1 Supporting children with developmental disorders and their families and preventing abuse 4.25 0.93 4.17 0.80 0.58 0.57 RF2 Connecting to social resources 4.56 1.17 4.57 0.87 −0.08 0.94 CF Total score 47.42 7.78 46.57 6.88 0.78 0.44 CF1 Understanding the position of children with developmental disorders and their families and connecting them with local residents 5.02 0.79 4.96 0.73 0.60 0.55 CF2 Understanding developmental disorders and supporting children with developmental disorders based on assessment 4.32 0.95 4.21 0.84 0.85 0.40 Understanding of welfare commissioners’ work Yes (n = 188) No (n = 32) t p Mean SD Mean SD RF Total score 42.98 8.31 43.66 5.01 −0.63 0.53 RF1 Supporting children with developmental disorders and their families and preventing abuse 4.19 0.88 4.24 0.52 −0.46 0.65 RF2 Connecting to social resources 4.55 1.01 4.66 0.72 −0.70 0.48 CF Total score 46.72 7.16 47.63 7.35 −0.65 0.52 CF1 Understanding the position of children with developmental disorders and their families and connecting them with local residents 4.96 0.74 5.08 0.77 −0.80 0.43 CF2 Understanding developmental disorders and supporting children with developmental disorders based on assessment 4.24 0.88 4.29 0.88 −0.31 0.76 Welch’s t-test results; Abbreviations: SD = Standard Deviation RF1 = Role Factor 1, RF2 = Role Factor 2, CF1 = Competence Factor 1, CF2 = Competence Factor 2 Discussion The results showed that 85.5% of the participants understood the work of the welfare commissioner. Regarding experience, 76.36% had direct experience working with children with developmental disorders and their families, and 32.7% had experience collaborating with welfare commissioners in working with such families. Further, 99% of the participants responded that collaboration with welfare commissioners was necessary in response to the item “necessity of collaboration with welfare commissioners.” Thus, most PHNs who participated in this study felt that providing support to children with developmental disorders and their families in collaboration with welfare commissioners was essential. The results of this study were similar to those found by Moen et al. (2014), who found that public health nurses’ support for parents and all families with children having disorders is crucial and that multidisciplinary collaboration at different levels is a significant part of it. However, in practice, our study found that such support was most often provided without a collaborative partner from welfare commissioners. The barriers impeding this collaboration are unclear. One potential barrier to PHNs and welfare commissioners working together is that the communication system between the two is inadequate. Alternatively, collaboration may be insufficient because PHNs are concerned about placing the burden of their work on the welfare commissioners’ shoulders. Going forward, it will be necessary to clarify these factors to promote collaboration between PHNs and welfare commissioners. The results of this survey revealed that PHNs have a shared set of values and the same expectations regarding welfare commissioners’ roles and competencies regardless of their own attributes. Recently, the progression of population aging and declining birth rates (Statistical Bureau of Japan, 2020), changes in family structure, and diversification of values and lifestyles have led to a gradual weakening of the foundation for mutual support in the community. Notably, a decrease in community members’ capacity to mutually support one another has been observed (Ministry of Education Culture Sports Science and Technology Japan, n.d.). This situation will probably require welfare commissioners to provide more one-on-one interactions and a more advanced level of support. Because welfare commissioners are selected from among the community residents, in most cases, they are unlikely to fulfill their duties based on expert knowledge. Despite this, the expectations of PHNs for welfare commissioners revealed in this study suggest that they are expected to have highly specialized competencies. A survey of civil-service commissioners in Tokyo, Japan (Sugihara, 2018) found that “support from formal and professional organizations had indirect effects on the willingness to continue working was mediated by an increase in psychosocial rewards and decrease in role ambiguity.” Therefore, there is a need for public health nurses to understand the activities and burdens of community welfare volunteers and to build bridges to improve the system. Welfare commissioners’ work to support children with developmental disorders and their parents and to improve support in the community is thought to prevent isolation and abuse in the communities of these children and their families (Adachi et al., 2019; DePanfilis, 2006). If welfare commissioners are expected to have such expertise, it is essential to hold training sessions to teach them specialized knowledge from the field of social welfare and to share information on difficult cases while ensuring that their training does not become burdensome. Moreover, hosting such highly specialized training sessions would help welfare commissioners understand the characteristics of developmental disorders and conduct public awareness campaigns related to developmental disorders for community members. While the welfare commissioner system is unique to Japan, a similar initiative to prevent child abuse by strengthening communities by improving communication with neighbors and volunteer activities is underway in the state of South Carolina in the southeastern United States (Haski-Leventhal et al., 2008). This type of daily communication with community residents is essential for welfare commissioners. It is also likely to lead to early detection and prevention of abuse (McDonnell et al., 2019). In the future, PHNs and welfare commissioners are expected to lead the way in establishing a system to monitor children with developmental disorders and their families (Giannotti et al., 2021). In doing so, it is possible to achieve a community-based symbiotic society in which people can help one another in cooperation with public services (Shikako-Thomas & Shevell, 2018). For this purpose, it is necessary for the governing authorities and relevant organizations to collaborate to improve the welfare commissioner system. Furthermore, to encourage welfare commissioners to provide ongoing support, it is crucial to consider the legislative and environmental improvements intended to increase motivation and enthusiasm among welfare commissioners. There is a need to foster communities in which all members can play a role, support one another, and participate in their own ways by increasing local residents’ capacity to support each other mutually. Limitations and Recommendations for Future Research Concerning future research topics, it is necessary to clarify the status of welfare commissioners’ thoughts on their own roles and competencies in supporting children with developmental disorders and their families. Based on these results, it is important to develop an educational program for welfare commissioners that will allow them to persist in ongoing support efforts for community members. Also, it is essential to support welfare commissioners in a way that helps them fulfill their role as members of a team that supports their community. Finally, it is necessary to validate these results using further surveys. Conclusion This study clarified the roles and competencies that PHNs expect welfare commissioners to support children with developmental disorders and their families. It was found that the roles comprise: 1) supporting children with developmental disorders and their families and preventing abuse and 2) connecting to social resources. Additionally, the competencies include 1) understanding the position of children with developmental disorders and their families and connecting them with local residents and 2) understanding developmental disorders and supporting children with developmental disorders based on assessment. Among these roles and competencies, PHNs emphasize the importance of connecting children with developmental disorders and their families to the community, preventing abuse, and providing support based on assessments. Moreover, PHNs felt that passing on information to other welfare commissioners and protecting individuals’ confidentiality were important considerations when providing support. There were no differences in PHNs’ expectations regarding the roles and competencies of welfare commissioners based on their own characteristics. Acknowledgment The authors would like to extend our deepest gratitude to all the public health nurses who assisted in the completion of this research. Declaration of Conflicting Interest The authors declare that there is no conflict of interest. Funding This work was supported by JSPS KAKENHI Grant Number 22K1102900. The funding source had no role. Authors’ Contributions All authors contributed to the conception of this study, drafting and revising the work critically, approved the final version, and agreed to be accountable for all aspects of the work. Authors’ Biographies Chihiro Kawai, RN, PHN, MSN, PhD candidate, Awa City Hall, Tokushima, Japan. Tomoya Yokotani, RN, MSN, PhD is an Assistant Professor at the Faculty of Wakayama Health Care Sciences, Department of Nursing, Takarazuka University of Medical and Health Care, Wakayama, Japan. Feni Betriana, S. Kep, Ns, MNS, PhD is a Lecturer at the Department of Fundamental Nursing, Faculty of Nursing, Prince of Songkla University, Hat Yai, Thailand. Hirokazu Ito, RN, MSN, PhD is an Assistant Professor at the Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan. Yuko Yasuhara, RN, MSN, PhD is an Associate Professor at the Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan. Tetsuya Tanioka, RN, MA, MSN, PhD, FAAN is a Professor at the Department of Nursing, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan. Kenji Mori, MD, PhD is a Professor at the Department of Child Health & Nursing and a Pediatric Neurologist, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-2-165 10.33546/bnj.2556 Original Research Investigating the complex relationships between leadership, psychological safety, intrinsic motivation, and nurses’ voice behavior in public hospitals using PLS-SEM https://orcid.org/0000-0003-1254-9108 Jaaffar Thuraisyah 1 https://orcid.org/0000-0003-2031-3381 Samy Naresh Kumar 2* 1 Faculty of Entrepreneurship and Business, Universiti Malaysia Kelantan, Malaysia 2 Malaysian Graduate School of Entrepreneurship and Business, Universiti Malaysia Kelantan, Malaysia * Corresponding author: Prof. Naresh Kumar Samy, PhD, Malaysian Graduate School of Entrepreneurship and Business, Universiti Malaysia Kelantan, Malaysia. Email: naresh@umk.edu.my Cite this article as: Jaaffar, T., & Samy, N. K. (2023). Investigating the complex relationships between leadership, psychological safety, intrinsic motivation, and nurses’ voice behavior in public hospitals using PLS-SEM. Belitung Nursing Journal, 9(2), 165-175. https://doi.org/10.33546/bnj.2556 18 4 2023 2023 9 2 165175 23 1 2023 27 2 2023 24 3 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Voice behavior among nurses in public hospitals lacks profound disclosure despite knowing its imperatives. This situation needs to be continuously studied, and the best practices discovered, disclosed, and implemented in hospitals that are serious in curbing unprofessional conduct while advancing healthcare requirements for the benefit of humanity. Objective This empirical research investigated the significant implications of psychological safety and intrinsic motivation in the mostly uncultivated link concerning the empowering leadership style and leader-member exchange (LMX) constructs and the practice of voice behavior among nurses in the selected Malaysian public hospitals. Methods Primary data of the study were from nurses employed in the selected large public hospitals within the Klang Valley, also known as the Greater Kuala Lumpur of Malaysia. A total of 366 complete and valid responses were collected with the help of head nurses via a self-administered survey in February 2020. The SmartPLS 4 for Windows software generated the standard partial least squares structural equation modeling (PLS-SEM) to estimate associations between research variables and evaluate the model’s strength in explaining the proposed constructs. Results This research disproved the indirect effects of psychological safety on the connection explorations between empowering leadership-voice behavior (β = 0.015, t-value = 0.300, 95% CI [-0.090, 0.110]) and LMX-voice behavior (β = 0.002, t-value = 0.285, 95% CI [-0.014,0.020]). Intrinsic motivation partially mediates the link between empowering leadership-voice behavior (β = 0.214, t-value = 7.116, 95% CI [0.160, 0.279]) and LMX-voice behavior (β = 0.114, t-value = 4.669, 95% CI [0.071, 0.168]) of the nurses. Conclusion Patients, non-governmental organizations, volunteers, nurses, and other hospital staff are vested in how voice behavior signifies in the healthcare context. Essential factors for nurses to become more outspoken are discovered in this study, providing nurse managers and other leaders with numerous recommendations for encouraging vocal behavior and bolstering psychological safety and intrinsic motivation. More competent nurses will improve workplace culture, deliver superior healthcare services, and manage publicly financed hospitals with an overall sense of trust, but only after a substantial effort to execute reforms. nurses voice behavior psychological safety intrinsic motivation leadership Malaysia ==== Body pmcBackground Advancing public hospitals to provide current services to the public necessitates the full participation of nurses from all departments. The involvement of nurses can be manifold, but the most vital and pressing issue is acknowledging nurses’ experiences which later formed into meaningful ideas for publicly funded hospital progress without compromising the standard feasible hospital daily operations. Public speakers, thinkers, scholars, and business leaders speak loud about present living environments, which are highly unpredictable, inexact, and multifaceted. Thus, the power of expression directed to general and specific misalignment of hospital-related innovation should be inevitably in practice. It is likely essential for nurses to remain focused while handling health care and management demands, similar to the reasoning in business organizations (Mowbray et al., 2021; Su et al., 2017). We have realized that the nurses act as the foreheads that induce directions for the hospitals thru knowledge sharing gathered from the stakeholders, particularly patients. If nurses decide not to or withdraw from expressing their concerns about innovative hospital practices and other organizational behavior glitches will marginalize opportunities for error detection, provision of solutions, and strategic implementations to avoid silent workplace unproductiveness and performance to the highest expectations (Kim & Ishikawa, 2021). Besides, the hospital management probably delays making vibrant decisions, improving department functioning, and sustaining hospital organizational efficiency (Hussain et al., 2019). Perhaps these will knock down their reporting to the public on managing entities with public funds. Thus, hospital management needs to place measures to nurture nurses’ continuous support in voicing their experiences and thoughts while performing their daily routines, fulfilling stakeholders’ interests, and attaining the hospital and national healthcare services missions. The study on voice behaviors is gaining continuous support across the research disciplines. Despite numerous perspectives, characteristics, and definitions available, for easy understanding, voice behavior is voicing concerns and thoughts for improving a situation (Morrison, 2014) or improving the service management system with required innovation from the hospital context. According to Dyne et al. (2003), speech is a tool for change-oriented communication and can improve otherwise dismal conditions. Van Dyne and LePine (1998) categorized vocal behavior as promoting or inhibiting. Voice behavior supporting employee suggestions for strengthening organizational work processes is promotive and must be continuously encouraged at all levels (Kakkar et al., 2016) and occasionally mistaken that promotive voice as a challenge to the authority of the organization’s management since it provides possibilities to alter the status quo of the personnel (Chen et al., 2018; Engemann & Scott, 2020). When nurses use prohibitive voice behavior, they are concerned about the workplace and have a chance to explain the potential hazards. Prohibitive voice behavior seen as favorable is proactive and focused on the future. Unacceptable speech patterns glance ahead or back. Voice-related actions go above and above to improve creativity and productivity and reduce errors at work (Morrison, 2014; Van Dyne & LePine, 1998). Inconsistent in-role behavior or disdain for one’s duties in one’s allotted position will result in unfavorable monetary sanctions and lost possibilities for promotion (Van Dyne & LePine, 1998). Consequently, many nurses facing difficult situations might choose to be silent. This condition needs to be continuously studied, and best practices learned and implemented in hospitals that are serious in curbing malpractices while advancing healthcare provisions for the betterment of humankind. Leadership is crucial in allowing nurses to constructively express their thoughts, agreeing with earlier pragmatic studies (Hsiung, 2012; Jada & Mukhopadhyay, 2019; Yan, 2018). However, despite these advancements in voice research, further investigation is essential to determine the underlying psychological mechanisms in leadership that influence nurses’ or other employees’ voice behavior (Engemann & Scott, 2020; Lam et al., 2018; Morrison, 2014). One of this paper’s intended outcomes is to suggest the significance of psychological security and underlying motivation drive in foreseeing nurses’ voice behavior. The foundation of the social exchange theorem propagated by Blau (1964) entails believing that leader and member reciprocity will yield healthy behaviors in the workplace. Corresponding to this theory, employees’ positive impressions of the organization’s treatment of them led them to express concern for the best practices that benefit all. Nurses are much more apt to speak their minds in conditions where they know they are protected and can trust the safety of those around them. So, it is the responsibility of hospitals to shield their nurses’ hearts and minds. Psychological safety means the employees do not worry about how others may see them professionally or personally (Kahn, 1990). There is a strong desire for empirical evidence supporting the connection between leadership and voice behavior. Vocal behavior is recognized widely as a crucial facet of employees’ citizenship behavior that complements multifaceted performance and hospital organizational development. Management is often put in danger by unresolved problems at the workplace. Intrinsically motivated nurses do what they do because they enjoy it, not because they hope for some external rewards (Deci & Ryan, 1985). Scholars have researched and reported a positive connection between an intrinsic member of staff motivation and performance in several contexts. Therefore, it is crucial to determine if empowered leadership can affect employee voice behavior by boosting innate motivation drive. Indirect Effects of Psychological Safety Clark (2020) defines the concept of psychological safety as the absence of worry about being ridiculed, excluded, or reprimanded because of one’s opinions or actions. A greater sense of comfort and lack of perceived risk, Kahn (1990) posited to increase employee responsibility. Searching the history, we note that Schein and Bennis (1965)’s research on organizational change explains that psychological safety increases chances for employees to take risks since they feel safe and capable of handling the consequences. Psychological safety is essential in simplifying thoughts and behaviors in any organization, particularly in group concentration phenomena (Edmondson & Lei, 2014). Therefore, it is critically important in managing the public hospital. Psychological safety in healthcare settings improves patient outcomes by encouraging nurses to report errors and participate in quality improvement initiatives (O'Donovan et al., 2021). Team members who offer constructive criticism of the hospital’s performances think through the repercussions of their actions before voicing them. They worried that others would misunderstand or reject their offer. These are common in organizations that do not encourage open dialogue and inquiry. However, Dutton et al. (1997) note that employees sometimes incorrectly judge whether it is safe to speak up. In this situation, confused nurses probably remain silent instead of actively engaging in voice behavior, knowing at the same time they are protected in the event of speaking up their minds (Detert & Edmondson, 2011). It is popular in the social science studies repeating Morrison (2014), who asserts that the opinions and actions of managers (in the context of a hospital, head nurse) significantly impact whether or not workers participate enthusiastically in voice behavior and make it part of the hospital culture. Nurses are more likely to use their voices in a positive work environment. The hospital culture also plays a significant role in encouraging nurses to raise concerns about their work. One way to build hospital employees’ psychological security is to have an approachable and open leader (Edmondson & Lei, 2014). The hospital department leaders can learn what nurses and other employees think and feel about workplace practices and encourage them to voice their opinions without any restrictions. Whistleblowing can happen positively within the hospital for progressive improvement, and most importantly, stakeholders’ interests are well taken care of. Nurses must also be confident that voicing their opinions will have no negative consequences. Rules, regulations, and procedures should be in place for all nurses to be comfortable, making voice behavior a standard norm in the hospital. When strong leadership exists, it fosters effective cultural practices within an organization (Schein & Bennis, 1965). Earlier research (Liu et al., 2021; Liu et al., 2017; Lu & Lu, 2020) indicated a significant leader-voice relationship mediated by psychological safety. Indeed, Leader-Member Exchange (LMX) philosophy (Graen & Uhl-Bien, 1995) alleges that superiors and direct reports have strong ties. Hence, the first research hypothesis for the study is H1: psychological safety significantly mediates the link between empowering leadership style and the voice behavior of nurses. Interestingly, long ago and significant to note that Katz and Kahn (1978) argue that organizations cannot succeed in their missions, produce quality work, or cooperate effectively unless there is a strong network of interpersonal relationships within the organization thriving for excellence (Carnevale et al., 2017). Nurses who form closer relationships with their superiors (substantial LMX relationships) are more open to contributing opinions and putting in the time and effort required to address workplace challenges because they are assured more trust and freedom. The leader is responsible for making the workplace safe for nurses to open up about their emotional well-being in two-person teams. Psychological safety with dynamic team relationships entails more awesome voice behavior and breaks the unhealthy silence among employees who prefer energetic, supportive, and productive work settings and organization growth strategies (Bienefeld & Grote, 2014; Brinsfield, 2013; Xue et al., 2020). Nurses with high psychological safety were presumed to express disagreement wisely, be brave in engaging with open criticism, and be bold in meeting and voicing out their immediate superior or the higher authorities if the lower management remains neutral. Consequently, the following hypothesis formed, H2: psychological safety significantly mediates the link between LMX and the voice behavior of nurses. Indirect Effects of Intrinsic Motivation People are intrinsically motivated because they value engaging in novel and challenging activities (Ryan & Deci, 2000). A person who is intrinsically motivated does what they do because they enjoy doing it and are interested in the task at hand (Conchie, 2013; Ryan & Deci, 2000). Employees’ favorable sentiments and overall sense of comfort might be a starting point for self-determination theory, which contends that sovereignty, capability, and affinity increase intrinsic motivation (Deci & Ryan, 2010). As a theory of motivation, intrinsic motivation has recently emerged as a critical factor in employees’ propensity to engage in creative problem-solving on the job. Leaders who excel at empowering their teams do so by delegating responsibility, giving employees a voice in critical decisions, and showing faith in their ability to tackle complex projects (Ahearne et al., 2005). It follows that leaders who insist on equitable distribution of authority can inspire employees to tap into their reserves of intrinsic motivation. Leaders who empower their followers do so by giving them more responsibility for making decisions, disclosing relevant information, praising the initiative, highlighting the importance of setting personal goals and providing a process that inspires them. Besides includes everyone in the group while supporting their right to make decisions. In the hospital context, nurses are prone to care for intrinsic motivation and positive organizational citizenship behavior when urged to manage responsibilities independently and decently and be duly liable for related consequences in the cause of performing their tasks within their workstations. Voice behavior is proactive and challenging, and hospitals that value it are more likely to provide their nurses with outlets to showcase their skills and ideas. The intrinsic motivation also includes voice behavior and other forms of positive deviation (Vadera et al., 2013). Furthermore, empirical studies (Conchie, 2013; Wu et al., 2019) have found direct and indirect links between intrinsically motivated individuals and the execution of voice behavior. Therefore, it hypothesized that H3: Intrinsic motivation significantly mediates the association between empowering leadership style and voice behavior of nurses. Previous research shows several outcomes significantly influenced by LMX (Erdogan & Liden, 2002; Ilies et al., 2007). However, few studies have examined the mechanism that links LMX and employee feedback (Wang et al., 2016). Firmly attached employees are motivated to do an excellent job because they feel they owe the organization for the good treatment they have received. Since voice behavior is a non-standard role, LMX’s high quality makes it simpler to actualize (Song et al., 2017). Strong LMX relationships spur more significant access to information, and the support of leaders toward the employees encourages them to speak up. Thus, the following hypothesis is relevant to test H4: Intrinsic motivation significantly mediates the association between LMX and the voice behavior of nurses. Hypothetical Groundings Many empirical and conceptual reports regarding voice behavior are within the theory of social exchange (SET), which is significant. Blau (1964) proposed a simple definition of social exchange in which individuals voluntarily engage in activities motivated by the expectation of receiving benefits from others. This definition describes the interaction between humans and the world around them. According to Scott et al. (2013), social exchange theory explains people’s feelings of inclusion or exclusion significantly shape their perspectives and actions. Data shows that interpersonal contact promotes knowledge sharing. Based on the premise that individuals have an innate need to communicate with and trade with others, social cohesion is crucial to a balanced and harmonious workplace. The research outcomes presented in this paper are grounded in the SET and LMX theories. Scholars such as Cropanzano et al. (2017) posit that SET is among the highly popularly used theory in research frameworks within managerial sciences and other disciplines such as sociology and social psychology. Key employees of an organization are considered living symbols of the whole because of the strong bonds employees have with the organization. Employees’ attitudes about the organization’s goals toward these individuals reflect how they treat them, so their treatment indicates their attitudes. Another factor to consider is ensuring organizational members feel valued. Consequently, they are more likely to participate in organization-related events that benefit each person (Ilyas et al., 2021; Jada & Mukhopadhyay, 2019; Jung et al., 2020). Notably, members who had a good experience, which means they will have robust and valuable interconnections forever with the work units reaching holistically to the organization. When people put in the effort to build meaningful relationships with one another, they reap emotional and behavioral benefits, as was found in a previous study (Cropanzano et al., 2003). Some scholars hold that SET harms processes of negative reciprocity, while others argue that it has an impartial or encouraging impact (Cropanzano et al., 2017; Cropanzano et al., 2003). Nurses not feeling pleased in the organization may be less likely to volunteer their time or ideas. Corresponding to the LMX model, influential leaders cultivate various connections with their subordinates. A leader’s actions are individually weighed (Graen & Uhl-Bien, 1995). Managers and employees alike, LMX theory posits, have multiple personas. Extraordinary LMX connections require positive belief, human acknowledgment, mutual authority, faithfulness, similarity, and undertakings of responsibilities and accountabilities (Graen & Uhl-Bien, 1995). Many have acclaimed the vitality of using balanced to superior LMX in improving assertiveness and encouraging employees to use their voices at the workplace (Botero & Van Dyne, 2009). These claims apply to organizations across the industry, including public hospitals. Ponder also that trust between subordinates and superiors is integral to healthy LMX relationships. The associates will likely take notice of their manager if they know that speaking up means losing personal capital or putting themselves in danger (Botero & Van Dyne, 2009). Employees who feel equality and fair treatment will positively impact the organization by being responsible individuals and standing for the organization’s success (Gigol, 2020). Employee-leaders-organization relationship is utterly related to feeling empowered, accepting responsibilities, dedication, and increased internal enthusiasm to progress in any circumstances on the job and organizational system (Chen et al., 2018; Duan et al., 2017; Lee et al., 2021). The unique individual, a work-related and mutually beneficial effort of establishing partnerships between employees and employers, is part of LMX’s philosophy (Carnevale et al., 2017). The same view is in the opinion of Graen and Uhl-Bien (1995) and also contended long ago by Van Dyne et al. (2008). Employees better understand their leaders’ perspectives and arguments in well-developed LMX interactions. These people are strongly presumed to contribute fresh forward-thinking to uplift organizational performances strategically. Further, members strive to benefit direct superiors and other coworkers. Moreover, studies (Botero & Van Dyne, 2009; Carnevale et al., 2017) have shown that LMX accurately predicts job performance outcomes. Methods Study Design This cross-sectional study seeks to gather data from nurses working in Malaysian public hospitals. With the data set, establishing a model of the interconnectivity of measurable antecedents (empowered leadership style and LMX), significant mediators (psychological safety and intrinsic motivation), and the voice behavior of nurses are the ultimate aims. Samples/Participants Staff nurses were selected randomly from the general medical, general surgical, obstetrics and gynecology, pediatrics, and orthopedic wards from seven large government hospitals in the Klang Valley of Malaysia. All the selected hospitals receive government funding and serve the public’s healthcare needs with little or no charges. Besides, the hospitals are large, able to help a higher-density population in the Klang Valley, and, most importantly, sufficiently equipped with modern technologies and healthcare practitioners. This study used Krejcie and Morgan (1970)’s table to determine the appropriate sample. This study’s population comprises 7446 registered staff nurses. Thus, the sample size needed is at least 367 nurses. The researchers inflated the sample size by 10%, resulting in 408 samples. The head nurses of the respective hospitals help deliver the self-administrative questionnaires to the selected nurses who have completed a minimum of a 2-3-year diploma and hold a bona fide license issued by the Malaysian Nursing Board. The final usable and valid survey responses for inclusion in the model and hypotheses testing totaled 366 data. Instruments This study used adapted constructs from established survey questionnaires that have multiple items. Thus no single-item measures in the survey instrument. Ahearne et al. (2005) designed a full 12-item scale that facilitated this study to measure empowering leadership style. Based on subordinate views, Liden and Maslyn (1998) initiated a multidimensional LMX construct consisting of 12 related items measuring four independent dimensions: 1. affect, 2. loyalty, 3. contribution, and 4. professional respect, which aid in gathering nurse respondents’ replies on LMX. Edmondson (1999) logically composed a 7-item scale that was appropriate, widely used, and strongly recommended for assessing psychological safety. The researchers found three items scale significant to assess intrinsic motivation adapted from the works of Amabile (1985) and Tierney et al. (1999). Finally, Van Dyne and LePine (1998) popularized a six-item measurement scale employed in this study to measure the dependent variable, voice behavior. The completed questionnaire included a commonly used five-point Likert scoring scale, with the lowest (1) indicating ‘strongly disagree’ and the highest (5) representing ‘strongly agree’. As part of the research ethics, researchers communicated and were granted permission by the instrument owners before adapting the items in the present questionnaire. The original measurement items were observed and showed that the reliability coefficients (Cronbach Alpha) exceeded the acceptable standard value of 0.7. The last section of the questionnaire requested the nurse demographic data of age, gender, ethnicity, marital, nursing experiences, and department. Indeed, the final survey questionnaire was examined by three experts for content validity for use in the local context. The researchers did not attempt to translate this study’s survey instrument into other languages. The standard English language used in the original measures is maintained since it is straightforward, easy to understand, and has no issue for the nurses to respond. Hence, the instrument is valid and reliable, considered excellent, and ready for the actual study. Data Collection This empirical study uses a cross-sectional survey, and required responses are collected using a structured questionnaire and self-administered. The researchers personally sent the questionnaires to the selected public hospitals. The head nurses were the contact point to help distribute and collect the completed questionnaires from the respondents-nurses in the selected hospital wards. It was the only feasible way to collect data from Malaysian public hospitals. Continuous follow-up with the head nurses finally yielded completed and valid 366 responses, accounting for an 89.71% effective response rate. The data collection process occurred for three weeks in February 2020. It was successfully ended right before the Malaysian government movement control order beginning the second week of March 2020 in response to the COVID-19 pandemic. Data Analysis Before data analysis, researchers ensured that the data was reasonably ready for investigation, which involved handling blank responses, coding, and categorizing the data. The preliminary data analysis and descriptive statistics were performed and generated with IBM SPSS Statistics version 26 software for windows. The interrelationships between the study variables weighed with the latest and famous software, SmartPLS 4, for Microsoft Windows. The multi-item measurements suit the reflective measurement model in which the inherent research constructs run the indicators with encouraging high-level intercorrelations. The chosen measures enable a unidimensional structure and robust internal consistency. The selected software employs a two-stage procedure: i) assessment of the reflective measurement model, which tests the validity and reliability of the measures, and ii) estimation of the structural model, which helps in forming the final model and to examine the research hypotheses. Hair Jr et al. (2021) and many other scholars (Ramayah et al., 2018; Sarstedt et al., 2020) contended that estimating path models using latent variables and their interactions has propelled the popularity of partial least squares structural equation modeling (PLS-SEM) technique, used across the disciplines. Ethical Considerations Medical Research Ethics Committee Malaysia approved this study (Approval reference: NMRR-15-129-25990). in seven selected hospitals within Klang Valley, Malaysia. The participants signed the informed consent before responding to the survey. The research objectives and other relevant instructions were briefed and stated in the questionnaire, and the participants received assurance of the confidentiality of the information collected. Furthermore, we ensured no direct interference during working hours; the contact person was the head nurses of the respective hospitals. Results Characteristics of the Participants The survey respondents included 8 (2.2%) males and 358 (97.8%) females. Females consistently dominate nursing, even though it is a norm in recent years for males to pursue nursing. One hundred seventy-one respondents were within the age range of 20-29 years. They accounted for the majority (46.7%) of the sampled responses. The subsequent largest was nurse respondents aged 30-39, with 105 (28.7%) respondents. In the 40-49 age group, 42 (11.5%) respondents, and 50-59 years comprised 48(13.1%) nurse respondents. Most respondents were Malays, with 331 respondents accounting for 90.4% of the sample. 266 (72.7%) respondents were married, followed by the single group, with 99 (27%) respondents. Only a minority declared themselves as widowed (0.3%). Looking at the responses for work experiences, 98 (26.8%) nurses had between 2-5 years of professional work experience, 72 (19.7%) with between 6-10 years, and 64 (17.7%) responded to accumulate more than 21 years and above work experience. Additionally, 57 respondents (15.6%) had a range of nursing experiences between 11-15 years. Fifty-five nurses, accounting for 15%, had a year or less of work experience. The smallest group was the 20 (5.5%) nurses with solid nursing experiences totaling 16-20 years. These findings showed that most public hospital nurses have extensive work experience. The respondents were from the general medical and general surgical departments, with 100 respondents (27.3%) and 98 respondents (26.8%). Sixty-eight respondents (18.6%) were from the pediatrics and 56 (15.3%) were from the orthopedic department. The least number of respondents were from the obstetrics and gynecology (O & G) department, accounting for 12% or 44 respondents of the samples. CMB - Common Method Bias Observing the VIF- variance inflation factor values generated by performing the complete collinearity data diagnostics for scanning issues of CMB is essential. The VIF values ranged from the lowest, 1.139, to the highest, 2.921, which promised that the model of this study was free of CMB. Kock (2017) recommended observing a threshold value of less than or equal to 3.3 to qualify for the claim for free of CMB in empirical research. The complete VIF values for the constructs empowering leadership (EL), leader-member exchange (LMX), psychology safety (PS), and voice behavior (VB) are in Table 1. One of the requirements to test the structural model after fulfilling the conditions for the measurement model is ensuring that the VIF indicators are within the acceptable threshold, which is less than 5.0 (Hair Jr et al., 2017; Ramayah et al., 2018). At this point, VIF values were within the approved range, and no multicollinearity that could jeopardize the assessment of the structural model discussed in the later part of this paper. Table 1 Collinearity statistics (VIF) Construct PS IM VB EL 1.139 1.139 2.921 LMX 1.139 1.139 1.262 PS 2.555 IM 1.985 Analyzing the Reflective Measurement Model The measurement model is the first to establish after the testing of the reliability and validity of the latent variables framed for a specific study. Once the measurement model fits the requirements, it enables the functions of the structural model in which the possible associations between the study constructs are analyzed and exposed with statistical facts—decisions on the proposed hypotheses and conclusions made at this stage. Hair et al. (2019); Hair Jr et al. (2021) provided a comprehensive guide to assess the reflective measurement model and the structural model estimation. The guidelines and suggestions helped make wise statistical decisions for this study. The construct measures reliability was assured by looking at Cronbach alpha (CA) and composite reliability (CR) scores. The statistical indicators obtained from the SmartPLS 4 software showed that the observable values of CA and CR passed the threshold value of 0.7. The convergent validity was assured by observing the importance of the outer loadings and the average variance extracted (AVE). The loadings (see Figure 1) surpassed the recommended threshold of 0.708. And the values of the AVE testing for the convergent validity were more outstanding than the recommended threshold value of 0.50 (see Table 2). In establishing the discriminant validity, assessing values of the Fornell-Larcker criterion, cross-loadings, and Heterotrait–Monotrait Ratio correlations (HTMT) are essential. These three approaches warrant the discriminant validity of the proposed research model. For simplification purposes, in this paper, the HTMT results are reported (see Table 2). All the HTMT correlation values were lower than 0.90, thus passing the standard cut-off point (Hair Jr et al., 2017; Ramayah et al., 2018). The reflective measuring model satisfies all of the requirements for a good fit and therefore enables the assessment of the structural model and testing of the four research hypotheses with PS and IM as the mediators on the test of relationships among EL, LMX, and VB. Table 2 Results of constructs reliability, convergent, and discriminant validities Constructs Reliability (CA & CR) Convergent Validity (AVE) Discriminant Validity: Heterotrait-Monotrait Ratio (HTMT) CA CR AVE EL LMX PS IM EL 0.943 0.952 0.663 LMX 0.860 0.915 0.783 0.363 PS 0.950 0.956 0.646 0.857 0.416 IM 0.927 0.941 0.695 0.642 0.478 0.757 VB 0.953 0.962 0.809 0.761 0.195 0.694 0.734 Figure 1 Path analysis diagram Assessment of Structural Model R-square values of endogenous latent variables are classified as robust (if R2 ≥0.75), moderate (if R2 ≥0.50 and <0.75), and weak (if R2 ≥0.25 and <0.50) following the recommendations of Hair et al. (2019); Hair Jr et al. (2017); Hair Jr et al. (2021). The model fit test results (see Table 3 and Figure 2) showed that El and LMX jointly contributed 66.7% and 40.4% variances in PS and IM, respectively. All the exogenous constructs explained 64.0% (R2 = 0.640) of the observed variance in VB. The analysis of effect size performed using the f-square value following the well-acknowledged guideline by Cohen (1988) guided the decisions: small effect (if f2 ≥0.02 and <0.15), medium effect (f2 ≥0.15 and <0.35) and substantial effect (if f2 ≥0.35). Following these references, only the PS construct did not affect the VB of nurses (f2 = 0.001). Other constructs’ effect sizes were between small and medium, as in Table 3. The Q-square values obtained through the blindfolding analysis using the SmartPLS 4 software indicated the direct and indirect models had good predictive relevance. Table 3 Model fit test results Exogenous Construct R-square Endogenous Construct f-square effect size Q-square Endogenous Construct EL Psychology Safety 1.550 (large) Psychology Safety LMX (0.667: Moderate) 0.038 (small) 0.458: Good predictive relevance EL Intrinsic Motivation 0.359 (large) Intrinsic Motivation LMX 0.102 (small) (0.403: Moderate) 0.310: Good predictive relevance EL Voice Behavior 0.257 (medium) Voice Behavior LMX 0.083 (small) (0.640: Moderate) 0.512: Good predictive relevance PS 0.001 (no effect) IM 0.264 (medium) Figure 2 Structural model Hypotheses Testing The bootstrapping indirect effects are more robust in reporting mediation analysis (Hayes, 2017; Ramayah et al., 2018). Indeed, concerning Hayes, the bias-corrected bootstrap confidence interval is the most excellent approach for detecting mediating effects in scientific research. The indirect results obtained through the bootstrapping analysis with 5000 re-samples showed that the hypotheses (H2: β = 0.24, t-value = 7.116) and (H4: β = 0.114, t-value = 4.669) were significant. Furthermore, the indirect effects bias-corrected bootstrap at 95% confidence interval for (H2: BCLL = 0.160, BCUL= 0.279) and (H4: BCLL = 0.071, BCUL = 0.168) did not straddle a value of zero (0) in between, indicating there were mediations and it was statistically significant. In conclusion, the decision was that IM partially mediated relationships between the constructs EL-VB and LMX-VB. The first and third hypotheses (H1 and H3) were insignificant since the observed t-values were 0.300 and 0.285, respectively. Looking at the indirect effects’ bias-corrected bootstrap at 95% confidence interval for H1[BCLL = -0.090, BCUL = 0.110] and H3[BCLL = -0.014, BCUL = 0.020] found to straddle a value of ‘0’ in between the lower and upper values, giving an indication there were no mediation effects. As a final remark on the hypotheses testing, PS did not mediate the connection between (EL & VB) and (LMX & VB). The complete summary of the mediation analysis results is in Table 4. Table 4 Results of the indirect effects Hypotheses Construct Relationship Std. Beta (β) σ t-value p-value BCLL BCUL Decisions H1 EL> PS-> VB 0.015 0.051 0.300 0.764 -0.090 0.110 Reject H2 EL -> IM -> VB 0.214 0.030 7.116 0.001 0.160 0.279 Accept H3 LMX -> PS->VB 0.002 0.008 0.285 0.776 -0.014 0.020 Reject H4 LMX -> IM -> VB 0.114 0.024 4.669 0.001 0.071 0.168 Accept Note: bias-corrected bootstrap confidence interval for upper level (BCUL), bias-corrected bootstrap confidence interval for lower level (BCLL) Discussions Scholarly concern, debates, and critics about employee voice and behavior skyrocketed in the latter part of the twentieth century (Kim & Ishikawa, 2021; Maynes & Podsakoff, 2014). Misconducts can uncover through easy, casual talks that relate forward-thinking ideas. Studies have shown various voice behaviors discovered in multiple settings, from formal grievance processes to whistleblowing. Many academics consider the voice more than a reaction to harmful stimuli (Chen et al., 2018). In addition, various employees’ comfort levels are observable when bringing up concerns and providing feedback (Ilyas et al., 2021). However, the specific position of both constructs for mediators, psychological safety, and intrinsic motivation on the connections between empowering leadership and the impetus of leader-member exchange for nurses voicing behavior in public hospitals remains uncultivated mainly. Thus, an empirical study with a relevant nurse sample enables learning the associations and the research finding summarized in this paper to fill necessary gaps while encouraging continuous research. The research findings indicate that psychological safety cannot significantly mediate the nurses’ dynamic voice behavior and antecedents, namely empowering leadership and leader-member exchange, specifically in public hospitals. Interestingly, it concurred that public hospitals help boost the nurses’ intrinsic motivation. This factor essentially worked as an intermediary on the research link between empowering leadership, LMX, and nurses’ voice behavior. Fairly treated workers are more likely to be productive and cooperative colleagues (Gigol, 2020). Employee exchange connection is positively related to feelings of emancipation, obligation, and increased internal dynamics of motivation to improve the surroundings directed toward the work ground (Bolino & Turnley, 2009; Chen et al., 2018; Duan et al., 2017; Lee et al., 2021). Psychological safety is frequently allied mainly with the constructs framed in this study, ‘empowering leadership’, ‘LMX’, and ‘voice behavior’. Employees are likelier to be happy and productive when they feel comfortable in their workplace and can express themselves openly and without fear of repercussions (Edmondson & Lei, 2014; Maynes & Podsakoff, 2014). However, we found that psychological safety seems to remain intrinsic and is not the primary concern of the nurses during the engagement with voice behaviors. Indeed, a public hospital with a good governance structure overrides the role of psychological safety compared with intrinsic motivation. Ensuring work stability during high volatility and uncertainty makes the nurses feel secure. In turn, the empirical evidence in this paper shows that it may encourage nurses to speak up. Furthermore, leaders with profound leadership behavior increased nurses’ intrinsic motivation and concurrently built up nurses’ voice behavior. Nurses’ innate drive helps develop interpersonal competence and inherent appeal that does not depend on tangible rewards. Nurses with professional nursing practice have proven to handle difficult situations, akin to the expressive note of Lyman et al. (2020) and Kee et al. (2021). Also, Malaysian public hospital nurses can speak up due to their knowledge, practice experience, work culture, and supportive leaders who believe in engaging nurses in every spear of innovative strategies. Tenancy grows in nurses’ roles over time, which may support their tendency to become more vocal in the workplace. Leaders’ inclusiveness and equality practices increase nurses’ voice behavior, and perhaps to Hanson et al. (2020), the reverse will delimit voice behavior among nurses at any stage in the organizational structure. Since their employer has shown a willingness to care for their well-being, nurses participating in the reciprocation process are firmly in anticipation to actively partake in hospital, work, and society-related actions. These moves could stimulate and grow the hospital’s innovative work-based behavior dedicated to sustainable performance (Ilyas et al., 2021; Jada & Mukhopadhyay, 2019; Jung et al., 2020; Svendsen et al., 2018). Nurses’ accumulated pleasant experiences and enhanced learning curves lead to a robust internal-external professional network, innovation, competencies, and profound provision of hospital services. Nursing professionals may be reluctant to raise concerns about unprofessional behavior or other areas where a value judgment implies fear of repercussions from superiors or coworkers (Gigol, 2020; Martinez et al., 2015). But, in the Malaysian context, this situation is curbed and is not an issue to be concerned about since the findings indicate that psychological safety does not rule out the strength of the voices. This study proves that for nurses who genuinely believe their voices are valued and translated into actions, redundancy in further voice actions will follow with the conjoin of intrinsic motivation. Due to advancements in the hospital service revolutions, breaking the status quo has become necessary; thus, the nurses’ fraternity is undoubtedly the supporting milieu for service victory. Indeed, the study’s findings encourage the growing knowledge of how leadership, intrinsic motivation, and psychological safety may affect nurses’ willingness to speak up, particularly in the public sector. With certain limitations, it is possible to capture the ideas presented in this research and apply them to private healthcare providers, hospitals, or any related field. The SET and LMX theories are utilized and supported throughout this research. However, some researchers find that SET favors positive reciprocity, while others find it detrimental (Cropanzano et al., 2017; Cropanzano et al., 2003). Limitations and Recommendations for Future Research The instrument’s reliability and validity are satisfactory. However, because the research focused on public hospitals, the study may have some flaws, and further research is needed to determine if or not other characteristics are just as important. Nevertheless, the research methods employed herein are valuable for application in a wide range of future studies, both in and out of the business world. The research approach is supposed to inspire academics, which will contribute to expanding our understanding of how employees in various work environments use their voices. Exploring the differences between employees’ formal and informal voice behaviors would be a great addition to future research. Implications of the Study to Nursing Practice Nursing is carried out methodically by following a deliberate, logical, and reasonable approach to problem-solving. From the initial assessment through the final review, the nursing process incorporates ongoing input from the patients, peers, their families, their communities, and other professionals’ connectivity. At this juncture, nurse voice behavior is a duty in executing responsibilities as imposed in this study. Nursing requires specific professional endorsement and registration or licensing by the authority. It is a trust given to a particular group of people passionate about caring behavior. Experiences gained via direct and indirect involvement in patient care, administrative work, education, training, research, consultation, mentoring, and coaching mold nurses into more conscious individuals. Their intellectual maturity encourages them to be more vocal for the betterment of humanity. Thus, competencies to engage in voice behavior while understanding the antecedents, potential limitations, and constructive remedies help the nursing fraternity be evergreen in making a difference and becoming change agents with the power of talk. The outcomes of this research are straightforward: intrinsic motivation encourages and surpasses psychological safety to express voice behavior. Utterly passionate about the core values of nursing practice, voice behavior advanced for its inherent satisfaction, challenges entailed tangible receivable such as rewards instead. At the peak of demonstrating the voice behavior, empowering leadership is necessary, then having a leader-member exchange governing. Those leading the nursing practice by all means challenged to change the conventional to empowering leadership style. Conclusion Understanding the practices, power, dysfunction, and prohibitions of voice behavior from time to time in the hospital setting is crucial for the hospital management and stakeholders such as patients, NGOs, volunteers, nurses, etc. The study finding paths several ideas for nurse managers and other leaders to support voice behavior while strengthening psychological safety and intrinsic motivation, demonstrating vital points for nurses to become more willing to speak up. Continuous professional nursing orientations, training, seminar, workshops, and alike provides an opportunity for enhancing proper voice behavior with the responsibilities of their role. Enhancing peer learning and establishing a knowledge management portal helps spread innovative thought, gain knowledge, and build self-confidence, improving voice behavior that enhances performances. Adding an encouraging culture of mentor-mentee will dynamically boost self-leadership qualities among nurses that entail positive voice behavior. Mentors (senior-junior partnership) can act as an informal, immediate point of expert reference to make nurses (mentees) feel more peaceful and vital to the job, increasing their chances of actively speaking up. Policy, procedures, and guidelines that officially permit open dialogue and inquiry must be transparent for everyone to gauge and embrace in their daily work routine. These can help overcome the feeling of insecurities nurses may experience at the beginning of their careers till the end. Although significant labor hours are needed in planning, organizing, leading, and strategically implementing changes, the outcomes are worth it for the nation. More competent nurses will advance work culture, provide excellent healthcare services and manage publicly funded hospitals with overarching trust. Acknowledgment The authors want to express special gratitude to the Medical Review and Ethics Committee (MREC), Ministry of Health Malaysia, for approving and allowing data collection at the respective public hospitals. In addition, they are thankful to the hospital directors, head nurses, and nurses who have voluntarily completed the survey. Declaration of Conflicting Interest The authors declared there is no conflict of interest. Funding The authors self-funded this study. Authors’ Contributions The authors contributed equally to the research concept, design, intellectual content, review of literature, data collection, data analysis, and manuscript writing. TJ organized approval and distributed the survey. NKS proofread the final manuscript. Authors are accountable at each stage of the research and approve the concluding version of the paper to be published. Authors’ Biographies Thuraisyah Jaaffar is a Doctoral Candidate at the Faculty of Entrepreneurship and Business, Universiti Malaysia Kelantan, Malaysia. Naresh Kumar Samy, PhD, is a Professor at the Malaysian Graduate School of Entrepreneurship and Business, Universiti Malaysia Kelantan, Malaysia. Data Availability The datasets generated during and analyzed in the study are available from the corresponding author upon reasonable request. Declaration of use of AI in Scientific Writing Nothing to declare. ==== Refs References Ahearne, M., Mathieu, J., & Rapp, A. (2005). To empower or not to empower your sales force? An empirical examination of the influence of leadership empowerment behavior on customer satisfaction and performance. Journal of Applied Psychology, 90 (5 ), 945-955. 10.1037/0021-9010.90.5.945 16162066 Amabile, T. M. (1985). Motivation and creativity: Effects of motivational orientation on creative writers. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-017 10.33546/bnj.2350 Theory and concept Development Patient and family-centered care for children: A concept analysis https://orcid.org/0000-0001-7270-0493 Seniwati Tuti 12* https://orcid.org/0000-0002-3369-2694 Rustina Yeni 3 https://orcid.org/0000-0003-4880-7439 Nurhaeni Nani 3 https://orcid.org/0000-0003-0659-1748 Wanda Dessie 3 1 Postgraduate Program, Faculty of Nursing, Universitas Indonesia, Depok, Indonesia 2 Pediatric Nursing Department, Faculty of Nursing, Universitas Hasanuddin, Makassar, Indonesia 3 Pediatric Nursing Department, Faculty of Nursing, Universitas Indonesia, Depok, Indonesia * Corresponding author: Tuti Seniwati, S.Kep.,Ns., M.Kes, Pediatric Nursing Department, Faculty of Nursing, Universitas Hasanuddin Jl. Perintis Kemerdekaan Kampus Tamalanrea KM.10 Makassar 90245, South Sulawesi, Indonesia. Email: tutiseniwati@unhas.ac.id Cite this article as: Seniwati, T., Rustina, Y., Nurhaeni, N., & Wanda, D. (2023). Patient and family-centered care for children: A concept analysis. Belitung Nursing Journal, 9(1), 17-24. https://doi.org/10.33546/bnj.2350 12 2 2023 2023 9 1 1724 05 10 2022 02 11 2022 08 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Family-centered care has evolved into patient and family-centered care. Although this is not a new concept; however, its application to nursing practice is very challenging among nurses due to its ambiguity. Objective This study aimed to clarify the concept of patient and family-centered care for children. Methods Walker and Avant’s concept analysis method was used. A literature search was also done using the following databases: Google Scholar, ProQuest, ScienceDirect, and Scopus, for articles published from 2011 to 2021. Results The defining attributes of patient and family-centered care are partnership, communication, respect, and compassion. Antecedents include patient and family involvement, readiness to collaborate and participate, competency and desire of the care professional team, supportive environment, and policies. Consequences of the patient and family-centered care include improved child outcomes and quality of life, promotion of patient safety, increased patient and family satisfaction, enhancement of humanistic values, reduction of hospitalization cost and length of stay, and decreased stress, anxiety, and depression in family members. Conclusion Four attributes of patient and family-centered care, its antecedents, and consequences may aid researchers in better understanding the concept and its application in nursing practice. This concept can also be used to establish quality care delivery strategies and promote professional relationships between nurses, patients, and families in clinical settings. children concept analysis family-centered care patient-centered care nurse ==== Body pmcBackground One crucial aspect of the development in children’s healthcare in recent years has been the realization of the importance of patient and family involvement (National Association of Pediatric Nurse Practitioners, 2013). Patient and family-centered care (PFCC) integrates patient-centered and family-centered care in the healthcare system primarily to improve health outcomes (Committee on Hospital Care and Institute for Patient-and Family-Centered Care, 2012). Historically, PFCC was established in 1992 as an evolution from family-centered care (Rawson & Moretz, 2016). The concept of patient and family-centeredness is used to indicate the focus of care. Patient-centered care (PCC) is focused on the patient as an individual, whereas family-centered care (FCC) prioritizes the family as the child’s primary social support system (Coyne et al., 2018). PFCC is defined as a way to design, implement, and assess health services based on commonly beneficial cooperation between patients, families, and healthcare professionals (Institute for Patient- and Family-Centered Care (IPFCC), 2017). PFCC practices encourage nurses to be active in involving children and their relatives in the care process, such as in terms of sharing information about parents’ experiences, participation in decision-making, and effective communication between them (Uhl et al., 2013). To effectively promote patient and family engagement in care, nurses can take the lead as one of the teams implementing patient and family-centered care (Grant & Johnson, 2019). Several studies have found that PFCC is considered to enhance the quality of service for children, such as increasing patient and family satisfaction, improving physical and mental health, decreasing the length of stay and medical error, and reducing treatment costs (Clay & Parsh, 2016; Everhart et al., 2019; Hassanian et al., 2018). However, some obstacles are reportedly encountered in its implementation arising from the nurse healthcare professional such as the desire of the nurse to implement PFCC, knowledge possessed, and emotional support of nurses (Abraham & Moretz, 2012; Mulyaningsih et al., 2021). In addition, nurses find it challenging to comprehend how to involve patients’ relatives in the treatment process, it primarily due to competing ideas about their job as a nurse, such as the notions that nurses are professionals, that nurses have legal accountability to care for the children, and that nurses must first determine the competence of parents before allowing them to participate (Harrison, 2010). Besides, the nurse assumes that the presence of the family 24 hours a day is considered annoying and tiring, especially when the family asks many questions when providing nursing care (Coats et al., 2018). One of the essential strategies for removing current obstacles is emphasizing leadership while developing a PFCC culture (Lloyd et al., 2018). Fostering knowledge of PFCC and its benefits is a crucial leadership role for facilitating nursing staff (Grant & Johnson, 2019). Understanding the PFCC framework in clinical nursing, including the basic concepts and its development, is necessary to provide for nurses through concept analysis. Previous studies have discussed the concept analysis of FCC and PCC in separate concepts. Most studies that identified the concept of FCC found that the family is the main focus of child care by advancing participation and collaboration with health professionals (Hutchfield, 1999; Mikkelsen & Frederiksen, 2011; Moradian, 2018; Smith, 2018). In contrast, PCC focus on the patient as the individual in care by encouraging caring, respect, and empowerment during the nursing process (Lusk & Fater, 2013; Morgan & Yoder, 2012). PFCC is not a new concept in nursing, considering that FCC and PCC have been widely discussed through concept analysis. However, there are differences in both concepts, which lie in their conceptual focus and central characteristics (Coyne et al., 2018). When the two concepts are combined and applied in nursing care, this difference becomes a barrier for nurses due to the ambiguity in its concept and implementation (Prior & Campbell, 2018). Therefore, reviewing the PFCC through concept analysis is essential to promote clarity while providing mutual understanding within nursing. Concept Analysis of PFCC A concept analysis approach was used for assessing the PFCC concept in nursing and the healthcare system. Concepts provide the ability to classify, formulate, label, discuss and effect a phenomenon of interest in a particular discipline. The analysis is the initial step or a heuristic in helping the authors to employ the studies’ findings in various ways to aid future scientific and research endeavors (Rodgers et al., 2018). The authors used Walker and Avant’s concept analysis method (Walker & Avant, 2014), described as follows. Selecting the Concept The concept was chosen based on interest in a topic related to the discipline (Walker & Avant, 2014). In this article, the authors intend to analyze the concept of PFCC, particularly for children, based on a literature review. Compared to patient-centered care, which focuses more on the individual patient, family-centered care is more concerned with the family as a whole (Coyne et al., 2018). The significance of fostering children’s physical and psychosocial development and families’ contribution to improving their children's health and well-being have benefited from PFCC approaches in recent years (Deepika & Rahman, 2020). Pediatric nurses are expected to provide PFCC in health services because the presence of the relative has been found to help in a child’s healing process, even during the COVID-19 pandemic (Goldschmidt & Mele, 2021). Determining All Uses of the Concept A literature review was used to determine how this concept was being used. The concept was identified by a literature search on the databases: Google Scholar, ProQuest, ScienceDirect, and Scopus, published from 2011 to 2021. The authors also used the dictionary as a source of literature on this concept. The authors consider not limiting all use of concepts from various disciplines such as nursing, medicine, psychology, and others (Walker & Avant, 2014). The keywords used during the literature search were: (patient and family-centered care) AND (children OR pediatric). Based on the literature search, the identified concepts can be seen through definitions from several existing sources (Table 1). Table 1 Patient and family-centered care concept definitions Authors (Year) Field Definition Institute for Patient- and Family-Centered Care (IPFCC) (2017) Medicine PFCC is defined as a way to design, implement and assess health services based on commonly useful cooperation between patient, family, and healthcare provider Fernandes et al. (2021) Nursing An important element in improving the quality of nursing care because it can raise humanistic values such as empathy, partnership, respect, service, and communication between patients, families, and nurses while in childcare Committee on Hospital Care and Institute for Patient-and Family-Centered Care (2012) Medicine A method for improving health outcomes by integrating patient-centered care and family-centered care throughout the health care system, whereby patients and families are partners in health care primarily in the provision of information for medical decision-making considerations Park et al. (2018) Nursing A critical approach that positively impacts patients (increases knowledge, self-care behavioral, satisfaction, and reduces the length of stay) and families (increases satisfaction, reduces anxiety) by involving them in the health care system DiGioia Iii and Greenhouse (2016) Medicine Treating patients and their families with care and respect, seeing them as partners and collaborators, and upholding their worth Brown et al. (2015) Medicine A collaborative effort to improve healthcare quality, safety, and delivery by health professionals, patients, and their relatives in every healthcare system. Involving the patient and families in the health care system by appreciating the value and treating them with great affection Grant and Johnson (2019) Nursing A useful approach for health workers, patients, and their families in planning, implementing and evaluating based on partnerships across all disciplines Rawson and Moretz (2016) Medicine A method of providing treatment in which the patient’s family and healthcare professional work together American College of Emergency Physicians (2019) Medicine A strategy used in the healthcare system that acknowledges the family’s crucial role and promotes collaboration between patients, families, and healthcare teams Mitchell et al. (2016) Medicine A strategy to deliver comprehensive care that recognizes the patient as a member of the family and they are jointly involved in the health care Abney-Roberts and Norman (2012) Nursing A concept that is familiar to most healthcare professionals and is essential in improving patient satisfaction, quality, and safety through the involvement of infants and their mothers during their inpatient stay Dudley et al. (2015) Medicine A strategy for enhancing the health and well-being of children and their families through associations, collaborations, and communications that are advantageous for patients, families, and medical providers Palokas et al. (2015) Nursing An approach that involves children and their families in the care process through a collaborative process, and effective communication among health workers, stakeholders, patients, and their families to promote service quality Deepika and Rahman (2020) Nursing An effective strategy for raising awareness among patients, families, and health workers of the significance of children’s physical and psychosocial development and the part that families play in fostering their health and happiness. Respect for every child and family is one of the principles of the PFCC Uhl et al. (2013) Nursing PFCC practices encourage nurses to play a proactive role in involving children and families in the care process, such as in terms of sharing information about parents’ experiences, participation in decision-making, and effective communication between parents and the team Determining the Defining Attributes Walker and Avant state that attributes are established by attempting to demonstrate the attribute clusters most frequently connected to the concept and that permit a study of broader insights into the concept (Walker & Avant, 2014). At this step, the authors try to find the word that appears the most frequently among all the existing definitions. Further, the authors grouped the possible words with similar meanings into keyword clusters. Finally, the authors determine the name or attribute of the concept that represents each of the existing keyword clusters (Walker & Avant, 2014). From 15 sources of articles that were relevant to the patient and family-centered care, the authors obtained four key attributes: partnership, communication, respect, and compassion (Table 2). Table 2 Attributes of patient-and family-centered care Keyword Clusters Sources Attributes Patient and family as a partner with the healthcare team Useful Cooperation Involving children and their relatives in the care process Patient and family participation Partnership across all disciplines Collaborative process Collaboration or Cooperation between patient, family, and health care provider Working together Participation in decision making (Abney-Roberts & Norman, 2012; American College of Emergency Physicians, 2019; Committee on Hospital Care and Institute for Patient-and Family-Centered Care, 2012; DiGioia Iii & Greenhouse, 2016; Dudley et al., 2015; Fernandes et al., 2021; Grant & Johnson, 2019; Institute for Patient- and Family-Centered Care (IPFCC), 2017; Mitchell et al., 2016; Palokas et al., 2015; Park et al., 2018; Rawson & Moretz, 2016; Uhl et al., 2013) Partnership Communication between patients, families, and nurses/health care provider Communications that are beneficial for the patient’s family and healthcare teams Effective communication Sharing information Provision of information Increases knowledge (Committee on Hospital Care and Institute for Patient-and Family-Centered Care, 2012; Dudley et al., 2015; Fernandes et al., 2021; Palokas et al., 2015; Park et al., 2018; Uhl et al., 2013) Communication Respect A respectful treatment Upholding patients and families worth Appreciating the value Respect for every child and family (Brown et al., 2015; Deepika & Rahman, 2020; DiGioia Iii & Greenhouse, 2016; Fernandes et al., 2021) Respect Empathy Treating patients and their families with caring Great affection Fostering happiness (Brown et al., 2015; Deepika & Rahman, 2020; DiGioia Iii & Greenhouse, 2016; Fernandes et al., 2021) Compassion Partnership In nursing, partnership means the ability to develop a relationship, coexist, and collaborate among patients, families, and nurses during healthcare delivery. The responsibility of nurses is to make sure that the child’s family can collaborate on a therapeutic plan (Kenyon & Barnett, 2001). Partnership in nursing refers to a relationship that consists of at least two people who work together to improve a patient’s health status, increase patient satisfaction, and a growing sense of well-being and sense of belonging by nurses (Jones et al., 2008). Communication Communication is exchanging knowledge, especially when doing so fosters understanding between individuals or organizations (Cambridge Dictionary, 2020a). Besides, the Merriam-Webster Dictionary (2022a) defines communication as transferring information between individuals using a shared set of gestures, symbols, or attitudes. In nursing practice, communication is a process that begins with establishing initial contact and lasts throughout the therapeutic relationship between nurses and patients (Kourkouta & Papathanasiou, 2014). During communication, nurses play a role in identifying patient needs, providing health information, providing comfort, and winning the patient’s trust (Fakhr-Movahedi et al., 2016). In hospitalized children, the family is an inseparable part of the child’s care, where the family is essential in providing support during the patient’s recovery and healing process. Communication establishes and maintains relationships between children and their families. Communication with children is conducted by listening, understanding, respecting, and offering them what they want and what their parents feel about them using appropriate vocabulary (Runcan et al., 2012). Respect Respect is paying close attention to anything or something in a situation. In addition, respect can also be interpreted as worthy of high regard (Merriam-Webster Dictionary, 2022b). In nursing, respect for people is characterized by attitudes, manners, and behaviors sensitive to each person’s dignity (Subramani & Biller-Andorno, 2022). Respect is a fundamental human right and morality based on human decency, worthiness, individuality, and self-determination. Respect is shown by unconditionally accepting, recognizing, and acknowledging the principles above in everyone as a guiding principle for behavior toward others (Browne, 1997). Compassion The definition of compassion is having empathy for the suffering or misfortune of others and a desire to assist them (Cambridge Dictionary, 2022b). Compassion refers to traits of warmth, goodness, and tenderness. Moreover, compassion is a trait that humans emerged for parenting and creating the ties of connection and cooperation necessary for group survival (Cole-King & Gilbert, 2011). Compassionate care is essential in providing nursing care that develops through experience and adaptation of existing nursing theories (Power, 2016). Compassionate care focuses on caring and providing care the way the person prefers. Nursing practice’s application of compassionate care entails negotiating the relationship between patients’ physical and emotional welfare to the nurses as the nursing care provider (Dewar et al., 2014). Model Case A girl, R, aged nine years, is a patient who confirmed positive for coronavirus and treated in the PICU room. Patient R underwent treatment due to respiratory distress. The nurse reported R’s progress on an ongoing basis to the physician and provided recommendations for what action could be taken next. As a result, physiotherapy and positioning intervention was implemented for R by involving family during practice by physiotherapist and nurse (partnership). Before the intervention, the nurse explained the aim of clinical procedures (communication) and allowed R’s parents to stay by her side during the process to reduce her fear (respect). Nurses interacted with children and their families during therapy with great warmth and promoted mutual caring (compassion). Borderline Case A boy, S, aged five years, was admitted to the pediatric ward with pneumonia. A nurse assessed S’s condition by touching him warmly and gently (compassion). S’s parents said their son had been coughing for three weeks and had started feeling short of breath one day ago (communication). The doctor examined S to confirm the assessment report obtained by the nurse. Next, the doctor and nurse provided joint planning for administering oxygen, nebulizer, and chest physiotherapy (partnership). Finally, the nurse explained the rationale behind the planned clinical procedure to R and his family. Contrary Case A 7-year-old boy, M, was being treated in the pediatric ward two days ago with a medical diagnosis of pneumonia. When the nurse conducted a respiratory check, the nurse asked M’s parents to stay away from the child to minimize distractions (no partnership). Next, the nurse gave oxygen insertion intervention to the patient, but suddenly the child looked scared and cried (no compassion). M’s mother asked the nurse what happened to her son and why no information was conveyed beforehand (no communication). However, the nurse did not respond to the parents’ questions and quickly left the room (no respect). Antecedents An antecedent is an event or set of related events that must occur or exist before an idea manifests (Walker & Avant, 2014). The antecedents of PFCC include patient and family involvement in the care process, patient and family readiness to collaborate and participate with caregivers, the competence of the care professional team and their desire to involve patients and their families in care, supportive environment, and hospital policies. Patient and family involvement includes aspects related to the presence, participation, needs, and advantages for the child and parents, their information needs, sense of responsibility and right to health, performance of care activities, and assistance given to health providers (Melo et al., 2014). A professional team’s goal to support parents in healthcare contexts is based on the family’s involvement in their child’s long-term condition (Smith et al., 2015). However, involving patients’ families in the healthcare system might be difficult. The attitudes and behaviors of healthcare workers hinder parents’ engagement in inpatient child care (Power & Franck, 2008). Pediatric nurses in Jordan were found to have considerably more positive opinions toward dealing with children than with their parents (Razeq et al., 2021). Moreover, parents assumed that their engagement in pediatric care was influenced by the physical and cultural environment of the room (Hill et al., 2019). Hospital policies are thought to have an impact on how PFCC is implemented (Baird et al., 2015). Consequences Consequences are events or happenings that take place as a result of the concept’s manifestation (Walker & Avant, 2014). Several studies report that PFCC positively impacts patients and their families. The consequences of PFCC significantly improve child outcomes, including quality of life in the physical and psychological domains (Minooei et al., 2016), promote patient safety (Khan et al., 2018), and reduce the length of stay and hospitalization costs (Nurhaeni et al., 2018; Turchi et al., 2014). In addition, the impact of PFCC significantly increases family satisfaction (Hassanian et al., 2018; Rostami et al., 2015), promotes humanistic values (Fernandes et al., 2021), and reduces stress, anxiety, and depression in family members (Park et al., 2018). The consequences of implementing PFCC are illustrated in Figure 1. Figure 1 Antecedents, attributes, and consequences of PFCC Empirical Referents The selection of empirical referents is the last step in concept analysis. Empirical referents are a class for actual events whose presence serves as an example of the context in which the idea is used. Empirical referents are intended to measure attributes and are not tools to measure concepts (Walker & Avant, 2014). The use of attributes for the partnership can be found in the instrument of the Pediatric Nurse Parent Partnership Scale (PNPPS) (Choi & Uhm, 2022; Choi & Bang, 2013), the Partnership Self-Assessment Tool (PSAT) (Center for the Advancement of Collaborative Strategies in Health, 2022; Weiss et al., 2002), and the Family – Professional Partnership Scale (FPPS) (Summers et al., 2005). The attribute of communication is found on the Health Professionals Communication Skills Scale (HP-CSS) (Juliá-Sanchis et al., 2020; Leal-Costa et al., 2016) and Communication Skill Attitude Scale (Panczyk et al., 2019; Rees et al., 2002). Meanwhile, attribute for respect and compassion are found on the Scale of Perception of Respect for and Maintenance of the Dignity of the Inpatient (CUPDPH) (Campillo et al., 2020) and the Compassion Competence Scale (Lee & Seomun, 2016). PNPPS is an instrument that mostly reflects the attributes of PFCC. However, the attributes of respect and compassion in PNPPS have yet to be fully explored. Therefore, modifying existing instruments or developing new tools that comprehensively represent all attributes is recommended. Implications to Nursing Knowledge and Practice The analysis concept of PFCC has implications for nursing knowledge and clinical nursing practice, especially for children during hospitalization. This review has four attributes: partnership, communication, respect, and compassion. The implications for nursing knowledge, this attribute can be an essential element for nurses in developing a care delivery model. The development of this care delivery model focuses on improving the relationship between the nurse, child, and caregiver. Meanwhile, in clinical nursing, nurses can provide care for the parents to assist children’s effective coping and address their comprehensive psychological requirements (Handayani & Daulima, 2020). In addition, this analysis can increase awareness among nurses to promote compassion and mutual respect between children and their families while providing nursing care. Conclusion Partnership, Communication, Respect, and Compassion were identified as the four attributes of PFCC for children. This review found that the implementation of PFCC had a positive impact on children and their families during hospitalization. However, an understanding of the factors influencing this implementation is an aspect that needs to be considered by healthcare providers. Therefore, nurses as a team in implementing PFCC can play a role in supporting the involvement of children and their families in the nursing care process. These findings recommend modifying existing instruments or creating new tools that comprehensively represent all attributes. Acknowledgment The authors acknowledge Universitas Indonesia and Universitas Hasanuddin for their tremendous support during the study. Declaration of Conflicting Interest The authors have no conflict of interest regarding this article. Funding Educational Fund Management Institution (LPDP Scholarship) - Ministry of Finance, Republic of Indonesia. Recipient: First author. Authors’ Contributions All authors contributed equally to this study, and they read and approved the final manuscript and were accountable and entirely responsible for its content. Authors’ Biographies Tuti Seniwati, S.Kep.,Ns., M.Kes is a Pediatric Nursing Lecturer at the Department of Pediatric Nursing, Faculty of Nursing, Universitas Hasanuddin, Makassar, Indonesia. Currently, she is studying in the Doctoral Nursing Program at the Faculty of Nursing, Universitas Indonesia. Her research interests focus on children with critical care, children with emergency care, child developmental care, and disaster areas. Prof. Yeni Rustina, S.Kp., M.App.Sc., Ph.D is a Professor at the Department of Pediatric Nursing, Faculty of Nursing, Universitas Indonesia. Her research interest focuses on the area of neonatology, particularly in the care of infants with low body weight. Dr. Nani Nurhaeni, S.Kp., MN is an Associate Professor at the Department of Pediatric Nursing, Faculty of Nursing, Universitas Indonesia. Her research area in pediatrics includes infectious diseases, especially pneumonia, growth and development, family empowerment, stunting, and health promotion. Dessie Wanda, S.Kp., M.N., Ph.D is an Associate Professor at the Department of Pediatric Nursing, Faculty of Nursing, Universitas Indonesia. Her research interests are in the area of pediatric nursing, clinical education, reflective practice, and qualitative research. Ethical Consideration Not applicable. Data Availability Not applicable. ==== Refs References Abney-Roberts, S. E., & Norman, C. (2012). Patient family centered care: It's more than open visitation. