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Author contributions | A.-H.H. and W.-H.C. were the main authors of this manuscript and participated in all the study design. W.T.-J.W. participated in data interpretation and contributed to important intellectual content. Y.-F.S. and W.-Y.C. were responsible for designing the study, monitoring the study execution, and drafting and revising the manuscript. All authors have read and approved of the manuscript. | PMC10317955 | ||
Data availability | The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10317955 | ||
Competing interests | The authors declare no competing interests. | PMC10317955 | ||
References | PMC10317955 | |||
Key Points | PMC10492187 | |||
Question | Is adaptive pharmacotherapy effective for smoking cessation compared with nonadaptive standard pharmacotherapy? | PMC10492187 | ||
Findings | In this randomized clinical trial, 188 smokers chose between varenicline and nicotine patches and were then randomized to adaptive or standard treatment. Biochemically verified 30-day continuous smoking abstinence at 12 weeks after the target quit date was significantly higher for the adaptive treatment group than the standard treatment group. | PMC10492187 | ||
Meaning | These findings suggest that adaptive pharmacotherapy was effective for smoking cessation.This randomized clinical trial assesses the efficacy of adaptive pharmacotherapy compared with standard pharmacotherapy using varenicline or nicotine patches for smoking cessation. | PMC10492187 | ||
Importance | Adaptive pharmacotherapy, ie, starting a medication regimen and then modifying that regimen based on patient response, is common in many medical domains but is not common in smoking cessation. Recently, studies have found that adaptive treatment using precessation nicotine patches is efficacious for smoking cessation; however, adaptive treatment using precessation varenicline and adaptive treatment in clinical practice settings have not been fully assessed. | PMC10492187 | ||
Objective | To determine whether adaptive pharmacotherapy leads to higher smoking abstinence rates than standard pharmacotherapy in a clinical practice setting. | PMC10492187 | ||
Design, Setting, and Participants | MAY | This double-blinded stratified placebo-controlled randomized clinical trial compared adaptive treatment with standard treatment for smoking cessation. The study was conducted at a university health system in Durham, North Carolina, from February 2018 to May 2020 and was stopped early due to COVID-19. Data were analyzed as intent-to-treat from May 24, 2021, to February 27, 2022. | PMC10492187 | |
Interventions | Participants were allowed to choose varenicline or nicotine patches and were then randomized to adaptive or nonadaptive (standard) treatment. Participants started on their chosen medication (adaptive) or placebo (standard) 4 weeks before their target quit day. Two weeks later, participants were assessed for treatment response. Adaptive participants who did not decrease daily cigarettes smoked by at least 50% (nonresponders) received bupropion in addition to their chosen medication. Participants in the adaptative treatment group who did decrease daily cigarettes smoked by at least 50% (responders) and participants in the standard treatment group received additional placebo bupropion. Participants in the standard treatment group received varenicline starting 1 week before the target quit date or nicotine patches starting on the target quit day. All participants received brief behavioral support. | PMC10492187 | ||
Main Outcome and Measures | The main outcome was biochemically verified 30-day continuous smoking abstinence 12 weeks after their target quit smoking day. Other measures included demographic characteristics, smoking history, and repeated smoking assessments. | PMC10492187 | ||
Results | Of the planned 300 participants, a total of 188 participants (mean [SD] age, 49.1 [12.5] years; 102 [54%] female) were enrolled before the trial was stopped because of the COVID-19 pandemic. A total of 127 participants chose to use varenicline, including 64 randomized to adaptive treatment and 63 randomized to standard treatment, and 61 participants chose to use nicotine patches, including 31 randomized to adaptive treatment and 30 randomized to standard treatment. At baseline, participants smoked a mean (SD) of 15.4 (7.3) cigarettes per day. At 12 weeks after the target quit day, biochemically verified 30-day continuous smoking abstinence was observed in 23 of 95 participants (24%) in the adaptive treatment group and 8 of 93 participants (9%) in the standard treatment (odds ratio [OR], 3.38; 95% CI, 1.43-7.99; | PMC10492187 | ||
Conclusions and Relevance | This randomized clinical trial found that adaptive pharmacotherapy was efficacious for smoking cessation treatment in a practice setting. | PMC10492187 | ||
Trial Registration | ClinicalTrials.gov Identifier: | PMC10492187 | ||
Introduction | precessation smoking reduction | Adaptive treatment, ie, assessing the patient’s response to an initial medication and then modifying the medication regimen based on the patient’s response, is a common medical practice.Regarding extended precessation pharmacotherapy, trials have now shown that 4, 6, and 12 weeks of precessation varenicline all show higher smoking abstinence rates than 1 week of precessation varenicline.Regarding assessment of response to precessation pharmacotherapy, studies have shown that precessation smoking reduction was associated with postcessation smoking abstinence when smokers used precessation varenicline or nicotine patches.Regarding adapting of medication regimens for nonresponders, a 2013 study | PMC10492187 | |
Methods | PMC10492187 | |||
