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Consent for publication | Not applicable. | PMC10024023 | ||
Competing interests | The authors declare that they have no conflicts of interests. | PMC10024023 | ||
References | PMC10024023 | |||
Keywords | One-carbon nutrients play an important role in epigenetic mechanisms and cellular methylation reactions. Inadequate intake of these nutrients is linked to metabolic perturbations, yet the current intake levels of these nutrients have rarely been studied in Asia. This cross-sectional study surveyed the usual dietary intake of one-carbon nutrients (folate, choline and vitamins B2, B6 and B12) among Thai university students aged 19–30 years ( | PMC10131051 | ||
Introduction | SPONTANEOUS ABORTION, FOLATE DEFICIENCY | One-carbon (1C) metabolism is a complex network of biochemical reactions that activates and transfers methyl groups. This network consists of folate, choline and methionine. The folate cycle produces nucleic acids that are used for DNA and RNA synthesisThe roles of vitamins B2, B6 and B12, folate and choline in one-carbon metabolism. BHMT, betaine-homocysteine Inadequate intake of 1C nutrients is associated with metabolic perturbations at various stages of life. The consequences of folate deficiency during pregnancy on spontaneous abortion and neural tube defects have been well studiedSurveys of dietary intake of 1C nutrients have been concentrated in Western countries, whereas studies in Asia and Africa are limited, and results varied. Mean folate intake levels in countries without mandatory B vitamin fortification varied from 170 μg dietary folate equivalence (DFE)/d in Ethiopia to 246 and 499 μg DFE/d in Sweden and Korea, respectivelyAmong the 1C nutrients, choline is a nutrient of concern for underconsumptionThe objective of the present study is to assess usual intake of 1C nutrients in young Thai adults. A cross-sectional survey was conducted on a sample of healthy Thai university students ( | PMC10131051 | |
Materials and methods | PMC10131051 | |||
Study design and population | A cross-sectional descriptive study design was used to survey the usual intake levels of 1C nutrients in 246 healthy adults (82 male and 164 female) 19–30 years of age. Sample size was determined to differentiate mean choline intake levels between sex using data from our pilot study with the effect size of 60 mg/d, | PMC10131051 | ||
Study protocol | CREST, RECRUITMENT | Participants were recruited from Chiang Mai University, Chiang Mai, Thailand via flyers and online postings. Study enrolments were regularly monitored for diversity of participants from various departments, and recruitment efforts were focused on under-represented groups, such as those who did not frequent the main campus area or post-graduate students. Screening was conducted using online questionnaires, and eligible participants were invited to a session at the Faculty of Agro-Industry at Chiang Mai University, Thailand.During the session, the participants were asked to sign a consent form and provide socioeconomic information, health habits such as dietary patterns, physical activity levels, alcohol consumption, smoking status, screen time and sleep quality on a questionnaire. The participants then underwent anthropometric assessment by trained personnel. Weight and height were measured using a calibrated scale (Seca GmbH and Co. KG). Waist and hip circumferences were measured according to World Health Organization guidelines, that is, waist circumference (WC) was measured at the midpoint between the last palpable rib and iliac crest, and hip circumference was measured at the widest position of the bottom | PMC10131051 | |
Dietary intake assessment | Cancer | CANCER | Dietary intake information was assessed via 24 h dietary recall interviews. Study personnel collected information on all food items that the participants consumed during the past 24 h (midnight to midnight) using the validated Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24) developed by the National Cancer Institute, Bethesda, MD, USA. ASA24 utilised the Automated Multiple-Pass Method, in which a list of consumed food items was compiled, followed by time and occasion of eating, and detailed descriptions of each food, including preparation methods, portion sizes and addition | PMC10131051 |
Usual intake of one-carbon nutrients | MSM | Dietary recall data were linked to the USDA food composition database, which contains data from the Food and Nutrient Database for Dietary Studies, Food Patterns Equivalents Database and NHANES Dietary Supplement DatabaseThe ASA24 nutrient intake data were used to calculate the usual intake of each 1C nutrient following the Multiple Source Method (MSM). MSM is a method for estimating the usual dietary intake from a 24 h recall or short-term assessments. This method can account for intra-individual variation and handle different distributions of nutrient data | PMC10131051 | |
Statistical analyses | Dietary data were inspected for outliers and extreme values. Health habit information was either categorised or used as a continuous variable. Specifically, smoking status was categorised into current or non-smokers based on smoking activity in the past 12 months. Vigorous physical activity was defined as an activity that exerts force and greatly increases respiration or heart rates, such as lifting or carrying heavy objects, building, plowing, running, playing basketball, for at least 10 min continuously. Moderate physical activity was defined as an activity that slightly increases respiration or heart rates, such as carrying small objects, fast-walking, cycling, swimming, golfing, for at least 10 min continuously. These definitions were clearly written in the questionnaires, and the obtained data was converted to hour/week. Alcohol consumption and screen time responses were numerical and based on the past 12 months and the past 30 d, respectively.Descriptive statistics (means, | PMC10131051 | ||
Results | PMC10131051 | |||
Participants socioeconomic status, health characteristics and dietary intake | ± | ADIPOSITY | The study participants had a mean age of 21 years, with most being undergraduate students who had not worked part-time and were living alone (Participant characteristics, health patterns and dietary intake (Values are mean ± Missing values are Visceral adiposity risk categories were based on wait-to-hip ratios as follows: low (female ≤0⋅80; male ≤0⋅95), moderate (female 0⋅81–0⋅85; male 0⋅96–1⋅00) and high (female >0⋅85; male >1⋅00).The participants were mostly non-smokers and had a mean alcohol consumption of 12 drinks/week. Males were more likely to be current smokers than females ( | PMC10131051 |
Usual intake and prevalence of inadequacy of one-carbon nutrients | ± | ADIPOSITY | Mean and median usual intakes of vitamins B2, B6 and B12 among participants were higher than the EAR set by the U.S. National Academy of Medicine, which is also used for Thai Dietary Reference Intake (Usual intake distribution of one-carbon nutrients by sex: vitamins B2 (a–male, b–female), B6 (c–male, d–female) and B12 (e–male, f–female), dietary folate (g–male, h–female) and choline (i–male, j–female). Lines indicated the estimated average requirement (EAR; for vitamins B2, B6 and B12, folate) or the adequate intake (AI; for choline) based on the U.S. National Academy of Medicine. Yellow areas indicated a proportion of samples that had inadequate intake of each nutrient.Usual one-carbon nutrient intake by characteristic and health subgroupsValues are the mean ± Visceral adiposity risk categories were based on wait-to-hip ratios as follows: low (female ≤0⋅80; male ≤0⋅95), moderate (female 0⋅81–0⋅85; male 0⋅96–1⋅00) and high (female >0⋅85; male >1⋅00).Median, 5th percentile and 95th percentile of usual one-carbon nutrient intake and percentage of participants with inadequate intakeAdequate intake was used for choline.Men consumed more folate and choline than women ( | PMC10131051 |
