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Participants | ankle sprain | All students (n = 114) enrolled in the subject were invited to participate and informed about the RCT including potential effects and demands of the intervention. Four students refused to participate in the study and eight students dropped out during the 14 weeks due to failure to complete the weekly questionnaire, general discomfort associated with the device, and an ankle sprain. In the end, 102 students finally completed the RCT. | PMC10559614 | |
Methods | Participants were randomly allocated to three groups (intervention, placebo, and control). Students allocated into the intervention group wore a superficial neuromodulation device (© 2020 Irmoki) while students remained seated at rest following lectures at University. The device consists of 4 wireless receptors to be placed on the distal third of the limbs by means of gloves and anklets and controlled through Bluetooth technology by a smartphone app (Fig.
Example of neuromodulation device placement of the intervention and placebo groups. Note: image provided by Irmoki company | PMC10559614 | ||
Data collection and analysis | fatigue, muscular soreness | Sociodemographical data were collected at baseline. Outcomes were gathered by means of an online questionnaire at baseline and after weeks 2, 4, 6, and 8 which retrieved data about fatigue, sleep quality, muscular soreness, stress level, and mood. In addition, participants in the intervention and placebo groups were asked about the expectation towards the intervention and the perceived potential alterations. | PMC10559614 | |
Procedures related to the implementation of the UR programme | PMC10559614 | |||
Participants | From 114 students enrolled in the subject, ergo involved in the implementation of the UR teaching strategies for 14 weeks, the same four students who refused to participate on the RCT also refused to answer the UR outcome evaluation questionnaires at the end of the semester. Thus, 110 responses were collected. In addition, the two lecturers completed the questionnaire. | PMC10559614 | ||
Methods | UR strategies were executed according to the subject´s syllabus. These were based, combined, and integrated on the theoretical topics described in Fig.
The strategies used during UR methodology implementationThe RCT, the implementation of UR strategies, and the evaluation were led by the two main lecturers of the subject. In addition, other lecturers from other subjects collaborated exclusively with the task of delivering and collecting the devices. In this sense, they also remained blinded to randomization and study information. | PMC10559614 | ||
Data collection and outcome measures | At the end of the semester, an ad hoc questionnaire completed by participants in the study collected several outcomes focused on four dimensions: (a) the integration of research knowledge related to the theoretical contents; (b) the development of research competencies; (c) the level of self-efficacy about the skills trained; and (d) the RCT procedures. The questions related to the first two dimensions were based on the validated version of the | PMC10559614 | ||
Statistical analysis | Statistical analysis was conducted using Jamovi (v. 1.6.23, The Jamovi Project, Sydney, Australia). Descriptive statistics were calculated with proportions and frequencies and the distribution of the investigated variables was presented with bar diagrams. | PMC10559614 | ||
Results | mistakes | 110 participants (sex: 48 M/54F; and age: 19.5 (1.63) years) completed the questionnaire about the impact of the UR teaching strategies. Figures
Results of the questionnaire: effect on integration of research knowledge related to the theoretical contents
Results of the questionnaire: effect on the development of research competences
Results of the questionnaire: effect on self-efficacy about the skills trained
Results of the questionnaire: Issues related to RCT implementation the aim of seeking across effectRegarding the development of research competencies, most students reported that UR had a positive or very positive impact on critical thinking (67% and 18%, respectively) and assessment of methodological quality (66% and 23%, respectively) (Fig. Self-efficacy about the skills trained was highly rated, and skills that benefited the most were the ability to understand and explain the placebo effect, the capacity to read and integrate the results of an RCT, and the ability to identify bias and methodological gaps related to the design and execution of a clinical trial (Fig. Students evaluated very positively the inclusion of an RCT as an active learning strategy. Aspects that received the best evaluation were the adequacy of the UR strategy with the implementation of the RCT in the subject, the active participation of students during the learning process, and the involvement and structured organisation shown by the teaching staff responsible for the project (Fig. Answers from the open question are presented in Table
Answers to the open questionOn the other hand, negative aspects identified by both lecturers include the excessive duration of the intervention, the extra daily burden of getting students to wear the devices to ensure adherence to the intervention and data collection, and the difficulty of combining it with other daily obligations. However, lecturers reported that confidence in the premise of fostering research awareness, seeing it as the first step on a progressive path within a built UR programme, the support among the academic staff involved and their research experience helped to overcome the obstacle. Lecturers considered that this educational approach helped students to get closer to the reality of research, feel the placebo effect first-hand, identify mistakes and limitations, and propose solutions based on self-criticism. Lecturers also concluded that the activity provided a valuable opportunity for active learning through real experimentation. | PMC10559614 | |
