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Effect sizes correction in significant one-way ANCOVA | The ANCOVA procedure in SPSS by default calculates effect size using partial eta squared (We calculated the The resulting | PMC10306226 | ||
Interpretation of corrected partial η | Note. HLL = Haizea-llevant.As can be seen from | PMC10306226 | ||
Discussion | SECONDARY | This study was a pilot Q-RCT of parent training for a remote booklet intervention with preschool children at risk of not reaching their developmental potential. Findings in the CARE booklet intervention (CBI) were in line with our prediction that the parental training interventions would enhance children’s developmental status and language-related skills. Also, follow-up testing on the CBI group revealed significant positive results in both primary and secondary outcomes, compared to the control group that had received local services only. This includes the effect of the decrease in HLL Delay items for the post-test measurements in the CBI group compared with the control group. In the ANCOVAs overall effects interpretation, medium-sized effects were found in one developmental dimension.The consideration of sociodemographic variables in the two-way ANCOVA analysis is informative for any future RCT, which requires a deep evaluation of home conditions and local services relating to the formal introduction to writing, alongside training in cognitive skills and performance with narrative devices. The results for the CBI group support the screening tool’s use as a practical approach to parental reporting that gives confidence in our ability to evaluate activities and interactions at home. Reduction in overall delays, and a medium-sized effect on narrative devices and fine motor-adaptive skills, confirm the CBI as a feasible solution to provide prompts, guidance, and scaffolding to parents and caregivers [Dosage intervention has had significant effects on previous parental training studies [The COVID-19 pandemic had causal effects on mental health and caregiving environments, particularly in contexts of poverty. These effects have been observed in Colombia and other LMICs, and have increased the risk of children not reaching their developmental potential [ | PMC10306226 | |
Limitations and future research | RECRUITMENT | All effect sizes in a pilot study should be interpreted with caution because there are several limitations due to the small sample size. A larger sample size is needed for a rigorous and detailed mapping of the effects of similar procedures on poor, low-income families in LMICs, including adequate controls for sociodemographic variation for future post hoc analysis after the two-way ANCOVA procedures to properly evaluate the CBI.Comparing the CBI with Colombian center-based interventions like the aeioTu program [Families allocated to the control (local services only) group were assigned to the control condition because they did not present themselves on the day of randomized allocation and cannot be considered a truly random control group. However, this reflects a real-life clinical and research situation. Future RCT studies should be completely coherent with randomized allocation and sufficient sample size to avoid potential biases and to increase statistical power to generalize the differences between groups detected.Another limitation of our study is related to our measure of development. The Haizea-Llevant observation table (HLL) is meant as a screening tool and not a diagnostic tool. A high number of Delay and Caution items in the HLL developmental dimensions should not be strictly interpreted as a delay relative to benchmarks in comparison with children of the same age. Therefore, the results were framed in terms of children being "at risk" of a loss of developmental potential, rather than as a diagnosis of a specific developmental delay.The generalizability of our findings may be affected by using a sample from a community-based services program. Participation in the nutritional program offered in the participating childcare center was voluntary, and parents who had concerns about their child’s development may have been more likely to stay in the program than parents who found their children to be on track. This could have inflated our estimates of the prevalence of risk for developmental delay. However, our sample had relatively similar proportions of various sociodemographic risk factors as the broader group of participants previously seen as at risk of developmental delay [A major limitation of this study is the lack of direct observational assessment of parent skills, such as caregiver social play sensitivity, which has been shown to produce significant positive changes in infants’ cognitive and socioemotional outcomes in previous parental and language interventions [The present study has highlighted significant practical and methodological challenges in conducting an RCT of a remote intervention for parents in low-income conditions with preschool children at risk of not reaching their developmental potential. One major obstacle in our study was the high rate of declining to join after the initial call, which affected our recruitment rate—more than half of the potential families who could have received the intervention (54.9%) opted not to participate. Unfortunately, the reasons for their decision were not collected. Recent meta-analyses and evidence-based studies [Moreover, future studies aiming to improve interaction skills between caregivers and children [ | PMC10306226 | |
Supporting information | (BIN)Click here for additional data file.The author expresses sincere gratitude to the families and mothers at Amiguitos Royal CC in Bogotá, as well as the internship students of the Pasantía de Cuidado y Desarrollo from the Department of Psychology at the Universidad de la Sabana. Special thanks are extended to Dr. Graham Schafer and Prof. Peter Cooper for their valuable comments on the initial research design, as well as their contributions towards the improvement and clarification of the study during its early stages. | PMC10306226 | ||
Background | Depression | Depression is common among adults who smoke cigarettes. Existing depression-specific cessation interventions have limited reach and are unlikely to improve smoking prevalence rates among this large subgroup of smokers. | PMC10652199 | |
Objective | depression | This study aimed to determine whether a mobile app–based intervention tailored for depression paired with a mailed sample of nicotine replacement therapy (NRT) is efficacious for treating depression and promoting smoking cessation. | PMC10652199 | |
Methods | depression, Depression, depressive symptoms | A 2-arm nationwide remote randomized clinical trial was conducted in the United States. Adults (N=150) with elevated depressive symptoms (Patient Health Questionnaire-8≥10) who smoked were enrolled. The mobile app (“Goal2Quit”) provided behavioral strategies for treating depression and quitting smoking based on Behavioral Activation Treatment for Depression. Goal2Quit participants also received a 2-week sample of combination NRT. Treatment as usual participants received a self-help booklet for quitting smoking that was not tailored for depression. Primary end points included Goal2Quit usability, change in depression (Beck Depression Inventory-II) across 12 weeks, and smoking cessation including reduction in cigarettes per day, incidence of 24-hour quit attempts, floating abstinence, and 7-day point prevalence abstinence (PPA). | PMC10652199 | |
