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Competing interests | FOUNDER | Dr. Patel is founder of Catalyst Health, a technology and behavior change consulting firm and is on medical advisory boards for Humana, Roche and GlaxoSmithKline. Dr. Volpp is a part-owner of VALHealth, a behavioral economics consulting firm. He has received research funding from Hawaii Medical Services Association, Humana, CVS, WW, Vitality/Discovery, and personal fees from Tandigm, Lehigh Valley Medical Center, and the Center for Corporate Innovation. No other authors declared competing interests. | PMC10203290 |
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References | PMC10203290 |
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Objective | Edited by: Guodong Zhang, Southwest University, ChinaReviewed by: Afsaneh Bakhtiari, Babol University of Medical Sciences, Iran; Fatemeh Nasiri Amiri, Babol University of Medical Sciences, Iran†ORCID: Akshay Anand, The objective of this study was to investigate the impact of Gestational Yoga-YOGESTA (Gestational Yoga), on the neuropsychology, quality of life, and personality of pregnant women. | PMC10520697 |
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Design | Open label, randomized controlled trial, used allocation concealment to allocate the treatment. | PMC10520697 |
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Setting | Department of Obstetrics and Gynecology and Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. | PMC10520697 |
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Participants | COMPLICATED PREGNANCIES | We recruited a total of 100 pregnant women visiting the Outpatient Department of Obstetrics and Gynecology. Participants were aged between 18 and 35 with uncomplicated pregnancies and they were randomly assigned to either the Yoga group (YG) or the usual care group (UCG). A total of 77 pregnant women completed both the pre- and post-survey, with 34 participants in the Yoga group and 43 in the Usual care group. | PMC10520697 |
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Intervention | Pregnant women in their second and third trimesters were provided with a 16-week online Prenatal Yoga intervention. The intervention began after enrollment in the 2nd trimester, specifically between the 16th and 20th week, and was conducted 5 days a week until delivery, with an average intervention period of 47.18 ± 2.031 (mean ± SEM) days. | PMC10520697 |
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Chief outcome measures | Depression, Anxiety | We measured Perceived stress, Depression, Anxiety, Stress, and quality of life by using standard questionnaires. | PMC10520697 |
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Results | depression, anxiety | PHYSIOLOGICAL STRESS | A total of 77 participants were included in the analysis, with 34 assigned to the Yoga group and 43 assigned to the control group. Most of the measured parameters demonstrated significant changes. The Yoga group exhibited a noteworthy decrease in perceived stress, depression, anxiety, and psychological stress, as well as an improvement in the psychological and environmental domains of QOL-BREF. Conversely, the control group demonstrated a significant increase in perceived stress, depression, anxiety, and psychological stress, along with a reduction in the physical, psychological, and social domains of QOL-BREF at the follow-up stage. Although the two groups were similar at baseline, the Yoga group showed substantial enhancements in perceived stress, depression, anxiety, physiological stress, and overall quality of life when compared to the control group at follow-up. | PMC10520697 |
Introduction | depression, anxiety | COMPLICATED PREGNANCIES, COMPLICATIONS | Pregnancy is marked by continuous physiological, metabolic, and mental challenges that can be difficult to adapt to. A woman’s neuropsychology and ability to manage these challenges effectively can play a crucial role in her adaptation to the physical and physiological demands of pregnancy. Stress, anxiety, and depression are common sources of distress during pregnancy that can have negative impacts on both maternal and fetal health (Existing research indicates that psychological distress can have a negative effect on the ability to participate in physical activity (Yoga is usually a mix of physical exercise, mental exercises, meditation, different types of deep breathing, stretching, and relaxation. The meditation component of Yoga promotes deep relaxation, which helps to calm the senses and improve the focus of the mind, thereby enhancing mental health. Practicing Yoga during pregnancy is known to promote a holistic connection between the mind, body, and fetus of expectant mothers (Moreover, it is important to note that there is limited awareness about mental health issues during pregnancy, and routine screening for such problems is not common practice, thereby neglecting their significance as high-risk factors in pregnancy (Through our examination of these variables in women with uncomplicated pregnancies, our aim is to shed light on the occurrence and progression of psychological distress during pregnancy. Additionally, we seek to explore the potential role of Yoga as a preventive intervention for managing psychological distress during this critical period. Furthermore, this investigation may yield preliminary data regarding the incidence of psychological distress among pregnant women, which can contribute to identifying mental health issues, associated risks for maternal and fetal complications, and the need for psychological counseling during antenatal checkups. | PMC10520697 |
Materials and methods | PMC10520697 |
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Study design and setting | depression, anxiety | RECRUITMENT | The YOGESTA (Gestational Yoga) trial was carried out at the Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India after taking approval from the institutional ethics committee PGIMER.This was an Open label, Parallel randomized controlled trial of online Yoga intervention among uncomplicated pregnant women. We recruited the participants in the 16th to 20th week of pregnancy and randomized them into Yoga and Usual care groups (UCG). Yoga group participants attended online morning Yoga classes from the time of recruitment until delivery, with daily attendance records and screenshots/videos of Yoga classes taken to ensure compliance with the intervention. UCG participants did not practice any Yoga or exercise during the study period. Assessment was done at two time points, baseline and follow-up. Baseline measurements were collected at the time of recruitment, i.e., between the 16th and the 20th week of pregnancy, and follow-up measurements were taken after 32 gestational weeks, using questionnaires to assess perceived stress (PSS); depression, anxiety, and stress (DASS); and quality of life (WHO-QOL BREF). The study design is both a between-subjects variable (comparing the Yoga group to the usual care group) and a within-subjects variable (comparing pre and post-intervention). The study was registered prospectively in the Clinical Trials Registry-India. | PMC10520697 |
