The effects of a structured 8-week aerobic exercise intervention on anti-Mullerian hormone levels and oxidised LDL-cholesterol in the polycystic ovarian syndrome

AIM: PCOS is the most common endocrine disorder of reproductive age women, affecting 4-12%. The condition is associated with reproductive and cardiometabolic complications including obesity, insulin resistance, hyperandrogenism and infertility. Women with PCOS have a two to four-fold higher prevalence of metabolic syndrome (and higher oxidised LDL) and higher concentrations of Anti-Mullerian hormone (AMH) compared to BMI-matched controls. The present study aims to determine whether physical activity reduces AMH and OxLDL levels and therefore improves fertility and cardiometabolic outcomes. METHODS: Women with PCOS (n=14) and healthy controls (n=11) completed an 8-week exercise programme consisting of 3 x 1-hour treadmill sessions per week at 60% VO2max. Blood samples were analysed for AMH and oxidised LDL concentrations using the ELISA method. Pre collected anthropometric and cardiorespiratory fitness markers were also analysed to determine any significant differences in means before and after the intervention. RESULTS: Within the longitudinal PCOS study, mixed two-way ANOVAs found no significant differences between AMH and oxidised LDL levels pre and post intervention in PCOS or controls, despite significant improvements in body mass, BMI, WC and VO2max evident in the PCOS group.CONCLUSION: Results from the PCOS intervention demonstrated no significant improvement of AMH or oxidised LDL levels in women with PCOS or controls following short-term structure moderate intensity exercise training. It did have a significant impact on anthropometric and cardiorespiratory fitness markers. Future research should place importance upon identifying and conducting research on the phenotypes of PCOS separately, particularly in relation to those phenotoypes with hyperandrogenism, as well as conducting exercise interventions over a longer duration

Physical activity and cardiovascular disease risk in women with polycystic ovary syndrome

Background Polycystic ovary syndrome (PCOS) is a complex, heterogeneous endocrinopathy affecting metabolic, reproductive, and cardiovascular health in women. Evidence indicates that women with PCOS present with a cluster of cardiovascular disease (CVD) risk factors. Physical activity (PA) interventions have been shown to reduce various CVD risk factors in women with PCOS. Research also suggests that sedentary behaviours have a distinct deleterious effect on cardiometabolic health. Thus, increasing PA and reducing sedentary behaviour may be a worthwhile therapeutic target to improve cardiovascular health in women with PCOS. The programme of research presented in this thesis investigates the feasibility and acceptability of two PA interventions to improve markers of CVD risk in women with PCOS using both quantitative and qualitive methods. Methods A systematic review and meta-analysis of the effects of exercise interventions on CVD risk factors in women with PCOS provided an evidence base on which to design a supervised exercise intervention. A feasibility randomised controlled trial (RCT) of two physical activity interventions for women with PCOS was conducted. Participants were randomised to either a supervised exercise intervention, a lifestyle physical activity intervention (LPAG) aimed at reducing sedentary behaviours, or a control group, for 12 weeks. Semi-structured interviews were conducted with a purposive sample of participants from each group on completion of the RCT to explore the acceptability of the interventions, and barriers and facilitators to PA. Results The systematic review and meta-analysis demonstrated that moderate intensity aerobic exercise interventions of ≥three months in duration, with a frequency of three sessions/week, had favourable effects on CVD risk factors. These results informed the design of the RCT. Thirty-six women with PCOS were enrolled onto the feasibility RCT (12 per group). The recruitment rate was 56% and adherence rate to the exercise intervention was considered moderate at 53%. The retention rate was high at 89%, with only five participants lost to follow-up. Adherence to the LPAG was 100%. Two non-serious adverse events were reported in the exercise group, unrelated to trial procedures. For the secondary outcomes, trend data indicates a 14% reduction in oxidised LDL concentrations in the exercise group. In addition, the data indicates weight loss (kg) of 3.4% and 3.6% in the exercise group and the LPAG, respectively. Qualitative data from the interviews (n=11) indicated that the interventions were well received, but acceptability could be improved by providing social connectivity and implementing measures that encourage the adoption of long-term health-promoting behaviours. Conclusions iii The findings suggest that the procedures for recruitment, allocation, and outcome measurements were acceptable. However, adherence to the supervised exercise intervention was below an acceptable rate. The qualitative component provides valuable contextual data that will be crucial to addressing adherence for both the progression to a full-scale RCT, and community interventions for women with PCOS