Discussion | The research-based activity framed in a UR programme consisting of the implementation of a real RCT in which students were involved as participants and researchers, supervised by qualified lecturers, showed positive effects on the acquisition of theoretical content, the development of research competences, the level of self-efficacy in research skills and knowledge about RCT procedures. Furthermore, it provided a novel experience for students, making the learning process more meaningful.Strategies such as journal clubs or conducting a systematic review or meta-analysis are common in UR programs [In our study, most students reported that UR had a positive or very positive impact on critical thinking and assessment of methodological quality. Likewise, student showed that the RCT implementation improved the ability to understand and explain the placebo effect, the capacity to read and integrate the results of an RCT. This means that the students integrated better key knowledge of RCTs, such us how design features, risk of bias or placebo effect may distort results and lead to incorrect conclusions and substantially modulate clinical decision-making in physiotherapy [According to the EBP approach of the physiotherapy degree curriculum developed at the University of Deusto, the emerging framework enabled the early integration of UR and other innovative educational methods. Moreover, the inclusion of EBP education in early stages is an accreditation requirement for many health professional disciplines [The students evaluated very positively the adequacy of UR strategy, the active participation, and the involvement and structured organisation shown by the teaching staff. In this sense, the early and first-hand RCT experience within a subject related to research methodology, where students are actively involved in carrying out real research practical activities, fieldwork and/or act as participants is unique. This experience gave the students the opportunity to practise and become proficient at it, which has been described as an effective method to develop more sophisticated levels of intellectual development [The positive effect related to the integration of the placebo effect was most often mentioned by the students. To the best of our knowledge, this is the only UR strategy that has led to a real experience of the placebo effect among physiotherapy students. When the placebo group was revealed, the students could integrate how different design features of a trial, co-interventions, sample contamination, ambiguity of symptom detection, patient’s or researcher’s biases can have a substantial impact on estimates of treatment effects. Therewith, we consider the impact on the students’ critical appraisal skill was truly outstanding through unusual, exciting, and surprising pedagogical learning.The acquisition of research theoretical knowledge related to scientific articles, journals, systematic review and PICO did not improve as much as other items. We conclude that the design of the RCT encouraged students to focus on the theoretical content that engaged them most actively. Otherwise, the RCT itself is not very related to this type of theoretical content. If the design used was a systematic review instead of an RCT, the opposite would probably be the case with regard to the topics of theoretical content which scored lower.Finally, the role of lecturers seems to be very important as an active knowledge transfer agent and the person who motivates, supervises, promotes, executes, and develops research linking students as technicians or voluntary participants during research procedures [ | PMC10559614 | ||
Limitations | BLIND | This study has some limitations. A systematic pre-post semester analysis and the lack of a control group of students without UR implementation are the most important. In this sense, a control group was very difficult to achieve because it was practically unfeasible to blind the students to the implementation of the RCT. However, this should be taken into account when interpreting the results obtained. In addition, a long-term view in line with other research and inquiry strategies are required to evaluate the effect on the students’ learning process. Further, increasing the sample size of students should also provide more insights into the teaching and learning capabilities of research. Finally, the lack of validated tools and the use of different points and not well-balanced scales when dimensions were assessed also could have had a negative impact. | PMC10559614 | |
Conclusion | This study presents a novel approach of the framework of UR in the unexplored healthcare discipline. Conducting an RCT is a challenging but valuable, useful, and effective way to integrate research and an inquiring attitude in physiotherapy students. Forms of teaching and learning focused on enhancing research and inquiring attitudes should be considered and integrated in the healthcare curriculum, especially in physiotherapy programmes, where students’ knowledge of RCT characteristics should be integrated early to ensure the transfer of EBP to provide the best care. In the future, this initiative should potentially be considered by lecturers, educational research promoters and stakeholders involved in UR programmes. | PMC10559614 | ||
Acknowledgements | The authors thank all the students who participated as volunteers and the teachers who were involved for their contribution to the study. Likewise, we also want to thank the company Irmoki for the loan of the devices. | PMC10559614 | ||
Authors‘ contributions | A.A., I.S. and M.A. conducted the RCT. I.S. and I.V. analyzed and interpreted the data. A.A. was a major contributor in writing the manuscript. All authors read and approved the final manuscript. | PMC10559614 | ||
Funding | This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. | PMC10559614 | ||
Data Availability | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10559614 | ||
Declarations | PMC10559614 | |||
Ethics approval and consent to participate | This study was approved by the Research Ethics Committee of the University of Deusto (ETK-21/21–22) and was undertaken according to the Helsinki declaration. Informed consent was obtained from all subjects. | PMC10559614 | ||
Consent for publication | Not Applicable. | PMC10559614 | ||
Competing interests | The authors declare no competing interests. | PMC10559614 | ||
List of Abbreviations | Evidence-based practiceUndergraduate researchRandomised controlled trial | PMC10559614 | ||
Background | tumor | TUMOR, SOLID TUMORS | The mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors. | PMC10702058 |
Methods | intolerable adverse events, unresectable malignant solid tumors | DISEASE PROGRESSION | Eligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability. | PMC10702058 |
Results | toxicity, hypertriglyceridemia, leukocytopenia | LEUKOCYTOPENIA, HYPERTRIGLYCERIDEMIA, DISEASE | Between June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7–60.6). In evaluable patients, the median progression-free survival was 29 days (range 29–141). | PMC10702058 |
Conclusions | SOLID TUMORS | LXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials. | PMC10702058 | |
Trial registration | NCT03125746(24/04/2017), | PMC10702058 | ||
Keywords | PMC10702058 | |||
Methods | PMC10702058 | |||
Patient eligibility | ONCOLOGY, SOLID TUMORS | Patients were eligible for enrollment based on the following criteria: 1) 18 to 65 years of age; 2) histologically or cytologically diagnosed with advanced malignant solid tumors; 3) failure of routine therapy or without conventional standard therapy; 4) Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1; 5) life expectancy of > 3 months; 6) adequate or acceptable organ and bone marrow function. The patients were excluded if they had received prior or current treatment with PI3K or mTOR inhibitors. | PMC10702058 | |