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-195 10.33546/bnj.1337 Original Research Symptom experience of adverse drug reaction among male and female patients with newly diagnosed pulmonary tuberculosis in Thailand Thontham Apichaya https://orcid.org/0000-0003-3076-9921 Polsook Rapin * Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand Corresponding author: Assistant Professor Police Captain Rapin Polsook, PhD, RN, Faculty of Nursing, Chulalongkorn University, Boromarajonani Srisatapat Building, Rama1 Rd, Floor 11 Patumwan, Bangkok 10330, Thailand. Telephone: 66-22181151, Cell phone: 66-8183-2109-5. Email: rapin.p@chula.ac.th; nitinggel@yahoo.com Cite this article as: Thontham, A., & Polsook, R. (2021). Symptom experience of adverse drug reaction among male and female patients with newly diagnosed pulmonary tuberculosis in Thailand. Belitung Nursing Journal, 7(3), 195-202. https://doi.org/10.33546/bnj.1337 28 6 2021 2021 7 3 195202 06 2 2021 07 3 2021 10 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Patients with newly diagnosed pulmonary tuberculosis often suffer from adverse drug reaction symptoms, which leads to the automatic discontinuation of anti-tuberculosis drugs. Thus, understanding symptom experience of adverse drug reactions is necessary. Objective This study aimed to examine differences in symptoms experienced in four dimensions: presence, frequency, severity, and distress of adverse drug reactions, between male and female patients. Methods This was a quantitative survey with a cross-sectional design, with data collected between January and April 2020. A total of 394 patients with newly diagnosed pulmonary tuberculosis was selected through a purposive sampling technique. The symptom experiences of adverse drug reactions were measured using a validated instrument. Data were analyzed using mean, standard deviation, and independent t-test. Results The most commonly reported symptom was itchiness (24.1% in males and 34.9% in females). Vomiting occurred as the most frequent symptom among males (x̄ ± SD = 2.73 ± .88), and fatigue was found to be the most severe and distressing symptom across male patients (x̄ ± SD = 2.50 ± 1.61 and 2.06 ± 1.30, respectively). In contrast, yellowing of the eyes and skin was most frequent and severe among females (x̄ ± SD = 3.17 ± .75 and 3.83 ± 1.47, respectively). In addition, flu-like symptoms were evaluated as the most distressing symptom for female patients (x̄ ± SD = 2.80 ± 1.09). The symptom burdens of the females ranged significantly and reached higher than those of the male patients at a p-value of .05 (t = 3.33). Conclusion Females taking anti-tuberculosis drugs should be carefully monitored to deal with adverse drug reaction symptoms. This finding would help to decrease the severity of disease and improve their quality of life. adverse drug reaction pulmonary tuberculosis symptom experiences quality of life drug-related side effects nursing Thailand ==== Body pmcTuberculosis (TB) is a transmissible disease and one of the ten leading causes of death worldwide (World Health Organization, 2020). TB is caused by bacillus Mycobacterium TB, which spreads through the air by, for example, coughing. In 2019, the World Health Organization (WHO) reported 87,789 new TB cases, and 85.0% of these relapses were pulmonary TB (WHO, 2019). In addition, the WHO indicated that Thailand is one of the top 20 countries affected by TB and that only 85.0% of new cases and relapses in 2019 had successful outcomes (WHO, 2019). Moreover, the Ministry of Public Health of Thailand reported that, among new TB cases, 68.9% were males over the age of 15, and 31.1% were female (Health Data Center, 2020). TB is treatable and preventable, and about 85.0% of people who develop TB can be successfully treated with regimental 6-month drugs, or first-line anti-TB drugs, which are Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), and Ethambutol (E) (WHO, 2019). Although most TB patients are under self-medication, a failure to take medication or premature discontinuation of medication caused by an adverse drug reaction (ADRs) from first-line anti-TB drugs occurs in approximately 60.0-83.5% of cases (Qureshi & Kausar, 2013; Abhijeet Singh, Prasad, Balasubramanian, Gupta, & Gupta, 2015). Previous studies have shown that the most common adverse symptoms of first-line anti-TB drugs are rashes, peripheral neuropathy, flu-like symptoms, arthralgia, hyperuricemia, nausea, vomiting, and optical neuritis (Mathew & Joseph, 2017; Naser et al., 2016; Saputra, Rakhmawati, Hendrawati, & Adistie, 2020; Anita Singh, Bhat, & Sharma, 2011). Moreover, drug interaction of first-line anti-TB drugs is the cause of drug-induced liver damage (Ramappa & Aithal, 2013). In addition, the literature shows that significant ADRs most commonly occur between one and five weeks after beginning the medication and that ADRs associated with anti-TB drugs persist, on average, for two months after patients start taking anti-TB drugs (Mathew & Joseph, 2017; Naser et al., 2016; Anita Singh et al., 2011). ADRs can also cause severe harm to patients, resulting in hospitalization. Many patients suffer from ADRs, leading to the automatic discontinuation of anti-TB drugs. However, patients who adhere to anti-TB drugs through the management or control of ADR symptoms increase their chance of recovery, reduce transmission, and improve their quality of life (QOL) (Pal, Duncombe, Falzon, & Olsson, 2013). Furthermore, the literature review found that gender differences are linked to ADRs in terms of physiological, hormonal, and genetic conditions, which has an impact on the pharmacokinetics and pharmacodynamics of a drug and may be the cause of the difference in ADRs between females and males. Some studies have focused on gender differences in the reporting of ADRs and found that females report ADRs more often than males. Several other studies have looked at a particular drug or class of drugs to look more closely at gender differences in the reporting of ADRs. They found that the reported prevalence was higher among females compared to males; however, differences in the rate of reporting by gender varied by category of event or sub-class of the drug (Rademaker, 2001; Watson, Caster, Rochon, & den Ruijter, 2019; Zucker & Prendergast, 2020). Nurses are caring for patients with newly diagnosed pulmonary TB and playing a role in assessing the ADRs between males and females in order to suggest appropriate strategies for the management of ADRs. Thus, a study of gender differences and symptom experience of ADRs among patients with newly diagnosed TB is needed. This study was undertaken to investigate related differences between genders in symptoms experienced in four dimensions: presence, frequency, severity, and distress of ADRs. Methods Study Design The study employed a cross-sectional survey designed to compare differences in ADRs according to gender. Sample and Setting Purposive sampling was used to approach participants from among Thai pulmonary TB patients. The study was undertaken in TB clinics, with permission from the institutional review board of seven hospitals in Bangkok, Thailand. The sample size was calculated by using Taro Yamane (Yamane, 1973); the level of statistics was set at a p-value of .05, and 10% was added to protect against a loss of data that could lower than the minimum simple size below the level that is acceptable to obtain the statistical power of analysis (Grove & Gray, 2018). Thus, a total of 394 newly diagnosed pulmonary TB patients were recruited into the study. The inclusion criteria for the participants were: (1) first-line anti-TB drugs received, (2) 25-59 years of age, (3) not receiving anti-HIV drugs, (4) being able to communicate in Thai, (5)having no cognitive impairment, nor complications from the disease; and (6) being willing to participate. However, participants with any physical disability (e.g., increased shortness of breath or increased cough) were excluded from this study. The purpose of this study, its potential benefits, risks, and the length of the interview were communicated to all patients. All participants signed a consent form, and the information on the topic was encoded for anonymity. Instruments In this study, symptom experiences have been defined as the perception of an individual symptom or a change in how a patient feels (Armstrong, 2003). The instrument to measure symptom experiences was developed based on symptom management by Dodd et al. (2001), along with a related literature review by the authors. The questionnaire is composed of two parts: a demographic questionnaire and a symptom experience questionnaire. The details of each questionnaire are as follows. 1) Demographic data questionnaire. The demographic data of participants, including age, gender, marital status, education, income, and type of health care coverage, were assessed. 2) Symptom experiences questionnaire. The question-naire consists of 35 items of symptoms in four dimensions: presence, frequency, severity, and distress. For presence dimension, participants were asked to rate as 0 = absent or 1 = present; frequency dimension was rated as 1 = rarely, 2 = sometimes, 3 = often, or 4 = always; severity, and distress dimensions were rated as 1= very low, 2 = low, 3 = moderate, 4 = high, or 5 = very high. A higher score indicates higher levels of symptom perception. The internal consistency reliability of the symptom experiences questionnaire was in four dimensions: presence, frequency, severity, and distress, with Cronbach’s alpha of .86, .81, .84, and .86, respectively. To calculate the score of symptom experience, we used a method for calculating symptom burden from the Chronic Kidney Disease Symptom Burden Index (CKD-SBI) questionnaire by Almutary, Bonner, and Douglas (2015). There was no difference between symptom experience and symptom burden in this study. The dimensions and scales are completely the same. The presence dimension ranges between 0 – 35, the frequency dimension ranges between 0 – 140, and severity and distress dimensions range between 0 - 175. Higher scores indicate greater symptom presence, frequency, severity, and distress. A total symptom burden score of the symptom experiences questionnaire is calculated by summing subscale score (presence, frequency, severity, and distress) then divided by 4 (a minimum score of four dimensions that could be achieved from only one symptom from a participant report), and then multiplied by a fixed number of .191 (a constant number - mathematical maneuver to convert the total of symptom experiences questionnaire to 100). The total score for the symptom experiences questionnaire ranged between 0 and 100 for each participant, which was calculated for all symptoms. In the interpretation of the symptom burden score, a score of 100 indicates that the participant had the highest symptom burden. Data Collection Simple random sampling was used to generate a probabilistic sample of newly diagnosed TB. Participants were selected from among the 50 districts in Bangkok, Thailand. The researcher divided the 50 districts into three areas by location in Bangkok: inner-city, urban fringe, or suburb. There were 23 hospitals in total: 16 inner-city hospitals, four urban fringe hospitals, and three suburban hospitals. The following numbers of the hospital in each zone were required for statistical analysis: inner-city = 3, urban fringe = 2, and suburb = 2. The number of hospitals needed in each zone is based on the proportion of affiliation with hospitals in Bangkok. Then, the proportion of patients available per hospital in each zone was calculated by quota sampling. Purposive sampling was used to select the study participants who met the inclusion criteria. The study was conducted at the TB clinics in seven hospitals in Bangkok, Thailand, after approval from each hospital’s Institutional Board (IRB). The researcher described the benefits and risks of protecting human rights in non-technical terms prior to obtaining patient approval to participate in the study. If patients met the inclusion criteria and accepted participation, they were asked to sign a consent form. Participants were then asked to complete the symptom experiences of the adverse drug reaction questionnaire. During the process of data collection, participants were able to decline or leave without consequence. It took approximately half an hour to complete each interview. The data were collected from January to April 2020. Data Analysis Statistical analysis was carried out with the software package SPSS Statistics version 22. The level of statistical significance was set at a p-value of .05. Normality testing used Q-Q Plots. As data were normally distributed, descriptive statistics and independent t-test were used for data analysis. Ethical Consideration The study was approved by: 1) Human Research Protection Unit, Faculty of Medicine Siriraj Hospital (REF: Si 864/2019), 2) The Research Ethics Review Committee for Research Involving Human Research Participants, Health Sciences Group, Chulalongkorn University (REF: 287/2562), 3) Nopparat Rajathanee Hospital Ethics Committee (REF: 4/2563), 4) Lerdsin Hospital Ethics Committee (REF: LH621088) and 5) Bangkok Metropolitan Administration Human Research Ethics Committee (REF: 24). Results Characteristics of Participants The baseline study consisted of 394 pulmonary TB patients, 62.2% of whom were males and 37.8% were females. Almost half of all males were between 30 and 49 years old. Over half of males were married (58.4%), and nearly half of males had completed primary education (40.4%). Almost half of the males had universal health care coverage (45.7%), and almost a third of males had a monthly income of between 1,001 and 15,000 Thai baht per month (28.6%), while more than half of females were aged 30 to 49 years and married (58.4%). Over a third of participants were attending secondary school (38.3%). Roughly half of the females were covered by universal health care coverage (49.7%) and just under one-third of females had no income (30.9%) (Table 1). Table 1 Demographic and clinical characteristics of the pulmonary tuberculosis patients (N = 394) Characteristics Male (N = 245) Female (N = 149) n (%) x̄ SD n (%) x̄ SD Age (Years) 42.7 11.4 41.8 11.0  25-29 49 20.0 25 16.8  30-49 105 42.9 74 49.7  50-59 91 37.1 50 33.6 Marital Status  Single 89 36.3 45 30.2  Widowed 5 2.0 6 4.0  Divorced 5 2.0 9 6.0  Separate 3 1.2 2 1.3  Married 143 58.4 87 58.4 Education  Uneducated 5 2.0 4 2.7  Primary School 99 40.4 53 35.6  Secondary School 85 34.7 57 38.3  Diploma 33 13.5 15 10.1  College or More 23 9.4 20 13.5 Occupation  Unemployed 60 24.5 46 30.9  Employee 111 45.3 54 36.2  Merchant 21 8.6 18 12.1  Company Employee 45 18.4 28 18.8  Government Service 8 3.3 3 2.0 Type of Healthcare Coverage  Universal Coverage 112 45.7 74 49.7  Civil Servant Medical Benefit Scheme 14 5.7 5 3.4  Social Security Scheme 110 44.9 62 41.6  Pay by Yourself 9 3.7 8 5.4 Monthly Income (Thai Bath) 11,791.4 9,747.7 9,776.5 8,757.4  No income 60 24.5 46 30.9  2,000 – 5,000 1 0.4 2 1.3  5,001 – 10,000 56 22.9 45 30.2  10,001 – 15,000 70 28.6 32 21.5  15,001 – 20,000 33 13.5 13 8.7  ≥ 20,000 25 10.2 11 7.4 Symptom Experiences in the Presence Dimension The three symptoms reported by the male patients that occurred most frequently in the presence dimension were itchiness (24.1%), decreased appetite (20.0,%) and numbness of the hands and feet (20.0%). In females, the three symptoms most frequently reported in the presence dimension were itchiness (34.9%), nausea (34.9%), and decreased appetite (24.2%) (see Table 2). Table 2 The top 20 highest symptom experiences that participants reported in present dimension (N = 394) Present Dimension Gender Symptom (N = 394) Male (N = 245) Female (N = 149) n % n % n % 1. Itchiness 111 28.2 59 24.1 52 34.9 2. Nausea 94 23.9 42 17.1 52 34.9 3. Decreased Appetite 85 21.6 49 20.0 36 24.2 4. Numbness of the Hands and Feet 79 20.1 49 20.0 30 20.1 5. Rash 70 17.8 39 15.9 31 20.8 6. Fatigue 57 14.5 34 13.8 23 15.4 7. Vomiting 53 13.5 22 9.0 31 20.8 8. Joint Pain 53 13.5 27 11.0 26 17.4 9. Insomnia 50 12.7 26 10.6 24 16.1 10. Muscle Pain 48 12.2 37 15.1 11 7.4 11. Dry Mouth 41 10.4 20 8.2 21 14.1 12. Blurred Vision 17 4.3 10 4.1 7 4.7 13. Headache 16 4.1 11 4.5 5 3.4 14. Abdominal Pain 15 3.8 9 3.6 6 4.0 15. Yellowing of Eyes and Skin 14 3.6 8 3.3 6 4.0 16. Dysuria 11 2.8 8 3.3 3 2.0 17. Mood Change 10 2.5 1 0.4 9 6.0 18. Flu-like Symptoms 8 2 3 1.2 5 3.4 19. Tinnitus 6 1.5 3 1.2 3 2.0 20. Swollen Face, Hands, and Feet 6 1.5 3 1.2 3 2.0 Symptom Experiences in the Frequency Dimension The three symptoms that occurred most frequently in males were vomiting (x̄ ± SD = 2.73 ± .88), fatigue (x̄ ± SD = 2.65 ± .95), and insomnia (x̄ ± SD = 2.62 ± .8. In comparison, the three most common symptoms among females were yellowing of the eyes and skin, insomnia, and fatigue (x̄ ± SD = 3.17 ± .75, 2.88 ± .85, and 2.78 ± .90, respectively) (see Table 3). Table 3 The top five highest symptom experiences that participants reported in frequency dimension (N = 394) Symptom Male Symptom Female Frequency Dimension Frequency Dimension 1 2 3 4 x̄ ±SD 1 2 3 4 x̄ ± SD 1) Vomiting 2 6 10 4 2.73±.88 1) Yellowing of eyes and skin 0 1 3 2 3.17±.75 2) Fatigue 4 11 12 7 2.65±.95 2) Insomnia 1 7 10 6 2.88±.85 3) Insomnia 2 10 10 4 2.62±.85 3) Fatigue 1 9 7 6 2.78±.90 4) Rash 6 12 16 5 2.51±.91 4) Rash 3 12 8 5 2.68±.98 5) Yellowing of eyes and skin 3 1 1 3 2.50±1.41 5) Vomiting 3 13 11 4 2.52±.85 Note: Possible range for symptom score was 1 to 4 (1 = rarely 2 = sometimes 3 = often 4 = always) Symptom Experiences in the Severity Dimension The three symptom experiences in the severity dimension that were found to be the most severe among males were fatigue, vomiting, and yellowing of eyes and skin (x̄ ± SD = 2.50 ± 1.61, 2.30±1.04, and 2.10 ± 1.55, respectively). Yellowing of eyes and skin, flu-like symptoms, and abdominal pain were the three symptom experiences found to be most severe in the symptom severity dimension among females (x̄ ± SD = 3.83 ± 1.47, 2.80±1.10, and 2.67 ± 1.21, respectively) (see Table 4). Table 4 The top five highest symptom experiences that participants reported in severity dimension (N = 394) Symptom Male Symptom Female Symptom Severity Dimension Symptom Severity Dimension 1 2 3 4 5 x̄ ± SD 1 2 3 4 5 x̄ ± SD 1) Fatigue 1 13 5 8 1 2.50 ± 1.61 1) Yellowing of Eyes and Skin 0 2 0 1 3 3.83 ± 1.47 2) Vomiting 5 9 4 4 0 2.30 ± 1.04 2) Flu-like Symptoms 1 0 3 1 0 2.80 ± 1.10 3) Yellowing of Eyes and Skin 5 0 0 3 0 2.10 ± 1.55 3) Abdominal Pain 1 2 1 2 0 2.67 ± 1.21 4) Flu-like Symptoms 1 1 1 0 0 2.00 ± 1.00 4) Vomiting 8 12 5 3 3 2.39 ± 1.26 5) Abdominal Pain 2 5 2 0 0 2.00 ± .71 5) Fatigue 6 8 4 4 1 2.39 ± 1.20 Note: Possible range for symptom score was 1 to 5 (1 = very low 2 = low 3 = moderate 4 = high 5 = very high) Symptom Experiences in the Distress Dimension The three symptoms that were found to be the most distressing among males were fatigue, flu-like symptoms, and muscle pain (x̄ ± SD = 2.06 ± 1.30, 2.00 ± 1.00, and 1.86 ± 1.13, respectively). The top three symptom experiences among females in the symptom distress dimension were flu-like symptoms, insomnia, and joint pain (x̄ ± SD = 2.80 ± 1.10, 1.96 ± 1.00, and 1.92 ± 1.38, respectively) (see Table 5). Table 5 The top five highest symptom experiences that participants reported in distress dimension (N = 394) Symptom Male Symptom Female Symptom Severity Dimension Symptom Severity Dimension 1 2 3 4 5 x̄ ± SD 1 2 3 4 5 x̄ ± SD 1) Fatigue 17 7 2 7 1 2.06 ± 1.30 1) Flu-like Symptoms 1 0 3 1 0 2.80 ± 1.10 2) Flu-like Symptoms 1 1 1 0 0 2.00 ± 1.00 2) Insomnia 10 7 5 2 0 1.96 ± 1.00 3) Muscle Pain 20 8 3 6 0 1.86 ± 1.13 3) Joint Pain 15 5 2 1 3 1.92 ± 1.38 4) Insomnia 13 7 3 3 0 1.85 ± 1.05 4) Fatigue 11 6 4 1 1 1.91 ± 1.13 5) Joint Pain 13 8 3 3 0 1.85 ± 1.03 5) Muscle Pain 4 3 3 1 0 0.91 ± 1.04 Note: Possible range for symptom score was 1 to 5 (1 = very low 2 = low 3 = moderate 4 = high 5 = very high) Symptom Burden Perceived Among the Participants The range of symptom burden reported by female patients (Mean= 2.97, SD= 3.48) reached significantly higher than that of the males (Mean = 1.88, SD = 2.46; t = 3.33; p = .05) (see Table 6). Table 6 The burden of symptoms in 4 dimensions (N = 394) Gender The Symptom Burden in Four Dimensions Mean SD t p-value Male (n = 245) 1.88 2.46 3.33 .001 Female (n = 149) 2.97 3.48 Discussion This study was undertaken to investigate related differences between genders in symptom experiences of ADRs among newly diagnosed pulmonary TB patients. In this study, it was found that more male patients experienced ADRs than did female patients. A possible explanation for this is that males usually participate in more social and work activities than do females, which promotes the transmission of the disease. Males are more likely to smoke and also have addictions to alcohol or drugs in comparison to females. This increases their risk for TB (Imam et al., 2020). Additionally, itching was the most common symptom among males (24.1%) and females (34.9%). This may be caused by Rifampicin as all study participants receive the same anti-TB drug regimen, which is widely used for intrahepatic cholestasis-related itching. Rifampicin is not only found in medications that cause liver damage, but it also inhibits the absorption of biliary acid by hepatocytes, increasing the concentration of biliary acid in plasma. However, it breaks down the entero-hepatic circulation of biliary acids on liver metabolic processes (Pongcharoen & Fleischer Jr, 2016). Previous studies have also commonly reported this side effect (Fei, Zainal, & Ali, 2018; Nazir, Farhat, Adil, & Asrafv, 2019; Sinha, Marak, & Singh, 2013). Vomiting was found to be more severe in males x̄ ± SD = 2.73 ± .88). Vomiting may be caused by anti-TB drugs such as Isoniazid, Ethambutol, and Pyrazinamide and is common in the early weeks of treatment (Raftery, Tudor, True, & Navarro, 2018). A possible explanation for this is that males may be more likely to consume alcohol, which can induce liver injury, and which also inhibits absorption irritation that can cause vomiting. So males are more likely to experience greater severity of vomiting than females (Iranpour & Nakhaee, 2019; Marçôa, Ribeiro, Zão, & Duarte, 2018). Yellowing of the eyes and skin was the most frequent and severe symptom among females (x̄ ± SD = 3.17 ± .75, and 3.83 ± 1.47, respectively). These symptoms can be caused by anti-TB drugs like Isoniazid and Rifampicin, which induce liver injury. Thus, if the liver is damaged, it may cause leakage of bilirubin from the liver into the bloodstream, and it may also leak into the surrounding tissues. This is known as hyperbilirubinemia and causes a yellow color in the skin and eyes (Anita Singh et al., 2011). One possible explanation for this difference between genders is that females usually have lower lean mass, reduced liver clearance, and differences in cytochrome P450 (CYP) enzyme activity than males. Additionally, the females may be reporting yellowing of eyes and skin as the most severe symptom due to the sclera changing from white to yellow and skin changing from their own skin color to yellow, which is a clinical symptom of hepatitis. In this case, these females need to stop anti-TB drugs, change regimens, or begin a new treatment regimen (Raftery et al., 2018). In our study, fatigue was found to be the most severe and distressing symptom reported by males (x̄ ± SD = 2.50 ± 1.61, and 2.06 ± 1.30, respectively). Fatigue can be caused by any anti-TB drugs (Raftery et al., 2018). This difference between genders could be explained by the fact that males usually have more social and labor-based activities than females and that associated issues like unhealthy diets, work duration, and sleep problems with fatigue are often linked to long-term health problems (Lin et al., 2015). Flu-like symptoms were the most distressing symptoms among female patients (x̄ ± SD = 2.80 ± 1.10). These symptoms can be caused by anti-TB drugs, which induce hypersensitivity, modified thermoregulation, the pharmacological action of the drug, idiosyncratic sensitivity of inherited biochemistry defects, and related administration. In the narrowest sense, as a sort of hypersensitivity, drug fever is a febrile reaction specific to the individual in the treatment process depending on the drug and the idiosyncrasy of the patient. Clinically, it occurs when anti-TB drugs become antigens after the formation of the complex. Therefore, most of the females suffered from a high fever. In most cases, the temperature reached a peak on the initial day, whereas body temperature increases caused by Rifampicin increase day by day and reach a peak of above 40 degree Celsius within 3 – 6 days (Fang et al., 2016; Yee et al., 2003). Based on the symptom burden data, gender was a significant variable in symptom burden at the p-value of .05 (t = 3.33) because of identifiable differences between females and males in terms of pharmacokinetic and hormonal factors when taking anti-TB drugs. Females have a slower gastric emptying time, leaner body mass indices, and differences in total body water compared to males, resulting in females absorbing more anti-TB drugs. As a result, females experienced a higher symptom burden level than males (Zucker & Prendergast, 2020). This study has several limitations. The results may lack international generalization due to the setting and cultural influences in Bangkok, Thailand. Other limitations were data-based and related to self-reported data, which could have caused an overestimated or underestimation of values. The instrument for measuring these variables has been used only once in a Thai context. Testing of validity and reliability within a Thai context is needed. Future studies should be conducted across an entire country's population to assess the change of symptom experience for ADRs among newly diagnosed pulmonary TB patients. Developing intervention programs for females to decrease ADR symptoms such as itchiness and nausea is needed to encourage the continuous taking of anti-TB drugs. This study can contribute to knowledge development and strengthen nursing science to care for patients with newly diagnosed pulmonary TB. The findings provide knowledge that offers direction for the development of interventions to decrease ADR symptoms regarding the differences between male and female patients. Such intervention should incorporate the promotion of strategies to manage ADR symptoms to enhance adherence to anti-TB drug regimens in order to reduce transmission and improve quality of life. Conclusion This study found that ADRs were more reported among male patients, but female patients reported a significantly higher symptom burden than males. The results of this study suggest that females receiving anti-TB drugs should be carefully appropriately monitored for symptoms of ADRs to deal with ADR symptoms. This would help patients continue taking anti-TB drugs, which should decrease the severity of the disease and improve their quality of life. Acknowledgment The authors thanked all participants for the time and effort devoted to this study and the staff of seven hospitals in Bangkok for their help during the data collection process. Declaration of Conflicting Interest There are no potential conflicts of interest to declare. Funding This study received funding from the Ratchadaphiseksomphot Endowment Fund, Chulalongkorn University, Bangkok, Thailand (GCUGR1125633058M). Authors’ Contribution All the authors participated in the final manuscript. A.T. and R.P. designed the study, collected data, analyzed the data, wrote, and revised the manuscript. Authors’ Biographies Apichaya Thontham is a Registered Nurse at the Siriraj Hospital, Bangkok, Thailand. She is also a master's student in the Nursing Science program at the Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand. Rapin Polsook, PhD, RN is an Assistant Professor at the Faculty of Nursing, Chulalongkorn University. She has published articles related to cardiovascular disease. She is a reviewer and a member of the editorial teams of the nursing journals. 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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-86 10.4103/jgid.jgid_229_22 Letters to Editor Pancolitis in Enteric Fever: A Rare Occurrence Kumar Prabhat Kumar Manish 1 Department of Internal Medicine, Kailash Hospital and Neuro Institute, Noida, Uttar Pradesh, India 1 Department of Gastroenterology, Kailash Hospital and Neuro Institute, Noida, Uttar Pradesh, India Address for correspondence: Dr. Prabhat Kumar, Department of Internal Medicine, Kailash Hospital and Neuro Institute, Sector-71, Noida, Uttar Pradesh, India. E-mail: drkumar.prabhat@gmail.com Apr-Jun 2023 31 3 2023 15 2 8687 07 12 2022 12 12 2022 13 12 2022 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body pmcDear Sir, Enteric fever is a common bacterial illness caused by ingesting contaminated food and water in developing countries. It includes typhoid fever, caused by Salmonella typhi and parathyroid fever, caused by Salmonella Paratyphi A and B. Paratyphoid fever is uncommon and relatively milder compared to typhoid fever. Gastrointestinal involvement is frequent in enteric fever; commonly involved sites are the terminal ileum, ileocecal valves, and ascending and transverse colon, respectively. Involvement of descending colon is rare. Herein, we present a rare case of pancolitis in paratyphoid fever. A 25-year-old male student presented with intermittent fever and loose stools for 1 week. On physical examination, he had a temperature of 39.4°C, a pulse rate was 110/min, and blood pressure was 120/70 mm Hg. No organs were palpable on per abdomen examination, and the rest of the systemic examination was essentially normal. Blood investigations showed a high erythrocyte sedimentation rate (60 mm/h) and C-reactive protein levels (182 mg/L) with normal total leukocyte count. Liver function tests showed transaminitis with raised aspartate transaminase-165 U/L and alanine transaminase-114 U/L levels. Urine and stool routine examination was normal. Ultrasound whole abdomen showed multiple mesenteric lymph nodes with inflammatory changes in the terminal ileum, cecum, and ascending colon. Contrast-enhanced computed tomography abdomen showed thickened terminal ileum and ileocecal region with multiple nonnecrotic mesenteric lymph nodes. Colonoscopy was done, which revealed multiple erosions and ulcerations starting from the rectum to the ileocecal region [Figure 1]. Biopsy samples from the colon and ileal region showed inflammatory changes with dense infiltration of neutrophils and lymphocytes. Blood culture done on the day of admission grew Salmonella Paratyphi A. He was treated with an injection of ceftriaxone 2 gm twice daily for 10 days, and his fever subsided on the 6th day of the antibiotic, along with improvement in abdominal symptoms. Figure 1 Colonoscopy showing (a) Ileal ulcer, (b) Erosions in ascending colon, (c and d) Erosions in the transverse colon, (e) Erosions in descending colon, (f) Erosions in the sigmoid colon The pathogenesis of enteric fever begins with the ingestion of bacilli in contaminated food items. This is followed by penetration through the intestinal mucosa and subsequent bacteremia to various organs, including Peyer’s patches in the terminal ileum.[1] Peyer’ patches become hyperaemic due to the presence of inflammatory cells and mucosal necrosis occurs, resulting in ulcer formation. The typical ulcer has a punched-out appearance and is oriented along the long axis of the bowel. Ulcer formation commonly occurs in the ileocecal region and ascending colon, although rarely on the left side of colon.[2] The terminal ileum has plenty of lymphoid aggregates, which explains the reason for most perforation occurring in its vicinity.[3] Further, the bacilli spread along the marginal arteries and affect other colon segments. However, left-side colonic involvement is rare, and we could not find any case of pancolitis in paratyphoid fever. A case series of seven patients with typhoid fever with lower gastrointestinal bleeding showed intact left colon in all patients.[4] This case emphasizes the need to have enteric fever also as a possibility in left-sided colonic lesions. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Raffatellu M Wilson RP Winter SE Bäumler AJ Clinical pathogenesis of typhoid fever J Infect Dev Ctries 2008 2 260 6 19741286 2 Hepps K Sutton FM Goodgame RW Multiple left-sided colon ulcers due to typhoid fever Gastrointest Endosc 1991 37 479 80 1916174 3 Lee JH Kim JJ Jung JH Lee SY Bae MH Kim YH Colonoscopic manifestations of typhoid fever with lower gastrointestinal bleeding Dig Liver Dis 2004 36 141 6 15002823 4 Mogasale V Ramani E Mogasale VV Park J What proportion of Salmonella Typhi cases are detected by blood culture?A systematic literature review Ann Clin Microbiol Antimicrob 2016 15 32 27188991

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-84 10.4103/jgid.jgid_144_22 Case Report Purple Urine Bag Syndrome in Urinary Tract Infection Jappi Yoseph Hadi Usman Department of Internal Medicine, Faculty of Medicine, Dr. Soetomo General Hospital, Airlangga University, Surabaya, Indonesia Address for correspondence: Dr. Usman Hadi, Department of Internal Medicine, Faculty of Medicine, Dr. Soetomo General Hospital, Airlangga University, 6–8 Mayjend Prof. Dr. Moestopo Street, Airlangga, Gubeng, East Java 60286, Surabaya, Indonesia. E-mail: usman.hadi2@fk.unair.ac.id Apr-Jun 2023 31 3 2023 15 2 8485 20 7 2022 06 10 2022 18 10 2022 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Purple urine bag syndrome (PUBS) is an unusual manifestation of urinary tract infection, characterized by purple discoloration of urine. Due to its rarity, it can be challenging for some physicians to manage it properly. In addition, its striking appearance can cause concern to some patients. This condition usually occurs in the debilitated geriatric population with prolonged use of an indwelling urinary catheter. However, our case highlights the development of PUBS in a young adult with a relatively short period of urinary catheterization. Purple urine bag syndrome urinary catheterization urinary tract infection ==== Body pmcINTRODUCTION Purple urine bag syndrome (PUBS) is a rare condition that occurs secondary to bacterial urinary tract infection (UTI).[1] The unique purple urine color is thought to be derived from the metabolism of tryptophan metabolite by certain bacteria in the urinary tract.[2,3] It is often associated with advanced age, prolonged use of indwelling urinary catheters, immobility, and constipation.[2] Despite being considered a relatively benign process, some cases of PUBS have been reported to cause sepsis, with an overall mortality rate of about 6.8% if not treated promptly.[1] Here, we report a case of a 23-year-old man who presented with purple-colored urine during the course of hospitalization for lupus nephritis, which was evaluated and managed for PUBS successfully. CASE REPORT A 23-year-old man, who was on his 7th day of hospitalization due to overload syndrome and lupus nephritis, had purple discoloration of urine [Figure 1]. He denied any fever, painful urination, or suprapubic pain. There was no history of drug or herbs consumption that potentially could produce purple urine. He had an indwelling Foley’s catheter for urine output monitoring since admission and received intravenous methylprednisolone and mycophenolic acid for lupus nephritis. His activity was largely restricted at bed during the last 10 days due to dyspnea and significant lower extremity edema. He also complained of constipation for the last 7 days. Figure 1 Characteristic purple discoloration of the urinary catheter His physical examination was unremarkable. The leukocyte count was 9.880/mm3 with neutrophil 81% and urinalysis revealed alkaline urine (pH 8,0), leukocyte + 3, erythrocyte + 1, protein + 3, and negative dipstick nitrite. Urinary sediment showed 15–20 white blood cells/high-power field and bacteria. Urine culture yielded Enterococcus faecalis with more than 105 CFU/mL, which is sensitive to ampicillin, nitrofurantoin, and teicoplanin. We gave intravenous ampicillin 1 g every 6 h, laxative (lactulose syrup), and changed the patient’s Foley’s catheter. On day 2 of ampicillin administration, the urine rapidly turned into yellow color. We switched intravenous to oral ampicillin by day 3, and ampicillin was continued for a total duration of 5 days. The patient had an uneventful recovery and was discharged with no symptoms on the 12th day of hospitalization. DISCUSSION PUBS is a rare condition first described in 1978 and characterized by an abnormal purple discoloration of urine.[1,3] The pathogenesis of PUBS involves a series of biochemical transformations of tryptophan metabolite, named indole, by bacteria in the urinary tract.[2-4] Indole is produced by the colonic bacterial metabolism of tryptophan. It enters portal circulation and is rapidly conjugated in the liver into indoxyl sulfate.[3] Indoxyl sulfate is a colorless compound and is normally excreted in the urine.[4] In people with UTIs due to certain bacteria containing phosphatase and sulfatase enzymes, indoxyl sulfate is further metabolized into indoxyl. Indoxyl will be oxidized into indigo (blue pigment) and indirubin (red pigment) within an alkaline urine situation, which mix together and react with the plastic of the urine tube into purple color.[5] Other rarer causes of purple urine in the absence of UTI include blue diaper syndrome (a hereditary disorder of tryptophan metabolism) and consumption of certain drugs or chemicals.[6] PUBS is most often reported in the geriatric population. Our patient is a young adult but had multiple risk factors of PUBS which may explain its occurrence at a young age. First, he had been used an indwelling Foley’s catheter for 7 days, was relatively immobile, and was being treated with immunosuppressants, all of which put him at risk of developing UTI. Second, urine culture yielded a significant amount of Enterococcus sp., one of the bacteria known to have phosphatase and sulfatase enzymes.[5,7] Third, he had constipation, which increased the transit time of dietary tryptophan and consequently the production of indole by bacteria in the colon.[4] Fourth, this patient’s underlying disease of lupus nephritis reduced renal excretion of indole and thereby increased indole concentration. Finally, the alkaline urine condition in this patient facilitated the oxidation of indole into purple pigment. The most common clinical presentation of PUBS is urine discoloration without symptoms of UTI, as in our patient.[6] Lack of UTI symptoms, in this case, could also be caused by the use of anti-inflammatory drugs. Treatment of PUBS is usually straightforward with the change or removal of Foley’s catheter, administration of appropriate antibiotics, and laxative if constipation is present.[8] The causative organism of UTI in our patient was E. faecalis, which is intrinsically resistant to most cephalosporins and increasingly resistant to quinolones, both of which are among the most commonly used antibiotics for UTI.[9-13] Therefore, it is recommended to follow a local antimicrobial susceptibility pattern in treating PUBS due to E. faecalis infection. With prompt management of UTI as its underlying cause, the prognosis of PUBS is generally favorable as in our case. Our case highlights the importance to consider UTI as the cause of PUBS and perform relevant laboratory investigations, even when signs and symptoms of UTI are lacking. This case also showed the possibility of PUBS to occur in a young adult when multiple risk factors of PUBS exist. Proper management of UTI leads to rapid resolution of PUBS. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Research quality and ethics statement The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, notably the CARE guideline, during the conduct of this report. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Yang HW Su YJ Trends in the epidemiology of purple urine bag syndrome: A systematic review Biomed Rep 2018 8 249 56 29564123 2 Kalsi DS Ward J Lee R Handa A Purple urine bag syndrome: A rare spot diagnosis Dis Markers 2017 2017 1 6 3 Khan F Chaudhry MA Qureshi N Cowley B Purple urine bag syndrome: An alarming hue?A brief review of the literature Int J Nephrol 2011 2011 419213 21977321 4 Sabanis N Paschou E Papanikolaou P Zagkotsis G Purple urine bag syndrome: More than eyes can see Curr Urol 2019 13 125 32 31933590 5 Vallejo-Manzur F Mireles-Cabodevila E Varon J Purple urine bag syndrome Am J Emerg Med 2005 23 521 4 16032624 6 Worku DA Purple urine bag syndrome: An unusual but important manifestation of urinary tract infection. Case report and literature review SAGE Open Med Case Rep 2019 7 1 4 7 Hadano Y Shimizu T Takada S Inoue T Sorano S An update on purple urine bag syndrome Int J Gen Med 2012 5 707 10 22969302 8 de Menezes Neves PD Coelho Ferreira BM Mohrbacher S Renato Chocair P Cuvello-Neto AL Purple urine bag syndrome: A colourful complication of urinary tract infection Lancet Infect Dis 2020 20 1215 32979332 9 Kristich CJ Rice LB Arias CA Enterococcal infection –Treatment and antibiotic resistance Gilmore MS Clewell DB Ike Y Shankar N Enterococci: From Commensals to Leading Causes of Drug Resistant Infection Boston Massachusetts Eye and Ear Infirmary 2014 10 Kitagawa K Shigemura K Yamamichi F Alimsardjono L Rahardjo D Kuntaman K International comparison of causative bacteria and antimicrobial susceptibilities of urinary tract infections between Kobe, Japan, and Surabaya, Indonesia Jpn J Infect Dis 2018 71 8 13 29093320 11 Utami MD Wahyunitisari MR Mardiana N Setiabudi RJ Bacterial and antibiogram profile of urinary tract infection patients in a tertiary hospital, Surabaya, Indonesia Folia Medica Indonesiana 2022 58 195 202 12 Parathon H Kuntaman K Widiastoety TH Muliawan BT Karuniawati A Qibtiyah M Progress towards antimicrobial resistance containment and control in Indonesia BMJ 2017 358 j3808 28874346 13 Hadi U Kuntaman Qiptiyah M Paraton H Problem of antibiotic use and antimicrobial resistance in Indonesia: Are we really making progress? Indones J Trop Infect Dis 2013 4 5 8

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-59 10.4103/jgid.jgid_213_22 Original Article Central Line-Associated Bloodstream Infections: Effect of Patient and Pathogen Factors on Outcome Arunan Bharathi Ahmed Nishat H. 1 Kapil Arti 1 Vikram Naval K. 2 Sinha Sanjeev 2 Biswas Ashutosh 2 Satpathy Gita 1 Wig Naveet 2 Department of Medicine and Microbiology, All India Institute of Medical Sciences, New Delhi, India 1 Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India 2 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India Address for correspondence: Dr. Nishat H. Ahmed, Ocular Microbiology Section, Dr. R.P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. E-mail: drnishathussain@gmail.com Apr-Jun 2023 31 5 2023 15 2 5965 09 11 2022 03 1 2023 02 2 2023 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Introduction: Patients on central lines are often having multiple morbidities, and invasive devices provide a niche for biofilm formation, which makes central line-associated bloodstream infections (CLABSIs), a serious concern in health-care settings, as the infections difficult to treat. In this study, we evaluated the common bacteria causing CLABSI, and various patient and pathogen factors affecting the clinical outcome. Methods: In the prospective observational study, patients diagnosed with CLABSI were recruited. Extensive clinical, microbiological, and other laboratory workup was done, and observations were recorded. Congo red agar method, tube test, and microtiter plate assay were used for eliciting the biofilm-forming attributes of the bacterial pathogens. Results: Klebsiella pneumoniae was responsible for 48% of CLABSI, followed by Coagulase-negative Staphylococci (16%) and Staphylococcus aureus and Acinetobacter baumannii (12% each). Fifty-six percent of the isolates produced biofilms. The median (interquartile range) duration of hospital stay till death or discharge was 30 (20, 43) days. The all-cause mortality was 44%. Patients having a deranged liver function on the day of diagnosis (P value for total bilirubin 0.001 and for aspartate transaminase 0.02), and those infected with multidrug-resistant organisms (P value = 0.04) had significantly poor prognosis. The difference in the demographic, clinical, laboratory profile, and outcome of patients infected with biofilm producers and nonproducers was not found to be statistically significant. Conclusion: The study throws light on various host and pathogen factors determining the cause and outcome of CLABSI patients. To the best of our knowledge, this is the first study trying to decipher the role of biofilm formation in the virulence of pathogens and the prognosis of CLABSI. Antimicrobial resistance biofilm formation central line-associated bloodstream infections central line ==== Body pmcINTRODUCTION Bloodstream infections are a serious concern in health-care settings, especially with the increase in the use of invasive devices in critically ill patients. The current incidence in India, according to the International Nosocomial Infection Control Consortium, has been reported to be around 4.11 per 1000 central line days, while regional studies report an incidence ranging from 2.3 to 13.8 per 1000 central line days.[1,2] Due to the morbidity, these infections pose. The Center for Disease Control (CDC) has introduced a surveillance definition, aiding in their early diagnosis and management.[3] Biofilms are colonies of microorganisms surrounded by an exopolysaccharide matrix. Almost 80% of infections caused in humans such as dental caries, otitis media, chronic sinusitis, endocarditis, and urinary tract infections are associated with biofilm formation.[4,5] Invasive devices form a niche for biofilm production. The device-related infections can range from prosthetic joint infections to the central line-associated bloodstream infections (CLABSI).[6] A multitude of factors such as delayed penetration of antimicrobials into the biofilm, altered growth rate of bacteria, and immune evasion by the microorganisms make them difficult to treat.[7] The link between biofilms and infections has been established, but their implication on the clinical course of the infection has not been well defined. In posttraumatic infected wounds, biofilm production has been shown to be an important virulence factor, leading to delayed healing.[8,9] Strains of Escherichia coli causing chronic urinary tract infections usually have potent biofilm-forming capability.[10] Such studies for other device-related infections, such as CLABSI are lacking. The use of central lines for indications such as hemodialysis, ionotropic support, administering chemotherapeutic drugs, or total parenteral nutrition is common practice in our tertiary care center, making CLABSI a common occurrence. Factors which influence the outcome of CLABSI include comorbidities such as diabetes mellitus, chronic kidney disease, immunosuppressed states, and infection by virulent multidrug-resistant (MDR) organisms.[11] We aimed to study the common bacteria causing CLABSI, their antimicrobial profile, the biofilm-forming ability, and the patient factors affecting the clinical outcome of these infections. We also compared three tests for studying the biofilm-forming attributes of the bacterial isolates. METHODS Study design and setting This was a prospective observational study conducted in a tertiary healthcare institute in New Delhi, India, between July 2019 and May 2021. This study was approved by the Institutional Ethics Committee (IECPG-498/July 17, 2019). The authors followed applicable EQUATOR Network guidelines, i.e. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines during the conduct of this research project. Participants The patients were admitted to wards and intensive care unit (ICU) under the department of medicine. Considering the prevalence of laboratory-confirmed CLABSI ranging from 22 to 43 over the past years, a sample size of 25 was arrived at for the study. Written informed consent was obtained from all patients or caregivers. The criteria for the inclusion in this study were patients aged more than 18 years and diagnosed with CLABSI according to the CDC surveillance definition.[3] The patients who had other identifiable sources of infection, like respiratory tract infections, urinary tract infections, infective endocarditis, meningitis, etc., and those <18 years of age were excluded from the study. Detailed history and thorough physical examination were done by infectious disease experts. Relevant laboratory parameters were monitored, and follow-up was done until death or discharge. Clinical and laboratory data were collected, both by direct observation and through electronic health records. The data were entered into a pro forma approved by the IEC. Microbiological processing Ten milliliters of blood, each from the central line and peripheral vein were drawn under sterile precautions and inoculated into adult BD BACTEC™ Plus Aerobic culture bottles. Samples from the flagged bottles were subcultured onto MacConkey agar and blood agar for colony growth and identification. Further bacterial speciation was done using matrix-associated laser desorption ionization-time of flight, and antibiotic susceptibility testing (AST) was done by the Kirby–Bauer disk diffusion method. Tests for biofilm production All bacterial isolates were stored in a nutrient butt at −20°C and revived for tests of biofilm production. A positive control (Staphylococcus epidermidis ATCC 35984), a negative control (S. epidermidis ATCC 12228), and a sterile control were used with each of the tests. Biofilm formation attributes of the bacterial isolates were tested using the three following methods: (a) The Congo red agar (CGA) method was done by plating a loopful of bacteria, in log phase, on CGA. The plates were read after incubation at 37°C for 24 h. A biofilm producer was identified by black crystalline colonies, whereas nonproducers grew as translucent colonies [Figure 1a and b].[12] (b) The tube test was carried out in test tubes containing the bacterial isolate inoculated in trypticase soy broth with 1% glucose. The test tubes were incubated at 37°C for 24 h. Then, they were decanted and washed with phosphate buffer saline (PBS). The biofilms formed at the bottom of the tube were identified by staining with 0.1% crystal violet. Depending on the intensity of the stain, the isolates were classified as nonbiofilm producers (0), weak (1+), moderate (2+), and strong (3 + and 4+) biofilm producers [Figure 1c].[12] (c) The third test was the quantitative microtiter plate assay, the gold standard in our study. The bacterial isolate was inoculated on a presterilized polystyrene 96-well microtiter plate with the culture media (trypticase soy broth with 1% glucose). After incubation, washing with PBS and staining with 1% crystal violet was done, and the plates were read using an ELISA reader at 570 nm. The optical density (OD) readings were used to classify bacteria as non, weak, moderate, and strong biofilm producers [Figure 1d].[12] The following calculations were used to calculate the OD cutoffs.[13] Figure 1 Methods of testing biofilm formation attributes of the pathogens: (a) Congo red agar showing black colonies with dry crystalline consistency indicating a biofilm-producing bacteria; (b) Congo red agar showing colonies of non-biofilm producing bacteria; (c) Test tube method for biofilm formation showing the range from nonbiofilm producer (0) to strong biofilm producer (4+); (d) microtiter plate assay OD (control) = average OD of negative control + (3 × standard deviation (SD) of negative control) Nonproducer = OD ≤ ODc Weak producer = > ODc ≤2 × ODc Moderate producer = >2 × ODc ≤4 × ODc Strong producer = >4 × ODc Statistical analysis The data were entered and maintained in a Microsoft Excel (2019) Sheet, and GraphPad Prism Version 8.4.2 was used for the statistical analysis. Continuous variables were represented using median and interquartile range (IQR) or mean and SD. Categorical variables were represented as number (percentages). MannWhitney U and unpaired t-test were used to compare continuous variables and Chi-square test for categorical variables. A P = < 0.05 was considered statistically significant. RESULTS Demographic profile and clinical profile of the participants A total of 25 patients were included in the study. The mean (SD) age of the population was 40.5 (16.8) years and 56% were males. Forty-four percent of the patients suffered from chronic kidney disease and 40% from diabetes mellitus [Table 1]. The triple lumen central venous catheter was the most common type of central line used (68%), with the right internal jugular vein being the most common site of insertion (48%). Table 1 Demographic profile of the study participants Parameter CLABSI patients (n=25), n (%) Age (years), mean (SD) 40.5 (16.8) Sex  Male 14 (56)  Female 11 (44) Comorbidities  Diabetes mellitus 10 (40)  Hypertension 8 (32)  Chronic kidney disease 11 (44)  Chronic liver disease 3 (12)  Immunocompromised state 2 (8)  Others 2 (8) CLABSI: Central line-associated bloodstream infection, SD: Standard deviation The most common clinical presentation indicating a bloodstream infection was fever, seen in 80% of the patients. Local site inflammation was present in 44%, and 36% of the individuals had new onset hypotension. On routine investigations, neutrophilic leukocytosis was the most common laboratory finding observed, occurring in 68% of the subjects. The median (IQR) leukocyte count on the day of the event was 10,900 (8700–17,600) and creatinine was 2.3 (0.6–4.7) [Table 2]. Table 2 Laboratory parameters of the study participants Parameter Value Total leukocyte counts on DOE  Mean (SD) 13,708 (8219.1)  Median (p25-p75) 10,900 (8700-17,600) Creatinine on DOE  Mean (SD) 3.1 (2.7)  Median (p25-p75) 2.3 (0.6-4.7) Hemoglobin on DOE  Mean (SD) 7.9 (1.7)  Median (p25-p75) 7.9 (6.8-8.8) Platelet on DOE  Mean (SD) 1,58,960 (1,32,078)  Median (p25-p75) 1,20,000 (70,000-1,77,000) INR on DOE  Mean (SD) 1.4 (0.3)  Median (p25-p75) 1.32 (1.2-1.5) Total bilirubin  Mean (SD) 1.24 (2)  Median (p25-p75) 0.4 (0.3-1.1) AST  Mean (SD) 61.9 (103.6)  Median (p25-p75) 30 (16-77) ALT  Mean (SD) 47.1 (70.5)  Median (p25-p75) 20 (9-57) DOE: Day of event, SD: Standard deviation, INR: International normalized ratio, AST: Aspartate transaminase, ALT: Alanine transaminase Bacterial isolates The most common pathogenic bacteria were Klebsiella pneumoniae, responsible for 12 cases (48%) of CLABSI. Coagulase-negative Staphylococci (CoNS) were implicated in four (16%) of the infections. Staphylococcus aureus and Acinetobacter baumannii each caused 3 (12%) of cases, whereas, Chryesobacterium indologenes, E. coli, and Enterococcus faecium caused one bloodstream infection each [Figure 2]. Figure 2 Bacteriological profile of CLABSI patients. CLABSI: Central line-associated bloodstream infections AST was done using the Kirby–Bauer disk diffusion method, and interpretation was done using clinical and laboratory standard institute (CLSI) guidelines. Gram-negative isolates were considered MDR if resistance was detected to more than three classes of antibiotics. This included extended-spectrum beta-lactamase producing and carbapenem-resistant Enterobacterales, difficult-to-treat Pseudomonas and carbapenem-resistant Acinetobacter. Staphylococci sp. were classified as MDR if they were cefoxitin resistant, which is a surrogate marker for methicillin resistance, rendering the isolate resistant to penicillins, cephalosporins, older beta-lactam-beta-lactamase inhibitor combinations, carbapenems, and aztreonam. Vancomycin-resistant Enterococcus sp. (VRE) was considered as MDR. Resistance pattern of the bacterial isolates Antibiotic susceptibility of the bacterial isolates was done for drugs recommended by CLSI. Nearly 94.1% (16/17) of the Gram-negative organisms were MDR, and all of them were carbapenem resistance on phenotypic testing. However, all the isolates were susceptible to colistin. The Gram-positive isolates included four methicillin-resistant and three methicillin-susceptible Staphylococci sp. None of the strains were vancomycin intermediate or resistant. The E. faecium isolate was resistant to penicillin and vancomycin [Figure 3]. We also compared the susceptibility pattern of the biofilm-producing and nonproducing isolates, and the difference was not statistically significant. Figure 3 Susceptibility profile of the bacterial isolates causing CLABSI; (a) Gram-negative isolates; (b) Gram-positive isolates. CLABSI: Central line-associated bloodstream infections Biofilm production For biofilm production, three tests, namely, (i) CGA method, (ii) tube test, and (iii) microtiter plate assay were carried out. The results of the microtiter plate assay were considered gold standard. Fourteen of the 25 isolates (56%) were found to be biofilm producers. The sensitivity, specificity, positive predictive (PPV), and negative predictive value (NPV) of the congo red agar (CRA) method were 66.7%, 44.4%, 54.6%, and 57.1%, respectively. The tube test had a sensitivity of 58.3%, specificity of 33.3%, PPV of 63.6%, and NPV of 28.6%, respectively. 87.5% of the Gram-positive bacterial isolates were biofilm producers in contrast to only 41.2% of the Gram-negative bacterial isolates (P = 0.04). All four CoNS and 66.7% of S. aureus isolates produced biofilms. Of the Gram-negative isolates, 41.7% of K. pneumoniae and 66.7% of the A. baumanii bacterial isolates produced biofilm [Figure 4]. Figure 4 Biofilm production attributes of different pathogenic bacterial species The demographic, clinical, laboratory profile, and outcome of the patients infected with biofilm producers and nonproducers were compared. The difference was not found to be statistically significant [Table 3]. Table 3 Demographic profile and comorbidities of patients with infections caused by biofilm-producing and nonbiofilm-producing bacteria Parameter Biofilm producers (n=14) Biofilm nonproducers (n=11) P Age (years), median (p25-p75) 38 (21.5-56.2) 45 (23-56) 0.70 Sex (%)  Male 42.9 45.5 0.99  Female 57.1 54.5 Comorbidities (%)  Diabetes mellitus 14.3 72.7 0.01  Hypertension 14.3 54.5 0.08  Chronic kidney disease 42.9 45.5 0.99  Chronic liver disease 14.3 9.1  Immunosuppressed 7.1 9.1  Cerebrovascular accident 0 9.1  Coronary artery disease 0 9.1 Outcome In the study population, the median (IQR) duration of hospital stay was 30 (20, 43) days. The all-cause mortality was 44% (11 of 25 patients). The patients who succumbed to the infection had, statistically significant, higher total bilirubin (P = 0.001), and aspartate transaminase (P = 0.02), on the day of diagnosis. In addition, infection caused by MDR organism was associated with higher mortality (P = 0.04). Of note, all five patients who were infected with non-MDR organisms survived. DISCUSSION Bloodstream infections or bacteremia usually present with systemic symptoms such as fever and hypotension. The surveillance definition of CLABSI according to CDC, also states these signs as criteria for diagnosis.[3] In our study, 80% of the cases diagnosed with CLABSI, presented with fever, and 36% had hypotension. Shin et al. in a follow-up study showed that fever had an odds ratio (OR) of 4.78 for predicting the development of bloodstream infection.[14] Purulent exit site, according to expert opinion, should also strongly raise suspicion for infection. Complicated catheter infection may be predicted if hemodynamic instability, local exit signs, or neutrophilia is present.[15] The risk factors leading to the development of CLABSI include chronic kidney disease, patients with extensive burns, and those requiring chemotherapy.[16] The incidence in chronic kidney disease patients on hemodialysis is about 17.7 episodes per 100 person-years, translating to almost a 26 times higher incidence than in the general population.[17] Other comorbidities such as type II diabetes mellitus and chronic liver disease are also frequent.[16] In our study, chronic kidney disease and diabetes mellitus were the most common. Another important factor considered in the surveillance of CLABSI is the number of central line days before the development of infection. In the present study, it ranged from 3 to 90 days, with a median of 10 days. This is akin to the published literature, with the median days ranging between 9 and 61 days.[18] Recent data have shown Gram-negative multidrug-resistant bacteria more commonly lead to CLABSI than Gram-positive skin commensals.[19] Various studies from India have shown that hospital-acquired pathogens, namely, K. pneumoniae, Pseudomonas aeruginosa, and A. baumannii are commonly implicated.[20] This is in contrast to data from NHSN, which states a dominance of Staphylococcus sp. (56%) followed by Gram-negative bacteria and fungi.[21] C. indologenes was an uncommon causative organism in one of our study subjects. It is a nonmotile, Gram-negative rod, known to be resistant to chlorine treatment. It can colonize hospital water supplies and infusions. Six infections caused by C. indologenes have been described in our institute, with the type of infections ranging from the respiratory tract to bloodstream infection. Infections by this organism in patients with intravascular devices are usually associated with biofilm production.[22] Most of our isolates were MDR, including 94.1% of the Gram-negative and 62.5% of the Gram-positive bacterial isolates. Of concern was the high prevalence of carbapenem resistance (94.1%) in the hospital-acquired Gram-negative bacteria. These rates are much higher than the ICMR surveillance data for 2020, where a resistance of about 30%–50% for Enterobacterales and 50%–70% for nonfermenting Gram-negative bacteria has been documented.[23] None of the Staphylococcus sp. was vancomycin resistant, which is similar to that reported by other Indian studies. The single Enterococcus isolate in our study was a VRE. Between January and December 2020, 9% of Enterococcus isolates from India were found to be vancomycin resistant.[23] On studying the biofilm formation attributes, Gram-positive bacteria were found to be more commonly associated with the formation of biofilms than Gram-negative bacteria. This finding is in concordance with existing literature where the biofilm formation ability of Gram-positive isolates is well documented.[24,25] A multivariate analysis by Barsoumian et al. has shown that infections caused by E. coli, P. aeruginosa, or MR-S. aureus were independent risk factors for biofilm production.[9] Multiple studies evaluating chronic wounds, a niche for biofilm production, found biofilm-forming S. aureus to be a major risk factor for their persistence.[26] Similarly, an in situ device also provides a niche for the formation of biofilms. This provides an additional advantage to biofilm-producing strains and leads to persistent, difficult-to-treat infections. This was demonstrated by Babushkina et al., who found that clinical strains of Enterobacterales causing implant infections had more prominent biofilm production than those aspirated from pus.[6] When compared with the microtiter assay, the CRA method showed moderate sensitivity and poor specificity. Previous studies on biofilm production have reported varied results. Studies on more than 100 strains of Staphylococcus sp., reported a very poor sensitivity <10% with a higher specificity of around 90%.[24] Arciola et al. compared the CRA method with polymerase chain reaction (PCR) for icaA locus of Staphylococcus sp., which is responsible for the biofilm-producing attribute. The results of both the tests were found to be comparable; hence, they concluded that CRA could be a rule in test.[25] The poor specificity in our study maybe due to the fact that the utility of CRA method with Gram-negative isolates is yet to be ascertained. Of the three S. aureus isolates we tested, two had similar results in CRA and microtiter plate assay. The sensitivity and specificity for the tube test as compared to microtiter plate assay is reported to be 76% and 97%, respectively.[24] Weak producers as reported in microtiter method can be missed by the tube test. S. aureus isolates had a good correlation of tube test and tissue microtiter plate assay. In the present study, we found no significant difference in the antimicrobial resistance between the biofilm producers and nonproducers. Prominent literature states that one of the most worrisome features of biofilm infections is its antimicrobial resistance. The mechanisms for this resistance are postulated to be multifaceted including delayed penetration of antimicrobial, altered growth rate of microorganism, and increased expression of resistance genes in the environment.[7] The reason for our biofilm-producing and nonproducing isolates showing similar susceptibility pattern may be explained by the method of AST. In this study, we used the Kirby–Bauer disk diffusion method, where the inoculum is in the planktonic stage. Broth microdilution assays where the bacteria are in the log phase and have an interface for biofilm formation maybe better suited.[27] The all-cause mortality from CLABSI was 44%; this is similar to the published rates of death from hospital-acquired bloodstream infections, which range from 45% to 70%.[20,28] An analysis of 166 cases by Atilla et al. reported that infection with Candida sp. and a higher APACHE II score on admission were independent risk factors for mortality.[16] In our analysis, underlying deranged liver function tests and infection due to an MDR organism showed a predilection for mortality. As the values of liver parameters are of the day of diagnosis of CLABSI, the out-of-range liver function tests can also be a consequence of multiorgan dysfunction occurring due to sepsis, which is independently known to add to poor prognosis. Furthemore, the duration of hospital stay increased by a median of 3 days in patients having healthcare-associated infections.[28] Biofilm formation is one of the virulence factors responsible for CLABSI, with about half of the infections being caused by biofilm-producing bacteria. Our study found no correlation between clinical outcome and biofilm production, this contrasts with literature on biofilm formation and chronic wound infections. The persistence of chronic wounds beyond 14 days despite appropriate antimicrobial therapy has been linked to the formation of biofilms.[4] This could be because bloodstream infections are systemic and influenced by a wide variety of factors, unlike localized wounds. Nevertheless, biofilm-forming capability of microorganisms is an important factor leading to the colonization of intravascular devices and dissemination of infection.[29] To the best of our knowledge, this is the first study trying to understand the role of biofilm production by the pathogens and their resistance pattern in progression and outcome of CLABSI. The study also endures a few limitations. First, the sample size was quite small, and to overcome the bias due to indications of long and complex surgeries requiring central line placement, and trauma; all the samples were collected from patients having medical indications of hospitalization. The bacterial isolates included were less due to the low culture positivity of CLABSI cases, which can be explained by the fact that patients usually receive various antibiotics before the admission. A bigger sample size might throw better light on understanding various factors affecting the course and outcome of CLABSI. Second, as biofilms are phenotypically and genotypically complex structures, understanding their functioning and pathogenicity requires broth dilution techniques and molecular methods. CONCLUSION The present study is the first one attempting to comprehend the interplay of various host and pathogen factors which affect the course and outcome of CLABSI. Studies with larger sample size and including patients from wards and ICUs of different departments such as surgery and trauma, and more detailed analyses will help in improved understanding of this complex interaction. The study has paved way for looking into details of one of the modifiable virulence factors-biofilm formation attributes of the bacteria. Future research directed on time taken for, and the role of specific drugs for prevention of biofilm formation, as well as specific drugs acting on Gram-positive and Gram-negative bacterial biofilms can be done for direct translation to the benefit of patients. Research quality and ethics statement This study was approved by the Institutional Ethics Committee (IECPG-498/17.07.2019). The authors followed applicable EQUATOR Network guidelines, i.e. STROBE Statement: Guidelines during the conduct of this research project. Financial support and sponsorship This study was financially supported by internal support from All India Institute of Medical Sciences, New Delhi, India. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Rosenthal VD Al-Abdely HM El-Kholy AA AlKhawaja SA Leblebicioglu H Mehta Y International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010-2015: Device-associated module Am J Infect Control 2016 44 1495 504 27742143 2 Deepti SS Sinha S Sharma SK Aggarwal P Biswas A Sood S Central venous catheter related bloodstream infections in medical Intensive Care Unit patients in a tertiary referral centre Indian J Chest Dis Allied Sci 2014 56 85 91 25230549 3 Bloodstream Infection Event (Central Line-Associated Bloodstream Infection and Non-central Line Associated Bloodstream Infection), in National Healthcare Safety Network- Device Associated Module. 2021. p. 3-10 Available from: https://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf [Last accessed on 2021 Feb 18] 4 Costerton JW Stewart PS Greenberg EP Bacterial biofilms: A common cause of persistent infections Science 1999 284 1318 22 10334980 5 Römling U Balsalobre C Biofilm infections, their resilience to therapy and innovative treatment strategies J Intern Med 2012 272 541 61 23025745 6 Babushkina IV Bondarenko AS Ulyanov VY Mamonova IA Biofilm formation by gram-negative bacteria during implant-associated infection Bull Exp Biol Med 2020 169 365 8 32748136 7 Donlan RM Biofilms and device-associated infections Emerg Infect Dis 2001 7 277 81 11294723 8 Akers KS Mende K Cheatle KA Zera WC Yu X Beckius ML Biofilms and persistent wound infections in United States military trauma patients: A case-control analysis BMC Infect Dis 2014 14 190 24712544 9 Barsoumian AE Mende K Sanchez CJ Beckius ML Wenke JC Murray CK Clinical infectious outcomes associated with biofilm-related bacterial infections: A retrospective chart review BMC Infect Dis 2015 15 223 26049931 10 Hannan TJ Totsika M Mansfield KJ Moore KH Schembri MA Hultgren SJ Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection FEMS Microbiol Rev 2012 36 616 48 22404313 11 Safdar N Kluger DM Maki DG A review of risk factors for catheter-related bloodstream infection caused by percutaneously inserted, noncuffed central venous catheters: Implications for preventive strategies Medicine (Baltimore) 2002 81 466 79 12441903 12 Basak S Khodke M Bose S Mallick S Detection of biofilm producing staphylococci: Need of the hour J Clin Diagn Res 2009 3 1915 20 13 Stepanović S Vuković D Hola V Di Bonaventura G Djukić S Cirković I Quantification of biofilm in microtiter plates: Overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci APMIS Acta Pathol Microbiol Immunol Scand 2007 115 891 9 14 Shin AY Jin B Hao S Hu Z Sutherland S McCammond A Utility of clinical biomarkers to predict central line-associated bloodstream infections after congenital heart surgery Pediatr Infect Dis J 2015 34 251 4 25232780 15 Buetti N Timsit JF Management and prevention of central venous catheter-related infections in the ICU Semin Respir Crit Care Med 2019 40 508 23 31585477 16 Atilla A Doğanay Z Kefeli Çelik H Demirağ MD S Kiliç S Central line-associated blood stream infections: Characteristics and risk factors for mortality over a 5.5-year period Turk J Med Sci 2017 47 646 52 28425261 17 Skov Dalgaard L Nørgaard M Jespersen B Jensen-Fangel S Østergaard LJ Schønheyder HC Risk and prognosis of bloodstream infections among patients on chronic hemodialysis: A population-based cohort study PLoS One 2015 10 e0124547 25910221 18 Al Lawati TT Al Jamie A Al Mufarraji N Central line associated sepsis in children receiving parenteral nutrition in Oman J Infect Public Health 2017 10 829 32 28330584 19 Habibi S Wig N Agarwal S Sharma SK Lodha R Pandey RM Epidemiology of nosocomial infections in medicine Intensive Care Unit at a tertiary care hospital in northern India Trop Doct 2008 38 233 5 18820195 20 Datta P Rani H Chauhan R Gombar S Chander J Health-care-associated infections: Risk factors and epidemiology from an Intensive Care Unit in Northern India Indian J Anaesth 2014 58 30 5 24700896 21 Kumbar L Yee J Current concepts in hemodialysis vascular access infections Adv Chronic Kidney Dis 2019 26 16 22 30876612 22 Sahu MK George N Rastogi N Bipin C Singh SP Uncommon pathogens causing hospital-acquired infections in postoperative cardiac surgical patients J Card Crit Care TSS 2019 3 089 96 23 Shallu D National Antimicrobial Resistance Surveillance Network (NARS-Net India) Annual Report 2019 43 Available from: ncdc.gov.in/WriteReadData/l892s/87909365291642417515.pdf [Last accessed on 2020 Jul 17] 24 Mathur T Singhal S Khan S Upadhyay DJ Fatma T Rattan A Detection of biofilm formation among the clinical isolates of Staphylococci: An evaluation of three different screening methods Indian J Med Microbiol 2006 24 25 9 16505551 25 Arciola CR Campoccia D Gamberini S Cervellati M Donati E Montanaro L Detection of slime production by means of an optimised Congo red agar plate test based on a colourimetric scale in Staphylococcus epidermidis clinical isolates genotyped for ica locus Biomaterials 2002 23 4233 9 12194526 26 Sanchez CJ Mende K Beckius ML Akers KS Romano DR Wenke JC Biofilm formation by clinical isolates and the implications in chronic infections BMC Infect Dis 2013 13 47 23356488 27 Melchior MB Fink-Gremmels J Gaastra W Comparative assessment of the antimicrobial susceptibility of Staphylococcus aureus isolates from bovine mastitis in biofilm versus planktonic culture J Vet Med Ser B 2006 53 326 32 28 Madani N Rosenthal VD Dendane T Abidi K Zeggwagh AA Abouqal R Health-care associated infections rates, length of stay, and bacterial resistance in an Intensive Care Unit of Morocco: Findings of the International Nosocomial Infection Control Consortium (INICC) Int Arch Med 2009 2 29 19811636 29 Lynch AS Robertson GT Bacterial and fungal biofilm infections Annu Rev Med 2008 59 415 28 17937586