Design, Funding, and Registration | This phase 2 double-blind placebo-controlled stratified randomized clinical trial was approved by the Duke University Health System Institutional Review Board, and all participants provided written informed consent prior to enrollment. The trial was designed to compare biochemically verified 12-week smoking abstinence in daily smokers randomized to adaptive or standard pharmacotherapy in a clinical practice setting. The trial protocol and statistical plan are provided in | PMC10492187 | ||
Participants | psychiatric illness, allergy | ALLERGY | The study was conducted at Duke University Health System, a large university health system in central North Carolina. Potential participants were daily smokers who had been referred to a clinical smoking cessation program. Potential participants were offered free medications and compensation for study participation. Inclusion criteria were that participants must be daily smokers for at least 1 year, aged at least 18 years, and willing to attempt smoking cessation. Exclusion criteria included pregnancy, use of multiple tobacco products, current use of smoking cessation medications, allergy or intolerance to study medications, medical illness requiring hospitalization, psychiatric illness requiring hospitalization, alcohol or sedative dependence requiring treatment, significant recent illicit substance use, or baseline exhaled | PMC10492187 |
Stratification, Randomization, and Blinding | After enrollment, participants were stratified by medication choice. Using FDA information, participants were asked to choose between using nicotine patches or varenicline. After stratification, participants in the varenicline and nicotine patch groups were randomized 1:1 to adaptive treatment or standard treatment groups. Randomization used a predetermined computer-generated random sequence within each stratified group to ensure an equal number of adaptive and standard participants among those who chose varenicline and those who chose nicotine patches. Participants and staff were blinded to group allocation. During study operations, only the research pharmacy staff was aware of group allocation, and they dispensed placebos with visually identical packaging for both medications. | PMC10492187 | ||
Interventions | PMC10492187 | |||
Behavioral Treatment | At the baseline visit, all participants were provided with 20 minutes of evidence-based smoking cessation counseling by a tobacco treatment specialist. Smoking cessation counseling including health education, motivational support, and instructions on medication use. | PMC10492187 | ||
Medication Treatment | Adaptive treatment participants were provided with their chosen medication (nicotine patch or varenicline) 4 weeks before the target quit day. Varenicline was up-titrated over the first week of treatment to 1 mg twice daily. The nicotine patch was started at 14 to 21 mg based on baseline cigarettes smoked per day. Standard treatment participants who chose to use varenicline were provided with a placebo during starting at 4 weeks before the target quit day, then received varenicline starting 1 week before the target quit day. Standard treatment participants who chose to use nicotine patches received placebo patches starting 4 weeks before the target quit day, then received real nicotine patches starting on the target quit day. All medications were continued for 12 weeks after the target quit day. Similar to a previous study on adaptive treatment that directed participants to continue ad libitum smoking during precessation treatment, | PMC10492187 | ||
Outcome Measures | psychiatric | Study participants were asked to attend 4 study assessment visits: the baseline visit, medication response visit (2 weeks before the target quit day), and 2 post–quit day visits (2 and 12 weeks after the target quit day). Participants were paid $190 if they completed all 4 study visits. Baseline variables included age, sex, race, ethnicity, smoking history, nicotine dependence, and psychiatric diagnoses. Race and ethnicity were determined via self-report. Race was classified as American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, more than 1 race, and unknown, and ethnicity was classified as Hispanic or Latino or not Hispanic or Latino. Race and ethnicity were included in the analysis as potential covariates of our primary outcome.The primary outcome was 30-day continuous smoking abstinence 12 weeks after the target quit day, verified by expired | PMC10492187 | |
Sample Size | The sample size was based on a 2-tail significance test with 80% power and a 15% attrition rate (from our previous studies at our center). We referenced smoking abstinence rates from available trials that did not enroll a clinical population, and showed an adaptive treatment rate of 39.7%, and standard treatment of 23.4% and an absolute difference between groups of 16.3 percentage points. The study was initially designed to have sample size of 300 participants but was stopped early due to COVID-19 pandemic–related restrictions on in-person visits. After restrictions were lifted, funding was no longer available for the study, and analyses were conducted on the enrolled sample. | PMC10492187 | ||
Statistical Analysis | The primary outcome for the study was 30-day continuous smoking abstinence 12 weeks after the target quit day, verified by expired | PMC10492187 | ||
Results | PMC10492187 | |||
Participants | The first enrollment was February 15, 2018, and the last study visit was March 11, 2020. The study goal was to enroll 300 participants, but it was stopped early due to the COVID-19 pandemic. Of 307 individuals screened, 24 were not interested in the study, and 95 were excluded based on exclusion criteria. A total of 188 participants (mean [SD] age, 49.1 [12.5] years; 102 [54%] female) were enrolled and randomized, with 127 participants choosing to use varenicline, including 64 randomized to adaptive treatment and 63 randomized to standard treatment, and 61 participants choosing to use nicotine patches, including 31 randomized to adaptive treatment and 30 randomized to standard treatment. At baseline, the mean (SD) Fagerstrom Test for Cigarette Dependence | PMC10492187 | ||