Participants | hypertension, anomalies | HYPERTENSION, HIGH-RISK PREGNANCIES, GESTATIONAL DIABETES, GESTATIONAL DIABETES MELLITUS | From November 2021 to January 2023, pregnant women who visited or tele-consulted with the Department of Obstetrics and Gynecology at PGIMER were recruited for the study by the first author, based on defined inclusion criteria, which included uncomplicated normal pregnancy aged between 18 and 35 years in the 16th to 20th week with a BMI < 30 and no associated anomalies such as hypertension or gestational diabetes. Pregnancies with any associated comorbidities like hypertension, gestational diabetes mellitus, small cervical length, low-lying placenta, and high-risk pregnancies were excluded from the study. The sample size was estimated based on the mean and standard deviation from published research which had delivered Yoga interventions to the pregnant population, using the formula Characteristics and demographic details of participants.Characteristics and demographics of participants in Yoga group ( | PMC10520697 |
Prenatal Yoga protocol | To cater to the changing physiological needs of pregnant women, our study aimed to implement gestational Yoga which we abbreviated as YOGESTA among uncomplicated pregnant women. YOGESTA consists of two distinct Yoga protocols for the 2nd and 3rd trimesters. The protocols incorporated a range of practices including stretching, breathing, relaxation, and meditation (details presented in Briefly, the protocol comprised of asana (physical postures), pranayama (breathing practices), kriya (tratak), meditation, and relaxation practices. | PMC10520697 |
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Instrumentation | Multiple scales were used in this research study, including the PSS-10, DASS-42, and WHO-QOL-26, to comprehensively assess psychological distress in pregnant women and evaluate the impact of Yoga on these parameters, ensuring a comprehensive and multi-dimensional assessment of psychological well-being and quality of life. | PMC10520697 |
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Perceived stress scale | The Perceived Stress Scale (PSS-10) is a 10-item stress assessment instrument originally, scale was developed in | PMC10520697 |
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Depression anxiety stress scale | depression, Depression, anxiety | The Depression Anxiety Stress Scale (DASS-42) is a self-report measure that assesses the severity of negative emotions. The scale consists of three subscales, namely depression, anxiety, and stress, which are measured separately. Scores on each subscale can range from normal to extremely severe, depending on the severity of the symptoms reported by the individual. The severity levels are categorized as normal, mild, moderate, severe, and extremely severe ( | PMC10520697 |
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Who- quality of life- BREF scale | Quality of life was measured using the WHO-QOL-BREF questionnaire which contains 26 original items, among which 2 items measure overall perception of quality of life and 24 items examines 4 domains (D1- Physical, D2- Psychological, D3- Social, and D4- Environmental) ( | PMC10520697 |
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Results | depression anxiety | COMPLICATIONS | In total, 100 participants gave their consent to participate and were randomized into Yoga (The two groups were found to be similar in terms of age, height, weight, BMI, occupation, education level, parity distribution, diet, socio-economic status, pregnancy method, and complications, indicating no significant differences between them in these demographic and lifestyle factors (All results are reported as Mean ± SEM and frequencies in %. Frequency percentage was reported as low, moderate, and high for PSS and normal, mild, moderate, severe, and extremely severe for DASS as per the standard questionnaire classification using descriptive statistics (Neuropsychological scoring within and between two groups.Baseline and follow-up changes in neuropsychology were compared between the Yoga group (Descriptive of PSS and DASS as per the severity.Percentage of PSS (perceived stress scale) and DASS (depression anxiety stress scale) as per the severity at baseline and at follow-up in Yoga group ( | PMC10520697 |
Perceived stress | When the average scores were compared, both groups reported the same level of stress at baseline (UCG: 16.79 ± 0.763, Yoga: 17.38 ± 0.943) without any significant differences (Between-group analysis at follow-up demonstrated a highly significant reduction in perceived stress in the Yoga group, with an average change of −7.425 (At baseline, the UCG reported a low level of perceived stress at 20.9%, while the remaining 79.1% reported a moderate level. These levels changed at follow-up, with only 11.6% reporting low stress, 67.4% reporting moderate stress, and 20.9% reporting high stress. However, the YG reported 26.5% low stress, 70.6% moderate stress, and 2.9% high stress at baseline, which changed to 55.9% low stress and 44.1% moderate stress after the intervention. | PMC10520697 |
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Quality of life | Initially, no significant differences in the quality of life (QOL) were observed between the two groups. However, during the follow-up period, the group that received usual care (UCG) showed a significant decline in physical, psychological, and social domains, with scores decreasing from 68.21 ± 1.672 to 59.28 ± 2.190 (Comparison of only follow-up data from both groups, the Yoga group demonstrated improved QOL, as evidenced by a significant average change of 8.486 (0.007), 12.607 ( | PMC10520697 |