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-90 10.4103/jgid.jgid_13_23 Letters to Editor Pulmonary Tuberculosis Presenting as Diffuse Alveolar Hemorrhage Pattar Shridhar Agarwal Mayank Shah Bishal Pathania Monika Department of Internal Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India Address for correspondence: Dr. Mayank Agarwal, Department of Internal Medicine, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand, India. E-mail: m.agarwal95@gmail.com Apr-Jun 2023 02 5 2023 15 2 9091 22 1 2023 24 2 2023 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body pmcSir, Hemoptysis is a common presentation of pulmonary tuberculosis; however, diffuse alveolar hemorrhage (DAH) is a rare association. DAH is a life-threatening medical condition which presents with hemoptysis, anemia, diffuse radiographic pulmonary infiltrates, and acute respiratory distress.[1] It is usually associated with autoimmune diseases such as systemic vasculitides, systemic lupus erythematosus, anti-glomerular basement membrane (GBM) disease, certain malignancies, and infections.[2,3] Cytomegalovirus, adenovirus, invasive aspergillosis, mycoplasma, influenza, and even staphylococcus infection have been associated with DAH.[3] However, pulmonary tuberculosis causing DAH has rarely been reported in the literature. An elderly woman presented with cough for 2 weeks which was associated with blood-stained sputum. She had one episode of frank hemoptysis (20–25 mL), following which she developed exertional dyspnea. There was no history of orthopnea, paroxysmal nocturnal dyspnea, palpitations, fever, joint pains, hematuria, lower limb swelling, and skin or face rash. She had a weight loss of approximately 6 kg over the last 2 months. At presentation, she was tachypneic and required oxygen support. Chest auscultation revealed coarse inspiratory crackles over both the lung areas. A chest radiograph was obtained, which showed diffuse infiltrates in both the lung fields. With a presentation of rapidly falling hematocrit and diffuse infiltrates on chest X-ray, differentials were pulmonary tuberculosis, fungal infection, carcinoma of the lung, bleeding disorder, and DAH. A high-resolution computed tomography was performed, which showed diffuse bilateral ground-glass opacities, suggesting the possibility of DAH [Figure 1]. She was taken up for bronchoscopy which revealed hemorrhagic aliquots confirming DAH. Further evaluation revealed a negative antinuclear antibody test, and complement levels were normal. Antibody panels, including antineutrophil cytoplasmic antibodies and anti-GBM antibodies, were also negative. Evaluation of bronchoalveolar lavage (BAL) fluid revealed hemosiderin-laden macrophages, stain for Pneumocystis jirovecii was negative, and no fungal elements were demonstrated. BAL fluid nucleic acid amplification test detected Mycobacterium tuberculosis. The patient was initially managed supportively by oxygen supplementation, and packed red blood cells were transfused for hemodynamic stabilization. After establishing the diagnosis of tuberculosis as the cause of her presentation, she was started on standard weight-based antitubercular therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol as per the National Tuberculosis Elimination Program strategy.[4] The patient was followed up regularly, and she responded well to antitubercular treatment. Figure 1 (a) Chest X-ray showing diffuse infiltrates in the bilateral lung. (b) HRCT chest showing diffuse bilateral ground-glass opacities (arrows) with few nodular opacities and tree-in-bud appearance. HRCT: High-resolution computed tomography Treatment of DAH aims at hemodynamic stabilization, ventilatory support, and treatment of the underlying etiology. For autoimmune diseases complicating with DAH, standard treatment options include high-dose corticosteroids, immunosuppressants, or plasmapheresis.[5] However, for infections causing DAH, immunosuppression is harmful, hence management is supportive care and specific antimicrobial agents when available.[3] Therefore, etiological diagnosis of DAH is important for correct treatment. Our patient responded well to antitubercular therapy, which was the mainstay of the treatment. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Research quality and ethics statement Authors followed applicable EQUATOR Network (https://www.equator-network.org/) guidelines, notably the CARE guideline, during the conduct of this report. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Kashif M Patel R Bajantri B Diaz-Fuentes G Legionella pneumonia associated with severe acute respiratory distress syndrome and diffuse alveolar hemorrhage –A rare association Respir Med Case Rep 2017 21 7 11 28348947 2 de Prost N Parrot A Cuquemelle E Picard C Antoine M Fleury-Feith J Diffuse alveolar hemorrhage in immunocompetent patients: Etiologies and prognosis revisited Respir Med 2012 106 1021 32 22541718 3 von Ranke FM Zanetti G Hochhegger B Marchiori E Infectious diseases causing diffuse alveolar hemorrhage in immunocompetent patients: A state-of-the-art review Lung 2013 191 9 18 23128913 4 National Tuberculosis Elimination Programme.| National Health Portal of India Available from: https://www.nhp.gov.in/revised-national-tuberculosis-control-programme_pg [Last accessed on 2022 Mar 13] 5 Newsome BR Morales JE Diffuse alveolar hemorrhage South Med J 2011 104 269 74 21606695

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-79 10.4103/jgid.jgid_102_22 Pictorial Education Characteristic Array of Imaging Markers in Central Nervous System Tuberculosis Das Shambaditya Ray Biman Kanti Pandit Alak Kumar Keshaw 1 Dubey Souvik Department of Neurology, Institute of Post Graduate Medical Education and Research, Bangur Institute of Neurosciences, Kolkata, West Bengal, India 1 Department of Radiology, Medanta Hospital, Patna, Bihar, India Address for correspondence: Dr. Souvik Dubey, Department of Neurology, Institute of Post Graduate Medical Education and Research, Bangur Institute of Neurosciences, 52/1A Shambu Nath Pandit Street, Kolkata- 700 025, West Bengal, India. E-mail: drsouvik79@gmail.com Apr-Jun 2023 31 3 2023 15 2 7980 25 5 2022 06 8 2022 25 8 2022 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body pmcA 50-year-old female presented to us with a low-grade fever along with night sweats for a month. This was associated with holocranial headache and photophobia for the last 10 days and gradually worsening sensorium for the last 7 days. On admission, the patient was stuporous. Neurological examination was marked by neck stiffness, very sluggishly reacting bilateral dilated pupil, panhyporeflexia, and bilateral extensor plantar response. Routine blood examination showed microcytic hypochromic anemia and markedly elevated erythrocyte sedimentation rate. Magnetic resonance imaging (MRI) brain revealed pachymeningeal enhancement and enhancement along the lining of the lateral ventricle and optic chiasm enhancement. There was associated asymmetrical ventricular dilatation, multiple ring-enhancing lesions, and small foci of diffusion-weighted image restrictions in the bilateral cerebral hemisphere. MRI spine showed diffuse meningeal and exiting root enhancement, longitudinally extensive transverse myelitis, and multiple ring-enhancing lesions in the cord and cord swelling [Figure 1]. Cerebrospinal fluid (CSF) examination indicated lymphocytic pleocytosis (cell count – 220), protein level was 300mg/dL (normal: 10–50mg/dL), glucose was 18mg/dL (serum glucose: 124mg/dL), and a positive cartridge-based nucleic acid amplification test results. Mantoux test was positive; serology for HIV was negative. A diagnosis of central nervous system (CNS) tuberculosis (TB) was made. Figure 1 MRI spine (T2 weighted), sagittal section shows intra-medullary hyperintensities along the entire length of cervical and visualized dorsal spine suggestive of LETM along with cord swelling (a); T1-weighted postcontrast sequence, sagittal section shows multiple intramedullary ring enhancing lesions suggestive of tuberculoma along with meningeal thickening and enhancement (b); enhancement along the exiting nerve root (c); MRI Brain T1 postcontrast axial section showing diffuse enhancement of optic chiasm suggestive of opticochiasmatic arachnoiditis (d); thick-walled ring enhancement in left frontal and thalamic region suggestive of tuberculoma and enhancement along the ependymal lining of lateral ventricle suggestive of ventriculitis and enhancement of the meninges over the right frontal lobe suggestive of meningitis (e); DWI sequence shows small true restriction in the right parietal lobe suggestive of acute infarct due to tubercular arteritis with asymmetric dilatation of left temporal horn of lateral ventricle suggestive of hydrocephalus (f); T1-weighted postcontrast sequence, axial section in the upper cervical region shows intramedullary ring enhancing lesions suggestive of tuberculoma (g); MRI: Magnetic resonance imaging, DWI: Diffusion-weighted images, LETM: Longitudinally extensive transverse myelitis The patient was immediately started on anti-tubercular drug, steroids, and antiepileptics. However, she succumbed after 4 days of hospitalization. TB is a curable and preventable disease that affected around 10 million cases globally in 2019, with Southeast Asia accounting for 44% of it. CNS involvement can be seen in 5%–10% of TB patients. Neuroimaging plays a crucial role in the early and accurate diagnosis of CNS-TB and its disabling complications. CNS-TB can have both meningeal and parenchymal involvement. Meningitis is the most common manifestation (90%), usually most pronounced in basal cisterns, and commonly complicated by communicating hydrocephalus. Ischemic infarcts (20%–40%) have a predilection to involve small-/medium-sized vessels, related to vascular compression and occlusion, commonly in the bilateral gangliothalamic region. Ventriculitis may be seen as a thickened and enhanced ependymal lining often leading to aqueductal obstruction due to inflammatory exudates. The most common parenchymal lesion is a tuberculoma. It is usually thick-walled, close to meninges, commonly located in the frontal and parietal region, and may conglomerate. Caseating tuberculoma with a liquid center and tuberculous abscess share similar imaging features. Both have central hyperintensities and a surrounding hypointense rim on T2WI with rim enhancement postcontrast. However, tuberculous abscess can be differentiated by its solitary occurrence, thin wall, larger size, and multiloculation.[1-4] Spinal cord involvement in TB may manifest in several forms such as TB radiculomyelitis, spinal tuberculoma, myelitis, syringomyelia, vertebral TB, and rarely spinal TB abscess. The MR imaging features of spinal TB meningitis include CSF loculation and obliteration of spinal subarachnoid space with loss of outline of the spinal cord in the cervicothoracic spine and matting of nerve roots in the lumbar region. Postcontrast study usually reveals nodular, thick, and linear intradural enhancement.[1-3,5] Imaging characteristics of CNS-TB can mimic other lesions such as brain tumors and it may not always be typical.[2,3] However, awareness of various imaging manifestations of CNS-TB on the part of the treating physician can lead to early diagnosis and institution of timely therapy, thereby minimizing morbidity and mortality. LEARNING POINTS TB can have multiple neuroaxial involvements with varied but characteristic radiological manifestations Neoplastic and inflammatory etiologies can be a close radiological mimic of CNS TB; however, in an appropriate clinical setting, a low index of suspicion for TB can aid in early diagnosis and minimizing mortality Although the pathophysiology of disseminated TB and tuberculoma is different, they may coexist which underpins the variation in immune response in the part of the host. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Research quality and ethics statement The authors followed applicable EQUATOR Network guidelines, notably the CARE guideline, during the conduct of this report. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Burrill J Williams CJ Bain G Conder G Hine AL Misra RR Tuberculosis: A radiologic review Radiographics 2007 27 1255 73 17848689 2 Khatri GD Krishnan V Antil N Saigal G Magnetic resonance imaging spectrum of intracranial tubercular lesions: One disease, many faces Pol J Radiol 2018 83 e524 35 30800191 3 Garg RK Malhotra HS Jain A Neuroimaging in tuberculous meningitis Neurol India 2016 64 219 27 26954796 4 Trivedi R Saksena S Gupta RK Magnetic resonance imaging in central nervous system tuberculosis Indian J Radiol Imaging 2009 19 256 65 19881100 5 Sanei Taheri M Karimi MA Haghighatkhah H Pourghorban R Samadian M Delavar Kasmaei H Central nervous system tuberculosis: An imaging-focused review of a reemerging disease Radiol Res Pract 2015 2015 202806 25653877

PMC010xxxxxx/PMC10353642.txt

==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-66 10.4103/jgid.jgid_185_22 Original Article Central Retinal Artery Occlusion in COVID-Associated Mucormycosis Srivastava Smiti Rani Sarkar Peyalee 1 Ganguly Purban 2 Mukherjee Debaleena 3 Ray Biman Kanti 3 Dubey Souvik 3 Pandit Alak 3 Sengupta Amitabh 4 Bandopadhyay Manimoy 5 Ghosh Asim Kumar 6 Poddar Kanika Gupta 7 Guha Soumyajit Ayub Asif 6 Department of Ophthalmology, IPGME and R and SSKMH, Kolkata, West Bengal, India 1 Department of Neurology, Bangur Institute of Neurosciences, IPGME and R and SSKMH, Kolkata, West Bengal, India 2 Division of Orbit and Oculoplasty, Regional Institute of Ophthalmology, Kolkata, West Bengal, India 3 Department of Neuromedicine, Bangur Institute of Neurosciences, IPGME and R and SSKMH, Kolkata, West Bengal, India 4 Department of Pulmonary Medicine, IPGME and R and SSKMH, Kolkata, West Bengal, India 5 Department of Anatomy, IPGME and R and SSKMH, Kolkata, West Bengal, India 6 Regional Institute of Ophthalmology, Kolkata, West Bengal, India 7 Department of Histopathology, AMRI Hospital, Kolkata, West Bengal, India Address for correspondence: Dr. Smiti Rani Srivastava, Department of Ophthalmology, IPGME and R and SSKMH, SSKM Hospital Road, Bhowanipore, Kolkata - 700 020, West Bengal, India. E-mail: drsmiti_srivastava@rediffmail.com Apr-Jun 2023 31 5 2023 15 2 6671 30 9 2022 24 12 2022 02 2 2023 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Introduction: Significant surge of mucormycosis was reported in the Indian Subcontinent during the second wave of the COVID-19 pandemic. COVID-associated mucormycosis (CAM) was defined as the development of features of mucormycosis with prior or current history of COVID-19 infection. Rapid angioinvasion is an important characteristic of mucormycosis. Authors intended to find out the prevalence of retinal arterial occlusion and its association with vascular embolic occlusion elsewhere in the body among CAM patients in this study. Methods: This was an observational study. All consecutive-confirmed cases of mucormycosis (n = 89) and age-/gender-/risk factor-matched controls (n = 324) admitted in the designated COVID center were included in the study. All cases and controls underwent comprehensive ophthalmological, otorhinological, and neurological examinations. All necessary investigations to support the clinical diagnosis were done. Qualitative data were analyzed using the Chi-square test. Quantitative data for comparison of means between the cases and controls were done using unpaired t-test. Results: Twenty-one (23.59%) patients manifested the defined outcome of central retinal artery occlusion (CRAO). Among age-matched control, with similar diabetic status, none had developed the final outcome as defined (P < 0.05). About 90.47% of subjects with CRAO presented with no perception of light vision. Thirteen subjects (61.9%) with the final outcome developed clinical manifestations of stroke during the course of their illness with radiological evidence of watershed infarction (P = 0.001). Orbital debridement was performed in 9 (42.85%) subjects while orbital exenteration was done in 8 (38.09%) subjects. Conclusions: CRAO in CAM patients was found to have aggressive nature turning the eye blind in a very short period of time. CRAO can serve as a harbinger for subsequent development of more debilitating and life-threatening conditions such as stroke among CAM patients. Central retinal artery occlusion COVID-associated mucormycosis stroke watershed infarction ==== Body pmcINTRODUCTION A significant surge of invasive fungal diseases was reported in the Indian Subcontinent during the second wave of the COVID-19 pandemic. This can be attributed to a number of factors such as diabetes, widespread use of steroids, increased antibiotic use, or some, yet to be known intriguing factors.[1] Mucormycosis is the second most common invasive fungal disease to affect the human population following aspergillosis. It was usually seen in the background of immunosuppression such as poorly controlled diabetes, hematological malignancies, and solid organ transplantation.[1-3] Angioinvasion is an important characteristic of mucormycosis. This causes rapid invasion of the fungus in the body. Most commonly this fungus invades the paranasal sinuses from the nose and ultimately reaches brain through orbit. This is known as rhino-orbito-cerebral mucormycosis (ROCM). Gastrointestinal, renal, pulmonary, and cutaneous mucormycosis is also reported in various literature. COVID-associated mucormycosis (CAM) was defined as the development of features of mucormycosis with prior or current history of COVID-19 infection. If ROCM is developing within 7 days of COVID infection, then it is called early CAM. If ROCM is developing 8 days or later up to 8 weeks following diagnosis of COVID-19 disease, then it is referred as late CAM.[1,4] Mucormycosis can lead to a wide array of ophthalmological manifestations in the form of conjunctival congestion, ptosis, proptosis, and diminution of vision owing to the involvement of the anterior or posterior chamber, optic nerve, sheath, and/or retinal vascular occlusion. Extraocular muscle involvement frequently leads to ophthalmoplegia.[5] The optic disc or papilla is the ophthalmoscopically visible tip of the intraocular portion of the optic nerve. The nerve head is a vertical ellipse and appears pinkish to yellowish-white. The ophthalmic artery and some filaments of the sympathetic carotid plexus accompany the nerve through the optic canal, within the same dural sheath. About 8–12 mm posterior to the globe, the artery enters the optic nerve and runs along its center to the optic disc, where it becomes the central retinal artery.[5,6] Since angioinvasion plays a key role in the spread of mucormycosis, central retinal artery occlusion (CRAO) might have been one of the significant factors leading to sudden irreversible loss of vision in CAM patients. The authors intended to find out the prevalence of retinal arterial occlusion and its association with vascular embolic occlusion elsewhere in the body among CAM patients. METHODS This observational study was conducted from May 2021 to July 2021 at a tertiary care referral-based institute, declared as apex hub for the management of mucormycosis. All consecutive-confirmed cases of mucormycosis (n = 89) and age-/gender-/risk factor-matched controls (n = 324) admitted in the designated COVID center for the same institute were included in the study. CRAO (International Classification of Disease-10 Code: H: 34.1) is defined as: Sudden profound loss of vision (monocular or binocular) Associated relative afferent pupillary defect (RAPD) in the affected eye On fundus evaluation, any two of the following apart from pale edematous ischemic retina: Cherry red spot in macula Retinal arteriolar attenuation with segmentation of blood Identification of the site of embolization. Cases were defined as subjects in whom mucormycosis was confirmed with clinical manifestations, radiological evidence of invasive fungal disease, and demonstration of fungus in tissue specimen by the presence of broad aseptate or pauci-septate hyphae with wide angle branching and evidence of tissue invasion (potassium hydroxide mount/histopathological examination [HPE]). Controls were defined as age-, gender-, and risk factor-matched subjects with COVID-19 disease requiring hospital admission during the study interval. All cases and controls underwent comprehensive ophthalmological, otorhinological, and neurological examinations. All necessary investigations to support the clinical diagnosis were done. The subjects underwent treatment in the form of clearance/tissue debridement surgery of the sinus, orbital floor clearance, or debulking or exenteration (depending on the amount of tissue invasion and visual acuity of the involved eye of the patient). The subjects also received injectable amphotericin B at 1 mg/kg body weight for 21 days, followed by the tablet posaconazole 300 mg OD for 90 days. All the exenterated orbital specimens were subjected to HPE, with tissue being subjected to standard hematoxylin and eosin staining along with the use of Gomori’s methenamine silver (GMS), periodic acid–Schiff stain. Prior written permission from the Institutional Ethics Committee was taken. The study was conducted maintaining the tenets of the Declaration of Helsinki, and the data were analyzed using the Chi-square test and unpaired t-test. RESULTS The total cases during the study period were 89 (mean age of 54.67 ± 9.23 years), out of whom 21 (23.59%) patients manifested the defined outcome of CRAO. Among the affected, the mean age was 53.85 ± 9.49 with 13 males (61.9%) and 8 (38.1%) females. Sixteen subjects (76.1%) were previously known diabetics on treatment while 5 (23.9%) had developed diabetes as per the American Diabetes Association criteria postdevelopment of COVID-19 disease. Among age-matched control, with similar diabetic status, none had developed the final outcome as defined (P < 0.05). The mean age of the controls was 56.34 (±10.34) with, 60.4% subjects (n = 196) with type 2 diabetes mellitus (P < 0.05). Out of 21 subjects with the final outcome (CRAO), perception of light was denied by 19 (90.47%) while in 2 (9.52%) subjects, finger counting was present. Among all the subjects who had developed CRAO manifested the clinical findings of proptosis of the affected eye were found in 8 (38.09%) with complete ophthalmoplegia being found in 15 (71.42%) and rest 9 (42.85%) having incomplete ophthalmoplegia with medial and inferior rectus palsy being most commonly documented. RAPD was found in 4 (19%) cases and the rest had fixed nonreacting pupils [Figure 1]. Figure 1 Features associated in subjects with outcome of CRAO. CRAO: Central retinal artery occlusion, RAPD: Relative afferent pupillary defect, VA: Visual acuity, PL: Perception of light Majority of our patients with CAM presented with fundal pictures showing retinal edema, attenuation of retinal arteries, and pale macula with cherry red spots [Figure 2]. Figure 2 Color fundus image of right eye showing retinal edema, pale macula with cherry red spot, and attenuation of retinal arterioles (acute stage, on presentation), suggestive of central retinal artery occlusion Orbital apex syndrome (in subjects with clinical suspicion and radiologic corroboration) was elicited in 13 (61.9%) subjects and 8 (38.09%) out of 21 subjects had clinicoradiological manifestations of cavernous sinus involvement [Figure 3]. Optic nerve sheath enhancement was found in 14 (66.66%) subjects. Digital fluorescence angiography (DFA) was done in 11 (52.4%) out of 21 patients as the rest (n = 10) were too moribund for the examination or had deranged renal profiles. Seven subjects (63.6%) showed cattle trucking and delayed arterial filling [Figure 4]. On ocular coherence tomography out of 16 patients who were physically fit to undergo the scan, the mean central macular thickness was 312.6 ± 28.7 μ. Figure 3 T1 weighted gadolinium contrast axial image of brain/orbit showing soft-tissue enhancement with optic nerve sheath enhancement, infiltration into the orbital apex (left) with involvement of cavernous sinus, destruction of medial orbital wall, and involvement of ethmoidal sinus. The Bblue arrow is pointing the thrombosed cavernous sinus Figure 4 Digital fluorescence angiography showing delayed filling up of retinal vessel in left eye with cattle trucking appearance Thirteen subjects (61.9%) with final outcome developed clinical manifestations of stroke during the course of their illness which was corroborated radiologically. All the subjects who had developed stroke, had watershed infarction (superficial and deep territories of middle cerebral artery (MCA), [Figure 5] while 5 (23.8% of subjects with stroke) had watershed infarction between anterior (anterior cerebral artery [ACA]) and MCA or between posterior (posterior cerebral artery [PCA]) and MCA due to involvement of the internal carotid artery (ICA) by angioinvasion or vasospasm, ipsilateral to the side of CRAO [Figure 6]. Figure 5 Diffusion-weighted magnetic resonance imaging image of coronal cut section of brain showing restriction in watershed zone of superficial and deep territories of left middle cerebral artery Figure 6 Magnetic resonance angiography of cerebral vessels showing filling defect (time of flight image) in cavernous part of right internal carotid artery Among patients of ROCM with manifestations of CRAO, undergoing surgical intervention, orbital debridement was performed in 9 (42.85%) subjects while orbital exenteration was done in 8 (38.09%) subjects. Among the exenterated tissue specimen undergoing biopsy angioinvasion was established in all (100%) by demonstration of broad aseptate/pauciseptate with wide angle branching hyphema within the central retinal artery, with the GMS stain at ×400 [Figure 7]. Figure 7 ×400 Gomori’s methenamine silver stain highlights the mucorales (mucormycosis: Broad aseptate wide-angled branching hyphae) within the lumen of the central retinal artery DISCUSSION Middle-aged (average age = 53.85) rural middle-class population with a male predominance (male: female = 1.6:1) were most commonly affected, reflecting the pattern of COVID-19 disease for greater affection of the male population.[1] All CAM patients had diabetes and 100% had features suggestive of COVID-19 disease with laboratory confirmation by reverse transcriptase–polymerase chain reaction method (P < 0.05). Steroid use was also found to be a risk factor for the development of CAM (77%, relative risk: 2.06, odds ratio: 2.89, P = 0.001). However, it was most prominently observed that the occurrence of multiple risk factors together increased the chances of CAM with diabetes being the most important. In a study where Yohai et al. analyzed the ophthalmic and nonophthalmic signs and symptoms during the course of ROCM, they found 60% of the subjects to be diabetic.[2] ROCM causes a diminution of vision owing to a multitude of underlying factors. Optic nerve involvement may occur at multiple levels: Intraocular portion or intraorbital portion; either by direct infiltration or compression by extraocular muscles; and soft tissue. Intracanalicular or intracranial portion of the optic nerve involvement is associated with orbital apex syndrome and cavernous sinus thrombosis. This has been well documented in the present study.[5-8] The retina is developmentally a part of the diencephalon and its blood supply is from ICA. The retinal vessels exhibit unique characteristics that can be directly and noninvasively examined during ophthalmoscopy. The most common established causes of CRAO are retinal embolism. Retinal embolism can be of three types: calcific, cholesterol, and platelet fibrin.[9] Mucormycosis is a known cause of central retinal and ciliary artery occlusion. Ferri and Abedi described an exenteration specimen of ROCM with thrombosed ciliary arteries.[8] Brown et al. reported one of eight and Bullock et al. one of two cases with acute retinal/choroidal artery obstruction, in mucormycosis (ROCM).[10,11] CRAO in ROCM has an incidence of 16%–20%.[5] It is attributed to the direct infiltration of a central retinal artery by the fungus which is known to have a predilection for internal elastic lamina of blood vessels. This propensity of invading the internal elastic lamina leads to hemorrhagic necrosis of the vessel wall, thrombosis within the lumen of the vessel (preconditioning) for the development of distant embolism, vasospasm leading to transient distal hemodynamic compromise, and external compression causing decreased distal blood flow.[12] In the study by Bhansali et al. on ROCM, vision loss was found in 80% of their cohort and 7 out of 35 had their vision loss attributed to CRAO.[5] In our study, 23.07% of the CAM cases had features suggestive of CRAO in concordance with previous studies. In cases of ROCM with loss of vision owing to CRAO, there is a simultaneous presence of pain from the involvement of other pain-sensitive structures such as the bony periosteum, extraocular muscles, surrounding paranasal sinuses, and involvement of meninges.[1] In all cases of CAM with CRAO, magnetic resonance imaging orbit showed radiological evidence of orbital invasion by the fungus. The spread occurred by bone necrosis along the medial orbital wall mostly from the maxillary sinus and nasal cavity which were almost universally involved in our study population. Involvement of the cavernous sinus and orbital apex was found in 8 (38%) and 13 (62%) subjects, respectively, among cases with defined final outcomes, which was in concordance with previous studies.[1,4,6,7] The central retinal artery pierces the optic nerve sheath to run along the substance of the optic nerve. In the total case population, optic nerve sheath enhancement was found 54 (59.34%) in subjects, out of which 14 (66.66%) developed CRAO, again substantiating direct angioinvasion in CAM as a cause of CRAO. Another aspect of this spectrum was the involvement of the cavernous part of the ICA as evidenced on magnetic resonance angiography brain in subjects who had developed CRAO. The patients (n = 11, 52.4%) who were medically fit, underwent DFA. DFA revealed delayed arterial filling, reduced arterial caliber, and cattle trucking of blood column in seven.[13] Optical coherence tomography showed increased thickness of inner retina in the early phase of/CRAO due to retinal edema.[14] All the exenterated tissue specimens underwent HPE which revealed angioinvasion by broad aseptate wide-angle branching fungus into the central retinal artery. This is definitive evidence of CRAO being a part of CAM due to angioinvasion by mucormycosis.[3] An important observation was that 13 (61.9%) out of 21 subjects with CAM-associated CRAO progress to develop stroke in the form of watershed infarcts. Extension of mucormycosis from the intra-orbital compartment to the cavernous sinus occurs through superior orbital fissure or extension of sinus pathology to cavernous sinus. Involvement of cavernous portion of the ICA vis-à-vis external compression/thrombus in situ/vasospasm led to the propensity to develop stroke.[1,12,15] Most common sites of stroke were watershed infarcts between superficial and deep territories of MCA. All 13 (100% with stroke) patients in the present study showed the same locations of infarcts. However, 5 (23.8% with stroke) subjects also had watershed infarcts between ACA/MCA and MCA/PCA. As the retina and the brain have a common blood supply from the ICA, any pathology affecting the ICA system can thus affect both. The large epidemiologic study of the Beaver Dam Eye Study, the pooled study of the Beaver Dam Eye Study, and the Blue Mountains Eye Study reported the association between retinal arteriolar emboli and incident stroke mortality. In a study, between 401 retinal artery occlusion subjects and 2003 sociodemographically matched comparison subjects, it was found that CRAO subjects exhibited a higher subsequent incidence of stroke during the 10-year follow-up after adjusting for hypertension/ischemic heart disease/atrial fibrillation/diabetes mellitus and dyslipidemia.[16] Hence, an association of CRAO as a predictor for stroke development is well established. Our study findings are also in concordance with the same.[15-18] Since mucormycosis is a rapidly invasive disease and early treatment is imperative, CRAO can serve as a harbinger for subsequent development of more debilitating and life-threatening conditions such as stroke. More aggressive therapy is warranted in such cases.[19,20] However, COVID-19 disease has also been implicated as an independent factor for the development of vasculitis-induced CRAO. Yet, in our study, none of the control population had any features suggestive of CRAO in sharp contrast to CRAO being documented in 21 out of 89 subjects in CAM.[21] However, due to a lack of adequate data, the authors could not document the exact mean time interval between the onset of CAM and CRAO. This may be considered a major limitation of the present study. CONCLUSIONS CAM saw an enormous surge during and following the months of rising COVID-19 cases in India (during the second wave). The disease had devastating presentations with most of the cases being attributed to ROCM. One of the most devastating outcomes was the loss of vision owing to a multitude of factors, CRAO being one of the significant causes. CRAO in CAM patients was found to have aggressive nature turning the eye blind in a very short period of time. The risk of progression of ischemic stroke was also found to be much higher in such patients in comparison to earlier literature. The presence of CRAO served as an early marker for the subsequent development of stroke and thereby poorer outcome in terms of mortality and morbidity. Any CAM patient with dimness of vision requires urgent ophthalmological review for early detection of vascular occlusion. This will help to preserve vision as well as predict the risk of developing ischemic stroke or morbid vascular occlusion elsewhere in the body. Research quality and ethics statement This study was approved by the Institutional Review Board/Ethics Committee (IPGME and R Research Oversight Committee, memo no-IPGME and R/IEC/2021/546). The authors followed applicable EQUATOR Network (https://www.equator-network.org/) guidelines during the conduct of this research project. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgment The authors acknowledge the staff and patients near relatives for their untiring effort to aid the publication. ==== Refs REFERENCES 1 Dubey S Mukherjee D Sarkar P Mukhopadhyay P Barman D Bandopadhyay M COVID-19 associated rhino-orbital-cerebral mucormycosis: An observational study from Eastern India, with special emphasis on neurological spectrum Diabetes Metab Syndr 2021 15 102267 34509790 2 Yohai RA Bullock JD Aziz AA Markert RJ Survival factors in rhino-orbital-cerebral mucormycosis Surv Ophthalmol 1994 39 3 22 7974189 3 Mukherjee B Raichura ND Alam MS Fungal infections of the orbit Indian J Ophthalmol 2016 64 337 45 27380972 4 Patel A Agarwal R Rudramurthy SM Shevkani M Xess I Sharma R Multicenter epidemiologic study of Coronavirus disease-associated mucormycosis, India Emerg Infect Dis 2021 27 2349 59 34087089 5 Bhansali A Bhadada S Sharma A Suresh V Gupta A Singh P Presentation and outcome of rhino-orbital-cerebral mucormycosis in patients with diabetes Postgrad Med J 2004 80 670 4 15537854 6 Schwartz JN Donnelly EH Klintworth GK Ocular and orbital phycomycosis Surv Ophthalmol 1977 22 3 28 333648 7 Badiee P Jafarpour Z Alborzi A Haddadi P Rasuli M Kalani M Orbital mucormycosis in an immunocompetent individual Iran J Microbiol 2012 4 210 4 23205254 8 Ferry AP Abedi S Diagnosis and management of rhino-orbitocerebral mucormycosis (phycomycosis). A report of 16 personally observed cases Ophthalmology 1983 90 1096 104 6646648 9 Varma DD Cugati S Lee AW Chen CS A review of central retinal artery occlusion: Clinical presentation and management Eye (Lond) 2013 27 688 97 23470793 10 Brown GC Magargal LE Sergott R Acute obstruction of the retinal and choroidal circulations Ophthalmology 1986 93 1373 82 3808598 11 Bullock JD Jampol LM Fezza AJ Two cases of orbital phycomycosis with recovery Am J Ophthalmol 1974 78 811 5 4418275 12 Talmi YP Goldschmied-Reouven A Bakon M Barshack I Wolf M Horowitz Z Rhino-orbital and rhino-orbito-cerebral mucormycosis Otolaryngol Head Neck Surg 2002 127 22 31 12161726 13 Hayreh SS Podhajsky PA Zimmerman MB Retinal artery occlusion: Associated systemic and ophthalmic abnormalities Ophthalmology 2009 116 1928 36 19577305 14 Kim H Kim HK Yang JY Kim SS Optical coherence tomography measurement and visual outcome in acute central retinal artery occlusion Korean J Ophthalmol 2018 32 303 11 30091309 15 Chodnicki KD Pulido JS Hodge DO Klaas JP Chen JJ Stroke risk before and after central retinal artery occlusion in a US cohort Mayo Clin Proc 2019 94 236 41 30711121 16 Klein R Klein BE Jensen SC Moss SE Meuer SM Retinal emboli and stroke: The beaver dam eye study Arch Ophthalmol 1999 117 1063 8 10448750 17 Ueda Y Kanazawa S Ohira A Miyamura N Takaki T Kitaoka T Retinal vascular obstruction and asymptomatic cerebral infarction Jpn J Ophthalmol 2002 46 209 14 12062229 18 Douglas DJ Schuler JJ Buchbinder D Dillon BC Flanigan DP The association of central retinal artery occlusion and extracranial carotid artery disease Ann Surg 1988 208 85 90 3389947 19 Abdollahi A Shokohi T Amirrajab N Poormosa R Kasiri AM Motahari SJ Clinical features, diagnosis, and outcomes of rhino-orbito-cerebral mucormycosis –A retrospective analysis Curr Med Mycol 2016 2 15 23 20 Lopez-Berestein G Liposomal amphotericin B in the treatment of fungal infections Ann Intern Med 1986 105 130 1 3717785 21 Sen M Honavar SG Sharma N Sachdev MS COVID-19 and Eye: A review of ophthalmic manifestations of COVID-19 Indian J Ophthalmol 2021 69 488 509 33595463

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-87 10.4103/jgid.jgid_236_22 Letters to Editor A Case of Sphingobacterium multivorum Bloodstream Infection in a Critically-Ill Patient Muzaffar Syed Nabeel Gurjar Mohan 1 Prajapati Shashank 2 Gupta Shikhar S 2 Roy Shubhajeet 2 Department of Critical Care Medicine, King George’s Medical University, Lucknow, Uttar Pradesh, India 1 Department of Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India 2 Faculty of Medical Sciences, King George’s Medical University, Lucknow, Uttar Pradesh, India Address for correspondence: Mr. Shubhajeet Roy, Faculty of Medical Sciences, King George’s Medical University, Lucknow, Uttar Pradesh, India. E-mail: shubhajeet5944.19@kgmcindia.edu Apr-Jun 2023 31 3 2023 15 2 8788 11 12 2022 12 12 2022 13 12 2022 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body pmcSir, Sepsis in intensive care units (ICUs) is common in immunocompromised individuals; herein, we discuss with the help of a case of sepsis due to Sphingobacterium multivorum in an uncontrolled diabetic individual. A 40-year-old male with poorly controlled diabetes mellitus presented to our ICU with right thigh cellulitis and diabetic ketoacidosis (DKA). Subsequently, he developed inferior wall myocardial infarction and right ventricular dysfunction. On examination, he was in altered sensorium, hemodynamically unstable, and had respiratory distress. He was managed for all the above-mentioned issues, which comprised management of DKA and acute coronary syndrome (dual anti-platelets, heparin, statins) and included life support therapies in the form of invasive mechanical ventilation, central line placement, IV fluid resuscitation (guided by two-dimensional echocardiography, lung ultrasonography, and hemodynamic and oxygenation parameters), vasoactive drugs and other drugs such as anti-platelets, therapeutic heparinization, and IV insulin infusion for glycemic control (with emphasis on electrolytes also). The patient stayed in ICU for a prolonged period due to neuromuscular weakness, nosocomial infections, and ischemic cardiomyopathy. Later on, he developed a grade III sacral bedsore also. One of the bugs was S. multivorum cultured from his peripheral blood during an episode of high-grade fever. S. multivorum is a rare but important cause of bloodstream infection in critically ill populations. The bacterium is categorized under the genus Sphingobacterium (formerly known as Flavobacterium) are nonfermenting, catalase and oxidase positive, nonmotile, nonspore-forming Gram-negative rod, naturally found in soil, water, and plant materials.[1] Their nomenclature is secondary to the presence of large quantities of cellular sphingolipids. These rarely cause human diseases, but still, there are certain case reports about their association with infections like respiratory tract infections in patients with cystic fibrosis, soft-tissue infections, septicemia in hemodialysis patients, and meningitis.[2] The two species most commonly implicated are S. spiritivorum and S. multivorum. These are commonly found as commensals on human skin and predispose immunocompromised individuals to infections. However, there are case reports published about Sphingobacterium leading to cellulitis in an immunocompetent person also. In this patient, the isolate was S. multivorum which had led to bacteremia after 6 weeks of ICU stay. To our knowledge, this is the third rare case from India regarding S. multivorum infection in health-care settings. The probable source could have been the grade IV infected sacral bedsore. The bacterium was sensitive to piperacillin/tazobactam and levofloxacin and was resistant to ceftazidime, amikacin, imipenem, carbapenem, and aztreonam. The patient was also sensitive to trimethoprim/sulfamethoxazole (TMP/SMX) and was treated with (TMP/SMX). Sensitivity to other antibiotics was not done. The sensitivity profile of S. multivorum in some case reports depicts in Table 1. Table 1 Sensitivity of sphingobacterium multivorum isolates in case reports Sensitivity Intermediate sensitivity Resistance Aydoğan et al., 2006[3] Cefotetan, cefuroxime, cefotaxime, ampicillin/sulbactam, amoxicillin/clavulanate, ticarcillin, ticarcillin/clavulanate, imipenem, ciprofloxacin, tetracycline, amikacin, gentamicin Ampicillin, ceftriaxone, cefoperazone, piperacillin TMP/SMX, aztreonam, cefazolin, ceftazidime, cephalothin, tobramycin Grimaldi et al., 2012[4] TMP/SMX, ciprofloxacin, levofloxacin, amoxicillin-clavulanate, ticarcillin-clavulanate None Penicillins, cephalosporins, carbapenems aminoglycosides Verma et al., 2014[5] Gatifloxacin Piperacillin/tazobactam Ticarcillin/clavulanate, ceftriaxone, ceftazidime, cefipime, cefpodoxime, cefoperazone, imipenem, meropenem, ofloxacin Our patient Piperacillin-tazobactam, levofloxacin None Amikacin, ceftazidime, imipenem, meropenem, aztreonam TMP/SMX: Trimethoprim-sulfamethoxazole The information given in our case may be helpful in broadening our knowledge about infections with such bacteria. As these bacteria are rarely causative, though they have the capability to cause infection in immunocompetent individuals, hence these bacteria cannot be fully ignored. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Konala VM Naramala S Bose S Gayam V Madhira BR Adapa S Bacteremia secondary to uncommon gram-negative bacilli transmitted from the canine in a patient with multiple myeloma J Investig Med High Impact Case Reports 2020 8 2 Barahona F Slim J Sphingobacterium multivorum: Case report and literature review New Microbes New Infect 2015 7 33 6 26236492 3 Aydoğan M Yumuk Z Dündar V Arisoy ES Sphingobacterium multivorum septicemia in an infant: Report of a case and review of the literature Türk Mikrobiyol Cemiy Derg 2006 36 44 8 4 Grimaldi D Doloy A Fichet J Bourgeois E Zuber B Wajsfisz A Necrotizing fasciitis and septic shock related to the uncommon gram-negative pathogen Sphingobacterium multivorum J Clin Microbiol 2012 50 202 3 22075581 5 Verma RK Rawat R Singh A Singh DP Verma V Sphingobacterium multivorum causing fatal meningoencephalitis: A rare case report Int J Res Med Sci 2014 2 1710 2

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-72 10.4103/jgid.jgid_134_22 Original Article Clinical Profile and Predictors of Mortality among Patients with Melioidosis Raj Sruthi Sistla Sujatha Sadanandan Deepthy M. 1 Kadhiravan Tamilarasu 2 Rameesh Basheer Mohamed Syed 2 Amalnath Deepak 2 Department of Microbiology, JIPMER, Puducherry, India 1 Department of Biostatistics, JIPMER, Puducherry, India 2 Department of Medicine, JIPMER, Puducherry, India Address for correspondence: Dr. Sujatha Sistla, Department of Microbiology, JIPMER, Puducherry - 605 009, India. E-mail: sujathasistla@gmail.com Apr-Jun 2023 31 5 2023 15 2 7278 01 7 2022 13 1 2023 28 4 2023 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Introduction: Melioidosis is an under-recognized but important infection with high mortality and morbidity. It is endemic along the coastal regions of the Southern part of India. The present study focuses on the varied clinical manifestations, associated risk factors, and outcomes in patients from the Southeastern part of India. Methods: Seventy patients from January 2018 to June 2021 from a Tertiary Care Hospital were included and prospectively followed up from 6 months to 3 years. Cox regression was performed to test for the association of various clinical and demographic factors with overall survival. Results: Diabetes and occupational exposure to soil and water (78.6%) followed by alcoholism (61.4%) were the most common risk factors for melioidosis. The most frequent presentation was sepsis (47.1%), followed by skin and soft tissue infection (32.9%) and pneumonia (25.7%). Mortality was 50%. Patients with sepsis had a 3.5-fold higher risk of mortality (adjusted hazard ratio = 3.50; P = 0.01) while other risk factors were not significantly associated with mortality. Conclusion: Lifestyle-dependent risk factors (diabetes, occupational exposure, and alcoholism) were most common among patients with melioidosis. Hospitalization among patients with sepsis is associated with high mortality despite the initiation of specific therapy. Burkholderia pseudomallei melioidosis mortality risk factors treatment ==== Body pmcINTRODUCTION Melioidosis is a potentially life-threatening infection caused by soil-dwelling Gram-negative bacilli, Burkholderia pseudomallei. It can cause either localized infection such as pneumonia, arthritis, abscesses, or systemic dissemination leading to sepsis. The presentation may be acute, chronic, fulminant, or indolent.[1] Early recognition and prompt initiation of antibiotics are essential for survival. Melioidosis is endemic to South East Asia and Northern Australia.[1] Most of the data on melioidosis from India comprises case series and a few retrospective single-center studies.[1-3] Puducherry, being a coastal region, has had sporadic cases of melioidosis in the past.[4,5] Therefore, a prospective study of laboratory-confirmed cases of melioidosis was carried out to document varied clinical manifestations and identify the factors associated with overall survival (OS) in melioidosis patients. METHODS This is a prospective study of 70 laboratory-confirmed melioidosis cases admitted to a Tertiary Care Institute in Southern India, from January 2018 to June 2021. The objective was to describe the clinical profile of confirmed cases; hence, the sample size was not calculated. The approval was obtained from Institutional Ethics Committee (JIP/IEC/2018/0230) for Human Studies and was conducted in accordance with the Declaration of Helsinki. During the study, the authors followed applicable EQUATOR Network guidelines. The clinical presentation, risk factors, treatment details, outcome, occupation and other sociodemographic details were recorded in a structured pro forma using Microsoft Excel. Specimens for microbiological investigations were processed as per standard procedures.[6] Isolates were confirmed by VITEK 2 system (bioMèrieux, Marcy-l'Étoile, France) and polymerase chain reaction targeting a Type III secretion system gene cluster (TTS1).[7] Most patients were followed up telephonically, for a minimum period of 6 months and a maximum of 3 years. The patients or their relatives were contacted to avoid a loss to follow-up. Definitions Acute presentation - symptoms present for <2 months.[8] Chronic presentation - symptoms present for more than 2 months.[8] Sepsis - patients with features of sepsis (hyper/hypothermia, leukocytosis, hypotension, pulse rate >90/min, respiratory rate >18/min) and isolation of B. pseudomallei from any clinical specimen.[9] Excessive alcohol consumption - alcohol consumption of more than 14 standard drinks/week or 4 drinks/day for men and more than 7 standard drinks/week or 3 drinks/day for women in accordance with the criteria established by the US National Institute on Alcohol Abuse and Alcoholism.[10] Superficial abscesses - abscesses involving skin and soft tissues. Deep organ abscess - abscess involving organs such as the brain, lungs, liver, spleen, prostate, etc. Anti-melioidosis treatment comprises initial intensive therapy and eradication therapy. The treatment of choice for the initial intensive therapy is intravenous ceftazidime (50 mg/kg up to 2 g) every 8 h or meropenem (25 mg/kg up to 1 g) every 8 h for a duration of 10–14 days. The treatment for eradication therapy is for a minimum of 12 weeks with co-trimoxazole (first choice) 160/800 mg tablets; two tablets every 12 h and co-amoxiclav or doxycycline 100 mg; twice a day is the second choice.[11-13] Statistical analysis The baseline characteristics were reported using descriptive statistics: categorical variables such as gender, occupation, chronic kidney disease (CKD), and diabetics were summarized as frequencies and percentages. The age which followed normal distribution was expressed as mean with standard deviation, whereas the variables that do not follow normal distribution such as duration of onset of symptoms to admission, admission to reporting, admission to start of specific therapy, and hospital stay were summarized using median along with the first and third quartiles (Q1, Q3). Kaplan–Meier method was used to plot the survival curve and log-rank test was used for the comparison of survival functions across different groups. Univariate Cox regression was used to find the demographic and clinical factors associated with OS. OS was defined as the time from a clinical diagnosis of melioidosis to death. Unadjusted hazard ratios (HR) along with their 95% confidence intervals (CI) were reported. The variables which were found to be significant predictors of mortality in the Univariate analysis were included in the multivariable Cox regression and adjusted HR along with their 95% CI were reported. All statistical analyses were performed using SPSS software version 19.0 (IBM; Armonk, NY, 112 USA) and R software version 4.0.5 (R Foundation for Statistical Computing, Vienna, Austria,2021) at 5% level of significance. P < 0.05 was considered to be statistically significant. RESULTS Patient demographics All the patients with melioidosis reported during the study were included (males n = 63, 90%). The mean age was 47.56 (14.55) years, with four children (10–14 years). There were 42 farmers (60%) and an additional 13 patients (n = 55, 78.6%) had occupational exposure to soil and water. Among the 13 patients, 4 were fishermen and 9 were construction workers [Table 1]. Table 1 Sociodemographic details and risk factors for melioidosis patients (n=70) Sociodemographic details and risk factors Males (63) Females (7) Age (years)  1–15 4 0  16–35 6 1  36–49 25 2  ≥50 28 4 Occupation  Farmers 38 4  Construction workers 9 0  Fishermen 4 0  Carpenters 3 0  Others* 8 0  Unemployed 1 3 Risk factors  Diabetes mellitus 49 6  Environmental exposure (soil/water) 51 4  Age 50 or above 28 4  Alcoholism 43 0  CKD 8 1  Renal transplant recipient 0 1  Absence of risk factors 4 1 *Teacher, students, auto drivers, and peanut vendor. CKD: Chronic kidney disease Presenting symptoms and clinical course Fever was the most common presenting symptom and was present in 60 (85.7%) patients, followed by cough and presence of abscesses in 23 (32.9%), breathlessness in 22 (31.4%), abdominal pain in 18 (25.7%), altered sensorium in 17 (24.3%), and joint pain in 15 (21.4%) patients (some patients had more than one presenting symptoms). Sixty-five (92.9%) patients had acute presentation while 5 (7.1%) had a chronic presentation. The median duration of symptoms before presentation, from date of admission to diagnosis (isolation of B. pseudomallei) and start of specific therapy were 12 days (Q1, Q3; 5, 30 days), 3 days (Q1, Q3; 2, 4 days) and 3 days (Q1, Q3; 1, 6 days), respectively. There were 47 (67.1%) bacteremic patients [Table 2]. Sepsis was present in 33 (47.1%) patients. Thirty-eight patients received meropenem and 20 patients received ceftazidime in intensive phase with an average duration of 26 days in the meropenem group and 14 days the in ceftazidime group. Twenty patients received cotrimoxazole and ten patients received doxycycline and three received a combination of cotrimoxazole and doxycycline in the continuation phase with 90 days. The median duration of hospital stay was 15 days (Q1, Q3; 3, 26 days). Table 2 Clinical details of melioidosis patients (n=70) Clinical details n (%) Bacteremia 47 (67.1) Sepsis 33 (47.1) Pneumonia 18 (25.7) Skin and soft tissue 23 (32.9) Intra-abdominal abscesses 12 (17.1) Lung abscess 2 (2.9) Prostatic abscess 4 (5.7) Renal abscess 1 (1.4) Parotid abscess 1 (1.4) Brain abscess 3 (4.3) Tubo ovarian abscess 1 (1.4) Osteomyelitis/septic arthritis 16 (22.9) Neurological disease 7 (10) A few patients had multiple presentations Overall mortality was 50%. Of these, ten patients expired before initiation of treatment while 24 deaths occurred during treatment. One patient had a relapse and expired during the second admission. Mortality was higher in patients with sepsis compared to patients without sepsis [Table 3]. About two-thirds (66%) of patients with bacteremia progressed to sepsis. Table 3 Clinical presentation and outcome in sepsis and nonsepsis melioidosis patients Clinical presentation* Total (70%), n (%) Deaths (35%), n (%) Sepsis 33 Nonsepsis 37 n (%) Deaths (%) n (%) Deaths (%) Superficial abscesses 23 (32.9) 9 (39.1) 9 (39.1) 7 (77.8) 14 (60.9) 2 (14.3) Deep organ abscesses 24 (34.3) 8 (33.3) 8 (33.3) 6 (59.0) 16 (66.7) 2 (12.5) Pneumonia 18 (25.7) 13 (72.2) 12 (66.7) 10 (83.3) 6 (33.3) 3 (50) Septic arthritis 15 (21.4) 10 (66.7) 10 (66.7) 8 (80) 5 (33.3) 2 (40) Neurological disease 7 (10) 3 (42.9) 2 (28.6) 1 (50) 5 (71.4) 2 (40) Bacteremia 47 (67.1) 32 (68.1) 31 (66) 25 (80.6) 16 (34) 7 (43.8) *Row percentage. A few patients had multiple presentations Pulmonary melioidosis accounted for 19 (27.1%) cases, (pneumonia alone 17, lung abscess alone 1, both pneumonia, and lung abscess 1) and 13 deaths [Tables 2 and 3]. Twenty-four patients had deep organ abscesses with spleen and liver being the most common sites. Septic arthritis was seen in 15 patients and osteomyelitis was seen in one patient [Tables 2 and 3]. Polyarthritis was present in five patients. Eleven of the 15 patients were bacteremic and five had septic shock. Infection was fatal in 10 of the 15 patients with septic arthritis [Table 3]. Seven (10%) patients (5 adults and 2 children) presented with neurological melioidosis of whom three had brain abscess, three had encephalitis, and one presented with myelitis [Table 2]. Melioidosis was suspected only in 12 (17.1%) patients on presentation. Community-acquired pneumonia, tuberculosis, septic shock of unknown cause, cerebral mucormycosis, and infected pancreatic pseudocyst were the other initial diagnoses. Factors for predicting mortality Diabetes and environmental exposure to soil/water (n = 55, 78.6%) were the most common risk factors for melioidosis followed by alcoholism (n = 43, 61.4%) [Table 1]. Among the various factors studied to predict the risk of death, presence of bacteremia increased the risk of death from melioidosis by 7.89-fold (unadjusted HR: 7.89, 95% CI: 2.41, 25.87, P = 0.001), compared to nonbacteremic melioidosis [Table 4]. Likewise, patients with sepsis had 6.19-fold higher risk of mortality (unadjusted HR: 6.19, 95% CI: 2.79, 13.73, P < 0.001) compared to patients without sepsis. However, age of 50 years or above, male gender, and the presence of any one risk factor or their absence did not influence the outcome [Table 4]. Table 4 Factors associated with mortality in melioidosis patients (n=70) Variables Nonsurvivors (35%), n (%) Survivors (35%), n (%) Unadjusted Adjusted HR (95% CI) P HR (95% CI) P Age  ≥50 (32) 16 (50.0) 16 (50.0) 0.92 (0.47–1.78) 0.80 - -  <50 (38) 19 (50.0) 19 (50.0) 1 Sex  Male (63) 31 (49.2) 32 (50.8) 0.87 (0.31–2.45) 0.79 - -  Female (7) 4 (57.1) 3 (42.9) 1 Diabetes  Yes (55) 28 (50.9) 27 (49.1) 1.24 (0.54–2.84) 0.61 - -  No (15) 7 (46.7) 8 (53.3) 1 CKD  Yes (9) 8 (88.9) 1 (11.1) 2.14 (0.97–4.73) 0.06 - -  No (61) 27 (44.3) 34 (55.7) 1 Alcoholism  Yes (43) 23 (53.5) 20 (46.5) 1.27 (0.63–2.56) 0.50 - -  No (27) 12 (44.4) 15 (55.6) 1 Occupational exposure  Yes (55) 30 (54.5) 25 (45.5) 1.96 (0.76–5.06) 0.16 - -  No (15) 5 (33.3) 10 (66.7) 1 Risk factors†  Present 32 (49.2) 33 (50.8) 0.81 (0.25–2.64) 0.72 - -  Absent 3 (60.0) 2 (40.0) 1 Bacteremia  Yes (47) 32 (68.1) 15 (31.9) 7.89 (2.41–25.87) 0.001 3.62 (0.96–13.72) 0.06  No (23) 3 (13.0) 20 (87.0) 1 Sepsis  Yes (33) 27 (81.8) 6 (18.2) 6.19 (2.79–13.73) <0.001 3.50 (1.44–8.54) 0.01  No (37) 8 (21.6) 29 (78.4) 1 Presentation  Acute (65) 31 (47.7) 34 (52.3) 0.60 (0.21–1.69) 0.33 - -  Chronic(5) 4 (80.0) 1 (20.0) 1 †Presence of any one risk factor. HR: Hazard ratio, CI: Confidence interval, CKD: Chronic kidney disease In the multivariable Cox regression analysis, only sepsis was found to be an independent predictor when adjusted for bacteremia (adjusted HR = 3.50; 95% CI: 1.44, 8.54, P = 0.01) [Table 4]. A log-rank test revealed that patients without bacteremia survived better when compared to patients with bacteremia [P < 0.001, Figure 1]. Likewise, better survival was noted in patients without sepsis compared to patients who had sepsis [P < 0.001, Figure 2]. Figure 1 Kaplan–Meier survival plots of patients stratified by bacteremia Figure 2 Kaplan–Meier survival plots of patients stratified by sepsis DISCUSSION Melioidosis is an emerging infectious disease in the tropics and is caused by B. pseudomallei. Exposure to soil and water harboring B. pseudomallei is considered one of the risk factors for acquiring this disease.[14] In the present study, 78.6% of the patients were farmers, fishermen, or manual laborers with occupational exposure to soil or water. Pneumonia is the most common clinical presentation in other studies from endemic regions.[1,8,9,15] In contrast, pneumonia accounted for only 25.7% in the present study similar to a study by Koshy et al., with 24.5% lung involvement.[2] Half of the 18 melioidotic pneumonia cases occurred during the monsoon months. The mode of acquiring acute melioidotic pneumonia is attributed to a shift toward inhalation, during heavy rains and cyclones.[1,14,16] Single/multiple abscesses of skin and internal organs are common presentations and are acquired by inoculation of B. pseudomallei through broken skin or through hematogeneous spread.[17] The incidence of skin and soft tissue infection varies from 13.1% to 48.4%.[2,4] The present study had 23 (32.9%) cases of skin and soft tissue infection. There were 9 cases of splenic and hepatic abscesses each. The greater frequency of splenic and hepatic abscesses when compared to prostatic abscesses mirrors the scenario in Thailand and Singapore.[18,19] In contrast, Australia reports a higher number of prostatic abscesses.[8] The incidence of genitourinary melioidosis in Indian studies varies from 6.5% to 14% which is similar to the present study (8.6%).[2,4] There were four patients with prostate abscess while renal and tubo-ovarian abscess was documented in one patient each. Parotitis in children appears to be common in Thailand with one study reporting 38% but was not seen in Australian children.[8,20] The current study included a single case of parotitis involving a 40-year-old female. Septic arthritis, a well-recognized manifestation of melioidosis, commonly involves joints of the knee and shoulder.[21] Bone and joint involvement in melioidosis range from 7.6% in Australia to 48% cases in Thailand.[22,23] B. pseudomallei is the most common cause of septic arthritis with a high (case fatality rate) in Northeast Thailand. An association of B. pseudomallei septic arthritis and blood culture positivity with in-hospital mortality was found in Thailand.[23] Similarly, in the present study, 73.3% of septic arthritis patients were bacteremic of whom 8 (72.7%) patients expired during the hospitalization. Patients with both prostate abscess and septic arthritis are likely to have melioidosis.[23] Therefore, in such patients, melioidosis should be considered as a differential diagnosis, in addition to tuberculosis which is prevalent in our region. Neuromelioidosis accounted for 3% and 5% of cases in Thailand and Australia, respectively[24] while it was encountered in 10% of our patients. Speculation over pathogenesis of neurological melioidosis suggests that it could be due to the direct entry of B. pseudomallei to the brain through hematogeneous spread or an exotoxin.[8,25] The clinical and radiologic signs of central nervous system melioidosis can mimic those of neurologic tuberculosis and arboviral encephalitis.[25] Hence, a positive culture report is required to confirm melioidosis and diagnoses should not be made on the basis of clinical signs alone. The drug of choice for the treatment of melioidosis is meropenem (25 mg/kg up to 1 g) intravenous every 8 h or ceftazidime (50 mg/kg up to 2 g) intravenous every 8 h. This intensive phase is for 14 days. The eradication phase with 3–6 months aims to kill any residual bacteria and minimizes the risk of relapse.[11] In our center, double-strength cotrimoxazole (160 mg trimethoprim - 800 mg sulfamethoxazole) twice a day or doxycycline (100 mg) twice a day alone or in combination are administered during the eradication phase. Although cotrimoxazole is the preferred drug for the eradication phase, doxycycline was used in cases with renal dysfunction or in patients allergic to cotrimoxazole. Of the 70 patients, specific therapy was initiated in 58 (82.9%) patients immediately after isolation of the organism (within 3 days of admission). Not all melioidosis cases necessarily need parenteral therapy. Mild, localized infections can be treated with oral therapy alone.[11] In our study too, a patient with a superficial abscess alone (without sepsis or other clinical manifestations) was treated with double-strength cotrimoxazole twice a day, for 3 months, and fully recovered. However, relapses are not uncommon and the long-term prognosis of these patients who did not receive eradication therapy may be poor. Relapse has been noted in 3.5% of the patients after 2–7 years even after the eradication phase.[2] In our study, a 45-year-old diabetic farmer with multiple leg abscesses and septic arthritis received complete specific therapy but returned with similar symptoms 6 months after completing therapy. However, due to the existing hospital policy during the ongoing COVID-19 pandemic, the patient could not be admitted. He was discharged on oral antibiotics but expired soon after. The risk of death in melioidosis may be influenced by a variety of host factors such as comorbidities and duration of treatment. Risk factors in children with melioidosis are less common and the mortality rate is low, compared to adults.[26] In the present study out of the four children, three survived. The only potential risk factor in them could be environmental exposure to contaminated soil or water. Diabetes mellitus is known to be the single most common risk factor associated with melioidosis due to impaired neutrophil function, as intact neutrophil function and innate immunity play a crucial role against B. pseudomallei infection.[1] However, in the present study as well as according to some published reports, diabetes mellitus did not pose an increased risk for death.[2,27] Other important risk factors include alcohol intake, chronic renal disease, chronic lung disease, malignancy, immunosuppression, and thalassemia.[8] In our study, 61.4% were alcoholics and 12.9% had CKD. Table 5 shows a comparison of clinical characteristics of melioidosis patients between the present study and previous studies from India. Higher mortality rates are documented in Indian studies 21% to 25.8% compared to other endemic countries.[4,8,19,28] The mortality rate in the present study was 50%. The reason for this high mortality is due to acutely ill bacteremic patients with pneumonia and septic arthritis. Sixty-five (92.9%) patients had acute presentation of which 21 (32.3%) patients presented with symptoms for less than a week. Thirteen (20%) patients died within the first 72 h due to a fulminant septicemic form of melioidosis, in contrast to other Indian studies. Table 5 Comparison with some previous studies from India Parameter Present study 2018–2021 Vidyalakshmi et al., 2005–2010[1] Saravu et al., 2001–2007[3] Koshy et al., 2008–2014[2] Basheer et al., 2014–2018[4] Location Puducherry Mangalore Manipal Vellore Puducherry Sample size 70 95 25 114 31 Mean/median age (years) 47.6 50 45 45.6 47.4 Most common risk factor (%) Diabetes and occupational exposure to soil and water (78.6) Diabetes (75.8) Diabetes (68) Diabetes (81.6) Diabetes (83.9) Acute presentation (%) 92.9 71.6 - 36 - Bacteremic cases (%) 67.1 38.9 36 55.2 90.3 Septicemia/septic shock (%) 47.1 23.2 28 - - Most common system/organ involved Soft tissue Lung Liver Spleen Soft tissue Pulmonary melioidosis (%) 25.7 34.7 48 24.5 29 Soft-tissue infection (%) 32.9 11.6 32 13.1 48.4 Neuromelioidosis (%) 10 1.1 4 2.6 12.9 Mortality (%) 50 9.5 8 14.9 25.8 A lower mortality rate of 9.5% was reported by Vidyalakshmi et al. from Mangalore.[1] Even though the acute presentation was seen in 71.6% of patients, only 38.9% were bacteremic, in contrast to the present study with 67.1% of bacteremic patients. The mortality rate reported in a recent study from Puducherry was 25.8% even though they had a much higher proportion of bacteremic cases (90% vs. 67%).[4] However, a direct comparison between the two centers may not be appropriate as in the other study, data on sepsis were not provided. The strengths of the study are its prospective design with long-term follow-up (ranging from 6 months to 3 years). None of the patients were lost to follow-up. However, a low sample size and being a single-centered study are some of the potential limitations. The clinical presentation and risk factors in our population shared overall similarities with other studies from India, with slightly fewer pneumonia cases and more neurological involvement. CONCLUSION In diabetic males and farmers presenting with sepsis, melioidosis should be considered as a differential diagnosis and meropenem should be started as empirical therapy in them with subsequent de-escalation in the absence of laboratory confirmation. Delayed hospitalization among patients with sepsis is associated with high mortality despite initiation of specific therapy. Research quality and ethics statement This study was approved by Institutional Ethics Committee) for Human Studies, JIPMER, Puducherry (JIP/IEC/2018/0230). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the STROBE guidelines, during the conduct of this research project. We also certify that we have not plagiarized the contents in this submission and have done a plagiarism check. We also certify that none of the authors is a member of the Editorial Board of the Journal of Global Infectious Diseases. Financial support and sponsorship This study was supported by the Jawaharlal Institute of Postgraduate Medical Education and Research (JIP/RES/INTRAMURAL/PHS1/2018-19) for conducting research. Conflicts of interest There are no conflicts of interest. Acknowledgment The authors sincerely thank JIPMER for the intramural research grant provided to conduct this study. ==== Refs REFERENCES 1 Vidyalakshmi K Lipika S Vishal S Damodar S Chakrapani M Emerging clinico-epidemiological trends in melioidosis: Analysis of 95 cases from western coastal India Int J Infect Dis 2012 16 e491 7 22512851 2 Koshy M Jagannati M Ralph R Victor P David T Sathyendra S Clinical manifestations, antimicrobial drug susceptibility patterns, and outcomes in melioidosis cases, India Emerg Infect Dis 2019 25 316 20 30666953 3 Saravu K Mukhopadhyay C Vishwanath S Valsalan R Docherla M Vandana KE Melioidosis in southern India: Epidemiological and clinical profile Southeast Asian J Trop Med Public Health 2010 41 401 9 20578524 4 Basheer A Iqbal N Sheeladevi C Kanungo R Kandasamy R Melioidosis: Distinctive clinico-epidemiological characteristics in Southern India Trop Doct 2021 51 174 7 32727288 5 Sharma G Viswanathan S Melioidosis: A 5-year review from a single 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Negl Trop Dis 2019 13 e0007312 31091290 10 Fleming MF Screening and brief intervention in primary care settings Alcohol Res Health 2004 28 57 62 19006992 11 Dance D Treatment and prophylaxis of melioidosis Int J Antimicrob Agents 2014 43 310 8 24613038 12 Wiersinga WJ Virk HS Torres AG Currie BJ Peacock SJ Dance DA Melioidosis Nat Rev Dis Primers 2018 4 17107 29388572 13 Chetchotisakd P Chierakul W Chaowagul W Anunnatsiri S Phimda K Mootsikapun P Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): A multicentre, double-blind, non-inferiority, randomised controlled trial Lancet 2014 383 807 14 24284287 14 Currie BJ Jacups SP Intensity of rainfall and severity of melioidosis, Australia Emerg Infect Dis 2003 9 1538 42 14720392 15 Tang RY Lim SH Lam JE Nurasykin S Eileen T Chan YW A 5-year retrospective study of melioidosis cases treated in a district specialist hospital Med J Malaysia 2019 74 472 6 31929471 16 Currie BJ Melioidosis: An important cause of pneumonia in residents of and travellers returned from endemic regions Eur Respir J 2003 22 542 50 14516149 17 Gibney KB Cheng AC Currie BJ Cutaneous melioidosis in the tropical top end of Australia: A prospective study and review of the literature Clin Infect Dis 2008 47 603 9 18643756 18 Chien JM Saffari SE Tan AL Tan TT Factors affecting clinical outcomes in the management of melioidosis in Singapore: A 16-year case series BMC Infect Dis 2018 18 482 30257647 19 Churuangsuk C Chusri S Hortiwakul T Charernmak B Silpapojakul K Characteristics, clinical outcomes and factors influencing mortality of patients with melioidosis in Southern Thailand: A 10-year retrospective study Asian Pac J Trop Med 2016 9 256 60 26972397 20 Dance DA Davis TM Wattanagoon Y Chaowagul W Saiphan P Looareesuwan S Acute suppurative parotitis caused by Pseudomonas pseudomallei in children J Infect Dis 1989 159 654 60 2926159 21 Thomas J Jayachandran NV Shenoy Chandrasekhara PK Lakshmi V Narsimulu G Melioidosis an unusual cause of septic arthritis Clin Rheumatol 2008 27 Suppl 2 S59 61 18506568 22 Morse LP Smith J Mehta J Ward L Cheng AC Currie BJ Osteomyelitis and septic arthritis from infection with Burkholderia pseudomallei: A 20-year prospective melioidosis study from Northern Australia J Orthop 2013 10 86 91 24403756 23 Teparrukkul P Nilsakul J Dunachie S Limmathurotsakul D Clinical epidemiology of septic arthritis caused by Burkholderia pseudomallei and other bacterial pathogens in Northeast Thailand Am J Trop Med Hyg 2017 97 1695 701 29016319 24 Currie BJ Fisher DA Howard DM Burrow JN Neurological melioidosis Acta Trop 2000 74 145 51 10674643 25 Deuble M Aquilina C Norton R Neurologic melioidosis Am J Trop Med Hyg 2013 89 535 9 23836574 26 Currie BJ Jacups SP Cheng AC Fisher DA Anstey NM Huffam SE Melioidosis epidemiology and risk factors from a prospective whole-population study in Northern Australia Trop Med Int Health 2004 9 1167 74 15548312 27 Tipre M Kingsley PV Smith T Leader M Sathiakumar N Melioidosis in India and Bangladesh: A review of case reports Asian Pac J Trop Med 2018 11 320 9 28 Radhakrishnan A Behera B Mishra B Mohapatra PR Kumar R Singh AK Clinico-microbiological description and evaluation of rapid lateral flow immunoassay and PCR for detection of Burkholderia pseudomallei from patients hospitalized with sepsis and pneumonia: A twenty-one months study from Odisha, India Acta Trop 2021 221 105994 34118206