The effects of exercise on cardiometabolic outcomes in women with polycystic ovary syndrome not taking the oral contraceptive pill: protocol for a systematic review and meta-analysis

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy, affecting 4–12% of reproductive-aged women. Women with PCOS often exhibit many metabolic abnormalities that are associated with an increased cardiovascular disease (CVD) risk, independent of obesity. Exercise interventions from 12 to 24 weeks have been shown to have positive effects on blood lipid profile, ovulation and insulin resistance in women with PCOS. However, no consensus on which exercise interventions are effective (i.e. duration, type of exercise, frequency), including for different phenotypes, currently exists. The aim of this systematic review and meta-analysis is to define effective types of exercise interventions to improve cardiometabolic profile, across the range of phenotypes of PCOS. Methods We will conduct electronic database searches, including randomised-controlled trials (RCT), quasi-RCT and clinical trials. Primary outcomes sought will be lipid profile, carotid-intima media thickness, fasting blood glucose, %HbA1c, blood pressure, waist circumference, waist-to-hip ratio, abdominal adiposity and inflammation markers. Secondary outcomes sought will be free and total testosterone, sex hormone binding globulin and insulin resistance. The Cochrane Risk Assessment Tool will be used to assess study quality. Data will be analysed in RevMan. Analysis of heterogeneity will be undertaken using the I2 statistic. Significant heterogeneity will be explored, and sensitivity analyses carried out as appropriate. A subgroup analysis based on androgen profile will be undertaken if data are sufficient. Discussion A large proportion of women are affected by PCOS. It is prudent to examine how CVD risk can be mitigated in this high-risk population, and this review aims to provide evidence-driven recommendations on the types of exercise interventions that are effective for this. The review will seek to provide recommendations regarding type, frequency and duration of exercise interventions to improve cardiometabolic profile in PCOS. The subgroup analysis may be able to highlight difference in intervention effects between normo-androgenic and hyper-androgenic profile. Limitations include heterogeneity across studies and a scarcity of clinical trials involving a PCOS control group not undertaking any intervention

The effects of physical exercise on cardiometabolic outcomes in women with polycystic ovary syndrome not taking the oral contraceptive pill: a systematic review and meta-analysis

Purpose: Women with polycystic ovary syndrome (PCOS) exhibit many metabolic abnormalities that are associated with an increased cardiovascular disease risk. Exercise may promote improvements in lipid profile and insulin sensitivity in women with PCOS. There is however, a knowledge gap on the optimal dose of exercise, regarding duration, intensity, type, and frequency of exercise. The aim of this systematic review and meta-analysis was to define effective types of exercise to improve cardiometabolic profile in PCOS. Methods: We included randomised controlled trials (RCT), quasi-RCT, and controlled clinical trials focusing on reproductive-aged women diagnosed with PCOS. Eligible interventions included those with at least two weeks of supervised exercise sessions. Primary outcomes were blood lipids, blood glucose, blood pressure, measures of abdominal adiposity, and inflammation markers. Secondary outcomes were total and free testosterone, sex hormone binding globulin, and measures of insulin resistance. Nine electronic databases were searched from inception to present for English language publications. The Cochrane Risk Assessment tool was used to assess bias in the included studies. Outcomes were quantitatively synthesised and a meta- analysis was performed. Pooled effect estimates and 95% confidence intervals were presented. Results: This systematic review identified three trials, including 231 participants with PCOS that examined the effect of structured, supervised exercise on cardiometabolic outcomes. Analysis of pooled data indicated statistical favourable effects of exercise on total cholesterol, fasting glucose, waist circumference and waist-to-hip ratio, systolic blood pressure, C-reactive protein, total testosterone, and sex hormone binding globulin using post-intervention scores. Conclusions: Moderate aerobic exercise interventions ≥3 months in duration, with a frequency of 3/week for at least 30-minutes, may have favourable effects on various cardiometabolic risk factors in women with PCOS. However, results should be interpreted with caution. Many of the outcomes were based on studies with serious methodological limitations, and only one "gold-standard" RCT was identified