Results | SE, depressive, SD, depressive symptoms | In total, 150 participants were enrolled between June 25, 2020, and February 23, 2022, of which 80 were female (53.3%) and the mean age was 38.4 (SD 10.3) years. At baseline, participants on average reported moderate depressive symptoms and smoked a mean of 14.7 (SD 7.5) cigarettes per day. Goal2Quit usability was strong with a mean usability rating on the System Usability Scale of 78.5 (SD 16.9), with 70% scoring above the ≥68 cutoff for above-average usability. Retention data for app use were generally strong immediately following trial enrollment and declined in subsequent weeks. Those who received Goal2Quit and the NRT sample reported lower mean depressive symptoms over the trial duration as compared to treatment as usual (difference of mean 3.72, SE 1.37 points less; | PMC10652199 | |
Conclusions | depression | A mobile app intervention tailored for depression paired with a sample of NRT was effective for depression treatment and smoking cessation. Findings support the utility of this intervention approach for addressing the currently unmet public health treatment need for tailored, scalable depression-specific cessation treatments. | PMC10652199 | |
Trial Registration | ClinicalTrials.gov NCT03837379; https://clinicaltrials.gov/ct2/show/NCT03837379 | PMC10652199 | ||
Introduction | depressive, depression, depressive symptoms | Despite significant declines over the last 50+ years in cigarette smoking prevalence among the general population, smoking rates remain astonishingly high among certain vulnerable subgroups. One such subgroup is the 48 million US adults with depressive symptomatology [Tailored cessation treatments that incorporate depression-specific psychosocial treatment components increase long-term quit rates by up to 50% among those with current depressive symptoms [An ideal depression-specific psychosocial treatment to adapt for digital delivery must be both evidence-based and simple so that the treatment can be easily understood via a self-guided digital platform. Behavioral activation (BA) is an evidence-based depression intervention that focuses on regular self-monitoring to (1) examine already occurring activities and (2) facilitate the incorporation of new activities consistent with individualized values or goals across life areas [Importantly, because medication management is a critical component of any tobacco cessation intervention [To address the lack of effective, scalable smoking cessation approaches for individuals with depressive symptoms, our team developed “Goal2Quit,” a BA-based self-directed mobile app intervention. Goal2Quit was paired with a short duration of mailed nicotine replacement therapy (NRT) with instructions provided in Goal2Quit that users should contact their primary care provider, their state quitline, or visit a local pharmacy to obtain additional NRT or other cessation medications. This nationwide decentralized randomized clinical trial aimed to examine the usability and uptake of Goal2Quit among adult smokers with depressive symptoms as well as its efficacy for improving depression and promoting smoking cessation. | PMC10652199 | |
Methods | PMC10652199 | |||
Ethical Considerations | The study and protocol were approved by the Medical University of South Carolina institutional review board (Pro00074015). Participants provided electronic written informed consent before enrollment. Trial information is presented according to the CONSORT (Consolidated Standards of Reporting Trials) and the trial was preregistered on ClinicalTrials.gov (NCT03837379). | PMC10652199 | ||
Participants | Study participants were recruited nationwide via web-based advertising (2020-2022). Consistent with guidelines for preventing participant deception in web-based nicotine and tobacco research studies [ | PMC10652199 | ||
Procedures | All study procedures were delivered fully remotely, consistent with a decentralized clinical trial design [To minimize fraud [ | PMC10652199 | ||
Interventions | PMC10652199 | |||
Goal2Quit | Goal2Quit treatment content is consistent with the original BA for smoking cessation group therapy manual [Goal2Quit was paired with a mailed 2-week sample of NRT, inclusive of 14 mg nicotine patches and 4 mg nicotine lozenges. As nicotine lozenges were provided in addition to nicotine patches, we opted for uniform NRT patch dosing.Goal2Quit. NRT: nicotine replacement therapy. | PMC10652199 | ||
TAU | depression, Cancer | CANCER | We selected TAU as an appropriate control since the central research question herein is whether Goal2Quit improves depression and smoking cessation outcomes relative to existing treatment services. Research staff provided participants with a digital copy of the National Cancer Institute’s “Clearing the Air: Quit Smoking Today” booklet [ | PMC10652199 |
Assessments | PMC10652199 | |||
Overview | All participants at baseline completed a general assessment of demographics as well as assessments of confidence in quitting smoking (0-10 Likert scale) [ | PMC10652199 | ||
Goal2Quit Usability and Uptake | Assessment of Goal2Quit usability and uptake included self-reported app usability and passively collected app analytics. At week 4, participants randomized to the Goal2Quit condition completed the System Usability Scale [ | PMC10652199 | ||
Depression | depressive symptoms | Participants self-reported depressive symptoms via the Patient Health Questionnaire-8 [ | PMC10652199 | |
Smoking Cessation | CPD | At each follow-up, participants self-reported (1) the number of cigarettes smoked per day over the last 7 days (also captured at baseline) and (2) the incidence of quit attempts lasting at least 24 hours since the prior assessment. Data regarding quit attempts were collapsed across time points to indicate any 24-hour quit attempt during the first 4, first 8, and all 12 weeks of follow-up. Data regarding CPD during the last week were coded as to whether the participant had reduced their mean CPD by at least 50% between baseline and week 4, week 8, and week 12. Those who reported any 7-day period of complete abstinence between baseline and week 12 were coded as having 7-day floating abstinence. At weeks 4, 8, and 12, those who reported smoking zero cigarettes over the last 7 days (prior to assessment) were coded as having 7-day point prevalence abstinence (PPA) for that time point. Cessation outcomes were based on self-report and were not biochemically verified. | PMC10652199 | |
Data Analytic Plan | CPD, depression, depressive symptoms | REGRESSION | All individuals randomized to Goal2Quit or TAU and not removed for fraud were included in analyses. Descriptive statistics for baseline variables, usability metrics, and app uptake were calculated for the overall sample and per group, as appropriate. Between-group changes in depressive symptoms and CPD were compared via general linear models to account for repeated measures across time within an individual as well as the main effects of the baseline level of the outcome, group, time, an interaction between group and time, and baseline covariates determined a priori (sex, CPD, and depression). For nonsignificant interaction terms, the interaction term was removed from the model. For all modeling and analyses, an α=.05 level of significance was applied. Other smoking cessation outcomes (quit attempts and abstinence) were evaluated using logistic regression models to determine if there were group differences after adjustment for sex, baseline CPD, and baseline depression at the time point of interest. Logistic regression models were also used to evaluate any effect of app use on cessation outcomes within the Goal2Quit group. All analyses using binary outcomes were analyzed via an intent-to-treat approach, such that individuals with missing data were included in the analysis and treated as not having achieved the cessation outcome of interest. For analyses of continuous outcomes such as CPD and BDI, missing data were left as missing for that visit, with models including all visits completed by an individual. | PMC10652199 |