Relationships between one-carbon nutrient intake and obesity measures | REGRESSION | Usual 1C intake levels were not associated with BMI, WC or WHR in the multiple linear regression models adjusted for sex, education, smoking, family income, age and energy intake (Associations between usual intake levels of one-carbon nutrients and body mass index, waist circumference and waist-to-hip ratiosLinear regression models adjusted for age, sex, education, smoking, family income and energy intake were used, with a significance threshold of Associations between usual intake levels of one-carbon nutrients and body mass index, waist circumference and waist-to-hip ratios (WHR) by sexLinear regression models adjusted for age, sex, education, smoking, family income and energy intake were used with a significant threshold of | PMC10131051 | |
Discussion | PMC10131051 | |||
Folate intake | The findings in the present study revealed that the majority of participants had inadequate folate intake. This is consistent with a previous study in Thai women of childbearing age, which reported that 65⋅5 % of women had low dietary folate levels and 18 % had low serum folate | PMC10131051 | ||
Choline intake | To our knowledge, this is the first study to estimate choline intake in a Thai population. Our results indicated that the mean choline intake was well below the AI levels for both men and women. This was likely due to the low consumption of choline food sources and not due to inadequate caloric intake, since most participants consumed enough energy according to the Thai Recommended Daily Intake. Indeed, the participants reported consuming small amounts of choline food such as eggs, beef, liver and other organ meat. This observation was consistent with a previous study that found that most Thai people consumed eggs only 3–4 day per week, or approximately ½−1 egg per dayUnderconsumption of choline was also observed in Western populations, with generally higher caloric and protein intake than in Thai populations. The mean usual choline intake in U.S. adults aged 19–30 years was 392 mg/d for men and 257 mg/d for women, and people who consumed eggs had almost twice as much choline intake as non-consumers | PMC10131051 | ||
Intake of other B vitamins | obesity | OBESITY | The intake of vitamins B2, B6 and B12 was adequate among study participants and was higher in men than in women. This is expected, as men also consume more calories than women. The intake of these B vitamins was not associated with socioeconomic backgrounds and health behaviours, suggesting that the overall dietary quality was homogenous in this sample. The lack of associations between vitamin B intake and obesity measures (BMI, WC and WHR) may be due to the small sample size and sample homogeneity. Nonetheless, an inverse association between vitamin B2 intake and BMI was observed in male participants. Vitamin B2 is a coenzyme of methylenetetrahydrofolate reductase (MTHFR), the rate-limiting enzyme in the folate cycle ( | PMC10131051 |
Conclusion | Usual intake of 1C nutrients in male and female young Thai adults was adequate for vitamins B2, B6 and B12. The majority of participants had inadequate folate intake and did not achieve recommended intake levels for choline. The intake levels of vitamin B2 and choline were inversely associated with BMI in men. These findings are in line with reports in Western countries, suggesting that inadequate intake of folate and choline is not geographically constrained. | PMC10131051 | ||
Acknowledgements | The authors would like to thank the Faculty of Agro-Industry and the Faculty of Medicine, Chiang Mai University, as well as all participants who contributed to this research.P. J.: Investigation, Data curation, Formal Analysis, Writing – Original draft; W. J.: Funding acquisition, Writing – Review & Editing; J. K.: Writing – Review & Editing; N. L.: Writing – Review & Editing; P. T.: Resources, Writing – Review & Editing; S. T.: Conceptualisation, Methodology, Writing – Review & Editing, Supervision, Funding acquisition.Data used in this study will be made available upon request.This study was supported by CMU Junior Research Fellowship Program, and the Coordinating Center for Thai Government Science and Technology Scholarship Students (CSTS), National Science and Technology Development Agency (NSTDA).All authors declare no conflict of interest. | PMC10131051 | ||
References | PMC10131051 | |||
Background | Maintaining oral health is essential for improving overall health of children living with HIV. Therefore, we evaluated the effectiveness of an oral health intervention for improving their oral and overall health. In addition, we examined their longitudinal association between changes in oral and overall health. | PMC10144884 | ||
Methods | We conducted a 2-year randomized controlled trial involving children living with HIV in Cambodia. Children aged 3–15 years and their caregivers were randomly allocated either to the intervention (group A) or control (group B) arm. A second control arm (group C) included children without HIV. The group A children received oral health education sessions and practiced home-based daily care. | PMC10144884 | ||
Results | In the baseline survey, 482 children participated (group A: | PMC10144884 | ||
Conclusions | Oral health intervention may improve oral care behaviors and potentially enhance overall health among children living with HIV in antiretroviral therapy in a resource-constrained setting. | PMC10144884 | ||
Trial registration | ISRCTN 15177479. | PMC10144884 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12916-023-02862-2. | PMC10144884 | ||
Keywords | PMC10144884 | |||
Background
| carious lesions, respiratory and cardiovascular diseases, cancer, AIDS-related, HIV infections, diabetes | DENTAL CARIES, CANCER, CHRONIC DISEASES, HIV INFECTIONS, DIABETES | In 2021, 1.7 million children were living with HIV worldwide [In children without HIV, oral health is associated with overall and long-term health. In general adult populations, poor oral health has been associated with chronic diseases, such as diabetes, respiratory and cardiovascular diseases, and cancer [An association between oral and overall health indicators, such as viral load and QOL, has been observed in children living with HIV [In Cambodia, there has been a considerable decrease in the rates of new HIV infections and AIDS-related mortality in the last two decades [The general children population in Cambodia carries a severe oral health burden caused by dental caries, with 57% of children aged 0–4 years having carious lesions [Therefore, this study aimed to evaluate the effectiveness of oral health interventions in improving the oral and overall health of children living with HIV receiving ART and compared the effects of the interventions between children with and without HIV. Furthermore, we examined the longitudinal association between oral and overall health changes. | PMC10144884 |
Methods | PMC10144884 | |||
Study design | coronavirus disease 2019, NPH | NPH, CORONAVIRUS DISEASE 2019 | This randomized controlled trial was conducted from February 2018 to April 2021 in the HIV clinic of the National Pediatric Hospital (NPH) in Phnom Penh, Cambodia. The original research plan included a 2-year intervention. However, owing to the coronavirus disease 2019 (COVID-19) pandemic, the endline study was postponed by 10 months. The study protocol has been published elsewhere [ | PMC10144884 |
Participants | NPH | NPH | The study population comprised children living with and without HIV. Of the 1113 eligible children in NPH, 482 were randomly included in the baseline survey (Fig. Flow diagram of the participants | PMC10144884 |
Sample size | Before the intervention, the minimum required sample size was 260 per group based on the decayed, missing, and filled permanent teeth (DMFT) score obtained from other studies [ | PMC10144884 | ||