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Discussion | anger, low back pain, anxiety, bending, meditation, breathing exercises, depression, Depression | BLOOD | Our study underscores the impact of advancing gestational age on the neuropsychology of pregnant women, which can increase their vulnerability to symptoms of stress, anxiety, and depression. The findings emphasize the significance of prioritizing the psychological well-being of expectant mothers, particularly through Yoga, which can enhance their psychological resilience, as evidenced by the positive outcomes reported by the Yoga group. While the study findings suggest that Yoga can enhance psychological resilience in pregnant women, it is crucial to acknowledge the challenges associated with engaging a large population in such interventions. Despite offering the intervention at no cost and making it convenient to attend from home, with flexible scheduling options, a considerable number of eligible participants declined to participate and a few dropouts also occurred. This may indicate a need for healthcare providers to increase awareness among the pregnant population about the potential benefits of such interventions. Nonetheless, for those who are willing and able to engage in such programs, Yoga can provide significant benefits in terms of building psychological resilience and improving overall wellbeing. The intervention of prenatal Yoga demonstrated significant improvement in the psychological health of pregnant women, as reflected by reduced levels of perceived stress, depression, anxiety, and psychological stress. Furthermore, the intervention contributed to an overall enhancement of the quality of life. The effect size for the differences observed in the Yoga group was moderate to large, with a Cohen’s d value of 0.5 or greater. These findings suggest that the prenatal Yoga intervention had a substantial impact on the psychological well-being of pregnant women. In this study, we used a prenatal Yoga protocol that incorporated safe and gentle practices such as stretching, mild bending, meditation, breathing exercises, and relaxation techniques. These practices are considered to be beneficial to pregnant women and have been widely used for the general maintenance of their health. However, scientific evidence to support these claims has been limited until now. This study aimed to bridge this gap by designing a Yoga intervention that specifically focused on improving the attention and mental wellness of pregnant women. The results of our study suggest that this approach was effective in improving the psychological resilience and mental well-being of pregnant women, thereby highlighting the potential benefits of non-pharmacological interventions for this population. It should be noted that the practices used in the Yoga protocol were safe and adapted to the unique needs of pregnant women. Our study findings are in line with a previous study conducted by Abbas Rakhshani et al., which also reported improvement in psychological, social, and environmental domains of quality of life (QOL) through integrated Yoga practice during pregnancy (Kusuka et al. (According to a study conducted by Field et al. (When compared to a waitlist control group, an RCT by Vieten et al. (Quality of life during pregnancy affects the pregnancy outcomes and impacts both the mother and the developing fetus. Depression and anxiety are independently associated with poor quality of life and vice versa which implies the need for healthcare professionals to give attention to the quality of life of women visiting prenatal clinics. Mild muscle relaxation exercise combined with music therapy has been shown to significantly improve quality of life parameters in pregnant women with low back pain (PSS measures the degree to which an individual perceives life to be unpredictable, uncontrollable, and overloaded for the previous month which can impact the psychological state of the individual. To predict specifically the role of Yoga in changing the perception toward their situation we individually compared the questions in the PSS scale, which depicts that after Yoga practice women were able to control their emotions in challenging situations, handle anger, and face difficulties with a more positive attitude, as suggested by the results. The present study specifically examines the effects of Yoga on both psychological distress and quality of life during pregnancy. By focusing on both outcomes, our study provides a comprehensive assessment of the potential benefits of Yoga during pregnancy. Additionally, it adds to the limited body of research on this topic, which will help inform healthcare providers and pregnant women about the potential benefits of incorporating Yoga into their prenatal care.Based on the findings, Yoga may be used as a primer to reduce or prevent stress, anxiety, and depression-like symptoms, and improve QOL during pregnancy. One of the limitations of the study is the small sample size. We suggest that similar kinds of studies can be done using similar Yoga protocols to evaluate the impact on psychological parameters, quality of life, and other pregnancy outcomes on a bigger sample size and using molecular markers of the same parameters assessed in the study. To gain a deeper understanding of the impact of prenatal Yoga on pregnant women, future studies may consider exploring the molecular-level changes by analyzing Umbilical Cord Blood. Various biological components like cells, serum plasma from Yoga practitioners can be transplanted into animals to see the changes driven by Yoga at cellular and molecular level. | PMC10520697 |
Conclusion | depression, anxiety, pregnancy-induced stress | Our study shows that the prenatal Yoga protocol used in this study was associated with reduced stress, anxiety, and depression among pregnant women. Therefore, this protocol can be used by pregnant women as a preventive as well as a therapeutic complementary measure for reducing pregnancy-induced stress, anxiety, and other psychological imbalances. Yoga appears to maintain good psychological health even in unhelpful emotional and mental states. Apart from psychological changes, our prenatal Yoga protocol was found to be helpful in alleviating overall quality of life by improving the quality of psychological and environmental health and balancing social and physical domains throughout the pregnancy. | PMC10520697 |
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Statistical analysis | Within-group analysis was done using paired | PMC10520697 |
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Limitations of the study | Interpretation of our study outcome is made with caution given the number of limitations to our study design. | PMC10520697 |
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Lack of blinding | Blinding of participants and researchers was not possible in this study due to the nature of the intervention. This may introduce bias in the assessment of outcomes and influence the results. | PMC10520697 |
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Self-report measures | The study relied on self-report measures, which are subjective and can be influenced by participants’ interpretation and response bias, which may potentially affect the validity of the results. | PMC10520697 |