Results | PMC10652199 | |||
Participant Characteristics | Depression | PCP | See CONSORT diagram. BDI: Beck Depression Inventory; BL: baseline; NRT: nicotine replacement therapy; PCP: primary care provider; PHQ-8: Patient Health Questionnaire-8.Participant demographics. | PMC10652199 |
Goal2Quit Usability and Uptake | SD | The mean Goal2Quit usability on the System Usability Scale at week 4 was 78.5 (SD 16.9), with 70% scoring above the ≥68 cutoff for above-average usability [ | PMC10652199 | |
Depression | worsening mood, depression, Depression, depressive symptoms | There was no evidence that the association between group and change in depressive symptoms varied over time (Regarding worsening depression over time, 37 participants reported worsening mood, defined as an increase of 10 or more points on the BDI-II since baseline, at some point during the study duration (23 Goal2Quit, 14 TAU) and 11 participants endorsed suicidality (4 Goal2Quit, 7 TAU).Change in (A) depressive symptoms and (B) CPD over time by treatment group. Raw means are depicted with corresponding SD. BDI-II: Beck Depression Inventory-II; BL: baseline; CPD: cigarettes per day. | PMC10652199 | |
Smoking Cessation | Across time points, all cessation outcomes favored Goal2Quit. Goal2Quit participants were more likely to have made a 24-hour quit attempt during the first 4 (17% vs 2%; There was no evidence that the association between group and change in CPD varied over time (Within the Goal2Quit group, total time spent using the app was significantly related to abstinence at week 12, with the odds of reporting 7-day PPA increasing 7% for every 5-minute increase in app use (odds ratio [OR] 1.07, 95% CI 1.01-1.13; Smoking cessation outcomes as a function of treatment group. TAU: treatment as usual. | PMC10652199 | ||
Discussion | CPD, depression, depressive symptoms | ABUSE | These results preliminarily indicate that Goal2Quit paired with a mailed sample of NRT (1) is usable by adults with depressive symptoms who smoke cigarettes, (2) is efficacious for depression treatment, and (3) promotes smoking cessation. Regarding usability and treatment engagement, outcomes can be compared to other available digital interventions. A recent, also fully decentralized, trial evaluating 2 app-based smoking cessation interventions found that 42.9% of users continued to use their intervention beyond 1 week of download and only 14.6% beyond 4 weeks [Regarding depression outcomes, Goal2Quit demonstrated efficacy for depression treatment. As compared to TAU, those who received Goal2Quit reported lower depression symptom severity over the course of the trial, with the most pronounced improvements occurring during the first 3 weeks after receiving the intervention, consistent with a prior in-person trial of BA for smoking cessation [Regarding smoking cessation, on all indicators, Goal2Quit outperformed TAU. Those who received Goal2Quit were more likely to attempt to quit and achieve abstinence. Similar to depression outcomes, the greatest decreases in CPD occurred early in the trial, between baseline and week 2. While these decreases also mirror patterns of early app engagement, these changes in smoking behavior are also likely related to the duration of NRT (2 weeks) provided in combination with Goal2Quit. Cessation outcomes can be compared to those of standard, in-person BA-based group therapy for smoking cessation among individuals with depressive symptoms as well as other app-based interventions for broader groups of individuals who smoke cigarettes. Participants in a prior trial who received in-person BA in addition to 8 weeks of NRT patches had biochemically verified cessation rates of 28.6%, 17.1%, 11.4%, and 14.3% at 1, 4, 16, and 26 weeks post the quit date, respectively [Given that the purported mechanism of BA is the completion of goal-driven activities, intervention refinements that specifically promote activity completion may help to bolster therapeutic effects in the future. On average, participants scheduled 72.8 activities across the 12-week study duration. This rate of activity scheduling is consistent with the original BA for smoking cessation treatment manual [The results of this study should be interpreted with limitations in mind. We were unable to disentangle the effects of the Goal2Quit app versus the NRT sample since the intervention group received both. However, this was an a priori decision as digital cessation interventions must be paired with pharmacotherapy to address both behavioral and physical symptoms of nicotine dependence. Additionally, all cessation outcomes were based on self-report. In our team’s prior remote trials, biochemically verified abstinence rates have been somewhat lower than self-reported abstinence [There are a number of additional important future directions stemming from this work. While digital interventions may increase treatment accessibility, sustainability must also be considered. Next steps should focus on the evaluation of effectiveness, implementation, and eventually embedding the intervention in clinical practice or other settings that can benefit [In conclusion, Goal2Quit paired with a brief, mailed sample of NRT was effective for the treatment of depression as well as smoking cessation among remotely enrolled adult smokers with depressive symptoms recruited from across the country. Findings support the utility of this intervention approach for addressing the currently unmet public health treatment need for tailored, scalable depression-specific cessation treatments.Funding for this research was provided by the National Institute on Drug Abuse (K23 DA045766). The funding source had no role in study design, data collection, data analysis, data interpretation, writing this report, or in the decision to submit this paper for publication. The authors would like to thank MountainPass Technology for their partnership in developing Goal2Quit and study staff members, including Johanna Hidalgo and Monika Schindwolf, for assistance in data collection.Authors' Contributions: JD and AEW had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design were contributed by JD, MJW, and VAD. Acquisition, analysis, or interpretation of data was conducted by all authors. The drafting of the paper was primarily carried out by JD and AEW. All authors participated in the critical revision of the paper, ensuring important intellectual content was addressed. Statistical analysis was performed by JD and AEW. Acquisition of funding was the responsibility of JD. Administrative, technical, or material support was provided by AEW, JK, and NN. Supervision duties were undertaken by JD and MJW.Conflicts of Interest: JD and JK are co-owners of Behavioral Activation Tech LLC, a small business that develops digital interventions for behavioral health treatment. Behavioral Activation Tech does not have a financial interest in Goal2Quit. JK is the owner and principal of MountainPass Technology LLC, the software development company that led the development of Goal2Quit. MountainPass Technology does not have a commercial interest in Goal2Quit. Intellectual property for Goal2Quit is owned by the Medical University of South Carolina.Goal2Quit uptake.Goal2Quit app retention (N=103).CONSORT-eHEALTH checklist (V 1.6.1). | PMC10652199 |