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-88 10.4103/jgid.jgid_235_22 Letters to Editor A Very Rare Combination of Hantavirus Cardiopulmonary Syndrome and Hanta Hemorrhagic Fever with Renal Syndrome Reddy Sudha Prasanth Narang Kunal Kumar Patil Suraj Rajendra Department of General Medicine, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India Address for correspondence: Dr. Sudha Prasanth Reddy, Department of General Medicine, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam - 603 103, Tamil Nadu, India. E-mail: sprashanthreddy100@gmail.com Apr-Jun 2023 02 5 2023 15 2 8889 10 12 2022 06 1 2023 07 1 2023 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body pmcSir, Hantavirus in humans is less commonly reported because the disease is either asymptomatic or mimics other common illnesses such as scrub typhus, leptospirosis, malaria, and dengue fever. The two variants of hantavirus are HCPS reported from Brazil, Argentina, Chile, and HFRS reported from European and Asian countries.[1-3] Herein, we present a unique case with classical features of HCPS and HFRS combination. A 21-year-old presented with complaints of 6 days of fever, upper abdominal pain, nausea, and body pain. Five days after the onset of fever, he developed breathlessness Grade-II (NYHA) that progressed to Grade-IV (NYHA) in a day, along with palpitations and headache. On examination, the patient was tachypneic with generalized sweating, Glasgow Coma Scale-15/15, pulse rate −130 bpm, blood pressure −100/60 mmHg, respiratory rate −60 cpm, saturation − 65% in room air, and 96% with continuous positive airway pressure. Mild icterus was present along with JVP elevation to 10 cm H20. Bilateral diffuse crepitations were present with tenderness over the right hypochondriac and epigastric regions. On catheterization, high-frothy, red-colored urine were collected. ABG showed metabolic acidosis with respiratory alkalosis. Investigations favored AKI and hemodialysis was planned. The patient had persistent thrombocytopenia and developed hypotension on his 2nd day. Two-dimensional echo showed global hypokinesia with reduced ejection fraction and he was started on noradrenaline infusion. The patient developed a conjunctival hemorrhage of the right eye on the 3rd day. Computed tomography (CT) abdomen and pelvis stated hepatosplenomegaly with mild ascites. Testing is done for scrub, leptospirosis, dengue, and malaria turned out to be negative. Acute inflammatory markers were highly elevated. The cardiac panel showed a picture of myocarditis. Blood and urine cultures were negative. After 4 days of intensive care unit (ICU) stay, the condition improved. The patient’s father also had similar complaints and was treated symptomatically in the ICU just 1 week before the events. Considering the similar presentation in two people living in close quarters, the patient was tested for and confirmed to be hantavirus immunoglobulin M (IgM) positive. Hantavirus infection is a very rare presentation in Asian countries. To hasten diagnosis, commercial enzyme-linked immunosorbent assay and indirect immunofluorescence assay were used to detect anti-hantavirus IgM and immunoglobulin G. After ruling out the most probable diagnoses and in view of acute pulmonary renal syndrome with highly suspicious infective etiology, the patient was tested and confirmed to be anti-hantavirus IgM positive with evident features of both HCPS and HFRS. High-resolution CT revealed confluent consolidation in bilateral lung fields with multicentric ground-glass patches in the upper lobe as seen in Figure 1. Figure 1 HRCT chest of the patient. HRCT: High-resolution computed tomography Although very rare, hantavirus should be considered a differential diagnosis because of its high mortality rate of almost 40%. Immediate medical intervention will be life-saving and early courses of anti-inflammatory measures could prevent cytokine storms.[4-6] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Research quality and ethics statement Authors followed applicable EQUATOR Network (https://www.equator-network.org/) guidelines, notably the CARE guideline, during the conduct of this report. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Available from: http://www.cdc.gov/ncidod/diseases/hanta/hps [Last accessed on 2021 Nov 16] 2 Avšič-Županc T Saksida A Korva M Hantavirus infections Clin Microbiol Infect 2019 21S e6 16 24750436 3 Sheedy JA Froeb HF Batson HA Conley CC Murphy JP Hunter RB The clinical course of epidemic hemorrhagic fever Am J Med 1954 16 619 28 13148204 4 Lee HW Baek LJ Johnson KM Isolation of Hantaan virus, the etiologic agent of Korean hemorrhagic fever, from wild urban rats J Infect Dis 1982 146 638 44 6127366 5 Brummer-Korvenkontio M Vaheri A Hovi T von Bonsdorff CH Vuorimies J Manni T Nephropathia epidemica: Detection of antigen in bank voles and serologic diagnosis of human infection J Infect Dis 1980 141 131 4 6102587 6 Avsic-Zupanc T Xiao SY Stojanovic R Gligic A van der Groen G LeDuc JW Characterization of Dobrava virus: A Hantavirus from Slovenia, Yugoslavia J Med Virol 1992 38 132 7 1360999

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-52 10.4103/jgid.jgid_179_22 Original Article Etiological Profile and Clinico Epidemiological Patterns of Acute Encephalitis Syndrome in Tamil Nadu, India Kumar Vijayan Senthil Sivasubramanian Srinivasan Padmanabhan Padmapriya Anupama Cherayi Padinjakare Ramesh Kiruba Gunasekaran Palani Krishnasamy Kaveri Kitambi Satish Srinivas 1 Department of Virology, State Viral Research and Diagnostic Laboratory, King Institute of Preventive Medicine and Research, Chennai, Tamil Nadu, India 1 Department of Translational Sciences, Institute for Healthcare Education and Translational Sciences, Hyderabad, Telangana, India Address for correspondence: Dr. Satish Srinivas Kitambi, Department of Translational Sciences, Institute for Healthcare Education and Translational Sciences, 10-2-311, Plot 187, Str 4, Cama Manor, West Marredpally, Secunderabad - 500 026, Telangana, India. E-mail: satish.kitambi@klife.info Apr-Jun 2023 02 5 2023 15 2 5258 20 9 2022 03 11 2022 15 12 2022 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Introduction: Establishing the etiological cause of acute encephalitis syndrome (AES) is challenging due to the distinct distribution of various etiological agents. This study aims to determine the etiological profiles of both viruses and bacteria and their associated clinico-epidemiological features among the AES suspected cases in Tamil Nadu, India. Methods: Samples of 5136 suspected AES cases from January 2016 to December 2020 (5 years) were subjected to the detection of etiological agents for AES through serological and molecular diagnosis methods. Further, the clinical profile, age- and gender-wise susceptibility of cases, co-infection with other AES etiological agents, and seasonality pattern with respect to various etiological agents were examined. Results: AES positivity was established in 1480 cases (28.82%) among the 5136 suspected cases and the positivity for male and female groups were 57.77% and 42.23%, respectively. The pediatric group was found to be more susceptible than others. Among the etiological agents tested, the Japanese encephalitis virus (JEV) was the predominant followed by Cytomegalovirus, Herpes Simplex virus, Epstein–Barr virus, Varicella Zoster virus, and others. Co-infection with other AES etiological agents was observed in 3.5% of AES-positive cases. Seasonality was observed only for vector-borne diseases such as JEV, dengue virus, and West Nile virus infections in this study. Conclusion: AES was found to be a significant burden for Tamil Nadu with a diverse etiological spectrum including both sporadic and outbreak forms. Overlapping clinical manifestations of AES agents necessitate the development of region-specific diagnostic algorithm with distinct etiological profiles for early detection and effective case management. Acute encephalitis diagnosis endemic etiology India leptospirosis scrub typhus viruses ==== Body pmcINTRODUCTION Acute encephalitis syndrome (AES) is characterized by an acute onset of fever and neurological manifestations such as disorientation, mental confusion, delirium, or coma. Viruses are the major causative organisms of AES, though other sources such as bacteria, fungus, parasites, and chemicals or toxins have been reported and definitive diagnosis remains elusive and challenging in most cases.[1] Occurrences of sporadic or outbreak forms are the most common epidemiological patterns of AES resulting in high mortality rates, especially among children aged below 12 years and the incidence rate was found to be about 1.4 per lakh pediatric population.[2] The causative agents of outbreaks of encephalitis largely depend on the geographic distribution of the etiological agent in addition to the environmental, seasonal, virus, and host factors. AES is a major public health problem in India necessitating its surveillance and monitoring through a diagnosis of causative agents indicated in AES. Since 1955, sporadic cases and outbreaks of AES in India have been attributed mainly to the Japanese encephalitis virus (JEV), which is also the leading cause of viral encephalitis in Asia resulting about 50,000 cases of death each year, especially among the pediatric population. It is reported that about 7,500 cases of Japanese encephalitis (JE) occur annually in India during epidemic periods with a morbidity rate ranging between 0.3 and 1.5 in 1 lakh population.[3] Indian states such as Uttar Pradesh (UP), Bihar, Assam, West Bengal, and Tamil Nadu are identified as JE endemic zones. However, other viruses such as Chandipura virus, Nipah virus, Enteroviruses, dengue, chikungunya, West Nile virus (WNV), Varicella Zoster virus (VZV), Parvovirus B4 and Herpes Simplex virus (HSV) are also reported to be the causative agents of AES in India suggesting that AES cases have shifted toward the JE etiology post-2012, especially in North-Eastern, Northern, and Southern India.[1,4-7] Recent outbreak investigations and surveillance studies have increasingly reported non-JE and non-viral etiologies in AES, indicating a changing epidemiological pattern or the use of efficient diagnostic tests.[5] In India, most of the AES cases have been investigated during outbreak investigations where the focus is only on one virus. Even in hospital-based studies, cases of dual infection have either been underreported or not been investigated properly. These findings suggest the necessity to adopt definitive diagnostic methods for treatment and management as well as to explore newer strategies for the prevention of AES beyond vector control and JEV vaccination. In the absence of vaccines against various AES etiological agents as well as considering the fact that AES in India has not been restricted to the JE etiology, diagnosis of infectious agents developing AES is necessary. Clinical and neurological tests can usually diagnose encephalitis condition but do not establish the etiologic cause that often remains unknown. Confirmative diagnosis of etiological viral agents of AES using improved detection methods supports surveillance and effective management of illness due to AES as some of these infections are treatable or preventable. Though cases of AES have been reported from several states of India such as Rajasthan, Odisha, Uttar Pradesh, West Bengal, and Maharashtra, the etiological agents have been identified in only 20%–30% of cases.[8] The profile of agents causing AES varies widely in the country.[1,9] Reports on the incidence and seasonality of AES across diverse geographical regions of India are available. However, the incidence of AES with respect to various etiological agents and the associated burden in Tamil Nadu is not characterized as reports on AES etiology are scarce. Hence, this study focuses on the diagnosis of AES causative agents in suspected samples collected during the years 2016–2020 with special reference to the context of Tamil Nadu state of India. In addition, this study provides the clinico-epidemiological features of AES due to common etiological agents for not only understanding the trend and status of AES in this tropical region but also for finding out the need of developing region-specific diagnostic algorithm for AES. METHODS Study region and case criteria This study was taken up to elicit the common causative agents of AES in a clinical setting in Tamil Nadu, India, from January 1, 2016, to –December 31, 2020. The cerebrospinal fluid (CSF) and serum samples for the routine viral diagnosis of AES cases from tertiary care Government Hospitals as well as Private Hospitals in various districts of Tamil Nadu were obtained and processed at the Department of Health Research (DHR)/Indian Council of Medical Research Grade 1 Viral Research and Diagnostic Laboratory (VRDL), King Institute of Preventive Medicine and Research (KIPMR), Chennai, which is also the State Apex Lab for Viral Diagnosis (DHR, Government of India). The study was approved by Institutional Ethical Committee. Inclusion criteria include samples that were collected from patients with AES as defined by the World Health Organization.[10] AES is defined as a person of any age, at any time of year with the acute onset of fever and a change in mental status and/or new onset of seizures (sudden violent attack of an illness). Patients suffering from other febrile illnesses or simple febrile seizures were excluded from the study. Blood and CSF samples were collected from suspected cases of AES with prior informed consent from the patients/parents/guardians. Proforma was filled in detail with patient information and signs and symptoms including fever, seizures, change in mental status, rashes, trauma, breathlessness, etc. Samples were labeled and transported to laboratory in the cold chain, serum separated and stored at –20°C till tested for enzyme-linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) tests. Samples were processed in accordance with established standard operating procedures in the laboratory. Serological studies Antibody detection from the suspected clinical samples is the most effective method of diagnosing AES. Nearly all AES-infected individuals are seropositive for immunoglobulin (Ig)M antibody within 14 days of the onset of symptoms. The National Institute of Virology, Pune, IgM antibody Capture ELISA is used for the diagnosis of JEV, Dengue, and Chikungunya infection. IgM ELISA is used for the detection of WNV and Scrub typhus (InBios International, USA). The HSV IgM antibodies in serum are detected using DIALAB kit. VZV, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Parvo B19, and Mumps were detected using IgM ELISA (NovaTec Immundiagnostica GmbH). Rubella was detected by the Anti-Rubella virus Glycoprotein IgM ELISA (Euroimmun). The IgM ELISA (PanBio, Australia) is used for the detection of Leptospira. ELISA experiments were performed following the Manufacturer’s Instructions. Polymerase chain reaction experiments PCR is a sensitive technique for identifying the viral genome of HSV, CMV, and Enterovirus in CSF. The CSF samples collected within 5 days from the date onset of illness were subjected to Conventional PCR and reverse transcription (RT)-PCR. Briefly, viral RNA and viral DNA from AES suspected samples were extracted using QIAmp Viral RNA mini kit and QIAmp DNA mini kit (QIAGEN, Germany) according to the Manufacturer’s Instructions. PCR (Pan HSV and CMV and RT-PCR (Pan enterovirus) experiments were performed as per the methods reported in the previous studies[11-13] [Table 1]. Each assay was run using a positive control and a negative control. Nucleic acid was either processed immediately for PCR amplification or stored at −80°C for further use. Table 1 Primers used for the detection of viruses causing acute encephalitis syndrome by polymerase chain reaction and reverse transcription-polymerase chain reaction Virus Gene target Primer Amplicon size Sequence 5’ - 3’ Pan HSV (nested PCR) Glycoprotein D Forward 382 bp (round 1) ATCCGAACGCAGCCCCGCTG Reverse TCCGG (G/C) GGCAGCAGGGTGCT Forward 289 bp (round 2) GCGCCGTCAGCGAGGATAAC Reverse AGCTGTATA (G/C) GGCGACGGTG CMV Hind III-X fragment Forward 406 bp GGATCCGCATGGCATTCACGTATGT Reverse GAATTCAGTGGATAACCTGCGGCGA Pan Enterovirus 5 NCR Forward 440 bp CAAGCACTTCTGTTTCCCCGG Reverse ATTGTCACCATAAGCAGCCA HSV: Herpes simplex virus, PCR: Polymerase chain reaction, CMV: Cytomegalovirus, NCR: Noncoding region Statistical analyses The retrospective statistical analysis was carried out using GraphPad Prism version 5.0, GraphPad Software, San Diego, CA. For studies on gender-wise distribution, intergroup comparison of variables was performed using Fisher’s exact test through Chi-square analysis. For age group distribution studies, regression analysis was performed for various etiological agents in AES. p < 0.05 was considered statistically significant. RESULTS AND DISCUSSION Patient characteristics The present study describes the etiological and clinico-epidemiological characteristics of AES in Tamil Nadu from January 2016 to December 2020. Samples from a total of 5136 suspected AES cases during the study were screened for the detection of etiological agents for AES through serological and molecular diagnosis. Among the screened cases, male and female groups respectively had 2911 (56.68%) and 2225 (43.32%) cases. AES positivity was established in 1480 cases (28.82%) and the positivity for AES etiological agents in male (57.77%; n = 855) and female (42.23%; n = 625) groups was not statistically significant (p = 0.009). Further, Fisher’s exact test on gender group with respect to total AES positivity showed that the groups exhibit significance (p < 0.05) though the groups showed insignificant p value for all other etiological agents except JEV indicating JEV was the predominant etiological agent among others in this study [Table 2]. It was observed that AES positivity was higher in males than females and the male group had more cases than females with respect to all the etiological agents studied except chikungunya virus (CHIKV), which was diagnosed equally among the gender groups. The study observations on 28.82% AES positivity among AES suspected cases could be correlated or compared with reports of other studies conducted in India. These studies have reported AES positivity in the range of 17.20%–29.81% in different parts of India, at Odisha (17.2%),[14] Uttar Pradesh (21.83%),[15] Rajasthan (22.73%),[9] and West Bengal (29.81%);[9] however, in contrast, other studies from India reported higher positivity ranging between 58.4% and 71.9% in some states, at Uttar Pradesh (58.4%),[16] at Karnataka (59.9%)[17] and at New Delhi (72%).[18] Our findings are also in agreement with earlier studies across the world, especially in developed countries as AES with unidentified etiology were observed among AES-suspected patients from the United States (59.5%), United Kingdom (60%), and Australia (69.6%) suggesting that this trend seems to occur even in the presence of extensive laboratory expertise.[19] It has to be noted that the number of AES cases varies from year to year. This variation in the sample size shown here directly corresponds to the number of samples that were sent to our laboratory for analysis. We have taken care to include all the samples in this study. The variation also depends on the number of patients that were diagnosed in that particular year and their samples sent to our laboratory for further analysis. Table 2 Age- and sex-wise distribution of acute encephalitis syndrome cases with established etiology Agent Age-wise distribution, positive (%) Gender-wise distribution, positive (%) 0-12 years (n=2757) 13-18 years (n=353) 19-30 years (n=557) 31-55 years (n=998) >56 years (n=471) p Males (n=2768) Females (n=2368) p JE (n=608) 236 66 94 128 84 0.0001 364 244 0.005 EBV (n=125) 58 17 19 22 9 0.01 74 51 0.27 HSV (n=188) 96 17 18 42 15 0.59 98 90 0.68 CMV (n=223) 109 24 40 39 11 0.0005 123 100 0.76 VZV (n=92) 22 13 22 24 11 <0.0001 52 40 0.69 Mumps (n=32) 25 1 0 4 2 0.068 23 9 0.06 Measles (n=5) 2 1 0 0 2 0.08 4 1 0.47 Rubella (n=5) 4 0 0 0 1 0.53 3 2 0.86 Dengue (n=33) 15 5 8 4 1 0.02 21 12 0.34 WNV (n=11) 4 1 2 3 1 0.81 7 4 0.73 Chikungunya (n=30) 4 3 5 8 10 <0.0001 15 15 0.80 EV (n=14) 5 3 3 3 0 0.09 8 6 0.98 Scrub typhus (n=52) 21 7 5 11 8 0.12 29 23 0.89 Leptospirosis (n=62) 32 4 6 9 11 0.21 34 28 0.98 Total 633 162 222 297 166 <0.0001 855 625 0.009 EBV: Epstein-Barr virus, HSV: Herpes simplex virus, CMV: Cytomegalovirus, VZV: Varicella-zoster virus, JE: Japanese encephalitis, WNV: West Nile virus, EV: Enterovirus Age-wise distribution for different etiological agents in positive cases in Table 2 reveals that the age group of 0–12 years has more cases than the other groups indicating that the pediatric group is more susceptible than others. Among pediatric suspects (n = 2757, age <12 years), the etiology of AES could be confirmed in 633 patients (22.96%), while among adults (n = 1352, age ≥12 years) the etiology could be confirmed in 322 patients (35.60%). The statistical analysis of overall AES positivity and individual etiological agents in the AES-positive cases with respective to AES suspects indicates statistical significance (p < 0.05) except the agents such as dengue virus (DENV), WNV, CHIKV, and Enterovirus suggesting that these viruses are not very significant causative agents of AES in this study. This observation is further confirmed by the data on the diagnosis of etiological agents in AES suspects and the study shows that JEV (11.84%) is the most predominant causative agent among AES suspects, which is followed by CMV (4.34%), HSV (3.66%), EBV (2.43%), VZV (1.79%), Leptospirosis (1.21%), Scrub typhus (1.01%), DENV (0.64%), Mumps (0.62%), CHIKV (0.58%), Enterovirus (0.27%) and WNV (0.21%) [Tables 2 and 3]. Several of the etiological agents were found predominantly in 0–12 years of group when compared to other age groups except CHIKV, WNV, and Enterovirus, which were detected more in adults. Besides, AES cases having co-infection with other etiological agents of AES (3.85%) were also observed in this study. Among the co-infection, notable cases are JEV with either HSV (n = 7) or CMV (n = 5), EBV with VZV (n = 9), and HSV with CMV (n = 7). It is also important to note that co-infection with more than two etiological agents (0.61% of total AES positives) were also observed. One sample was found to be positive for three different arboviruses such as JEV, CHIKV, and DENV. Among the cases of co-infection, the predominant agent was JEV which is followed by EBV and HSV in the study. A study reported JEV positivity (16.2%) among AES suspects and JEV was the predominant causative agent followed by DENV and HSV.[16] Co-infection of more than one AES etiological agent was reported by few studies. A report observed the co-infection of arboviruses such as JEV with WNV in an AES patient.[20] In another study, co-positivity of AES agents such as JEV and DENV, HSV and Mumps, and Measles and Mumps was found in 1.3% of AES-confirmed cases.[16] Table 3 Clinical profile of patients diagnosed with varied acute encephalitis syndrome etiology (percentage positivity) and unknown etiology among acute encephalitis syndrome suspected samples Symptoms JE (n=608; 11.84%), n (%) EBV (n=125; 2.43%), n (%) HSV (n=188; 3.66%), n (%) CMV (n=223; 4.34%), n (%) VZV (n=92; 1.79%), n (%) Mumps (n=32; 0.62%), n (%) Measles (n=5; 0.1%), n (%) Rubella (n=5; 0.1%), n (%) Dengue (n=33; 0.64%), n (%) Fever 473 (77.80) 90 (72) 162 (86.17) 144 (64.57) 63 (68.48) 15 (46.88) 3 (60) 3 (60) 31 (93.94) Seizure 271 (44.57) 66 (52.8) 99 (52.66) 109 (48.88) 40 (43.48) 15 (46.88) 0 2 (40) 12 (36.36) Headache 122 (20.06) 3 (2.4) 13 (6.91) 1 (0.45) 2 (2.17) 0 0 0 4 (12.12) Myalgia 56 (9.21) 2 (1.6) 7 (3.72) 3 (1.35) 0 0 0 0 3 (9.09) Arthralgia 40 (6.27) 0 0 0 0 0 0 0 2 (6.06) Altered sensorium 265 (43.59) 45 (36) 73 (38.83) 59 (26.46) 23 (25) 18 (56.25) 3 (60) 4 (80) 9 (27.27) Neck rigidity 156 (25.66) 27 (21.6) 94 (50) 36 (16.14) 10 (10.87) 11 (34.38) 1 (20) 2 (40) 9 (27.27) Irritability 208 (34.21) 42 (33.6) 62 (32.98) 72 (32.29) 18 (19.57) 16 (50) 0 3 (60) 11 (33.33) Change in mental status 240 (39.47) 36 (28.8) 60 (31.91) 50 (22.42) 27 (29.35) 18 (56.25) 2 (40) 5 (100) 9 (27.27) Somnolence 75 (12.34) 12 (9.6) 18 (9.57) 22 (9.87) 7 (7.61) 12 (37.5) 1 (20) 1 (20) 1 (3.03) Vomiting 10 (1.64) 4 (3.2) 0 7 (3.14) 1 (1.09) 0 0 0 3 (9.09) Diarrhoea 5 (0.82) 2 (1.6) 7 (3.72) 0 0 0 (0) 0 0 0 Symptoms Dengue (n=33; 0.64%), n (%) WNV (n=11; 0.21%), n (%) CHIKV (n=30; 0.58%), n (%) EV (n=14; 0.27%), n (%) Scrub typhus (n=52; 1.01%), n (%) Leptospirosis (n=62; 1.21%), n (%) Unknown etiology (n=3656; 71.18%) n (%) p Fever 31 (93.94) 6 (54.55) 29 (96.67) 8 (57.14) 51 (98.07) 56 (90.32) 2572 (70.35) 0.52 Seizure 12 (36.36) 5 (45.45) 13 (43.33) 5 (35.71) 22 (42.31) 16 (25.81) 1489 (40.73) 0.68 Headache 4 (12.12) 0 0 2 (14.29) 3 (5.77) 30 (48.39) 119 (3.25) <0.0001 Myalgia 3 (9.09) 0 5 (16.67) 1 (7.14) 0 18 (29.03) 107 (2.92) <0.0001 Arthralgia 2 (6.06) 0 9 (30) 0 0 7 (11.29) 24 (0.66) <0.0001 Altered sensorium 9 (27.27) 0 9 (30) 2 (14.29) 16 (30.77) 1 (1.61) 1438 (39.33) <0.0001 Neck rigidity 9 (27.27) 0 5 (16.67) 1 (7.14) 16 (30.77) 0 838 (22.92) <0.0001 Irritability 11 (33.33) 4 (36.36) 6 (20) 1 (7.14) 19 (36.54) 0 590 (16.14) 0.0017 Change in mental status 9 (27.27) 3 (27.27) 4 (13.33) 2 (14.29) 21 (40.38) 6 (9.68) 798 (21.83) 0.0011 Somnolence 1 (3.03) 0 2 (6.67) 0 3 (5.77) 0 189 (5.17) 0.0023 Vomiting 3 (9.09) 1 (9.09) 1 (3.33) 1 (7.14) 0 17 (27.42) 156 (4.27) <0.0001 Diarrhoea 0 0 1 (3.33) 1 (7.14) 0 11 (17.74) 82 (2.24) <0.0001 JE: Japanese encephalitis, EBV: Epstein-Barr virus, HSV: Herpes simplex virus, CMV: Cytomegalovirus, VZV: Varicella zoster virus, WNV: West Nile virus, CHIKV: Chikungunya virus, EV: Enterovirus Viral and bacterial etiological profiles of acute encephalitis syndrome and their clinical spectrum Among the causative organisms identified, JEV was predominant in all the study years except 2017, which had more EBV positives, and the total number of JEV-positive cases in the study period was 608 (41.08%) among the total AES positives [Figure 1]. The highest number of JEV (n = 270) was observed in the year 2019 and this was two- to three-fold higher than the cases of previous years suggesting the increased incidence of JEV in recent years. JEV has been reported as the main cause of encephalitis in tropical countries including India wherein it occurs both sporadically and in outbreaks with high mortality. An earlier study from Tamil Nadu reported that JEV etiology was confirmed in 27.3% of the hospitalized encephalitic children.[21] In another study conducted in Assam, JE etiology was confirmed in 30% of total AES suspects.[22] However, there are studies from India that report the predominant causative agent was not JEV but HSV,[9,14] EBV,[17] Enterovirus-71,[15,23] scrub typhus,[24] and co-infections reflecting the changing landscape of AES in India. Although HSV is the chief causative agent of acute-onset sporadic encephalitis in developed countries, data on its significance on AES is largely unknown. Figure 1 Year-wise distribution of AES cases. AES: Acute encephalitis syndrome Apart from JEV, herpesviruses such as EBV, VZV, and CMV were identified as other important AES causative agents in all the study years whereas HSV was the significant causative agent in the year 2020 followed by JEV. Scrub typhus and Leptospirosis were observed in AES suspects during the years 2016–2018 but absent in the years 2019 and 2020 and this might be due to a reduction in referral of cases for these agents or low incidence of AES cases due to these pathogens. The positivity for these agents was low (1.01%–1.21%) among the AES positives in this study. These nonviral agents present a range of AES symptoms including neurological manifestations such as seizures and change in mental status. It was reported that about 20% of AES cases were due to scrub typhus (Orientia tsutsugamushi infection) in Assam, India.[25] Another study reported that 62.7% of AES patients from Gorakhpur of Uttar Pradesh had O. tsutsugamushi IgM, with a case-fatality rate of 16.2%.[26] Neurological manifestations were indicated in substantial scrub typhus patients from Tamil Nadu.[27] These findings suggest that Scrub typhus can be considered as part of the surveillance algorithm for AES cases in India. It is to be noted that the AES positivity varies across different states of India and it depends on various factors such as the geographical location, type of etiological agents included in the diagnosis panel; study samples, diagnostic methods included in the study; regions characterized for etiological endemicity, significance of vector distribution and their increased density, especially for agents with definite seasonality, occurrence of any epidemic during the study, etc. The most common clinical presentation was fever followed by seizure, altered sensorium, irritability, and change in mental status through other symptoms such as headache, vomiting, neck rigidity, and diarrhea were also present in several cases [Table 3]. Observations on clinical presentations of AES cases will also support syndromic case management in situations lacking a laboratory investigation facility. However, several of the etiological agents produce similar symptoms in AES suspects, definitive diagnosis is essential for case management [Figure 2]. Figure 2 Symptoms of AES cases. AES: Acute encephalitis syndrome Seasonality of acute encephalitis syndrome A definite seasonality was observed for JEV, DENV, and WNV infections in this study; the high positivity was observed from October to December including North East Monsoon and Winter seasons in this tropical region of India coinciding with increased population density of vector mosquitoes [Figure 3]. Mean rainfall and temperature profiles were presented for this tropical study region [Figure 4]. Such seasonal distribution was not clearly observed for other etiological agents. In many states, AES outbreaks occur during the rainy season and are associated with high mortality rates. Seasonality was reported for JEV and dengue infections and high positivity was observed from July to November in the Northern states, which includes monsoon and post-monsoon seasons.[16] However, such seasonal distribution was not evident for other viral agents of AES.[1] With the onset of winter, JE incidence declined substantially.[28] Reports also showed that there was a seasonal variation, AES becomes epidemic between March and July and peak incidence was seen in June.[29] The study also reported that AES becomes epidemic in Lychee season, April–June. In the present study, AES-suspected samples were received from several districts of Tamil Nadu, and AES positivity was observed in samples from the districts such as Chennai, Thiruvallur, Kanchipuram, Tiruvannamalai, Vellore, Krishnagiri, Dharmapuri, Villupuram, Cuddalore, Thanjavur, Thiruvarur, Tiruchirapalli, Pudukkottai, Perambalur, Nagapattinam, Erode, Salem, Tiruppur, Coimbatore, Theni, Tirunelveli, Madurai, Tuticorin, and Pondicherry (Union Territory) suggesting the magnitude of burden due to AES as well as distribution of various AES causative agents in this state. AES can occur as both vector borne or sporadic, however, the vector-born accounts for the maximum cases in tropical and subtropical countries[30] such as India/Tamil Nadu. This is particularly challenging because control of vector population, such as mosquitoes has a direct impact on the prevalence of AES and the number of cases that are detected each year. Figure 3 Seasonal distribution of AES cases (January 2016–December 2020). AES: Acute encephalitis syndrome Figure 4 Rainfall and Temperature profiles of the study period Encephalitis is of public health importance worldwide because it has high morbidity and mortality. The National Vector-borne Disease Control Program reported more than 50,000 cases of AES in India during 2013–2017 with mortality rate of 12.23% and states such as Uttar Pradesh, Assam, West Bengal, Odisha, Tamil Nadu, Karnataka, and Manipur accounted for most cases in these recent years.[31] Tamil Nadu has accounted for 6.36% among these reported cases and the state has shown a substantial increase in the number of cases reported during the years. In the year 2017 alone, the state has witnessed 10% of total AES cases reported in the country and among the total AES cases, JEV etiology is established in 8.87% suggesting the importance of the detection of non-JE etiology in AES. Although AES cases are frequently being reported in India, examining the actual burden as well as establishing the etiology is associated with diagnostic challenges even in an established resource set up beside the fact that a wide range of Central nervous system disorders, both infectious and noninfectious, may present the illness alike. The symptoms and clinical presentations manifested by a range of pathological agents in AES often look similar, which is a major diagnostic challenge in establishing the etiology. There is a paucity of data on the regional epidemiology and etiology of AES in India. Though epidemics have a singular etiology, sporadic cases could be due to multiple etiologies requiring the diagnosis of the spectrum of agents for effective surveillance. Currently, there is no single method available for facilitating the simultaneous detection of all pathogens causing AES. The study has a limitation in terms of not accounting for the mortality among the AES suspects as well as long-term sequelae of patients. It is also limited by the fact that other possible etiologies and co-infections have not been addressed in this study. Notwithstanding these limitations, the study has focused in detail on establishing both the important viral and nonviral etiologies of AES with a high number of AES suspect samples. Besides, the study has given the etiologic and epidemiological spectrum of AES relevant to the region which would be helpful for the policymakers to take specific action not only for prevention and control of AES but also for definitive management of the patients that may improve the outcome both in terms of morbidity and mortality. CONCLUSION The diverse etiological and clinical spectrum of AES including both sporadic and outbreak forms underscores the prevailing burden in Tamil Nadu, a state in South India. Overlapping clinical manifestations of AES agents and varying AES epidemiological profiles across India substantiate the need of developing region-specific surveillance algorithm for AES based on the distribution of etiological agents and prioritization of diagnostic tests to advance the confirmation of etiology in more AES suspects and reporting of AES more effectively than before. Research quality and ethics statement This study was conducted after obtaining ethical permission from the King Institute for Preventive Medicine and Research Institutional Review Board and the approval number is IRB# KIPM/IEC/017. The authors followed applicable EQUATOR Network (https://www.equator-network.org/) guidelines during the conduct of this research project. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgments We are grateful to the DHR, New Delhi, for financial support for all the diagnoses described in this study and also for establishing State VRDL, where these experiments were carried out. The authors would like to thank Institute for Healthcare Education and Translational Sciences and Kitambi Foundation for generously supporting this study. ==== Refs REFERENCES 1 Joshi R Kalantri SP Reingold A Colford JM Jr Changing landscape of acute encephalitis syndrome in India: A systematic review Natl Med J India 2012 25 212 20 23278779 2 Kakkar M Rogawski ET Abbas SS Chaturvedi S Dhole TN Hossain SS Acute encephalitis syndrome surveillance, Kushinagar district, Uttar Pradesh, India, 2011-2012 Emerg Infect Dis 2013 19 1361 7 23965505 3 Ravi V Mani RV Govekar SR Desai A Lakshman L Ravikumar B Aetiology and laboratory diagnosis of acute encephalitis syndrome with special reference to India J Commun Dis 2014 46 12 23 4 Reuben R Gajanana A Japanese encephalitis in India Indian J Pediatr 1997 64 243 51 10771844 5 Kumar R Viral encephalitis of public health significance in India: Current status Indian J Pediatr 1999 66 73 83 10798039 6 Benjamin LA Lewthwaite P Vasanthapuram R Zhao G Sharp C Simmonds P Human parvovirus 4 as potential cause of encephalitis in children, India Emerg Infect Dis 2011 17 1484 7 21801629 7 Ghosh S Basu A Acute encephalitis syndrome in India: The changing scenario Ann Neurosci 2016 23 131 3 27721580 8 Tunkel AR Glaser CA Bloch KC Sejvar JJ Marra CM Roos KL The management of encephalitis: Clinical practice guidelines by the infectious diseases society of America Clin Infect Dis 2008 47 303 27 18582201 9 Tiwari JK Malhotra B Chauhan A Malhotra H Sharma P Deeba F Aetiological study of viruses causing acute encephalitis syndrome in North West India Indian J Med Microbiol 2017 35 529 34 29405145 10 Recommended Standards for Surveillance of Selected Vaccine Preventable Diseases Geneva WHO 2003 11 McIver CJ Jacques CF Chow SS Munro SC Scott GM Roberts JA Development of multiplex PCRs for detection of common viral pathogens and agents of congenital infections J Clin Microbiol 2005 43 5102 10 16207970 12 Cotte L Drouet E Bissuel F Denoyel GA Trepo C Diagnostic value of amplification of human cytomegalovirus DNA from gastrointestinal biopsies from human immunodeficiency virus-infected patients J Clin Microbiol 1993 31 2066 9 8396587 13 Zoll GJ Melchers WJ Kopecka H Jambroes G van der Poel HJ Galama JM General primer-mediated polymerase chain reaction for detection of enteroviruses: Application for diagnostic routine and persistent infections J Clin Microbiol 1992 30 160 5 1370845 14 Rathore SK Dwibedi B Kar SK Dixit S Sabat J Panda M Viral aetiology and clinico-epidemiological features of acute encephalitis syndrome in eastern India Epidemiol Infect 2014 142 2514 21 24476571 15 Beig FK Malik A Rizvi M Acharya D Khare S Etiology and clinico-epidemiological profile of acute viral encephalitis in children of western Uttar Pradesh, India Int J Infect Dis 2010 14 e141 6 20106698 16 Jain P Jain A Kumar A Prakash S Khan DN Singh KP Epidemiology and etiology of acute encephalitis syndrome in North India Jpn J Infect Dis 2014 67 197 203 24858609 17 Ramamurthy M Alexander M Aaron S Kannangai R Ravi V Sridharan G Comparison of a conventional polymerase chain reaction with real-time polymerase chain reaction for the detection of neurotropic viruses in cerebrospinal fluid samples Indian J Med Microbiol 2011 29 102 9 21654102 18 Karmarkar SA Aneja S Khare S Saini A Seth A Chauhan BK A study of acute febrile encephalopathy with special reference to viral etiology Indian J Pediatr 2008 75 801 5 18769890 19 Huppatz C Durrheim DN Levi C Dalton C Williams D Clements MS Etiology of encephalitis in Australia, 1990-2007 Emerg Infect Dis 2009 15 1359 65 19788802 20 Khan SA Dutta P Chowdhury P Borah J Topno R Mahanta J Coinfection of arboviruses presenting as acute encephalitis syndrome J Clin Virol 2011 51 5 7 21382746 21 Kabilan L Ramesh S Srinivasan S Thenmozhi V Muthukumaravel S Rajendran R Hospital- and laboratory-based investigations of hospitalized children with central nervous system-related symptoms to assess Japanese encephalitis virus etiology in Cuddalore District, Tamil Nadu, India J Clin Microbiol 2004 42 2813 5 15184479 22 Kakoti G Dutta P Ram Das B Borah J Mahanta J Clinical profile and outcome of Japanese encephalitis in children admitted with acute encephalitis syndrome Biomed Res Int 2013 2013 152656 24490147 23 Joshi R Mishra PK Joshi D Santhosh SR Parida MM Desikan P Clinical presentation, etiology, and survival in adult acute encephalitis syndrome in rural Central India Clin Neurol Neurosurg 2013 115 1753 61 23643180 24 Jain P Prakash S Tripathi PK Chauhan A Gupta S Sharma U Emergence of Orientia tsutsugamushi as an important cause of acute encephalitis syndrome in India PLoS Negl Trop Dis 2018 12 e0006346 29590177 25 Khan SA Bora T Laskar B Khan AM Dutta P Scrub typhus leading to acute encephalitis syndrome, Assam, India Emerg Infect Dis 2017 23 148 50 27875108 26 Murhekar MV Mittal M Prakash JA Pillai VM Mittal M Girish Kumar CP Acute encephalitis syndrome in Gorakhpur, Uttar Pradesh, India –Role of scrub typhus J Infect 2016 73 623 6 27592263 27 Murhekar MV Acute encephalitis syndrome and scrub typhus in India Emerg Infect Dis 2017 23 1434 28726620 28 Kumari R Joshi PL A review of Japanese encephalitis in Uttar Pradesh, India WHO South East Asia J Public Health 2012 1 374 95 28615603 29 Sudhir SK Prasad MS Acute encephalitis syndrome (AES) associated with sociocultural and environmental risk factors in infants/children of Muzaffarpur, Bihar hospital based, prospective study J Evid Based Med Health 2018 5 23 6 30 Chen YH Huang KY Liu CC Weng YM Who is at risk?A critical case of Japanese encephalitis J Acute Med 2022 12 122 5 36313605 31 National Vector Borne Disease Control Program. Ministry of Health and Family Welfare, Government of India. State wise Number of AES/JE Cases and Deaths from 2010 to 2017

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-81 10.4103/jgid.jgid_76_22 Case Report A Case of Combined Infection with Tick-Borne Encephalitis and Lyme Borreliosis with Severe Meningoencephalitis and Complete Recovery Ostapchuk Yekaterina O. 12 Dmitrovskiy Andrey M. 13 Pak Elena A. 4 Perfilyeva Yuliya V. 12 1 Almaty Branch of the National Center for Biotechnology, Almaty, Kazakhstan 2 Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin’s Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan 3 National Scientific Center for Especially Dangerous Infections, Almaty, Kazakhstan 4 Taraz City Multidisciplinary Hospital, Taraz, Kazakhstan Address for correspondence: Dr. Andrey M. Dmitrovskiy, Almaty Branch of the National Center for Biotechnology, 14 Zhahanger St., Almaty 050054, Kazakhstan. E-mail: am_dmitr@mail.ru Apr-Jun 2023 31 3 2023 15 2 8183 19 4 2022 29 7 2022 13 10 2022 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Here, we present a case of severe meningoencephalitis caused by combined infection with tick-borne encephalitis (TBE) and Lyme borreliosis (LB) in a 25-year-old woman in a rural area of Zhambyl region, Kazakhstan. She presented with fever, nausea, vomiting, weakness, sweating, severe headache, arthralgia, and malaise. The course of illness was further complicated by encephalitis with symmetric lesions of the midbrain cerebral peduncles and serous meningitis. TBE and LB co-infection were established by a two-fold increase in serum IgG titers between day 21 and day 25 of illness. Both infections responded well to combined therapy with human TBE immunoglobulins, antibiotics, antiviral drugs, glucocorticoids, and diuretics. The outcome of the disease was favorable and the patient recovered completely. Borrelia burgdorferi s. l Kazakhstan lyme neuroborreliosis meningoencephalitis tick-borne encephalitis tick-borne encephalitis virus ==== Body pmcINTRODUCTION In Central Europe and many parts of Asia, tick-borne encephalitis virus (TBEV) and Borrelia burgdorferi sensu lato (s. l.), the causative agents of tick-borne encephalitis (TBE) and Lyme borreliosis (LB) are the two most important tick-borne pathogens that can lead to severe neurological complications.[1] Although several cases of co-infection with TBE and LB have been reported, there are limited data on the severe cases with prolonged meningoencephalitis followed by complete recovery of the patient.[1-3] Here, we describe a case of severe TBE and Lyme neuroborreliosis (LNB) co-infection in a woman from the Zhambyl region of Kazakhstan. CASE REPORT A 25-year-old woman presented with a fever lasting 9 days. She was inactive, had nausea, vomiting, weakness, sweating, severe headache, arthralgia, and malaise. Low titers of antibodies to Brucella bacteria were noted in the indicative Haddlson (+) and confirmatory Wright (1:50) agglutination reactions. Urinalysis showed elevated protein levels and the presence of leukocytes and erythrocytes [Table 1]. A presumptive diagnosis of brucellosis was made, and the patient started empiric treatment with nonsteroidal anti-inflammatory drugs, glucocorticoids, and kanamycin. Table 1 Laboratory findings Test Illness days Normal range Day 10 Day 12 Day 15 Day 18 Day 21 Day 30 Day 37 Day 39 Blood tests  WBCs (×103/µL) 8.8 - - - 12.9 - - 12.3 4.5-13.5  Band neutrophils (%) 2 - - - 10 - - 4 0-5  Segmented neutrophils (%) 68 - - - 62 - - 85 40-60  Monocytes (%) 7 - - - 14 - - 6 2-11  Lymphocytes (%) 23 - - - 14 - - 5 20-40  ESR (mm/h) 8 - - - 23 - - 3 <15  Total protein (mg/dL) 68.5 - - - 61.8 - 65.2 - 60-83  Glucose (mg/dL) - - - - 73 - - - 70-100  Creatinine (mg/dL) - - - - 16.0 - - - 0.45-1.05 Urine tests  Total protein (mg/24 h) - - - - 198 - - 132 <100  RBCs (/hpf) 1 - - - 1 - - 2 ≤2  WBCs (/hpf) 2 - - - 3 - - 7 ≤2–5  Squamous epithelial cells (/hpf) 2 - - - 2 - - 1 ≤15-20 CSF tests  WBCs (cells/ml) - - 85.2 13.2 - 9.6 - - 0-5  Lymphocytes (cells/ml) - - 81.6 13.2 - 3.6 - - 1-7  Total protein (mg/dL) - - 165.0 49.5 - 66.0 - - 15-60  Pandy’s test - - 3+ 1+ - 1+ - - Negative Culture tests  CSF culture Negative Negative - - - - - - Negative  Blood culture Negative Negative - - - - - - Negative WBCs: White blood cells, ESR: Erythrocyte sedimentation rate, RBCs: Red blood cells, CSF: cerebrospinal fluid, hpf: High power field On day 13, the patient showed convulsions, unconsciousness, stupor, mild neck muscle stiffness, and clonic muscle spasms of the upper and lower limbs. Magnetic resonance imaging (MRI) examination revealed brainstem encephalitis with symmetric lesions in the midbrain cerebral peduncles, dyscirculatory encephalopathy, and signs of increased intracranial pressure. Analysis of the cerebrospinal fluid (CSF) showed mild pleocytosis with high lymphocyte counts and protein concentrations. Blood and CSF culture results were negative [Table 1]. On day 16, pupils were constricted and fixed to the center. Acute meningoencephalitis of unknown etiology was diagnosed and treatment was supplemented with intravenous medovir and ofloxacin. On day 20, the patient was unable to fix her gaze, opened her mouth with difficulty, and the movement of the eyeballs was limited. Tongue tremors, hypomimia, and extrapyramidal muscle hypertonus were observed. The patient had no control over pelvic functions. On day 21, the serologic analysis revealed negative results for IgM and positive results for IgG antibodies against TBEV and B. burgdorferi s. l. On day 25, the serological analysis showed a two-fold increase in IgG titers against both TBEV and B. burgdorferi s. l. Human immunoglobulin against TBEV (international nonproprietary name – immunoglobulin encephalitis Ixodidae) and ceftriaxone (14.3 mg/kg × 2 doses for 13 days) intravenously were added to the treatment. Over the next 12 days, the patient’s level of consciousness improved and facial and ocular palsies disappeared. The meningeal symptoms disappeared on day 34, and the patient was completely afebrile on day 38 after the onset of symptoms. She was discharged on day 39 with near complete improvement and underwent long-term rehabilitation. One year after discharge, she had fully recovered and showed no neurologic sequelae. DISCUSSION Clinical recognition of combined infections is always complex because of overlapping or distorted manifestations of one or both joint infections. This case illustrates the challenges in establishing a diagnosis in a patient with TBE and LNB co-infection that resulted in severe meningoencephalitis. Acute onset of symptoms, toxemia, meningoencephalitis syndrome, lymphocytic pleocytosis in the CSF, flaccid paralysis, cranial nerve involvement, and facial hypomimia are equally compatible with TBE or LNB.[2] The clinical diagnosis of double infection was supported by a two-fold increase in the titers of IgG antibodies against TBEV and B. burgdorferi s. l. in paired serum samples. TBE develops within a few weeks,[4] and the presence of TBE-specific IgM antibodies is usually recommended to confirm the diagnosis of TBE. Interestingly, in our case, IgM antibodies against TBEV were negative despite the acute illness. Several studies have described the same phenomenon.[5] Based on the clinical signs, MRI data, and laboratory findings, we consider the diagnosis of TBE in the patient to be well-established. Laboratory diagnosis of LB is more difficult because infection with other tick-borne diseases or some viral and bacterial infections can lead to false-positive test results for LB.[6] Encephalitic symptoms caused by LNB occur in the late stage of the disease and may be observed months or even years after primary infection. In these cases, positive IgG and negative IgM results are considered reliable for establishing the diagnosis of LNB.[7] In our case, an increased titer of IgG antibodies to B. burgdorferi s. l. in paired sera collected at a short interval supported the diagnosis of LNB. The establishment of the diagnosis in our case was also challenged by the fact that TBE and LB are not endemic in the Zhambyl region of Kazakhstan.[8] Examination of the patient revealed that she had recently traveled to the endemic areas for TBE and LB, Almaty Region of Kazakhstan.[8] The patient denied a tick bite and symptoms of LB in the past, which is not unusual. It was demonstrated that only 50%60% of patients with TBE and LB report tick bites.[4,7] In Kazakhstan, TBE frequently causes meningoencephalitis leading to postencephalitic syndrome and long-term neurological morbidity.[4] Around 31.8% of TBE cases with meningoencephalitis results in upper limb paresis.[9] In the presented case, despite the severe form of meningoencephalitis, the outcome was favorable; the patient recovered completely and had no neurologic sequelae. After a diagnosis of co-infection with TBE and LNB was made, the patient was treated with human immunoglobulins against TBEV and ceftriaxone. Ceftriaxone is a preferred drug for LNB therapy.[1] Although there is no specific antiviral treatment for TBE,[4] intravenous human immunoglobulins against TBE have long been used for postexposure prophylaxis and TBE treatment. The efficacy of intravenous immunoglobulins against TBEV has not been demonstrated in clinical trials, several studies have reported their efficacy in the treatment of various clinical forms of TBE.[10] Therefore, we believe that co-infection with TBE and LNB can be successfully treated with a combination of human immunoglobulins against TBEV and antibiotics. Furthermore, this study demonstrates that patients with acute neurologic symptoms traveling to endemic areas should be evaluated for TBE and LB. The study has several limitations. The TBEV RNA detection in the serum, CSF, or urine during the acute phase of infection was not performed due to the lack of diagnostic resources in the hospital. Furthermore, anti-TBEV antibodies were not tested in CSF, whereas it is recommended to perform for confirmation of the diagnosis. Research quality and ethics statement The authors followed applicable EQUATOR Network (http://www. equator-network. org/) guidelines, notably the CARE guideline, during the conduct of this report. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship This study was supported by the Science Committee of Science of the Ministry of Education and Science of the Republic of Kazakhstan under #AP14870683 “Distribution and genetic characterization of causative agents of tick-borne relapsing fevers (Relapsing Fever Borrelia) in the southern region of Kazakhstan”. Conflicts of interest There are no conflicts of interest. ==== Refs REFERENCES 1 Bröker M Following a tick bite: Double infections by tick-borne encephalitis virus and the spirochete Borrelia and other potential multiple infections Zoonoses Public Health 2012 59 176 80 21848518 2 Amosov ML Lesnyak OM Obraztsova RG Melnikov VG Bardina TG Andreeva YA Clinical characteristics of tick-borne encephalitis in mixed infection with Lyme borrelliosis Vopr Virusol 2000 45 25 8 3 Etenko DA Gromova OA Subbotin AV Semenov VA Combination therapy for the focal form of mixed tick-borne encephalitis and borreliosis infection Neurol Neuropsychiatr Psychosom 2016 8 26 30 4 Kahl O Vatslavovna Pogodina V Poponnikova T Süss J Zlobin V A short history of TBE Dobler G Erber W Bröker M Schmitt HJ The TBE Book 2nd ed Ch. 1 Singapore Global Health Press 2019 11 8 Available from: https://doi.org/10.33442/978-981-14-0914-1_1 [Last accessed on 2021 Nov 10] 5 Vilibic-Cavlek T Barbic L Stevanovic V Petrovic G Mlinaric-Galinovic G IgG avidity: An important serologic marker for the diagnosis of tick-borne encephalitis virus infection Pol J Microbiol 2016 65 119 21 27282004 6 Lyme Disease: Diagnosis and Testing. Centers for Disease Control and Prevention Available from: https://www.cdc.gov/lyme/diagnosistesting/index.html [Last accessed on 2021 May 21] 7 Rauer S Kastenbauer S Hofmann H Fingerle V Huppertz HI Hunfeld KP Guidelines for diagnosis and treatment in neurology –Lyme neuroborreliosis Ger Med Sci 2020 18 Doc03 32341686 8 Perfilyeva YV Shapiyeva ZZ Ostapchuk YO Berdygulova ZA Bissenbay AO Kulemin MV Tick-borne pathogens and their vectors in Kazakhstan –A review Ticks Tick Borne Dis 2020 11 101498 32723625 9 Malov IV Borisov VA Tarbeev AK Aitov KA Ixodid Tick Infections in the Practice of a District Physician Irkutsk Ministry of Public Health and Social Development of Russian Federation Irkutsk Stat Medical Universiti Irkutsk 2007 10 Olefir UV Merkulov VA Vorobieva MS Rukavishnikov AV Shevtsov VA Russian preparation of human immunoglobulin for urgent prophylaxis and treatment of tick-borne encephalitis Immunologiya 2015 36 353 7

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-41 10.4103/jgid.jgid_90_23 Editorial Commentary State of the Globe: Navigating the Impact of SARS-CoV-2 Mutations on COVID-19 Testing Varshney Rohit Kumar Department of Emergency Medicine, Teerthanker Mahaveer Medical College and Research College, TMU, Moradabad, Uttar Pradesh, India Address for correspondence: Dr. Rohit Kumar Varshney, Department of Emergency Medicine, Teerthanker Mahaveer Medical College and Research College, TMU, Moradabad, Uttar Pradesh, India. E-mail: rohitmaxy@gmail.com Apr-Jun 2023 31 5 2023 15 2 4142 21 5 2023 21 5 2023 21 5 2023 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body pmcThe SARS-CoV-2 virus has been a persistent challenger from 2019 causing the ongoing COVID-19 pandemic. The occurrence of numerous mutations over the passage of time leads to the emergence of new variants. These variants have posed significant challenges to our efforts to control the spread of the disease. One particular area where their impact has been felt is in COVID-19 testing. In this editorial, we would try to explore the consequences of SARS-CoV-2 mutations on COVID-19 testing and discuss the strategies to address these challenges. As viruses replicate, they naturally accumulate mutations in their genetic material. The SARS-CoV-2 virus is no exception, and it has undergone several significant mutations. Some of the most well-known variants include the Alpha, Beta, Gamma, and Delta variants, each with its unique set of mutations.[1] These variants have shown increased transmissibility, altered disease severity, and, in some cases, reduced susceptibility to certain therapeutics. SARS-CoV-2 mutations have introduced new challenges to COVID-19 testing efforts worldwide. Diagnostic tests, such as polymerase chain reaction (PCR) and antigen tests, rely on detecting specific genetic sequences or viral proteins associated with the virus.[2] Mutations in these regions can potentially affect the accuracy and sensitivity of these tests. First, some mutations can lead to false-negative or false-positive results. A false-negative result could occur if the mutation alters the primer binding sites in the PCR test, leading to decreased sensitivity and missed detection. Conversely, false-positive results might arise if the mutation leads to cross-reactivity with non-SARS-CoV-2 viruses or other respiratory pathogens. Second, the increased transmissibility of certain variants can result in higher viral loads in infected individuals. This heightened viral load can impact the timing of test positivity, leading to earlier detection or shorter incubation periods. It necessitates careful consideration of the optimal testing window for accurate diagnosis. To combat the challenges posed by SARS-CoV-2 mutations, several strategies need to be implemented:[3] Genetic surveillance: Increased genomic surveillance is crucial for tracking the emergence and spread of new variants. This involves sequencing the viral genomes from positive samples to identify mutations and their potential impact on testing and public health measures Test optimization: Continuous evaluation and adjustment of testing protocols are necessary to ensure their effectiveness against new variants. This includes the regular assessment of primer and probe sequences used in PCR tests, as well as the development of new tests targeting different regions of the virus Diversification of testing approaches: Employing multiple testing methods, such as combining PCR and antigen tests can enhance accuracy and compensate for limitations posed by specific mutations. Serological testing can also provide valuable information about past infections and immune responses Vaccine monitoring: Ongoing surveillance of vaccine efficacy against emerging variants is crucial. Monitoring breakthrough infections among vaccinated individuals can help identify the need for booster doses or modifications to existing vaccines. The Food and Drug Administration (FDA) provides the following recommendations to developers regarding the impact of viral mutation on the performance of diagnostic tests:[4] Developers are advised to design their tests in a manner that minimizes the influence of viral mutations on test performance Regular monitoring for viral mutations that might affect test performance Test limitations should be clearly communicated in the test’s labelling. The tests designed to target and detect specific known variants are likely to become outdated rapidly due to the ongoing mutation of the virus. Given this situation, the FDA believes that whole genome sequencing tests may be the most suitable option for genotyping claims. These tests have the capability to detect both known and emerging mutations and variants. Developers of “sequencing tests” who seek Emergency Use Authorization with a genotyping claim are advised to initiate early discussions with the FDA. By following these recommendations, developers can contribute to the development of effective diagnostic tests that account for viral mutations and provide accurate results for patient care. The impact of SARS-CoV-2 mutations on COVID-19 testing highlights the need for continuous adaptation and vigilance in our testing strategies. As the virus evolves, so must our diagnostic approaches. Collaboration between researchers, public health agencies, and healthcare providers is paramount to stay ahead of the virus and effectively respond to the challenges it presents. By embracing innovative solutions and maintaining a robust surveillance system, we can ensure accurate testing and better control of the COVID-19 pandemic. ==== Refs REFERENCES 1 Duong D Alpha, Beta, Delta, Gamma: What's important to know about SARS-CoV-2 variants of concern? CMAJ 2021 193 E1059 60 34253551 2 Udugama B Kadhiresan P Kozlowski HN Malekjahani A Osborne M Li VY Diagnosing COVID-19: The disease and tools for detection ACS Nano 2020 14 3822 35 32223179 3 Goławski M Lewandowski P Jabłońska I Delijewski M The reassessed potential of SARS-CoV-2 attenuation for COVID-19 vaccine development –A systematic review Viruses 2022 14 991 35632736 4 Creager R Blackwood J Pribyl T Bassit L Rao A Greenleaf M RADx variant task force program for assessing the impact of variants on SARS-CoV-2 molecular and antigen tests IEEE Open J Eng Med Biol 2021 2 286 90 35257097

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==== Front J Glob Infect Dis J Glob Infect Dis JGID J Global Infect Dis Journal of Global Infectious Diseases 0974-777X 0974-8245 Wolters Kluwer - Medknow India JGID-15-43 10.4103/jgid.jgid_178_22 Original Article Distribution and Functional Analyses of Mutations in Spike Protein and Phylogenic Diversity of SARS-CoV-2 Variants Emerged during the Year 2021 in India Gopalan Vidya Chandran Aswathi Arumugam Kishore Sundaram Monisha Velladurai Selvakumar Govindan Karthikeyan Azhagesan Nivetha Jeyavel Padmapriya Dhandapani Prabu 1 Sivasubramanian Srinivasan Kitambi Satish Srinivas 2 Department of Virology, King Institute of Preventive Medicine and Research, Chennai, Tamil Nadu, India 1 Department of Microbiology, Dr. ALM Post Graduate, Institute of Basic Medical Sciences, University of Madras, Chennai, Tamil Nadu, India 2 Department of Translational Sciences, Institute for Healthcare Education and Translational Sciences, Hyderabad, Telengana, India Address for correspondence: Dr. Satish Srinivas Kitambi, Institute for Healthcare Education and Translational Sciences, 10-2-311, Plot 187, Str 4, Cama Manor, West Marredpally, Secunderabad - 500 026, Telengana, India. E-mail: satish.kitambi@klife.info Apr-Jun 2023 17 5 2023 15 2 4351 20 9 2022 27 11 2022 04 1 2023 Copyright: © 2023 Journal of Global Infectious Diseases 2023 https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Introduction: Prolonged COVID-19 pandemic accelerates the emergence and transmissibility of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants through the accumulation of adaptive mutations. Particularly, adaptive mutations in spike (S) protein of SARS-CoV-2 leads to increased viral infectivity, severe morbidity and mortality, and immune evasion. This study focuses on the phylodynamic distribution of SARS-CoV-2 variants during the year 2021 in India besides analyzing the functional significance of mutations in S-protein of SARS-CoV-2 variants. Methods: Whole genome of SARS-CoV-2 sequences (n = 87957) from the various parts of India over the period of January to December 2021 was retrieved from Global Initiative on Sharing All Influenza Data. All the S-protein sequences were subjected to clade analysis, variant calling, protein stability, immune escape potential, structural divergence, Furin cleavage efficiency, and phylogenetic analysis using various in silico tools. Results: Delta variant belonging to 21A, 21I, and 21J clades was found to be predominant throughout the year 2021 though many variants were also present. A total of 4639 amino acid mutations were found in S-protein. D614G was the most predominant mutation in the S-protein followed by P681R, L452R, T19R, T478K, and D950N. The highest number of mutations was found in the N-terminal domain of S-protein. Mutations in the crucial sites of S-protein impacting pathogenicity, immunogenicity, and fusogenicity were identified. Intralineage diversity analysis showed that certain variants of SARS-CoV-2 possess high diversification. Conclusions: The study has disclosed the distribution of various variants including the Delta, the predominant variant, in India throughout the year 2021. The study has identified mutations in S-protein of each SARS-CoV-2 variant that can significantly impact the virulence, immune evasion, increased transmissibility, high morbidity, and mortality. In addition, it is found that mutations acquired during each viral replication cycle introduce new sub-lineages as studied by intralineage diversity analysis. Clade COVID-19 India mutations phylogeny severe acute respiratory syndrome coronavirus-2 spike protein ==== Body pmcINTRODUCTION Since the identification of a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus in December 2019 in China, the world has observed many different variants with multiple mutations in the SARS-CoV-2 genome. The features of high transmission potential and replication of SARS-CoV-2 increase the possibility of accumulation of numerous virus adaptive mutations.[1] The WHO has developed a two major variant classification system such as variants of concern (VOC) and variants of interest (VOI). At present, there are mainly five VOC: Alpha (21A), beta (20H), gamma (20J), delta (21A, 21I, 21J), and Omicron (21K, 21 L) and five VOI: Kappa (21B), Epsilon (21C), Eta (21D), Iota (21F), and Mu (21H) (https://www.who.int/en/activities/tracking -SARS-CoV-2-variants/;.https://covariants.org). COVID-19 pandemic is marked with rapid emergence of numerous variants and phenomenal phylogenic diversity among variants was observed in the year 2021 including the most virulent variant Delta. The spike protein of SARS-CoV-2 plays a major role in cellular entry by interaction with human angiotensin-converting enzyme 2 (ACE2) receptor. The high-affinity binding of the spike protein receptor-binding domain (RBD) to hACE2 is an essential prerequisite for the rapid transmission of SARS-CoV-2 in humans. The SARS-CoV-2 variants such as Alpha, Beta, Gamma, Delta, and Omicron with mutations at the RBD display increase in viral infectivity and immune evasion.[2] Two main RBD conformations have been described for S-protein, standing-up, and lying-down states, with high and low affinity to ACE2, respectively. These states are influenced by the number and distribution of N-glycosylation and O-glycosylation sites in RBD impacting the interaction of S-protein of SARS-CoV-2 with the host cell and further transmissibility.[3] Observations on the changes in the states have been reported for emerging variants such as Omicron.[4] Preactivation of the S-protein by proteolytic cleavage is essential for viral entry into the host cells and mutations in proteolytic cleavage site of S-protein may affect the viral internalization process thus associated with altered transmissibility, virulence, and cell tropism.[5] There is also a need to closely monitor the antigenic evolution of S-protein in the circulating viruses through identifying the dynamic patterns of mutations indicative of positive selection for S-protein variants. Studies on the distribution of variants belonging to various clades and frequency and functional significance of mutations in S-protein genes of Indian SARS-COV-2 genomes are limited.