Study design | DLTs, neutropenia, fever, toxicity, PD, Cancer | ADVERSE EVENT, DISEASE PROGRESSION, NON-INFECTIOUS PNEUMONIA, NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, DISEASE, SOLID TUMORS, ABNORMAL RENAL FUNCTION, ADVERSE EFFECT, CANCER | This was a single-center, open-label, phase I study to determine the safety, PK, the maximum tolerated dose (MTD), and preliminary efficacy of LXI-15029 monotherapy in Chinese patients with advanced malignant solid tumors. LXI-15029 capsules (provided by Shandong Luoxin Pharmaceutical Group Co., Ltd.) were administered orally twice daily (BID) under the fasting state. A conventional 3 + 3 dose escalation design was used to explore the MTD. At least three participants with evaluable dose-limiting toxicity (DLT) and tolerability were included in each dose group. According to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3 (NCI-CTCAE 4.0.3), DLTs were defined as adverse events (AEs) or abnormal laboratory values unrelated to disease progression and reasonably likely to be related to the investigational product within 30 days after the first dose (cycle 1), as grade 2 non-infectious pneumonia or abnormal renal function (increased creatinine), any grade 3 non-hematological AEs, grade 3 neutropenia with fever or thrombocytopenia, or any grade 4 hematological AEs.At least three participants were enrolled in each cohort. Participants were enrolled in the next dose cohort if no DLT was observed within 30 days after the first dose. If one case of DLT occurred, three additional participants would be enrolled in this cohort. Then, if no additional DLT occurred, participants were enrolled in the next higher-dose cohort. If additional DLTs occurred, the current dose was considered intolerable and enrollment in this cohort was discontinued. The decision to explore intermediate doses or define the previous dose level as the MTD was made by the Safety Review Committee (SRC). Participants with unevaluable DLT were replaced by another participant with evaluable DLT.The starting dose of LXI-15029 as a non-cytotoxic antitumor drug in this first-in-human phase I clinical trial was calculated as ≥ 1/5 of the no observed adverse effect level (NOAEL) in non-rodent animals, obtained in preclinical trials. The participants received LXI-15029 monotherapy in each dose cohort and multiple doses of LXI-15029 for 4 weeks (cycle 1) following a 1-day washout period after a single dose of LXI-15029. The participants continued therapy with LXI-15029 if good safety and tolerability were assessed by the investigators after one cycle of treatment. Five ascending dose groups of LXI-15029 BID (10, 20, 40, 60, and 80 mg) were planned to be evaluated, with 3 to 6 evaluable patients who received LXI-15029 monotherapy in each cohort. The following cohort was given dose escalation until the intolerable dose. The investigators could select higher doses (i.e., 110 and 150 mg, with reference to the modified Fibonacci method) if the 80 mg BID dose was well tolerated. The participants continued therapy with LXI-15029 until progressive disease (PD), the occurrence of intolerable toxicity, or withdrawal of consent.All interventions in this study were conducted in accordance with the Declaration of Helsinki guidelines of the International Conference for Harmonization/Good Clinical Practice guidelines and approved by the Independent Ethics Committee (IEC) of the National Cancer Center/Cancer Hospitals. Written informed consent was obtained from all study participants before enrollment. The first registration at ClinicalTrial.gov is 24/04/2017 with full registration number NCT03125746. | PMC10702058 |
Endpoints | Tumors, SD | DISEASE, SECONDARY, TUMORS | The primary endpoint was the safety and tolerability of LXI-15029 monotherapy, including confirmation of MTD. The secondary endpoints were the PK parameters and investigator-assessed antitumor effect, including objective response rate (ORR, defined as the proportion of patients with complete response [CR] and partial response [PR] as the best overall response), disease control rate (DCR, defined as the proportion of patients with CR, PR or stable disease [SD] ≥ 6 weeks) and progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | PMC10702058 |
PK analysis | BLOOD | Blood samples for PK analysis of LXI-15029 were collected on day 1 (pre-dose, 20 min, 40 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, and 48 h), cycle 1 day 8 (pre-dose), cycle 1 day 15 (pre-dose), and cycle 1 day 28 (pre-dose, 20 min, 40 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h). The blood samples were stored at -70°C until testing. The concentration of LXI-15029 in plasma was measured using the validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. The concentration–time information of LXI-15029 was summarized based on pre-dose and post-dose data of each patient, to explore the linearity of exposure with single dose and steady-state situations, the time to reach steady state and the predictability of single to multiple doses PK. PK parameters were calculated separately for single and repeated doses using descriptive statistics. PK analysis was performed by Covance Central Laboratory using the validated software Phoenix WinNonlin Version 8.1 (Pharsight, Mountain View, CA). A standard non-compartmental method was used to calculate the peak plasma concentration (C | PMC10702058 | |
Patient assessments and evaluation | toxicity | All patients who received at least one dose of LXI-15029 were included in the safety and toxicity evaluations. Safety evaluations were performed on days 1, 8, 15, and 22 in cycle 1 and once every month after that. The safety assessments included vital signs, laboratory tests, and an electrocardiogram. Safety data were evaluated separately. At the end of the study, all safety data were analyzed appropriately according to the statistical analysis plan. The AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 24.0). The AE severity was graded according to the NCI-CTCAE 4.03.The antitumor effects of LXI-15029 monotherapy was evaluated based on ORR, DCR, and PFS according to RECIST version 1.1 on week 4 and every 8 weeks thereafter, and the best overall response was confirmed at least 4 weeks after the initial response. | PMC10702058 | |
Statistical analysis | EVENT | All safety, tolerance, PK, and antitumor data from each dose group were tabulated and summarized according to the statistical analysis plan. The statistical analysis of the study was descriptive. The continuous variables were described as mean ± standard deviation or median (minimum, maximum). For the PK data, geometric mean and geometric mean coefficient of variation were also provided. The categorical variables were described as n (%). PFS was summarized using the Kaplan–Meier method. Percentiles (25%, median, 75%) of the event time distribution were presented along with their two-sided 95% confidence interval (CI). All data processing, summaries, and analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA). | PMC10702058 | |