Abbreviations | activationBeck Depression | behavioral activationBeck Depression Inventory-IIConsolidated Standards of Reporting Trialscigarettes per daynicotine replacement therapyodds ratiopoint prevalence abstinenceResearch Electronic Data Capturetreatment as usual | PMC10652199 | |
CONFLICT OF INTERESTS STATEMENT | diabetic retinopathy, cardiovascular comorbidities, CVD, Hanhart, diabetes | DIABETIC RETINOPATHY, MYOCARDIAL INFARCTION (MI), ACUTE MI, CARDIOVASCULAR DISEASE, KIDNEY DISEASE, CVD, ADVERSE EVENTS, ADVERSE EFFECTS, HANHART, DIABETES |
Bloomgarden reviewed a variety of relevant studies summarizing new approaches to the treatment of diabetes citing a study showing that anti‐vascular endothelial growth factor (VEGF) treatment of over 14 000 patients with diabetic retinopathy (DR) was associated with increased likelihood of myocardial infarction (MI) and overall cardiovascular disease (CVD), although with the annotation that the association may be confounded by the relationship between cardiovascular comorbidities and more severe degrees of DR.Indeed, in a recent retrospective longitudinal population‐based analysis of 1 731 782 individuals, Zafar et al reported that, in patients with DR, intravitreal anti‐VEGF injections were associated with an increase in the likelihood of systemic adverse events, such as acute MI, CVD, or kidney disease.Unlike patients reported in registration and other randomized clinical trials, patients with DR in the clinical practice setting are possibly at greater risk of serious adverse effects.Joel Hanhart and Sohee Jeon have nothing to disclose. Raimo Tuuminen is a scientific advisor (advisory board, honoraria) to Alcon Laboratories, Inc., Allergan, Inc., and has received clinical trial support (study medicines) from Bayer AG and Laboratoires Théa. | PMC10590675 |
ACKNOWLEDGEMENT | None. | PMC10590675 | ||
REFERENCES | PMC10590675 | |||
Purpose | esophageal cancer | OESOPHAGEAL CANCER | Participation in a post-treatment exercise program improves cardiorespiratory fitness and aspects of quality of life for esophageal cancer survivors. For optimal effects, high adherence to the exercise intervention is important. We assessed which facilitators and barriers to exercise adherence are perceived by esophageal cancer survivors, who participate in a post-treatment exercise program. | PMC10164010 |
Methods | The current qualitative study was performed within the randomized controlled PERFECT trial, in which we investigated effects of a 12-week supervised exercise program with moderate-to-high intensity and daily physical activity advice. Semi-structured interviews were conducted with patients randomized to the exercise group. A thematic content approach was used to derive perceived facilitators and barriers. | PMC10164010 | ||
Results | Thematic saturation was reached after inclusion of sixteen patients. Median session attendance was 97.9% (IQR 91.7–100%), and relative dose intensity (compliance) to all exercises was ≥90.0%. Adherence to the activity advice was 50.0% (16.7–60.4%). Facilitators and barriers were captured in seven themes. The most important facilitators were patients’ own intention to engage in exercise and supervision by a physiotherapist. Barriers were mainly experienced in completion of the activity advice, and included logistic factors and physical complaints. | PMC10164010 | ||
Conclusions | Esophageal cancer | ESOPHAGEAL CANCER | Esophageal cancer survivors are well capable to attend a moderate-to-high intensity post-treatment exercise program, and to fulfill the exercises according to protocol. This is facilitated by patients’ own intention to engage in exercise and supervision of the physiotherapist, and only minimally affected by barriers as logistic factors and physical complaints. | PMC10164010 |
Implications for cancer survivors | cancer | CANCER | When implementing postoperative exercise programs in clinical care, it can be useful to be aware of perceived facilitators and barriers of cancer survivors in order to achieve optimal exercise adherence and maximize beneficial exercise effects. | PMC10164010 |
Trial registration | Dutch Trial Register NTR 5045 | PMC10164010 | ||
Keywords | PMC10164010 | |||
Introduction | esophageal cancer, cancer, fatigue, Esophageal Cancer | CANCER, OESOPHAGEAL CANCER, ESOPHAGEAL CANCER | Patients who have been treated for cancer may experience cancer-related and treatment-related side effects impairing quality of life in the short and long term. Participation in (post-treatment) exercise programs has been proven to beneficially affect several health-related outcomes, such as fatigue, physical fitness, and quality of life [Like any medical intervention, uptake of the exercise program (adherence) by the patient is important to achieve optimal effects. For exercise programs, it is therefore important that participating patients are present at the prescribed exercise sessions (attendance). Also, benefits of an exercise program may be largest if patients fulfill all components of the exercise program according to the exercise protocol (compliance or relative dose intensity (RDI)). Attendance and RDI are the two components that are united in the broader concept “adherence” [In the Physical ExeRcise Following Esophageal Cancer Treatment (PERFECT) trial, we randomized esophageal cancer survivors between usual care and a 12-week post-treatment exercise program. The exercise program consisted of both aerobic and resistance exercises, performed at moderate-to-high intensity and individualized to the patients’ fitness level before start of the program [When applying exercise programs in regular clinical cancer care, adherence rates ideally should be comparably high as found in this trial. An understanding of which elements help or hamper patients to complete the exercise program as prescribed can support in designing exercise programs for clinical practice. Information on barriers for attending exercise sessions or not fulfilling specific components of the exercise program can help to improve the program and decrease dropout rates, while information on facilitators can indicate which aspects of the program should be retained or even extended for optimal adherence. For the current study, we performed semi-structured telephone interviews with patients participating in the PERFECT exercise program, to identify facilitators and barriers to exercise adherence. | PMC10164010 |
Methods | The current research question was investigated within the multicenter randomized controlled PERFECT study (NTR5045). The PERFECT study was approved by the Medical Ethics Committee of the UMC Utrecht and the local Ethical Boards of participating hospitals. Informed consent was obtained from all participants included in the study. A detailed description of the trial design has been published elsewhere [ | PMC10164010 | ||
Outcome measures | PMC10164010 | |||
Adherence | To monitor session attendance, each physiotherapist reported on presence of the patient at each training session in a case report form. In addition, to monitor the relative dose intensity for the different exercise components, heart rates and duration were documented for the aerobic training and resistance and number of sets and repetitions of each muscle strength exercise for the resistance training. Adherence to the exercise advice of being physically active for at least 30 min per day and adherence to the Dutch Physical Activity Guidelines, i.e., engaging in at least 150 min of exercise per week | PMC10164010 | ||