[6] Hence, in this study, we retrieved 87,957 complete genomes of SARS-CoV-2 deposited from India in Global Initiative on Sharing All Influenza Data (GISAID) during the whole year 2021 and subjected to the studies on clade diversity and phylogenetic analysis to uncover the intra-lineage diversity of the SARS-CoV-2 variants. Besides, this study also focuses on the analyses of mutations and their frequency in the various regions of S-protein from all variants and functional significance of mutations affecting glycosylation patterns, protein stability, immunity, and virulence. METHODS Genome retrieval and clade analysis A total of 87,957 annotated SARS-CoV-2 whole genome sequences from the various parts of India deposited as on December 31, 2021 in GISAID (https://www.gisaid.org/) were retrieved. Sequences were aligned using Multiple Alignment using Fast Fourier Transform with SARS-CoV-2 Wuhan-Hu-1 strain (NC_045512.2) used as reference. All the sequences assembled in BioEdit. V.7 for spike gene trimming. The Nextclade-Nextstrain pipeline (https://clades.nextstrain.org/) was used for the clade analysis of SARS-CoV-2 sequences. Mutation profiling, frequency, and functional analyses The analyses of mutation profiling, frequency, and functional analyses including stability were performed with reference sequence SARS-CoV-2 Wuhan-Hu-1 strain (NC_045512.2). CoV surver mutation tool (https://www.gisaid.org/epiflu-applications/covsurver-mutations-app) was used to predict the nonsynonymous mutations in the spike gene and sequence analysis pipeline tool (https://cov.lanl.gov/content/sequence/TRACK_MUT/trackmut. html) was used for the analyses of frequency of mutation over time in India (source: GISAID). ESC_Comprehensive resource of immune escape variants in SARS-COV-2 was used to detect the immune escape mutants in S-protein (http://clingen.igib.res.in/esc/). The impact of mutations on S-protein stability was predicted using tools such as sorting intolerant from tolerant (SIFT) (https://sift.bii.astar.edu.sg/www/SIFT_seq_submit2.html), PROVEAN (Protein Variation Effect Analyzer) (http://provean.jcvi.org/seq_submit.php) and DUET (http://biosig.unimelb.edu.au/duet/stability). A SIFT score of 0.0–0.05 indicated a deleterious effect. The functional effects of protein variants were assessed using the PROVEAN web server, using a default threshold value of − 2.5 and the values below and above the threshold value were considered as deleterious and tolerant. The PDB structure (6VXX) was used as the reference for structural divergence and DUET analysis. DUET score displayed the predicted change in folding free energy upon mutation (ΔΔG in kcal/mol), with negative and positive values indicated destabilizing mutation and stabilizing mutation, respectively. RaptorX (http://raptorx.uchicago.edu/) is used to predict the secondary structure for different variants of SARS-CoV-2 spike protein. The impact of mutations in S-protein on Furin cleavage efficiency was studied by using ProP-1.0 Server (https://services.healthtech.dtu.dk/service. php? ProP-1.0) to predict the Furin cleavage site upon subjecting the mutations in the protease cleavage site (PCS) to Pro. P analysis. The score of reference S-protein mutations was compared with variants to predict the efficiency of Furin cleavage. Phylogenetic analysis of severe acute respiratory syndrome coronavirus-2 variants The Relative Synonymous Codon Usage (RSCU) of different variants was analysed using MEGA-X. Heat Map was constructed using CIM-miner (https://discover.nci.nih.gov/cimminer/). The average evolutionary divergence rate was estimated using Kimura-2 parameter model and phylogenetic tree construction was performed using MEGA-X. Supplementary files can be obtained by contacting the corresponding author. RESULTS Clade analysis The NEXTCLADE analysis of 87,957 SARS-CoV-2 sequences revealed that these strains were distributed into 21 different clades as represented by Nextstrain [Figure 1]. Some of the variants such as 19A, 19B, 20A, 20B, 20C, and 20D that were found since the early phase of pandemic during 2020 were also distributed in the year 2021. Among these 21 clades, 20A (7.9%) was more prevalent in early 2021 followed by 19B, 20B, 20C, 20D, 20E, and 20G. 19A, the first clade observed in the year 2020, persisted throughout the year and was less frequent (0.19%). The clades 19B (5.9%) and 20A (7.9%) were found to be highly distributed during the initial months (January to March 2021) but subsequently decreased. The VOC belonging to Alpha (20I) was observed in high prevalence (5.5%) from January to May 2021 and drastically reduced in December 2021. The VOC Beta (20H) was found to be sporadic (0.3%) from January to June 2021 and eventually decreased in the following months. The VOC Gamma (20J) (0.01%) had a negligible presence only from March to May and during August 2021. The VOC delta was the most predominant clade for the year 2021; however, the distribution of variants belonging to Delta clade were insignificantly lower than the other variants during the early months (January to March) of 2021 and a sweeping increase was observed from April 2021. The Delta variant was found to have three sub-lineages such as 21A, 21I and 21J. From January to June 2021, 21A (Delta) (33.3%) was more prevalent which was followed by 21J (26.7%) and 21I (Delta) (10.7%). The sub-lineage 21A (Delta) had decreased from July 2021, but there was a predominant increase in the other two sub-lineages. The distribution of clade 21B (Kappa) (5.6%) was elevated from February to May 2021 and decreased thereafter. The variants of clade 21C (Epsilon) (0.04%), 21F (Iota), and 21H (Mu) (0.05%) appeared in negligible fractions. The clade 21D (Eta) (0.29%) was observed only from January to June 2021. By the end of the year 2021, a new variant omicron had emerged and the study could identify two Omicron sub-lineages such as 21K (BA.1 Omicron) and 21 L (BA.2 Omicron). The presence of 21K (BA.1 Omicron) (0.24%) was first observed in November and there was a sudden spurt in their distribution in December 2021 whereas 21 L (BA.2 Omicron) (0.03%) was less prevalent when compared to 21K and observed only in December [Table 1]. Figure 1 Distribution of SARS-CoV-2 clades in India during the whole year 2021. SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2 Table 1 Clade distribution profile of severe acute respiratory syndrome coronavirus-2 isolates (n=87,957) in India during the year 2021 Clade January February March April May June July August September October November December 19A 25 16 9 24 6 5 30 4 0 1 2 0 19B 837 1130 646 476 315 133 76 66 44 52 64 2 20A 1062 1082 721 774 538 364 135 170 130 88 69 15 20B 90 176 218 182 336 206 48 49 47 33 32 1 20C 67 147 143 32 32 28 40 7 6 8 1 4 20D 1 2 1 14 4 0 0 0 0 0 1 0 20E 19 16 6 3 2 4 3 2 0 0 1 0 20G 2 2 5 6 0 0 0 0 0 0 0 0 21A (Delta) 44 22 362 3798 4742 3459 2550 2108 2020 1529 772 279 21I (Delta) 7 10 143 1267 1895 1150 961 742 499 222 73 23 21J (Delta) 29 57 126 1457 2508 2128 2661 2645 2744 1618 1007 426 21B (Kappa) 31 382 1503 1481 234 37 8 7 3 0 0 0 20H (Beta) 1 26 94 65 16 6 0 0 0 0 0 0 20I (Alpha) 70 407 1778 1235 61 24 2 7 2 2 2 0 20J (Gamma) 0 0 2 1 1 0 0 1 0 0 0 0 21C (Epsilon) 0 0 1 4 10 1 3 0 2 1 1 0 21D (Eta) 2 34 106 32 13 3 0 0 0 0 0 0 21F (Iota) 0 0 0 0 2 0 0 0 0 0 0 0 21H (Mu) 0 0 1 6 16 3 1 4 1 1 2 0 21L (Omicron) 0 0 0 0 0 0 0 0 0 0 0 22 21K (Omicron) 0 0 0 0 0 0 0 0 0 0 7 148 Mutation profile of S-protein A total of 4639 amino acid mutations were found in S-protein from the 87957 Indian sequences [Supplementary File 1]. There were 3052 and 1550 mutations present in the S1 and S2 domains, respectively with the highest number of mutations in the N-terminal domain (NTD; 1752 mutations) followed by (RBD; 820 mutations), Heptad Repeat 1 (HR1; 170 mutations), Heptad Repeat 2 (HR2; 143 mutations), Cytoplasm domain (CD; 85 mutations), (PCS; 75 mutations), Fusion peptide (FP; 72 mutations), Transmembrane domain (TMD; 57 mutations), and Signal peptide (SP; 37 mutations) [Table 2]. Among the 4639 mutations, 30 mutations were notably more predominant, in which D614G was present in 99% of Indian isolates (n = 86663) followed by P681R (n = 68348, 78%) of PCS, L452R (n = 61310, 70%), T478K (n = 55694, 63%) of RBD, T19R (n = 56027, 64%) of NTD [Figure 2; Supplementary File 2]. The results of mutation tracking analyses revealed the mutation frequency over time, in which D614 is completely replaced to G614. Variant specific mutations such as L452R, T19R, T478K, P681R, D950N, E156G, T95I, and G142D were originated in January and their presence was recorded throughout the year. Mutations D1118H, E484K, S982A, T716I, A570D, E154K, Q1071H, and H1101D could only be seen from January to May 2021. Among the 30 distinct amino acid mutations found in Omicron variants, 12 mutations notably existed from January 2021 while the other 18 mutations peaked only in December 2021. Few mutations such as G446V, P499R, and S371F were observed to be increased from August, October, and December, respectively. Among the 4,639 mutations, 1,947 mutations were observed once and 2692 mutations have repetition in 87,957 sequences. A total of 1201 mutated sites were found in S-protein of which only 174 had mutated once and the remaining 1027 sites carry more than one mutation. Table 2 Amino acid substitution mutations observed across various regions of S-protein of Indian severe acute respiratory syndrome coronavirus-2 isolates S-Protein Positions Number of mutations Number of amino acid sites mutated Signal peptide 1-13 37 13 N-terminal domain 14-305 1752 292 Receptor binding domain 319-541 820 220 Protease cleavage site 675-692 75 18 Fusion peptide 788-806 72 19 Heptad Repeat1 912-984 170 72 Heptad Repeat2 1163-1213 143 48 Transmembrane domain 1214-1237 57 23 Cytoplasm domain 1238-1273 85 29 Figure 2 The mutation frequency of S-protein. The mutation frequency were plotted with respective position of S-protein. SP: Signal Peptide, NTD: N Terminal Domain, RBD: Receptor binding domain, PCS: Protease cleavage site, FP: Fusion peptide, HR1: Heptad Repeat 1, HR2: Heptad Repeat 2, TD- Transmembrane Domain, CD: Cytoplasm Domain Mutations affecting glycosylation patterns Analysis of N-linked glycosylation (NGS) and O-linked Glycosylation (OGS) sites were performed for 87,957 isolates. S-protein carries 22 and 26 amino acid sites as NGS and OGS moieties, respectively. It was found that mutation in these sites resulted in loss of both NGS and OGS moieties. Two deletions were observed in these sites, one at 1194 position (NGS) and another at 1161 position (OGS), respectively. Even though there were 5 VOC and 5 VOI, none of the variant-specific mutation occurred in NGS and OGS moieties except one OGS mutation S982A in Alpha variant [Figure 3; Supplementary File 3]. Figure 3 (a) Mutations in N-glycosylation sites; (b) Mutations in O-Glycosylation sites. All glycosylation sites were marked to their respective sites on the trimeric S-protein and the corresponding mutations were marked as single letter amino acid code Immune escape mutations in S-protein Analysis showed 29 mutations in NTD and 469 mutations in RBD were found to have immune escape function. Common mutations among the variants such as N501Y (Alpha, Beta, Gamma, Omicron), K417N (Beta, Omicron), E484K (Beta, Gamma, Iota, Eta), L452R (Delta and Kappa) and T478K (Delta and Omicron) were resistant to neutralizing antibodies and could act as escape mutants. It was observed that Omicron had the highest immune escape potential with 19 escape mutations in S-protein followed by Gamma (8), Beta (5), Kappa (5), Iota (4), Delta (3), Eta (3), and Alpha (2) [Supplementary File 4]. Effect of mutations on stability and structural divergence of S-protein Among the 4639 mutations, SIFT score predicted 1414 mutations were deleterious and 2771 mutations were neutral. Using PROVEAN score prediction tool, 638 mutations were found to be deleterious and 3547 mutations were neutral. Only 535 amino acid mutations were predicted to have potentially deleterious functional consequences on S-protein by both the mutation score prediction tools. A total of 2668 mutations were predicted to be neutral by SIFT and PROVEAN tools showing that these mutations might exhibit positive selection pressure for virus adaptability. It was observed that only 12 mutations such as T716I, R190S, T1027I, V1176F, D950N, Y145D, L212I, Y505H, T547K, N764K, N856K, and N969K present in different variants of SARS-CoV-2 could display deleterious effect on S-protein. Mutations in the RBD of different variants possess no deleterious effect on S-protein. For DUET score prediction, SARS-CoV-2 spike protein (PDB_ID– 6VXX) was used and the results revealed 6 mutations in NTD and 13 mutations in the RBD of SARS-CoV-2 variants were found to destabilize S-protein. Mutations present in the PCS of variants such as N679K, P681H, and P681R could showed stabilizing effect, whereas Q677H in Eta variant displayed destabilizing effect on S-protein. Mutations were not observed in FP of S-protein of variants except N764K in Omicron variant and it had the stabilizing effect on the protein. The functional effect of several mutations could not be predicted due to the absence of position in PDB structure [Supplementary File 5]. The S-protein of major variants of SARS-CoV-2 in the current study was subjected to secondary structure prediction using the RAPTORX tool including the reference S-protein (NC_045512) [Table 3]. Analysis revealed that the alpha variant had increased β-pleated sheet but reduced coil structure; Delta variant had increased coil but decreased β-sheet structure. Gamma and Omicron variants had increased alpha helix and β-pleated sheet and had similar secondary structure conformation to reference S-protein. The PDB structures of S-protein in SARS-CoV-2 variants (PDB-ID-Alpha [7 LWV], Beta [7 LYN], Gamma [7V79], Delta [7V7Q], and Omicron [7TNW]) were retrieved and analyzed for tertiary structure variation in NTD and RBD regions using pair wise structure alignment tool in PDB with S-protein (PDB-ID-6VXX) as reference. The results showed that Omicron had unique α-helix at 142-145 amino acid residues in NTD which was absent in other variants. The Delta and Gamma variants had α-helix at position 436–441 in RBD, but the structure was absent in Alpha, Beta, and Omicron variants. In contrast, Omicron, Alpha, and Beta had α-helix at 346–350 in RBD but were not observed in Delta and Gamma variants [Figure 4]. Table 3 Proportion of α-helix, β-pleated sheet and coil in tertiary structure of S-protein in Indian severe acute respiratory syndrome coronavirus-2 variants S-Protein of SARS-CoV-2 variants Alpha helix (%) Beta sheet (%) Coil (%) Reference (NC_045512) 19 31 48 Alpha spike 19 32 47 Beta spike 19 31 48 Gamma spike 20 31 48 Delta spike 19 30 49 Omicron spike 20 31 48 SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2 Figure 4 (a) NTD in Alpha variant; (b) NTD in Beta variant; (c) NTD in Gamma variant; (d) NTD in Delta variant; (e) NTD in Omicron variant; (f) RBD in Alpha variant; (g) RBD in Beta variant; (h) RBD in Gamma variant; (i) RBD in Delta variant; and (j) RBD in Omicron variant. Black and red arrows indicate the presence and absence of α-helix respectively. NTD: N Terminal Domain, RBD: Receptor binding domain Influence of mutations on Furin cleavage potential The S-protein sequences with mutation in the PCS region were subjected to Pro. P tool to predict the Furin cleavage potential based on scores. We compared the mutations with score 0.620 of reference S-protein. Mutations with score >0.620 had increased cleavage efficiency and values < 0.620 had decreased cleavage efficiency [Supplementary File 6]. Analysis of 73 mutations revealed that 31 mutations had increased cleavage potential, whereas 32 mutations decreased the cleavage potential. The mutations P681H and P681R had increased furin cleavage function. The mutation in Arginine residue (R685) leads to the absence of the cleavage site. Mutation S686A had increased the cleavage, whereas mutation V687 decreased the cleavage potential. Moreover, deletion at position 679 and 681 also increases the cleavage potential. Mutations present in the neighboring residues of the cleavage site also influences the cleavage potential. Evolutionary analysis of severe acute respiratory syndrome coronavirus-2 variants The RSCU was analyzed for all the spike coding sequence of SARS-CoV-2 variants Mega X [Supplementary File 7]. Notably, all the variants were possessing similar codon usage with small difference in the frequency of usage. It was found that a rare codon CGA which codes for Arginine was present only in Omicron. The total number of codons in Omicron (1265 codons) was less than the sequences of other variants that had 1274 codons, and this could be probably due to the deletion mutations in Omicron variant. No drastic difference was observed in the codon usage of variants, suggesting the genomic conservancy among the variants for their survival and evolution [Figure 5a]. Only 14,937 high quality S-protein genes were taken for studying region-specific average evolutionary divergence. The results showed that PCS had more divergence rate of 1.11 × 10−2 s/s/y followed by NTD (3.27 × 10−3), RBD (2.52 × 10−3), and SP (1.53 × 10−3). The other regions such as FP, HR1, HR2, TM, and CD had very low divergence rate [Figure 5b]. Intra lineage diversity among the SARS-CoV-2 variants were analyzed by random selection of 100 genes of S-protein from each variant and subjected to phylogenetic analysis with NC_045512 as reference. The results revealed that strains belong to Alpha and Beta variants were less diverse suggesting the sequences were closely related among themselves. Highly diverse sequences were observed in Delta, Kappa, Eta, and Omicron variants, with six different clusters in Delta and Omicron, followed by five clusters in Kappa and Eta variants [Figure 6]. Figure 5 (a) Heat map of RSCU values for the spike coding sequence of SARS-CoV-2 variants. Codons with higher and lower RSCU values are highlighted in red and blue respectively; (b) The average evolutionary rate for different regions of S-protein. SP: Signal Peptide, NTD: N-Terminal Domain, RBD: Receptor Binding Domain, PCS: Protease Cleavage site, FP: Fusion Peptide, HR1: Heptate Repeat 1, HR2: Heptate Repeat 2: TRD- Transmembrane Domain, CPD: Cytoplasm Domain, RSCU: Relative synonymous codon usage Figure 6 The phylogenetic tree was constructed by Maximum-Likelihood method having the root as SARS-CoV-2 Wuhan-Hu-1 Spike sequence (NC_045512.2). Intra-lineage diversity of (a) Alpha; (b) Beta; (c) Delta; (d) Eta; (e) Kappa; and (f) Omicron variants. SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2 DISCUSSION Progression of COVID-19 pandemic favors the emergence of new SARS-CoV-2 variants through accumulation of adaptive mutations, especially in S-protein resulting in increase in the transmissibility of variants. This underscores the importance of tracking the evolution of S-protein in SARS-CoV-2 by means of mutational, phylogenetic and functional analyses. The changing phylodynamics indicates the necessity to conduct countrywide or regional studies on clade distribution patterns along with mutational analyses that will provide new insights on their epidemiology as well as for evolving therapeutic and prophylatic measures. In this study, we report the phylogenetic distribution of variants based on the SARS-CoV-2 genomes deposited in GISAID from India, mutation frequency and functional analyses of amino acid mutations in S-protein with respect to alteration in glycosylation patterns, immune escape features, protein stability, and evolution. Though large number of SARS-CoV-2 complete genomes from various parts of India have been sequenced and deposited in GISAID, few studies are available on clade distribution, frequency, and functional significance of mutations of SARS-CoV-2 isolates from India.[6,7] Genomic surveillance studies in India had reported the emergence of Delta variant by the end December 2020 and this variant had gradually replaced Alpha variant in May 2021.[8,9] The current study also records the dominancy of Delta variant throughout 2021, and branching of the variant into three sub-lineages namely 21A, 21I and 21J during the year 2021. Sub-lineage 21A (Delta) was more predominantly observed from January to June 2021 which was followed by sub-lineages 21J and 21I. The prevalence of 21A decreased by July 2021 while 21J and 21I remained predominant thereafter. A new variant, Omicron was observed by the end of 2021. Our previous study had revealed the presence of 557 amino acid substitutions in S-protein of SARS-CoV-2 isolates circulated in India during 2020.[6] The present study observed a total of 4639 mutations in S-protein of all genomes deposited in the year 2021 denoting about 8-fold increase in the rate of mutation occurrence against the previous year. It is clearly observed that there was an increase in the events of mutational occurrence as well as emergence of diverse variants when the pandemic progresses from the early stage. Four hundred and four substitution mutations were found to exist in both years 2020 and 2021. Notably, D614G was profoundly present in 86,663 sequences (99%) in 2021, followed by P681K (78%), L452K (70%), T19K (64%), T478K (63%), D950N (52%), E156G (27%), E157del (27%) and R158 (27%). Among these high frequent mutations, E156G, E157del and R158 are reported to enhance neutralizing antibodies resistance and infectivity.[10] Other mutations that were observed in the study such as L452R, Y453F and N501Y on RBD were found to increase the binding affinity of S-protein with hACE2 receptor resulting in increase in infectivity.[11] The study also reported that these three mutations were found in Beta variant thereby increasing the binding affinity by 3-fold than the primitive strain and the double mutation E484K/N501Y in Mu variant which was observed in low frequency from the present study was found to have stronger binding affinity than single mutation N501Y.[12] A study reported that RBD-specific mutation V367F also has higher affinity to hACE2 receptor.[13] The N-linked glycans play an important role in structural and functional dynamics of RBD of S-protein. Mutations at N165 and N234 glycosylation sites in NTD region can reduce the binding of S-protein with hACE2 receptor due to RBD shift in the down state.[14] The current study observed mutations at both these sites including N165M, N165Y, N165V, N165Q and N165del at position 165, and N234R, N234F, N234Y, N234T, N234K and N234D at position 234. A study reported that mutation at N801 and N1194 in N-glycan site disrupted S-protein trimerization.[15] The present study reports such mutations N801Y, N801H and a stop mutation at position 801, and a deletion at 1194 position. The study has identified several mutations that have increased cleavage potential at PCS (675–692 amino acid region) essential for viral entry into the host cell. Among the mutations, P681H and P681R exhibited increased furin cleavage function. Variants with mutation P681H are found to have more molecular flexibility for facilitating furin binding to cleavage site.[16] P681R mutation at PCS boosts the cleavage of S1 and S2, accelerates viral fusion and thus leading to increased infectivity of cells.[17,18] The fitness of SARS-CoV-2 virus for survival was driven by mutations possessing intra and interprotomer interactions. The D614 in prototype S-protein forms H-bonds with K854 and T859 when the RBD is in close conformation and these bonds are lost during the RBD open conformation. This interprotomer H-bonding is absent in D614G mutant leading to reduction of energy required for the conformational transition.[19] It was reported that the Alpha variant with mutation A570D, D614G, S982A and D1118H enables local side chain rearrangements, giving rise to additional interprotomer contacts.[20] The residues S929 and D936 are engaged in side chain H-bonds with S1196 and R1185 of HR2 during the postfusion conformation of the protein and bringing the viral and cellular membrane for fusion. It was observed that mutations in this position D936Y result in loss of inter monomer H-bond which results in reduced protein assembly.[21] Reports suggest that there are only minor structural differences in S-protein of SARS-CoV-2 variants;[22] however, it is reported that Omicron has higher fraction of α-helix (23.46%) than Delta (22.03%)[23] and the same was observed in the present study. A study discloses that S-protein of SARS-CoV-2 Wuhan reference strain contains mixture of RBD open and closed conformations while S-protein of Omicron has predominantly RBD open conformation. Mutation Q853K in S-protein of Omicron can alter the disordered loop resulting in tighter S1/S2 packing. Further, mutations such as T547K, N764K can promote S1/S2 packing. Overall mutations in S-protein of Omicron introduce new inter-domain and inter-subunit interactions which stabilizes RBD open conformation.[4] A study on S-protein of SARS-CoV-2 demonstrated the importance of TMD in cellular membrane fusion and virus entry. Any mutation that alter the aromatic and Cysteine rich residues of TMD can affect membrane fusion and entry.[24] In this study, we have observed mutations such as W1214R, Y1215H, C1235F, C1235R, C1236F, C1236V and C1236S in aromatic and Cysteine residues of TMD. New mutations that are acquired during each replication results in the intra lineage diversity of SARS-CoV-2.[25,26] This study reports that Delta and Omicron variants have highly diverse sequences among themselves giving rise to numerous new sub-lineages and sub-variants such as 21A, 21I, 21J in Delta variant and 21 L and 21K in Omicron variant due to accumulation of numerous mutations at high frequency other than clade specific signature mutations. Among the Omicron sub-variants and VOCs, we identified several such mutations that were shared among the isolates belonging to various clades. These unique mutations make the isolates to be distributed diversely within the clade of phylogenetic tree. This suggests that occurrence of such mutations are contributing not only to the antigenic diversity of S-protein but also to facilitate potentially the emergence of more subclades or new subvariants with acquisition of few other mutations. Multiple inter-variant recombination events may have contributed to the shared presence of different mutations between the VOCs. For example, the BA.1 subvariant has three more Alpha-related mutations (del69-70, delY144) than BA.2, suggesting that Alpha or other unknown variants that carry these mutations may have contributed to the emergence of the BA.1 subvariant.[27] In view of rapid emergence of new variants with phenomenal diversity in the global distribution of variants, continuous monitoring of genomic evolution of SARS-CoV-2 is essential for supporting tasks on vaccine design and development programmes and devising control and preventive measures to manage this infection. CONCLUSIONS The study has revealed the dynamics of rapidly diversifying SARS-CoV-2 variants and subvariants with a phenomenal observation of shifting of clade predominance within 2 years of the introduction of virus in India. The functional evaluation of several mutations in S-protein, after analyzing all the sequences deposited throughout the year 2021, reveals the significance of various mutations in virulence, immune escape features and disease severity. The findings of the study may support researchers to understand the phylodynamic characteristics, molecular epidemiology and mutation based functional characteristics of variants and sub-variants of SARS-CoV-2. Research quality and ethics statement This study was approved by the Institutional Review Board/Ethics Committee. This work only requires analysis of openly available information and does not require patients or patient samples or data. The authors followed applicable EQUATOR Network (https://www. equator-network. org/) guidelines during the conduct of this research project. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgements We are grateful to all the authors, originating and submitting laboratories from Global Initiative on Sharing All Influenza Data (GISAID’s EpiCov database) for enabling the sequences available for use in our study. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-62 10.33546/bnj.1192 Review Article Factors related to Internet and game addiction among adolescents: A scoping review https://orcid.org/0000-0002-1799-4473 Juthamanee Siripattra 1* https://orcid.org/0000-0001-6694-8679 Gunawan Joko 2 1 Faculty of Nursing, Rajamangala University of Technology Thanyaburi, Thailand 2 Belitung Raya Foundation, East Belitung, Bangka Belitung, Indonesia * Corresponding author: Siripattra Juthamanee, MNS, RN, Faculty of Nursing, Rajamangala University of Technology Thanyaburi. 39 Moo 1, Klong 6, Khlong Luang Pathum Thani 12110, Thailand. Email: ying.nu19@gmail.com Cite this article as: Juthamanee, S., & Gunawan, J. (2021). Factors related to Internet and game addiction among adolescents: A scoping review. Belitung Nursing Journal, 7(2), 62-71. https://doi.org/10.33546/bnj.1192 29 4 2021 2021 7 2 6271 01 9 2020 23 10 2020 18 3 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Understanding factors influencing Internet and game addiction in children and adolescents is very important to prevent negative consequences; however, the existing factors in the literature remain inconclusive. Objective This study aims to systematically map the existing literature of factors related to Internet and game addiction in adolescents. Methods A scoping review was completed using three databases - Science Direct, PROQUEST Dissertations and Theses, and Google Scholar, which covered the years between 2009 to July 2020. Quality appraisal and data extraction were presented. A content analysis was used to synthesize the results. Results Ultimately, 62 studies met inclusion criteria. There were 82 associated factors identified and grouped into 11 categories, including (1) socio-demographic characteristics, (2) parental and family factors, (3) device ownership, Internet access and location, social media, and the game itself, (4) personality/traits, psychopathology factors, self-efficacy, (5) education and school factors, (6) perceived enjoyment, (7) perceived benefits, (8) health-compromising behaviors, (9) peers/friends relationships and supports, (10) life dissatisfaction and stress, and (11) cybersafety. Conclusion Internet and game addiction among adolescents are multifactorial. Nurses should consider the factors identified in this study to provide strategies to prevent and reduce addiction in adolescents. adolescent addictive behavior Internet gaming influencing factors nursing ==== Body pmcInternet addiction has become a significant concern in the public and scientific communities today. Although the Internet has become an indispensable tool in the adolescent population for entertainment, communication, information, academic search, and social recognition (Frangos et al., 2011), there is strong evidence that those who addict to the Internet has a negative influence on their lives, such as sleep, academic performance, and relationship with others (Milani et al., 2018). It is also similar to individuals who enjoy games. Although games have become a major leisure activity for releasing stress, heavy users tend to be isolated and lack confidence and social skills (Herodotou et al., 2012). There have been a wide variety of terms examining the Internet and gaming addiction, such as “Internet gaming disorder”, “problematic online gamers”, “problem video game use”, “problematic Internet use”, “Internet addictive behavior”, “digital game addiction”, “excessive use of the Internet and online gaming”, “online game addiction”, “persistence of Internet addiction”, “smartphone addiction”, “unregulated Internet use”, “pathological Internet use”, and “overuse of Internet”. In this study, we use the terms “Internet and game addiction” for the sake of consistency. Although the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has described game addiction (American Psychiatric Association, 2013), it is still a lack of evidence to consider the condition as a unique mental disorder. In addition, this condition is only limited to gaming, not including the general use of the Internet, social media, smartphones, and online gaming. Therefore, it has led to a degree of ambiguity in understanding the concept of Internet and gaming addiction, which needs further clarification. However, in this review, we did not limit our exploration to gaming only. All terms related to the Internet, social media, and online or offline gaming, with the use of mobile phones, computers, or laptops, were included because all of them were mainly about non-substance addiction, which has a lot in common with substance addictions. Despite multiple constructs of addiction in the literature, in this study, addiction is defined based on the following four points, including 1) excessive use, or increasing time and frequency, 2) persistent, maladaptive preoccupation, and craving, or feeling an irresistible urge to play computer games, 3) having characteristics of withdrawal behaviors, tolerant behavior, loss of control, negative repercussions, 4) having negative effects on academic or work performance, interpersonal relationships, financial or physical problems, and gaining or losing weight (Chen et al., 2015; Hu et al., 2017; Milani et al., 2018; Müller et al., 2015). If there are no negative consequences, it will not be considered an addiction because it can be an adaptive user instead of a maladaptive user. It is undebatable that Internet and gaming addiction has tremendous impacts on adolescents. Therefore, its related factors warrant further exploration. Although previous studies have found several factors influencing Internet and gaming addiction, such as individual characteristics (Rho et al., 2016), parenting behavior (Kwak et al., 2018), education (Karaca et al., 2020), and other factors. However, these factors are somewhat inconclusive. Therefore, the aim of this study was to explore the factors related to Internet and game addiction in adolescents. The research question in this review was, “what are the factors associated with Internet and game addiction in adolescents?” This study is expected to help pediatric nurses or mental health nurses to reduce addiction among adolescents. Methods Search Methods Three databases used in this study, including Science Direct, ProQuest, and Google Scholars. The key words include “Internet AND game AND addiction OR addictive behavior OR behavior AND antecedents OR factors AND consequences AND adolescents AND young adolescents AND early adolescents AND children.” The reason we included children due to the fact that many addictions adolescents start during the children period. The search strategy was just limited to ten years, ranged from January 2009 - July 2020 to get the current literature. Inclusion and Exclusion Criteria The inclusion criteria of the article were all research studies with qualitative and quantitative approaches, full-text articles and theses or dissertations, and available in English. The exclusion criteria were review articles, editorials, letters to editors, magazines, or gray literature. Screening The screening of the article was done by both authors, which included the title, abstract, and full-text. All articles that meet inclusion criteria were included. Data Extraction Data were extracted using a table, which consists of the author’s name, year, country, objective, theoretical framework, attributes/dimensions, antecedents, instru-ments, and study design. Quality Appraisal To ensure the quality of each study, a quality appraisal tool adapted from previous studies (Gunawan et al., 2018; Keyko et al., 2016) was used for the correlational study. Each study was categorized as high (10-14), moderate (5-9), and low (0-4) quality. For qualitative studies, the Critical Skills Appraisal Program (CSAP) was used (Casp, 2010). Areas for assessments were research design, measu-rement, sampling, data collection, ethical issues, and data analysis. Data Analysis Content analysis was used to synthesize the results from both the quantitative and qualitative studies (Grove et al., 2012). This content analysis is specifically to merge the factors into categories. Results Search Results There were 36,672 potential articles identified from the initial search (Table 1). In the stage of title screening, we removed 30,150 articles due to unrelated topics with Internet and game addiction, and 6,522 articles were left for further evaluation. In the stage of abstract screening, 5,445 articles were excluded due to inadequate in terms of inclusion criteria, and 1,077 articles were retained for further exploration. Ultimately, 62 articles were included (see Figure 1). The characteristics of the included studies can be seen in the supplementary file. Figure 1 The Review Process based PRISMA Flow Chart Table 1 Database Searching Database 2009 – July 2020 Retrieved Science Direct 6,727 PROQUEST Dissertations and Theses 11,945 Google Scholar 18,000 Total retrieved titles 36,672 Quality Assessment Majorities of the studies employed a correlational cross-sectional study design. Six studies used a longitudinal design, and one study was qualitative. Among 62 studies, only 22 studies used probability sampling, 11 studies used non-probability sampling, and 29 studies did not report sampling methods. In the quality assessment of all studies, 52 studies were at medium level and ten studies at a high level. The majority of the studies used three scales for measuring Internet and game addiction as developed by Lemmens et al. (2009), Chen et al. (2003), and Young (1998). There were various countries identified in the studies, including Serbia, Germany, Greece, Iceland, The Netherland, Poland, Romania, Spain, Geneva, Taiwan, Australia, Turkey, United Kingdom, China, Hong Kong, Italy, Norway, Malaysia, Mongolia, Korea, Czech Republic, France, Singapore, Iran, Thailand, India, United States, and Nigeria (see Supplementary file). Analytical Findings A total of 82 factors were identified and synthesized into 11 categories, including 1) socio-demographic charact-eristics, 2) parent and family factors, 3) devise ownership, Internet access, and location, social media, and the game itself, 4) personality/traits, psychopathology factors, self-efficacy, 5) education and school factors, 6) perceived enjoyment, 7) perceived benefits, 8) health-compromising behaviors, 9) peers/friends relationships and supports, 10) life dissatisfaction and stress, and 11) cybersafety (see Table 2). Table 2 Factors related to the game or Internet addiction Related Factors Authors 1. Socio-Demographic Characteristics  Age (Bianchini et al., 2017; Hyun et al., 2015; Karaca et al., 2020; Lim & Nam, 2018; Müller et al., 2015; Rehbein et al., 2010; Tsitsika et al., 2014)  Gender (Chen et al., 2015; Choo et al., 2015; Dhir et al., 2015; Frangos et al., 2011; Hyun et al., 2015; Lee et al., 2017; Lin et al., 2011; Müller et al., 2015; Samarein et al., 2013; Spilkova et al., 2017; Sul, 2015; Toker & Baturay, 2016; Walther et al., 2012)  Residence type (alone, with parents, with relatives) (Frangos et al., 2011)  Individual marital status (Rho et al., 2016)  Parental marital status (Frangos et al., 2011; Müller et al., 2015)  Parental education (Karaca et al., 2020; Müller et al., 2015; Tsitsika et al., 2014; Wu, Zhang, et al., 2016)  Parental employment status (Karaca et al., 2020)  Parental economic/income status (Toker & Baturay, 2016; Walther et al., 2012; Wu, Zhang, et al., 2016) 2. Parent and Family Factors  Parent factors   • Parent-child relationship (Choo et al., 2015; King & Delfabbro, 2017)   • Parental monitor/control (Bonnaire & Phan, 2017; Ding et al., 2017; Li et al., 2014; Walther et al., 2012; Wu, Zhang, et al., 2016)   • Parental conflict (Bonnaire & Phan, 2017)   • Parent positive support (Li et al., 2014)   • Parental neglect (Kwak et al., 2018)   • Parental knowledge (Tian et al., 2019)  Family factors   • Family relationship (Bonnaire & Phan, 2017)   • Multicultural families (Choi & Yoo, 2015)   • Dual-income families (Choi & Yoo, 2015)   • Family function (Charoenwanit & Sumneangsanor, 2014)   • Family leisure (Sul, 2015) 3. Device Ownership, Internet Access, Location, Social Media & Game Itself  Device ownership (Smith et al., 2015; Toker & Baturay, 2016)  Access /Subscription to Internet (Frangos et al., 2011; Wu, Zhang, et al., 2016)  Game itself   • Games genre (Lee & Kim, 2017; Müller et al., 2015)   • Online and computer games (Toker & Baturay, 2016; Tsitsika et al., 2014)   • Structural characteristics of video game (Hull et al., 2013)   • Gaming cost (Rho et al., 2016)  Social media applications (Kuss et al., 2013)  Location (such as the bedroom) (Smith et al., 2015) 4. Personality/Traits, Psychopathology Factors, & Self-Efficacy  Personality/ traits   • Self-esteem (Billieux et al., 2015; Charoenwanit & Sumneangsanor, 2014; Hyun et al., 2015; Walther et al., 2012)   • Impulsivity (Walther et al., 2012)   • Sensation seeking (Walther et al., 2012)   • Aggression/Rule-breaking behavior/irritability (Tsitsika et al., 2014; Walther et al., 2012)   • Extraversion (Andreassen et al., 2013; Kuss et al., 2013; Samarein et al., 2013)   • Introversion (Torres-Rodríguez et al., 2018)   • Neuroticism (anxiety, anger, depression, loneliness, hostility, emotional stability) (Andreassen et al., 2013; Dong et al., 2013; Hyun et al., 2015; Jeong et al., 2015; Kuss et al., 2013; Mehroof & Griffiths, 2010; Samarein et al., 2013; Tsitsika et al., 2014; Vukosavljevic-Gvozden et al., 2015; Walther et al., 2012) (Chang et al., 2014; Hyun et al., 2015; Jeong et al., 2015; Laconi et al., 2017; Lin et al., 2011; Moslehpour & Batjargal, 2013; Tsitsika et al., 2014; Vukosavljevic-Gvozden et al., 2015; Walther et al., 2012)   • Conscientiousness (Samarein et al., 2013; Stavropoulos et al., 2016)   • Agreeableness (Andreassen et al., 2013; Kuss et al., 2013; Samarein et al., 2013; Walther et al., 2012)   • Resourcefulness (Kuss et al., 2013)   • Openness to experience (Andreassen et al., 2013)   • Psychoticism/socialization (Dong et al., 2013)   • Self-control (Li et al., 2014)   • Effortful control (Ding et al., 2017)   • IQ (Hyun et al., 2015)  Psychopathology   • Obsessive-compulsive (Vukosavljevic-Gvozden et al., 2015) (Torres-Rodríguez et al., 2018)   • Interpersonal sensitivity (Vukosavljevic-Gvozden et al., 2015) (Torres-Rodríguez et al., 2018)   • ADHD (Chen et al., 2015; Hyun et al., 2015; Walther et al., 2012)   • Irrational beliefs/ ubiquitous trait (Lee et al., 2017; Vukosavljevic-Gvozden et al., 2015)   • Autistics traits (Chen et al., 2015)   • Paranoid ideation (Torres-Rodríguez et al., 2018; Vukosavljevic-Gvozden et al., 2015)   • Impaired social adjustment (Chen et al., 2015)   • Self-devaluation (Torres-Rodríguez et al., 2018)   • Borderline (Torres-Rodríguez et al., 2018)   • Attention problem (Peeters et al., 2018)   • Insecure attachment (Lin et al., 2011)   • Somatization (Vukosavljevic-Gvozden et al., 2015)   • Anxiety (trait anxiety, state anxiety, and phobic anxiety) (Mehroof & Griffiths, 2010; Torres-Rodríguez et al., 2018; Vukosavljevic-Gvozden et al., 2015)   • Perseverative errors (Hyun et al., 2015)   • Lie (Dong et al., 2013)  Self-efficacy (Jeong et al., 2015; Lin et al., 2011; Walther et al., 2012) 5. Education & School Factors  Academic performance (Chen et al., 2015; Lin et al., 2011; Wu, Zhang, et al., 2016)  School bonding/ Relationship with teachers (Chang et al., 2014; Lee & Kim, 2017)  School well-being (Rehbein et al., 2010) 6. Perceived Enjoyment  The feeling of excitement, relief from negative emotion, passing time (Billieux et al., 2015)  Entertainment (Moslehpour & Batjargal, 2013)  Flow (Hull et al., 2013; Sun et al., 2015)  Leisure environment (Lee & Kim, 2017)  Gratification, general happiness (Dhir et al., 2015; Hull et al., 2013)  Perceived visibility & enjoyment (Sun et al., 2015)  Preoccupation (Lee et al., 2017) 7. Perceived Benefits  Using the Internet to communicate on important matters (Adiele & Olatokun, 2014)  Making money (Adiele & Olatokun, 2014)  Use for learning (Lee et al., 2017)  Making friends (Billieux et al., 2015; Kim & Kim, 2017; Moslehpour & Batjargal, 2013; Porter et al., 2010)  Online self-identity (Kim & Kim, 2017)  Getting-sex oriented materials (Adiele & Olatokun, 2014) 8. Health-Compromising Behaviors  Smoking (Chang et al., 2014; Frangos et al., 2011; Spilkova et al., 2017; Toker & Baturay, 2016)  Drinking (alcohol & coffee) (Frangos et al., 2011) (Spilkova et al., 2017)  Using drugs (Frangos et al., 2011) 9. Peers/Friends Relationships and Supports  Peer relationship & support (Kwak et al., 2018; Lee & Kim, 2017; Wu, Ko, et al., 2016; Wu, Zhang, et al., 2016)  Peer affiliation (Ding et al., 2017)  Community attendance (Rho et al., 2016) 10. Life Dissatisfaction & Stress (Moslehpour & Batjargal, 2013; Peeters et al., 2018) 11. Cybersafety (Smith et al., 2015) Discussion There were eleven groups of factors that emerged in the findings of this study as following. Socio-Demographic Characteristics There were eight factors of the Internet and game addiction according to socio-demographic characteristics: (1) Age, there were seven studies have provided the significant correlation between age and Internet and game addiction (Bianchini et al., 2017; Hyun et al., 2015; Karaca et al., 2020; Lim & Nam, 2018; Müller et al., 2015; Rehbein et al., 2010; Tsitsika et al., 2014). Karaca et al. (2020) revealed that Internet and game addiction was significantly in the older age of adolescents than in the younger age group. Rehbein et al. (2010) found that 15-year-old children were shown the specific risk factors of addiction at the age of ten years; (2) Gender, 13 studies discussed the linkage between gender and Internet and game addiction, which predominantly specific to males (Chen et al., 2015; Choo et al., 2015; Dhir et al., 2015; Frangos et al., 2011; Lin et al., 2011; Müller et al., 2015; Samarein et al., 2013; Sul, 2015; Toker & Baturay, 2016; Walther et al., 2012) than females (Lee et al., 2017). Hyun et al. (2015); Spilkova et al. (2017) stated that females are more prone to online communication and social media use, while males are more likely to online gaming; (3) Residence type, Frangos et al. (2011) revealed that those who were not staying with parents are highly associated with Internet addiction; (4) Individual marital status, Rho et al. (2016) found that those who are single are more prone to Internet addiction than those who are married; (5) Parental marital status, Frangos et al. (2011); Müller et al. (2015) revealed that those who have divorced parental condition are more addicted to Internet or game online; (6) Parental education, Wu, Zhang, et al. (2016) said mother’s and father’s education significantly correlate with Internet addiction. Karaca et al. (2020) found that those having parents who completed high school or a higher education level are more likely to be addicted to online game addiction. Conversely, Müller et al. (2015) revealed that those who have a mother with no formal education (not father’s education) are more addicted to Internet gaming addiction; (7) Parental employment status, Karaca et al. (2020) found that a mother who is employed is considered a factor of online game addiction in adolescents; (8) Parental economic/income status, Toker and Baturay (2016) and Wu, Zhang, et al. (2016) found that socioeconomic status or per capita annual household income is significantly related to the addiction rate. Walther et al. (2012) and Wu, Zhang, et al. (2016) revealed that high economic status tends to have problematic computer gaming in adolescents. Parent and Family Factors We discussed parent and family factors separately. For parental factors, there were six factors associated with the Internet and game addiction: (1) Parent-child relationship, Choo et al. (2015) revealed that parent-child relationship is an important predictor of the Internet or game addiction although King and Delfabbro (2017) stated that parent-child relationships have a weak correlation with Internet addiction; (2) Parental monitor/control, Bonnaire and Phan (2017); Wu, Zhang, et al. (2016) found that parental monitoring is correlated with Internet and game addiction. Walther et al. (2012) emphasize that lower parental monitoring is consistently associated with addictive behaviors. But, Ding et al. (2017) explained it differently that deviant peer affiliation is partially mediated the correlation between parental monitoring and Internet addiction, while Li et al. (2014) said that Internet addiction was explained positively by parents’ negative control; (3) Parental conflict, Bonnaire and Phan (2017) found that parental conflict is significantly related to Internet gaming addiction; (4) Parent positive support, Li et al. (2014) found that parents’ positive support was negatively correlated with Internet addiction; (5) Parental neglect, Kwak et al. (2018) found that smartphone addiction was significantly influenced by parental neglect; and (6) Parental knowledge, Tian et al. (2019) found that those with low parental knowledge are more addicted than those with high parental knowledge. For family factors, the studies indicated that those with poorer family relationships, multicultural and dual-income families, and poor family function are likely to be addicted more to the Internet and game addiction (Bonnaire & Phan, 2017; Choi & Yoo, 2015; Sul, 2015). In addition, Sul (2015) revealed that family leisure is one factor that correlates with Internet game addiction, in which the adolescents could join the family to enjoy the environment. Device Ownership, Internet Access, Location, Social Media & Game Itself According to Smith et al. (2015) and Toker and Baturay (2016), device and computer ownership are related to game addiction. Additionally, Frangos et al. (2011) said that subscription to the Internet is associated with Internet addiction, while Wu, Zhang, et al. (2016) found Internet café where adolescents could access the Internet is related to addiction. Of course, without online and computer games or social media applications, the addictive behavior will not occur (Kuss et al., 2013; Toker & Baturay, 2016; Tsitsika et al., 2014). Müller et al. (2015) said that all game genres are related to Internet gaming disorder. Lee and Kim (2017) found that simulation, RPG, and casual games were positively correlated with addictive behavior. In addition, structural characteristics of the game influence the level of addiction (Hull et al., 2013), while Rho et al. (2016) revealed that gaming cost is also an important factor of the Internet and game addiction. Besides, Smith et al. (2015) found that bedroom location is associated with video-game play, which leads to addiction. Personality Factors/ Traits, Psychopathology Factors, and Self-Efficacy There were 15 personality factors or traits that are related to Internet and game addiction, including low self-esteem (Billieux et al., 2015; Charoenwanit & Sumneangsanor, 2014; Hyun et al., 2015; Walther et al., 2012), high impulsivity and sensation seeking (Walther et al., 2012), aggression/ rule breaking behavior/ irritability (Tsitsika et al., 2014; Walther et al., 2012), extraversion (Andreassen et al., 2013; Kuss et al., 2013; Samarein et al., 2013), introversion (Torres-Rodríguez et al., 2018), neuroticism (anxiety, anger, depression, loneliness, hostility, emotional stability) (Andreassen et al., 2013; Dong et al., 2013; Hyun et al., 2015; Jeong et al., 2015; Kuss et al., 2013; Mehroof & Griffiths, 2010; Samarein et al., 2013; Tsitsika et al., 2014; Vukosavljevic-Gvozden et al., 2015; Walther et al., 2012) (Chang et al., 2014; Hyun et al., 2015; Jeong et al., 2015; Laconi et al., 2017; Lin et al., 2011; Moslehpour & Batjargal, 2013; Tsitsika et al., 2014; Vukosavljevic-Gvozden et al., 2015; Walther et al., 2012), conscientiousness (Andreassen et al., 2013; Kuss et al., 2013; Samarein et al., 2013; Stavropoulos et al., 2016), agreeableness (Andreassen et al., 2013; Kuss et al., 2013; Samarein et al., 2013; Walther et al., 2012), resourcefulness (Kuss et al., 2013), openness to experience (Andreassen et al., 2013), psychoticism/ socialization (Dong et al., 2013), low self-control (Li et al., 2014), and effortful control (Ding et al., 2017), IQ (Hyun et al., 2015). Specifically, Andreassen et al. (2013) found that extraversion is positively associated with Internet and game addiction, while Kuss et al. (2013); Samarein et al. (2013) found that extraversion is negatively correlated with the addiction. Neuroticism (Andreassen et al., 2013; Samarein et al., 2013) and resourcefulness (Kuss et al., 2013) are positively related to addiction, while conscientiousness (Andreassen et al., 2013; Kuss et al., 2013; Samarein et al., 2013; Stavropoulos et al., 2016), agreeableness (Andreassen et al., 2013; Kuss et al., 2013; Samarein et al., 2013), and openness to experience (Andreassen et al., 2013), are negatively correlated to addiction. For effortful control, Ding et al. (2017) found that the correlation between parental monitoring and deviant peer affiliation is moderated by effortful control, which in turn increases Internet addiction. Psychopathology Factor There were direct and indirect relationships between psychopathology factors and the Internet and game addiction. Vukosavljevic-Gvozden et al. (2015) found that somatization, phobic anxiety, depression, obsessive-compulsive, interpersonal sensitivity, anxiety, paranoid ideation, hostility, and psychoticism are mediating factors of game addiction. In comparison, Torres-Rodríguez et al. (2018) found that obsessive–compulsive, interpersonal sensibility, paranoia, self-devaluation, and borderline are direct factors of Internet and game addiction. Lee et al. (2017) also found that ubiquitous trait is directly associated with addiction. The other direct factors of addiction include ADHD (Chen et al., 2015; Hyun et al., 2015; Walther et al., 2012), autistics traits (Chen et al., 2015), impaired social adjustment (Chen et al., 2015), attention problem (Peeters et al., 2018), insecure attachment (Lin et al., 2011), perseverative errors (Hyun et al., 2015), and lie (Dong et al., 2013). For anxiety, Mehroof and Griffiths (2010) found that online gaming addiction was significantly associated with trait and state anxiety. While phobic anxiety, according to Vukosavljevic-Gvozden et al. (2015), is considered a mediator of game addiction. In regards to self-efficacy, Jeong et al. (2015) found that game addiction is negatively influenced by general self-efficacy but positively affected by game self-efficacy. Lin et al. (2011) also found that lower refusal self-efficacy of Internet use increases addiction, and Walther et al. (2012) revealed that social self-efficacy is related to game addiction. Education & School Factors There are three education and school factors: 1) academic performance, Chen et al. (2015) and Lin et al. (2011) found that Internet addiction was significantly correlated with poor academic performance. Wu, Zhang, et al. (2016) emphasized that the adolescents who had very poor academic performance were 2.4 times were more likely to report Internet addiction than those who had first-class academic performance; 2) school bonding or relationship with teachers, Chang et al. (2014) found that there was an increase in online activities for those with lower school bonding in grade 10. Similar to Lee and Kim (2017), who revealed that the respondents with less satisfaction with their relationships with teachers were more likely to be game addicts; 3) school well-being, Rehbein et al. (2010) revealed that students with low experienced school well-being are related to game addiction. Perceived Enjoyment Perceived enjoyment is considered a direct factor of addiction, which consist of the feeling of excitement, relief from negative emotion, passing time (Billieux et al., 2015), entertainment (Moslehpour & Batjargal, 2013), flow (Hull et al., 2013; Sun et al., 2015), leisure environment (Lee & Kim, 2017), gratification (Dhir et al., 2015; Hull et al., 2013), perceived visibility and enjoyment (Sun et al., 2015), and preoccupation (Lee et al., 2017). In terms of flow, Sun et al. (2015) added that flow directly affects addiction but also acted as mediating variable of perceived visibility and enjoyment. Perceived Benefits Adiele and Olatokun (2014) found that the benefits or extrinsic factors of Internet addiction were for communication on important matters, making money (especially amongst females), getting-sex oriented materials. Billieux et al. (2015); Kim and Kim (2017); Moslehpour and Batjargal (2013); Porter et al. (2010) revealed that making friends is the reason for addiction. Additionally, Lee et al. (2017) stated that the Internet was used for learning, while Kim and Kim (2017) found that online self-identity is also one of the reasons for addiction. Health-Compromising Behaviors The health-compromising behaviors that are associated with the Internet and game addiction are likely related to smoking (Chang et al., 2014; Frangos et al., 2011; Spilkova et al., 2017; Toker & Baturay, 2016), drinking alcohol (Frangos et al., 2011; Spilkova et al., 2017), and using the drug (Frangos et al., 2011). Interestingly, Frangos et al. (2011) also said that drinking coffee is one factor of addiction. Peers/Friends Relationships and Supports The relationships between peer and support and Internet and game addiction have been discussed in four studies (Kwak et al., 2018; Lee & Kim, 2017; Wu, Ko, et al., 2016; Wu, Zhang, et al., 2016). Kwak et al. (2018) said that smartphone addiction was negatively influenced by the relational maladjustment with peers, while Wu, Ko, et al. (2016) stated that peer influences (invitation to play, frequency of Internet game use, and positive attitudes toward Internet gaming) were positively associated with Internet gaming addiction. Peer influence was also mediated through the positive outcome expectancy of Internet gaming. According to Ding et al. (2017), peer affiliation is considered a mediating variable of the relationship between Internet addiction and perceived parental monitoring. Rho et al. (2016) stated that Internet gaming community meeting attendance is also the factor of addiction. Life Dissatisfaction & Stress Moslehpour and Batjargal (2013) found that stress is the factor that influences Internet addiction among adolescents, while Peeters et al. (2018) found that life dissatisfaction was the predictor of Internet addiction. Cybersafety Only one study discusses the relationship between cybersafety and game addiction, as indicated by Smith et al. (2015). This is, however, considered as an important factor that parents should discuss cyber safety as the protective factor of Internet or game addiction. Summary of the Findings The strong evidence of the number of studies in our review can be compared with a large volume of literature on the Internet and gaming addiction among adolescents. To understand the issues related to addiction, it is necessary to understand how factors are correlated with another from 11 categories retrieved by this review. The majority of the factors are found to be directly associated, while some are mediated by the others, specifically between personality/traits, psychopathology factors, and addiction. However, if all those factors are seen from internal and external categories, socio-demographic characteristics, personality/traits, psychopathology factors, self-efficacy, perceived enjoyment, perceived benefits, health-compromising behaviors, life dissatisfaction, and stress can be considered internal factors. While parent and family factors, devise ownership, Internet access and location, social media, and the game itself, education and school factors, peers or friends’ relationships and supports, and cybersafety are considered external factors. This study provides a comprehensive review of the factors associated with the Internet and gaming addiction among adolescents. However, those factors need further validation and determine how they are related to each other. This study’s limitation may include that the Internet and gaming addiction in some studies were not well defined. Hence, it is possible that some important articles might not be included in this study. In addition, if the Internet and gaming addiction is considered different and in terms of the target population between children and adolescents, then the findings of this study are limited. However, this study provides the implication for pediatric nurses or community nurses in dealing with adolescents with Internet and gaming addiction. The factors identified in this study can be used as basic information to provide intervention to decrease addiction levels. Conclusion Understanding the factors related to Internet and game addiction can help the development of adolescents. This systematic review shows that factors related to the Internet and gaming addiction are multifactorial and not well understood. There were 82 factors identified and categorized into 11 groups: (1) socio-demographic characteristics, (2) parent and family factors, (3) devise ownership, internet access, and location, social media, and the game itself, (4) personality/traits, psychopathology factors, self-efficacy, (5) education and school factors, (6) perceived enjoyment, (7) perceived benefits, (8) health-compromising behaviors, (9) peers/friends relationships and supports, (10) life dissatisfaction and stress, and (11) cybersafety. Further research is needed to validate the factors and clarify the linkage among factors. Supplementary Material Factors related to Internet and game addiction among adolescents: A scoping review Click here for additional data file. Declaration of Conflicting Interest The authors have no conflict of interest to declare. Funding This research received no specific grant from any funding agency. Authors’ Contributions All authors contributed equally to conceptualization, methodology, validation, literature review, data collection, analysis, data interpretation, and writing and editing of the manuscript. Both authors agreed with the final version of the article. Data Availability Statement All data generated or analyzed during this study are included in this published article (and its supplementary information file). Authors Biographies Siripattra Juthamanee, MNS, RN is a Lecturer at the Faculty of Nursing, Rajamangala University of Technology Thanyaburi, Thailand. Joko Gunawan, PhD, RN is a Director of Belitung Raya Foundation, Bangka Belitung, Indonesia. ==== Refs References Adiele, I., & Olatokun, W. (2014). Prevalence and determinants of Internet addiction among adolescents. Computers in Human Behavior, 31 , 100-110. 10.1016/j.chb.2013.10.028 American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-3-151 10.33546/bnj.1412 Theory and Concept Development Self-control in old age: A grounded theory study https://orcid.org/0000-0002-1987-4854 Caorong Laarni A. * College of Health Sciences, Mindanao State University – Marawi, Philippines Corresponding author: Dr. Laarni A. Caorong, RN, MAN, College of Health Sciences, Mindanao State University – Marawi, 5th East Tubod, Iligan City 9200, Philippines. Mobile: +639-213-403-270. Email: laarni.caorong@msumain.edu.ph Cite this article as: Caorong, L. A. (2021). Self-control in old age: A grounded theory study. Belitung Nursing Journal, 7(3), 151-162. https://doi.org/10.33546/bnj.1412 28 6 2021 2021 7 3 151162 28 2 2021 29 3 2021 03 5 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Self-control is associated with multiple positive outcomes. There are several studies on self-control, yet no literature describing the mechanism of self-control in old age. Objective This study aims to develop a substantive theory on the exercise of self-control in old age. Methods Grounded Theory methodology developed by Glaser & Strauss was utilized in the conduct of this study with ten (10) older adults as participants following the set of inclusion and exclusion criteria. Individual in-depth interviews of 30-45 minutes were observed to gather the needed verbatim narrative responses from each participant after careful consideration of the ethical procedures approved by the University research ethics board. Major themes with their respective sub-themes were generated after rigorous analysis of the participants’ responses following the steps provided by Glasser & Strauss in conducting grounded theory studies. Results This study resulted in the formulation of three propositions such as: (1) Older adults exercise self-control differently, (2) several personal motivations are involved in the exercise of self-control, and (3) the exercise of self-control leads to life satisfaction. From the propositions emerged the Theory of Self-control in Old age, which states that the process of self-control encompasses the human capability of exercising self-restraint to overrun different types of desires, passions, and temptations. The theory posits that older adults vary in their exercise of self-control depending upon their personal motivations. The theory also assumes that the exercise of self-control results in life satisfaction as displaying self-control is attributed to a host of positive life outcomes. Conclusion The present study has important implications in the field of gerontology and health care services since the older population is growing, and so does the demand for health care services. The need to understand the choices and decisions of older adult clients is fundamental in individualizing the health care services that may be designed and provided for them. self-control grounded theory old age inductive approach nursing ==== Body pmcIn life, human beings struggle to make optimal decisions so often, which require the exertion of self-control. Self-control is crucial before making any personal decision or choice (De Ridder et al., 2012). The decisions may involve economic choices, decisions about lifestyle preferences, moral choices, and personal predilections (Baumeister et al., 2007). Self-control is mainly the restraint that people use on their desires and impulses (Baumeister, 2012). More specifically, it is the capability to overrule or override one’s response. Self-control is a self-initiated practice in which the individual himself instigates the process (Duckworth et al., 2014). Late-life is often seen as a stage where there are multiple losses in various life domains. Empirical evidence shows that a decrease in physical function and cognitive ability is prevalent in late life, attributed to the biological changes in aging (Baltes & Mayer, 2001; Sadang & Palompon, 2021; Salthouse, 1996; Schaie, 1989). Considerably, the decline of the physical function of old people as well as the older adults’ mental agility is linked with the aging changes at the biological level (Baumeister & Alquist, 2009). Resultantly, there is a decrease and loss of physical and cognitive functioning. As defined in this study, self-control is a cognitive process governing one’s emotions, actions, and feelings. Notably, the exercise of self-control involves cognitive function. The link between the cognitive decline in aging and the capacity to exercise self-control in old age remains largely unknown although this might have a bearing on the older adults’ decisions affecting health, financial, social, and other life domains. Self-control is consequential; thus, this essential concept needs further investigation (Baumeister et al., 2007). Population growth and longevity of older people mean that the health care decisions they make, the investments they focus on, and the general choices they take in life will become increasingly important to the society other than themselves (Boals et al., 2011). The exercise of self-control comes into the picture when an older adult is faced with a decision to take. The decisions to control, restrain, suppress or act out are but consequential and will affect the older adult himself and other people (Tangney et al., 2004). Remarkably, older adults display various life decisions in terms of their physical health, how they engage socially with others, in financial matters, and others (Sadang & Palompon, 2021). Varied life avenues require the demonstration of self-control. The practice, according to many researchers, yields positive outcomes (Tangney et al., 2004). Although this is common knowledge, yet many older adults come up with poor choices in terms of health practices, fail in financial management, and sometimes have a strained relationship with other people as a result of the poor exercise of self-control (De Ridder et al., 2012). This requires deeper understanding and investigation. Since the exercise of self-control is consequential, the idea of delving deeper into this concept is not only vital but relevant. Existing literature states that self-control is an essential element for attaining one’s goals, being successful in one’s undertaking, and resisting ones’ selfish and one’s potentially harmful impulses. Since desires and temptations are ever-present, there is a need to exercise self-control. Although there were studies on children’s self-control in relation to their success in later life (Mischel & Ebbesen, 1970; Mischel et al., 1989), the mechanism of self-control in old age has not been well documented. Hence, the knowledge on the exercise of self-control in old age in terms of their health practices and behaviors and their social and financial dealings requires deep elaboration. The foregoing clearly shows the need to investigate the mechanism of self-control in old age to provide an elaborate description of how it is exercised in later life and its impact on the various life aspects of older adults. Hence, the purpose of this study was to generate a substantive theory of self-control among older adults in old age. The knowledge thereof will provide a succinct idea and understanding about this human quality trait which is deemed essential before making optimal life decisions. The present study has important implications in the field of gerontology and also in health care services since the older population is growing over the past years. Hence, there is an expectation obviously of a growing demand for health care services. So, there is a need for health care professionals to understand elderly clients. The need to understand the choices and decisions of older adult clients is fundamental in individualizing the health care services that may be designed and provided for them. Methods Design The Grounded Theory method developed by Glaser and Strauss (1967) was followed in undertaking this research study with the main aim of generating a substantive theory of self-control in old age. Systematic collection of qualitative data was employed to selected participants to gather datasets by carrying out a one-on-one in-depth interview to obtain a rich description of how people in old age exercise self-control. In this research study, the participants’ subjective experiences were explored to better understand their exercise of self-control in late life (Streubert & Carpenter, 2011). The purpose of Grounded Theory is to explore and describe a phenomenon in naturalistic settings. The target of Grounded Theory is to reach a conceptual theory that can explain and predict the experiences of the interview persons in relation to their life conditions (Glaser & Strauss, 1967). Moreover, an inductive approach to theory development was utilized. The process involved in this study included gathering qualitative data, analyzing the data collected, developing hypotheses and propositions, and finally generating a substantive theory (Streubert & Carpenter, 2011). The theory develops and evolves during the actual research process as an interplay between data collection and analysis ensues. Participants The participants were selected following inclusion criteria, which included the following: (a) willingness to participate in the research study, (b) 60 years old and above, (c) resident of Iligan City, (d) no cognitive disabilities, and (e) able to articulate and express thoughts, ideas and experiences. The cognitive level was assessed through the usage of a short portable mental questionnaire (Pfeiffer, 1975). Exclusion criteria were: (a) those who were cognitively impaired, (b) physically and psychologically frail, and (c) those who were unwilling to participate in the study. Sampling Theoretical sampling was employed in the study involving ten (10) older adults from Iligan City, Philippines. Theoretical sampling is the process of generating theory from the data (Glaser & Strauss, 1967). In this study, theoretical sampling was methodologically followed throughout the interview process. Data Gathering Process A face-to-face interview using an in-depth interview was conducted by the researcher in collecting qualitative data. The interview session was carried out within 30-45 minutes until data saturation was reached and theoretical sampling was attained. The conversation was recorded in an audio recorder, and permission was sought to record the conversation explaining its necessity to capture every single detail of the dialogue. A semi-structured interview style was employed, and guide questions were used. Ethical Considerations Ethics approval of the protocol by the Cebu Normal University-Research Ethics Committee (CNU-REC) with CNU-REC code 229/2019-02 Caorong was secured as part of the research protocol. Permission and approval from the Office of the Senior Citizens Affairs (OSCA) – Iligan Chapter president was also observed prior to the conduct of this study. Each of the participants was given a copy of the informed consent duly approved by the CNU-REC. The researcher comprehensively explained the content of the informed consent in the dialect that the participant understood. After a thorough explanation and discussion, the participants were asked to sign the informed consent form. The researcher assured that participation is voluntary and that at any given rate if the study participant should wish to stop participating, it should be recognized and respected. Analysis After having gone through some initial analysis of the data gathered, the researcher made some notes on what key concepts needed elaboration. The research participants were then asked about the concepts that needed elaboration until key and important concepts were described, elaborated, and clarified. When there was a redundancy of the information gathered from the research participants, this signaled that there was already data saturation. Constant comparison was made by comparing the findings with the existing findings. This method was essential in constructing theoretical categories which represented the core categories or concepts of the study on self-control in old age (Streubert & Carpenter, 2011). Grounded Theory involves several steps such as coding, memo writing, theoretical sampling, and the method of constant comparison (Glaser & Strauss, 1967). In this study, reading the qualitative data several times was done, and for chunks of data that had been gathered, labels were then made. The labels were based on the meaning that emerged from the data. After open coding one set of data, interconnections between categories and codes were created. The process is called axial coding. At this stage of the data analysis, the researcher integrated the categories identified in the axial coding process. The selection of the core categories was made by systematically relating the categories discovered. Moreover, the categories were then validated through finding existing relationships. Further development was made by filling in categories that require more refinement and development (Streubert & Carpenter, 2011). Memo writing was an essential aspect of the coding process (Glaser & Strauss, 1967). This was initiated as soon as coding was started. It involved theorizing and commenting about the codes. Reflections and ideas about codes and relationships between codes were made, which created the link between raw data and formal theorizing and hypothesis creation (Streubert & Carpenter, 2011). The research participants’ perceptions, ideas, and experiences of self-control were explored and investigated using open ended-questions. The guide questions were primarily rooted from the main research question, which was ‘how do individuals in old-age exercise self-control’. The idea was to ground the data which were systematically collected to describe self-control in old age. Moreover, probing questions or statements were used to prompt answers and explanations. Statements such as ‘please elaborate or expound’, ‘tell me more’, ‘can you please clarify’, ‘what was the outcome’, ‘please, expound’, ‘I’d like to hear more’, etc. were used. Results and Discussion In this section, the basic description of the participants and their self-control process are presented. Ten older adults who were residents of Iligan City were recruited to join the research. All of the older adults who participated were within the age range of 62-92 years. Fifty percent (50%) of the participants were male. Table 1 indicates the basic information of the participants. Table 1 Participants’ Profile Code Age Gender Religion Marital status TOM 64 Male Islam Married ZEN 69 Female Iglesia ni Cristo Widowed ROB 63 Male Roman Catholic Widowed REM 76 Female Roman Catholic Widowed DEB 64 Female Seventh Day Adventist Married DAN 92 Male Islam Married MAX 78 Male Roman Catholic Married TEL 62 Female Protestant Widowed CEL 70 Female Islam Separated TED 78 Male Roman Catholic Married Through constant comparative analysis, theoretical categories emerged, which were essential in the identification of the core theoretical categories which would substantiate the theory of control in old age. Four theoretical categories were formulated from the sixteen sub-categories identified about the theory of self-control in old age, namely: (1) self-introspection and assessment, (2) decision and choice of action, (3) action, reaction and conduct as an indication of self-control, and (4) outcome and impact of self-control. Theoretical Category 1: Self-introspection and Assessment The process of self-control is initiated by an older adult who engages personally in self-introspection and assessment. By introspection, the cognitive thought process is activated when a situation arises. This involves self-appraisal by an older adult concerning the advent of the situation or experience. Self-introspection primarily involves examination or assessment of one’s thought and emotional processes. The reflection involves looking into and considering one’s experience, valuing one’s moral standards, and taking into consideration the lessons gained from the past experiences. sub-category 1: Involvement of thinking and assessment In exercising self-control, the older adults engaged the thought process through thinking and considering the next course of action or response. The display of self-control by the older adults involves not only the concept of thinking but also discerning in deep thought the possibilities and consequences of one’s action or response. This stage of the process encompasses the process of assessment. “You really have to engage in thinking. Thereafter, you can make a decision. It is really a personal decision and that you are aware that there are consequences of your choices and decision which would impact you.” ROB sub-category 2: Valuing moral standards This pertains to the strong influence and consideration of moral standards in self-control exercised by the older participants. As many older adults have a strong sense of spirituality, their exercise of self-control is driven by a highly personal motive of being afraid to commit sins and because of the fear of God and wanting to please Him. “Well, the motivation for a religious person, for example, is avoidance of sin because the moment you don’t control yourself, you transgress the criteria of moral… or you violate the sharia (law). That’s the bottom line.” TOM sub-category 3: Knowledge and lessons gained through experience The learnings gained from their past experiences gave them significant reasons to avoid experiencing the same situation again, such as having experienced conflict within the family as well as suffering due to poor health choices before. “Hypothetically, you can control, or you can tame yourself to exercise self-control. You learn from exercising it. And you develop already that kind of self-discipline. You can now internalize through yourself the virtue of discipline or the virtue of self-control how to attain self-control.” TOM Theoretical Category 2: Decision and Choice of Action Self-control as a process involves the ability of an individual to govern one’s actions, feelings, or emotions. The process also involves deciding and choosing the next course of action. The choice of action comes out after having engaged in self-introspection or assessment. The decision is as well influenced by thinking of the positive and negative consequences of the actions. Furthermore, deciding the next course of action includes the consideration of the health-related changes as well as the current circumstance that the older adult is experiencing. The decision is also driven by outer and inner personal motives. sub-category 1: Involvement of personal decision and choice The exercise of self-control involves decision-making and choosing the next course of action or behavior to employ. The individual himself does the exercise of self-control. Older adults view self-control as a process involving personal decisions and choices. The decision process includes weighing the pros and cons of a certain action or the negative or positive consequences of the decision before coming up with a choice on what to take and do as the next course of action. “Self-control is a mental process. For instance, in a certain situation, I choose not to get affected since I am afraid of another (heart) attack. In such a case, I really weigh things out. For example, I would not readily react to provocations to abate a situation because it could very well lead to conflict. Self-control is a cognitive process. It is a self-initiated process.” ROB sub-category 2: Thinking of the consequence of one’s decision In the exercise of self-control, before the older adult decides what to do next, he looks at the possible consequences of his decision and his choice of action. The older adult’s choice of action is in consideration of the consequences both positive and negative of one’s decision and choice of action. “Before going to America, I was actually engaged in all sorts of vices. I was involved in drinking intoxicants and gambling. I did all those vices, but when I left the country, I also left those vices. I controlled myself to leave those vices so that I would not have any problems with my family and children. My family remains intact after leaving those vices. I actually now live a comfortable life.” TED sub-category 3: Consideration of age and health-related changes Older adults go through several changes in cognition, emotion, physical strength, and health, among other human aspects. The decision and choice of action by the study participants were actually influenced by their current state of health as they now are keen on considering the different changes they are experiencing. Current changes in the aspect of health, for instance, had made them become motivated to demonstrate more self-control. They have changed their old practices to what now is necessary and recommended for them to do. “I usually do physical exercises every morning for 15-20 minutes. I usually force myself to get up so that I could expose my body to the sunlight before 8 am. This is so that I would be exposed to the sunlight for Vitamin D.” REM sub-category 4: Consideration of current life circumstance This category reflects that older adults go through varied life circumstances. Obligations and duties do not stop with aging. Certain responsibilities and obligations by older adults need to be fulfilled and accomplished. Many older adults exercise self-control to carry through their responsibilities in life. “If I won’t control my spending and just squander my money carelessly, then for sure I will not have enough money for future use. Although I wanted to eat rice, I restrain myself because eating rice could potentially cause my sugar to rise. I am also financially incapable of affording rice for myself and my helper’s consumption.” REM sub-category 5: Inner motivations of the exercise of self-control According to the participants, their exercise of self-control includes inner motivations. Such inner motivation included the want to avoid sin and to abide by moral standards. Fear of God also surfaced as an inner motive in self-control exercise as well as giving value to the Divine commands. “The number one reason why I exercise self-control is because of fear to commit sin to God. I also don’t like any trouble, and I don’t want to experience a headache.” REM sub-category 6: Various outer motivations of the exercise of self-control Other than the inner motives of exercising self-control, various outer motivations of the exercise thereof were also discovered. The various outer motivations in the exercise of self-control among the study participants included wanting to maintain social relationships intact, promoting health status, and managing financial resources well for future use. “If I would not control my spending and just squander my money carelessly, I would not have enough funds for future use. There are really times that I suffer an asthma attack. During those times, there is really a need for me to purchase my asthma medication which costs over a thousand pesos. So, I really need to have some money on those times.” REM Theoretical Category 3: Action, Reaction or Conduct as Indications of Self-control The third theoretical category reflects the decision and choice of the individual who