Recruitment and randomization | NPH | NPH | Children living with HIV were identified from the patient list of the NPH HIV clinic. The participants were randomly assigned to either the intervention or control group, allowing equal allocation of same-aged children. A computerized algorithm was used to perform randomization by a data analyst who was not a primary member of the study team. Three districts in Phnom Penh had the highest number of children living with HIV who participated in this study. We randomly selected one village from each of the three districts and randomly recruited eligible children without HIV using the resident lists obtained from the village heads. Participants’ enrollment and intervention assignment were not concealed due to the nature of the intervention design. | PMC10144884 |
Interventions | DENTAL CARIES | The children in group A and their caregivers received oral health education sessions every four months, with a total of six sessions during the intervention period. During the sessions presentation materials and videos (e.g., how to prevent dental caries and what food is good or bad for the teeth) were used (Additional file | PMC10144884 | |
Outcome measures | DISEASE PROGRESSION, SECONDARY | The primary outcome associated with oral health was the change in DMFT or the decayed, missing, and filled deciduous teeth (dmft) scores, and the secondary outcome was the viral load. Initially, the CD4 count was considered the secondary outcome. However, after initiating the study, only viral load was used to measure disease progression in children living with HIV in Cambodia. Therefore, viral load was used as the study outcome, as shown in the revised online protocol (ISRCTN15177479). For oral health outcomes, we collected data regarding oral hygiene indicators (salivary pH, salivary flow quantity, debris index score, and oral health-related QOL [OHQOL]) and oral healthcare behavioral indicators (dental visits, brushing frequency and duration, and oral care support from caregivers). To measure the overall health outcomes, we collected information regarding height for age, body mass index (BMI) for age, and overall QOL in addition to viral load. | PMC10144884 | |
Data collection | NPH | NPH | We conducted the baseline surveys from February to April 2018 and the endline survey from February to April 2021. The children and their caregivers were interviewed using a structured questionnaire. We also collected data on children’s oral health status, weight, and height. For children in groups A and B, data regarding viral load were also collected from the medical records of NPH. Additional file | PMC10144884 |
Questionnaire | pain | Trained research assistants interviewed children and caregivers. The questionnaires collected information regarding the sociodemographic, oral care behavior, overall health-related QOL, and OHQOL.Regarding oral healthcare behaviors, the participants were asked whether they had visited a dentist over the last 12 months owing to pain or other problems related to teeth, their frequency of brushing per day, duration of teeth brushing per occasion, and whether their caregiver had ever helped them with teeth brushing.The overall health-related QOL was evaluated using the Pediatric Quality of Life Inventory (PedsQL™ 4.0) [ | PMC10144884 | |
Registered medical records | NPH | NPH | Data regarding viral load were collected from the registered medical records of the NPH by research assistants. The latest information regarding viral load was obtained before the baseline survey and after the endline survey. | PMC10144884 |
Oral status examination | NPH | To evaluate children’s oral health status, we collected data regarding the number of DMFT/dmft, debris index, salivary pH, and salivary flow rate. A lower DMFT/dmft score and debris index, and a higher salivary flow rate and salivary pH indicated better oral health status. The dentists of NPH collected the complete oral health data with the help of dental assistants based on the WHO guideline [ | PMC10144884 | |
Body weight and height | Data regarding children’s body weight and height were collected and converted to the | PMC10144884 | ||
Statistical analyses | teeth dentition | First, we conducted descriptive analyses of the basic characteristics of the participants. The outcomes were examined for data with normal distribution, and skewed data were log-transformed. Second, bivariate analyses were performed to identify differences in variables in the baseline survey between groups A and B and between groups A and C to evaluate the efficacy of the intervention in improving oral and overall health outcomes. Third, we conducted mixed-model analyses between groups A and B and between groups A and C. The model was adjusted for age, sex, intervention type (intervention or control), time (baseline or endline), and interaction between intervention type and time. Fourth, mixed-model analyses of group A were performed to assess the longitudinal association between changes in oral and overall health outcomes. In addition to oral health outcomes, the model was adjusted for age, sex, and time (baseline or endline). Each oral health outcome was assessed separately with the overall health outcomes to prevent multicollinearity. Oral health outcomes were examined for association with overall health outcomes with continuous variables, while the association with viral load was examined with a binary variable with the mean as the cutoff. We also stratified children’s dentition types at the baseline (mixed dentition and permanent teeth dentition) and performed above mentioned mixed model analyses. We did not conduct stratified analyses on the deciduous teeth dentition as the sample size was not large enough. The threshold for statistical significance was | PMC10144884 | |
Results | PMC10144884 | |||
Retention rate at the endline survey | We started recruiting baseline survey participants in February 2018 and followed up with them until April 2021. The mean attendance of group A in six oral health education sessions was 83.3%. Finally, 86.3% ( | PMC10144884 | ||
Discussion | infections, HIV exhibited better oral hygiene | DENTAL CARIES, INFECTIONS | To the best of our knowledge, this was the first randomized controlled trial that evaluated the effectiveness of oral health interventions in improving oral health outcomes among children living with HIV. We compared outcome indicators between children living with HIV receiving and not receiving the intervention and between children living with HIV receiving the intervention and children without HIV not receiving any intervention.Oral health intervention improved the oral health care behaviors of children living with HIV compared to the control groups’ children. However, the differences in oral hygiene did not significantly differ between them. Those were similar even after stratification by mixed or permanent dentition type. The results are consistent with previous systematic reviews and meta-analyses of intervention studies involving the general child and adolescent populations [We found that children without HIV exhibited better oral hygiene, as assessed via the DMFT/dmft scores and salivary flow rate, than children living with HIV receiving the intervention. A similar association was observed in our cross-sectional analysis using this trial’s baseline data [Longitudinal changes in oral hygiene outcomes due to the intervention were associated with changes in viral load and BMI for age in children living with HIV. Specifically, greater dental caries in permanent teeth was associated with viral load detection. Although this relationship has been known in a cross-sectional study [This study had certain limitations. The endline survey was delayed for 10 months because of the COVID-19 pandemic. The time gap and COVID-19 prevention and intervention measures might have influenced the direct impact of the intervention (e.g., oral healthcare behaviors, including oral hygiene for preventing infections, and interruptions in dental services in the study site and community). The children without HIV who dropped out from the study during the follow-up were older and moved elsewhere for higher schooling. Older children are likely to have higher DMFT scores in permanent teeth and better oral hygiene care skills, which might have affected our results. Despite these limitations, our study demonstrated a robust design involving children living with and without HIV recruited from a large health facility and comparable community. Hence, our results have critical implications for HIV care services for children and research on oral hygiene, development, and overall health. | PMC10144884 |