Facilitators and barriers | A topic list and an interview protocol were prepared before the start of the interview series, after examination of relevant literature and discussion within the study team. All semi-structured interviews, except one, were performed within 14 days of completing the exercise program and were audio-recorded and transcribed verbatim (LW and ACM). | PMC10164010 | ||
Data analysis | Descriptive statistics were used to summarize characteristics of the study population. Attendance rates were computed as the number of supervised exercise sessions attended, divided by the number of sessions prescribed. The RDI (i.e., compliance) was calculated as the ratio of total completed to total planned cumulative dose for the exercise program. The percentage of weeks in which patients adhered to the exercise advice of being physically active for at least 30 min/day was calculated, as well as the percentage of weeks in which patients adhered to the Dutch Physical Activity Guidelines (engaging in at least 150-min exercise per week). Quantitative data were analyzed using IBM SPSS StatisticsTranscribed interviews were imported in NVivo 11 for thematic analysis. All transcripts were coded by two researchers independently (LW and JKV), who met regularly to resolve differences in coding for each transcript. Coded text was compared across transcripts to identify broader themes, capturing patients’ perceptions on barriers and facilitators. Thematic saturation was reached after 16 interviews, i.e., the final three interviews did not generate new themes. | PMC10164010 | ||
Facilitators and barriers | exercisesDiversity | DILATION, HOLIDAYS | We identified 7 overarching themes that captured patients’ perceived facilitators and barriers during their participation in the exercise program: intention to engage in exercise, supervision, psychosocial context, physical condition, logistics, content of the exercise program, and information about the exercise program and training progress (Table Overarching themes that capture patients’ perceived facilitators and barriers to exercise adherenceMotivation and commitmentPersonal goalsFunPast positive exercise experiencesEmotionsLimited body confidenceNot feeling like itMotivating influenceExpertiseMental supportObligationSocial supportEmbedding in daily lifeEsophageal dilation therapyGeneral physical complaintsPre-existing injuriesAvailability of equipmentLocationWeather circumstancesTimeFlexibility appointmentsConflicting activitiesNational holidays and vacationWeather circumstancesInflexibility appointmentsIndividualization of exercisesDiversity of exercise componentsLimited variation in exercisesIntensified training loadKnowledge on training scheduleProgressQuantification of physical activity | PMC10164010 |
Facilitators | First, patients reported their own intention to engage in exercise as the most important facilitator to adhere to the exercise program. Most patients were highly motivated to contribute to their own recovery and were convinced that the exercise program would help them to improve their health. Their own personal goals of improving condition, strength, and health increased their commitment. Also, previous positive training experiences, e.g., pre-operatively, had a positive influence on fulfillment of the exercise program. In addition, some indicated exercising to be a pleasant activity, which made it easier to adhere.Second, supervision by the physiotherapist was considered to be a strong facilitator. Within this theme, several aspects had beneficial influence on exercise adherence. With the physiotherapist encouraging the patients while performing the exercises, patients felt motivated to challenge themselves, even when they had a hard time with the exercises. In addition, some reported to experience mental support by the physiotherapists and many especially valued the medical expertise and knowledge on correct performance of all exercises, which made them feel comfortable to perform the prescribed program. Last, patients felt obligated to go to the two weekly appointments with the physiotherapist, which was for many of them a great help to bring up the necessary discipline to exercise (quote 1).“Yes, because it is in any case very important to exercise and if that is compulsory, because you have to do it, you also put aside hesitations to actually doing it. I mean, if something is obligatory, you commit to it, and that in itself is a very good thing.”With regard to the content of the exercise program, patients indicated that RDI was promoted if the components were individualized to patients’ preferences and if exercises were adjusted in case of pre-existing injuries. Also, variation in exercises, such as alternating leg and arm strength exercises, made the exercise program more attractive to comply to. Patients further reported to feel encouraged when they experienced progress in their physical condition and daily activities (quote 2).“I loved it. It made it most clear to me that I was on the mend, it was measurable, I immediately noticed that my energy was improving. Even when I was really tired at some day, I knew: When I have been to physiotherapy, I will feel better.”In line with experiencing progress themselves, patients indicated that adherence was promoted by receiving information on their training progress, i.e., quantification of training results, as well as information on the training schedule. Regarding the physical activity advice, collecting information through apps with pedometers (on their own initiative) helped three patients to achieve the prescribed guideline of activity per day. In addition, the psychosocial context influenced adherence to the home-based exercise guideline. Performing activities together with a partner and embedding the activities in daily life, e.g., walking with the dog, supported performing physical activity on a regular base.Last, logistic factors such as short distance to the training facility, having enough time for exercising (e.g., being retired), and flexibility of the appointments (e.g., in case of conflicting activities) were all mentioned as facilitators. Furthermore, the availability of equipment and good weather circumstances made it easier to fulfill the physical activity advice. | PMC10164010 | ||
Barriers | dizziness, muscle pain | HOLIDAYS, ESOPHAGEAL DILATION | The most important barriers were captured by the themes “physical condition” and “logistics”. Esophageal dilation, commonly performed in post-esophagectomy patients, hampered both attendance and RDI: Due to the hospital visits, appointments with the physiotherapist could be affected and patients needed some time to fully recover from the treatment and sedation (quote 3).“Well, every time I had to go back to the hospital and they had to dilate me [esophagus]. Yes, that day itself you are always... Because 24 hours prior you are not allowed to eat anything. The day itself you are travelling to the hospital all day. Sometimes the day after, you felt a bit drowsy due to the sedation. So, sometimes it was more difficult to keep going with the program.”In few other cases, patients could not comply with the exercises because of other physical complaints, such as dizziness, not feeling well, or pre-existing injuries. Regarding logistics, for the supervised part, mainly national holidays and vacation, and impossibility of changing the training schedule to other days or daytimes, were mentioned as barriers. For the exercise advice, weather circumstances (rain for some, high temperatures for others) influenced adherence, as well as conflicting activities, such as doing the housekeeping and job obligations. To a lesser extent, absence of the physiotherapist could act as a barrier.When patients felt psychologically unhappy or when they just did not feel like exercising, it was more difficult to adhere to the program. Also, limited body confidence, which had developed after surgery, resulted in an insecure feeling when performing the exercise components. Feelings of insecurity were also caused by a lack of knowledge on exercise side effects, e.g., muscle pain. Last, regarding the contents of the program, a perceived lack of variation in exercises was a barrier to some, and intensification of the training load to others. | PMC10164010 |