Supervised aerobic exercise training and increased lifestyle physical activity to reduce cardiovascular disease risk for women with polycystic ovary syndrome: a randomized controlled feasibility trial

Background: Polycystic ovary syndrome (PCOS) is a complex, heterogeneous endocrinopathy. Women with PCOS often present with cardiovascular disease risk factors. Physical activity (PA) interventions reduce cardiovascular disease risk factors in women with PCOS. However, sedentary behaviors have a distinct deleterious effect on cardiometabolic health. Increasing PA and reducing sedentary behaviors may be a worthwhile therapeutic target to improve cardiovascular health in this population. This study investigated the feasibility of 2 PA interventions to decrease cardiovascular disease risk in women with PCOS. Methods: This was a feasibility randomized controlled trial of 2 PA interventions in 36 women with PCOS. Participants were randomized to a supervised exercise intervention (n = 12), a lifestyle physical activity group intervention aimed at reducing sedentary behaviors (n = 12), or a control group (n = 12), for 12 weeks. Primary outcomes included the feasibility and acceptability of the interventions and procedures. Results: Recruitment rate was 56%. Adherence rate was 53% and 100% to the exercise intervention and lifestyle PA intervention, respectively. Secondary outcome data indicate a reduction in oxidized low-density lipoprotein concentrations in the exercise group, and weight loss in both intervention groups. Conclusions: The procedures for recruitment, allocation, and outcome measurements were acceptable. However, before progression to a full-scale trial, adherence to the exercise program should be addressed

A cross-over, randomised feasibility study of digitally printed versus hand-painted artificial eyes in adults: PERSONAL-EYE-S - a study protocol [version 2; peer review: 2 approved]

Background/objectives: Around 11,500 artificial eyes are required yearly for new and existing patients. Artificial eyes have been manufactured and hand-painted at the National Artificial Eye Service (NAES) since 1948, in conjunction with approximately 30 local artificial eye services throughout the country. With the current scale of demand, services are under significant pressure. Manufacturing delays as well as necessary repainting to obtain adequate colour matching, may severely impact a patient’s rehabilitation pathway to a normal home, social and work life. However, advances in technology mean alternatives are now possible. The aim of this study is to establish the feasibility of conducting a large-scale study of the effectiveness and cost-effectiveness of digitally printed artificial eyes compared to hand-painted eyes. Methods: A cross-over, randomised feasibility study evaluating a digitally-printed artificial eye with a hand-painted eye, in patients aged ≥18 years with a current artificial eye. Participants will be identified in clinic, via ophthalmology clinic databases and two charity websites. Qualitative interviews will be conducted in the later phases of the study and focus on opinions on trial procedures, the different artificial eyes, delivery times, and patient satisfaction. Discussion: Findings will inform the feasibility, and design, of a larger fully powered randomised controlled trial. The long-term aim is to create a more life-like artificial eye in order to improve patients’ initial rehabilitation pathway, long term quality of life, and service experience. This will allow the transition of research findings into benefit to patients locally in the short term and National Health Service wide in the medium to long term. ISRCTN registration: ISRCTN85921622 (prospectively registered on 17/06/2021

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570