Conclusions | HIV in low- and middle-income countries. | Oral health education improved the oral care behaviors of children living with HIV in a resource-constrained setting. In addition, over time, improved oral hygiene outcomes were associated with improved overall health outcomes, such as viral load, BMI for age, and QOL, among children living with HIV. Therefore, oral interventions may be provided to improve the overall health of children living with HIV in low- and middle-income countries. | PMC10144884 | |
Supplementary Information | HIV and without HIV | APPENDIX |
Additional file 1: Appendix 1. Training Schedule. Appendix 2. Outcome measures. Appendix 3. Participants’ characteristics at the baseline and endline surveys. Appendix 4. Followed-up and lost-to-follow up participants. Appendix 5. Differences of baseline and endline oral hygiene status in each participant group. Appendix 6. Age group stratified effect of the intervention on oral and overall health outcomes between the intervention and control groups of children living with HIV. Appendix 7. Age group stratified effectiveness of the intervention in improving oral and overall health outcomes between children living with HIV and without HIV. Appendix 8. Dentition type stratified longitudinal association between oral health outcomes and overall health outcomes changes in the intervention group. Appendix 9. Age group stratified longitudinal association between oral health outcomes and overall health outcomes changes in the intervention group. | PMC10144884 |
Acknowledgements | The authors acknowledge all the children and their caregivers, the staff at the National Pediatric Hospital, Cambodia, and the research staff for their contributions to this study. This research was supported by JSPS KAKENHI Grant Number JP17H04658. The content of the article is solely the responsibility of the authors and does not necessarily represent the official views of the funding agency. | PMC10144884 | ||
Authors’ contributions | SE | Conceptualization: KK, JY, ST, MM, SY. Data curation: ST, SE. Formal analysis: KK, AS. Funding acquisition: KK. Investigation: CH, ST, SO, MM. Methodology: KK. Project administration: ST, SE. Supervision: SY, MM. Writing – original draft: KK. Writing – review and editing: JY, ST, MM, SO, CH, SY, KN, AS, SE. The authors read and approved the final manuscript: All authors. | PMC10144884 | |
Funding | This research was supported by JSPS KAKENHI Grant Number JP17H04658. | PMC10144884 | ||
Availability of data and materials | The data that support the findings of this study are available from the corresponding author, upon reasonable request. | PMC10144884 | ||
Declarations | PMC10144884 | |||
Ethics approval and consent to participate | This study was approved by the Institutional Review Board of Kyushu University, Japan (approval/29067), and the National Ethics Committee for Health Research, Ministry of Health, Cambodia (approval/289NECHR). The participants joined voluntarily and written informed consent was obtained from all caregivers. | PMC10144884 | ||
Consent for publication | Not required. | PMC10144884 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10144884 | ||
References | PMC10144884 | |||
Background | cardiovascular disease | EVENTS, SECONDARY, CARDIOVASCULAR DISEASE | A complete list of the REVEAL Collaborative Group members can be found in the Supplemental Material.Despite optimized risk factor control, people with prior cardiovascular disease remain at high cardiovascular disease risk. We assess the immediate‐ and longer‐term impacts of new vascular and nonvascular events on quality of life (QoL) and hospital costs among participants in the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) trial in secondary prevention. | PMC7615160 |
Methods and Results | myocardial infarction, cancer, −0.067, Myocardial infarction, nonhemorrhagic stroke, heart failure | MYOCARDIAL INFARCTION, ADVERSE EVENTS, CANCER, EVENT, MYOCARDIAL INFARCTION, REGRESSION, EVENTS, HEART FAILURE | Data on demographic and clinical characteristics, health‐related quality of life (QoL: EuroQoL 5‐Dimension‐5‐Level), adverse events, and hospital admissions during the 4‐year follow‐up of the 21 820 participants recruited in Europe and North America informed assessments of the impacts of new adverse events on QoL and hospital costs from the UK and US health systems' perspectives using generalized linear regression models. Reductions in QoL were estimated in the years of event occurrence for nonhemorrhagic stroke (−0.067 [United Kingdom], −0.069 [US]), heart failure admission (−0.072 [United Kingdom], −0.103 [US]), incident cancer (−0.064 [United Kingdom], −0.068 [US]), and noncoronary revascularization (−0.071 [United Kingdom], −0.061 [US]), as well as in subsequent years following these events. Myocardial infarction and coronary revascularization (CRV) procedures were not found to affect QoL. All adverse events were associated with additional hospital costs in the years of events and in subsequent years, with the highest additional costs in the years of noncoronary revascularization (£5830 [United Kingdom], $14 133 [US Medicare]), of myocardial infarction with urgent CRV procedure (£5614, $24722), and of urgent/nonurgent CRV procedure without myocardial infarction (£4674/£4651 and $15 251/$17 539). | PMC7615160 |
Conclusions | cardiovascular disease, Stroke | CARDIOVASCULAR DISEASE, STROKE, SECONDARY, EVENTS, HEART FAILURE | Stroke, heart failure, and noncoronary revascularization procedures substantially reduce QoL, and all cardiovascular disease events increase hospital costs. These estimates are useful in informing cost‐effectiveness of interventions to reduce cardiovascular disease risk in secondary prevention. | PMC7615160 |
Registration | URL: | PMC7615160 | ||
Subject Categories | This article was sent to Saket Girotra, MD, SM, Associate Editor, for review by expert referees, editorial decision, and final disposition.Supplemental Material is available at For Sources of Funding and Disclosures, see page 11. | PMC7615160 | ||
Nonstandard Abbreviations and Acronyms | coronary revascularizationgeneralized linear modelRandomized Evaluation of the Effects of Anacetrapib Through Lipid Modification
| PMC7615160 | ||
Clinical Perspective | PMC7615160 | |||
What Is New? | stroke, heart failure, myocardial infarction, cardiovascular disease | MYOCARDIAL INFARCTION, CARDIOVASCULAR DISEASE, STROKE, EVENT, SECONDARY, EVENTS, HEART FAILURE |
The study estimates the impacts of new major cardiovascular events on quality of life and hospital care costs in contemporary patients with well‐managed secondary cardiovascular disease from the perspectives of the UK and US health systems.In the year of event occurrence, nonhemorrhagic stroke, heart failure admission, and noncoronary revascularization were associated with the largest reductions in quality of life, whereas no quality of life reductions were observed for myocardial infarction and coronary revascularization.Coronary and noncoronary revascularization procedures were associated with the largest additional hospital costs. | PMC7615160 |
What Are the Clinical Implications? | cardiovascular disease, stroke, CVD, heart failure, deaths | MYOCARDIAL INFARCTION (MI), CARDIOVASCULAR DISEASE, CARDIOVASCULAR DISEASE, CVD, STROKE, SECONDARY, EVENTS, HEART FAILURE |