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Sample characteristics | anomalies | COMPLICATIONS | The study included only uncomplicated pregnant women aged between 18 and 35 years with a BMI < 30 and no associated anomalies. These narrow inclusion criteria may limit the generalizability of the findings to a broader population of pregnant women with different characteristics or complications. | PMC10520697 |
Compliance and adherence | The study aimed to ensure compliance with the intervention through daily attendance records and submission of screenshots/videos of Yoga classes. However, the accuracy and completeness of self-reported compliance data may be influenced by participants’ motivation, memory recall, and social desirability bias. | PMC10520697 |
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Online intervention | The Yoga intervention was delivered online via Google Meet, which may have limitations compared to in-person classes. Factors such as internet connectivity, video and audio quality, and participants’ familiarity with technology could impact the effectiveness and engagement with the intervention. | PMC10520697 |
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Strengths of the study | PMC10520697 |
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Randomized controlled trial design | The study utilized a randomized controlled trial design, which is considered reliable for evaluating the effectiveness of interventions. Random allocation of participants into the Yoga group and usual care group helps minimize selection bias and increases the internal validity of the study. | PMC10520697 |
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Prospective registration | The study was prospectively registered in the Clinical Trials Registry-India, which promotes transparency and helps prevent selective reporting of outcomes. This enhances the credibility and reliability of the study findings. | PMC10520697 |
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Well-defined protocols | The study implemented two different Yoga protocols for the second and third trimesters of pregnancy, adapted from established sources and reviewed by an obstetrician and an institutional ethical committee. This standardized approach ensures consistency in the intervention delivery and allows for the reproducibility of the study in future research. | PMC10520697 |
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Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10520697 |
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Ethics statement | The studies involving human participants were reviewed and approved by Institutional Ethical Committee-Post Graduate Institute of Medical Education and Research (PGIMER). The patients/participants provided their written informed consent to participate in this study. | PMC10520697 |
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Author contributions | RECRUITMENT | AA conceptualized the whole study, edited the manuscript, and provided resources to complete the study. PN collected and sorted data, wrote the manuscript, and analyzed data. KK guided in doing neuropsychology of participants and reviewed and validated data and manuscripts. PS and VS provided the participants and assisted in the recruitment of participants. All authors contributed to the article and approved the submitted version. | PMC10520697 |
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Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10520697 |
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Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The authors appreciate all participants for taking part in this study and all Yoga trainers who delivered Yoga classes to participants. | PMC10520697 |
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Supplementary material | The Supplementary material for this article can be found online at: Click here for additional data file.Click here for additional data file. | PMC10520697 |
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References | PMC10520697 |
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Background | dizziness, vertigo | Vestibular rehabilitation (VR) is the preferred treatment for chronic vestibular symptoms such as dizziness and vertigo. An internet-based programme was developed to increase uptake of VR. The authors have previously reported that internet-based VR resulted in a clinically relevant decrease of vestibular symptoms for up to 6 months, compared with usual care. | PMC10394610 |
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Aim | chronic vestibular syndrome | To evaluate long-term outcomes of internet-based VR in patients with chronic vestibular syndrome. | PMC10394610 |
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Design and setting | chronic vestibular syndrome | A randomised controlled trial was conducted in Dutch general practice involving 322 participants aged ≥50 years with chronic vestibular syndrome. Participants were randomised to stand-alone VR, blended VR (with physiotherapy support), and usual care. Usual care participants were allowed to cross over to stand-alone VR 6 months after randomisation. | PMC10394610 |
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Method | dizziness-related impairment, depressive, anxiety, vertigo | Participants were approached 36 months after randomisation. The primary outcome was the presence of vestibular symptoms as measured by the vertigo symptom scale—short form (VSS–SF). Secondary outcomes were dizziness-related impairment, anxiety, depressive symptoms, and healthcare utilisation. | PMC10394610 |
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Results | At 36-month follow-up, 65% of participants filled in the VSS–SF. In the usual care group, 38% of participants had crossed over to VR at 6 months. There were no significant differences in vestibular symptoms between VR groups and usual care (mean difference = −0.8 points, 95% confidence interval [CI] = −2.8 to 1.2, for stand-alone VR; −0.3, 95% CI = −2.2 to 1.7, for blended VR). In VR groups, clinically relevant improvement compared with baseline was maintained over time. | PMC10394610 |
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Conclusion | chronic vestibular syndrome | Internet-based VR provides a maintained improvement of vestibular symptoms for up to 36 months in patients with chronic vestibular syndrome. | PMC10394610 |
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INTRODUCTION | dizziness, vertigo | GPs often encounter patients with vestibular symptoms, such as dizziness and vertigo. | PMC10394610 |
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METHOD | PMC10394610 |