Baseline Variables in the Study Cohort | Abbreviation: FTND, Fagerstrom Nicotine Dependence Test. | PMC10492187 | ||
Participant Recruitment Flowchart | All enrolled participants were included in intention-to-treat analyses used to determine primary outcome. | PMC10492187 | ||
Efficacy | Among all participants, intent-to-treat 12-week postquit biochemically verified 30-day continuous smoking abstinence was 23 of 95 participants (24%) in the adaptive group and 8 of 93 participants (9%) in the standard treatment group (OR, 3.39; 95% CI, 1.43-7.99; | PMC10492187 | ||
Mean Expired Carbon Monoxide ( | Significant group-by-time interaction across all postbaseline time points: | PMC10492187 | ||
Safety | cancer, death, disability | ADVERSE EVENTS, CANCER, EVENTS, ADVERSE EVENT | Among all 188 participants, we identified 1 serious adverse event: 1 participant (2%) in the varenicline standard treatment group died. This death was determined to be related to stage 4 cancer and not study-related. There were no other reports of death, life threatening events, hospitalization, persistent or significant disability or incapacity. Among all participants, 9 reported moderate side effects (requiring medical evaluation or change in daily routine) (4 participants in the varenicline adaptive group; 1 participant in the varenicline standard group; 3 participants in the nicotine patch adaptive group; 1 participant in the nicotine patch standard group). When mild adverse events (requiring no medical evaluation or a change in daily routine) were included, 159 participants reported at least 1 adverse event ( | PMC10492187 |
All Adverse Events Reported | anger, headaches, anxiety, constipation, dizziness, agitation, insomnia, nausea,, dry mouth | ADVERSE EVENTS, DRY MOUTH | Abbreviation: GI, gastrointestinal.Includes mild and nonstudy related adverse events.Includes constipation, dry mouth, nausea, vomiting, and gas.Includes anxiety and anger or agitation.Includes insomnia and vivid dreams.Includes dizziness and headaches. | PMC10492187 |
Discussion | psychiatric comorbidity, psychiatric illness | This randomized clinical trial found that adaptive treatment was more efficacious than standard treatment for daily smokers recruited from a smoking cessation clinic and allowed to choose between varenicline and nicotine patches. Additionally, the results suggest that adaptive treatment with extended (4-week) precessation varenicline may be more effective than standard varenicline treatment starting 1 week before the target quit date. This study contributes to the existing literature, which thus far only supports the use of adaptive treatment using precessation nicotine patches and has not assessed smokers in clinical settings. The trial used a clinical population with minimal exclusion criteria so that findings might be more readily generalizable to smokers seen in a clinical setting. A component of this trial’s design was allowing participants to select their medication. Another important element was to use minimal exclusion criteria, such that only 31% of screened participants were excluded from the trial. This resulted in a study sample with rates of psychiatric comorbidity (30.8%) similar to that in US smokers (35%).An important perspective on trial outcomes is provided by studies showing that varenicline plus bupropion was more effective than varenicline alone with continuous 12-week postquit smoking abstinence between groups (OR, 1.89; 95% CI, 1.07-3.35; To our knowledge, this is first trial that tested adaptive smoking cessation treatment in a clinical population with minimal exclusion criteria. As such, our best estimates for smoking abstinence in the standard treatment group were derived from randomized trials that used more restrictive eligibility criteria, eg, excluding smokers with physical or psychiatric illness. | PMC10492187 | |
Limitations | This study has some limitations, including the exclusion of people with symptomatic alcohol dependence or substance use. Additionally, few or no Alaska Native, American Indian, Asian, Hispanic or Latinx, multiracial, or Pacific Islander people enrolled, limiting generalizability to these populations. Additionally, study participants were given free medications and modest compensation for study visits, which are both elements that reduce generalizability. Another limitation emerged from the fact that that the study was stopped early due to COVID-19, resulting in a sample size of 188 instead of 300, with our lower sample size resulting in the relatively wide 95% CI for our main outcome. The relatively high percentage (27%) of participants lost to follow up might be explained by modest compensation and high comorbidity. Participants with missing abstinence data were counted as nonabstinent, which adds to the uncertainty of study outcomes. An additional limitation is that the study was designed to compare adaptive treatment as a whole with standard treatment as a whole and was not designed to assess individual components of adaptive treatment (effects of extended precessation treatment, effects of adding a second medication for nonresponders). Overall, these limitations were seen as decreasing the strength of but not negating our conclusions. | PMC10492187 | ||
Conclusions | This randomized clinical trial in daily smokers from a smoking cessation clinic with medication choice and limited exclusion criteria found higher smoking abstinence rates among participants randomized to adaptive compared with those randomized to nonadaptive pharmacotherapy. Specifically, these findings provide support for the use of precessation varenicline and precessation nicotine patches in an adaptive treatment regimen in which bupropion is provided to treatment nonresponders. This study’s design provides greater generalizability to clinical populations. Our findings support an evolving body of literature on adaptive treatment. | PMC10492187 | ||
References |
Trial Protocol and Statistical Analysis Plan
Click here for additional data file.