The contemporary impacts of new cardiovascular events on quality of life and costs reported in this study could inform cost‐effectiveness evaluations of newer interventions for secondary cardiovascular disease prevention in the United Kingdom and United States.Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, accounting for a third of deaths globally,Cardiovascular events such as myocardial infarction (MI), stroke, and heart failure have been associated with substantial long‐term impacts on QoLThe REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) trial | PMC7615160 |
Methods | EVENTS | The data underlying this article are available in the article and in its online A total of 21 820 REVEAL participants, recruited in Europe and North America from 2011 to 2013 and followed for an average of 4 years until 2017, contributed to the main analyses in the current study. Data on the 8629 participants recruited in China were excluded from the main study analyses because of large differences in hospitalization rates for events and much longer inpatient stays, suggesting different hospital care patterns compared with the other study regions. Previous studies have also reported that EuroQoL 5‐Dimension (EQ‐5D) scores exhibit a larger ceiling effect in a Chinese population suggesting cultural influences limiting comparisons with Western populations. | PMC7615160 | |
Key Disease Events | vascular death, death, stroke, cancer, diabetes | ADVERSE EVENTS, STROKE, DISEASE, CANCER, EVENTS, HEART FAILURE, DIABETES | After randomization, follow‐up assessments in the study were conducted at 2 months, 6 months, and every 6 months thereafter, and information was sought for serious adverse events including those resulting in hospital admissions. Key disease events considered in the present study were postrandomization MI, nonhemorrhagic stroke, urgent coronary revascularization (CRV) procedure, nonurgent CRV procedure, hospitalization for heart failure, noncoronary revascularization procedure, incident cancer, incident diabetes, vascular death, and nonvascular death. All reports of possible such events, except diabetes, were centrally adjudicated by clinicians without prior knowledge of the treatment allocations according to prespecified criteria. | PMC7615160 |
Health‐Related QoL | ADVERSE EVENTS | Participants' health‐related QoL was assessed using the EQ‐5D‐5‐Level (5L) questionnaire,Previous research has indicated that an individual's QoL was affected most by recent experiences of adverse events with impact on QoL diminishing thereafter. | PMC7615160 | |
Hospital Costs | EVENTS, DISEASE, EVENT | For each study participant, hospital episodes were defined using the hospital admissions data during follow‐up; hospital admissions with overlapping lengths of stay were combined. For UK perspective, hospital episodes were mapped to Healthcare Resource GroupsTo evaluate the immediate and longer‐term impacts of new key disease events on hospital costs, hierarchical temporal event history categories were generated for each year of follow‐up in the study with respect of the first occurrence of events of each type since randomization. These temporal categories were no new event, new event occurred | PMC7615160 | |
Statistical Analysis | PMC7615160 | |||
Specification of Regression Models | heart failure | INTERACTIONS, EVENT, DISEASE, REGRESSION, EVENTS, HEART FAILURE | The generalized linear model (GLM) framework was adopted to facilitate modeling the QoL and annual hospital costs. For the QoL analysis, QoL utility at final follow‐up was modeled using the GLM with a Gaussian family distribution and linear link function, adjusting for participant QoL at randomization. Study participants who died before QoL measurement or did not provide QoL measure at study end were excluded from QoL analysis. For the hospital cost analysis, in view of the substantial proportion of annual periods without hospital care costs, the 2‐part (part 1: logistic model for likelihood of incurring any cost, part 2: magnitude of cost, conditional on incurring cost) GLM specifications with Gaussian, Poisson, and gamma family distributions, in conjunction with identity and log link functions, were compared. Tests of appropriateness of distribution and link function and model fit statistics guided the choice of the final GLM specifications. Urgent and nonurgent CRV events and hospital admissions for heart failure always occurred in hospital. Therefore, these events' respective annual periods of occurrence were excluded from the estimation of the first part of the 2‐part models with the probability of incurring hospital costs then assumed certain (100%). SEs in the hospital cost regression model were adjusted for clustering by participant to account for correlation between the multiple annual periods for individual participants during follow‐up.In both the QoL and hospital cost regression models, adjustments were considered for participants' demographic and clinical characteristics and hierarchical temporal event history categories. The small amount of missing data for covariates was imputed with mean values by sex, smoking status, and trial arm. Backward and forward covariate selections were carried out on all events of interest with their hierarchical temporal event history categories and the full set of participant characteristics. With the exception of covariates for age and sex that were always retained, only covariates statistically significant at 1% level were retained in final models. Interactions between co‐occurring events were tested when such co‐occurrences exceeded 5% of the total combined number of contributing events. The F‐test (at 1% significance level) was used to assess statistical differences in the effects between each 2 consecutive hierarchical temporal event history categories from the most distant temporal category (more than 3 years since the qualifying event) backwards to the most recent category (ie, ≤1 year from event/year of event). Lack of evidence for a statistically significant difference at each step led to combining respective temporal categories and reestimating the model before the next step.The additional annual hospital costs in year of occurrence of disease events were estimated using the recycled prediction method | PMC7615160 |
Scenario Analyses | ADVERSE EVENTS, REGRESSION | In scenario analyses, the QoL reductions and additional annual hospital costs associated with adverse events were reestimated by only including the UK study participants in analysis from the UK perspective, and separately, only including the participants recruited in North America in the analysis from the US perspective. Furthermore, results from scenario analysis excluding the adjustment for participant baseline QoL were reported (for use in situations when no baseline QoL is available). In a further scenario analysis, the QoL regression model was estimated only among study participants recruited in China and using the Chinese EQ‐5D tariff.All analyses were conducted using R 3.4.2. The study was approved by Oxfordshire Research Ethics Committee (REC) B (10/H0605/83). All the patients provided written informed consent. | PMC7615160 | |
Results | PMC7615160 | |||