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Study design | A pragmatic, three-armed, individually randomised controlled trial was conducted involving 59 Dutch general practices. The Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines for non-drug treatment interventions were followed and the trial was registered in the Netherlands Trial Register (reference: NTR5712). A detailed research protocol and the results of the short-term effectiveness analysis at 6 months were published previously. | PMC10394610 |
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Participants | head movements, fits, vestibular syndrome | VESTIBULAR DISORDER | Electronic medical records were used to identify patients aged ≥50 years who visited their GP with a vestibular symptom in the past 2 years. The GP screened potentially eligible participants to exclude those with medical contraindications for making the required head movements, serious comorbid conditions that precluded participation in an exercise programme, an identifiable non-vestibular cause of their symptoms, or current enrolment in a related study. Trial information and a form to express interest was provided to potential participants. Physicians in the research team checked the eligibility criteria of interested patients by telephone. The inclusion criteria were:
good command of the Dutch language;access to the internet and an email account;persisting vestibular symptoms at time of inclusion, present for ≥1 month; andvestibular symptoms exacerbated or triggered by head movements.How this fits inThese inclusion criteria were used to identify participants with a chronic vestibular syndrome, as defined by the Bárány Society in the International Classification of Vestibular Disorders, | PMC10394610 |
Randomisation and blinding | BLIND | After the informed consent procedure, participants were sent an email with a link to the trial website. On completion of the baseline questionnaire, the software program allocated them to internet-based VR (stand-alone VR), internet-based VR with support (blended VR), or usual care. The randomisation process was fully automated and concealed from the research team. Due to the nature of the trial interventions, it was not possible to blind participants, physiotherapists, and research assistants. | PMC10394610 |
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Interventions | PMC10394610 |
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Stand-alone internet-based VR | Vertigo | VERTIGO | Stand-alone VR participants received access to the Vertigo Training internet-based intervention. Vertigo Training was a Dutch translation of the safe and effective British internet-based VR intervention Balance Retraining (freely available from | PMC10394610 |
Blended internet-based VR with physiotherapy support | Vertigo | VERTIGO | Blended VR participants were granted access to the same online Vertigo Training intervention as the stand-alone VR participants. In addition, they were visited twice at home by a trained physiotherapist during the 6-week intervention period. These 45-minute physiotherapy sessions took place in the first and third week. The physiotherapist provided information about the background of vestibular symptoms and VR, and talked about doubts and concerns the participant might have. They also taught participants how to use the online intervention, took participants through a set of VR exercises, advised on coping with obstacles to adherence, and encouraged participants to continue the exercises. Blended VR participants also received the standard level of care from their own GP with no restrictions. | PMC10394610 |
Usual care | Usual care participants received standard care from their own doctor without restrictions. The authors provided participating doctors with written instructions, asking them to diagnose and treat all causes of vestibular symptoms according to the guidelines of the Dutch College of General Practitioners. | PMC10394610 |
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Primary and secondary outcomes | vertigo, vestibular disorder | VESTIBULAR DISORDER | Measurements were collected at baseline, 3-, 6-, and 36-months’ follow-up. At baseline, participants provided information on their age, sex, level of education, living situation, comorbidities, vestibular diagnosis, frequency and average duration of vestibular symptoms, and the time since their vestibular disorder was diagnosed. The primary outcome was vestibular symptoms as measured by the vertigo symptom scale—short form (VSS–SF). | PMC10394610 |
Statistical analysis | An intention-to-treat analysis was performed to compare stand-alone VR and blended VR versus usual care. A linear mixed-model analysis was used to account for repeated measures within individuals. In a longitudinal dataset, this technique accounts for missing data without performing multiple imputations. | PMC10394610 |
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RESULTS | PMC10394610 |
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Post-hoc sensitivity analyses for non-response bias and attrition | To assess non-response bias and attrition the authors conducted several sensitivity analyses. The baseline characteristics for participants who filled in the 36-month follow-up and those who did not are described separately in Supplementary Table S3. Participants who completed 36-month follow-up had a relatively higher level of education, were less likely to live alone, and more often followed the per-protocol treatment. The results of a subsequent complete case sensitivity analysis, where only the patients who filled in the 36-month were included, showed similar results to the primary analysis (Supplementary Table S4). Lastly, a per-protocol analysis with participants who filled in the 36-month follow-up showed that VR participants who followed all sessions had fewer vestibular symptoms at long-term follow-up, indicating a positive effect of better engagement (Supplementary Table S5). | PMC10394610 |
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DISCUSSION | PMC10394610 |
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Summary | dizziness, depressive, anxiety | ADVERSE EVENTS | At 36-month follow-up, vestibular symptoms did not significantly differ between participants who received internet-based VR and usual care. The same applies with regard to impairment experienced due to dizziness, anxiety, and depressive symptoms. Nevertheless, clinically relevant improvements in internet-based VR groups were maintained over time. Recovery of usual care participants who crossed over at 6 months further indicates the value of online VR when vestibular symptoms do not improve spontaneously. There were no clear differences in healthcare utilisation between groups at long-term follow-up, and serious adverse events due to VR were unlikely. Many patients reported continuing VR exercises long after the end of the 6-week intervention period. | PMC10394610 |