Data Sharing Statement
Click here for additional data file. | PMC10492187 | ||
Background | pain, Varicocele | SECONDARY, VARICOCELE | Varicocele occurs as a result of dilatation of the pampiniform plexus in the spermatic veins. In this study, our primary aim was to evaluate the effect of Transversalis Fascia Plane Block (TFPB) on pain scores in the postoperative period in patients undergoing varicocelectomy surgery, and our secondary aim was to evaluate the effect of TFPB on analgesic consumption. | PMC9903451 |
Methods | INFILTRATION, LOCAL INFILTRATION | The study was initiated following local ethics committee approval, and sixty ASA I-II patients > 18y scheduled to undergo varicocelectomy and who consented to participation were enrolled. Before the procedure, the patients were randomly assigned two groups: Transversalis Fascia Plan block group (Group TFPB) or surgical incision site infiltration group (Group I).All surgeries were carried out under general anesthesia, and microsurgery using the subinguinal approach. After surgical suturing, TFPB and local infiltration blocks were applied prior to termination of anesthesia.For each block, 20 mL of 0.25% bupivacaine was utilized. Patients' demographic information, passive and active VAS ratings after surgery, usage of non steroidal anti-inflammatory medications and rescue analgesia, and the requirement for rescue analgesia, were recorded. | PMC9903451 | |
Results | A total of 60 patients were included in the study. In terms of demographic data, there was no difference between the groups. At all hours, there was a statistically significant decrease in favor of Group TFPB in terms of active and passive VAS scores ( | PMC9903451 | ||
Conclusion | INFILTRATION | This study has shown that TFPB can provide a more effective analgesia when compared to surgical site infiltration. | PMC9903451 | |
Keywords | PMC9903451 | |||
Background | postoperative pain, pain, inguinal hernia, Varicocele | SECONDARY, VARICOCELE, VARICOCELE | Varicocele is caused by the dilatation of the pampiniform plexus in the spermatic veins and is observed in 15–20% of post-pubertal men [Many techniques exist for the surgical treatment of varicocele including, open techniques (retroperitoneal, inguinal and scrotal approaches), surgical ligation, laparoscopic approach and inguinal and subinguinal microsurgery [General anesthesia, central anesthetic interventions and local anesthesia can be used for analgesia and anesthesia in varicocelectomy surgery, which includes dissection of the skin and subcutaneous tissues as well as the ligation of the spermatic vein [Transversalis fascia plane block (TFPB) aims to provide analgesia for invasive procedures of the inguinal and subinguinal areas by blocking the subcostal (T12), ilioinguinal (L1) and iliohypogastric (T12-L1) nerves. Several studies have reported TFPB as the analgesic method of choice for procedures involving the T12-L1 dermatome region, including iliac bone graft harvesting, cesarean section, and inguinal hernia repair [Although varicocele surgery is described as mild in terms of pain, the fact that the pain associated with surgical incision can be removed entirely with TFPB. In this study, the primary objective was to assess the effect of TFPB on postoperative pain scores in patients undergoing unilateral varicocelectomy surgery, and the secondary objective was to assess the effect of TFPB on consumption of analgesics. | PMC9903451 |
Methods | PMC9903451 | |||
Study design | systemic disease, Postoperative pain, communication difficulties, liver insufficiency, cognitive problems, allergic reactions | SYSTEMIC DISEASE, CHRONIC RENAL FAILURE, INFILTRATION, ALLERGIC REACTION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COAGULOPATHY, CHRONIC PAIN | This randomized, controlled study was registered with clinicaltrials.gov (ref: NCT05172882, first registration date was 29/12/2021) following local institutional review board of the Ethical Committee for Clinical Research of the Medical Faculty of Ataturk University, Erzurum, Turkey. The trial was conducted between November 2021 and April 2022. The study included ASA (American Society of Anesthesiology) Class I-II patients aged > 18y, and informed written consent was obtained. Patients with known allergic reactions to any of the study's drugs (bupivacaine and other analgesic drugs), severe systemic disease (chronic renal failure, liver insufficiency, chronic obstructive pulmonary disease, etc.), all chronic pains or history of analgesic use for long-duration or coagulopathy, patients with cognitive problems or unable to understand study protocol and communication difficulties, BMI greater than or equal to 30 and patients who refused participation in the study were excluded.Before the procedure, the patients were randomly assigned to one of two groups: TFPB group (Group TFPB) and surgical incision site infiltration group (group I) using a computer-generated randomization table. The patient study numbers and study group information were organized in two columns. The third column was created using the "RAND" function to randomly select the data in the first two columns. In this manner, patients were assigned to study groups in this column randomly. Postoperative pain evaluation was performed by a researcher who was not involved in the perioperative period of the study. | PMC9903451 |
Management of surgery, anesthesia and TFP block | STERILE, INFILTRATION, CAVITY, LOCAL ANESTHETICS | Patients were placed in the supine position. Following patient monitoring with electrocardiography (ECG), non-invasive blood pressure (NIBP) and peripheral oxygen saturation (SpOPostoperatively, TFPB and infiltration analgesia were performed by experienced anesthesiologists or urologists, respectively. TFPB was performed under sterile conditions using a linear ultrasound probe (Esaote®, Mylab 5, Florence, Italy) and a 80 mm block needle (B.Braun®, Melsungen, Germany) was used to administer local anesthesic below the transversus abdominis muscle into the perirenal adipose tissue, taking into account the borders of the abdominal cavity. Local anesthetic used in both Group TFPB and group I consisted of 20 ml of 0.25% bupivacaine. In group I, the local anesthetic was administered into the cutaneous and subcutaneous tissues. (Fig. Anatomic illustration and ultrasonographic image of transversalis fascia plane block intervention. In both groups, interventions were performed at the end of the surgery before anesthesia was terminated. Patients who required additional surgery apart from varicocelectomy or intubation due to airway management issues were excluded from the study. | PMC9903451 | |