Study Participants | PAD, cancer, stroke, peripheral artery disease, diabetes | MYOCARDIAL INFARCTION, PERIPHERAL ARTERY DISEASE, STROKE, DISEASE, CANCER, PAD, CHRONIC KIDNEY DISEASE, HEART FAILURE, CEREBROVASCULAR DISEASE, DIABETES | At randomization, the mean age across the 21 820 participants contributing to the main analyses was 67 years, 85.7% were men, 62.6% reported history of MI alone, 11.1% cerebrovascular disease alone, 5.7% peripheral artery disease alone; and the remaining participants reported prior disease histories in 2 or more of these categories or none of these conditions (Table Baseline Characteristics of the 21 820 REVEAL Participants Randomized in Europe and North AmericaCEV indicates cerebrovascular disease; MI, myocardial infarction; PAD, peripheral artery disease; and REVEAL, Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification.The estimated glomerular filtration rate was calculated with the use of the Chronic Kidney Disease Epidemiology Collaboration equation. The missing data were imputed with mean values by sex, smoking status, and trial arm before further analyses.During the 4 years of study follow‐up, 989 out of 21 820 participants (4.5%) experienced an MI, 735 (3.4%) had an urgent CRV, 1047 (4.8%) had a nonurgent CRV, 549 (2.5%) had a nonhemorrhagic stroke, 647 (3.0%) were hospitalized for heart failure, 901 (4.1%) had a noncoronary revascularization, 1618 (7.4%) had an incident cancer, 840 (3.8%) developed incident diabetes, 708 (3.2%) died from a vascular cause, and 960 (4.4%) died from a nonvascular cause. | PMC7615160 |
EVENTS, EVENT | The QoL analysis included 19 321 participants (88.5%) who completed both the baseline and final follow‐up EQ‐5D‐5L questionnaires. At the final study follow‐up, the mean QoL utility was 0.81 (SD 0.20) (UK perspective) and 0.83 (SD 0.21) (US perspective), with 6312 of the 19 321 participants (32.7%) reporting full health (ie, no problems in each of the 5 EQ‐5D dimensions). Worse QoL was observed in the year of event and in the following years for most events (Figure | PMC7615160 | ||
Quality of life utility of participants by category of new adverse event and time since event occurrence. | nonfatal adverse events, SD, diabetes | EVENTS, EVENT, DIABETES | UK (All 21 820 participants contributed to the cost analyses. The average annual hospital costs across all participants were £607 (SD £2402) and $2114 (SD $6188) from the UK and US health care systems perspectives, respectively. Hospital costs were reported in 20% of the 96 962 person‐years of follow‐up during the study. Hospital costs peaked in the year of event occurrence, and, except for incident diabetes, remained significantly elevated in subsequent years following nonfatal adverse events as compared with patients without a history of respective events (Figure | PMC7615160 |
Mean annual hospital costs before, in year of, and in subsequent years of first new adverse event occurrence. | UK ( | PMC7615160 | ||
REGRESSION | The linear regression models of QoL at final follow‐up for the UK and US health care perspectives respectively, are presented in Figure | PMC7615160 | ||
Quality of life (QoL) reductions associated with new adverse events in secondary prevention of CVD, UK and US perspectives. | death, anxiety/depression, cancer, nonhemorrhagic stroke, heart failure, diabetes | MYOCARDIAL INFARCTION, OBESE, CARDIOVASCULAR DISEASE, ADVERSE EVENTS, CVD, EVENT, CANCER, ATRIAL FIBRILLATION, ADVERSE EVENT, REGRESSION, EVENTS, HEART FAILURE, DIABETES | Data of the 19 321 REVEAL participants randomized in Europe and North America was used in both analyses from the UK and US perspectives. EQ‐5D utility values for all 19 321 contributing participants were calculated using the UK or US EQ‐5D value sets, respectively. EQ‐5D is a standardized instrument used to measure health‐related QoL across 5 domains (mobility, self‐care, usual activities, pain/discomfort, anxiety/depression). By combining the scores of each dimension, the EQ‐5D generates a health state profile, which can be converted into a single summary index score. The index score represents an individual's overall health status on a scale where 1.0 denotes perfect health, 0.0 represents death, and negative values indicate health states considered worse than death. QoL reductions associated with adverse events, by duration of time between latest adverse event from each category and EQ‐5D QoL measure at the end of the trial (≤1 year, 1–2 years, and >1 or >2 years), were estimated using a linear regression model with adjustments for sociodemographic and clinical characteristics. We were unable to detect QoL reductions associated with myocardial infarction, coronary revascularization (urgent, nonurgent), and incident diabetes, so these events were not included in the model. CVD indicates cardiovascular disease; EQ‐5D, EuroQol‐5 Dimensions; N, number of people who experienced the event in the study before QoL measure at final follow‐up in the study; QoL, quality of life; REVEAL, Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification; UK, United Kingdom; and US, United States.For nonhemorrhagic stroke, this impact on QoL persisted in all subsequent years. For other adverse events, QoL improved in subsequent years though for most remained lower compared with not experiencing new event. Reductions in QoL were observed in years following heart failure admission (United Kingdom: 1–2 years after year of event: −0.094 [95% CI, −0.123 to −0.064], >2 years: −0.013 [95% CI, −0.040 to 0.013]; United States: 1–2 years after year of event: −0.086 [95% CI, −0.117 to −0.056]; >2 years: −0.032 [95% CI, −0.058 to −0.007]), noncoronary revascularization (United Kingdom: 1–2 years after year of event: −0.041 [95% CI, −0.064 to −0.017], >2 years: 0.000 [95% CI, −0.018 to 0.018]; United States:1–2 years after year of event: −0.048 [95% CI, −0.072 to −0.023]; >2 years: −0.018 [95% CI, −0.035 to −0.001]) and incident cancer (for all years following the year of event United Kingdom: −0.032 [95% CI, −0.044 to −0.019]; United States: −0.036 [95% CI, −0.048 to −0.023]) (Figure We were unable to detect reductions in QoL associated with MI, CRV (urgent or nonurgent), and incident diabetes so these events were not included in the final models. Independent of the occurrence of adverse events, older age, being female, a current smoker, obese, having atrial fibrillation, and reduced kidney function were all associated with lower QoL (Table The impacts of event were similar in scenario analyses of QoL reduction using only UK or North American participant data, though with increased uncertainty due to the smaller number of events (Table | PMC7615160 |
Hospital Care Costs Models and Impacts of Adverse Events on Hospital Care Costs | vascular death, death, stroke, cancer, heart failure | ADVERSE EVENT, ADVERSE EVENTS, CANCER, STROKE, EVENTS, EVENTS, HEART FAILURE | The results from the specification tests and comparison of predictive performance of different model specifications are reported in Table Additional Annual Hospital Costs Associated With Selected New Adverse Events From the UK and US (Medicare) Health Care PerspectivesData of 21 820 REVEAL study participants recruited in Europe and North America contributed to this analysis of hospital inpatient care costs. Hospital admissions were costed using UK National Health Service or US Medicare program reference costs, respectively. All hospital costs at 2019 prices. Events referred to Statistically significant (Statistically significant (Other interactions (MI and vascular death, nonhemorrhagic stroke and vascular death, and incident cancer and nonvascular death) were observed for both UK and US annual hospital costs.In the United Kingdom, the highest additional annual hospital costs were in the year with noncoronary revascularization £5830 [95% CI, 5437 to 6248], nonfatal MI with urgent CRV £5614 [95% CI, 5179 to 6089], urgent CRV without MI £4674 [95% CI, 4254 to 5149], and nonurgent CRV without MI £4651 [95% CI, 4338 to 4988]. Additional hospital costs were also observed in the year with heart failure admission, nonhemorrhagic stroke, MI without CRV, incident cancer, nonhemorrhagic stroke, and nonvascular or vascular death (Table Most of the adverse events were also associated with additional long‐term annual hospital costs, with admission for heart failure, noncoronary revascularization, and incident cancer associated with the largest long‐term impacts from both the US and UK perspectives (Table Results were similar in scenario analyses that used only UK and only North American participants when reporting additional annual hospital costs associated with events, although uncertainty increased due to smaller number of contributing events (Table An Excel program for the implementation of the health‐related QoL and hospital care cost models accompanies the article (Data | PMC7615160 |