Strengths and limitations | This study has several strengths. This was a large, well-designed trial and participants showed good adherence to the intervention.There are also some limitations. The response rate at 6-month follow-up was higher than at 36-month follow-up. The number of participants at 36-month follow-up was lower than the 80 participants per group in the original power calculation for 6-month follow-up. | PMC10394610 |
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Comparison with existing literature | To the authors’ knowledge, this is the first randomised controlled trial of VR with a long-term follow-up. | PMC10394610 |
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Implications for research and practice | reduction of vestibular symptoms, chronic vestibular syndrome | Results from this trial show that internet-based VR can provide a long-term reduction of vestibular symptoms in primary care patients with chronic vestibular syndrome. The favourable conclusions of this 36-month follow-up show that this safe and inexpensive treatment is ready to be made available for daily general practice. Future research questions are therefore mostly aimed at implementation. The authors are currently working on a large implementation research project to make stand-alone VR freely available to all in Dutch general practice (I-RECOVER trial). By assessing adoption, coverage, and sustainability of online VR, the authors aim to bridge science and daily general practice, providing patients and GPs with an easy solution to treat chronic vestibular syndrome.The authors thank all participants and GPs who participated in the trial. | PMC10394610 |
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Funding | This study was funded by
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Ethical approval | The study protocol was approved by the medical ethics committee of the VU University Medical Center. All participants included in the study provided written informed consent. | PMC10394610 |
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Data | Data are available on reasonable request. Requests for sharing study data can be made on specific grounds, either 1) with the aim of corroborating the study results in the interest of public health, or 2) in the context of an audit by a competent authority. Sufficient information needs to be provided to confirm that the request is made for one of the above-mentioned purposes, including a sound justification and, in case of a request with a view to corroborate study results, a protocol on the research for which the data will be used or a plan for quality control checks, as applicable. | PMC10394610 |
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Provenance | Freely submitted; externally peer reviewed. | PMC10394610 |
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Competing interests | All authors have completed the ICMJE uniform disclosure form at | PMC10394610 |
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Discuss this article | Contribute and read comments about this article: | PMC10394610 |
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REFERENCES | PMC10394610 |
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Abstract | Sponsor and Principal Investigator: John L. Reagan. | PMC10166163 |
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Background | multiple myeloma, toxicity | MULTIPLE MYELOMA | Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. | PMC10166163 |
Methods | MULTIPLE MYELOMA | We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. | PMC10166163 |
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Results | toxicity | PERIPHERAL NEUROPATHY, RECRUITMENT | The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. | PMC10166163 |
Conclusion | MULTIPLE MYELOMA, ONCOLOGY | Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).This phase IIBrown University Oncology Research Group trial investigated the effectiveness of an all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. | PMC10166163 |
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Lessons Learned | multiple myeloma, dermatologic adverse, Toxicity | MULTIPLE MYELOMA | Study enrollment for front-line therapy in multiple myeloma can be limited by the rapidly expanding landscape of available approved drugs in this setting.Toxicity rates for this regimen were higher than expected, with >40% of patients experiencing Grade 3 dermatologic adverse events, possibly impacting drug efficacy.The response rates and survival data with the combination of metronomic cyclophosphamide with ixazomib and dexamethasone for the treatment of multiple myeloma in the front-line setting do not support future study of this regimen in this space. | PMC10166163 |
Discussion | venous and arterial thromboembolism, diarrhea, cytopenias, ’s 2 stage, hypokalemia | MULTIPLE MYELOMA, TERATOGENESIS, CYTOPENIAS, RECRUITMENT, ONCOLOGY, MYELOMA, BROWN | While lenalidomide, bortezomib, and dexamethasone (RVD), with the addition or substitution of daratumumab in recent years, is the preferred initial treatment for most patients with newly diagnosed multiple myeloma, there are several alternative options that may be of benefit to select patient subgroups. Lenalidomide is associated with significant risk of teratogenesis as well as diarrhea, cytopenias, hypokalemia, and an increased risk of venous and arterial thromboembolism.In this phase II Brown University Oncology Research Group trial, we investigated the effectiveness of an all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. Daily cyclophosphamide dosing, known as metronomic dosing, has been evaluated in several prior studies showing clinical response.Simon’s 2 stage (MiniMax) design was used to evaluate response. Responses were determined using the 2016 IMWG response criteria and derived from the consensus guidelines for the uniform reporting of myeloma clinical trials.(The study was terminated due to slow recruitment but with a total of 12 patients treated. Response rates and survival were below those seen in similar studies as well as below standard of care options, with only 16.7% of patients obtaining a very good partial response (VGPR) and a median progression-free survival (PFS) of 16 months ( | PMC10166163 |
Additional Details of Endpoints or Study Design | PMC10166163 |