exercises self-control. These are manifested or indicated in his or her actions, reactions, or conduct. Under this theoretical category are sub-categories such as restraining the self from acting out, resisting temptation and passion, and suppressing inner feeling, involving struggles to control the self as well as the changing degree of self-control. The third theoretical category is supported by the following subcategories below: sub-category 1: Restraining self from acting out This sub-category reflects the manifestation of self-restraint by an individual who exercises control in terms of his actions. By restraining himself, he is engaged in a deliberate action of his choosing. The choice of action is processed within himself taking on different considerations such as the possible consequences. “Sometimes I get angry with my husband over minor things such as when our kitchen is messy. At home, I really like things to be in their proper places, but my husband has this habit of putting candy wrappers on my vases which I dislike. When that happens, I gently reprimand him. I now have self-restraint, but before, I usually throw things at him and sometimes even give him a smack.” DEB sub-category 2: Resisting temptation and passion Human beings are surrounded by different and varying types of desires, passions, and temptations. However, there are temptations and desires that need to be resisted because of the harm they could bring. This is where the exercise of self-control is needed. The exercise of self-control against the desires and passion of an individual entails struggle and effort. “Well, of course, with the basic control is fasting. It should also be observed throughout your daily life. For example, if you can control partaking food like this one (points at the food on the table) … learning from this virtue for your daily life, you can control not taking any food like taking any sweets, palatable food, cold drinks and all that. You can control yourself even if it is palatable or satisfying through drinking cold water. I don’t even care for cold water or sweets or chocolate. I don’t care for those. I just take vegetable, and I cannot even finish a cup of rice. So that is the result of fasting.” TOM sub-category 3: Suppressing inner feelings Expressing emotions and feelings are inherent in a man. There are constant engagements and interactions among people anytime and anywhere. The experience may often evoke the expression of feelings and emotions, yet, consequently, certain situations necessitate the exercise of self-control to keep the good social relationship going and avoid unnecessary expressions of words that may not be received well by others. “I know how to control myself. For instance, when provoked, I am aware that I should not get angry because it could cause my blood pressure to rise. In such a case, what I do is restrain myself. When it comes to food prohibitions, I just eat a little to ease my desire. That, I think is practicing self-control.” ROB sub-category 4: The changing degrees of self-control This subcategory entails the varying degrees and levels of the display of self-control among older adults. There are older adult participants who had more self-control, or their level of self-control now had increased due to age. Yet, some older adults also are less able to control themselves by giving in to desires and whims. Hence the older participants really have varying degrees or levels of self-control. “There is actually a great impact that my self-control now has increased. For instance, before I really wanted that those who are indebted to me will really pay me back. Nowadays, I still allow other people to borrow money from me, yet I consider lending people money like an act of charity.” REM sub-category 5: Struggles in controlling self For older people, exercising self-control involves the element of struggle. This occurs because there are outward and inward pressures of either satisfying one’s desire or refraining from doing something or acting out, which requires effort and conscientiousness. “For example, I am not in contact with my wife, and you are still an organism (me). What is the mechanism of self-control that you are not in contact with your wife? No cohabiting. No sexual pleasure. You cannot also commit Zina (adultery) because that is haram (prohibited)…I don’t look at naked bodies. If it’s in front of me, I look away, and it’s very hard, especially for the male. I turn away. I have interest, but I refrain. Who is not interested after all?” TOM Theoretical Category 4: Outcome and Impact of Self-control The final theoretical category encompasses the different outcomes, results, and impact of exercising self-control. Many of the older adults expressed that exercising self-control led to positive outcomes. However, there are negative outcomes as well of displaying low self-control. Additionally, the results of displaying self-control as emphasized by the older adults do not only impact other people but also relatively impact them. They even conveyed that exercising self-control made them feel happy and satisfied. sub-category 1: Feeling of satisfaction and happiness This subcategory is the reflection of the ultimate result of exercising self-control which is the feeling of happiness and satisfaction. Several older adults who joined the study stated when asked, ‘what do they feel upon exercising self-control?’, that they feel happy and satisfied. This may be due to them doing actions they are so strongly motivated to act about or behave a certain way that they feel strong about, giving them happiness and satisfaction. Furthermore, not all older adults happen to have perfect self-control. There are older people who display a lesser degree of self-control given a situation. The next subcategory under this last theoretical category exhibits the consequences of not practicing control or having less self-control. “I feel happy because I can please Allah. I can please the Lord, and Allah loves the people who exercise self-control. He loves people who renounce the world. So…you control, you fast, you renounce, you deprive yourself… that would make Allah very happy.” TOM sub-category 2: Consequences of losing control The results of having less or no self-control are generally linked to negative consequences such as conflicts with other people, trouble, and strained relationships with others people. These occurrences were experienced by the older adults themselves, as discovered from the in-depth interview. “I really cannot control my self especially when it comes to reprimanding my children. I will not stop saying things until I have said what I needed to say to my children, even if it is hurtful to them. That is my weakness. I also am not able to control myself when I am angry at my spouse.” DEB With the establishment of the core categories supported by the identified subcategories and the participants’ narrations, comes now the understanding of the process of self-control in old age. The process begins with the older adults engaging initially in what is called self-introspection followed by the act of choosing and deciding. The decision and choice of the older adults will then be reflected in their actions and conduct, which would then yield some outcome and impact. Hypotheses Derived from the Results The generation of the substantive theory was derived through employing the constant comparative analysis method of the qualitative data, which were systematically gathered. The analysis resulted in the identification and formulation of subcategories and theoretical categories respectively, which in turn became the basis of developing and generating the research hypotheses. The developed hypotheses showcase the relationships between variables identified which emerged from grounding the qualitative data sets. The exploration and analysis resulted in the following hypotheses: Hypothesis 1: Self-control is a personal decision which is self-initiated by an older adult driven by one’s own personal motive The hypothesis identified depicts that the exercise of self-control by an older adult is self-initiated—each older adult exercises self-control differently. The driving force for the exercise and practice of self-control depends on one’s own personal motives or specific personal goals. This assumption was induced from the narratives of the selected study participants. Some participants practice or exercise self-control in order to maintain good relations with other people, while others practice self-control to follow moral standards or in consideration of the health-related changes they experience. The different personal motivations of the older adults in their exercise of self-control are highly personal. They significantly vary in their personal motivations. The personal motivations to exercise self-control are influenced by past experiences and the lessons gained from those experiences. Hypothesis 2: There is a relationship between health status, interpersonal relationships, spirituality, financial status, and the exercise of self-control among older adults It was established from the data collected one motivation of the older adults in their exercise of self-control is the consideration of the health-related changes they now experience in late life. Some research participants revealed that they are now more careful in terms of their food intake. They avoid doing things that may aggravate their current health condition or health issues. They further revealed that they had to struggle to engage in physical exercises to improve their health status and avoid foods not recommended for them to eat even if the food is of their liking. On the other hand, they are aware that they are already in their sunset years, and this realization increases their spiritual connection. Many participants said that they restrain themselves from giving in to some of their desires since they are afraid of God and are therefore afraid to commit sins. When confronted with situations where giving in would lead them to commit sin, they would readily exercise and practice self-control to avoid sinning. Hypothesis 3: Older adults who have high self-control have better life satisfaction When asked what emotions they feel when they exercise self-control in a given situation, several participants answered that they feel happy and have personal satisfaction. As an example, they said that avoiding argumentation or refraining from speaking back ill words has preserved their good relationships with other people, and as a result, they feel happy. Maintaining good relationships with loved ones, family, relatives, neighbors, and other people are considerable factors for life satisfaction. Propositions Derived from the Hypotheses The following are the propositions formulated from the generated hypotheses grounded from the qualitative data obtained. Proposition 1: Older adults exercise self-control differently The first proposition was derived from the first hypothesis, which states that self-control is a personal decision which is self-initiated by an older adult driven by one’s own personal motive. People exert self-control on a daily basis across different life domains such as in health, in their interpersonal relationships and dealings, in financial matters, and others. Since human beings are in constant interaction with their environment, the exercise of self-control is vital. Human beings possess the capability of exercising self-control which involves the thought process of decision making and choosing which action or behavior to exercise, display or demonstrate. The exercise of self-control differs from one older adult to another as individuals have different personal motives and capabilities and are unique in many ways. Self-control, according to Vohs and Baumeister (2004), is the ability of a person to suppress or inhibit behaviors or responses intentionally and consciously. Similarly, self-control is seen as the capacity of an individual to alter responses in terms of morals, values, ideals, and expectations of other people behind some long-term goals (Baumeister et al., 2007). In the field of psychology and philosophy, there is a contention that self-control is needed to suppress an immediate urge to consume. Not smoking cigarettes, not drinking alcoholic beverages, or not consuming fatty foods are just some examples of exhibiting self-control. Those who claim to show self-control prefer rewards or benefits in the future, such as longer lives and better health (Henden, 2008). The term self-control is often used in many disciplines, which may often also refer to self-regulation, conscience, willpower, and delayed satisfaction (Moffitt et al., 2011). As defined by Henden (2008), self-control refers to a person’s capacity in a lesser or larger degree. There are individuals with a low level of self-control who may have distinct characteristics in terms of attitude and behavior. These individuals may also have the tendency to pursue immediate gratification rather than delaying it. There are also explorations in the behavioral science that inspect self-control demonstration in early childhood and determine the changes of the self-control practice during the life course (Jackson et al., 2009; Kochanska et al., 2001). Persons with high self-control, on the other hand, are seen to be more successful in handling relationships with other people as well as having more satisfying relations with them (Finkel & Campbell, 2001). The impact of exercising self-control also to cope with stress and maintain psychological health is also found to be positive (Englert & Bertrams, 2015). Several researches consider self-control to range from poor to good behavioral control (Dick et al., 2010). Many investigators had the assumption which suggests that an individual’s ability to regulate self or not differs in a qualitative sense (Friese & Hofmann, 2009; Hofmann et al., 2009; Strack & Deutsch, 2004). Good self-control is said to involve a conscious regulatory process that includes several subcomponents. They include one’s ability to adjust and monitor one’s behavior when anticipating results, delaying gratification, suppressing problematic behavior, and being goal-directed. On the other side, individuals who are unable to control themselves are more spontaneous with their actions sidetracking the necessity of conscious planning. They are also unable to delay gratification or even appropriately modify responses (Pearson et al., 2013). In accomplishing daily-mundane tasks, which often require decision-making, self-control is indeed needed. However, many people find it extra challenging to exert self-control which leads to failure in accomplishing tasks such as eating healthy, doing exercise to saving money (Baumeister et al., 1998; Baumeister et al., 2007; Carver & Scheier, 2001). Proposition 2: There are various motivations involved in the exercise of self-control The next proposition was developed from the assumption that there is a relationship between health status, interpersonal relationships, spirituality, financial status, and the exercise of self-control among older adults. It could be argued that there are various motivations behind the exercise of self-control by an individual. The inner drives and motivations come in different forms as human beings inherently have different aspirations and life goals and aims. Self-control is established as a person’s ability to regulate his own thoughts, actions, and feelings (De Ridder et al., 2012). Moreover, the practice of self-control helps resolve motivational conflicts experienced by an individual between short-term and long-term goals (Fujita, 2011). Persons who are good at controlling themselves easily resist temptations that would otherwise be in conflict with the valued long-term pursuits. Essentially, persons of this type are certainly engaged in action and behaviors that help achieve or attain goals and motivations. Motivations are classified as either intrinsic or extrinsic. The reason behind the action or behavior of a person in a particular way is driven by his or her motivations. Intrinsic motivation implies that an individual engages in activity because the person finds it enjoyable, satisfying, or interesting as his or her inner motivation. On the other hand, extrinsic motivation means that a person is driven to do things that will lead him to achieve some personal gains such as money (Deci & Ryan, 1985; Ryan & Deci, 2000). Henden (2008) suggested that self-control involves the notion of a person having the capacity to bring one’s action in line with his intention in seemingly competing motivations. This could be elucidated when a person has the intention to resist, for instance, another cigarette and was able to resist it despite having a strong desire for it. Edmund argues that self-control is a form of intentional control over one’s behavior; thus, self-control is a person’s ability to control himself. According to Baumeister et al. (2007), there is a need to resist temptations as these may bring about long-term consequences. For instance, one must attempt to resist the temptation to eat unhealthy food, or to go to sleep for extended hours or act in a violent manner since undeniably failure to repel impulses and temptations may lead to crime, alcoholism, teen pregnancy, drug addiction, venereal diseases or underachievement in education among other (Baumeister & Alquist, 2009; Baumeister et al., 2007). Proposition 3: The exercise of self-control leads to life satisfaction The hypothesis that older adults who exercise self-control have better life satisfaction is the basis for the above proposition. Findings of this current study show that older adults who exercise self-restraint on matters they feel strong about and are motivated to do about find themselves feeling happy after exercising self-control. The feeling of happiness is associated with the positive outcomes of the exercise of self-control, such as maintaining good interpersonal relationships. Self-control is a strong determining factor for success in life (De Ridder et al., 2012). There are a number of adaptive outcomes associated with the exercise of self-control which include better interpersonal relationships, better physical health, and better intellectual performance (Finkel & Campbell, 2001; Schmeichel et al., 2003; Will Crescioni et al., 2011). Exercising high self-control is a pertinent aspect of a person’s behavior for a person to have a successful and healthy life (De Ridder et al., 2012; Tangney et al., 2004). It was found out that behaviors such as minimized aggression, reduced criminality (Dewall et al., 2007), better interactions (Finkel & Campbell, 2001), less abuse of alcohol, smoking, and other prohibited substances (Sayette, 2004), and high self-esteem and improved interpersonal skills were all related to the practice of high self-control. Moreover, Hofmann et al. (2014) stated that self-control is a person’s ability to override one’s inner response and to interrupt undesirable behavioral inclinations or impulses. Additionally, greater self-control is also positively attributed to psychological adjustments and negatively predicts psychopathology (Tangney et al., 2004). It was also found out that the more self-control a person exhibits, the fewer are the experiences of symptoms and stress while having better mental health (Boals et al., 2011). This finding was corroborated by the results of the study by Jensen-Campbell and Malcolm (2007) and Bogg and Roberts (2004), that there is a link between self-control and higher quality and satisfying relationships. The essence of self-control in reaching significant life outcomes is widely known. Empirical evidence shows that high self-control practice positively predicts well-being, satisfaction with life, and positive affect. High self-control here means the ability of a person to regulate his thoughts, feelings, and behaviors (De Ridder et al., 2012; Hofmann et al., 2014). There is a well-established relationship between self-control and optimal functioning (Tangney et al., 2004). They also posited that people’s capacity to practice self-control displays their adaptive nature, which has some implications that they also live more happy and healthy lives. Moreover, there is also evidence pointing out that people with a higher level of self-control are seen to feel satisfied with their lives as well as experience positive emotions more than those who have low levels of self-control (De Ridder et al., 2012; Hofmann et al., 2014). Additionally, self-control was seen by many researchers to be elemental in one’s personality trait. Having conscientiousness is attributed to longevity, physical health, and other relevant health behaviors (Bogg & Roberts, 2004; Friedman et al., 1993; Goodwin & Friedman, 2006). Succinctly, self-control is a catchall essential human trait necessary for attaining a good life; thus, self-control demonstration is associated with a number of positive life outcomes. The Theory of Self-control in Old age The theory of self-control in old age assumes that self-control is a self-initiated process of governing one’s actions, emotions, and feelings driven by one’s own personal motives. It is also assumed that older adults exercise self-control differently as there are various personal motivations involved in the exercise thereof. Moreover, it is posited that the exercise of self-control among older adults leads to life satisfaction. The theory suggests that the ability to exercise self-control involves introspection and assessment and the thought process of deciding and choosing what actions or behavior to display, and the individual himself does the exercise of self-control. The theory suggests that self-control involves deciding and choosing an action or behavior that is highly grounded on the person’s inner drive and personal motivations. It also involves weighing and assessing possible consequences of one’s action before initiating a response or action. The theory generated could be classified as a middle-range theory since it addresses specific phenomena by explaining what exercise of self-control is in old age, why it occurs, and how it occurs among older adults. This middle-range theory on the exercise of self-control in old age suggests that older adults vary in their exercise of self-control. The degree of self-control is linked to one’s own personal motives and one’s attainment of specific aims and life objectives. The theory further suggests that there are different factors and motivations involved in the exercise of self-control among older adults. The display of self-control presupposes various personal motives such as attaining personal interest and general well-being, maintaining social status or standing, having better interpersonal relationships, accomplishing personal obligations and responsibilities, and having better health. Furthermore, the theory assumes that the practice or exercise of self-control results in personal satisfaction as displaying self-control is attributed to a host of positive life outcomes. The diagram shows that the exercise of self-control among older adults entails the involvement of varying motivational factors. It is assumed in the theory that the motivating factors include the aspect of wanting to maintain health, accomplishing obligations, maintaining social status, having better relationships, and attaining general well-being. As seen in the figure, attaining life satisfaction is an outcome for exercising self-control, as presented in Figure 2. Figure 1 The schematic diagram of the axial coding process Figure 2 Schematic diagram of the Theory of Self-control in Old age Conclusion The exercise of self-control in old age is a necessary aspect of any choices and decisions in life besides being consequential. The choices and decisions of older people in varied life avenues necessitate the practice of self-control as outcomes will have an impact not only on them but also on other individuals and society in general. Older people are not exempt but are also faced constantly with life decisions and choices in terms of their physical health, social relationships, and economic choices as such the practice of self-control is necessary as positive outcomes are expected. The present study has important implications in the field of gerontology and health care services since the older population is growing, and so does the demand for health care services. The need to understand the choices and decisions of older adults is foundational in individualizing health care services. Further, the theory also provides a broader view and a better perspective in understanding older adults in their life choices and decisions. Acknowledgment The author would like to acknowledge the support and contribution of the following organization and individuals: (1) Mindanao State University – Marawi headed by the System President, Dr. Habib W. Macaayong, (2) Cebu Normal University in Cebu City, Philippines where she took up her terminal doctoral degree in nursing, (3) the dean of her home College, Dr. Naima D. Mala, (4) her dissertation adviser, Dr. Daisy R. Palompon, (4) her dissertation panel members, (5) Dr. Jonaid M. Sadang for his assistance during the processing of this publication, (6) family and friends, (7) BNJ editors & peer-reviewers for their great contribution in refining this work, and of course (8) all the participants who have been generous in sharing their respective rich experiences during the data collection process. Declaration of Conflicting Interest There is no conflict of interest. Funding This research work was supported by Mindanao State University – Marawi under the APDP Scholarship. Author Biography Dr. Laarni A. Caorong, RN, MAN is an Associate Professor V at the College of Health Sciences, Mindanao State University – Marawi, Philippines. She is currently designated as BSN Program Level – I Coordinator and a member of various working committees in the said College. Data Availability Statement The full transcribed verbatim responses of the participants were kept in a password-protected computer during the analysis of this research work and was permanently deleted after the completion of her dissertation paper for confidentiality and ethical purposes. ==== Refs References Baltes, P. B., & Mayer, K. U. (2001). The Berlin aging study: Aging from 70 to 100. New York, NY, US: Cambridge University Press. Baumeister, R. F. (2012). Self-control—The moral muscle. The Psychologist, 25 (2 ), 112–115. Baumeister, R. F., & Alquist, J. L. (2009). Is there a downside to good self-control? Self and Identity, 8 (2-3 ), 115-130. 10.1080/15298860802501474 Baumeister, R. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-006 10.33546/bnj.2396 Review Article Self-care educational guide for mothers with gestational diabetes mellitus: A systematic review on identifying self-care domains, approaches, and their effectiveness https://orcid.org/0000-0002-5948-0948 Haron Zarina 12 https://orcid.org/0000-0001-9956-4727 Sutan Rosnah 1* https://orcid.org/0000-0002-4764-5178 Zakaria Roshaya 3 https://orcid.org/0000-0003-0856-0697 Abdullah Mahdy Zaleha 4 1 Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia 2 Department of Nursing, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia 3 Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia 4 Department of Obstetrics & Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia * Corresponding author: Rosnah Sutan, M.D., M.P.H., PhD, Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia Jalan Yaakob Latif, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia. Email: rosnah_sutan@yahoo.com Cite this article as: Haron, Z., Sutan, R., Zakaria, R., & Abdullah Mahdy, Z. (2023). Self-care educational guide for mothers with gestational diabetes mellitus: A systematic review on identifying self-care domains, approaches, and their effectiveness. Belitung Nursing Journal, 9(1), 6-16. https://doi.org/10.33546/bnj.2396 12 2 2023 2023 9 1 616 28 10 2022 30 11 2022 08 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Gestational Diabetes Mellitus (GDM) is a common form of poor carbohydrate intolerance, prevalent among pregnant women and associated with unhealthy lifestyle behaviors. Given the dearth of information on self-empowerment among mothers with GDM, a self-care health education package needs to be developed to prevent related complications. Objective This review aimed to identify self-care approaches, domains, and their effectiveness for a proper self-care educational guide package for women with GDM. Design A systematic review using electronic literature databases published between January 2016 and December 2022 was conducted. Data Sources Web of Science, Scopus, and Ovid databases were used. Review Methods This review utilized the PICO (Population, Intervention, Comparison, and Outcomes) framework to screen the retrieved articles for eligibility in which mothers with GDM, educational materials, standard practice or intervention, and effectiveness were considered the PICO, respectively. The CIPP (Context, Input, Process, Product) model served as a framework for adopting the education development model. Mixed methods appraisal tool was used for quality assessment. Data extraction and synthesis without meta-analysis were presented as evidence tables. Results A total of 19 articles on GDM were included in the final analysis (16 Intervention studies, two qualitative studies, and one mixed-methods study). Four broad domains emerged from the analysis: 1) information or knowledge of GDM, 2) monitoring of blood glucose levels, 3) practice of healthy lifestyles, and 4) other non-specific activities. The majority of the articles employed a face-to-face approach in executing the educational group sessions, and most studies disclosed their positive effects on GDM management. Other methods of evaluating intervention effectiveness were described as improved self-care behavior, increased satisfaction score, enhanced self-efficacy, good glucose control, and better pregnancy outcome. Conclusion Knowledge or information about GDM, healthy diet, and exercise or physical activity was found to be the most applied domains of intervention. Framework domains based on the present review can be used in the future development of any interventional program for GDM women in enhancing health information reaching the targeted group in promoting self-efficacy. PROSPERO registration number CRD42021229610. gestational diabetes mellitus self-care self-management health education blood glucose ==== Body pmcBackground Gestational Diabetes Mellitus (GDM) is a common health condition diagnosed irrespective of income country status and has been reported as an increasing trend in the past 20 years (Bahram Mohebbi et al., 2019; Carolan-OIah, 2016; Rollo et al., 2020). GDM is often related to maternal and fetal complications because of maternal hyperglycemia, one of the primary predictors of maternal-fetal complications (Borgen et al., 2019; Lefkovits et al., 2019). Maternal complications of GDM include preeclampsia and birth trauma, while in the fetus, it can cause macrosomia, shoulder dystocia, intrauterine death, and stillbirth (Carolan-Olah et al., 2017a; Lefkovits et al., 2019; Mustad et al., 2020; Rasekaba et al., 2016). Health empowerment intervention strategies may improve glucose levels for mothers with GDM to reduce the risk of complications (Borgen et al., 2017; Lefkovits et al., 2019; Mirfeizi M, 2017; Rollo et al., 2016). Several studies have found that blood glucose monitoring and lifestyle modifications, such as glucose, improve health outcomes without complications (Allehdan et al., 2019; Carolan-Olah & Sayakhot, 2019; Kennelly et al., 2016; Sayakhot et al., 2016). Nevertheless, these approaches are challenging for women with GDM because they require learning and adopting self-care skills in a short time (American Diabetes Association, 2019). The self-care has been defined as an individual’s, family’s, and community’s ability to improve and sustain well-being, avoid diseases and cope with the health-related condition themselves or with the assistance of a healthcare provider (Carolan-OIah, 2016; Lefkovits et al., 2019). Self-care is an essential component of health empowerment and has been used for GDM management in preventing maternal and fetal complications (Mohebbi et al., 2019). In addition, the World Health Organization (WHO) also recommends that women recognize their potential for safer pregnancy (Carolan-OIah, 2016). In GDM management, health education intervention is an essential component of self-care to train self-care skills, blood glucose monitoring, behavioral change, healthy lifestyle, decision-making, and others (Carolan-OIah, 2016; Ge et al., 2016; Hussain et al., 2015; Kusumaningrum et al., 2022; Tavakkoli et al., 2018; Wah et al., 2019). Therefore, it is imperative to produce a GDM health education intervention package to improve the quality of health services and strengthen individual self-care skills. The content of the GDM package should be simple, comprehensible, accessible, and interesting for women with GDM. The model framework for the development of educational packages commonly uses the CIPP (context, input, process, and product) model for intervention evaluation and data extraction. The CIPP is widely used for the review of programs or projects and was developed to provide systematic information for decision-making and proactive evaluation (Aziz et al., 2018). However, limited studies use the CIPP model. Therefore, a systematic literature review on GDM education is essential for guiding the development of health education packages. The present study aimed to identify self-care domains, approaches, and techniques for a self-care educational guide package for women with GDM appropriate for their country and culture. Methods Search Strategy A systematic review of original research using a quantitative or qualitative study method on GDM education was conducted. The protocol was registered in PROSPERO under the scope for synthesis without meta-analyses (SWiM) (Campbell et al., 2020). Published data were obtained from Web of Science, Scopus, and Ovid electronic databases. The review search was based on TITLE-ABS-KEY (development OR develop OR developing) AND (health education package OR health education module OR health education intervention OR health teaching OR health intervention OR self-management OR self-intervention) AND (control of glucose level OR glucose management OR glycaemic control OR glycaemic management) AND (Gestational Diabetes Mellitus OR diabetes in pregnancy OR pregnant women with diabetes) (see supplementary file). Selection of Studies A list of titles selected was screened, and relevant abstracts were assessed based on the inclusion criteria: a journal article, written in English, and published between 1 January 2016 and 19 December 2022. The PICO model was used that covers the targeted population, type of intervention, a comparative group for intervention, and study outcomes (Table 1). Table 1 PICO strategy description Acronym Definition Description P Patient and problem Inclusion criteria: Pregnant women with GDM at 20 to 36 weeks of gestation. The exclusion criteria were women with pre-gestational and diabetes type 1 or 2 I Intervention Education materials or programs for women with GDM C Control or comparison Only received standard care, no intervention or another intervention O Outcome Effective and not effective assessment Data Extraction The criteria used in the CIPP model can be defined in various ways depending on the program assessment by multidiscipline (Lee et al., 2019). In this present study, data extraction utilized a standardized CIPP model (supplementary file), which was performed by the first authors (ZH and RS) and reviewed by the second author (RS) to verify the extracted data. Quality Appraisal Assessment Extracted relevant literature was assessed using the Mixed Methods Appraisal Tool (MMAT) (Hong et al., 2018). Five research designs were included in the MMAT for quality appraisal assessment, as shown in Table 2 (randomized controlled trials), Table 3 (non-randomized controlled trials), Table 4 (qualitative studies), and Table 5 (mixed-methods study). The MMAT enables researchers to critically select quality empirical studies through a proper risk of bias screening based on the study methodology reported. This quality appraisal eliminated non-empirical papers, including review articles and theoretical papers, from being included in this study. Table 2 Quality appraisal of quantitative studies (randomized controlled trials) Criteria (Rasmussen et al., 2020) (Zandinava et al., 2017) (Mackillop et al., 2018) (Kolivand et al., 2019) (Al-Ofi et al., 2019) (Guo et al., 2019) (Mirghafourvand et al., 2019) (Gharachourlo et al., 2018) (Ammulu et al., 2019) (Tian et al., 2021) (He et al., 2022) (Xie et al., 2022) Clear research question (s) Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Collected data addresses the research questions Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Randomization appropriately performed Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes The groups comparable at baseline Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Complete outcome data Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Outcome assessors blinded to the intervention provided Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Participants adhere to the assigned intervention Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Table 3 Quality appraisal of quantitative studies (non-randomized controlled trials) Criteria (Mohebbi et al., 2019) (Kim et al., 2019) (Al-Hashmi et al., 2018) (Rokni et al., 2022) Clear research question(s) Yes Yes Yes Yes Collected data addresses the research questions Yes Yes Yes Yes Participants representative of the target population Yes Yes No Yes Measurements appropriate regarding both the outcome and intervention (or exposure Yes Yes No Yes Complete outcome data Yes Yes Yes Yes Confounders accounted for in the design and analysis? Yes Yes Yes No During study period, intervention administered (or exposure occurred) as intended Yes Yes Yes Yes Table 4 Quality appraisal of qualitative studies Criteria (Skar et al., 2018) (Carolan-Olah & Sayakhot, 2019) Clear research question(s) Yes Yes Collected data addresses the research questions Yes Yes Qualitative approach is appropriate to answer the research question Yes Yes Qualitative data collection methods adequate to address the research question Yes Yes Findings adequately derived from the data Yes Yes The interpretation of results sufficiently substantiated by data Yes Yes Coherence between qualitative data sources, collection, analysis, and interpretation Yes Yes Table 5 Quality appraisal of a mixed-methods study Criteria (Surendran et al., 2021) Clear research question(s) Yes Collected data addresses the research questions Yes Is there an adequate rationale for using a mixed-method design to address the research question? Yes Are the different components of the study effectively integrated to answer the research question? Yes Are the outputs of the integration of qualitative and quantitative components adequately interpreted? Yes Are divergences and inconsistencies between quantitative and qualitative results adequately addressed? Yes Do the different components of the study adhere to the quality criteria of each tradition of the methods involved? No The authors followed the MMAT guideline for quality appraisal assessment using three main steps. Firstly, both authors (ZH and RS) independently assessed articles retrieved for quality appraisal and reached a consensus for an agreement. All eligible studies were evaluated based on the two initial MMAT screening questions: (1) Are there clear research questions? and (2) Do the collected data allow us to address the research question? If the answer to one or both questions is "No" or "Can't tell," it was assumed that the paper was not an empirical study and could not be evaluated further. Secondly, the relevant category of the study was selected to assess the description of the conduct of the study based on the criteria listed in the MMAT. The criteria respect the distinctive methodological qualities unique to each component utilized. Thirdly, each study design was evaluated in meeting the criteria by indicating “Yes,” “No,” or “Can’t Tell”. If the criteria were not satisfied, it would be indicated by the letter “No.” Finally, the other authors (ZAM and RZ) came in when disagreements between the 1st and 2nd authors were not obtained. Data Analysis Content analysis with the CIPP model and Atlas Ti version 8.0 software was employed to summarize the specific data garnered from the studies, and the findings were tabulated. This method was applied in this review, given its capacity to extract qualitative and quantitative data for analyses (Aziz et al., 2018). Results Characteristics of Included Studies Figure 1 shows the process of reviewing evidence from three main web databases. There were 5878 articles identified from the databases, and 4,897 articles remained after the exclusion of the duplicate articles. The titles and abstracts of these articles were then reviewed to eliminate papers irrelevant to the research objectives. Finally, the full texts of the presumably relevant articles along with their references were screened. Only 19 articles were found to be pertinent to this study. Figure 1 Flow diagram on the data extraction using PRISMA chart The 19 articles were assessed and summarized based on the CIPP model and finally reported the findings according to the SWiM checklist (Campbell et al., 2020) (supplementary file). Only sixteen quantitative studies, two qualitative and one mixed-methods study, were included. There were twelve randomized control trials (RCT) (Al-Ofi et al., 2019; Ammulu et al., 2019; Gharachourlo et al., 2018; Guo et al., 2019; He et al., 2022; Johnson & Berry, 2018; Kolivand et al., 2019; Mackillop et al., 2018; Mirghafourvand et al., 2019; Rasmussen et al., 2020; Tian et al., 2021; Xie et al., 2022; Zandinava et al., 2017), four quasi-experimental (Al-Hashmi et al., 2018; Kim et al., 2019; Mohebbi et al., 2019; Rokni et al., 2022), two interpretative phenomenological analysis (IPA) designs (Carolan-Olah et al., 2017b; Skar et al., 2018), and one mixed-methods study (Surendran et al., 2021) Only three studies applied theory in their research, and all used the Health Belief Model (Mohebbi et al., 2019; Skar et al., 2018; Surendran et al., 2021). This review identified 2,237 women with GDM (1108 in the intervention group, 1094 in the control group, and 35 in the qualitative). Results of Quality Appraisals The results of quality appraisals of this present study are shown in Table 2 to Table 5. Results of Content Analysis Identifying self-care domains Four main domain groups of intervention for GDM self-care: (1) knowledge or Information about GDM, (2) blood glucose monitoring, (3) healthy lifestyle (healthy diet or nutrition and exercise or physical activity), and (4) others (Figure 2). Figure 2 Intervention domain for self-care educational guide for mothers with GDM (1) Knowledge information on GDM A total of 12 articles (about half of the total articles reviewed) applied the knowledge or information on the GDM domain in their intervention (Al-Hashmi et al., 2018; Al-Ofi et al., 2019; Ammulu et al., 2019; Guo et al., 2019; He et al., 2022; Kolivand et al., 2019; Mackillop et al., 2018; Mohebbi et al., 2019; Skar et al., 2018; Tavakkoli et al., 2018; Zandinava et al., 2017). Knowledge or information on GDM includes the definition, causes, symptoms, treatment, and complications of GDM on the mother and fetus and their prevention. Only two studies provided knowledge and education on insulin, including self-injection, using a model (Kolivand et al., 2019; Tavakkoli et al., 2018). Consequently, higher scores for self-efficacy and pregnancy outcomes were observed in the intervention groups (Mackillop et al., 2018), which significantly improved their lifestyle (Tavakkoli et al., 2018). All studies that implemented this domain positively impacted the outcomes evaluated. Most of the activity strategy for the educational session was delivered through various teaching methods, such as lectures, PowerPoint presentations, and videos, and only one study applied role play (Mohebbi et al., 2019). Participants were allowed to ask questions at the end of the education session, which were answered by the educator. While strategy setting an achievable goal and motivational message were used by the studies applied HBM (Al-Hashmi et al., 2018; Mohebbi et al., 2019; Surendran et al., 2021) to enhance self-efficacy. The duration of the intervention varies between one and multiple sessions, ranging from 30 to 60 minutes in every session. All knowledge on GDM was delivered directly to the participants except for one study (Mohebbi et al., 2019) that encouraged family involvement for social support to motivate encouragement, empathy, concern, or caring. The majority of the education session delivered by nurses or nurse-midwifery or researchers, and two studies (Mohebbi et al., 2019; Zandinava et al., 2017) did not mention who gave the education session. (2) Blood glucose monitoring Ten studies monitored fasting blood glucose (FBG) and one or two hours postprandial (Al-Ofi et al., 2019; Guo et al., 2019; He et al., 2022; Kim et al., 2019; Kolivand et al., 2019; Rasmussen et al., 2020; Rokni et al., 2022; Tian et al., 2021; Xie et al., 2022; Zandinava et al., 2017), whereas only five studies measured hemoglobin A1c (HbA1c) (Al-Ofi et al., 2019; Guo et al., 2019; Kim et al., 2019; Mackillop et al., 2018; Mohebbi et al., 2019). FBG was reported to be significant in six studies (Guo et al., 2019; He et al., 2022; Rasmussen et al., 2020; Rokni et al., 2022; Tian et al., 2021; Xie et al., 2022), while four studies found it significant for the one hour or two-hour postprandial blood glucose assessment (Al-Ofi et al., 2019; Guo et al., 2019; Kolivand et al., 2019; Zandinava et al., 2017). While three studies found HbAIc to be significant (Guo et al., 2019; Kim et al., 2019; Mohebbi et al., 2019), another two found it to be not significant but decreased in mean (Al-Ofi et al., 2019; Mackillop et al., 2018). Only five articles reported activity strategies to assess glucose levels using a routine monitoring system. Another five studies used either mobile apps or telemedicine for glucose level measurement and monitoring (Al-Ofi et al., 2019; Guo et al., 2019; Mackillop et al., 2018; Rokni et al., 2022; Skar et al., 2018) while WeChat was employed in two studies (He et al., 2022; Tian et al., 2021). In most articles, the duration of monitoring blood glucose levels ranges from four to six weeks at weekly intervals, whereas only Mohebbi et al. (2019) recorded a monitoring period between 3 and 10 months. The activity target for blood glucose monitoring is to get the participant to adhere to the behavior changes and control the glucose level. In terms of activity strategies, the main target for monitoring blood glucose levels was for the participant to stick to the recommended behavioral changes for optimal control. A comparative study between mobile application blood glucose management systems and clinic standard care monitoring that served as an alerting system also emphasized hypoglycemia or hyperglycemia in their education (Mackillop et al., 2018). Therefore, any type of application is crucial to alert women with GDM about their health status. In most studies, either a nurse or nurse-midwifery was responsible for teaching the participants how to practice self-blood glucose monitoring. (3) Healthy lifestyle Healthy diet or nutrition All articles reviewed had diet or nutrition as a self-care intervention. Nevertheless, the studies focused solely on exchanging carbohydrates and none on the involvement of the glycaemic index concept. Only one study emphasized high energy content and carbohydrate for morning intake and low evening intake and kept glucose levels measured four times a day (Rasmussen et al., 2020). The study showed that the group with high carbohydrate intake in the morning had better glucose level control and improved insulin sensitivity. A dietician delivered an education session for nutrition activity strategies and a healthy diet. Different techniques, such as nutrition classes or direct teaching, were used in the process, and most sessions were individualized. One to four educational sessions were performed, with each session ranging from 30 to 45 minutes. The findings from this review disclosed the significance for participants and dieticians to reach an agreement regarding the daily calorie intake as per the standard GDM guidelines. This activity aims to bring the glucose level to the normal range by following the recommended menu. Exercise and physical activity This domain was applied the most as a self-care education package intervention in this review (Al-Hashmi et al., 2018; Ammulu et al., 2019; Carolan-Olah et al., 2017b; Kim et al., 2019; Kolivand et al., 2019; Mirghafourvand et al., 2019; Mohebbi et al., 2019; Tavakkoli et al., 2018; Zandinava et al., 2017). Exercise or physical activity showed positive outcomes and was able to modify the participants’ lifestyles to become healthier. However, only one study demonstrated no impact on the participants’ quality of life, contrary to other studies that proved exercise or physical activity effectively improved quality of life when the same parameters were examined (Zandinava et al., 2017). Motivational counseling is vital to promote self-efficacy among participants without interruption throughout the sessions (Ammulu et al., 2019; Kim et al., 2019; Tavakkoli et al., 2018). Generally, education sessions for motivational counseling using video, counseling, and role-playing as the teaching methods lasted from 30 to 45 minutes. The present review depicted that it takes approximately two to four weeks to complete the education session for the activity. Nevertheless, Kim et al. (2019) demonstrated the efficacy of using the website approach to monitor the exercise pattern among participants. In the study, the nurses placed a phone call to serve as a reminder for participants to perform the exercise and achieve the targeted goal (Rokni et al., 2022). (4) Other domains Mental health and emotional support Three studies reported on mental health education (He et al., 2022; Kolivand et al., 2019; Tavakkoli et al., 2018), and only a study specified the importance of emotional skill training (Tavakkoli et al., 2018). The factors evaluated were blood anxiety, depression score, glucose level, self-efficacy, lifestyle, and pregnancy outcome. The study’s findings revealed that women with GDM in the intervention group had better anxiety levels and lifestyle, decreased mean glucose levels, significant self-efficacy, as well as better neonatal outcomes. We have discovered that activity strategy for emotional skills (Tavakkoli et al., 2018), coping strategies, and follow-up (He et al., 2022) in GDM at any level of health literacy rise with good communication skills and counseling. Therefore, counseling techniques using lectures, PowerPoint presentations, role-playing, and individualized or focus group discussions specifically on “healthy lifestyle” were commonly employed throughout educational sessions. The duration of the counseling reported for one session ranges between 30 - 40 minutes, and the number of sessions is divided into two to three sessions. Counseling strategies should be emphasized on basic nutrition education, essential diets, awareness of the adverse effects of nutrition on health status, and the importance of regular physical activities in improving self-care. The counseling can be delivered by a trained nurse and nutritionist. Weight management Only three studies included this domain in the intervention, and they measured FBG, two hours postprandial, and HbAIc (Al-Ofi et al., 2019; Guo et al., 2019; Kim et al., 2019) besides other outcomes. The finding revealed significant differences for FBG, one or two hours postprandial (Al-Ofi et al., 2019; Guo et al., 2019), and only one study showed a significant difference in weight management (Al-Ofi et al., 2019). Approaches and techniques Most of the interventional studies used a face-to-face educational group session approach. Seven studies provided booklets or pamphlets as educational materials (Al-Hashmi et al., 2018; Kolivand et al., 2019; Mirghafourvand et al., 2019; Rasmussen et al., 2020; Rokni et al., 2022; Tavakkoli et al., 2018; Zandinava et al., 2017), while six studies used mobile applications (Al-Ofi et al., 2019; Guo et al., 2019; Mackillop et al., 2018; Skar et al., 2018; Surendran et al., 2021), two studies used WeChat (He et al., 2022; Tian et al., 2021), one study used web-based (Kim et al., 2019) and two studies applied counseling sessions (Ammulu et al., 2019; Kim et al., 2019) as shown in Figure 3. Most of the studies assessed participants four weeks after intervention. Two studies performed assessments six weeks after delivery, whereas one study conducted assessments three and six months after the intervention, and four other studies implemented baseline assessments (supplementary file). Figure 3 Summary of approaches obtained from systematic review analysis There were two studies (Ammulu et al., 2019; Kim et al., 2019) focused on counseling strategies to improve the lifestyles of respondents by measuring the quality of life (Ammulu et al., 2019), health literacy, and lifestyle scores (Kim et al., 2019). Both studies aimed for healthy lifestyle changes via the sub-domains of knowledge on coping with GDM; communication skills; physical exercise; psychological, diet therapy; pharmacological and emotional skills. Counseling intervention was performed in groups, and it concluded that counseling by midwives significantly helped mothers with GDM to modify their unhealthy lifestyles and increase health literacy (Tavakkoli et al., 2018). In agreement, another study demonstrated a positive impact on the management of GDM after conducting counseling sessions at baseline and one-month post-intervention (Mohebbi et al., 2019). In contrast, only three studies applied a theory in their health education training and used the Health Belief Model (Mohebbi et al., 2019; Skar et al., 2018; Surendran et al., 2021). Most of the findings and evidence revealed that nurses and midwifery nurses were mainly responsible for delivering most educational interventions. Discussion Identifying Self-Care Domains In this review, 19 articles were assessed and summarized based on the CIPP model. The present study identified four main domain groups of intervention for GDM self-care: (1) knowledge or Information about GDM, (2) blood glucose monitoring, (3) healthy lifestyle (healthy diet or nutrition and exercise or physical activity), and (4) others. Several studies showed that pregnant women with GDM who had less knowledge of GDM had higher blood glucose levels and a poorer attitude towards self-care compared to pregnant women with GDM who had good knowledge or information about the condition (Ge et al., 2016; Hussain et al., 2015; Mensah et al., 2019). Therefore, women with GDM recommend having a good understanding of the disease once diagnosed because knowledge will allow an individual to process and use the information to guide health decisions, which has been a major concern in those studies (Bhowmik et al., 2018; Liu et al., 2020; Muhwava et al., 2019). It also focused on understanding health information in everyday situations, such as healthy behaviors, healthy lifestyles, and health terms (Hussain et al., 2015; Liu et al., 2020). In addition, the studies showed that participants were likely to have received information on the risk of GDM complications in the fetus, which may have encouraged adherence to GDM self-care plans (Al Hashmi et al., 2022; Kennelly et al., 2016). Hence, delivering GDM knowledge to pregnant women with GDM through self-care health education should be considered a vital intervention domain. Women with GDM can improve their self-care abilities with adequate treatment and education (Mirfeizi M, 2017; Mohanty et al., 2020) as health education is an essential component in addressing major health concerns such as maternal and infant mortality, and healthy life promotion programs (Bhowmik et al., 2018; Draffin et al., 2017; Muhwava et al., 2019). Currently, self-care education has progressed from a purely educational and passive approach to one that emphasizes empowerment, decision-making skills, and self-care, and WHO suggests it (World Health Organization, 2019). All pregnant women with diabetes should begin self-care education and support as soon as diabetes is diagnosed (Crawford, 2017). However, glucose measurements such as FBS, postprandial, and HbA1c were not significantly different between the groups (intervention and control) in all the articles reviewed. These findings were contrary to the previous integrative review of educational and interventional programs for GDM management (Carolan-OIah, 2016). The inconsistency may be due to participants’ poor compliance with the management or the intervention introduced. Nevertheless, this hypothesis cannot be confirmed as only one study demonstrated good compliance and ideal blood glucose results following the intervention. Apart from that, all studies emphasized healthy eating or carbohydrate exchange, but none of these reviews mentioned the Glycaemic Index (GI) concept. GI is a scale that ranks carbohydrates in different diets based on their impact on postprandial glucose response; foods with a high GI caused more substantial blood glucose swings than those with a lower GI (Anuar et al., 2020). Studies showed that without limiting dietary carbs, low-GI dietary treatments reduced the postprandial blood glucose and the number of insulin demands in women with GDM (Anuar et al., 2020; Carolan-OIah, 2016; Lefkovits et al., 2019). Furthermore, the Cochrane review (Han et al., 2017) and other studies recommended that women with GDM should be emphasized that foods with a low GI should be substituted for items with a high GI (Anuar et al., 2020; Brown et al., 2017; Crawford, 2017; Hasbullah et al., 2020). Therefore, besides the carbohydrate exchange, the addition of the GI concept is recommended in the future development of self-care educational intervention packages for GDM based on the culture and settings. In this review, exercise and physical activity have been the most used self-care education package interventions and demonstrated a positive impact on glycaemic control and pregnancy outcome (Al-Hashmi et al., 2018; Ammulu et al., 2019; Carolan-Olah et al., 2017b; Kim et al., 2019; Kolivand et al., 2019; Mirghafourvand et al., 2019; Tavakkoli et al., 2018; Zandinava et al., 2017). Increasing awareness regarding exercise or PA will lead to improved individual self-care and higher quality of life (Anjana et al., 2016; Gilbert et al., 2019; Mohanty et al., 2020; Pinidiyapathirage et al., 2018). However, Cochrane updates and the NICE Guideline reported that when compared to routine antenatal care, exercise programs such as individualized exercise with regular advice, weekly supervised group exercise sessions, or home-based stationary cycling, either supervised or unsupervised, had no discernible effect on improving insulin sensitivities (Brown et al., 2017). On the contrary, an integrated review concluded that increased activity levels are most effective at lowering maternal blood glucose levels and insulin requirements during pregnancy (Carolan-OIah, 2016). Therefore, we suggest that exercise or physical activity in self-care among mothers with GDM should be studied to indicate whether it is effective in controlling GDM or inversely to fill the gap in this review. Approaches and Techniques Most of the studies in this review used group training sessions, which had a better impact on the respondents, thus proving that the group approach is more effective than individual sessions in health education (Kolivand et al., 2019; Mirghafourvand et al., 2019; Mohebbi et al., 2019; Rasmussen et al., 2020; Tavakkoli et al., 2018; Zandinava et al., 2017). Besides, most studies approached participants between 24 to 28 weeks of gestation. Unlike other types of diabetes, GDM recedes after childbirth. Therefore, self-care education must be carried out intensively to enhance self-care for women with GDM to achieve well-controlled glucose levels and produce good pregnancy outcomes(Mensah et al., 2019; Wah et al., 2019). In this review, we have found that various educational intervention strategies are used in managing GDM. Almost all the studies analyzed reported combination interventions, combining multiple interventions to treat GDM. The combination of input for the self-care education intervention covers knowledge of GDM, physical activity, nutrition, self-management education intervention, glucose monitoring, and practicing healthy eating. The majority of the educational intervention was delivered by nurses or midwifery nurses. A study on diabetes awareness among the public in Malaysia found that respondents who received information from medical practitioners showed a better understanding compared to getting information from other sources such as internet sources, friends, or relatives (Qamar et al., 2017). Furthermore, according to Yong et al. (2018), health education interventions for mothers with GDM from medical practitioners such as nurses were essential to increase knowledge about GDM so they can perform good self-care in managing GDM. This is in line with the recommendations by the WHO (Mensah et al., 2019), where they have recommended that health education be delivered by medical practitioners such as nurses and doctors to improve the quality of self-care in the treatment and management of a disease. Some other researchers in their study found that mothers with GDM who had poor knowledge about GDM experienced higher blood glucose levels compared to mothers with GDM who had good knowledge, and they also showed a bad attitude toward self-care (Ge et al., 2016; Ghasemi et al., 2021; Kolivand et al., 2018). Three studies were found to apply a theory that used the Health Belief Model (HBM) in their health education training (Mohebbi et al., 2019; Skar et al., 2018; Surendran et al., 2021). Hence, it is suggested to test other behavioral theories to change the behaviors of GDM women toward GDM management. It is essential to understand the patient’s behavior using the behavioral approach to offer guidance on determinants of health behavior and health services (Isa et al., 2017; Lucille S. Eller et al., 2018; Matarese et al., 2018). It can also offer new approaches to nursing practices to improve patient care efficacy (Sleet & Dellinger, 2020). Self-efficacy also may assist patients or mothers with GDM in removing obstacles self-care and adhering to long-term health gains (Yang et al., 2022). Furthermore, good self-efficacy and self-care behaviors in GDM management can help prevent or delay the development of type II diabetes and lower the risk of developing maternal and neonatal type II diabetes in the future (Isa et al., 2017; Mensah et al., 2019). Implications for Practice The findings of the present review provided evidence of the benefits of GDM educational and interventional approaches for pregnant women with GDM. A self-care health educational GDM package reviewed was based on four domains. The most preferred method to achieve effectiveness was highlighted as the face-to-face approach. Thus, a combination of face-to-face sessions, digital e-book resources, and printed booklets was employed to enhance usage compliance. In order to assist women with GDM to retain the self-care knowledge gained post-nursing intervention, it is essential to equip them with informational materials that can be easily recalled and utilized as additional reference or guide at home. Providing written health information could also improve the association between healthcare providers and patients. Furthermore, the use of GDM educational intervention in assessing the effectiveness should emphasize the positive effects of self-management in enhancing self-efficacy, higher satisfaction scores, optimal glucose control, monitoring, and better self-care behavior. The evidence of the present review will be used for future nursing studies in developing a self-care health education package for GDM that covers information about GDM, healthy lifestyles such as healthy eating or diet, and exercise to help in blood glucose control in preventing GDM complications. The package will be prepared as a booklet as suggested and well accepted as positive feedback is given. In addition, the provision of printed educational materials can improve patients’ health literacy and their personal responsibility, motivation, and attitude toward health. Health education intervention is highly recommended in health promotion to increase self-efficacy, a key domain in improving self-care ability, the quality of nursing care, and facilitated shared care approach between client and the health care providers. Aside from that, a previous study on women’s GDM experiences emphasized the significance of creating GDM management as a routine in accordance with the life, values, and goals of the woman, as well as the necessity for the addition of individually customized and cultural relevant information. Limitations The use of only English-written papers and the restricted years of publication placed a limitation on this review. Despite that, this review managed to discover valuable findings and information that can be used as materials for the development of future GDM health educational interventions or programs for GDM women. Conclusion Self-care education for women with GDM had a positive impact on GDM outcomes. Knowledge or information about GDM, healthy diet, and exercise or physical activity were the most applied domains of intervention. Thus, these domains should be emphasized in the future development of any interventional program for GDM women. This study might also help healthcare providers design self-care interventions for pregnant women with GDM according to individual needs to enhance their self-efficacy. Finally, most of the studies used a face-to-face educational group session approach and demonstrated a positive impact on the management of GDM. Supplementary Material Self-care educational guide for mothers with gestational diabetes mellitus: A systematic review on identifying self-care domains, approaches, and their effectiveness Click here for additional data file. Acknowledgment The publication of this manuscript was supported by the Universiti Kebangsaan Malaysia. Declaration of Conflicting Interest The authors declared no conflict of interest. Funding The authors declared no grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Authors’ Contributions This study is a Doctoral project of the first author under the supervision of the second author and co-supervised by the third and fourth authors. RS, ZH, ZAM, and RZ conceived the scope of the review to meet the study objectives. Literature screening and review, data extraction and verification, and qualitative synthesis were conducted by ZH and verified by RS and RZ. ZH drafted the first iteration of the manuscript. All authors contributed substantially to the manuscript’s critical review, editing, and revision. All authors approved the final version of the manuscript. Authors’ Biographies Zarina Haron, MSc (Women Health), RN is a Doctoral Research student at the Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia. Rosnah Sutan, MD, MPH, PhD is an Associate Professor at the Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia. Roshaya Zakaria, PhD, MSc, RN is a Senior Lecturer at the Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia. Zaleha Abdullah Mahdy, has Master in Ob-Gyn, Medical Doctorate (MD) and works as a Senior Professor at the Department of Obstetrics and Gynecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia. Data Availability See supplementary file. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-139 10.33546/bnj.1491 Letter to Editors Violence against nurses: A serious issue in Indonesia https://orcid.org/0000-0002-6092-9992 Tosepu Ramadhan 1* https://orcid.org/0000-0002-4776-5241 Nuru Hasanuddin 2 https://orcid.org/0000-0001-9098-8865 Irfani Tri Hari 3 1 Faculty of Public Health, University of Halu Oleo, Southeast Sulawesi, Indonesia 2 Faculty of Health Science, Dehasen University, Indonesia 3 Department of Public Health and Community Medicine, Faculty of Medicine, Sriwijaya University, Palembang, Indonesia * Corresponding author: Ramadhan Tosepu, Ph.D, Faculty of Public Health, University of Halu Oleo, Jl.H.E.Mokodompit, Anduonohu, Southeast Sulawesi, Indonesia. Email: ramadhan.tosepu@uho.ac.id Cite this article as: Tosepu, R., Nuru, H., & Irfani, T. H. (2021). Violence against nurses: A serious issue in Indonesia. Belitung Nursing Journal, 7(2), 139-140. https://doi.org/10.33546/bnj.1491 29 4 2021 2021 7 2 139140 18 4 2021 19 4 2021 19 4 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. physical abuse verbal abuse violence nurses hospitals criminals mental health Indonesia ==== Body pmcUnfortunately, violence against nurses has just gone viral today in Indonesia. The violence occurred at Siloam Hospital Sriwijaya, Palembang City, on 15 April 2021, experienced by a nurse named Christina Ramauli Simatupang. Although violence against nurses or healthcare workers is not a new problem, it has always been a serious issue and should never be accepted as a part of the job. This letter prompts a discussion about the violence against the hospital nurse, and solutions to prevent and stop it are suggested. Violence and Its Effects Healthcare worker violence in the hospital setting is a growing issue worldwide (Ramacciati et al., 2018). It is like a silent epidemic that leads to the influence of productivity, job performance, and depression, or other health problems. The most healthcare worker suffered from this phenomena was nurses, and the main perpetrator is patients or their family and event nurses colleagues (Chang & Cho, 2016). Approximately 95.5% of the nurses, in a time frame of 12 months, were reported violence in the workplace (Ramacciati et al., 2018). In Indonesia, work-related violence among nurses is reported as physical assault, verbal violence, sexual harassment, intimidation, and the threat of a lawsuit perpetrated mostly by the patients and their families (Yosep et al., 2019). Having seriousness of abusing to the nurse in Palembang city, Indonesia, lately is facing several problems. Physical assaults and verbal violence perpetrated by the patient’s family towards the nurse affect mental health problems (Yosep et al., 2019). Mental health is the common stressor that leads to work-associated stress, which can convert into physiological distress among nurses, especially in the hospital (Yosep et al., 2021). In hospital-based collaboration, nurses need to maintain their professional ability to work, maintain standards and continuously improve their standards of care. Physiological distress may have debilitating effects that reduce work output, increase absenteeism, and decrease professional ability (Gunawan et al., 2020). These problems require continuous monitoring and evaluation. Hospital management should have an intention to developing protections and mental health programs for the nurses. Preventing and Stopping the Violence Numerous studies postulated the factors why the violence remains to happen in the hospital setting, including environmental risk factors, low staffing levels, inadequate security personnel, and inappropriate policy and law (Hassankhani et al., 2018; Manton, 2017). The question is how to respond to this reality and minimize the problem. Annual education or course is one of the best solutions to increase the knowledge of the nurses to prevent violence. However, it is not sufficient to resolve the issue, and this way should not be addressed to the nurse solely (Manton, 2017). Security guards, hospital staff, managers, and other health professionals should be involved (Hassankhani et al., 2018). Moreover, the personnel should promote the development of supportive and helpful strategies to improve communication and adaptive skills (Hassankhani et al., 2018). In addition, in carrying out nursing service activities, nursing competency standards should be used, with the fundamental responsibility of the nurses, namely improving health, preventing disease, restoring, and reducing suffering (Ministry of Health, 2020). Furthermore, in the hospital services, all administrators should refer to Law Number 44 of 2009 concerning hospitals, which focuses on legal certainty and protection to improve, direct and provide a basis for hospital management (Government of Indonesia, 2009). State policy in the form of laws in the health sector is a juridical basis that can serve as guidelines for the general public and healthcare workers. Legal protection, legal certainty, and legal justice for the community and healthcare workers are essential. With the existence of regulations in the health sector, the rights and obligations of healthcare workers and the community are protected, and there is legal certainty (Koswara, 2018). Legal protection and legal certainty for healthcare workers as health service providers is an opportunity and an encouragement to provide the best health services for people in every territory of the Republic of Indonesia. At this point, a nurse who becomes a victim deserves legal protection. Legal protection protects human rights that are harmed by others, and that protection is given to the community. This case can be included in Article 351, paragraph 1 of the Criminal Code concerning persecution (Handoko, 2018). In conclusion, the acts of violence against nurses must be according to the prevailing laws and regulations. The perpetrators of the violence must be given the appropriate punishment, which can be a lesson for the community. Furthermore, the victims of the violence must be protected by legal and health protections. Acknowledgment The authors acknowledge Dr. Joko Gunawan for critically providing the feedback of the article. Declaration of Conflicting Interest The authors declare no conflicts of interest. Funding None. Author Biographies Ramadhan Tosepu, SKM., M.Kes., Ph.D is a Lecturer of the Public Health Faculty, Halu Oleo University, Indonesia. He is also the Head of the Department of Public Health, Postgraduate Study of the Halu Oleo University, Indonesia. Hasanuddin Nuru, S.Kep., Ns., M.Kes., Ph.D is a Lecturer at the Faculty of Health Science, Dehasen University, Indonesia. He is also assigned as an Acting Head of Nursing and Midwifery Department and a Head of Education and Training Department in RSUD Daya Kota Makassar, Indonesia. dr. Tri Hari Irfani, MPH is a Lecturer at the Department of Public Health and Community Medicine, Faculty of Medicine, Sriwijaya University, Palembang, Indonesia. ==== Refs References Chang, H. E., & Cho, S.-H. (2016). Workplace violence and job outcomes of newly licensed nurses. Asian Nursing Research, 10 (4 ), 271-276. 10.1016/j.anr.2016.09.001 28057313 Government of Indonesia. (2009). Law No 44 year 2009 concerning hospital. Jakarta: Government of the Republic of Indonesia. Gunawan, J., Aungsuroch, Y., Fisher, M. L., Marzilli, C., & Liu, Y. (2020). Factors related to the clinical competence of registered nurses: Systematic review and meta-analysis. Journal of Nursing Scholarship, 52 (6 ), 623-633. 10.1111/jnu.12594 32862486 Handoko, D. (2018). Kitab undang-undang hukum pidana [Book of criminal law]. Pekanbaru, Indonesia: Hawa dan AHWA. Hassankhani, H., Parizad, N., Gacki-Smith, J., Rahmani, A., & Mohammadi, E. (2018). The consequences of violence against nurses working in the emergency department: A qualitative study. International Emergency Nursing, 39 , 20-25. 10.1016/j.ienj.2017.07.007 28882749 Koswara, I. Y. (2018). Perlindungan tenaga kesehatan dalam regulasi perspektif bidang kesehatan dihubungkan dengan undang-undang nomor 36 tahun 2009 tentang kesehatan dan sistem jaminan sosial [Protection of health workers in the perspective of the health sector is linked to law number 36 of 2009 concerning health and the social security system]. Jurnal Hukum POSITUM, 3 (1 ), 1-18. 10.35706/positum.v3i1.2663 Manton, A. (2017). The issue of violence in the emergency setting. Journal of Emergency Nursing, 43 (6 ), 495-496. 10.1016/j.jen.2017.09.012 29100564 Ministry of Health. (2020). Ministry of Health Decree No HK.01.07/Menkes/425/2020 concerning nursing profession standard. Jakarta, Indonesia: Ministry of Health of the Republic of Indonesia. Ramacciati, N., Ceccagnoli, A., Addey, B., Lumini, E., & Rasero, L. (2018). Violence towards emergency nurses: A narrative review of theories and frameworks. International Emergency Nursing, 39 , 2-12. 10.1016/j.ienj.2017.08.004 28927973 Yosep, I., Mediani, H., & Lindayani, L. (2021). Working alliance among mental health nurses in Indonesia: A comparative analysis of socio-demographic characteristics. Belitung Nursing Journal. 10.33546/bnj.1259 Yosep, I., Mediani, H. S., Putit, Z., Hazmi, H., & Mardiyah, A. (2019). Mental health nurses’ perspective of work-related violence in Indonesia: A qualitative study. International Journal of Caring Sciences, 12 (3 ), 1871-1878.