Acknowledgements | We would like to thank all participants, physiotherapists, and the professional staff at UMC Utrecht, Utrecht; Hospital Group Twente (ZGT), Almelo; and Catharina Hospital, Eindhoven for their invaluable participation in this trial. | PMC10164010 | ||
Authors’ contributions | AMM | RECRUITMENT | AMM, PDS, and JKV planned the project. RH, JPR, GAPN, EAK, and PDS were responsible for patient recruitment. JKV, ACMH, and LW collected the data. JKV, ACMH, LW, AEH, and AMM were responsible for data handling, data analysis, and interpretation. JKV wrote the first draft, and all authors contributed and approved the final version of the manuscript for publication. | PMC10164010 |
Funding | Cancer | CANCER | The PERFECT study was funded by the World Cancer Research Fund, The Netherlands (WCRF NL, project number 2013/997). They had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. | PMC10164010 |
Declarations | PMC10164010 | |||
Ethical approval | This study was performed in line with the principles of the Declaration of Helsinki. The PERFECT study was approved by the Medical Ethics Committee of the UMC Utrecht and the local Ethical Boards of participating hospitals. Informed consent was obtained from all participants included in the study. | PMC10164010 | ||
Competing interests | The authors declare no competing interests. | PMC10164010 | ||
References | PMC10164010 | |||
1. Introduction | Endothelial dysfunction, fasting blood glucose, arterial stiffness | ENDOTHELIAL DYSFUNCTION, ARTERIAL STIFFNESS, DILATION, OXIDATIVE STRESS, COLD, ENDOTHELIAL DYSFUNCTION | Postmenopausal women (PMW) may experience endothelial dysfunction associated with arginine (ARG) deficiency relative to asymmetric dimethylarginine (ADMA) caused by oxidative stress. Endothelial dysfunction contributes to increased blood pressure (BP) responsiveness to sympathoexcitation induced by the cold pressor test (CPT). We investigated the effects of citrulline alone (CIT) and combined with the antioxidant glutathione (CIT+GSH) on vascular function. Forty-four healthy PMW were randomized to CIT (6 g), CIT+GSH (2 g + 200 mg: SetriaThe endothelium has a major role in the regulation of vascular function and structure by releasing vasodilatory molecules [Impaired endothelial function, assessed as low brachial artery flow-mediated dilation (FMD), begins before and progresses after menopause in healthy women [Dietary strategies to increase circulating ARG may improve vascular function. The effectiveness of short-term oral ARG supplementation for improving FMD was observed in healthy older adults [The purpose of this study was to investigate the effects of supplementing with CIT alone and CIT+GSH on vascular function, assessed by brachial FMD, arterial stiffness (pulse wave velocity, PWV), and BP reactivity to CPT in postmenopausal women. Moreover, we assessed fasting blood glucose (FBG), serum levels of ARG and its metabolites, and markers of oxidative stress. Our hypothesis was that CIT alone and CIT+GSH supplementations would increase brachial FMD and attenuate BP responses to sympathetic activation induced by CPT compared to a placebo in postmenopausal women. | PMC10097312 |
2. Materials and Methods | PMC10097312 | |||
2.1. Participants | CVDs | TYPE 2 DIABETES, CARDIOVASCULAR DISEASES | Participants were healthy postmenopausal women aged 51–74 years. All participants had absence of menstruation for at least 1 year and were sedentary (<120 min/week of exercise). Potential participants were excluded if they had diagnosed cardiovascular diseases (CVDs), type 2 diabetes, a body mass index > 34.9 kg/m | PMC10097312 |
2.2. Experimental Protocol | SECONDARY | This was a double-blind, placebo-controlled, parallel design study. The randomization was performed by a researcher not involved in laboratory measurements using a block scheme stratified by age and systolic BP (SBP) with a computer program [The primary endpoint was the change in endothelial function, as assessed by brachial FMD. The secondary endpoints were reductions in PWV at rest and BP responses to CPT. Tertiary endpoints were changes in serum glucose, insulin, ARG, CIT, ORN, ADMA, arginase I, and oxidative markers.Participants completed a health-history questionnaire and were familiarized with the protocol. Height and weight were measured using a stadiometer and beam scale (free-standing portable height rod and weigh beam, Detecto, Webb City, MO, USA), and waist circumference was measured using a non-elastic tape. Body mass index was calculated as weight (kg) divided by height squared (m | PMC10097312 | |
2.3. Measurements | All measurements were performed in the morning after an overnight fast and 24 h abstinence from caffeine, alcohol, prescription medications, and physical activity. All vascular measurements were conducted in the supine position after at least 20 min of rest in a quiet, dimly lit, and thermoneutral environment. Following 4 weeks of intervention, all measurements were repeated in the same order and conducted at baseline. | PMC10097312 | ||
2.3.1. Flow-Mediated Dilation | Endothelial function was assessed by brachial FMD. The right brachial artery was scanned ~2–3 cm proximal to the antecubital fossa using a 12-MHz linear array Doppler ultrasound probe (LogiQ S7 expert, GE Medical Systems, Milwaukee, WI, USA) at an insonation angle < 60°. Following a 2 min baseline diameter and mean blood velocity recording, the occlusion cuff on the proximal forearm was rapidly inflated to 250 mmHg using an automated pump (E20, Hokanson, Bellevue, WA, USA). Following a 5 min occlusion period, the cuff was rapidly deflated while the diameter and mean blood velocity were continuously recorded for 3 min using open-source software (OBS Studio). Baseline and peak diameters were measured using an automated edge-detection software (Quipu Cardiovascular Suite, Pisa, Italy). Baseline diameter was measured as the average vessel diameter during the 2 min baseline, and peak diameter as the largest diameter detected post-occlusion. FMD is expressed as a percentage change from the baseline diameter: FMD% = ([peak diameter − baseline diameter]/baseline diameter) × 100. | PMC10097312 | ||
2.3.2. Pulse Wave Velocity | Carotid-femoral PWV (cfPWV, aortic), carotid-radial PWV (crPWV, brachial), carotid-distal PWV (cdPWV, systemic), and femoral-ankle (dorsalis pedis artery) PWV (faPWV, leg) were determined by applanation tonometry (Complior Analyse, Alam Medical, Vincennes, France; for faPWV: SphygmoCor CPV, AtCor Medical, Sydney, Australia). Distances between arterial sites in each segment were measured with a segmometer (Mitutoyo, Aurora, IL, USA). PWV was calculated as the distance of the arterial segment divided by the transit time of the pulse. cfPWV was multiplied by 0.80 to account for the distance between the carotid artery site and the suprasternal notch [ | PMC10097312 | ||