Outcomes and postoperative analgesic management | pain | Patients' demographic data, such as age, weight, and height, ASA classification, duration of anesthesia and surgery, passive (at rest) and active (from supine to 45° sitting position) postoperative VAS scores at 1, 2, 4, 8, 12, and 24 h after surgery (VAS 0 = no pain, VAS 10 = worst pain imaginable) were recorded.The patients were administered 1000 mg paracetamol iv around 30 min before the procedure ended. Following the procedure, the patients were observed in the recovery unit for follow-up. In the postoperative phase, patients in both groups were administered 1000 mg of paracetamol at 6-h intervals after first dose is given. When the VAS score was determined to be ≥ 4, 1 mg/kg tramadol was administered as a rescue opioid analgesic. IV 50 mg dexketoprofen was administered in the ward when the VAS score was greater than 2. | PMC9903451 | |
Sample size and statistical analyze | Data from a preliminary study taking into account average VAS score at 2Statistical analysis was performed using statistical program (SPSS Statistics version 20.0-IBM, Armonk, NY,USA). Data normality was evaluated using the Kolmogorov–Smirnov test. Mann Whitney-U test was used for continuous data that did not show normal distribution. Independent t-test was used for normally distrubuted data. Fisher Exact test was used to evaluate categorical data. | PMC9903451 | ||
Discussion | hernia, nerve injuries, pain, decreases pain, somatic innervation | INFILTRATION, CREST, COMPLICATION, PNEUMOTHORAX | To the best of our knowledge, this is the first study to evaluate the effectiveness of TFBP block for postoperative analgesia after varicocelectomy surgery. Our study has shown that when compared to local anesthetic infiltration of the surgical site, TFBP block decreases pain scores, non-steroid analgesic requirement and rescue analgesia consumption.Subinguinal incisions are often preferred in microsurgical varicocelectomy because the spermatic cord is more superficial and the anatomy is simpler. As a result, there is far less dissection, manipulation, and pain. This leads to less discomfort, less need for analgesics and earlier mobilization. As a result, microsurgical varicocelectomy with accelerated recovery after surgery (ERAS) is performed on a regular basis in our clinic. Furthermore, as effective postoperative analgesia is essential for ERAS, TFPB is commonly used in patients undergoing varicocelectomy in our clinic, as part of multimodal analgesia.The somatic innervation of the subinguinal incision used in varicocelectomy surgery is through the subcostal nerve (T12-L1), ilioinguinal nerve (L1) and the iliohypogastric nerve (T12-L1) [When the abdominal muscles are evaluated, the rectus muscles are near the linea alba. Traveling to the lateral part of the abdomen, there are three muscles: superficial to deep, the external oblique, internal oblique, and transversus abdominis muscles. TAP block is performed between the internal oblique and transversus abdominis muscles. This interfascial area is vast compared with the perirenal fat tissue compartment. The transversalis fascia is a thin fibrous membrane structure located behind the transversus abdominis muscle that limits perirenal fat tissue. The TFPB can be used to block the subcostal, ilioinguinal, and iliohypogastric nerves while they are running through the perirenal adipose tissue [TFBP was first reported in inguinal hernia surgery, appendectomy and in bone harvesting from the iliac crest. Thereafter, TFPB applications were reported for similar surgeries where somatic innervation was also from T12 and L1. TFBP application was compared to spinal anesthesia for postoperative analgesia in cesarean section and those undergoing TFBP were found to have lower morphine consumption [Increased success and decreased complication rates, such as unintended vascular access, pneumothorax, nerve injuries, etc., have been observed with peripheral nerve blocks performed under ultrasound guidance. Especially in cases where neurostimulation cannot be used, such as plane blocks, ultrasound can further increase the success of the block.This study has some limitations. Firstly; TFPB block was administered during general anesthesia after the end of surgery. Dermatomal analysis were not evaluated after surgical procedure. Secondly, the VAS scoring system was used to assess the patients' pain levels. Although the evaluation is done by a single author, individual variability in pain reactions in visual evaluation should be considered [To conclude, this study has demonstrated that when compared to surgical site infiltration, which is safer and available, TFPB leads to more effective analgesia in patients undergoing varicocelectomy surgery and may be an important part of multimodal analgesia in these patients. | PMC9903451 |
Acknowledgements | Not applicable | PMC9903451 | ||
Authors’ contributions | OI | MEA | ECC, OI, and MEA contributed to study conception and design. AMY, EOA, IHT, and AA contributed to study conduct. ECC and IHT contributed to data analysis. AMY, MEA, and AA contributed to manuscript preparation. ECC is a guarantor. The author(s) read and approved the final manuscript. | PMC9903451 |
Funding | Authors received no outside funding. The authors received no financial support for the research and/or authorship of this article. There are no any conflict of interests in this study. | PMC9903451 | ||
Availability of data and materials | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Erkan Cem Celik e-mail:drerkancem@yahoo.com. | PMC9903451 | ||
Declarations | PMC9903451 | |||
Ethics approval and consent to participate | Ethics approval was approved with 16.01.2020–1/4 approval number from local ethic commitee (Ataturk University Ethic Commitee). After approval from ethic commitee it was registered with clinicaltrials.gov (ref: NCT05172882, first registration date was 29/12/2021). All patients enrolled in this study were evaluated before anesthesia by anesthesiologists above the attending doctor and signed informed consent forms, and the research was performed in accordance with the Declaration of Helsinki. If the patient refused to participate in the study or the surgical method was changed, the study was stopped. | PMC9903451 | ||