Results | PMC10702058 | |||
Preliminary efficacy data | PD, tumor, fibrosarcoma, SD | TUMOR, FIBROSARCOMA | Of the 24 participants who completed the treatment plan, 20 were evaluated for therapeutic efficacy. The tumor target lesions ranged from one to five. The lung, liver, and lymph nodes were the most common target lesion sites. Efficacy was evaluated based on the oncological evaluation analysis set and investigator assessment as per RECIST 1.1. No participants achieved CR or PR. The best overall response was assessed as SD, and the DCR was 40% (8/20; 95% CI 21.7–60.6). No DCR-dose correlation was observed. One participant with fibrosarcoma received 20 mg BID LXI-15029 and had SD at cycles 1 to 11 and then PD at cycle 12; the duration of SD was 344 days.Survival analysis showed that the overall median PFS of the participants from the date of the first dose of LXI-15029 was 29 days (95% CI: 29–141) (Fig. Progression-free survival of 20 evaluable participants | PMC10702058 |
Discussion | tumor, pneumonia, cancers, stomatitis, hyperlipidemia, toxicities, cancer, hepatotoxicity, sarcoma, Cancer | TUMOR, PNEUMONIA, CANCERS, STILL, HYPERLIPIDEMIA, STOMATITIS, CANCER, DISEASE, HYPERGLYCEMIA, SARCOMA, BONE MARROW SUPPRESSION, NEUROENDOCRINE CARCINOMA, CANCER | The discovery of mTOR represents a fundamental breakthrough in the understanding of cell growth, metabolism, and disease [The serious toxicities of PI3K/AKT/mTOR inhibitors limit their clinical use and approval, including hyperglycemia, hyperlipidemia, bone marrow suppression, pneumonia, stomatitis, and hepatotoxicity [The PK profile showed that LXI-15029 was absorbed rapidly, and the arithmetic mean of tMany studies aim to understand the potential resistance mechanisms of mTOR-targeted therapies, which is necessary for the rational application of mTOR inhibitors for the effective treatment of cancer. mTOR inhibitors interrupt the phosphorylation of substrates and block relevant signal transduction, thereby inhibiting the cell cycle, tumor metabolism, and cell survival and exerting antitumor effects through binding with the mTOR binding site [Cancer immunotherapy is another promising approach for mTOR dual blockers. Cell-based and in vivo research showed that mTOR inhibitors can enhance the efficacy of various tumor immunotherapy methods by elevating PD-L1 expression in tumor cells and inhibiting the activation of T memory cells [Notably, about 50% of the participants had rare cancers such as sarcoma and neuroendocrine carcinoma, which have achieved few treatment breakthroughs. The results in this study suggest favorable efficacy for these rare cancers. Still, patients who are more likely to benefit from mTOR inhibitors remain to be further explored. Patients resistant to targeted therapy such as epidermal growth factor receptor tyrosine kinases inhibitors might be potential beneficiaries since they often have activation of the PI3K/AKT/mTOR pathway. Moreover, some ongoing clinical trials could suggest that mTOR dual inhibition might be beneficial in patients harboring NFE 2L2, STK11, RICTOR, or other specific genetic alterations (NCT04518137) or combined with anti-PD-1 antibody (NCT04337463) or antineoplastic exportin-1 (XPO1) inhibitors (NCT04998760) [The limitations of this study included the small sample size, the single-center design, and the lack of tissue and serum collection before and during the study. Collection of tissue and serum samples in future studies would allow exploring predictive biomarkers and facilitate observing the changes in the PI3K/AKT/mTOR signaling pathway and related specific genetic alterations, which will further improve treatment strategies and guide the better selection of responsive patients [ | PMC10702058 |
Conclusions | SOLID TUMORS | LXI-15029 monotherapy demonstrated a favorable safety profile, tolerability, and preliminary antitumor activity in Chinese patients with advanced malignant solid tumors. PK-guided dosing might improve the efficacy and safety of LXI-15029, leading to further investigation in a larger population-based phase II study and evaluation of an effective combination with immunotherapy or other target therapy. | PMC10702058 | |
Acknowledgements | We thank the participants in this study and gratefully acknowledge the collaboration of all investigators for their contributions. We thank W Wang, YH Wang, and MJ Li from Shandong Luoxin Pharmaceutical Group Co., Ltd. for assisting us with data analysis. We thank MedSci for editorial language assistance. | PMC10702058 | ||
Authors’ contributions | Conception and design: Q Li and B Xu. Development of methodology: Q Li, J Wang, and B Xu. Acquisition of data (acquired and managed patients, provided facilities, etc.): J Wang, L Gui, J Wang, Y Chi, Q Li, Y Mu, and B Xu. Analysis and interpretation of data (e.g., statistical analysis, computational analysis): Q Li and J Wang. Writing, review, and/or revision of the manuscript: J Wang, Q Li, and B Xu. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J Wang, Z Liu, L Gui, Q Li, and Y Mu. Study supervision: Q Li and B Xu. | PMC10702058 | ||
Funding | This study was sponsored by Shandong Luoxin Pharmaceutical Group Co., Ltd., National Key Research and Development Program of China (No. 2018YFC1312101), and the Chinese Academy of Medical Science Innovation Fund for Medical Sciences(No. CIFMS-2021-I2M-1–014). | PMC10702058 | ||
Availability of data and materials | The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request. | PMC10702058 | ||
Declarations | PMC10702058 | |||
Ethics approval and consent to participate | Cancer | CANCER | All interventions in this study were conducted in accordance with the Declaration of Helsinki guidelines of the International Conference for Harmonization/Good Clinical Practice guidelines and approved by the Independent Ethics Committee (IEC) of the National Cancer Center/Cancer Hospitals (Approved No.16–166/1245). Written informed consent was obtained from all study participants before enrollment. | PMC10702058 |
Consent for publication | Not applicable. | PMC10702058 | ||
Competing interests | The authors declare no competing interests. | PMC10702058 | ||
References | PMC10702058 | |||