2.3.3. Brachial and Aortic Blood Pressures at Rest and During the CPT | brachial mean arterial pressure | COLD | Brachial SBP and diastolic BP (DBP) were measured using an automated oscillometric device (HEM-705CP; Omron Healthcare, Vernon Hill, IL, USA). Radial artery pressure waves recorded using applanation tonometry were calibrated with brachial mean arterial pressure (MAP) and DBP. Aortic hemodynamics were obtained via a validated transfer function (SphygmoCor CPV; AtCor Medical, Sydney, Australia). A minimum of two high-quality readings (operator index ≥ 80%) were obtained at rest and during the CPT and the average was used for analysis. The participants introduced their right hand up to the wrist in cold water at 1–4 °C for 2 min. The increase in BP from rest to the second minute of the CPT (Δ) was used for the analysis, since greater sympathetic activity occurs at this time point [ | PMC10097312 |
2.3.4. Serum Biomarkers | HF Quadrupole-Obitrap mass | INSULIN RESISTANCE | Fasted blood samples were collected from the antecubital vein at baseline and at 4 weeks. Serum samples were collected using silicone-coated tubes and stored at −80 °C until subsequent analysis of the biomarkers. Glucose (EIAGLUC; Invitrogen, Carlsbad, CA, USA) was measured using the glucose oxidase method. Insulin was measured using an ELISA kit (80-INSHUE01.1, ALPCO Diagnostics, Salem, NH, USA). The homeostatic model assessment for insulin resistance was calculated as [fasting glucose (mg/dL) × fasting insulin (μIU/mL)]/405. Glutathione peroxidase (ab102530; Cambridge, UK), malondialdehyde (Abcam 233571; Cambridge, UK), and superoxide dismutase (ab119520; Cambridge, UK) were analyzed using the colorimetric method. Arginase-1 (BMS2216; Invitrogen, Carlsbad, CA, USA) and oxidized low-density lipoprotein (CSB-E07931h; Cusabio Biotech, Houston, TX, USA) were measured using ELISA kits. Serum ARG, CIT, ORN, and ADMA were analyzed using an AbsoluteIDQ p400 HR kit (Biocrates, Innsbruck, Austria), which is a combined flow injection and high-performance liquid chromatography–tandem mass spectrometry assay. The tandem mass spectrometry platform consisted of a Thermo Scientific Vanquish HPLC coupled to the Thermo Scientific Q-Exactive HF Quadrupole-Obitrap mass spectrometer. | PMC10097312 |
2.4. Statistical Analysis | Sample size was estimated based on data that showed increased FMD after ARG supplementation in older adults [ | PMC10097312 | ||
3. Results | PMC10097312 | |||
3.1. Participant Characteristics | Participants were recruited from June 2020 to December 2021. Thirty-nine participants randomized to the placebo (Participant characteristics at baseline did not differ among the groups, except for FBG ( | PMC10097312 | ||
3.2. Flow-Mediated Dilation and Arterial Stiffness | Baseline FMD and PWV segments did not differ among the groups. There was a time-by-group interaction for FMD. CIT+GSH increased the FMD by 2.9% ( | PMC10097312 | ||
4. Discussion | peripheral muscular arteries [Impaired FMD, hypertension, prediabetes | OXIDATIVE STRESS, HYPERTENSION, PREDIABETES, OXIDATIVE STRESS | This study examined the effects of 4 weeks of CIT and CIT+GSH supplementation on vascular function and BP responsiveness in healthy postmenopausal women. We found that CIT+GSH supplementation improved endothelial function through an increase in the ARG/ADMA ratio. Although CIT supplementation increased serum ARG levels and the ARG/ADMA ratio, it did not statistically improve FMD. In addition, CIT+GSH supplementation attenuated BP responsiveness to CPT. These data show that CIT+GSH supplementation has protective cardiovascular effects at rest and during sympathetic stimulation (CPT) in healthy postmenopausal women.FMD decreases progressively throughout the stages of the menopausal transition in healthy women [Recent data showed that FMD values lower than 5.4% are indicative of impaired endothelial function in apparently healthy adults [Age associated arterial stiffening affects the aorta to a greater extent than peripheral muscular arteries [Impaired FMD and increased sympathetic activity are associated with the increased risk of incident hypertension in healthy postmenopausal women [ADMA competes with ARG for binding to eNOS, thereby a decrease in ARG/ADMA leads to reduced NO production [Despite greater increases in the serum ARG levels and ARG/ADMA ratio, FMD did not improve after CIT supplementation alone. This discrepancy in the findings may be explained by the healthy status of the participants. In agreement with our findings, ARG supplementation for 4 weeks increased serum ARG levels by almost double but failed to improve FMD in healthy postmenopausal women [Oxidative stress markers were not improved by both supplementations. In healthy adults, 200–1000 mg of GSH daily for 4 weeks did not improve microvascular endothelial function and malondialdehyde levels [There are some limitations in the present study. The sample size was relatively small and included healthy postmenopausal women. FBG was not considered for randomization, which resulted to be higher in the CIT+GSH group. Future studies might investigate the effects of CIT and CIT+GSH in individuals with prediabetes. A GSH dose greater than 200 mg daily for longer than 4 weeks of supplementation may reduce markers of oxidative stress, as previously shown [ | PMC10097312 |
5. Conclusions | EVENTS, PHYSIOLOGICAL STRESS | Four weeks of CIT+GSH supplementation improves brachial artery FMD in apparently healthy postmenopausal women with slightly elevated FBG. CIT+GSH reduced brachial PWV and attenuates BP responses to sympathetic activation. These beneficial effects on the endothelial function and BP reactivity may be attributed to an increased ARG/ADMA ratio. Therefore, CIT+GSH supplementation may reduce the risk of cardiovascular events during physiological stress in postmenopausal women. Although CIT supplementation alone caused greater increases in the serum ARG levels and ARG/ADMA ratio, it did not improve FMD or BP responses to CPT in healthy postmenopausal women. | PMC10097312 | |
Author Contributions | A.F., M.M. and D.N. were responsible for the study design. A.F. was responsible for the conduction of the study. A.M., S.M.F., M.A.M., Y.K. and K.N.D. performed the experiment and data collection. A.F., A.M., S.M.F., M.A.M., Y.K. and K.N.D. participated in the data analysis and interpretation. A.F., M.A.M., Y.K. and K.N.D. wrote the manuscript. All authors have read and agreed to the published version of the manuscript. | PMC10097312 | ||
Institutional Review Board Statement | The experimental protocol and informed consent was approved by Texas Tech University Institutional Review Board. | PMC10097312 | ||
Informed Consent Statement | Written informed consent was obtained from all subjects involved in the study. | PMC10097312 | ||
Data Availability Statement | The data presented in this study are available upon request from the corresponding author. | PMC10097312 | ||
Conflicts of Interest | M.M. and D.N. are employees of Kirin Holdings Co., Ltd. M.M., D.N. and Kirin had no influence on participant handling, data collection, analysis or interpretation, and manuscript writing. The other authors declare no conflict of interest. | PMC10097312 | ||
Abbreviations | PMC10097312 | |||