Consent for publication | Not applicable. | PMC9903451 | ||
Competing interests | The authors declare no competing interests. | PMC9903451 | ||
References | PMC9903451 | |||
Key Points | PMC10034574 | |||
Question | cancer | CANCER, ADVANCED CANCER | Can unsupervised machine learning identify older adults with advanced cancer who are at high risk of adverse outcomes based on patient-reported symptoms prior to cancer treatments? | PMC10034574 |
Findings | death | SECONDARY, ADVANCED CANCER | In this secondary analysis of a randomized clinical trial with 706 older adults with advanced cancer, a k-means algorithm identified 3 patient clusters characterized by symptom severity (low, moderate, and high) that were associated with increased risk of unplanned hospitalization and death. | PMC10034574 |
Meaning | death | SECONDARY, ADVANCED CANCER | These findings suggest that machine learning may be used to guide the development of risk stratification tools with the potential to assist clinicians in identifying older adults with high risk of hospitalization and death.This secondary analysis of a randomized clinical trial uses unsupervised machine learning to evaluate the association between symptom severity clusters among older patients with advanced cancer and adverse outcomes. | PMC10034574 |
Importance | cancer | ADVERSE EVENTS, CANCER, ADVANCED CANCER | Older adults with advanced cancer who have high pretreatment symptom severity often experience adverse events during cancer treatments. Unsupervised machine learning may help stratify patients into different risk groups. | PMC10034574 |
Objective | To evaluate whether clusters identified from baseline patient-reported symptom severity were associated with adverse outcomes. | PMC10034574 | ||
Design, Setting, and Participants | cancer, death, Toxicity, Cancer | ADVERSE EVENT, CANCER, ADVANCED CANCER, SECONDARY, CANCER | This secondary analysis of the Geriatric Assessment Intervention for Reducing Toxicity in Older Patients With Advanced Cancer (GAP70+) Trial (2014-2019) included patients who completed the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) before starting a new cancer treatment regimen and received care at community oncology sites across the United States. An unsupervised machine learning algorithm (k-means with Euclidean distance) clustered patients based on similarities of baseline symptom severities. Clustering variables included severity items of 24 PRO-CTCAE symptoms (range, 0-4; corresponding to none, mild, moderate, severe, and very severe). Total severity score was calculated as the sum of 24 items (range, 0-96). Whether the clusters were associated with unplanned hospitalization, death, and toxic effects was then examined. Analyses were conducted in January and February 2022. | PMC10034574 |
Exposures | Symptom severity. | PMC10034574 | ||
Main Outcomes and Measures | Unplanned hospitalization over 3 months (primary), all-cause mortality over 1 year, and any clinician-rated grade 3 to 5 toxic effect over 3 months. | PMC10034574 | ||
Results | lung cancer | LUNG CANCER, GASTROINTESTINAL CANCER | Of 718 enrolled patients, 706 completed baseline PRO-CTCAE and were included (mean [SD] age, 77.2 [5.5] years, 401 [56.8%] male patients; 51 [7.2%] Black and 619 [87.8%] non-Hispanic White patients; 245 [34.7%] with gastrointestinal cancer; 175 [24.8%] with lung cancer; mean [SD] impaired Geriatric Assessment domains, 4.5 [1.6]). The algorithm classified 310 (43.9%), 295 (41.8%), and 101 (14.3%) into low-, medium-, and high-severity clusters (within-cluster mean [SD] severity scores: low, 6.3 [3.4]; moderate, 16.6 [4.3]; high, 29.8 [7.8]; | PMC10034574 |
Conclusions and Relevance | death | In this study, unsupervised machine learning partitioned patients into distinct symptom severity clusters; patients with higher pretreatment severity were more likely to experience hospitalization and death. | PMC10034574 | |
Trial Registration | ClinicalTrials.gov Identifier: | PMC10034574 | ||
Introduction | fatigue, cancer, pain, insomnia, Cancer | CANCER, ADVANCED CANCER, CANCER | Older adults with advanced cancer usually present with a wide range of physical and psychological symptoms, such as insomnia, fatigue, and pain, prior to cancer treatments.In recent years, patient-reported outcomes (PROs) have been increasingly used as a measure to capture symptom burden in patients with cancer.To standardize the analysis of PRO-CTCAE data, the NCI formed a Cancer Treatment Tolerability Consortium with 4 research teams in 2018, as part of the Cancer Moonshot initiative.To mitigate knowledge gaps, this study aimed to (1) identify patient clusters based on pretreatment PRO-CTCAE severity items using an unsupervised machine learning approach; (2) examine differences in patient characteristics and individual and total symptom severity by clusters; and (3) evaluate the longitudinal associations of patient clusters with unplanned hospitalization, overall mortality, and clinician-rated toxic effects. We hypothesized that the patterns of unplanned hospitalizations, mortality, and toxic effects will differ by symptom clusters. | PMC10034574 |
Methods | PMC10034574 | |||
Data Source | cancer | CANCER, SECONDARY, ADVANCED CANCER | This secondary analysis used data from a nationwide, multicenter, cluster-randomized study that found that providing GA information to community oncologists reduced clinician-rated grade 3 to 5 toxic effects in older adults with advanced cancer starting a new cancer treatment regimen (GAP70+ study). | PMC10034574 |
Study Measures | death | SECONDARY | The GAP70+ trial collected 27 PRO-CTCAE symptom items with multiple attributes.The primary outcome of this study was whether a participant experienced unplanned hospitalization(s) within 3 months of starting a new treatment regimen. Any planned or scheduled admissions were excluded from the analysis. The secondary outcomes included all-cause mortality over 1 year of study enrollment and any grade 3 to 5 toxic effects within 3 months. Data on hospitalization and date of death were captured by practice staff. All clinician-reported grade 3 to 5 toxic effects were prospectively collected and reviewed using the NCI CTCAE version 4. | PMC10034574 |