ABSTRACT. | infection, malaria infection, malnutrition, ’ | MALARIA, INFECTION, MALARIA, INTERACTION, MALNUTRITION, FRANCIS | Financial Support: This study was supported by the Bill & Melinda Gates Foundation (Grant no. OPP1187628).Authors’ addresses: Elisabeth Gebreegziabher and Elodie Lebas, Francis I. Proctor Foundation, University of California San Francisco, San Francisco, CA, E-mails: The relationship between malaria infection and malnutrition is complex. Using data from a randomized controlled trial of 450 children 0–5 years of age in Burkina Faso, we examined the effect of malaria infection on short-term changes in anthropometric measures, the effect of malnutrition on malaria infection, and whether age modified the effect of baseline anthropometric measures on malaria infection. Malaria infection, assessed by blood smear microscopy and weight, height, mid-upper arm circumference, height-for-age z-score, weight-for-age z-score, and weight-for-height z-score were measured at three time points: baseline, 2 weeks, and 6 months. We used generalized estimating equations adjusted for sex, age, breastfeeding, maternal education, and study treatment (azithromycin versus placebo) for all analyses. Interaction terms were used to assess effect modification by age. Among the 366 children with no malaria infection at baseline, 43 (11.6%) had malaria infection within 6 months. There were no important differences in anthropometric measures at 2 weeks and 6 months between those with and without malaria infection at baseline. There were no significant differences in prevalence of malaria infection by baseline anthropometric measures. Age (0–30 months versus 30–60 months) modified the effect of baseline weight and height on malaria infection. Among those aged 0–30 months, for each kilogram increase in weight, malaria infection increased by 27% (95% CI: 6–53%), and for each centimeter increase in height, it increased by 9% (95% CI: 1–17%), but there were no differences for those aged 30–60 months. | PMC9978547 |
INTRODUCTION | malaria, Malnutrition, malaria infection, malnutrition | MALARIA, MALNUTRITION, UNDERNOURISHED, MALNUTRITION | Malnutrition and malaria continue to be major causes of morbidity and mortality in low- and middle-income countries. Globally, 8.9% of the population in 2019 was undernourished,The association between malaria infection and malnutrition is complex, and the directionality of these associations is poorly understood.To better understand the relationships between malaria infection and malnutrition, we used longitudinal 6-month follow-up data from 450 children 0–5 years of age enrolled in a randomized controlled trial in Burkina Faso. The objectives of this study were to examine the effect of malaria infection on short-term changes in anthropometric measures, the effect of malnutrition on malaria infection prevalence, and whether age modified any of these relationships. | PMC9978547 |
MATERIALS AND METHODS | PMC9978547 | |||
Study design, setting, and population. | SECONDARY | For this secondary analysis, we used data from a randomized controlled trial (GAMIN) conducted between 2019 and 2020 to evaluate the potential effect of azithromycin on intestinal microbiome changes and child growth. | PMC9978547 | |
Data collection and measures. | ® | Data were collected at three time points: baseline, 2 weeks, and 6 months after enrollment. Anthropometric measures, including weight, height, and mid-upper arm circumference (MUAC) were taken at each study visit. Weight was measured using the SECA 847 scale (Chino, CA) to weigh infants and children to the nearest 0.1 kg. The scales were calibrated each morning by using a 5-kg weight test. Length/height was measured using a ShorrBoard® (Weigh and Measure, LLC, Olney, MD) to the nearest centimeter. MUAC was measured using a standard MUAC tape. Height-for-age z-score (HAZ), weight-for-age z-score (WAZ), and weight-for-height z-score (WHZ) were calculated according to 2006 WHO standards | PMC9978547 | |
Covariates. | infection, malnutrition | MALARIA, INFECTION, MALNUTRITION | Potential confounders of the association between malnutrition and malaria infection were selected a priori using a directed acyclic graph and based on previous literature. | PMC9978547 |
Statistical analysis methods. | malaria, infection, malaria infection, malnutrition | MALARIA, INFECTION, REGRESSION, MALNUTRITION | For all analyses, we used generalized estimating equations (GEEs) with robust standard errors to account for repeated observations in children. Six observations with extreme HAZ, WAZ, or WHZ scores (z-score > 6 or < −6) (To examine the effect of baseline anthropometric measures on point prevalence of malaria infection, we restricted our study sample to those who had no malaria infection at baseline (To assess whether the child’s age modified the effect of baseline malnutrition on the prevalence of malaria infection, an interaction term between age (dichotomized as 0–29 and 30–60 months, based on the median age of the study population) and baseline anthropometric measures was included in the GEE models to assess effect modification on the multiplicative scale. The effect of each baseline measure on point prevalence of malaria infection within the strata of age was calculated. We plotted the predicted prevalence of malaria infection with baseline anthropometric measures for each age group to visualize any differences in the malnutrition–malaria infection association in younger and older children.As a sensitivity analysis, we assessed the study characteristics of those who were lost to follow-up (LTFU) using logistic regression of predictors of missing visits. Predictors included in the model included baseline malaria infection, baseline anthropometric measures, sex, age group, breastfeeding, maternal education, and study treatment (azithromycin versus placebo).SAS 9.4 (SAS Institute, Cary, NC) was used for data cleaning and descriptive analyses. Stata version 14.2 (StataCorp, College Station, TX) was used for all other analyses. | PMC9978547 |
RESULTS | malaria infection statusMUAC | Characteristics of study participants are shown in Characteristics of children enrolled in the GAMIN trial in Burkina Faso by baseline malaria infection statusMUAC = mid-upper arm circumference. | PMC9978547 | |
Effect of malaria infection on anthropometric measures. | infection, malaria infection | MALARIA, INFECTION | In the adjusted analysis, children with malaria infection at baseline had slightly lower mean height, MUAC, HAZ, and WAZ at 2 weeks and 6 months after enrollment compared with children without malaria infection, although these estimates did not reach statistical significance (Unadjusted and adjusted mean difference in anthropometric measures at 2 weeks and 6 months by malaria infection status with 95% CIMUAC = mid-upper arm circumference. Covariates adjusted in models included age, sex, study treatment, maternal education, and breastfeeding.Adjusted anthropometric measures at each visit by baseline malaria infection status. HAZ = height-for-age z-score; MUAC = mid-upper arm circumference; WAZ = weight-for-age z-score; WHZ = weight-for-height z-score. | PMC9978547 |
Sensitivity analyses. | malaria, infection | MALARIA, INFECTION | In a sensitivity analysis controlling for age in months in models stratified by age groups (0–30 and 30–60 months), we found that results were very similar with regard to point estimates and statistical significance. The only change was for children aged 0–30 months, where the effect of baseline height on the prevalence of malaria infection changed from borderline statistically significant to borderline insignificant (RR = 1.09; 95% CI: 1.01–1.17 versus RR = 1.08; 95% CI: 1.00–1.17 in sensitivity analysis). In the sensitivity analysis of LTFU, none of the covariates were significantly associated with missing the third or both follow-up visits. | PMC9978547 |