References | brachial artery flow-mediated dilation | DILATION, OXIDATIVE STRESS, ARTERIAL STIFFNESS | CONSORT flow chart of participants through the study. CIT, citrulline, CIT+GSH, and CIT+glutathione.Changes (Δ) in brachial artery flow-mediated dilation (ΔFMD%) from 0 to 4 weeks. Abbreviations: CIT, citrulline; CIT+GSH, CIT+glutathione. * Relationship between changes (Δ) in the brachial artery flow-mediated dilation (ΔFMD%) from 0 to 4 weeks and baseline (0 week) FMD%. Abbreviations: CIT, citrulline; CIT+GSH, CIT+glutathione.Changes (Δ) in (Changes (Δ) in serum levels of arginine (Participant characteristics and treatments.Values are the mean ± SD or number (Brachial artery endothelial function and arterial stiffness.Values are the mean ± SD. Abbreviations: cfPWV, carotid-femoral PWV; crPWV, carotid-radial PWV; cdPWV, carotid-distal PWV; CIT, citrulline; CIT+GSH, CIT+glutathione; faPWV, femoral-ankle PWV. Brachial and aortic blood pressures at rest and during CPT.Values are the mean ± SD. Abbreviations: AIx, augmentation index normalized to the heart rate of 75; CIT, citrulline; CIT+GSH, CIT+glutathione; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure; Tr, reflection time. Serum markers of arginine metabolism, glucose control, and oxidative stress.Data are the mean ± SD. | PMC10097312 |
Introduction and hypothesis | pelvic organ prolapse | The present study describes an extended follow-up study after 12 years and focusses on subjective outcomes of women who underwent surgery for recurrent pelvic organ prolapse in the randomized index study. | PMC10287778 | |
Methods | One hundred and ninety-four (194) women had been randomized in the original study and in the present study, 45 (47%) in the vaginal mesh repair versus 43 (43%) women with conventional vaginal native tissue repair completed the long-term questionnaires. The mesh used was a first-generation non-absorbable mesh kit. All types of conventional vaginal native tissue repairs were allowed, and additional vaginal native tissue repairs were allowed in the mesh group. The questionnaires as applied at baseline were used. The Patient Global Impression of Improvement questionnaire (PGI-I) was the primary outcome. | PMC10287778 | ||
Results | At 12 years, 30 (71%) women in the mesh group versus 23 (59%) women in the native tissue repair group reported to be PGI-I (very) much improved ( | PMC10287778 | ||
Conclusions | pelvic organ prolapse | There was no difference in subjective outcome between the groups, but there was a statistically significant higher number of women who had needed further operations. This study confirms that vaginal mesh should not be used in all women with recurrent pelvic organ prolapse. | PMC10287778 | |
Keywords | PMC10287778 | |||
Introduction | pain/dyspareunia | PELVIC ORGAN PROLAPSE, COMPLICATIONS | Pelvic organ prolapse (POP) is a common health problem worldwide and has a high impact on quality of life [Mesh exposure and severe pain/dyspareunia are much feared long-term complications of vaginal mesh surgery [A limited number of randomized controlled trials (RCT) compared the safety and efficacy of synthetic non-absorbable mesh with native tissue repair in daily clinical practice (i.e., mixed patient groups, with both primary and recurrent POP) [ | PMC10287778 |
Materials and methods | SUI, Defecatory Distress, pain | PROLAPSE, INCONTINENCE | The original trial [An extended follow-up was approved by the Medical Ethics Committee, region Arnhem-Nijmegen, The Netherlands, on 28 April 2014 under no. NL46834. 091.14 and (All participants completed the Dutch version of the validated questionnaires: Patient Global Impression of Improvement questionnaire (PGI-I), EuroQol-5D (EQ-5D), Urogenital Distress Inventory (UDI), Defecatory Distress Inventory (DDI), Incontinence Impact Questionnaire (IIQ), and Visual Analogue Scale (VAS) pain score [The PGI-I is a seven-point Likert scale to rate the patient-reported response of a condition (prolapse) to therapy (surgery), where 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, and 7 = very much worse. These mean scores are presented per treatment group as well as the percentage of women reporting their improvement very much better or much better. The EQ-5D records the patient’s self-rated health on a five-point scale (excellent, very good, good, fair, or poor). The UDI, DDI, and IIQ are each subdivided into five domains, with subscales ranging from 0 to 100 and higher scores indicating more bother and worse QoL. The VAS pain ranged from 0 to 10 and was assessed as spontaneous pain and pain on activity.The primary outcome of this extended follow-up study was defined as the difference in PGI-I score between the mesh group and the native tissue repair group. Secondary outcomes were patient-reported retreatment for POP, SUI, and mesh exposure, and further questionnaire scores.Missing data of women who were lost at 12-year follow-up were not imputed. Analysis was carried out according to the intention-to-treat principle. Per protocol analysis was performed to rule out a dilution of real effects due to mesh surgery during repeat surgery in the native tissue repair group. Descriptive statistics with mean scores and standard deviations and numbers with percentage were used to summarize outcomes. Statistical significance was analyzed using independent samples | PMC10287778 |
Authors’ contributions | K.B. Kluivers: design of the study, the acquisition, analysis, and interpretation of data, drafting the manuscript and thereby final approval of the version to be published; M. Kamping: acquisition, analysis, and interpretation of data, final approval of the version to be published; A.L. Milani: design of the study, the acquisition, analysis, and interpretation of data, revising manuscript critically for important intellectual content and final approval of the version to be published; J. IntHout: analysis and interpretation of data, revising manuscript critically for important intellectual content, and final approval of the version to be published; M.I. Withagen: design of the study, acquisition, analysis, and interpretation of data, revising manuscript critically for important intellectual content, and final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are answered. | PMC10287778 | ||
Funding | An unrestricted educational grant from Ethicon Women’s Health & Urology to Radboud University Medical Center. Ethicon was not involved in the study setup, design, data acquisition, data analysis, data interpretation, editing, or any other aspect of this study. | PMC10287778 | ||
Declarations | PMC10287778 | |||
Conflicts of interest | None. | PMC10287778 | ||
References | PMC10287778 | |||
Aims/hypothesis | glucose tolerance [IGT]) and, impaired fasting glucose [IFG] and/or impaired, prediabetes | TYPE 2 DIABETES, PREDIABETES | In sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA. | PMC10474205 |
Methods | coronavirus disease 2019, prediabetes | CORONAVIRUS DISEASE 2019, PREDIABETES | Adults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat. | PMC10474205 |
Results | In total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days ( | PMC10474205 | ||
Conclusions/interpretation | HIV and prediabetes, diabetes | BLOOD, DIABETES | Blood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV. | PMC10474205 |
Trial registration | The trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( | PMC10474205 | ||
Funding | This research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research. | PMC10474205 | ||
Graphical Abstract | PMC10474205 | |||
Keywords | PMC10474205 |
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