Discussion | death, stroke, cancer, coronary and cerebrovascular diseases, cognitive decline, cardiovascular adverse | CVD, STROKE, EVENT, CANCER, ADVERSE EVENTS, DISEASE, SECONDARY, OTHER CARDIOVASCULAR CONDITIONS, EVENTS, HEART FAILURE | In this study, a number of key vascular and nonvascular events experienced by patients with a history of CVD were found to have important and long‐lasting impacts on QoL and hospital costs. These impacts were derived using high‐quality data from a large study with adjudicated event end points and about 4 years of follow‐up. In both UK and US health care system perspectives, patients experiencing stroke, heart failure, noncoronary revascularization, and incident cancer incurred the largest QoL reductions, whereas CRV and noncoronary revascularization procedures were associated with the largest additional hospital costs. Although the QoL reductions associated with adverse events were largely comparable, it was considerably more expensive to receive treatment in the United States.Study data from Europe and North America were used, together with respective UK or US QoL utility weights and unit costs, to assess the impacts of adverse events on QoL and hospital inpatient costs from the UK and US perspectives, respectively. Only about 20% to 40% (United Kingdom) or 30% to 45% (North America) of key disease events occurred among participants recruited in the United Kingdom or North America, respectively, and analyses using these smaller numbers of events produced less precise estimates as indicated by sensitivity analyses. Furthermore, there were no important differences in likelihood of inpatient admission and, following use of the same QoL utility weights and unit costs, nor were there differences in the QoL utility and hospital inpatient costs associated with key disease events between participants recruited in the United Kingdom, North America, and the rest of Europe. We have also reported in sensitivity analyses separate estimates derived using only participants recruited in United Kingdom and only participants recruited in North America, with estimates in line with the main study findings. Moreover, the study assessed the impact of events on all subsequent inpatient hospital costs, cardiovascular and nonvascular, in recognition of the increased risk, not only of recurrent cardiovascular events and other cardiovascular conditions but also of cognitive decline,QoL reduction associated with cardiovascular adverse events in predominantly secondary CVD prevention populations have been previously reported from the perspectives of UKWe report estimates of hospital care costs associated with new cardiovascular events in patients with a history of CVD from both UK and US public health care perspectives. Although the additional costs were highest in the year of event, costs were also increased in subsequent years, and analyses that fail to accurately incorporate these long‐term costs may produce serious underestimates of the health care costs of these events and the savings from averting them. The comparability of estimated costs with previous work is limited by different patient populations and costing methodologies. Nevertheless, a similar ordering of costs by event types have been reported.Our study has a number of limitations. First, we focused on a number of major vascular events targeted in secondary cardiovascular prevention and therefore of interest in policy analyses of new cardiovascular therapies. Second, the study is based on clinical trials data and there may be volunteer bias whereby healthier individuals enrolled in the study. This is a common limitation that needs to be balanced against the high quality of data collected in clinical trials, which can be used for analyses such as these. Nevertheless, efforts to collect sufficiently detailed data in the real world should be made. Third, study participants who died (1668 [7.6%]) or did not provide a QoL measure at the end of the study (831 [3.8%]) did not contribute to the QoL modeling so there may be bias. In applications, QoL is used concurrently with survival in assessing the net effects of treatments and our analysis is in line with how these estimates are intended for use. This does make the assumption that the estimated QoL reductions apply up to the time before death in those participants who died. This may not be true if, for example, participants who survived have experienced better recovery from adverse events and thus may have better QoL than participants who experienced an event and later died before QoL measurement. Fourth, hospital costs included in the present study likely underestimate the total hospital care cost for 2 reasons. No data were available in the study about patients' use of hospital outpatient services and therefore these costs were not included. Furthermore, US Medicare and UK National Health Service costs were used, which are lower than private health care costs. Therefore, the costs presented reflect only the respective country's public health care admissions and costs. Finally, we also did not assess the primary and ambulatory care costs associated with adverse events. Previous CVD burden studies have indicated that the inpatient hospital care costs account for the majority of health care costs of coronary and cerebrovascular diseases (57% and 79%, respectively in 2015, United KingdomDespite these limitations, our study benefits from high‐quality detailed data of a large trial cohort that allowed us to report that the occurrence of key vascular and nonvascular events in patients with well‐managed CVD continues to affect significantly individuals' QoL and hospital care resources. | PMC7615160 |
Conclusions | CVD | CVD, EVENTS | In conclusion, the impacts of vascular and nonvascular events on QoL and hospital costs reported in this study could inform assessments of net effects and cost‐effectiveness of further CVD therapies to reduce CVD risk in people with history of CVD. To assist such applications, an Excel program for the implementation of the health‐related QoL and hospital care cost models is available with the article (Data | PMC7615160 |
Sources of Funding | Myocardial Infarction, Thrombolysis | HEART, MYOCARDIAL INFARCTION | This work was supported by grants from Merck & Co., Inc. to the University of Oxford. Support was also provided by the British Heart Foundation (including direct support for Professor Hopewell through grant FS/14/55/30806), the UK Medical Research Council (which funds the Medical Research Council Population Health Research Unit in a strategic partnership with the University of Oxford), the UK National Institute for Health Research Clinical Research Network, Health Data Research UK, the National Institute for Health Research Oxford Biomedical Research Centre, and the National Institute for Health Research Barts Biomedical Research Centre (NIHR203330). The REVEAL trial was designed, conducted, analyzed, and interpreted by independent investigators in the Clinical Trial Service Unit at the University of Oxford (the regulatory trial sponsor), Oxford, UK in collaboration with the Thrombolysis in Myocardial Infarction Study Group at Brigham and Women's Hospital and Harvard Medical School in Boston, MA, along with other members of the Steering Committee and Merck & Co, Inc., NJ. Merck funded the trial and provided trial drugs. The coauthors prepared the article, which was reviewed and approved by the trial Steering Committee. The decision to submit it for publication was independent of all funding sources. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. | PMC7615160 |