Statistical Analysis | Our first step grouped patients into clusters with similar mixes of symptom severity using an unsupervised machine learning algorithm (k-means with Euclidean distance). We selected k-means because of its computational efficiency and intuitive visualization of the data points related to their respective clusters.After establishing symptom severity clusters, we compared sociodemographic and clinical variables as well as outcome measures by cluster. To examine the validity of the clustering, we compared the severity attributes of individual items and total severity score by cluster. Differences across clusters were tested using analysis of variance for continuous variables and χClustering was implemented using the Cluster package in R version 4.0 (R Project for Statistical Computing). The remaining statistical analyses were performed in SAS version 9.4 (SAS Institute) and Stata version 16.0 (StataCorp), with 2-tailed | PMC10034574 | ||
Results | Of the 706 older adults included in the analysis (eFigure in | PMC10034574 | ||
Clustering of Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events Severity Items | Three clusters were found using the k-means method with Euclidean distance. For the purpose of data visualization, the x- and y-axes are principal components of the 24 PRO-CTCAE severity items. | PMC10034574 | ||
Associations of Symptom Severity Clusters With Longitudinal Adverse Outcomes | cancer type, cancer | CANCER | Abbreviations: HR, hazard ratio; NA, not applicable; RR, risk ratio.Models included practice site as random effect.Multivariable models adjusted for age, sex, cancer type, cancer treatment, number of Geriatric Assessment domain impairments, study group, Karnofsky performance status.Practice site random effect was excluded because the model did not converge. | PMC10034574 |
Discussion | cancer, death | CANCER, SECONDARY, ADVANCED CANCER | In this secondary analysis of a large national randomized trial of more than 700 older adults with advanced cancer receiving active treatment, we identified 3 main symptom clusters (low, moderate, and high severity) using a clustering algorithm. The symptom severity score of patients in each cluster differed. Patients in moderate- and high-severity clusters at baseline were more likely to experience unplanned hospitalization and have worse overall survival but had similar risks of toxic effects. Our results demonstrate that unsupervised machine learning methods can be used to identify patients who are at higher risk for adverse outcomes based on their baseline patient-reported symptoms.Unsupervised machine learning proves to be an effective bottom-up method of stratifying patients into distinct symptom severity clusters. Both the total severity score and all individual items were higher in the moderate- and high-severity clusters compared with those in the low-severity cluster, confirming the validity of the k-means algorithm. Compared with traditional methods of determining patient subgroups, k-means is more flexible and does not need human input (eg, determining the cutoff values). Another strength of the unsupervised algorithm is that no outcome measure is needed to identify the clusters.A simple algorithm that does not require large computational resources, k-means has promising potential in clinical research and practice.A major finding of this study is that older adults with advanced cancer in the moderate- and high-severity clusters were more likely to experience unplanned hospitalization. This finding is consistent with prior literature that observed an association between higher baseline symptom burden and adverse outcomes in patients with cancer.Our results also suggest that moderate to severe baseline symptom severity are independently associated with all-cause mortality in older adults with advanced cancer receiving palliative systematic treatment. This suggests that assessment of symptom burden prior to treatment initiation contributes clinically useful prognostic information for treatment decision-making among older adults. Because of the expected limited survival in this population, baseline symptom burden could be more clinically meaningful for estimating outcomes than the response to treatment, the traditional oncology clinical trial end point.We hypothesize 3 possible mechanisms to explain the higher risks of hospitalization and death among patients in the moderate- and high-severity clusters. First, patients in the moderate- and high-severity clusters had more symptomatic burden that was not fully captured by GA and KPS, contributing to their vulnerabilities. These patients could potentially benefit from palliative care during their cancer treatments to reduce their symptom burden and improve their quality of life.Our study has clinical and public health implications. First, unsupervised machine learning may offer an option to obtain summary information from PRO-CATE, for which no total score was available. Second, the association between symptom severity at the initiation of a new palliative regimen and adverse outcomes among older adults with advanced cancer suggests that PRO-CTCAEs can provide information in addition to GA and KPS. The inclusion of patient-centered assessment tools, such as PRO-CTCAEs, in clinical practice can assist clinicians in treatment decision-making and supportive care recommendations. | PMC10034574 |
Limitations | Our study has limitations. Patients included were mostly non-Hispanic White with high levels of education; they do not represent the entire US population. The k-means algorithm is sensitive to outliers in the clustering variables, although all clustering variables ranged from 0 to 4. Euclidean distances might be distorted by the potential collinearity among the clustering variables. We only included PRO-CTCAE severity attributes; future analyses should expand to other attributes. Additionally, our k-means algorithm needs external validation. | PMC10034574 | ||
Conclusions | SECONDARY | In this secondary analysis of a cluster trial of more than 700 older adults, unsupervised machine learning effectively identified patients with similar characteristics and stratified patients into clusters based on symptom severity. Our findings reinforce the importance of routine symptom assessment prior to treatment initiation as a best practice standard. PRO-CTCAEs assessed at treatment initiation can add information to the GA and performance status on patient vulnerability and inform potential treatment tolerability. Machine learning may be used to guide the development of risk stratification tools with the potential to assist clinicians in identifying older adults with a high risk of adverse outcomes. | PMC10034574 | |