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Patients | toxicity | RECRUITMENT | From August 12, 2015 to March 29, 2019, a total of 18 patients underwent screening for the trial with 12 patients ultimately enrolled and treated. The trial was stopped prior to the 20 patients enrollment goal due to slow recruitment. Characteristics of the enrolled patients are listed in the Patient Characteristics section. Median age was 63.5 with a male predominance (83%). At the time of data cut-off 12 patients had completed a total of 62 cycles of treatment with the median number of cycles being 6 (range 2-9). Five of the 12 patients did not complete the initial 6 cycles of induction therapy (2 toxicity, 2 progression, and 1 early transplant after cycle 4). Only one patient proceeded to the maintenance phase of treatment and received 3 cycles of maintenance therapy before progression. Seven of the 12 patients ultimately went on to autologous stem cell transplantation. | PMC10166163 |
Study Treatment | toxicity, neutropenia, neuropathy | NEUTROPENIA, FEBRILE NEUTROPENIA, NEUROPATHY, THROMBOCYTOPENIA, APPENDIX | In this phase II single-center trial all patients received the same induction treatment. Induction treatment consisted of 6 cycles of therapy. Cycle 1 consisted of ixazomib 4 mg and dexamethasone 20 mg each given once weekly on days 1, 8, and 15 with continuous cyclophosphamide at a dose of 50 mg per day. Cycle length was 28 days with continuation of cyclophosphamide during week 4 of each cycle. If treatment was tolerated in cycle 1 (see below) patients then received ixazomib 4 mg and dexamethasone 20 mg twice weekly (on days 1, 4, 8, 11, 15, and 18) during cycles 2-6 with no change in the continuous cyclophosphamide (50 mg/day). Cycle lengths remained 28 days for the remaining 5 cycles.To proceed from once-weekly cycle 1 to twice-weekly cycles 2-6 dosing, patients could not have experienced grade ≥3 neutropenia or thrombocytopenia, febrile neutropenia, treatment related grade ≥3 non-hematology toxicity or treatment related grade ≥2 neuropathy. If any of the above were experienced, dose modifications were implemented which can be found in the Supplementary Appendix.After the completion of 6 cycles of induction therapy, patients had the option of proceeding to autologous stem cell transplantation or maintenance therapy. Patients who went on to autologous transplant came off study and were followed per schedule evaluation. Patients not going on to autologous transplant continued with maintenance therapy which consisted of ixazomib at 4 mg days 1, 8, and 15 of a 28-day cycle for 1.5 years (to complete 2 years of protocol treatment) or until relapse. | PMC10166163 |
Objectives and Endpoints | Toxicities, death, diarrhea, toxicities, cytopenias, vomiting, rash, nausea, | PERIPHERAL NEUROPATHY, CYTOPENIAS, MYELOMA, ENCEPHALOPATHY | The primary end point of this study was to evaluate the overall response rate to induction therapy (ORR). Response rates were evaluated using the International Myeloma Working Group Response Criteria. Secondary objectives included evaluation of toxicities, PFS, and overall survival (OS). Toxicities of interest included cytopenias, nausea, vomiting and diarrhea, rash, peripheral neuropathy, and posterior reversible encephalopathy. PFS was defined as the time from registration to the date of first documented progression or death. OS was defined as the time from registration to the date of death.An ORR of ≥80% was judged as promising for further evaluation. Further evaluation would not be warranted if the ORR was <50%. Simon’s 2 stage (MiniMax) design was used. In the first stage, 5 or more responses in 7 enrolled patients were required to proceed. In the second stage, an additional 13 patients were to be enrolled for a total sample size of | PMC10166163 |
Outcome Notes | PMC10166163 |
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Primary Endpoint | toxicity, rash | DISEASE, BEST, SECONDARY | The median duration of follow up for the entire study group was 30 months (range 14-66) The ORR was 58.3% with 2 patients achieving a VGPR (16.7%) and 5 patients achieving a partial response (41.7%) (Best response by M protein/free light chain.Per trial protocol, 7 patients were initially enrolled and evaluated for response. Amongst these 7 patients 5 responses were seen. Four patients had a best response of PR and 1 patient had a VGPR. Only 5 more patients were recruited prior to closure of the study for a total of 12 patients for evaluation of efficacy. Among these first 7 patients 3 patients ultimately had progressive disease by the end of initial induction therapy, including progression in 2 patients who initially had a response (1 PR and 1 VGPR). One patient discontinued treatment due to toxicity, a grade 3 maculopapular rash felt to be secondary to Ixazomib. By the end of induction only 2 out of the first 7 patients had completed induction therapy and continued to have a response but neither of these patients achieved a VGPR. A swimmer’s plot of these first 7 patients and their response course is depicted in | PMC10166163 |
Secondary Endpoints | Secondary objectives included evaluation of PFS and OS. Median PFS was 16 months (95% CI 4 to not reached) and Median OS was 43 months (95% CI 28 to not reached; Progression-free survival (PFS) and overall survival (OS) estimates. ( | PMC10166163 |
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Safety and Toxicity | toxicities, Toxicities | ADVERSE EVENT | The safety profile of toxicities of interest is listed in Toxicities.Adverse events. | PMC10166163 |
Assessment, Analysis, and Discussion | multiple myeloma, SWOG | MULTIPLE MYELOMA | In this phase II trial, we found that response rates and survival with oral metronomic cyclophosphamide, ixazomib, and dexamethasone for patients with newly diagnosed multiple myeloma were below those seen in other studies using similar drugs. In our study only 16.7% of patients obtained a VGPR and 58.3% of patients a PR or better (Response rates and survival are also superior in other standard of care options for front-line treatment for multiple myeloma. In patients who received RVD in the SWOG S0777 trial 27.8% of patients and 81.5% of patients achieved a VGPR or PR or better, respectively.There are several possible reasons for the low response rate and worse survival seen in our study. Metronomic cyclophosphamide may be inferior to standard weekly cyclophosphamide dosing, especially in the newly diagnosed setting. Metronomic cyclophosphamide has been evaluated in several studies; however, its efficacy has largely been seen in the relapsed/refractory setting.Several other factors may have also limited the efficacy evaluation of our study. Enrollment to the study was limited by several factors and we did not reach our goal of 20 patients for full efficacy evaluation. Study enrollment was started in August 2015 and between initial protocol development and first cohort enrollment several studies have been published showing the efficacy of alternative treatment options. These include phase I/II data of carfilzomib-lenalidomide–dexamethasone (KRd) in 2015, the formal the publication of the SWOG S077 data in 2017, and the addition or substitution of daratumumab to the backbone of RVD as early as 2019.While our sample size was limited our data do not suggest benefit of further study of this specific drug regimen in the first-line setting except in unique patient populations that may not be able to tolerate alternative treatment options. Given the larger patient size in the Dimopoulos et al. study (of all oral weekly cyclophosphamide, ixazomib, and dexamethasone) and the improved response rates it would suggest that an all-oral therapy with weekly cyclophosphamide as opposed to metronomic dosing could be considered. | PMC10166163 |