Disclosures | Drs Lui, Williams, Keng, Sammons, and Chen; Professors Hopewell, Gray, Bowman, and Mihaylova; and Professor Sir Landray are employed by the Nuffield Department of Population Health, University of Oxford. The Nuffield Department of Population Health has a staff policy of not taking any personal payments directly or indirectly from industry (with reimbursement sought only for the costs of travel and accommodation to attend scientific meetings; see | PMC7615160 | ||
Supporting information | Data S1–S3Tables S1–S9References 41–44Click here for additional data file. | PMC7615160 | ||
Acknowledgments | The authors thank the REVEAL trial participants, the local clinical center staff, regional and national coordinators, and members of the steering committee, lipid monitoring committee, and data monitoring committee. | PMC7615160 | ||
References | PMC7615160 | |||
Methods | This pilot study was a single site randomised, double-blind, placebo-controlled, crossover study. Testosterone (exercise and testosterone cream) and placebo (exercise and placebo cream) were each delivered for 12 weeks, with a two-week wash-out between the two periods. The primary outcome measure was improvement in quadriceps isokinetic muscle strength. Secondary outcomes included assessment of isokinetic peak flexion force, walk capacity and patient reported outcomes, and other tests, comparing results between the placebo and testosterone arms. A 12-month Open Label Extension (OLE) was offered using the same outcome measures collected at 6 and 12-months. | PMC10089314 | ||
Results | DISEASE, SECONDARY, ADVERSE EVENTS | 14 men completed the trial. There were no significant improvements in quadriceps extension strength or lean body mass, nor any of the secondary outcomes. Improvement in the RAND Short Form 36 patient reported outcome questionnaire ‘emotional wellbeing’ sub-category was reported during the testosterone arm compared to the placebo arm (mean difference [95% CI]: 6.0 points, [95% CI 1.7,10.3]). The OLE demonstrated relative disease stability over the 12-month period but with a higher number of testosterone-related adverse events. | PMC10089314 | |
Conclusions | DISEASE | Adding testosterone supplementation to exercise training did not significantly improve muscle strength or physical function over a 12-week intervention period, compared to exercise alone. However, the combination improved emotional well-being over this period, and relative stabilisation of disease was found during the 12-month OLE. A longer duration trial involving a larger group of participants is warranted. | PMC10089314 | |
Data Availability | INFECTIOUS DISEASES | The data cannot be shared publicly due to the small sample size meaning that the data contains potentially identifying or sensitive patient information. The participants of the study could easily identify themselves and other participants. This is particularly the case in Perth, where the community of individuals with IBM regularly meet up together, and are also aware who in the community participated in the study. The data is of a sensitive nature. Data are available from the Institute of Immunology and Infectious Diseases for researchers who meet the criteria for access to confidential data upon reasonable request. The institutional body can be contacted through the email | PMC10089314 | |
Introduction | muscle hypertrophy | DISEASE, ACQUIRED SKELETAL MUSCLE DISEASE, INCLUSION BODY MYOSITIS, INFLAMMATORY MYOPATHIES | Inclusion body myositis (IBM) is the most commonly acquired skeletal muscle disease associated with ageing, with men three times more likely than females to be diagnosed [Exercise has long been considered a vital component of the therapeutic approach in inflammatory myopathies, improving overall quality of life and assisting with maintenance and even improvement of strength and function [Testosterone also improves muscle strength through increased erythropoiesis and protein synthesis leading to muscle hypertrophy [The purpose of this pilot study was to conduct a randomised double-blind, two-arm crossover trial to assess whether testosterone on a background of exercise training would further improve measures of muscle strength, physical function and quality of life in men affected by IBM over and above exercise alone. This study is the first to apply a combination of testosterone supplementation and exercise training in this disease. It was hypothesised that testosterone supplementation in male IBM patients undertaking prescribed exercise would improve muscle strength, physical function and quality of life compared to exercise alone. | PMC10089314 |
Participants and methods | PMC10089314 | |||
Study design | INFECTIOUS DISEASES | This trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12618000755235), and approved by the Human Research Ethics Committee at Murdoch University (approval number 2017/262). Data was collected at the Academic Medical Centre, Institute for Immunology and Infectious Diseases (IIID), Murdoch University.The study design and methodology has been described within a previously published protocol [ | PMC10089314 | |
Trial design. | BLIND | All participants underwent randomisation and were allocated to either the placebo or testosterone arm.Block randomisation was used to allocate treatment kits 1:1 to either testosterone or placebo at the central pharmacy. Randomised treatment kits were then allocated to participants in consecutive order at their Baseline visit (i.e. First participant enrolled received Treatment Kit no.1). Block size was determined by the central pharmacy. The random allocation sequence was generated by the Central Pharmacy (Lawley Pharmaceuticals). Participants were enrolled by the study PI and research nurses. Treatment kits (and therefore intervention) was assigned by allocation of the next available sequentially numbered Treatment Kit at site. Screening occurred between 10The exercise training program was prescribed by an accredited exercise physiologist and accredited physiotherapist and comprised of light/moderate resistance training, balance training and moderate aerobic exercise component, as detailed in the protocol [The pilot study was conducted as a double blind study. Participants, care providers and study team members were blind to intervention until unblinding of the allocations following database lock. An unblinded safety monitor provided review of safety bloods. | PMC10089314 | |
Outcome measures | BBS | SECONDARY | Outcome measurements were performed at the baseline, placebo (either week 12 or 26) and testosterone (either week 12 or 26) arms. The primary outcome measure was improvement in quadriceps isokinetic muscle strength assessed using a HUMACNORM isokinetic dynamometer (Stoughton, Massachusetts, USA) on the right leg at 30 and 60 degrees from full extension (0 degrees). Many studies have demonstrated inter-test reliability using the HUMACNORM isokinetic dynamometer [These secondary outcomes were used as they are commonly employed in the clinical and research setting. The Berg Balance Scale (BBS) is used to assess balance through a series of static and dynamic activities. The BBS has high inter-rater reliability (intraclass correlation coefficient = 0.99) and test-retest reliability (intraclass correlation coefficient = 0.98) in older populations [Patient reported outcomes regarding physical function and quality of life were assessed using the IBM-Functional Rating Scale (IBM-FRS) and the RAND Short Form 36 (RAND-SF-36) respectively [No changes were made to primary or secondary outcomes once the trial had commenced. The OLE study utilised the main study endpoints. Some timepoint deviations occurred during the OLE due to due to Coronavirus-related disruption. | PMC10089314 |
Data analysis | Data analysis was conducted in R statistical program using the package ggplot2 [ | PMC10089314 | ||
Results | PMC10089314 | |||
Participant characteristics | In total, 20 males were assessed for eligibility for the study and six were excluded as they did not meet the selection criteria ( | PMC10089314 |
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