Background | Participant feedback is an important consideration for increasing intervention acceptability, yet whether incorporating such feedback actually improves acceptability is rarely tested. | PMC10463387 | ||
Purpose | The present study describes a theory-based approach to assessing whether refining an intervention based on participant feedback increases acceptability. | PMC10463387 | ||
Methods | Three hundred and ninety-three UK adults who had previously self-harmed were exposed to the same intervention at baseline and, six months later, were randomly allocated to receive either: (a) the same version of the intervention (control group), or (b) a version of the intervention that had been refined following participant feedback (experimental group). The main outcome measure was acceptability ratings for each of the seven domains specified in the Theoretical Framework of Acceptability (TFA). | PMC10463387 | ||
Results | Mixed ANOVAs, with control versus experimental group as the between-participants factor and time (baseline versus follow-up) as the within participants factor showed no significant changes in acceptability. | PMC10463387 | ||
Conclusions | The null effects reported here imply that participants found both the original and modified versions of the intervention equally acceptable, and that our process of refining an intervention based on participant feedback did not impact on acceptability. Nevertheless, we have operationalised a robust approach for examining whether participant feedback impacts on the acceptability of an intervention. Further research is required to understand better how participant feedback should be incorporated into the development of healthcare interventions. | PMC10463387 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12889-023-16344-w. | PMC10463387 | ||
Keywords | PMC10463387 | |||
Background | Various factors affect the successful implementation of an intervention, such as its feasibility, desirability, and perceived appropriateness [Involving people in the design and modification of interventions is recognised as an important stage in ensuring acceptability [The first limitation concerns the lack of study methods explicitly testing the acceptability of a modified intervention following participant feedback. This is important because, to our knowledge, no experimental studies have been conducted that evaluate whether changes made to an intervention in response to participant feedback elicited improvements in acceptability.The second limitation concerns the lack of use of theoretical frameworks to guide the investigation of acceptability. The Theoretical Framework of Acceptability (TFA) [ | PMC10463387 | ||
Aims | The aims of the present study were to operationalise an approach to intervention acceptability that: (a) ensures that a large representative sample of people with lived experience is involved in the process of refining an intervention to increase acceptability; and (b) adopts a theory-driven, experimental approach to evaluating whether refining an intervention based on participant feedback increases acceptability. | PMC10463387 | ||
Methods | PMC10463387 | |||
Overview | Ethical approval was obtained from The University of Manchester Research Ethics Committee (ref: 2020-8446-15312). All methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki). The study was conducted in three phases as part of a larger six-month follow-up study examining the effectiveness of an intervention for reducing self-harm (ClinicalTrials.gov Identifier: NCT04420546). In phase 1, we focused on intervention development, and phase 2 focused on developing and testing an experimental approach to evaluating whether refining an intervention based on participant feedback increases acceptability. Phase 3 is currently ongoing, and is focused on evaluating the effectiveness of the intervention. | PMC10463387 | ||
Phase 1: intervention development | PMC10463387 | |||
Development of the volitional help sheet for self-harm | The intervention is based on the concept of implementation intentions [Participant suggestions for refining the intervention were coded to the specific constructs of the TFA as part of our qualitative analyses conducted during our prior intervention development work on the original intervention [The original and modified versions are presented in Figs.
Volitional help sheet for self-harm (control condition)
Volitional help sheet for self-harm (experimental condition) | PMC10463387 | ||
Phase 2: main study | PMC10463387 | |||
Participants | A national community sample of people in the UK who had previously self-harmed were recruited via a survey panel company (YouGov), as part of a larger study (ClinicalTrials.gov Identifier: NCT04420546). Participants were incentivised in line with YouGov’s points system (respondents accumulate points for taking part in surveys, which can then be exchanged for cash or entry into a prize draw). A screening question was asked to ensure that the final sample contained people with a prior history of self-harm: “Have you ever intentionally hurt yourself/self-harmed?” Response options were “yes, I have,” “no, I have not,” or “prefer not to say.” The final sample was based on respondents answering, “yes, I have.” | PMC10463387 | ||
Design | A mixed-measures design was employed with one between-participants factor ( | PMC10463387 | ||
Procedure | self-harm | At baseline, after participants gave informed consent, all were presented with the original intervention aimed at reducing self-harm. Participants were then randomised via online survey software to receive, at six-month follow-up, either: (a) the same version of the intervention, or (b) a version of the intervention that had been changed following participant feedback. Whilst participants were not expected to use the intervention in the period between baseline and follow-up, the volitional help sheet is intended to provide people with a means of responding to critical situations (where the urge to self-harm may be heightened), with automatic coping plans that were formed during the baseline period. | PMC10463387 |
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