DISCUSSION | malaria, infection, malaria infection | MALARIA, INFECTION | Our findings show that in this study population, baseline malaria infection did not affect growth at measurements 2 weeks and 6 months later. The effect of baseline anthropometric measures on the prevalence of malaria infection varied by child age. An increase in anthropometric measures at baseline increased the prevalence of malaria infection in children aged 0–30 months but not in those 30–60 months. Older children (aged 30–60 months) with lower height, HAZ, and MUAC and younger children (aged 0–30 months) who had higher weight-related measures (i.e., had higher weight, WAZ, and WHZ) had a higher prevalence of malaria infection. | PMC9978547 |
Effect of malaria infection on anthropometric measures. | malaria | MALARIA, MALNUTRITION | Previous studies found mixed results regarding the effect of malaria on growth and malnutrition. Some studies found that malaria could impair growth. | PMC9978547 |
Effect of anthropometric measures on the prevalence of malaria infection. | malaria, malaria infection | MALARIA, INFECTION | For the effect of baseline anthropometric measures on the prevalence of malaria infection, in the adjusted analysis, there was no substantial increase or decrease in the prevalence of malaria infection for increasing anthropometric measures. Although the findings from previous studies are mixed, this result is in line with some of the studies that found that anthropometric indices were not important predictors of malaria. | PMC9978547 |
Effect modification by age. | malaria, micronutrient deficiencies, malaria infection, protein-energy malnutrition, malnutrition | MALARIA, PROTEIN-ENERGY MALNUTRITION, MALNUTRITION | In this study, we found that the effect of baseline anthropometric measures on malaria infection prevalence varied by age. In those aged 30–60 months, there was a slight decrease in the prevalence of malaria infection as baseline measures increased, although the CIs did not reach statistical significance. Contrary to some of the studies mentioned above that found no effect, some studies found that malnutrition increasedIn children aged 0–30 months, lower anthropometric measures were protective of malaria infection (Although the assessment of effect modification was exploratory, differences in the effect of malnutrition on malaria infection by age group may be suggestive of distinct pathophysiologic pathways. Specific micronutrient deficiencies such as vitamin A, zinc, and protein-energy malnutrition have been associated with increased risk of malaria, | PMC9978547 |
Strengths and limitations. | malaria infection, malnutrition | MALNUTRITION | This study had some limitations. First, we had a relatively small sample size, which could limit our statistical power to detect more subtle differences. However, several other studies, particularly longitudinal studies on this topic, also had similar sample sizes ranging between 202 and 847 participants.This study also had several strengths, including its longitudinal data, which allowed us to establish temporality and comprehensively evaluate bi-directional effects in the same population. This may also be one of the few (if any) studies to assess the role of age in modifying the effect of malnutrition on the prevalence of malaria infection. | PMC9978547 |
CONCLUSION | malaria, infection, malaria infection, malnutrition | MALARIA, INFECTION, MALNUTRITION | The effect of malnutrition on the prevalence of malaria infection may vary by age. The prevalence of malaria infection increased with increasing anthropometric measures among children aged 0–30 months, whereas it slightly decreased for children aged 30–60 months. Children aged 30–60 months with lower height, HAZ, and MUAC and younger children (aged 0–30 months) who had higher weight and WAZ and WHZ z-scores had a higher prevalence of malaria infection. We recommend that future studies examine age-related and other factors that may exacerbate or mitigate the effect of malnutrition on malaria infection. It may also be useful to examine these associations at both individual and community levels. | PMC9978547 |
REFERENCES | PMC9978547 | |||
Purpose | pain | The aim of this study was to explore the isolated and combined effects of caffeine and citrulline malate (CitMal) on jumping performance, muscular strength, muscular endurance, and pain perception in resistance-trained participants. | PMC10468939 | |
Methods | Using a randomized and double-blind study design, 35 resistance-trained males ( | PMC10468939 | ||
Results | Compared to the placebo condition, isolated caffeine ingestion and co-ingestion of caffeine and CitMal significantly enhanced strength in 1RM bench press (Cohen’s | PMC10468939 | ||
Conclusion | Caffeine ingestion appears to be ergogenic for muscular strength and muscular endurance, while adding CitMal does not seem to further enhance these effects. | PMC10468939 | ||
Supplementary Information | The online version contains supplementary material available at 10.1007/s00394-023-03212-x. | PMC10468939 | ||
Keywords | Open access funding provided by Nord University | PMC10468939 | ||
Introduction | Caffeine is a highly popular ergogenic supplement used among athletes and non-athletes alike [Another supplement that has gained popularity in recent years is citrulline malate (CitMal), which represents a combination of L-citrulline and malic acid. L-citrulline is a non-essential amino acid primarily found in foods such as watermelon and cucumber [Historically, research has mainly explored the effects of a given supplement when provided in isolation. This approach is adopted from a methodological standpoint as it allows for the controlled intake of other substances that may enhance exercise performance [ | PMC10468939 | ||
Methods | PMC10468939 | |||
Study design | PP pain | A randomized, double-blind, placebo-controlled, crossover trial (Fig. Overview of the study design. CMJ countermovement jump, RM repetitions maximum, SQ squat, BP bench press, AMRAP as many repetitions as possible, PP pain perceptionTimeline of test day. Questionnaire one was only given on familiarization (personal data, weight, food log, caffeine log, resistance training experience). Questionnaire two included evaluation of the effectiveness of the blinding. CMJ countermovement jump, RM repetition maximum, SQ squat, BP bench press, AMRAP as many repetitions as possible | PMC10468939 | |
Supplementation | All supplement conditions had a similar color and taste as they were mixed in 500 mL of Fun Light zero-calorie sweetened water (200 mL water and 300 mL non-caloric Fun light sweetener; Fun Light | PMC10468939 | ||