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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-131 10.33546/bnj.1398 Original Research Relationships between symptom control, medication management, and health literacy of patients with asthma in Vietnam https://orcid.org/0000-0003-2459-9321 Kim Cuc Doan Thi 1 https://orcid.org/0000-0001-7642-7586 Methakanjanasak Nonglak 2* https://orcid.org/0000-0002-9007-7049 Thuy Trang Ho Thi 3 1 Faculty of Nursing, Da Nang University of Medical Technology and Pharmacy, Vietnam 2 Faculty of Nursing, Khon Kaen University, Thailand 3 Faculty of Nursing, Hue University of Medicine and Pharmacy, Hue University, Vietnam * Corresponding author: Assistant Professor Nonglak Methakanjanasak, Faculty of Nursing, Khon Kaen University, 123 Mittaparp Road, Muang, Khon Kaen, Thailand 40002. Phone: (+66) 926651549 | Fax: 043 – 424809. Email: nonchu@kku.ac.th Cite this article as: Kim Cuc, D. T., Methakanjanasak, N., & Thuy Trang, H. T. (2021). Relationships between symptom control, medication management, and health literacy of patients with asthma in Vietnam. Belitung Nursing Journal, 7(2), 131-138. https://doi.org/10.33546/bnj.1398 29 4 2021 2021 7 2 131138 01 2 2021 02 3 2021 06 4 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Asthma is a significant health issue among Vietnamese adults in both urban and rural areas. The disease needs serious concern to minimize impact and improve the situation. Objective This study aimed to describe the level of health literacy, symptom control, and medication management and determine the relationships among them in patients with asthma in Da Nang, Vietnam. Methods A cross-sectional descriptive study was conducted among 84 patients with asthma. The questionnaires were used in this study, including demographic form, the Short-Form Health Literacy questionnaire (HL-SF12), Asthma Control Test (ACT), and Medication Adherence Reporting Scale for Asthma (MARS-A). Pearson product-moment correlation was applied to determine the relationship between health literacy, symptom control, and medication management. Results The score revealed for general-health literacy, symptom control, and medication management were 28.70 (SD = 9.66), 17.72 (SD = 4.67), and 3.63 (SD = 0.75), respectively. Health literacy level had moderate positive relationships with symptom control (r = 0.41) and medication management (r = 0.44). Conclusion The patients had limited health literacy, partially controlled symptom, and poor adherence to the medication. Health literacy level had moderate positive relationships with symptom control and medication management. These findings are crucial for effective treatment and management of the disease in Vietnam. To improve medication management and symptom control among patients with asthma, nurses should concern patients’ health literacy level. asthma health literacy medication therapy management symptom control adult nursing Vietnam ==== Body pmcGlobally, asthma prevalence is on the rise, such that 339.4 million people were affected in 2018 (The Global Asthma Network, 2018). Of importance, over 80% of asthma-related deaths occur in low-and lower-middle-income countries (World Health Organization, 2019). In Vietnam, asthma is a major health issue among adults in both urban and rural areas. The number of asthma in adults aged 21 to 70 is 3.9% to 5.6% (Lâm et al., 2011). As such, it has caused an enormous impact on the health and economy of the country. According to a study, the total economic burden of asthma is estimated to range from $34.7 to $55.3 for outpatient and $45.1 to $107.2 for inpatient annually (Le et al., 2019). Studies have shown that asthma causes disability, limited activity, poor quality of life, and poor use of medical resources (Alpaydin, Bora, Yorgancioglu, Coskun, & Celik, 2012). Asthma affects individuals and affects both the patient’s family and society. The essential aspects for improving outcomes in patients with asthma are health literacy, symptom control, and medication management. Health literacy (HL) refers to a person’s ability to respond to the knowledge, motivation, and skills of finding, understanding, appraising, and applying health information to make judgments and decisions in daily life related to health care, disease prevention, and health promotion to improve the quality of life throughout life. Health literacy is crucial but limited among the patients in low-income countries (Sørensen et al., 2015; Sørensen et al., 2012). Although Duong et al. (2019) reported that the health literacy index for the general people in Vietnam was low (29.5 ± 9.5), no study reported health literacy in patients with asthma. Therefore, it is to mention that limited health literacy is significant, and it has a relationship with a low level of symptom control and medication management. Symptom control refers to monitoring and identifying significant signs that help patients with asthma make suitable changes in their physical activity level and commence appropriate medication regimens (Global Initiative for Asthma, 2020). In Vietnam, only 40.4% of patients are known to have controlled asthma (Nguyen, Huynh, & Chavannes, 2018). Medication management involves self-adjustment of medication to respond to acute symptoms and changes in peak expiratory force. No doubt, adherence to treatment is essential to optimize the benefits of therapy (Sarker et al., 2020). Studies related to health literacy, symptom control, and medication management in patients with asthma are limited in Vietnam. Therefore, this study was conducted to better understand these aspects in patients. Once the relationships are clarified, it will help understand the difference between what the patients currently do and what the ideal patients should do to manage their disease effectively. More significantly, it can promise an effective nursing strategy to improve symptom control and medication management for asthma adults using education strategies appropriate for populations with limited health literacy. This study aimed to investigate the level of health literacy, symptom control, and medication management and determine the relationships among them in patients with asthma in Da Nang, Vietnam. Methods Study Design and Setting This cross-sectional descriptive study was conducted among patients with asthma visiting the Internal Respiratory Clinic at C hospital located in central Vietnam city of Da Nang. The city is situated about 764 km from Hanoi’s capital city and is inhabited by over a million people. C hospital is a central level hospital under the Ministry of Health with a 700-bed capacity (Da Nang Portal, 2020). This hospital was selected for the study because it is a general hospital located in the city center with a high patient flow, including patients with asthma. Around 200 patients visit the clinic for medical care and follow-up each month. Participants The target population of the study was patients diagnosed with asthma by a physician at the respiratory clinic. The participant’s inclusion criteria were adults ≥18 years, diagnosed with asthma at least six months prior to the study, and able to communicate, read, and understand the Vietnamese language. Contrarily, the patients who were having cognitive impairment with a score lower than 24 points (out of 30) when measured by Mini-Mental State Examination (MMSE) Vietnamese version, a critical condition such as a sign of asthma attack (such as cough, dyspnoea, wheezing, chest tightness), and requiring emergency care, and unwillingness to participate in the study were excluded. The sample size was estimated using a power analysis. The level of significance was set at 0.05 and the standard power at 0.80. As reported earlier, a small effect size of 0.28 was applied (Aberson, 2010). The estimated sample size was 76; upon an additional 10% drop-out rate, the final sample size increased to 84 participants. The participants were selected by a simple random sampling technique from the list of outpatients visiting the hospital clinic. Next, the researcher assigned code numbers for each patient on a paper slip kept them into a box, mixed well, and selected 84 random numbers. Some of the selected patients did not attend the hospital clinic due to the COVID-19 pandemic. The researcher selected other participants repeating the steps described above. Instruments The tools used in the research were questionnaires in four parts, including Demographic form, The short-form health literacy questionnaire (HL-SF12), Asthma Control Test (ACT), and Medication Adherence Reporting Scale for Asthma (MARS-A). The questions on the demographic characteristics of participants, such as age, gender, education level, health insurance, occupation, income, duration of asthma, were developed by the researcher. HL-SF12 was developed by Duong et al. (2019) based on the conceptual framework of the HLS-EU-Q47 (Sørensen et al., 2013). In brief, there are 12 items in four dimensions: assessing (items 1, 5, 9), understanding (items 2,6,10), appraising (3,7,11), and applying (items 4,8,12), which can further be categorized into three domains: health care HL (HC-HL), disease prevention HL (DP-HL), and health promotion HL (HP-HL). Each question was scored by a 4-point Likert-type rating scale (very difficult =1 to very easy=4). The mean score of specific health literacy indices was standardized on a metric between 0 and 50, using a formula described in HLS-EU Consortium (HLS-EU Consortium, 2012). Health literacy was then divided into levels as 0-25: inadequate, >25-33: problematic, >33-42: sufficient, and >42-50: excellent. The values of Cronbach’s α and the goodness-of-fit index of the HLS-SF12 in the general Vietnamese population were 0.87 and 0.97. The Asthma Control Test (ACT) developed by Nathan et al. (2004) was used to measure symptoms for asthmatic patients under the routine care of a specialist in this study. The ACT has also been reassessed for its reliability, efficacy, and responsiveness in patients not monitored by asthma experts (Schatz et al., 2006). Internal consistency reliability of the ACT was 0.85 (baseline) and 0.79 (follow-up). Test-retest reliability was 0.77. The questionnaire includes five items assessing asthma symptoms (daytime and nocturnal), use of rescue medications, the effect of asthma on daily functioning, and a patient’s self-assessed level of asthma control past four weeks. Each item was measured in a 5-point Likert-type rating scale, a score ranging from 5 (poor control) to 25 (complete control) when a higher score indicates better symptom control. The total score of this scale is 25 and is divided into levels as 5–14: uncontrolled, 15–19: partially controlled, 20–25: controlled. The Medication Adherence Reporting Scale for Asthma (MARS-A) was used to assess medication management in patients with asthma. The scale was developed relying on a generic version of MARS used to measure oral medication adherence (Cohen et al., 2009). The MARS-A is a 10-item tool with several desirable characteristics for assessing inhaled corticosteroid (ICS) use. The MARS-A included both generic and specific questions about medication. It also assesses medication use behaviors, including regular versus as-needed use and intentional versus unintentional non-adherence. The participants expressed their response for 10 statements with 5- points Likert scale ranging as following 1= Always, 2 = Often, 3 = Sometimes, 4 = Rarely, 5 = Never. The participant who had higher mean scores for all items indicates better adherence. The mean score of the questionnaire ranges from 1 to 5. Participants with a mean MARS-A score equal to 4.5 or more were interpreted as having good adherence. The MARS has high inter-item reliability (Cronbach α = 0.85) and good test-retest reliability (r = 0.65; p < 0.001). Permission to use the instruments in the current research was received from the original authors. Instrument translation The original instruments HL-SF12, the ACT, and the MARS in English were translated into the Vietnamese language. The translation process was conducted according to the translation method described earlier (Cha, Kim, & Erlen, 2007). In brief, the original instruments in the English version were independently translated into the Vietnamese language by two bilingual experts. Two Vietnamese versions were then compared and combined into one Vietnamese version. A third bilingual translator translated the Vietnamese version back into English. Finally, the back-translated English version was compared with the original version of the instrument by the researcher and a native English person to determine the linguistic unity among both versions. Validity and reliability of instruments The content validity of three instruments was validated by a panel of three experts, including a medical doctor specialized in asthma, a nurse lecturer with expertise in asthma, and a nurse with working experience in patients with asthma. The Content Validity Index for Items (I-CVI) of each item of HL-SF12, ACT, and MARS-A was higher than 0.83, and I-CVI of the total score of each part for HL-SF12, ACT, and MARS-A were 0.97, 0.96, and 0.96, respectively. According to the report, the CVI higher than 0.79 percent indicates appropriateness (Abdollahpour, Nejat, Nourozian, & Majdzadeh, 2010). The Vietnamese translated versions of HL-SF12, ACT, and MARS-A were tested for their internal consistency and reliabilities through a pilot study in a different set of 30 patients having similar characteristics. The Cronbach’s α for each instrument recorded was 0.88 (HL-SF12), 0.88 (ACT), and 0.89 (MARS-A). According to the classification of Lakshmi and Mohideen (2013), Cronbach’s α for three instruments was at an acceptable level. Data Collection Upon getting ethical clearance and approval from the hospital, data were collected by the researcher between 1 October to 15 November 2020. Initially, the researcher contacted and explained the objectives and procedures of the study to the head nurses and staff nurses and asked them to select participants who meet the study’s criteria except for cognitive status. The selected participants were contacted by the head nurse to ask if they allow the researcher to contact for participation. Upon agreement, an appointment was set to meet at the clinic within a month. Next, on the day of the visit to the clinic, the researcher explained the objective, benefits, ethical issues, and human rights protection and invited the patients to participate in the research. On willingness to participate, the researcher requested to use MMSE for their cognitive status. Upon meeting the criteria (score of MMSE ≥ 24), they were asked to sign a consent form. Then the questionnaire was provided to fill up, which took about 30 minutes. The researcher was around to explain any confusion, and when any missing data was found, participant’s responses were confirmed before leaving. Participation in the study was voluntary, and they were free to refuse or withdraw without impacting the healthcare service they were receiving in the hospital. The researcher followed guidelines for Human Research during the COVID-19 outbreak issued by Khon Kaen University Thailand and the Ministry of Health of Vietnam during data collection. Data Analysis Data were analyzed by Statistical Package for Social Science (SPSS) version 23.0. Descriptive statistics, including frequency, percentage, range, mean, and standard deviation, were used to describe demographic characteristics, health literacy levels, asthma symptom control, and medication management. Pearson product-moment correlation was computed to explore the relationship between health literacy and symptom control, medication management. The Pearson analysis assumptions were tested, including normality of variables health literacy, symptom control, and medication management. All variables were normally distributed. The strength of correlations was classified as r > 0.50 (strong relationship), r ≥ 0.30 to 0.50 (moderate relationship) and r > 0 to 0.30 (weak relationship) (Grove, Burns, & Gray, 2013). Ethical Consideration The study was approved by the Ethical Committee of Human Research, Khon Kaen University, Thailand (HE632191), and the Institutional Ethics Committee of Hue University of Medicine and Pharmacy, Vietnam (H2020/441). Furthermore, the research was authorized by C Hospital before instigation. All data collected was anonymous and was used only for research purposes. Results Characteristics of the Participants The age of the participants in the study ranged from 21 to 87 years, with a mean age of 62 years (SD = 13.43). The percentage of female participants (53.57%) was higher when compared to males (46.43%). More than half of the participants (57.14%) were in the job retirement group, followed by the officer group (21.43%). The most common educational levels were college or higher, high school, and secondary school, with 34.52%, 32.14%, and 26.20 %. A total of 97.62 % of participants had health insurance, whereas income varied between 1 million VND and 30 million VND, with an average of 5.42 (SD = 3.41). The majority of participants (47.62 %) had asthma for five or more years (Table 1). Table 1 Demographic characteristics of the study participants (N = 84) Characteristic Number Percentage Age (years) Mean = 62.67    SD = 13.43    Min = 21    Max = 87 Gender Female 45 53.57 Male 39 46.43 Education level No school 0 0 Primary school 6 7.14 Secondary school 22 26.20 High school 27 32.14 College or higher 29 34.52 Occupation Officer 18 21.43 Housewife 9 10.72 Small business 7 8.33 Famer 2 2.38 Retire 48 57.14 Income (million VND) Mean = 5.42    SD = 3.41    Min = 1    Max = 30 Having health insurance Yes 82 97.62 No 2 2.38 Duration of asthma 6 months-1 year 6 7.14 1-3 years 23 27.38 3-5 years 15 17.86 ≥ 5 years 40 47.62 Level of Health Literacy, Symptom Control, and Medication Management The General – Health Literacy (GEN-HL) among the study participants ranged from 8.33 to 47.22 with a mean of 28.70 (SD = 9.66). Moreover, a mean score of three domains of health literacy, including HC-HL, DP-HL, and HP-HL, was revealed to be 28.31 (SD = 10.88), 26.73 (SD = 9.79), and 31.25 (SD = 11.62), respectively. The mean score of health literacy was similar to general health literacy (Table 2). Table 2 Domain of health literacy (N = 84) The domain of health literacy Mean ± SD Minimum Maximum General HL (GEN-HL) 28.70 ± 9.66 8.33 47.22 Healthcare (HC-HL) 28.13 ± 10.88 8.33 45.83 Disease prevention HL (DP-HL) 26.73 ± 9.79 0 50 Health promotion HL (HP-HL) 31.25 ± 11.62 4.17 50 Figure 1 shows that health literacy levels in four dimensions, namely inadequate, problematic, sufficient, excellent, were 35.72 %, 28.57%, 29.76%, and 5.95%, respectively. Limited health literacy (index of health literacy ≤ 33) of the participants was 64.29%. The disease-prevention domain was highest with 67.86%, whereas the health care and health promotion domains were quite similar, 53.57% and 54.77%. Figure 1 Level of health literacy index The score of symptom control among respondents ranged from 8 to 25, with a mean of 17.72 (SD = 4.67). The participants who had controlled asthma were the highest with 39.29%. Moreover, the patients in the partially controlled group were higher than the uncontrolled group, 35.71% compared to 25.00%. Next, the mean score of medication management measured by the MARS-A was 3.63 (SD = 0.75). The majority of the participants (81%) had poor adherence to the medication. The percentage mentioning that I only use it when I felt breathless was highest (62.00%), followed by I forgot to take it (61.91%). Furthermore, about half of patients who reported that they either used the ICS when needed, altered the dose, stopped taking it for a while were 54.77%, 52.38%, 51.19%, respectively. One-third of the participants reported that they decided to miss out on a dose (36.91%) or only used the ICS before performing something that might make them breathless (32.10%). The percentages of participants who reported that they tried to avoid using it and used it as a reserve if other treatment did not work were low, with 25% and 20.25%, respectively (Table 3). Table 3 Patients’ engagements in each action of poor adherence (N = 84) MARS-A item Always, Often, Sometimes (%) Rarely (%) Never (%) Mean ± SD I only use it when I need it 54.77 33.33 11.90 3.07 ± 1.22 I only use it when I feel breathless 62.00 19.00 19.00 3.14 ± 1.24 I decide to miss out a dose 36.91 26.19 36.90 3.83 ± 1.13 I try to avoid using it 25.00 23.80 51.20 4.21 ± 0.93 I forget to take it 61.91 23.81 14.28 3.29 ± 1.01 I alter the dose 52.38 22.62 25.00 3.56 ± 1.05 I stop taking it for a while 51.19 21.43 27.38 3.58 ± 1.08 I use it as a reserve if my other treatment doesn’t work 20.25 33.33 46.42 4.18 ± 0.96 I use it before doing something which might make me breathless 32.10 31.0 36.90 3.92 ± 1.08 I take it less than instructed 55.95 19.05 25.00 3.46 ± 1.12 Relationship between Health Literacy and Symptom Control, Health Literacy, and Medication Management As shown in Table 4, there was a significant relationship between health literacy with symptom control and medication management. The relationship with symptom control (r = 0.41), and medication management (r = 0.44) were moderately positive (p < 0.001). Table 4 Relationship of health literacy with symptom control and medication management (N = 84) Variable Symptom control Medication management Health literacy Symptom control 1.000 Medication management 0.18 1.000 Health literacy 0.41** 0.44** 1.000 ** Correlation is significant at the 0.01 level (2-tailed) Discussion This study aimed to investigate the level of health literacy, symptom control, and medication management among patients with asthma in Da Nang, Vietnam. The results revealed that the HL score in the patients was problematic (28.57%), which was similar to decade-old research in the country reporting the score of 29.70 ± 8.20 in participants aged 66.9 years (Van Hoa, Giang, Vu, Van Tuyen, & Khue, 2020). Another report also revealed a low HL score in Vietnam when Taiwan had the highest level in Asian countries (Duong et al., 2019). The HL score of participants in this study was lower than in Europe (33.8 ± 8.0) (Sørensen et al., 2015). Moreover, the mean score of disease prevention HL was low (26.73 ± 9.79) in the study. This emphasizes the need to consider the effectiveness of disease prevention interventions in the community. Limited health literacy (index of health literacy ≤33) of participants in this study was 64.29%. This result was similar (63.7%) to the study from the Northern Province of Vietnam in 2014 (Pham, 2014). However, the limited HL in this study was much higher than international findings. A survey among 353 asthmatic adults in Chicago showed 34.2% limited literacy skills (Curtis, Moore, Patton, O’Connor, & Nugent, 2018). This could be due to the age factor. More than half (57.1%) were retired from the job and were having difficulties accessing the medical information and understanding, appraising, and applying in the study. This finding demonstrated that the participants who have high limited HL might lead their health behavior to become poor in the future. Moreover, the symptom control among the patients in the study was partially controlled. A total of 39.29% of participants had controlled asthma. When combined, the number of partially controlled and uncontrolled patients was 60.71%. These findings are similar to previous studies reported from Vietnam, Bangladesh, and Japan (Adachi et al., 2019; Mohammod, Kunsongkeit, & Masingboon, 2019; Nguyen et al., 2018). On the other hand, there are studies reporting a low level of controlled asthma (21-29.4%) than our study (Gebremariam et al., 2017; Tarraf et al., 2018). Our high scores could be due to many factors such as health insurance, duration of asthma, and education level of the patients. In the study, about 97.62 % of participants had health insurance, nearly half of the participants had more than five years of asthma, and 66.66% were above high school education. More importantly, patients in the study were recruited from a central level hospital, and it has previously been shown that patients with asthma attended by a specialist doctor are more likely to manage better (Gebremariam et al., 2017). There are no published studies evaluating medication management in asthmatic patients in Vietnam, and the findings in the study have identified existing problems. Only 19% of the participants had good medication management, with a mean MARS-A score of 3.63 (SD = 0.75). Similar to us, a study from Kuwait reported merely 17.4% of participants having good adherence to medicine (Albassam, Alharbi, & Awaisu, 2020). It is estimated that only one-third of patients with asthma in Saudi Arabia are poorly controlled (BinSaeed, 2015). Vietnamese people often have the habit of buying medicine by themselves without following the instructions of their doctors. In addition, policies on drug trading are not yet strict. Therefore, patients often do not take asthma controller medications as prescribed. Additionally, social distancing and lockdown during data collection in the COVID-19 pandemic may have caused poor medication management in this study. Of importance, health literacy was significantly related to symptom control. This relationship was positively moderate (r = 0.41, p < 0.001). Earlier, a study indicated that 14% of the children whose parents scored low HL had less controlled asthma compared with 30% of those who had adequate HL (OR: 2.66 (95% CI: 1.55–4.56). This relationship remained significantly associated with health insurance and age (Krishnan, Rohman, Welter, & Dozor, 2018). Limited HL has also been associated with increased symptoms, impaired function, significant health care use, and significant adverse outcomes in adults with asthma (Paasche-Orlow et al., 2005). Furthermore, health literacy was significantly related to medication management. This relationship was positively moderate (r = 0.44, p < 0.001). Patients with low HL often have negative beliefs about asthma medications, such as not believing they need as many medications as their doctor prescribed or misconceptions about asthma medications. A report in 2015, including eight outpatients clinics in the USA, revealed that participants with limited HL were significantly associated with medication management (22.5% versus 46.4%, p <0.001) (Federman et al., 2014). However, a meta-analysis study has shown that health literacy is positively and weakly associated with medication management (r = 0.14, 95% CI = 0.08, 0.19) (Miller, 2016). The current findings imply that health policymakers and health care providers, especially nurses, should design and implement education programs on symptom control and medication management among patients with asthma to improve outcomes. Meanwhile, it is to mention that this study has some limitations. Firstly, as a cross-sectional descriptive study, data were collected only once, but the symptom control, medication management among patients with asthma may get changed. Secondly, the self-report questionnaire used may have caused the introspective ability and social desirability effect. Finally, because of the impact of the COVID-19 pandemic, the pulmonary function parameters such as forced exhalation volume in one second, peak expiratory flow were not measured in this study to assess the asthma classification, which in turn may have affected symptom control and medication management. Conclusion The study revealed that patients with asthma had limited HL, including partially controlled symptoms and poor adherence to medication in Vietnam. Moreover, a moderate positive relationship between health literacy and symptom and medication management was discovered. Health education programs based on the level of health literacy among patients are suggested. Additionally, a study with a large sample size, including participants from various parts of the country and predicting other significant factors related to symptom control and medication management, is recommended. Acknowledgment The authors would like to express gratitude to the participants who volunteered in his research. We also would like to express deep thanks to the Research and Training Center for Enhancing Quality of Life of Working-Aged People and the Department of Student Development and Alumni Affairs at the Faculty of Nursing Khon Kean University for partial funding of this research. Declaration of Conflicting Interests The authors declare no conflict of interest in this study. Funding This research was funded by the Research and Training Center for Enhancing Quality of Life of Working-Age People and the Department of Student Development and Alumni Affairs at the Faculty of Nursing, Khon Kean University, Thailand. Authors’ Contribution DTKC developed the research proposal, conducting data collection, data management, and analysis and drafting the manuscript. NM and HTTT supervised the proposal development, ethical approval process, questionnaire validation process, data collection, data management, and analysis. All authors have read and approved the final manuscript. Authors’ Biographies Doan Thi Kim Cuc, RN is a Lecturer at the Faculty of Nursing, Da Nang University of Medical Technology and Pharmacy, Vietnam. Nonglak Methakanjanasak, PhD is an Assistant Professor at the Faculty of Nursing, Khon Kaen University, Thailand. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-9-1-054 10.33546/bnj.2379 Original Research Factors influencing illness uncertainty in parents of children with congenital adrenal hyperplasia in a developing country: A cross-sectional study https://orcid.org/0000-0003-4134-8989 Larasati Irene Astrid 1 https://orcid.org/0000-0002-9104-3860 Saktini Fanti 23 https://orcid.org/0000-0001-5450-2813 Winarni Tri Indah 3 https://orcid.org/0000-0003-2893-5628 Ediati Annastasia 4 https://orcid.org/0000-0001-5965-1981 Utari Agustini 35* 1 Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia 2 Department of Histology, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia 3 Center for Biomedical Research (CEBIOR), Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia 4 Faculty of Psychology, Universitas Diponegoro, Semarang, Indonesia 5 Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro/Diponegoro National Hospital, Semarang, Indonesia * Corresponding author: Agustini Utari, MD, PhD, Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro / Diponegoro National Hospital Jl. Prof. H. Soedarto, Tembalang, Tembalang, Semarang, Central Java, Indonesia 50275. Email: agustiniutari@gmail.com Cite this article as: Larasati, I. A., Saktini, F., Winarni, T. I., Ediati, A., & Utari, A. (2023). Factors influencing illness uncertainty in parents of children with congenital adrenal hyperplasia in a developing country: A cross-sectional study. Belitung Nursing Journal, 9(1), 54-61 https://doi.org/10.33546/bnj.2379 12 2 2023 2023 9 1 5461 20 10 2022 21 12 2022 08 1 2023 © The Author(s) 2023 2023 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Illness uncertainty in parents of children with congenital adrenal hyperplasia (CAH) refers to parents’ inability to create meaning in events related to their children having CAH. This may influence their role in caring for children with CAH. Objective The study aimed to determine factors associated with illness uncertainty experienced by parents of children with CAH in a developing country. Methods A cross-sectional study was conducted on 80 parents (43 mothers and 37 fathers) of children with CAH, selected using consecutive sampling methods. The Parent’s Perception of Uncertainty Scale (PPUS) was used to measure the illness uncertainty levels. Data were collected from March 2020 to October 2020. Independent t-test and chi-square test were used to determine factors (parent’s gender, age, educational level, monthly household income, number of children with CAH, history of child death due to CAH, child’s age when first diagnosed with CAH, duration of therapy, gender change, type of CAH (salt wasting/SW or simple virilizing/SV), current gender, and genitoplasty) influencing illness uncertainty in parents. Results The mean scores of PPUS were 42.3 ± 12.91, and the majority of parents had a low PPUS score (49; 61%). Parents of children with SW-CAH showed higher uncertainty (44.2 ± 12.77) than those with SV-CAH (32.6 ± 8.86; p = 0.003). Parents who lost their children due to CAH were more likely to report a moderate illness uncertainty than parents who never experienced child mortality due to CAH (χ2(1, 80) = 4.893; p = 0.027). Conclusion The factors significantly affecting uncertainty in parents of children with CAH determined in this study might help healthcare professionals, including nurses, to play a pivotal role in giving pertinent information regarding their children’s health, disease, and therapy to help manage parental uncertainty. congenital adrenal hyperplasia uncertainty in illness parents developing country Indonesia ==== Body pmcBackground Congenital adrenal hyperplasia (CAH) is the most common cause of ambiguous genitalia in 46,XX disorders (differences) of sex development (DSD) in a newborn characterized by enzyme deficiency involved in steroidogenesis in the adrenal gland, in which 90% of cases are caused by 21-hydroxylase deficiency (Idris et al., 2014; Juniarto et al., 2018; Pezzuti et al., 2014; Tsuji et al., 2015; Zainuddin et al., 2019). This will result in cortisol and aldosterone deficiency and excessive androgen hormone production (Speiser et al., 2018; Szulczewski et al., 2017), with the incidence ranging from ~1:14,000 to 1:18,000 (Speiser et al., 2018). Data from the Indonesian Pediatrics Society registry in 2009 showed there were 69 children with CAH [56 (81%) girls and 13 (19%) boys]. However, this number surged to 439 children (303 (69%) girls and 136 (31%) boys) in 2020 (Armstrong et al., 2020). In addition, the Center for Biomedical Research (CEBIOR) recorded 84 patients with CAH were evaluated from 2004 to 2016 jointly by a multidisciplinary team from the Dr. Kariadi Hospital and Faculty of Medicine Diponegoro University, Semarang (Juniarto et al., 2018). Unlike many Western countries, a newborn screening program to detect CAH is unavailable in Indonesia (Gidlöf et al., 2014; Held et al., 2015; Odenwald et al., 2015; Speiser et al., 2018; Tsuji et al., 2015). This causes many late-diagnosed CAH cases (Ediati et al., 2015), which leads to delayed treatment (Juniarto et al., 2018), virilization, masculinization (Bizic et al., 2018), psychological problems like gender dysphoria (Juniarto et al., 2018), stigmatization (Ediati et al., 2017), emotional and behavior problem (Ediati et al., 2015), cross-gender role behavior (Ediati et al., 2017; Idris et al., 2014), and fertility issues (Witchel, 2017). Because of these, parents may develop illness uncertainty, leading to developing psychological problems, such as stress (Hullmann et al., 2011; Wisniewski & Sandberg, 2015), depression (De Silva et al., 2014; Perez et al., 2019), and anxiety (McConkie-Rosell et al., 2018; Perez et al., 2019; Wisniewski & Sandberg, 2015). Furthermore, parents of children with CAH in Vietnam reported that the scarcity of CAH medicines and low incomes, particularly from remote and rural families, caused many parents to be unable to afford the drugs their children need (Armstrong et al., 2020). In addition, the diagnosis and treatment delay due to ambiguous genitalia uncovered cost of laboratory workup by National Health Assurance (or called JKN – Jaminan Kesehatan Nasional), and inaccessible fludrocortisone brings complexities in the management of CAH in a developing country like Indonesia (Armstrong et al., 2020). Illness uncertainty, described as the inability to determine the meaning of illness-related events, has several factors that may contribute to its development: symptom pattern, event familiarity, event congruence, cognitive capacity, education, social support, and credible authority (Mishel, 1988). Understanding what causes uncertainty may help nurses and other healthcare professionals with patients’ experiences regarding their illnesses. In addition, a patient should develop a coping mechanism to cope with the uncertainty, and nurses play a critical role in helping patients to comprehend illness uncertainty and cope. This could help patients and their families increase their quality of life (Smith & Liehr, 2018). A previous study reported that mothers and fathers of DSD children scored higher uncertainty but lower than parents of children with chronic illness (Perez et al., 2019). Unfortunately, the study was conducted not only on parents of children with CAH but also on parents of children with 46, XX DSD, 46,XY DSD, and sex chromosomal DSD. To our knowledge, this is the first study of illness uncertainty in parents of children with CAH in a developing country. This study aimed to identify factors contributing to illness uncertainty in parents to promote early detection, prevention, and better management of children with CAH. Methods Study Design A cross-sectional study was conducted from March 2020 to October 2020 at the pediatric endocrinology clinic, National Diponegoro Hospital (RSND) in Semarang, Central Java, Indonesia, among parents who had children with CAH. Samples/Participants Consecutive sampling was used by inviting all parents of children with CAH registered in the pediatric endocrinology clinic. The sample size was calculated using a 95% of confidence interval, 5% of margin error, and 5% of the population proportion. The sample size calculation was done using a sample size calculator (https://www.calculator.net/sample-size-calculator.html) based on an estimate of 90 young patients with CAH and resulted in a minimum sample of 41 participants. Of 90 young patients with CAH, the parents of 44 patients participated in the study. The participants of this study consisted of 37 fathers and 43 mothers who had children with CAH. Parents aged 18 years or older who have children diagnosed with CAH aged 0-18 years were included in this study. Parents of children with other severe congenital disorders were excluded. Instruments A semi-structured questionnaire was utilized to assess sociodemographic data, such as parents’ gender, age, educational level, and monthly household income. In addition, data regarding the affected child were obtained from the medical records consisting of the date of birth, current gender, age at the start of treatment, duration of therapy, type of CAH (salt wasting/SW or simple virilizing/SV), genitoplasty, gender change status, sibling with CAH, and deceased CAH sibling. In this study, parents were divided into two age groups using mean age as a cut-off (below or above mean age). Upper secondary education is defined as someone whose latest education is a secondary school, including high school and vocational school, or below. Bachelor’s or equivalent education refers to someone who attained tertiary school, including a diploma, undergraduate, graduate, and postgraduate. Only parents of female children with CAH were included in the genitoplasty analysis. The original version of the Parent Perception of Uncertainty Scale (PPUS) was translated and validated into Bahasa Indonesia by Ediati et al. (2020) on 70 parents of children with CAH and diabetes mellitus (DM). Originally, PPUS comprised four factors (ambiguity, lack of information, lack of clarity, and unpredictability) that yielded 31 items. The construct validity of the Indonesian version of PPUS (PPUS-Indonesia) was explored using confirmatory factor analysis and revealed a one-factor model with satisfactory reliability (Cronbach’s alpha 0.903). The PPUS-Indonesia consisted of a 20-item parent-reported measure that assesses the level of illness uncertainty in parents. The following are sample items in the Indonesian version of PPUS: “Saya tidak tahu apa yang tidak beres dengan anak saya.” (I don’t know what is wrong with my child); “Saya tidak yakin apakah anak saya membaik atau makin parah.” (I am unsure if my child’s illness is getting better or worse); “Tujuan setiap pengobatan jelas bagi saya.” (The purpose of each treatment is clear to me). Item responses are rated on a 5-point Likert scale ranging from “strongly agree” to “strongly disagree” and scored 1 to 5, resulting in a possible total score ranging from 20 to 100. A higher PPUS score indicates greater levels of perceived uncertainty. The total score of PPUS is categorized into three groups: low (20-46), moderate (47-73), and high (74-100). Data Collection Data were collected by the researchers themselves. The researchers conducted a personal interview using the questionnaire for the 23 illiterate participants. In contrast, for the well-educated participants, the researchers gave two options for participants to fill out the questionnaire while being accompanied or interviewed. Data Analysis Data were analyzed using IBM SPSS (Statistical Package for the Social Sciences) version 26 (IBM, New York). Comparisons between numerical variables were analyzed using an independent t-test, while categorical variables were analyzed using the chi-square test. Fisher's exact test was applied for variables not aligned with the chi-square assumption, i.e., type of CAH and genitoplasty. Both bivariate analyses were conducted to identify the significant factors of parental uncertainty. The significant level was set at <0.05. Sensitivity analysis using Fisher’s exact test was performed by splitting the analysis based on the parent’s gender to compare the variables found to be significant in the chi-square test, i.e., type of CAH and child death due to CAH, and hypothetically categorized PPUS score. In addition, multivariate analysis using logistic regression was conveyed for the parents’ gender, number of children with CAH, child death due to CAH, and type of CAH. Ethical Considerations The ethical committee of the Faculty of Medicine, Universitas Diponegoro, Semarang, approved the study protocol (No. 483/EC/KEPK/FK UNDIP/XI/2019). Prior to the study, all participants received the study information and were free to decide on their participation in the study. Participants who joined the study voluntarily signed written informed consent. Results Participants consisted of 37 (46%) fathers and 43 (54%) mothers of children with CAH. The mean age of the participants was 35 ± 7.7 years, with most of them [44 (55%)] aged ≥ 35 years. The majority of parents (74%) had an upper-secondary education. Overall, 84% of parents had children with SW-CAH. Data from two parents were excluded from bivariate analysis by genitoplasty and the child’s current gender because they were parents of two children with CAH raised as a boy and a girl. Therefore, their response on PPUS-Indonesia might be biased as it is difficult to specify whether their response on uncertainty was referring to the son or daughter conditions or might not have represented both genders equally. Among 56 parents of girls with CAH, only 14% of their children had undergone genitoplasty (Table 1). Table 1 Characteristics of participants Fathers (n = 37) Mothers (n = 43) Total (n = 80) n (%) n (%) n (%) Parent-Related Factors  Age  < 35 years 14 (35) 23 (54) 36 (45)  ≥ 35 years 24 (65) 20 (47) 44 (55)  Educational level  Upper secondary 29 (78) 30 (70) 59 (74)  Bachelor’s or equivalent 8 (22) 13 (30) 21 (26)  Household monthly income (IDR)  < 2.000.000 (< ±$140) 15 (41) 17 (40) 32 (40)  ≥ 2.000.000 (≥ ±$140) 22 (60) 26 (61) 49 (60) Child-Related Factors  Number of children with CAH  More than one 11 (30) 13 (30) 24 (30)  One 26 (70) 30 (70) 56 (70)  Child death due to CAH  Yes 8 (22) 10 (23) 18 (23)  No 29 (78) 33 (77) 62 (78)  Type of CAH  Salt wasting 30 (81) 37 (86) 67 (84)  Simple virilizing 7 (19) 6 (14) 13 (16)  Child’s gender change due to CAH  Yes 9 (24) 10 (23) 19 (24)  No 28 (76) 33 (77) 61 (76)  Child’s age when first diagnosed with CAH  < 3 months 18 (49) 23 (53) 41 (51)  ≥ 3 months 19 (51) 20 (47) 39 (49)  Duration of therapy  < 3 years 16 (43) 20 (47) 36 (45)  ≥ 3 years 21 (57) 23 (53) 44 (55)  Child’s current gender (n = 78)  Male 10 (28) 12 (29) 22 (28)  Female 26 (72) 30 (71) 56 (72)  Genitoplasty (n = 56)ǂ  Yes 4 (15) 4 (13) 8 (14)  No 22 (85) 26 (87) 48 (86) ǂ Genitoplasty analysis was performed only on the parents of girls with CAH The majority of parents in the study showed a low level of uncertainty, as indicated by an average score of PPUS at 42.3 ± 12.91. Although none reported a high level of uncertainty, 39% of parents reported a moderate level of uncertainty (Table 2). Table 2 Parental uncertainty based on PPUS score hypothetical category Score category¶ Low Moderate High Mean ± SD Father (n = 37) 20 (54%) 17 (46%) 0 (0%) 44.8 ± 13.22 Mother (n = 43) 29 (67%) 14 (33%) 0 (0%) 40.1 ± 12.37 Total (n = 80) 49 (61%) 31 (39%) 0 (0%) 42.3 ± 12.91 ¶ Low = 20-46; Moderate = 47-73; High = 74-100 Table 3 displays the comparison analysis results between parent-related and child-related factors and the PPUS score. Parents of children with SW-CAH showed a higher score of uncertainty (44.2 ± 12.77) than parents of children with SV-CAH (32.6 ± 8.86). In addition, the type of CAH significantly affected the uncertainty perceived by parents (p = 0.003). Table 3 Comparison analysis between parent-child-related factors and PPUS score Mean (SD) Mean difference (CI 95%) Median (Minimum-Maximum) p-value§ Parent-Related Factors  Gender (n = 80) 4.7 (10-10.4) 0.101  Father (n = 37) 44.8 (13.22)  Mother (n = 43) 40.1 (12.37)  Educational level (n = 80) 3.2 (4.4-10.9) 0.394  Upper secondary (n = 59) 43.1 (11.86)  Bachelor’s or equivalent (n = 21) 39.9 (15.56)  Age (n = 80) 0.230  < 35 years (n = 39) 42.5 (20-68)  ≥ 35 years (n = 41) 39.0 (20-63)  Household monthly income (n = 80) 0.582  < IDR 2.000.000,00 (n = 32) 43.0 (20-67)  ≥ IDR 2.000.000,00 (n = 48) 39.5 (20-68) Child-Related Factors  Number of children with CAH (n = 80) 1.7 (4.6-8.0) 0.599  One (n = 24) 43.5 (13.08)  More than one (n = 56) 41.8 (12.92)  Child death due to CAH (n = 80) 5.4 (1.4-123) 0.116  Yes (n = 18) 46.5 (12.48)  No (n = 62) 41.1 (12.87)  Type of CAH (n = 80) 11.6 (4.2-18.9) 0.003*  Salt wasting (n = 67) 44.2 (12.77)  Simple virilizing (n = 13) 32.6 (8.86)  Gender change due to CAH (n = 80) 0.1 (6.7-6.9) 0.975  Yes (n = 19) 42.4 (11.61)  No (n = 61) 42.3 (13.38)  Child’s age when first diagnosed with CAH (n = 80) 1.1 (4.7-6.9) 0.703  < 3 months (n = 41) 42.8 (12.25)  ≥ 3 months (n = 39) 41.7 (13.70)  Child’s current gender (n = 78) 2.2 (4.3-8.6) 0.679  Male (n = 22) 44.1 (14.81)  Female (n = 56) 41.9 (12.17)  Genitoplasty (n = 56) 6.3 (15.5-3.0) 0.178  Yes (n = 8) 36.5 (12.56)  No (n = 48) 42.8 (12.00)  Duration of therapy (n = 80) 0.247  < 3 years (n = 55) 42.5 (20-68)  ≥ 3 years (n = 25) 39.0 (20-63) Note: IDR=Indonesian Rupiah § The independent t-test was performed * Significant at p < 0.05 Table 4 demonstrates the results of the comparison analysis of parent-child-related factors between low and moderate levels of uncertainty. Significant differences in illness uncertainty were found between groups of parents with SW-CAH and SV-CAH, as well as parents with and without experience of child mortality due to CAH. All parents of children with SV-CAH reported low uncertainty, whereas parents of SW-CAH reported lower to moderate uncertainty (p = 0.001). Parents who had lost their children due to CAH were more likely to have a moderate level of illness uncertainty, whereas parents who never experienced child mortality due to CAH were more likely to report a low level of illness uncertainty (χ2(1, 80) = 4.893; p = 0.027). No significant differences were found across different groups based on parent-related and child-related factors between low and moderate levels of uncertainty. In our data, two factors are associated with illness uncertainty in parents of children with CAH. First, parents with a history of child death due to CAH. They were more likely to report moderate uncertainty than parents without experience of child death due to CAH. Second, CAH type. None of the parents from the simple virilizing CAH group reported a moderate level of uncertainty. In contrast, almost half of the parents from the salt-wasting group reported a moderate level of uncertainty. Table 4 Comparison analysis between parent-child-related factors and PPUS score hypothetical category Low Moderate p-value‡ Parent-Related Factors  Gender (n = 80) 0.220  Father (n = 37) 20 (54.1%) 17 (45.9%)  Mother (n = 43) 29 (67.4%) 14 (32.6%)  Educational level (n = 80) 0.943  Upper secondary (n = 59) 36 (61.0%) 23 (39.0%)  Bachelor’s or equivalent (n = 21) 13 (61.9%) 8 (38.1%)  Age (n = 80) 0.982  < 35 years (n = 39) 22 (61.1%) 14 (38.9%)  ≥ 35 years (n = 41) 27 (61.4%) 17 (38.6%)  Household monthly income (n = 80) 0.779  < IDR 2.000.000,00 (n = 32) 19 (59.4%) 13 (40.6%)  ≥ IDR 2.000.000,00 (n = 48) 30 (62.5%) 18 (37.5%) Child-Related Factors  Number of children with CAH (n = 80) 0.176  One (n = 24) 12 (50.0%) 12 (50.0%)  More than one (n = 56) 37 (66.1%) 19 (33.9%)  Child death due to CAH (n = 80) 0.027**  Yes (n = 18) 7 (38.9%) 11 (61.1%)  No (n = 62) 42 (67.7%) 20 (32.3%)  Type of CAH (n = 80)˥ 0.001**  Salt wasting (n = 67) 36 (53.7%) 31 (46.3%)  Simple virilizing (n = 13) 13 (100.0%) 0 (0.0%)  Gender change due to CAH (n = 80) 0.377  Yes (n = 19) 10 (52.6%) 9 (47.4%)  No (n = 61) 39 (63.9%) 22 (36.1%)  Child’s age when first diagnosed with CAH (n = 80) 0.684  < 3 months 26 (63.4%) 15 (36.6%)  ≥ 3 months 23 (59.0%) 16 (41.0%)  Child’s current gender (n = 78) 0.702  Male (n = 22) 14 (63.6%) 8 (36.4%)  Female (n = 56) 33 (58.9%) 23 (41.1%)  Genitoplasty (n = 56)˥ 0.318  Yes (n = 8) 6 (75.0%) 2 (25.0%)  No (n = 48) 27 (56.3%) 21 (43.8%)  Duration of therapy (n = 80) 0.982  < 3 years (n = 55) 22 (61.1%) 14 (38.9%)  ≥ 3 years (n = 25) 27 (61.4%) 17 (38.6%) Note: IDR=Indonesian Rupiah ‡ The chi-square test was applied, with the exclusion of type of CAH and genitoplasty ˥ The Fisher’s test was applied ** Significant at p < 0.05 Sensitivity analysis using Fisher’s exact test was performed for two variables found to be significant in the chi-square test, i.e., type of CAH and child death due to CAH. Each variable was split based on the parent’s gender, and a comparison was made between these two variables and PPUS score hypothetical category. Illness uncertainty was significantly different between fathers of SW-CAH and SV-CAH. All fathers of SV-CAH reported a low level of uncertainty (p = 0.009) (Table 5). Table 5 Sensitivity analysis, split by parent’s gender, between child death due to CAH and type of CAH and PPUS score hypothetical category Low Moderate p-value‡ Child death due to CAH (n = 80)  Father (n = 37) Yes (n = 8) 3 (37.5%) 5 (62.5%) 0.428 No (n = 29) 17 (58.6%) 12 (41.4%)  Mother (n = 43) Yes (n = 10) 4 (40.0%) 6 (60.0%) 0.055 No (n = 33) 25 (75.8%) 8 (24.2%) Type of CAH (n = 80)  Father (n = 37) Salt wasting (n = 30) 13 (43.3%) 17 (56.7%) 0.009** Simple virilizing (n = 7) 7 (100.0%) 0 (0.0%)  Mother (n = 43) Salt wasting (n = 37) 23 (62.2%) 14 (37.8%) 0.155 Simple virilizing (n = 6) 6 (100.0%) 0 (0.0%) ‡ The Fisher’s test was applied. ** Significant at p < 0.05 Logistic regression, which was conducted for parents’ gender, the number of children with CAH, child death due to CAH, and type of CAH, found no significant impact on the PPUS score hypothetical category. Discussion The study aimed to investigate factors influencing illness uncertainty experienced by parents of children with CAH in a developing country. Our study findings showed that there were two factors affecting illness uncertainty in parents of children with CAH: the type of CAH and the presence of child mortality due to CAH. The chi-square test was performed to analyze the presence of child mortality, which was in line with the chi-square assumptions. Parents of children with the salt-wasting type of CAH and parents who experienced the loss of their children due to CAH are more likely to report higher illness uncertainty than other parents who have not. The study findings are important as higher uncertainty among parents of children with CAH reflects the need to seek appropriate information related to CAH and its treatment to reduce the uncertainty level of parents. Parents of children with CAH in the present study reported somewhat low to moderate levels of uncertainty, and none reported a high level of uncertainty. A previous study about psychological distress experienced by parents of children with DSD showed a comparable level of uncertainty (Suorsa et al., 2015). This might indicate that their children with CAH have received medical treatment and regularly visit the pediatric endocrinology clinic to maintain their health. The role of healthcare professionals in delivering appropriate information regarding CAH to parents and the availability of guidelines about CAH that parents can refer to (Speiser et al., 2018) may play an essential role in reducing illness uncertainty in these parents of children with CAH. In addition, social support is also available by using social media (WhatsApp group) of parents who have children with CAH (Mishel, 1988) may reduce uncertainty experienced by parents of children with CAH. But still, some parents experienced a moderate level of illness uncertainty. More efforts are needed to identify relevant information to reduce the illness uncertainty for these parents. Do they receive less or too much information regarding CAH, and what kind of CAH-related information do they need to reduce illness uncertainty on these parents should be investigated in the follow-up study because lack or too much information, as well as seeking or avoiding information, may influence uncertainty (Kerr & Haas, 2014). Most participants were parents of children with salt-wasting type CAH (44.2 ±1 2.77), and they had a significantly higher mean score of PPUS than children with simple virilizing type CAH (32.6 ± 8.86). According to Utari et al. (2016), 10 out of 79 (13%) children registered with CAH in Central Java, Indonesia, had died because of adrenal crises since 2009. The lack of newborn screening for CAH leads to delayed diagnosis and treatment. In addition, the most severe form of CAH, the salt-wasting type, made the body unable to regulate salt (sodium) levels in the blood because of a lack of aldosterone, making it prone to salt-wasting crisis (Falhammar et al., 2014). This made salt-wasting CAH contribute to a higher level of uncertainty. Therefore, patients with CAH need hydrocortisone and fludrocortisone for cortisol and aldosterone replacement therapy, respectively. However, fludrocortisone is unavailable in Indonesia (Armstrong et al., 2020) and might further increase the illness uncertainty among parents. A significant difference in illness uncertainty was discovered between fathers of SW-CAH and fathers of SV-CAH. A previous study on parents of children with DSD found contradictory results where mothers scored higher uncertainty despite being insignificant (Perez et al., 2019). Our result might be explained by the patriarchy that most Indonesians embraced. Most of the participants of this study came from rural areas. In addition, most mothers who participated in this study were housewives and unemployed; thus, the only source of income for the family came from the fathers. Therefore, even though mothers might be involved in the general decision-making process, as the head of the family, the final decision is for the fathers to decide (Ferdoos & Zahra, 2016; Sarwono, 2012). Child mortality due to CAH significantly affected illness uncertainty in parents. Parents of children with CAH who had lost their children due to CAH were more likely to report a higher level of uncertainty than parents who had never had such a grief loss. The result was similar to psychological distress experienced by parents of children who died from cancer (Sirkiä et al., 2000; Stroebe et al., 2006). Child loss was one of the deepest griefs experienced by parents (Davies, 2004). If a child died, the parent’s hope about the future would die, too (Christ et al., 2003). Parents who have encountered child loss might have an intense fear of losing the other child or, in CAH cases. Facing conflicting information about caring for children with CAH, therefore, might need specific support during bereavement (Gijzen et al., 2016). Further investigation is needed to explore the experiences of 18 parents who lost their children due to CAH and whether they need specific support and knowledge related to CAH to reduce the illness uncertainty of these particular parents. The findings reported two factors significantly affecting illness uncertainty in parents with CAH. However, illness uncertainty did not significantly differ in most factors investigated, i.e., parental gender, age, educational level, monthly household income, number of children with CAH, child’s gender change due to CAH, child’s age when first diagnosed with CAH, child’s current gender, history of genitoplasty, and therapy duration. This might be because, nowadays, parents can easily search for their children’s condition on the internet before a medical appointment (Molzon et al., 2014). On the contrary, a previous multicenter study on parents of children with DSD found that parents of boys reported a higher illness uncertainty compared to parents of girls, and parents who were unsure of the gender of their child also reported greater uncertainty (Suorsa et al., 2015). Implications of the Study for Nursing Practice Nurses’ primary role was taking care of the patient, attending to their physical needs and holistically, including psychosocial, cultural, and social needs (Hodges & Tod, 2007). Children were incapable of taking care of themselves hence needing parents or caregivers. Child’s illness might cause uncertainty and psychological distress and uncertainty in parents (De Silva et al., 2014; Hullmann et al., 2011; Kerr & Haas, 2014; McConkie-Rosell et al., 2018; Perez et al., 2019; Suorsa et al., 2015; Szulczewski et al., 2017; Wisniewski & Sandberg, 2015). The uncertainty caused the parents to be unable to define the outcomes and assign a value to events relating to their child’s illness. Therefore, nurses need to understand the circumstance of uncertainty and its related factors to help the patient and their family, particularly parents, to comprehend illness uncertainty and develop a healthy coping mechanism, thus enhancing their quality of life (Brimble, 2007). Limitations of the Study The sample size was moderate, and it would be better to find another sample size estimation using two mean difference sample tests or two proportional difference sample tests. This was a one-centered study, so the data collected might not be as diverse as the data retrieved from multiple centers; besides, collecting data from a multicenter was challenging during the COVID-19 pandemic. Therefore, conducting a multicenter study is recommended to collect more data and diverse results in future research. Our study was conducted on parents who had managed their children with CAH for years. Many factors might influence the degree of uncertainty. Some of them were support from other parents of children with CAH and information they got from health care professionals over time. Despite the uncertainty they face regarding their children’s illness, parents of children with CAH can seek support from other parents with CAH and receive sufficient information and support from medical professionals. Conclusion Parents of children with CAH had a low level of uncertainty; however, some parents still experienced moderate uncertainty. Salt-wasting type CAH and a history of child death due to CAH significantly affected parental uncertainty because of the impendence of salt wasting crisis and limitation of drug availability for salt-wasting type CAH. Therefore, these groups of parents would particularly need more support and attention and thus benefit from getting social support from other parents of children with CAH and regularly going to the medical appointment to consult and receive appropriate information from health care professionals. Nurses’ roles in caring for the patient extend beyond the physical need and providing holistic care, including psychosocial, cultural, and spiritual needs. In addition, nurses also played a role in educating the patient and their family so they could better understand the patient’s health, illnesses, and treatments, thus reducing uncertainty. Acknowledgment The authors would like to thank all parents who participated in the study for their willingness to share their thoughts and concern in raising their children through the study. Declaration of Conflicting Interest The authors declare no conflict of interest in this study. Funding This work was funded by Research Grant from the Faculty of Medicine, Diponegoro University, Semarang, Indonesia (1150/UN 7.5.4.2.11PP/PM/2020). Authors’ Contributions The authors confirm their contribution to the paper as follows: study conception and design: AU, FS, IAL; data collection: IAL, FS, AU; analysis and interpretation of results: AE, AU, FS, IA; draft manuscript preparation: IAL, FS, TIW, AE, AU. All authors reviewed the results and approved the final version of the manuscript. Authors’ Biographies Irene Astrid Larasati, MD is a Medical Doctor in Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia. Fanti Saktini, MD, MSc is a Psychiatrist, a Lecturer, and a Researcher at the Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia. Prof. Tri Indah Winarni, MD, PhD is a Lecturer in the Faculty of Medicine, Universitas Diponegoro, a Researcher at the Center for Biomedical Research (CEBIOR), and a Member of the Advisory Board of the Indonesian Society of Human Genetics. Annastasia Ediati, PhD is a Lecturer, a Researcher, and a Psychologist at the Faculty of Psychology, Universitas Diponegoro, Semarang, Indonesia. Agustini Utari, MD, PhD is a Head of the Pediatric Endocrinology Division, Department of Pediatrics, Faculty of Medicine, Universitas Diponegoro, and a Member of the Strategic Advisory Group on Non-Communicable Disease (NCD) of the International Pediatric Association (IPA). Data Availability The datasets generated during and analyzed during the current study are available from the corresponding author upon reasonable request. ==== Refs References Armstrong, K., Benedict Yap, A., Chan-Cua, S., Craig, M. E., Cole, C., Chi Dung, V., Hansen, J., Ibrahim, M., Nadeem, H., & Pulungan, A. (2020). 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-2-88 10.33546/bnj.1298 Original Research Health literacy and health-promoting behaviors among adults at risk for diabetes in a remote Filipino community https://orcid.org/0000-0002-8887-0371 Ydirin Christian Sandor B. * University of the Philippines Open University, Los Baños, Laguna 4031, Philippines * Corresponding author: Christian Sandor B. Ydirin, MAN, BSN, RN, CCRN, University of the Philippines Open University, Los Baños, Laguna 4031, Philippines. Email: christiansandor.ydirin@upou.edu.ph Cite this article as: Ydirin, C. S. B. (2021). Health literacy and health-promoting behaviors among adults at risk for diabetes in a remote Filipino community. Belitung Nursing Journal, 7(2), 88-97. https://doi.org/10.33546/bnj.1298 29 4 2021 2021 7 2 8897 07 1 2021 17 2 2021 01 3 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Diabetes risk assessment is an essential preboarding tool before implementing health literacy programs to change an adult’s health behavior positively. Research has shown an association between health literacy and health behaviors, but there is a dearth of literature that delineates the difference between the health literacy and health behaviors of adults according to their diabetes risks; high risk vs. low risk. Objective This study aimed to determine the difference between the health literacy and health behaviors of adults and establish the relationship between the two variables when classified according to their diabetes risks. Methods This study utilized a descriptive cross-sectional design with 400 adults in a remote Filipino community in November 2019. Data were gathered using the Health Promoting Lifestyle Profile II (HPLP II) and Health Literacy Survey-Short Form 12 (HLS-SF12) questionnaires. Descriptive statistics, independent t-test, and Pearson’s r were used to analyze the data. Results There is a significant difference between the health literacy index scores (p < .05); but no significant difference between the health behavior mean scores (p > .05) of adults when grouped according to their diabetes risks. Health literacy is significantly (p < .05) correlated with health behaviors of adults, with a moderate positive correlation in the high-risk group (r = .43), and both weak positive correlation in the low-risk group (r = .13) and entire group (r = .17). Conclusion All adult inclusion efforts in promoting health literacy, with emphasis on the high-risk group, are needed to improve awareness of the degree of diabetes risks. Nurses should take an active role in the assessment of diabetes risks, evaluation of results, and implementation of interventions that could increase health literacy to facilitate the development of healthy behaviors. Stakeholders are urged to advance the availability of evidence-based lifestyle interventions to reduce the growth in new cases of diabetes. adult health literacy health behavior risk assessment nursing Philippines ==== Body pmcDiabetes risk assessments are essential information that could be utilized in promoting health education among adults at risk for the disease. The impact of diabetes risk factors on health outcomes can be overestimated when ascertaining the disease based on medical diagnoses rather than on risk assessments (Feldman et al., 2017). In health promotion activities, health education is essential, wherein the role of health literacy is indispensable. However, health literacy should not be assessed as an isolated concept but should be evaluated in combination with health behaviors (Yeh et al., 2018). In this research, Diabetes Mellitus Type 2 (DM2) is a lifestyle-related disease taken into the limelight. The International Diabetes Federation (2014) estimated that there are 3.2 million cases of DM2 in the Philippines with a 5.9% prevalence rate in adults between the ages of 20-79 years, with more than half of the population remained to be undiagnosed. In one of the regional administrative units of the Philippines, Western Visayas has been reported to have one out of five adults having diabetes (Conserva, 2014), with a similar statistic applicable to the whole nation, wherein one out of five Filipinos either has pre-diabetes or diabetes. On a local municipal unit, there is an annually increasing case of diabetes among adults in President Roxas, Capiz, with a prevalence rate of 1.4% (Pilar, 2018). This number shows those who were only diagnosed with diabetes. Still, nothing is known about those at risk for the disease, leaving the percentage as an underestimation of the true prevalence of undiagnosed diabetes in the municipality. The report enumerated several reasons for the increase in diabetes cases, such as the unhealthy lifestyle of the community, incidental screening of few adults seeking treatment at the rural health unit, and regular services in nearby accessible barangays. Several studies pointed out the benefits of diabetes risk assessment, with suggested approach including employment of a diabetes risk assessment questionnaire (Lindström et al., 2010; Pippitt et al., 2016), application of screening using a home-based approach (Pastakia et al., 2013) and targeted implementation in racial, ethnic and remotely underserved individuals to improve its advantage (Wilson et al., 2010). Two population studies concluded that people with undiagnosed diabetes considerably underestimate their probability of developing the disease (Adriaanse et al., 2008; Kowall et al., 2017). Relatively, the conduct of diabetes risk assessment is essential to include the entire population, but the economy of its practice is challenged. On a particular note, if significant differences could be determined between the health outcomes of persons with high and low risk for diabetes, practical implications can be derived thereafter. In addition to diabetes risk assessment, the health literacy and health behaviors of adults in remotely located upland barangays are not assessed because of their inaccessibility to the healthcare facility and the large disparity between the health budget and maintenance and operating costs (Pilar, 2018). It is noted that patients seek medical consultation when they are very sick and that low health literacy affects health behaviors, with lifestyle diseases such as diabetes (Gloor, 2014). In the Philippines, it is disturbing to note that despite the country’s high reading and writing literacy, it appears that this does not always translate to high health literacy (Agosto et al., 2018; Maduramente et al., 2019). There is a dearth of literature that presents correlations between health behaviors and health literacy in marginalized groups, more lacking when classified according to their diabetes risk. To the best of the author’s knowledge, only one study (Sutherland et al., 2012) have classified diabetes risk and investigated its association with health behaviors, with the exclusion of health literacy in its variables. There is a need for additional studies with a higher hierarchical sampling design that could support the importance of nurse-directed assessment of diabetes risk. Conclusive shreds of evidence that could show significant differences in health behaviors and health literacy between adults with low or high risk for developing diabetes imply that risk assessment is a practical and strategical approach before implementing health promotion activities, whether on a large scale or a targeted population. At present, only a few studies are being conducted that classify the adult population according to their diabetes risk (Sutherland et al., 2012) and most lacking or probably none when relationships between their health literacy and health behaviors are further examined. On the contrary, numerous studies have revealed an association between health behaviors and health literacy in different populations (Chahardah-Cherik et al., 2018; Hansen et al., 2015; Kim et al., 2018; Suka et al., 2015; Yeh et al., 2018). These studies focus only on the urban population and adults diagnosed with diabetes or, otherwise, healthy persons. Thus, this study aims to delineate differences between health literacy and health behaviors among adults, when categorized according to their diabetes risk, and establish the relationship between these variables. Methods Study Design A descriptive correlational research design with a cross-sectional approach was utilized in this study. It was carried out in Barangay Vizcaya, President Roxas, Capiz, Philippines, during the whole month of November 2019. Sample/Participants A sample from the population of the aforementioned location, with low-income, remotely located, and medically underserved adults were selected. Barangay Vizcaya, with a population of 2,464 and an average household size of 5.37, was chosen as the accessible population. As one of the most populous Barangay compared to the other 22 Barangays of the municipality, it was selected to expect a higher return rate. The sample size was determined using the G*Power 3.1 (Faul et al., 2009) calculator for sample size, with a priori power analysis for Pearson’s r correlation for two independent samples; calculated based on the power of 80%, .05 alpha level of significance and the smallest effect size of .1. The largest required sample size was 433. The researcher deliberately allotted a total of 500 randomly selected participants to increase the return rate. From the accessible population, stratified random sampling was employed to systematically choose the sample according to age and sex. Inclusion criteria encompassed those who were never diagnosed with diabetes, not taking insulin or oral medications for blood glucose control, able to hear and understand a common language (Hiligaynon, English or Tagalog), and all adults aged 18-59 years old with signed written informed consent. Exclusion criteria included those who were pregnant, lactating, with illness having a likely prognosis of less than one-year, psychiatric illness, those who were less than 18 years old and refused to participate. Using the inclusion and exclusion criteria, minus the unreturned questionnaires and tool with missing data, a total of 400 eligible participants were included in the final sample of the research, with an overall response rate of 80%. Measures Pilot and Pre-testing. The simplified Finnish Diabetes Risk Score (FINDRISC) Questionnaire, Health Literacy Survey Short Form 12 (HLS-SF12), and Health-Promoting Lifestyle Profile II (HPLP II) instruments were all originally written in English. The HLS-Asian Tagalog (Agosto et al., 2018) and the HPLP II Hiligaynon (Beliran & Legaspi, 2014) were utilized in this study after being granted permission for its use. Permission to use the original HPLP II (Walker & Hill-Polerecky, 1995) and HLS-SF12 (Duong et al., 2019) were obtained. Since previous studies were conducted in urban settings, pilot testing among 30 conveniently selected adults in the accessible population was carried out. These participants were not included in the final sample population. The reliability testing for the translated versions of HLS-SF 12 and HPLP II resulted in acceptable Cronbach’s alpha coefficients of .71 and .89, respectively. Since subscales were utilized, composite reliability for both HLS-SF12 and HPLP II was also determined, resulting in composite reliability coefficients of .93 and .90, respectively. Sociodemographic Questionnaire & Diabetes Risk Score. A researcher-made questionnaire to determine the sociodemographic characteristics was constructed. Individual characteristics such as age bracket, sex, civil status, educational attainment, monthly income, employment status, type of family structure, health status, presence of health insurance, and a number of doctor’s visits in the last year were obtained using the researcher-made questionnaire for sociodemographic. Permission to use the original (Lindström et al., 2010) and the simplified (Ku & Kegels, 2013) FINDRISC questionnaire were obtained from the authors. The simplified tool was utilized to determine the diabetes risk scores. The decision was based on its applicability to Filipinos and the need for less expertise and equipment in a resource-constrained setting without compromising its performance. A cut-off diabetes risk scores greater than or equal to seven (≥7) was the decisional score for the participants to be considered at high risk for diabetes, which is in line with previous studies (Ku & Kegels, 2013). Health Promoting Behavior Questionnaire. The HPLP II is a 52-item, four-point, Likert-styled instrument consisting of the following subscales: spiritual growth, interpersonal relations, nutrition, physical activity, health responsibility, and stress management. The HPLP II measured the health behavior scores of the participants. The 4-point response scale consists of 1 representing “never”, 2 as “sometimes”, 3 as “often”, and 4 as “routinely”, which was used to determine the frequency of each behavior. The tool has been reported to have established content validity, construct validity, criterion-related validity, and reliability, with an alpha coefficient of internal consistency of .94 and alpha coefficients ranging from .79 to .87 for all subscales. On the other hand, the HPLP II Hiligaynon reported acceptable face validity and internal consistency of the translated questionnaire. The recommended use of means rather than sums of scale items to retain the metrics of item responses and to allow meaningful comparison of scores across subscales was implemented. A mean of ≥ 2.50 was considered to be a positive health behavior, in line with previous studies (Beliran & Legaspi, 2014; Sutherland et al., 2012). Health Literacy Questionnaire. Duong et al. (2019) advanced the use of a new comprehensive HLS-SF12, originally derived from the original HLS-EU-Q47, consisted of 12 items and validated among different groups of the Asian population. The instrument includes the three subscales: healthcare, health promotion, and disease prevention. It consists of a 4-point response scale, which translates 4 as “very easy”, 3 as “easy”, 2 as “difficult”, and 1 as “very difficult”, to determine the level of difficulty of each item in different components. The HLS-SF12 English version demonstrated high alpha coefficient reliability of .85, good criterion-related validity, and a high level of item-scale convergent validity (Duong et al., 2019). On the other hand, the HLS-EU-Q47 Tagalog (Briones, 2017) reported general health literacy Cronbach’s alpha coefficient of .91 and subscale Cronbach’s alpha coefficients ranging from .80 to .85. The general indices for