Conflict of Interest | TG | CROSS | John L. Reagan reported consulting/advisory relationships with Rigel, Pfizer, and Bristol Myers Squibb. Adam J. Olszewski reported consulting/advisory relationships with TG Therapeutics, Genmab, Schrodinger, and Blue Cross and Blue Shield of Rhode Island, research funding from Adaptive Biotechnologies, Genentech/Roche, TG Therapeutics, Spectrum Pharmaceuticals, Celldex, Precision Biosciences, and Genmab. Eric S. Winer reported consulting/advisory relationships with for Jazz Pharmaceutical, Pfizer, Takeda, Novartis, and Curis. The other authors indicated no financial relationships. | PMC10166163 |
Data Availability | The data underlying this article will be shared on reasonable request to the corresponding author. | PMC10166163 |
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References | PMC10166163 |
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1. Introduction | obesity, obese, nutritional deficiencies, overweight or obesity, overweight–obese, weight loss | OBESITY, OBESE, SECONDARY, NUTRITIONAL DEFICIENCIES, DISEASES | Evidence of the effectiveness of zinc (Zn) and selenium (Se) on resting metabolic rate (RMR) and physical function parameters in people with overweight and obesity is scarce, while the effects of zinc and selenium on thyroid function and body composition are still a topic of debate and controversy. The aim of this randomized, double-blind, and placebo-controlled trial was to examine the effects of a hypocaloric diet and Se–Zn co-supplementation on RMR, thyroid function, body composition, physical fitness, and functional capacity in overweight or obese individuals. Twenty-eight overweight–obese participants (mean BMI: 29.4 ± 4.7) were randomly allocated (1:1) to the supplementation group (According to the World Health Organization, the number of obese people has almost tripled since 1975 [The causes of obesity are complex and can be classified as primary and secondary, with an interaction between biological, behavioral, and psychosocial factors taking place [Growing evidence confirms that obesity increases the risk for nutritional deficiencies due to poor diet quality and a disruption of the bioavailability and metabolism of numerous nutrients despite the high caloric intake that characterizes the specific population [A systematic review of the literature indicated that people with obesity have lower levels of some antioxidants, including zinc (Zn) and selenium (Se) [Numerous systematic reviews and meta-analyses have highlighted that Se and Zn supplementation may positively affect many aspects of health in people with or without diseases and pathological conditions [Even though a diet plan can induce weight loss by creating a negative energy balance, maintaining weight loss can sometimes be challenging in the long term [Two studies examining the effects of Zn on human RMR or Basal Metabolic Rate (BMR) showed some positive results [Hawkes and Keim [In several studies, the low RMR of individuals with obesity was associated with lower cardiorespiratory fitness levels, probably due to limited physical activity levels [A recent review found that a poor Zn status in healthy individuals, as a result of a dietary consumption below the recommended daily allowances (RDA), can negatively affect their physical performance [The aim of this randomized control trial was to examine the effects of Zn and Se co-supplementation on RMR, thyroid function, exercise performance, and body composition in people with overweight or obesity undergoing a hypocaloric diet. | PMC10386647 |
2. Materials and Methods | PMC10386647 |
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2.1. Study Design | overweight or obesity | This was a randomized, double-blind, and placebo-controlled trial involving adult men and women with overweight or obesity (BMI ≥ 25). After the initial screening, twenty-eight participants (mean BMI: 29.4 ± 4.7) were randomly allocated (1:1) to the supplementation group ( | PMC10386647 |
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2.2. Intervention | Participants in the supplementation group received 25 mg/day of Zn gluconate and 200 mcg/day of Se L-selenomethionine and the controlled group received placebo supplements of identical color and shape, containing starch ( | PMC10386647 |
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2.3. Blinding and Randomization | A table of random numbers was used so each participant could have the same chance of receiving either the Zn–Se supplement or placebo tablets. This way, the investigators could not predict which treatment was next. In addition, as the placebo tablets were identical to the supplements, neither the investigator doing the assessments nor the study participants could identify to which study group the participant belonged. | PMC10386647 |
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2.4. Anthropometry and Body Composition | Weight was measured using a calibrated scale (Seca, Hamburg, Germany) with minimum clothes and without shoes. Height was measured without shoes by the use of a wall-mounted stadiometer with a precision of 0.5 cm. BMI was estimated using the formula weight (kg)/height | PMC10386647 |
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2.5. Participants’ Adherence | ’ | The participants’ adherence to the supplements was estimated by the number of remaining tablets. Participants’ data were analyzed if the compliance was ≥90%. | PMC10386647 |
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2.6. Thyroid Function Assessment | THYROID | Thyroid hormones were assessed biochemically by measuring serum TSH, FT3, and FT4 concentration [ | PMC10386647 |
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2.7. Resting Metabolic Rate | RMR was estimated using indirect calorimetry (Quark CPET, Cosmed, Rome, Italy). The tests were conducted early in the morning, with participants lying quietly on a reclined bed for 15 min in a dark, quiet room. Then, the respiratory face mask was placed, measuring RMR for the remaining 15 min. All participants abstained from strenuous exercise for at least 48 h before measurement and from eating for 12 h prior to measurement [ | PMC10386647 |
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