Adverse events | nausea, insomnia, disability | ADVERSE EVENTS, ADVERSE EVENT | The incidence and severity of adverse events were tracked during the testing sessions and throughout the remainder of the testing day. Specifically, during the testing sessions, the participants were encouraged to provide details about any adverse events (e.g., nausea). After the testing was completed, the participants were also required to record any additional adverse events (e.g., insomnia, irregular heartbeat, etc.). If an adverse event occurred, the participants were required to note its description, the likelihood of its association with the intervention (not related, unlikely, possibly, probably, definite), severity (life-threatening, required hospitalization, resulted in persistent disability, or non-serious), and its intensity (mild, moderate, severe, life-threatening) [ | PMC10468939 |
Measurements | PMC10468939 | |||
Countermovement jump | Each testing session started with the CMJ test on a force plate (Muscle lab, Ergotest Technology AS, Porsgrunn, Norway), which was used to evaluate jump height (cm), maximal power (W), rate of force development (kN/s), and peak force (N/kg). The CMJ was performed with feet shoulder-width apart and hands on the hips during the whole jump. From a standing position, participants were required to squat to a self-selected depth and then perform a maximal vertical jump. The feet had to be straight during the flight time. Jump height was calculated with impulse (Muscle lab, Ergotest Technology AS, Porsgrunn, Norway). As a warm-up, the participants performed three submaximal CMJ trials with approximately 50%, 75%, and 90% intensity (45 s of rest between attempts). Following the warm-up, three CMJ attempts were performed, and the participants rested 15 s between each attempt. Highest values for each of the analyzed variables were used for statistical analysis. | PMC10468939 | ||
1RM squat and bench press | Participants completed a 1RM test for both the squat and the bench press. In both exercises, a five sets warm-up protocol was utilized. In the first set, the participants completed several repetitions only with the barbell. Then, they completed 8, 6, 3, and 2 repetitions with loads amounting to 40%, 60%, 70%, and 80% of their estimated 1RM, respectively [ | PMC10468939 | ||
Repetitions to failure and pain perception | Muscular failure, muscular failure, pain | Muscular endurance was evaluated by having the participants complete one set of repetitions to muscular failure in the squat and bench press using 60% of 1RM (from 1RM measured at each trial). During the set, the number of completed repetitions was counted out loud by the test leader. No breaks were allowed between repetitions. Technical requirements were the same as in the 1RM tests. Muscular failure was defined as not being able to complete a full repetition without assistance or failing to keep up the standardized tempo set by the test leader on two consecutive repetitions. Specifically, if a participant included too long of a pause (> 1 s) between muscle actions, a warning from the test leader was provided; if the same occurred in the next repetition, this was deemed as muscular failure, thus denoting the end of the test. Within 15 s of completion of the test, the participants were required to rate their perceived pain on an 11-point numerical rating scale, with the instructions that 0 points were equivalent to “no pain” and 10 points were their “worst imaginable pain” [Mean ± standard deviation for each condition | PMC10468939 | |
Statistical analyses | pain | The normality of data distribution was examined and confirmed using the Shapiro–Wilk test. A one-way analysis of variance (ANOVA) with repeated measures was conducted to explore the differences in performance outcomes (jump height, RFD, force, power, 1RM squat, 1RM bench press, number of repetitions in the squat and bench press) and subjective responses (pain perception) between the four conditions. In the case of a significant main effect from the ANOVA, the Sidak post hoc test was used to identify where the difference occurred (i.e., between which pairs). If the assumption of sphericity was violated, the Greenhouse–Geisser adjustment was used. All performance results are presented as mean ± standard deviations. Effect size ( | PMC10468939 | |
Results | PMC10468939 | |||
Countermovement jump | There was no significant main effect for CMJ height [F(3, 31) = 1.28; | PMC10468939 | ||
Muscular strength | Percent change in strength from placebo to caffeine and CitMal supplementation are presented in Fig. Percentage difference compared to placebo. Mean ± 95% confidence interval for Data are presented as group mean ± 95% confidence interval and individual data (dark points are males and white points are females) for Data are presented as group mean ± 95% confidence interval and individual data (dark points are males and white points are females) for Summary of the pair wise comparisons between the conditions | PMC10468939 | ||
Muscular endurance | pain | A significant main effect was found for the number of repetitions in the squat [F(3, 29) = 5.40, A significant main effect was found for the number of repetitions in the bench press [F(3, 33) = 7.66, There was no significant effect for pain perception following the completion of the repetitions to failure test in squat [F(3, 29) = 0.73, | PMC10468939 | |
Effectiveness of the blinding | In the effectiveness of the blinding evaluation, 46% (16/35), 46% (16/35), 26% (9/35), and 23% (8/35) of the participants correctly guessed the placebo, caffeine, caffeine and CitMal, and isolated CitMal conditions, respectively. | PMC10468939 | ||
Adverse events | dizziness, nausea, headache | ADVERSE EVENTS, EVENTS, ADVERSE EVENT | Seven adverse events were reported. These adverse events included headache (three), nausea (three), and dizziness (one). Six out of seven adverse events were reported as ‘probably’ when investigating the relationship to the supplements, and one adverse event was categorized as ‘definite’. Six adverse events that were categorized as ‘probably’ were also considered ‘non-serious’. From an intensity standpoint, three adverse events were categorized as ‘mild’, and four as ‘moderate’. Notably, all seven adverse events were reported when participants received both caffeine and CitMal combined, and five out of the seven adverse events were reported by female participants. Finally, besides these seven events, one participant threw up 22 min after supplement ingestion of both caffeine and CitMal. For this participant, testing that day was terminated and successfully conducted another day. | PMC10468939 |