HLS-SF12 were standardized to unified metric scores from 0 to 50 using the formula index= (M-1) x (50/3). The health literacy index was obtained by calculating the total scores of the individual’s responses to all 12 items. The classification of health literacy indexes and its descriptive interpretation were as follows: 0-25, inadequate; >25-33, problematic; >33-42, sufficient, and >42-50, excellent (Sørensen et al., 2013). Data Collection After completion of written informed consent, the survey was initiated. Each participant was assigned with a serial number to ensure anonymity. The identifying number was double-checked with the name on the master list, while the serial number was written on the consent form and every page of the research instrument. The responses were recorded on the simplified FINDRISC questionnaire, and the waist circumference (cm) of each participant was measured. Ten barangay health workers were officially hired to help in the conduct of the survey. All have attended the orientation and skills check-off for proper data collection and waist circumference measurement. Consistency in data collection was ensured through carrying out uniform protocols, adapted from WHO STEPS Surveillance Manual 2008, which included step-by-step details for measuring waist circumference and obtaining self-reported answers. Diabetes risk scores were derived from participant’s responses and values of waist circumference. For the health literacy and health behavior questionnaires, an item-by-item and word-by-word reading of the respective instrument was employed. The choices for the answers after each item were repeatedly provided, using a cue card as a memory aid for the participants. All the responses were recorded after that. Data Analysis All raw data were encoded in Microsoft Excel©2014 and exported to the IBM©2019 software for SPSS©2019 statistical testing. Data were analyzed using descriptive statistics, Levene’s, independent t, and Pearson’s r correlation tests. Statistical significance was set at < .05. Parametric statistics were used to determine significant differences between the health literacy and health behaviors of adults, grouped according to diabetes risk, and determine the relationship between the two variables. The homogeneity in the sample variance was met as evidenced by the p-values for health literacy indexes and health behavior scores, p = .487 and p = .072, respectively, which meant that the requirement of equal variance for utilizing parametric testing is appropriate. Since adults at high risk and low risk for diabetes were two sub-samples in a given total sample, Levene’s test was appropriate to determine equality in variance (Derrick et al., 2018). To quantify the degree of difference between groups, Hedges g was utilized in this study. This is an appropriate measure of effect size when two sample sizes have a similar standard deviation but different sample sizes (Borenstein et al., 2011). Moreover, it is emphasized that the effect size (ES) presented in this study was based on a correlation effect size due to the research design. This is represented as a typology of corrES (Fitz-Gibbon, 2002). Hedges g above .4 is interpreted as medium corrES in meta-analysis studies (Brydges, 2019; Gignac & Szodorai, 2016). Ethical Considerations Research ethics committee approval from OVCAA UP Open University Los Banos, Laguna, Philippines was accomplished through the application for ethical review before the conduct of the study (Document date and number: 11 March 2019; 0111-1900-0064-8507). The pro-curement of written informed consent and an official permit from the barangay ensured individual and collective autonomy. The consent was written in the language understood by the participants. Moreover, the following elements were explained: the purpose of the study, expected duration of participation, description of procedures to be followed, disclosure of confidentiality, minimal risk involvement, compensation, principal researcher’s contact information, refusal to participate, and voluntary withdrawal options at any time without penalty or loss of benefits. Results In general, the participant’s age ranged from 18 to 59 years (M=36.19, SD=11.58) and were predominantly males (53.3%); young adults (18 to 44 years old) (71.3%), married or in a common-law relationship (70.8%), had at least a high school level of education (47.3%), and in a nuclear type of family structure (62.7%). Almost three-quarters (71.8%) claimed to have health insurance, with almost all of the population (92.8%) reported having no medical condition. This may owe an explanation to just above half (57.0%) of the population seeking doctor’s consultation one to three times in the last year. Only half of the participants (50.2%) reported to have been employed, and the majority of them have the lowest bracket of family income amount of ≤5,000 Php per month (84.3%) (Table 1). Table 1 Distribution of participants according to socio-demographic and health characteristics Characteristics Frequency Percentage Entire group 400 100 Age  18-44 (young adult) 289 72.3  45-54 (middle-aged) 81 20.2  55-59 (older adult) 30 7.5 Sex  Male 212 53.2  Female 188 46.8 Civil status  Married/Common Law 283 70.8  Single 88 22.0  Widowed 21 5.3  Separated 8 2.0 Educational level  Elementary 132 33.0  Highschool 189 47.2  Vocational 8 2.0  College 71 17.8 Work status  Employed 201 50.2  Unemployed 199 49.8 Family structure  Nuclear 251 62.7  Extended 128 32.0  Dyad 8 2.0  Single 13 3.3 Monthly income  ≤ 5,000 (lowest) 337 84.2  5,001-9,999 (lower) 56 14.0  ≥ 10,000 (low) 7 1.8 No. of doctor visits in the last year  Never 158 39.5  1-3 228 57.0  4-6 10 2.5  ≥ 7 4 1.0 Health insurance  With 287 71.8  Without 113 28.2 Health status  With a diagnosed medical condition 29 7.2  Without diagnosed medical condition 371 92.8 Diabetes risk status  High risk 106 26.5  Low risk 294 73.5 The data in Table 1 also presents a remarkably lower percentage of the adults reported to have a diagnosed medical condition (7.2%); however, it may not reflect the real situation since it appears that just about less than a half (39.5%) of the adults claimed never to seek a doctor in the last year. Based on diabetes risk assessments, out of 400 respondents, 106 participants (26.5%) were classified as high risk for diabetes, while 294 respondents (73.5%) were grouped as low risk for diabetes. Table 2 shows the differences in health literacy indexes between adults at high and low risk for diabetes. Although the results showed the presence of low levels of health literacy, both in the high-risk group (M = 25.20, SD = 4.76) and low-risk group (M = 27.66, SD = 4.69), there is sufficient evidence that supports a significant difference between the health literacy index mean scores of adults among the two groups, t (398) = -4.61, p = .000, at .05 level of significance. The high-risk group (M = 25.20, SD = 4.76) showed significantly worse health literacy indexes compared to the low-risk group (M = 27.66, SD = 4.69). Moreover, correlation effect size, corrES = .52 (Hedges g), revealed a medium effect, which meant that the level of risk for developing diabetes had a moderate magnitude effect on the differences between their health literacy levels. Specifically, among the three health dimensions of health literacy, the disease prevention subscale obtained the lowest health literacy indexes for both groups, high risk (M = 24.21, SD = 6.30) and low risk (M = 26.81, SD = 5.94). Table 2 Differences in the means of health literacy index, grouped according to diabetes risks: high risk vs. low risk Health literacy index M SD t-value corrES (Hedges ‘g) p-value Healthcare  High 25.47 6.18 -4.98 .56 .000*  Low 28.64 5.40 Disease prevention  High 24.21 6.30 -3.79 .43 .000*  Low 26.81 5.94 Health promotion  High 25.90 5.61 -2.49 .28 .013*  Low 27.59 6.11 General health literacy  High 25.20 4.76 -4.61* .52 .000*  Low 27.66 4.69 Overall health literacy index 27 5 * p < .05 (significant) Table 3 shows the differences in the mean scores of health behaviors between adults at high and low risk for diabetes. The health behaviors of adults at high risk (M = 2.32, SD = .708) and low risk (M = 2.29, SD = .635) were both considered as negative health-promoting behaviors. Consistently, statistical testing showed no significant difference between the health behaviors of adults grouped according to their diabetes risk, t (398) = -.81, p = .420. Analysis of the subscales showed consistently negative behaviors in five health behavior subscales, except in the spiritual growth, which had a positive health behavior for both adults at high risk (M = 2.66, SD = .647) and low-risk group (M = 2.53, SD = .596). Among the six subscales of health behaviors, the lowest health behavior mean scores were in the physical activity subscale, both in the high risk (M = 1.94, SD = .720) and the low-risk group (M = 1.99, SD = .635). The highest health behavior scores were in the spiritual growth subscales. Table 3 Differences in the means of health-promoting behaviors, grouped according to diabetes risks: high risk vs. low risk Health behaviors M SD t-value p-value Nutrition  High 2.24 .702 -1.23 .220  Low 2.33 .626 Health responsibility  High 2.28 .607 2.46 .215  Low 2.20 0.555 Spiritual growth  High 2.66 .647 1.88 .061  Low 2.53 .596 Stress management  High 2.38 .719 -.84 .440  Low 2.32 .673 Physical activity  High 1.94 .720 -.67 .503  Low 1.99 .635 Interpersonal relationship  High 2.41 .662 .72 .475  Low 2.36 .601 General health behaviors  High 2.32 .708 -.81 .420  Low 2.29 .635 Overall health behaviors 2.3 .672 * p < .05 (significant) Table 4 shows that there is a statistically significant relationship (p < .05) but a moderately positive correlation (r = .43) between the health literacy and health-promoting behaviors of adults at high risk for diabetes. Furthermore, a statistically significant relationship (p < .05), but a weak positive correlation (r = .13) exists between health literacy and health behaviors among adults in the low risk for diabetes group. Correspondingly, the same significant relationship (p < .05) but a weak positive correlation (r = .17) exists when adults were taken as an entire group. Table 4 Correlation between health literacy indexes and health behavior scores, grouped according to high risk, low risk, and the entire group Variables r p-value Interpretation High .43 .000* Significant moderate positive Low .13 .029* Significant weak positive Overall .17 .000* Significant weak positive * p < .05 (significant) Discussion The results practically implied that both adults at high and low risk for diabetes have difficulties finding, understanding, judging, and applying health information with the worst regards to disease prevention. Adults at high risk for diabetes have difficulty accessing information regarding medical issues and accessing the information on their risk factors for health, as they have the lowest mean scores in their capacity to find information regarding healthcare and access information regarding disease prevention. It is also important to note that adults in the high-risk group had difficulty applying health information regarding what determines the promotion of health in their physical and social environment, such as doing physical exercises. On the other hand, having a relatively higher literacy index in utilizing information in seeking care and health treatments has favorable and unfavorable consequences. A favorable example of which is when adults at low risk for diabetes can make informed decisions on medical issues; however, the challenge lies in the decision making regarding the proper time to consider a situation to be an emergency. Furthermore, the disparity between the non-uniform trends of health literacy scores in health promotion and healthcare dimensions between the two groups could be ascribed to a greater percentage of the adults, classified as low risk for diabetes, and categorized as having the lowest socio-economic status, taking more advantage of available free healthcare services compared to their high-risk counterpart. However, this is still considered as suboptimal visits to a healthcare provider, with the study results showing just a slightly higher percentage of adults visiting a medical doctor at least 1-3 times (57%) in a year compared to those who had never seen one (39.5%). The study results are consistent with the results of other research that involved populations with lower socio-economic status in local studies (Agosto et al., 2018). This is also parallel to the findings of most international studies among general adults (Choi et al., 2013; Coffman et al., 2012; Jordan & Hoebel, 2015) that revealed low, limited, problematic, or inadequate health literacy descriptions among its study population. However, the study results contrast to the results of studies that showed sufficient and acceptable health literacy (Chahardah-Cherik et al., 2018; De Castro et al., 2014; Tol et al., 2014) among adults with diagnosed diabetes. The difference in the results could be credited to the fact that the population mentioned in these studies was among adults already diagnosed with diabetes compared to the studies discussed earlier, among general adults. Furthermore, a higher prevalence of limited health literacy was reported in the population surveyed in the community compared with those who attended primary care or hospitals (Abdullah et al., 2019). In terms of health behaviors, the results of this study are the same as the results of other studies conducted on other chronic diseases (Maheri et al., 2016; Mohsenipoua et al., 2016) and adults stratified to different levels of diabetes risk (Sutherland et al., 2012), which revealed that the levels of physical activity and the levels of spiritual growth are the subscales with the lowest and highest levels, respectively. The data imply that in adults with a high risk of diabetes, the physical dimensions represented by the subscales of nutrition and physical activity were uniformly lower than those in the low-risk group. In contrast, health behavior subscales of those adults at high risk for diabetes that appeal to the psychological, spiritual, and social aspects had consistently higher scores than their low-risk counterparts. It could mean that adults in the high-risk group have relatively lower physical health behavior scores but somewhat higher psychosociospiritual health behavior scores than those in the low-risk group. A study among diabetic and non-diabetic adults in Brazil (De Oliveira et al., 2018) showed partially consistent analogous results where people with diabetes had better dietary habits than those without diabetes but still had risk behaviors such as insufficient physical activity. It is remarkable to note that if adults at high risk for diabetes are to be considered as future diabetics, while adults at low risk for diabetes remained to be non-diabetics, it could imply that health behaviors in different subscales could vary in results, but in non-uniform directions. To wit, one subscale may connote desirable health behaviors but the others like the opposite. The results of this study are similar to the results of a study among low income, low education, middle-aged Hispanics (Sutherland et al., 2012), which reported a higher mean score of health responsibility, interpersonal relationship, and stress management on those adults with a higher risk for diabetes than those adults with lower risk. In the case of health responsibility, an example to better understand this situation is that in developing countries, health decisions are often not made by individuals but are made collectively by family members. This is a cultural difference among Filipino adults, especially in a rural setting. On a particular issue, an individual, such as a husband, would decide on behalf of his wife. Overall, the level of health behaviors among adults at high risk and low risk for diabetes is just the same. This is consistent with the findings of a study among low-income Latino adults that states no significant differences between adults in different levels of diabetes risk when it comes to their level of engagement in physical activity, the extent of monitoring nutrition, and owing to one’s own health responsibility (Sutherland et al., 2012). The results of statistical testing that revealed no significant difference between the health behavior mean scores of adults at high and low risk for diabetes denote that adoption of risk reduction behavior among the entire population of adults, with special regards to the level of physical activity and nutrition, are homogeneously low. Thus, an all-adult inclusion effort is needed to improve awareness of the degree of risk for developing diabetes, increase promotion of healthy behaviors and advance the availability of evidence-based lifestyle interventions to reduce the growth in new cases of diabetes. The results of this study could not rule out the effect of the adult’s level of risk for diabetes on the level of their health behaviors. However, it could imply that the sample of the adult population seems to give priority to better their spirituality than to adopt healthy behaviors in other subscales, as evidenced by higher spiritual behaviors scores. Most studies consistently report a low level of health behaviors among adults in a low-income and rural setting. A probable explanation about the lacking influence of diabetes risk level on health behaviors could be supported by the absence of studies from low and middle-income countries that could show the association between health behaviors and reduction in diabetes risk, particularly one that employed higher hierarchical research evidence. This result is further supported by a sensitivity analysis study (Feldman et al., 2017), which revealed no single health behavior that drives the relationship between diabetes risk and health behaviors, suggesting that there could be interactive effects with other variables. One suggestive independent variable in this study is health literacy, where a significant difference between adults at high and low risks for diabetes exists. The study revealed a significant positive relationship between health literacy and health behaviors. This implies that the adult’s health literacy indexes have significantly influenced their health behaviors. Limitations on the interpretative value of correlation results were present, but with the utilization of the Health Promotion Model (Pender et al., 2011) and the Health Literacy Conceptual Model (Sørensen et al., 2013) as the theoretical basis of this study, the existing relationship between health literacy and health behavior is supported. This is consistent with the results of other researchers who worked on the population of adults with known cardiovascular diseases (Aaby et al., 2017), infectious respiratory diseases (Sun et al., 2013), and diabetes (Chahardah-Cherik et al., 2018; Kim et al., 2018; Yeh et al., 2018). The moderate magnitude of correlation could be credited to the non-uniform variation of the direction of scores in all the subscales of health-promoting behavior. A significant weakening in the correlation could be ascribed greatly to surprisingly higher spiritual behavior scores among adults, which could pull up higher a supposedly low general health behavior scores in relation to a uniformly lower health literacy index. Numerous literatures exist about the relationship between health literacy and health behaviors among healthy adults (Hansen et al., 2015; Suka et al., 2015) or even individuals with other disease risks (Sun et al., 2013; Wong et al., 2018). However, there is a conflicting study that reports no significant association between health literacy and some measures of health outcomes in a random sample of adults who were already diagnosed with diabetes (Singh & Aiken, 2017) in Western Jamaica. Furthermore, a meta-analysis report (Al Sayah et al., 2015) among 723 eligible studies about the relationship between health literacy and health outcomes also proposes that there is still insufficient or inconsistent evidence that independently associates health literacy with health outcomes adults diagnosed with diabetes. Thus, it is still premature to advance research with higher hierarchical evidence since there are still no sufficient data to suggest the independent relationship between health literacy and health outcomes. The study utilized a large sample size, implemented a random probability sampling technique, and garnered a high response and return rate. This was a good representation of the target population regarding adults in the rural setting. It was found out that even in the remote rural setting, health literacy had a significant positive relationship with health behaviors. Healthcare workers, including nurses, need to focus on increasing the health literacy of adults, especially those who are at high risk for diabetes, to facilitate the development of healthy behaviors. Moreover, the risk assessment was only limited to diabetes risk factors such as age, sex, waist circumference; family history of diabetes, high blood sugar, and high blood pressure; and measurement of waist circumference to estimate diabetes risk levels. Health literacy and health behaviors might be different in adults who have already been diagnosed with diabetes. However, the tool for assessing diabetes risk could help healthcare workers who have less training since it is practical, cost-effective, and easy to implement. The result of non-significant differences between the health behaviors of adults at high and low risk for diabetes should not be misunderstood as a failure of the study, but instead, a springboard for another research to scrutinize the characteristics of these adults that influence their health behaviors. Adults at high risk for diabetes had low health behavior scores, but their health behavior subscale scores in spiritual growth, health responsibility, and interpersonal relationships were better compared to their low-risk counterparts. Further study of the characteristics of adults at high risk for diabetes that makes them have better scores in the aforementioned subscales of health behavior is recommended. On the other hand, the significant difference between the health literacy of the two groups of adults had practical implications. The prioritization of health education among those at high risk for diabetes should be in place, as the economy of practicing health information campaigns has always been costly. However, the needs of those adults at low risk should also not be overlooked, as the health behaviors for both groups had no significant difference. Disease prevention, being the subscale with the worst health literacy index for both adults at high and low risk for diabetes, should be a major concern in implementing health promotion projects. A greater number of adults have low health behaviors in nutrition, physical activity, and health responsibility, more so a higher percentage of adults in the low-risk group. Improving the health literacy of adults regarding where to find information on proper nutrition, practical exercises, and family members’ inclusion in support of one’s health responsibility is a target objective. Limitations Caution is advised about the temporality of the results between variables. Since this a cross-sectional study, direct causality cannot be inferred. This study was only limited to diabetes risk factors such as age, sex, waist circumference; family history of diabetes, high blood sugar, and high blood pressure; and measurement of waist circumference to estimate diabetes risk levels. Health literacy and health behaviors might be different in adults who have already been diagnosed with diabetes, as well as in other settings and populations. Conclusion The classification of adults according to diabetes risks had brought light to the fact that adults in the accessible population do not only have a low level of health literacy but an alarming inadequate health literacy. This is remarkably evident in adults at high risk for diabetes, inclined to have worse health literacy compared to those adults who have a low risk for diabetes. Thus, the total inclusion of adults with low health literacy in health education could avoid the worsening effects of diabetes in the underprivileged population. The significantly positive correlation between health literacy and health behavior should be a calling for political will to push for government officials, legislators, and stakeholders to institutionalize programs that could increase health information competencies, such as making health information available in strategic health stations, taking advantage of multimedia broadcast advertisements, disseminating free health information through text messaging, and utilizing language appropriate, and “no read-no write” friendly pamphlets. Furthermore, the local government unit is suggested to capitalize on pre-existing public education infrastructures to deliver health information among the locales, as remediation for the low health literacy, as well as a starting solution for disease prevention against diabetes. Acknowledgment The author wishes to thank all the participants for participating in the study and the barangay health workers to engage in data collection. The author is grateful to Quennie R. Ridulme, MAN, RN, for her mentorship and guidance and to Ryan Michael Oducado, PhD, RN, RM, LPT, for suggesting revisions in the manuscript suitable for publication. Declaration of Conflicting Interest The author reports no actual or potential conflicts of interest. Funding The author independently funded the study. Author Biography Christian Sandor B. Ydirin, MAN, RN, CCRN is an alumnus and the first Chancellor’s lists graduate of the Master of Arts in Nursing Program of the University of the Philippines Open University, Los Banos, Philippines. Author Contribution CSY solely conceptualized the study, actively supervised data collection, was intensively involved in data analysis, and exclusively approved the final manuscript. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-043 10.33546/bnj.1297 Original Research Protective role of resilience on COVID-19 impact on the quality of life of nursing students in the Philippines https://orcid.org/0000-0002-2244-1056 Guillasper Jean Nunez 1 https://orcid.org/0000-0001-9107-3069 Oducado Ryan Michael Flores 2* https://orcid.org/0000-0002-6349-5560 Soriano Gil Platon 34 1 Nueva Ecija University of Science and Technology, College of Nursing, Cabanatuan City, Nueva Ecija, Philippines 2 West Visayas State University, College of Nursing, Iloilo City, Philippines 3 San Beda University, College of Nursing, Manila, Metro Manila, Philippines 4 Wesleyan University Philippines, Graduate School, Cabanatuan City, Nueva Ecija, Philippines Corresponding author: Dr. Ryan Michael F. Oducado, West Visayas State University, College of Nursing, La Paz, Iloilo City, Philippines, 5000. Email: rmoducado@wvsu.edu.ph Cite this article as: Guillasper, J. N., Oducado, R. M. F., & Soriano, G. P. (2021). Protective role of resilience on COVID-19 impact on the quality of life of nursing students in the Philippines. Belitung Nursing Journal, 7(1), 43-49. https://doi.org/10.33546/bnj.1297 22 2 2021 2021 7 1 4349 07 1 2021 07 2 2021 20 2 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Studies have shown that resilience has a buffering effect on mental health problems. However, the influence of resilience on the impact on the Quality of Life (QoL) in the context of the COVID-19 pandemic has not been well documented. Objective This study examined the influence of resilience on the COVID-19 impact on QoL among nursing students. Methods A cross-sectional research design was utilized. Three hundred and forty-five students of a government-funded nursing school in the Philippines responded in the web-based survey. Data were gathered using two adopted instruments from 18 to 31 August 2020. Test for differences and correlational analyses were performed. Results The COVID-19 pandemic had a moderate impact on the QoL of nursing students. The COVID-19 impact on QoL significantly varied with sex and the nearby presence of COVID-19 cases. Bivariate analysis revealed a significant moderate inverse relationship between psychological resilience and the impact of COVID-19 on QoL. Conclusion Resilience has a protective influence on the impact on QoL concerning main areas of mental health in the context of the COVID-19 pandemic. Understanding the factors and developing interventions that build the resilience of students is a focal point of action for nursing schools. COVID-19 mental health nursing quality of life resilience Philippines ==== Body pmcAs of 6 January 2021, the number of Coronavirus Disease 2019 (COVID-19) confirmed cases worldwide had reached 84,780,171, including 1,853,525 deaths (World Health Organization, 2021). In the Philippines, the number of infected with COVID-19 has reached 480,737, with 9,347 deaths (Philippine Department of Health, 2021). During these difficult times, every one of us finds ourselves in dire straits due to healthcare problems, physical and mental exhaustion, and academic burnout caused by the COVID-19. Health protocols were then implemented to take efficient actions to eradicate and slow down the spread of the disease, and with that, due to numerous cases of COVID-19 since December 2019, and taking into account the potential spread of COVID-19 in schools, respective countries were suddenly forced to shift from face-to-face classes to online classes (Guillasper et al., 2020; Moralista & Oducado, 2020; Silva, 2020). From that standpoint, the pandemic has caused students, as well as staff and faculty, to experience psychological distress because of the sudden changes in their everyday living. The COVID‐19 outbreak has significantly impacted nursing students (Usher et al., 2020), and nursing students’ stress increased during the lockdown period (Gallego-Gómez et al., 2020). Mental health problems have become critical issues during the pandemic and in the new normal era (Gunawan et al., 2020). These pandemic-related changes, particularly in regards to online classes, social distancing - since social support plays a significant role in easing risks and is known as a coping strategy, and anxiety due to health and economic concerns are likely to remain as a long-term stressor (Liu et al., 2020). On the other hand, putting the pandemic aside, several studies show that nursing students face a great number of difficulties during clinical practices to improve their professional skills (Akhu-Zaheya et al., 2015). The stress experienced by nursing students in the clinical setting is mainly affiliated to care of the patient, death of a patient, nursing diagnosis, and the negative impact given by hospital staff and clinical instructors (Bhurtun et al., 2019) and that clinical setting stressors are much perceived in comparison to academic and external stressors (Jimenez et al., 2010). On that note, with the countless problems encountered by nursing students, resilience is a key component to recuperate and recover from such distress and issues. Resilience is defined as the ability to overcome adversity and cope effectively in problems faced - which also includes how one learns to develop stronger flexibility from situations encountered (Rutter, 2008; Thomas & Revell, 2016). Since the nursing profession is stressful, this can impact students having a myriad of adverse outcomes on the quality of learning and the QoL (Goff, 2011). Thus, the ability of nursing students to bounce back or personal resilience is essential to acquire internal control, empathy, positive self-concept, organization, and optimism in their everyday challenges. Coherence with family, social environment, physical environment, wisdom, and supportive mindset can help boost one’s values, resulting in healthier outcomes, and help those traumatized with distress effectively adapt instead of rooting through their vulnerability (Mcallister & Mckinnon, 2009). Without a doubt, nursing is one of the most challenging professions there is in the world; it requires a whole lot of passion, perseverance, and heart from nurses to face another tomorrow. This leads to show how resiliency holds so much vitality in the field of nursing (Chow et al., 2018). Resilience, or the ability to recover or bounce back from stress (Smith et al., 2008), is a process of progressive success in facing adversities (Chow et al., 2018) which anyone could learn through experiences. Meanwhile, previous studies conducted before the pandemic have shown that resilience has a buffering effect or protective role on mental health problems, depression, and stress among nursing students (Mcdermott et al., 2020; Sam & Lee, 2020). However, the role of resilience on the impact on the QoL during or in the context of the COVID-19 pandemic among nursing students has not been explored or investigated. To our knowledge, this is one of the first papers that looked into the role of resilience among nursing students in the context of the COVID-19 pandemic. It was earlier proposed how resilience varies across cultures due to ecological and cultural indexes that may be found across different nations (Ungar, 2008). Moreover, despite the availability of studies that looked into the mental health of students during the pandemic, these were conducted among the general population and students in higher education (Aristovnik et al., 2020; Tee et al., 2020), but research specifically among nursing students in the Philippines is scarce. Studies conducted among nursing students, on the other hand, focused on levels of stress (Alateeq et al., 2020; Aslan & Pekince, 2020) and fear (Oducado, Tuppal, et al., 2021) and not particularly on the COVID-19 impact on QoL concerning mental health. Hence, the study was conducted to determine the influence of resilience on the impact of COVID-19 on the QoL concerning mental health among nursing students. In addition, since prior studies have shown that stress, fear, and other negative emotional responses related to the COVID-19 pandemic varied according to some personal characteristics (Alateeq et al., 2020; Aristovnik et al., 2020; Aslan & Pekince, 2020), it may also be necessary to examine whether COVID-19 impact among nursing students significantly differ according to demographic characteristics, the existence of a local case of COVID-19 near their residence, and the presence of any medical condition that might increase their risk for severe illness from COVID-19. Methods Study Design A cross-sectional research design was employed in this study. Participants Three hundred and forty-five (n=345) responded in the online survey. A response rate of 59.38% (345/581) was obtained in this study. This study was conducted in one government-funded nursing school in the Central Luzon part of the Philippines. Instruments The Brief Resilience Scale (BRS) and COVID-19 Impact on Quality of Life (COV19-QoL) were adopted for this study. Permission to use the scales was granted by tool developers. The BRS by Smith et al. (2008) was utilized to measure nursing students’ ability to recover or bounce back from stress. Participants answered on a five-point Likert scale (1 – “strongly disagree” to 5 – “strongly agree”). The BRS had a reported Cronbach’s α = .80-.91 (Smith et al., 2008). The COV19-QoL by Repišti et al. (2020) was used to assess the impact of the pandemic on the QoL in relation to mental health for the last seven days. Participants responded on a five-point Likert scale (1 – “totally disagree” to 5 – “completely agree”). The COV19-QoL had a reported Cronbach’s α = .90 among Filipino samples (Rabacal et al., 2020). The following scale of means was used to interpret that data: low = 1.00-2.33; moderate = 2.34-3.66; and high = 3.67-5.00. The survey was administered in the English language. Demographic information (sex, year level, place of residence, estimated monthly family income) were also collected. The participants were also asked about the presence of a local case of COVID-19 near their residence and if they have any medical condition that might increase their risk for severe illness from COVID-19. Data Collection The web-based survey was administered for two weeks or fourteen days from 18 to 31 August 2020. The online survey was the only practicable means of gathering data during the COVID-19 outbreak. The link to the online survey via Google forms was sent to the email address and Facebook groups of the students. Students were also encouraged to share the link of the survey with their classmates. Ethical Considerations This study was approved by the San Beda University-Research Ethics Board (SBU-REB) with Protocol Number 2020-041. Administrative clearance was also granted to conduct the research. Full disclosure about the study was given at the start of the survey. Students were reminded that they have the freedom to participate in the study, which will not affect their grades. They were also informed that proceeding and completing the survey implies consent to participate in the study voluntarily. Identifiable information was coded to maintain anonymity and confidentiality. Data were stored in password-protected computers for access and retrieval. There were no missing data in our study since all questions were made mandatory before completing the survey. Data Analysis Statistical data analysis was carried out via the IBM SPSS version 23. Descriptive statistics for continuous variables were expressed as mean (M), standard deviation (SD), while categorical variables were expressed as frequency (f) and percentage (%). The Kolmogorov-Smirnov and Shapiro Wilk tests suggested that data do not significantly deviate from the normal distribution. The t-test for the Independent Samples and one-way ANOVA with Scheffe post hoc test were used to test for differences, while the Pearson’s product-moment correlation coefficient was utilized to correlate selected variables. A p-value less than .05 was considered significant. Results Presented in Table 1 are the demographics and descriptive data of the independent variables of the study. The mean age of participants was 19.92 (SD = 1.26). The majority were females (80.6%), in second-year level (47.8%), living in rural areas of the province (56.8%), reported the presence of a COVID-19 case near their residence (44.9%), and had no medical condition that might increase the risk for severe COVID-19 illness (89.6%). Most students had an estimated monthly family income of less than 400 USD: 200 USD to less than 400 USD (35.1%) and less than 200 USD (33%). The composite score in the BRS was 3.04 (SD = .51). Table 1 Demographics and descriptive data of independent variables (N = 345) Variables M SD n % Sex  Male 67 19.4  Female 278 80.6 Year level  Third & Fourth 50 14.5  Second 165 47.8  First 130 37.7 Place of residence  Urban/City 149 43.2  Rural/Town 196 56.8 Estimated monthly family income  PHP 20,000 and above (400 USD and above) 110 31.9  PHP 10,000 to 19,999 (200 to < 400 USD) 121 35.1  PHP below 10,000 (< 200 USD) 114 33.0 Presence of COVID-19 case near their residence  Yes 155 44.9  No 99 28.7  Unsure 91 26.4 Presence of a medical condition  Yes 36 10.4  No 309 89.6 Age (years) 19.92 1.26 Resilience 3.04 .51 Note: 1 USD = 50 PHP Table 2 shows that the composite score in the COV19-QoL was 3.35 (SD = .80). The COVID-19 pandemic had the highest impact on nursing students’ personal safety (M = 3.91; SD = 1.04) and had the lowest impact on nursing students’ feeling of depression (M = 2.99; SD = 1.30). Table 2 COVID-19 impact on QoL Items on COV19-QoL M SD I feel that my personal safety is at risk 3.91 1.04 I feel more tense than before 3.61 1.05 I think my quality of life is lower than before 3.39 1.00 I think my mental health has deteriorated 3.13 1.18 I think my physical health may deteriorate 3.05 1.06 I feel more depressed than before 2.99 1.30 Composite score 3.35 .80 It is shown in Table 3 that there were significant differences in the COVID-19 impact on QoL of nursing according to sex (t = -2.713; p = .008) and the presence of a COVID-19 case near their residence (F = 5.622; p = .004). The bivariate analysis also revealed a significant moderate inverse relationship (r = -.363; p = .000) between psychological resilience and the impact of COVID-19 on QoL concerning main areas of mental health. Table 3 Differences in and correlation with COVID-19 impact on QoL Variables M SD t statistics p-value Sex† -2.713* .008  Male 3.10 .856  Female 3.41 .764 Year level‡ .054 .605  Third & Fourth 3.30 .736  Second 3.39 .784  First 3.31 .822 Place of residence† .464 .643  Urban/City 3.37 .814  Rural/Town 3.33 .774 Estimated monthly family income‡ .917 .401  PHP 20,000 and above (400 USD and above) 3.27 .870  PHP 10,000 to 19,999 (200 to < 400 USD) 3.41 .758  PHP below 10,000 (< 200 USD) 3.35 .743 Presence of COVID-19 case near their residence‡ 5.622* .004  Yes 3.44 .788  No 3.12 .783  Unsure 3.42 .763 Presence of medical condition† .452 .653  Yes 3.39 .095  No 3.34 .046 Age§ -.060 .263 Resilience§ -.363* .000 † t-test for the independent group ‡ ANOVA with Scheffe post hoc test § Pearson’s r * p < .05 Discussion This study looked into the association of resilience on the COVID-19 impact on the QoL of nursing students. This study indicated that resilience was inversely or negatively related to the impact of COVID-19 on QoL among nursing students. The result suggests that the higher the resilience, the lesser is the impact of COVID-19 on the QoL of nursing students. This finding is consistent with other studies disclosing the inverse or negative association between resilience with patterns of COVID-19 stress, fear, anxiety, and depression (Barzilay et al., 2020; Ferreira et al., 2020; Oducado, Parreño-Lachica, et al., 2021; Zhang et al., 2020). The finding of the study further indicates that resilience has a protective role or buffering effect on the negative impact of the COVID-19 pandemic. Nursing schools may need to craft interventions that build the resilience of nursing students. Because resilience can be seen as a dynamic adaptation process (Chmitorz et al., 2018), students can be potentially trained to harness their resilient traits. A resilience-training program (Helmreich et al., 2017; Joyce et al., 2018) may be conducted to improve students’ ability to respond to stressful events and other negative psychological and emotional distress like during the COVID-19 pandemic. Moreover, we also found that the COVID-19 impacted the QoL of nursing students to a moderate extent. Similarly, a moderate level of stress was noted among nursing students in Turkey during the COVID-19 pandemic (Aslan & Pekince, 2020), and students in the Philippines reported moderate to severe psychological impact of the COVID-19 pandemic (Tee et al., 2020). Meanwhile, the mean composite score in the COV19-QoL scale was 3.04 in this study was slightly higher compared to the QoL of people with no mental health-related diagnoses in Croatia (M = 2.91) (Repišti et al., 2020) and Filipino teachers in the Philippines (M = 2.75) (Rabacal et al., 2020). Nevertheless, the finding of this study proposes that the COVID-19 pandemic has undoubtedly affected the lives of nursing students. This necessitates the development of preventive strategies to address the impact of COVID-19 on the QoL of nursing students. This study also demonstrated that the impact of the COVID-19 on QoL was significantly higher among female nursing students. Consistent with the literature, females had higher stress levels than their male counterparts in a sample of nursing students in Turkey (Aslan & Pekince, 2020), students in Saudi Arabia (Alateeq et al., 2020), residents in Australia (Rahman et al., 2020) and teachers and students in the Philippines (Oducado, Rabacal, et al., 2021; Tee et al., 2020). Even the result of a global survey in higher education also noted that females are more affected by the pandemic in their personal and emotional lives (Aristovnik et al., 2020). Along with hormonal changes and their thoughts about their social situation, women tend to be more emotional; thus, they may perceive a more significant impact of stressful life events like the COVID-19 pandemic (Alateeq et al., 2020; Aristovnik et al., 2020; Aslan & Pekince, 2020). In this study, the impact of COVID-19 on QoL was significantly higher among nursing students who were unsure or who knew of a nearby presence of a COVID-19 case near their residence. It is also noteworthy that nursing students posted the greatest impact of COVID-19 on their personal safety in our study. Similarly, studies noted that higher levels of anxiety, anger, and fear were associated with closer spatial distance from active COVID-19 cases (Huang et al., 2020; Oducado, Tuppal, et al., 2021). Perhaps, students may perceive that the presence of COVID-19 case near their residence may increase their risk of getting infected by the coronavirus thus may have reported a greater impact on their QoL. Personal experience with coronavirus was a significant predictor of risk perception (Dryhurst et al., 2020); at the same time, perceived risk was significantly related to COVID-19 stress (Oducado, Rabacal, et al., 2021). Correspondingly, providing care to known or suspected cases and direct contact with a confirmed case of COVID-19 were associated with a higher level of fear (Rahman et al., 2020) and depression (Tee et al., 2020). This study is not without shortcomings that could be addressed in future research. This study only involved nursing students in one school in the Philippines. The findings of this study cannot be generalized to all nursing students locally and internationally. The research design (cross-sectional) cannot conclude the causal effect among the study variables; likewise, it cannot track temporal changes over time. Hence, our study only examined the correlation and not the causal effect between resilience and COVID-19 impact. Also, the use of online survey questionnaires lends itself to social desirability and self-reported bias. Nonetheless, the present study contributes to a better understanding of the impact of the COVID-19 pandemic among nursing students. Conclusion The COVID-19 outbreak has eventually affected the QoL of nursing students. It is casting concern not only on their physical health and safety but also on their psychological health and mental well-being related to QoL. Additionally, female nursing students and those in nearby presence of COVID-19 case or unsure of a COVID-19 case near their residence are more vulnerable to the impact of COVID-19 on their QoL. Failure to recognize the negative effect of the COVID-19 pandemic and other major life events on the QoL of nursing students may result in detrimental consequences. Furthermore, our study concludes by highlighting the protective and cushioning role of psychological resilience on the QoL in the context of the COVID-19 pandemic. Resilience is a vital psychological factor and personal resource that makes nursing students less susceptible to the negative impact of the COVID-19 outbreak and helps reduce the adverse impact of the pandemic on the QoL of nursing students. Understanding the factors and developing strategies that build the resilience of students is a focal point of action for nursing schools. Acknowledgment We would like to thank all the nursing students who willingly participated in the study. Declaration of Conflicting Interest The authors have no conflict of interest to declare. Funding This research did not receive any specific grant from funding agencies. Author Contribution All authors have made a substantial contribution from conception to the finalization of this study. JNG was in charge of the acquisition of data and revising the article for important intellectual content. RMFO was involved in the conception and design of the study, analysis, and interpretation of data, and drafting the article. GPS was part of the conception and design of the study and revising the article for important intellectual content. All authors approved the final version of the article. Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Author Biographies Jean Nunez Guillasper, PhD, RN is the Dean and a Professor at Nueva Ecija University of Science and Technology, College of Nursing, Cabanatuan City, Nueva Ecija, Philippines. Ryan Michael Flores Oducado, PhD, RN, RM, LPT is an Assistant Professor at West Visayas State University, College of Nursing, Iloilo City, Philippines. 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==== Front Belitung Nurs J Belitung Nurs J BNJ Belitung Nursing Journal 2528-181X 2477-4073 Belitung Raya Foundation BNJ-7-1-015 10.33546/bnj.1234 Original Research Factors influencing readmission among Thais with myocardial infarction https://orcid.org/0000-0003-3076-9921 Polsook Rapin * https://orcid.org/0000-0001-9205-1814 Aungsuroch Yupin Faculty of Nursing, Chulalongkorn University, Bangkok, Thailand Corresponding author: Assist. Prof. Rapin Polsook, PhD, RN, Faculty of Nursing, Chulalongkorn University, Boromarajonani Srisatapat Building, Rama1 Rd, Floor 11 Patumwan, Bangkok 10330, Thailand. Telephone: 66-22181151, Cell phone: 66-8183-2109-5. Email: rapin.p@chula.ac.th; nitinggel@yahoo.com Cite this article as: Polsook, R., & Aungsuroch, Y. (2021). Factors influencing readmission among Thais with myocardial infarction. Belitung Nursing Journal, 7(1), 15-23. https://doi.org/10.33546/bnj.1234 22 2 2021 2021 7 1 1523 27 10 2020 11 11 2020 07 1 2021 © The Author(s) 2021 2021 https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which allows others to remix, tweak, and build upon the work non-commercially as long as the original work is properly cited. The new creations are not necessarily licensed under the identical terms. Background Readmission among patients with myocardial infarction is costly, and it has become a marker of quality of care. Therefore, factors related to readmission warrant examination. Objective This study aimed at examining factors influencing readmission in Thai with myocardial infarction. Methods This was a cross-sectional study with 200 participants randomly selected from five regional hospitals in Thailand. All research tools used indicated acceptable validity and reliability. Linear Structural Relationship version 8.72 was used for the data analysis. Results The findings showed that the hypothesized model with social support, depression, symptom severity, comorbidity, and quality of life could explain 4% (R2 = 0.04) of the variance in readmission (χ2 = 1.39, df = 2, p < 0.50, χ2/df = 0.69, GIF = 1.00, RMSEA = 0.00, SRMR = 0.01, and AGFI = 0.98). Symptom severity was the most influential factor that had a positive and direct effect on the readmission rate (0.06, p < 0.05). Conclusion These findings serve as an input to decrease readmission in patients with myocardial infarction by reducing the symptom severity and comorbidity and promoting a better quality of life. myocardial infarction readmission Thailand nursing Faculty of Nursing Chulalongkorn University Bangkok Thailand ==== Body pmcReadmission among myocardial infarction (MI) patients (MIPs) has become the principal marker of the quality of care (Dunlay et al., 2012; Kwok et al., 2018). Despite improvements in acute care and survival after hospitalization, readmission remains an important contributor to health care costs (O'brien et al., 2017; Southern et al., 2014). A previous study found that 62% of MIPs are readmitted within one year (Southern et al., 2014). There are several reasons for readmission, such as poor adherence to advice for health (i.e., adhere to medicine, nutrition, and restricted fluids), emotional or mental factors (i.e., mood status, substance abuse, and impairs the cognitive function), environment, insufficient discharge program, and other health problems (Annema et al., 2009; Jenghua & Jedsadayanmata, 2011; Ryan et al., 2014). Thus, readmission remains a significant health problem, a frequent, high cost of care, and a life-threatening event, as well as it is related to the quality of care (Hasan et al., 2010; Jencks et al., 2009). In Thailand, MI is a leading cause of death, from 2014 to 2018 (Charupronprasit et al., 2017). However, there is very little information on readmission among MIPs. Although a previous study found that the rate of readmission of MIPs was 14.07%, caused by chest pain and chronic kidney failure (Jenghua & Jedsadayanmata, 2011), it is impossible to draw a reliable conclusion from this finding. In addition, an abundance of research documents on readmission have been conducted in the United States (USA), where factors related to readmission have been reported, but may not entirely apply to Thailand (Coffey et al., 2012; Hasan et al., 2010; Polsook et al., 2013, 2016). Numerous interventions have successfully reduced readmission rates among MIPs, such as discharge programs, advising and counseling programs, and medication regimen programs (Annema et al., 2009; Jenghua & Jedsadayanmata, 2011; Ryan et al., 2014). However, the percentage of readmission in MIPs is continue to rise. In Thailand, little investigation has been carried out on the factors related to readmission among MIPs. Since characteristics of Thai’s culture are incompatible with the USA, it is logical to suspect that findings of research in the USA may partially differ from the situation in Thailand because of the different cultural characteristics, such as income and education, which were reported to be connected to readmission (Annema et al., 2009; Coffey et al., 2012; Hasan et al., 2010; Jencks et al., 2009). As the biggest health care professionals’ group, nurses contribute in a positive and negative way to the problem of health care quality. Nurses have an intimate understanding of patient needs and important roles in caring for patients and family, and uniquely position them to positively affect their hospital experiences and subsequent outcomes (Duffy, 2009, p. 6). The quality of care is a model designed to support the understanding of the connection between quality health care and caring (Duffy, 2009, p. 35). This model is composed of three elements of a quality caring model (Duffy, 2009). The structure is the first element, which consists of the resources of the institution, provider credentials, and characteristics of the patient. This paper focused on the characteristic of the patients because we were required to emphasize the independent variables associated with the patients. The process is the second element, which refers to the actions done for the patient, including both the practical and relational aspects of care. The outcomes are the third element, which refers to the consequences of the health care process (Duffy, 2009; Polsook & Aungsuroch, 2020). This study focuses on the characters of MIPs, because we aimed to maneuver the variables associated with the patients beforehand, emerging a procedure to enhance the result of care (Polsook & Aungsuroch, 2020). The pursuing variables linked to readmission in MIPs have been recorded. These factors are social support, depression, comorbidities, symptom severity, and quality of life (QOL) (Annema et al., 2009; Polsook & Aungsuroch, 2020). The connection amongst variables can be illustrated as follow: (1) social support is a significant predictor of QOL and high level of social support relevant to the high quality of life resulting in decreased readmission in MI (Bennett et al., 2001; Volz et al., 2011); (2) depression is negatively associated to QOL and linked to readmission (Faller et al., 2010; Heo et al., 2009); (3) symptom severity has a strong association with QOL, with higher severity of symptoms related low QOL and frequency readmission (Faller et al., 2010; Giamouzis et al., 2011); (4) comorbidity is a significant predictor of readmission and comorbidity is a disease and overload connected with rising readmission (Benbassat & Taragin, 2000; Hasan et al., 2010; Kansagara et al., 2011); and (5) patients who have experiences with physical and emotional symptoms result in reduced QOL, which is connected to the higher incidence of readmission (O'loughlin et al., 2010; Sethares & Elliott, 2004). Given the linkage of the variables on readmission, this study aimed to test a model to explain how those potential factors influenced readmission in Thai MIPs. Methods Study Design This research employed a descriptive cross-sectional design. Sample and Setting The population in this research was Thais with myocardial infarction. A total of 200 MIPs were recruited from excellence center hospitals across Thailand. The sample size was derived from Hair et al. (2010), which at least 200 samples recommended for a complex model with more constructs. Additionally, the adequate sample size for path analysis is ten times for each parameter. This research had 13 parameters; thus, a sample size of 130-260 was the requirement to match the complexity to the path model. A modified multi-stage sampling method was used to select the samples from hospitals based in the Northern, Southern, Central, and Northeastern regions of Thailand. The inclusion criteria were: (i) recently readmitted in an inpatient cardiology department in one of five selected hospitals in Thailand, (ii) aged ≥ 20 years, and (iii) having no cognitive impairment or disease complications based on their current medical record. If the participants had any exacerbations of the disease, such as shock, acute pulmonary edema, acute shortness of breath, and acute chest pain, during collecting data were excluded. Instruments The questionnaire on sociodemographic characteristics was designed to gather sociodemographic data, including gender, age, marital status, type of health care coverage, readmission, comorbidity, and symptom severity (Polsook & Aungsuroch, 2020). Readmission refers to the number of MIPs repeatedly hospitalized within 12 months of discharge from the index hospitalization collected from their medical records (Polsook & Aungsuroch, 2020). Comorbidity refers to the presence of additional conditions co-occurring with MIPs and was collected from the medical record (Polsook & Aungsuroch, 2020). The severity of symptoms was used in the Canadian Cardiac Society (CCS) classification to categorize angina pectoris, including Class I – angina pectoris during intensive or long-term physical activity, Class II – angina pectoris with moderate exertion, Class III – undergoing angina with mild exertion, and Class IV – undergoing angina at rest (Polsook & Aungsuroch, 2020; Sangareddi et al., 2004). Multidimensional Scale of Perceived Social Support (MESSI) (Zimet et al., 1988) was used to measure social support. This scale was translated into a Thai version by Wongpakaran and Wongpakaran (2012). The scale consists of 12 items to evaluate perceived social support from friends, family, and significant others. A seven-point (1–7) Likert scale was used, ranging from 1 to 7, with a total score for 12 items of 12–84. A higher rating is an indication of a higher level of social support. Cronbach’s alpha coefficient was 0.89 (Phromsornt et al., 2019; Polsook & Aungsuroch, 2020). Cardiac Depression Scale (CDS) was used to measure depression. The scale consists of 26 items to measure sleep, uncertainty, mood, hopelessness, inactivity, anhedonia, and cognition (Hare & Davis, 1996; Oldridge, 1997). This scale was translated into a Thai version by Polsook and Aungsuroch (2019). The CDS uses a 7-point scale from 1 to 7, with a score excess of 100 is delineated as strong depression (Kiropoulos et al., 2012). Cronbach’s alpha coefficient of the Thai version was 0.82 (Polsook & Aungsuroch, 2019). Quality of life Index-Cardiac version IV Thai version (QLI-cardiac IV) was translated into a Thai version by Saengsiri and Hacker (2015): The QLI-cardiac IV was developed to assess the QOL regarding the life’s satisfaction of cardiovascular patients. This instrument includes about 70 items to measure the satisfaction of patients with several aspects of life (35 items) and assessed the importance of those same aspects (35 items). The scale used on a 5-point scale ranging from 0 to 5 and a final rating scale ranging from 0 to 30. A rating between 21 and 30 is described as a high QOL. Cronbach’s alpha coefficient of the Thai version was 0.91 (Polsook & Aungsuroch, 2019; Saengsiri & Hacker, 2015). Data Collection Data collection was carried out after the approval of each hospital's Institutional Review Board (IRB) was obtained. The researcher illuminated and clarified the study objectives, data collection procedures, expected outcomes, and the study’s benefits to the physicians and nurses of each cardiology inpatient department in the chosen hospitals. One nurse with experience in taking care of cardiovascular patients was assigned as a research assistant. The researcher trained and evaluated the research assistants in regards to the questionnaire administration, informed consent procedures, and the participant information sheet. Research assistants were also trained to interview the participants by reading the questionnaires word by word. Participants who met the inclusion criteria were then invited to participate in this study. They were informed of the study objective, data collection process, and their rights to decide to participate or refuse to participate in the study. Those participants who still agreed to participate in this study were asked to sign an informed consent form. The researcher explained that there was no harm to the participants in this study and that it would take 30–45 min to complete all the questionnaires. During data collection, participants were able to refuse or leave the study at any time without any consequence (Polsook & Aungsuroch, 2020). Data Analysis The Statistical Package for Social Science (SPSS) program version 22 was used for data analysis, particularly in descriptive statistics. Linear Structural Relationship (LISREL) version 8.72 was used for path analysis, accepting significance at the p < 0.05 level. The statistical criteria by Hair et al. (2010) were used to evaluate the overall model-fit-index and the hypothesis according to the four criteria outlined as follows. Firstly, the χ2 test was used to evaluate the appropriateness of the hypothesized model. The model was considered a good fit if the χ2 value was not significant (p > 0.05) and if χ2 /df was less than 2. Secondly, the Root Mean Square Error of Approximation (RMSEA) and Standardized Root Mean Square Residual (SRMR) were used to measure the overall model fit. RMSEA value of less than 0.05 was considered a good fit model, while a value between 0.05–0.08 was considered an adequate fit model. In addition, the SRMR value should be less than 0.05 for a good fit model. Thirdly, a goodness-of-fit (GFI) ≥ 0.95 and adjusted GFI (AGFI) ≥ 0.90, were also used for examining the goodness-of-fit statistics. Finally, if the hypothesized model fit the data, the path coefficients and R2 were then estimated, and the effects of the independent variables on the dependent variable were determined. The goodness-fit-indices were used to determine whether the model adequately fitted the data (Hair et al., 2010) Ethical Consideration This study was approved by the IRBs of the excellence center care hospitals from all regions of Thailand. Those IRBs included the IRB of Hatyai hospital (Approval Number 85), the IRB on Human Right Related to Research Involving Human Subjects of the Faculty of Medicine Ramathibodi Hospital Mahidol University (Approval Number 2558/716), IRB of the Faculty of Medicine Chiang Mai University (Approval Number 2558-03518), IRB of the Faculty of Medicine Chulalongkorn University (Approval Number 074/59), and IRB of Khon Kaen University (Approval Number 00001189) (Polsook & Aungsuroch, 2020). Results Characteristics of Participants Most of the participants were aged ≥ 61 years (62.5%), predominantly male (63%), and married (78.5%). Just over half of the participants (54.5%) utilized the Universal Coverage Scheme (the 30-Baht Scheme) of Thailand. The highest proportion of participants with an education level was primary school (52.0 %), followed by high school (24.5%), and higher education (19.5%). According to the classification of symptom severity by the CCSV (Sangareddi et al., 2004), 28.5% of the participants were in class 1, 33% in class II, 19.5% in class III, and 19% in class IV. The majority of participants had one (40.5%) or no (24.5%) comorbidity. In addition, most of them (88%) were readmitted only 1 or 2 times within 12 months after the initial hospital discharge is shown in Table 1. Details about each variable's characteristics are presented in Table 2. Table 1 Demographic and clinical characteristics of the myocardial infarction patients (N=200) Characteristics Number (n) Percent (%) Age  20–40 10 5  41–60 65 32.5  ≥ 61 125 62.5 Gender  Male 126 63  Female 74 37 Marital status  Single 10 5  Married 157 78.5  Widowed 28 14  Divorced 5 2.5 Education level  Non-education 8 4  Primary school 104 52  High school 49 24.5  Higher education 39 19.5 Type of health care coverage  Universal Coverage Scheme (30-Baht Scheme) 109 54.5  Social security 12 6  Pay by themselves 5 2.5  Government coverage 74 37 Canadian Cardiovascular Society Classification  Class 1 57 28.5  Class 2 66 33  Class 3 39 19.5  Class 4 38 19 Comorbidities  No comorbidity 49 24.5  One comorbidity 81 40.5  Two comorbidities 37 18.5  Three comorbidities 33 16.5 Readmission (within 12 months of discharge from hospital)  1–2 times 176 88  3–4 times 20 10  5–6 times 2 1  7–8 times 0 0  9–10 times 2 1 Table 2 Characteristics of study variables Variable Mean Standard deviation Interpretation Readmission 1.16 0.53 1–2 times Social support 64.03 13.66 High Depression 86.34 26.27 Not depressed Quality of life 24.66 2.94 High Comorbidity 2.27 1.01 One comorbidity Symptom severity 2.30 1.08 Class II Relationships Between Variables The relationships among the social support, depression, symptom severity, comorbidity, QOL, and readmission were examined using the Bivariate Pearson’s correlations (Table 3), with the extent of the relationships defined by the following criteria: r > 0.50 = strong / high relationship, 0.30 ≥ r ≤ 0.50 = moderate relationship, and r < 0.30 = weak/low relationship (Burns & Grove, 2005). The social support had a low negative correlation with readmission (r = -0.06, p < 0.05), depression and symptom severity had a low positive correlation with readmission (r = 0.11, and r = 0.10, p < 0.05), and no correlation was found between readmission and comorbidity and QOL (r = 0.00 and r = 0.00, p < 0.05). Depression, symptom severity, and comorbidity all had a low negative relationship with the social support (r = -0.16, -0.04, and -0.05, respectively; p < 0.05). The QOL had a low positive relationship with social support (r = 0.25, p < 0.05) and a moderate negative correlation with depression (r = -0.39, p < 0.05), a low negative correlation with comorbidity (r = -0.15, p < 0.05) and symptom severity (r = -0.18, p < 0.05). The symptom severity had moderate positive correlation with depression (r = 0.36, p < 0.05), while comorbidity had a weak positive correlation with depression (r = 0.13, p < 0.05) and symptom severity (r = 0.20, p < 0.05). Table 3 Pearson’s relationships among readmission, social support, depression, symptom severity, comorbidity, and the QOL Readmission Social support Depression Symptom severity Comorbidity QOL Readmission 1.000 Social support -0.06 1.000 Depression 0.11 -0.16* 1.000 Symptom severity 0.10 -0.04 0.36** 1.000 Comorbidity 0.00 -0.05 0.13 0.20** 1.000 QOL 0.00 0.25** -0.39** -0.18* -0.15* 1.000 * p < 0.05 ** p < 0.01 QOL=Quality of life Model Testing The results from the hypothetical pattern matched the empirical evidence and could explain 4% (R2 = 0.04) of the variance in readmission by social support, depression, symptom severity, comorbidity and QOL (χ2 = 1.39, df = 2, p = 0.50, χ2/df = 0.69, GIF = 1.00, RMSEA = 0.00, SRMR = 0.01, and AGFI = 0.98). Twenty-eight percent (R2 = 0.28) of the variance in the QOL was explained by the social support, comorbidity, symptom severity, and depression; 3% (R2 =0.03) of the variance in depression was explained by social support, comorbidity, and symptom severity; and 4% (R2 =0.04) of the variance in symptom severity was explained by comorbidity (Table 4). Table 4 The proportion of the variance in the dependent variable that is predictable from the independent variables Variables Influencing variables R2 Readmission Social support Comorbidity Symptom severity 0.04 Depression Quality of life Quality of life Social support Comorbidity 0.28 Symptom severity Depression Depression Social support Comorbidity 0.03 Symptom severity Symptom severity Comorbidity 0.04 R2 = The coefficient of determination The results of the final model testing as shown in Figure 1 are summarized in accordance with the hypothesized model as follows. The QOL had a direct positive impact (0.02) on readmission, while social support and depression did not directly affect readmission (0.00, 0.00). Besides, symptom severity had a direct positive impact (0.06) on readmission, contrasting with comorbidity that had a direct negative impact (-0.02) on readmission. Social support had a positive direct effect (0.06) on QOL and a negative effect (-0.01) through QOL on readmission. Comorbidity had a direct negative impact (-0.40) on QOL and a negative effect (-0.27) through QOL on readmission. Symptom severity had a negative effect (-0.47) on QOL and had a negative effect (-0.01) through QOL on readmission. Depression had a negative effect (-0.05) on QOL, while social support had a positive effect (0.22) on depression. Besides, comorbidity had a positive effect (3.64) on depression. It also had a positive effect (0.22) on symptom severity and a negative effect (-0.66) on social support. Figure 1 Final model of readmission among myocardial infarction Discussion This study revealed that social support did not affect the readmission of MIPs. Most of the participants were elderly, and their social support was at a moderate level. Because Thailand had an extended family, most participants live with their families, where there is a possibility that family members may have been involved in the patient's care and support (Polsook et al., 2013, 2016). This finding was supported by Leifheit-Limson et al. (2012), who reported that a high social support level was associated with lower hospital readmission of MIPs. Similarly, Mcneely et al. (2016) found that high social support in MIPs who received the percutaneous coronary intervention was associated with a lower rehospitalization rate. Additionally, we found that social support had a direct positive impact on depression, where most of the MIPs in this study had a high social support level living with their extended family and were not depressed. Leifheit-Limson et al. (2012) found that a low social support level was related to more depressive symptoms among MIPs, and a high social support level resulted in a low level of depression. It is supported by Compare et al. (2013) and Liu et al. (2017) reported that an elevated level of social support lowered depressive symptoms among heart patients. This study also found that social support had a positive impact on the QOL and a negative indirect impact on readmission through the QOL. Since most participants had an elevated QOL and social support level, they were only readmitted one or two times within the 12 months after initial hospital discharge. This result supported previous studies in that social support had a positive impact on the QOL among MIPs (Kang et al., 2018). In addition, the QOL, an outcome measurement after acute MI, was lower in the early recovery period when there was an inadequate social support level (Leifheit-Limson et al., 2012). Likewise, a high social support level in MIPs was linked to a high QOL and reduced readmission (Martínez-García et al., 2018). In this study, depression was not an effect on readmission, a negative indirect effect on readmission through the QOL, and a negative direct impact on the QOL. This reflected that most of the MIPs were not depressive, having a high QOL and low readmission rate of only one–two times within the 12 months after initial hospital discharge. In agreement, a high level of depression was reported to be related to hospital readmission and a decreased QOL (Kang et al., 2018), while depression was also associated with readmission in acute coronary syndrome (Edmondson et al., 2014). The symptom severity was found to have a negative direct impact on the QOL and a positive direct effect on readmission. As already pointed out, most of the MIPs in this study had a high QOL and symptom severity of only class I (28.5 %) or class II (33%) of the CCSC, which their low symptom severity resulted in a high QOL and reduced readmission rate. This result supported previous studies that low symptom severity was linked to delayed readmission (Kwok et al., 2018) and an increased QOL (Kang et al., 2018) among acute MIPs. Likewise, the symptom severity, such as physical symptoms and limitations in daily activities due to heart failure, affected the QOL (Heo et al., 2009). Low symptom severity was linked to a higher QOL (Adebayo et al., 2017). In our study, nearly half of the participants had one comorbidity. About one-third had no comorbidity, no depression, a high QOL, and a low readmission rate (one or two times within 12 months after hospital discharge). Thus, the participants’ low comorbidity was related to their low level of depression, which resulted in a high QOL and a low readmission rate. In agreement, MIPs who received a percutaneous coronary intervention had a high rate of readmission if they had comorbidity (Kwok et al., 2018; Southern et al., 2014), while the presence of more comorbidities had a higher risk of hospital readmission (Andrés et al., 2012; Kwok et al., 2017), as well as high symptom severity and readmission risk (Desta et al., 2017; Fanari et al., 2017; Mcneely et al., 2016). In addition, MIPs who had comorbidity were associated with depression and linked to readmission (Mcgowan et al., 2004). The results also revealed that lower comorbidity led to lower symptom severity and high QOL. These results are also in line with a previous study (Bahall & Khan, 2018), while a low symptom severity, such as shortness of breath and chest pain, related to a high QOL in heart failure patients (Lawson et al., 2018; Nuraeni et al., 2019). Besides, QOL has been shown to directly impact the readmission rate, which a high QOL was associated with a low rate of readmission. Previous studies found that a poor QOL led to a higher rehospitalization rate and was associated with readmission (Adebayo et al., 2017; Tully et al., 2016). This study has several limitations. The self-reporting used in this study might cause overvalued or undervalued data, which could be a limitation. The instruments to measure the potential variables were only used once in the context of Thailand. Thus, assessing validity and reliability within Thailand's context is required to confirm the instruments' reliability. Based on the findings of this study, a longitudinal study should be done to measure and adjust these variables with readmission in MIPs to provide a further causal explanation of readmission in MIPs and its predictors. However, our findings can contribute to knowledge development for strengthening nursing science for caring MIPs. The results provide knowledge that offers directions for the development of interventions to decrease readmission in MIPs. It should promote social support to enhance the QOL and develop strategies to control the severity of symptoms to mitigate readmission in MIPs. Conclusion Based on these findings, the severity of the symptoms and QOL of MIPs were correlated to readmission. Nurses should develop strategies to control or decrease symptom severity and develop an intervention protocol to reduce readmission in MIPs. This should integrate the promotion of social support to enhance the QOL to decrease readmission and increase care quality for MIPs. Acknowledgments The authors acknowledge the participants for their time and effort they invested in this study. Declaration of Conflicting Interest There are no potential conflicts of interest to declare. Funding This study was funded by the Ratchadaphiseksomphot Endowment Fund, Chulalongkorn University, Bangkok, Thailand (CU-GR_60_38_36_03). Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Author Contribution All authors contributed to the final manuscript. R.P. designed the study, collected data, analyzed the data, wrote and revised the manuscript. Y.A. designed the study, wrote and revised the manuscript. Author Biographies Rapin Polsook, PhD, RN is an Assistant Professor at the Faculty of Nursing, Chulalongkorn University. She has published articles related to cardiovascular disease. She is a reviewer and member of the editorial team of the nursing journals. 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