Discussion | lower-body muscular endurance, pain | This is the first study to explore the effects of co-ingestion of caffeine (5 mg/kg) and CitMal (12 g) compared to either supplement in isolation or placebo. The main findings of this study were that the isolated ingestion of caffeine and co-ingestion of caffeine and CitMal was ergogenic for upper-body muscular strength and endurance, and lower-body muscular endurance. We did not detect any additional effects of co-ingesting CitMal with caffeine, suggesting that combining these supplements may not provide additive effects compared to isolated caffeine ingestion. For CMJ variables, and pain perception, there were no differences between the treatments, and CitMal supplementation in isolation did not have an ergogenic effect on any outcome. As such, these results only partially confirm our initial hypothesis. | PMC10468939 | |
Countermovement jump | Caffeine consumption alone and combined with CitMal did not influence jump height in our study. The lack of an effect on CMJ measurements is contrary to other research on caffeine [Besides the two treatments with caffeine, isolated ingestion of CitMal did not enhance jumping performance. Rapid force production is necessary to enhance performance in the CMJ test, which is not likely to be achieved with CitMal ingestion. Indeed, CitMal ingestion is likely to be ergogenic in exercise of longer duration, whereas the performance benefit during short burst exercises is likely to be trivial or non-existential. Our results for jumping performance are similar to those from Glenn et al. [ | PMC10468939 | ||
Muscular strength | In the present study, caffeine alone and caffeine plus CitMal increased maximal strength compared to placebo. The ergogenic effects of caffeine on maximal strength are well-established [While caffeine provided an ergogenic effect, isolated CitMal ingestion did not influence maximal strength. In the currently available studies exploring CitMal, there is a distinct lack of those that evaluated the effects of CitMal on 1RM performance. However, they have used other measurements of maximum strength. For example, one study provided 8 g of CitMal and evaluated peak force during different muscle actions. In line with our 1RM data, the ingestion of CitMal did not enhance isometric, concentric, or eccentric peak force [ | PMC10468939 | ||
Muscular endurance | upper-body muscular endurance | STILL | Caffeine alone and caffeine co-ingested with CitMal improved lower-body and upper-body muscular endurance with a moderate effect size. While an ergogenic effect was found in both conditions, there were no differences between isolated caffeine vs. caffeine and CitMal combined.An ergogenic effect of caffeine on muscular endurance has been commonly observed in the literature. For example, Norum et al. [We did not detect a significant effect of isolated CitMal ingestion on muscular endurance. Still, it should be mentioned that the mean difference highly favored the CitMal condition compared to placebo. Mean differences favored CitMal in the squat by 1.9 repetitions (95% confidence interval: − 0.3, 4.0 repetitions) and in the bench press by 1.2 repetitions (95% confidence interval: − 0.04, 2.4 repetitions). In line with our findings, a recent meta-analysis by Vårvik et al. [The results in the present study suggest that the combination of caffeine and CitMal is not likely to have additive ergogenic effects on muscular endurance. There are several possible reasons for such a lacking additive effect. First, when compared to placebo, isolated CitMal was not found to be ergogenic—even though the effects highly favoured the CitMal condition. Given that CitMal did not demonstrate significant ergogenic effects in isolation, it seems logical that adding this supplement to caffeine would not yield greater performance benefits than ingesting caffeine alone in our study. Nevertheless, since the potential ergogenic effect of CitMal on muscular endurance appears to be very small [ | PMC10468939 |
Pain perception | pain | In the analysis for pain perception, we did not find a significant main effect. Previous studies observed that caffeine ingestion reduces pain perception [ | PMC10468939 | |
Adverse events | nausea, gastrointestinal problems | From a safety perspective, the co-ingestion of caffeine and CitMal could lead to gastrointestinal problems. Indeed, several participants reported nausea, but only following the combined ingestion of caffeine and CitMal. Interestingly, the incidence of side-effects was more common in women. The reason for that may be because the relative dose of CitMal was larger for women than men (0.14 g/kg for males and 0.18 g/kg for females). In addition, ingestion of caffeine alone has also been previously reported to cause gastrointestinal problems [ | PMC10468939 | |
Limitations and strengths of the study | VASODILATATION | One of the limitations of the present study is that we did not measure plasma concentrations of caffeine and citrulline. Secondly, we did not measure possible mediators of the supplements that could have given more insight into the potential interactions between them, such as vasoconstriction and vasodilatation. Thirdly, the majority of participants in the present study were classified as moderate caffeine consumers (Despite the outlined limitations, there are also certain strengths of the study that should be considered. For example, we included a fairly large number of both male and female participants. We evaluated multiple performance outcomes, including jumping-related outcomes (i.e., jump height, RFD, peak force, and peak power), muscular strength and endurance. The barbell back squat and bench press exercises were used to evaluate muscular strength and endurance, miming real-life conditions given the common use of these exercises in various strength and conditioning programs [ | PMC10468939 | |
Conclusions | This is the first study to explore the effects of co-ingestion of caffeine (5 mg/kg) and CitMal (12 g) compared to either supplement in isolation or placebo. We found that the ingestion of caffeine alone or combined with CitMal improved maximal strength and muscular endurance, but there were no additive effects of combining these supplements. There was no significant difference between the conditions for CMJ-derived variables. CitMal provided in isolation was not ergogenic for any of the analyzed outcomes. In summary, caffeine ingestion appears to be ergogenic for muscular strength and muscular endurance, while adding CitMal does not seem to further enhance these effects. | PMC10468939 | ||
Supplementary Information | Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 153 KB) | PMC10468939 | ||
Funding | Open access funding provided by Nord University. No funding received. | PMC10468939 | ||
Data availability | On reasonable request data can be shared. | PMC10468939 | ||
Code availability | Not applicable. | PMC10468939 | ||
Declarations | PMC10468939 | |||
Conflict of interest | Markus Haugen has received payment for sports nutrition consultancy work with Empire Athletics, Norway. The other authors declare that there is no conflict of interest regarding the content of this article. | PMC10468939 |
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