Genome-wide association study identifies genetic regulation of oestrone concentrations and association with endometrial cancer risk in postmenopausal women.

BACKGROUND: Oestrone, predominantly made in fat, is the main circulating oestrogen and important for target tissue oestradiol production in women after menopause. The present study was undertaken to determine the genetic regulation of blood oestrone, measured with precision, in postmenopausal women and to explore associations between the identified genetic loci and endometrial cancer in a large, independent cohort. METHODS: A genome-wide association study (GWAS) was undertaken in women aged at least 70 years to identify genetic associations with blood oestrone concentrations measured by liquid chromatography and tandem mass spectrometry. The GWAS included participants from the Sex Hormones in Older Women (SHOW) study, a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial. Of the 6358 women providing a biobank sample at enrolment, 4951 unrelated women of European ancestry, not taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids were included in the GWAS. Single nucleotide polymorphisms (SNPs) from loci identified below the genome-wide significance threshold were then tested in an independent cohort (the UK Biobank) for association with endometrial cancer risk, using logistic regression and adjusting for age, body mass index (BMI) and the top 10 genetic principal components. FINDINGS: The median age of the 4951 women included in the GWAS was 75.9 years (range 70-94.8 years). The GWAS identified four independent SNPs associated with oestrone concentrations (p < 5 × 10-8). Among them, the effect (minor) alleles rs34670419-T, rs2846729-T and rs2414098-T were associated with lower oestrone concentrations. Carrying these effect alleles was associated with lower oestrone concentrations in a dose-dependent manner. The effect allele rs56400819-A was associated with higher oestrone concentrations. When applied to UK Biobank, carrier status for rs2414098-T associated with the CYP19A1 gene which encodes the aromatase enzyme required for oestrogen synthesis was significantly associated with lower endometrial cancer risk (adjusted odd ratio [aOR] 0.87 [95% CI 0.82-0.93]; p = 6.69 × 10-5 for women across all ages and aOR 0.89 [95% CI 0.83-0.96]; p = 0.003 for postmenopausal women). None of the models that included age, body mass index (BMI), the top 10 genetic principal components, parity and diabetes mellitus explained more than 7.6% of the variation in risk. INTERPRETATION: We have shown genetic regulation of oestrone concentrations in postmenopausal women, and that SNPs associated with oestrone were also associated with endometrial cancer risk, independent of BMI, parity and diabetes mellitus. Although the apparent contribution was modest, the biological influence of oestrone concentrations may be greater through conversion to oestradiol in endometrial tissue. FUNDING: The ASPREE trial was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (Grant U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (Grant 34047, 1127060); Monash University (Australia); and the Victorian Cancer Agency (Australia). The ASPREE Healthy Ageing Biobank was funded by the CSIRO (Flagship Grant), the National Cancer Institute (Grant U01 AG029824) and Monash University. This analysis of sex hormones was funded by an NHMRC of Australia Project Grant (No. 1105305). SRD holds an NHMRC Investigator Grant (2016627). PL is supported by a National Heart Foundation Future Leader Fellowship (102604).

A systematic review and critical appraisal of menopause guidelines.

OBJECTIVE AND RATIONALE: To identify and appraise current national and international clinical menopause guidance documents, and to extract and compare the recommendations of the most robust examples. DESIGN: Systematic review. DATA SOURCES: Ovid MEDLINE, EMBASE, PsycINFO and Web of Science ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Practice guidance documents for menopause published from 2015 until 20 July 2023. Quality was assessed by the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. RESULTS: Twenty-six guidance papers were identified. Of these, five clinical practice guidelines (CPGs) and one non-hormonal therapy position statement met AGREE II criteria of being at least of moderate quality. The five CPGs listed symptoms associated with the perimenopause and menopause to be vasomotor symptoms (VMS), disturbed sleep, musculoskeletal pain, decreased sexual function or desire, and mood disturbance (low mood, mood changes or depressive symptoms). Acknowledged potential long-term menopause consequences were urogenital atrophy, and increased risks of cardiovascular disease and osteoporosis. VMS and menopause-associated mood disturbance were the only consistent indications for systemic menopausal hormone therapy (MHT). Some CPGs supported MHT to prevent or treat osteoporosis, but specific guidance was lacking. None recommended MHT for cognitive symptoms or prevention of other chronic disease. Perimenopause-specific recommendations were scant. A neurokinin 3B antagonist, selective serotonin/norepinephrine (noradrenaline) reuptake inhibitors and gabapentin were recommended non-hormonal medications for VMS, and cognitive behavioural therapy and hypnosis were consistently considered as being of potential benefit. DISCUSSION: The highest quality CPGs consistently recommended MHT for VMS and menopause-associated mood disturbance, whereas clinical depression or cognitive symptoms, and cardiometabolic disease and dementia prevention were not treatment indications. Further research is needed to inform clinical recommendations for symptomatic perimenopausal women.

Associations Between Blood Concentrations of Sex Hormones and Physical Function in Community-Dwelling Older Women: A Prospective Cohort Study.

BACKGROUND: Blood concentrations of testosterone and estrone tend to increase in women aged ≥70 years, whereas concentrations of their precursor hormone dehydroepiandrosterone decline. It is unknown whether these changes influence physical function. We investigated whether concentrations of these hormones were associated with grip strength and self-reported physical function in community-dwelling older women. METHODS: A total of 9 179 Australian women, aged ≥70 years, were recruited to the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Sex hormones were measured in Sex Hormones in Older Women, an ASPREE substudy, by liquid chromatography-tandem mass spectrometry in 6 358 women. The associations between hormone concentrations and physical function (handgrip strength and self-reported physical function assessed by SF-12v2 physical component summary [PCS]) were examined using multiple linear regression. RESULTS: The median age of the 5,447 participants was 74.0 (interquartile range 71.7-77.6) years. Testosterone concentrations above the lowest quartile were associated with less decline in grip strength (mean -1.39 [95% CI -1.54 to -1.24] vs -1.75 [-2.00 to -1.50] kg, p = .02), and dehydroepiandrosterone concentrations above the lowest quartile were associated with less decline in grip strength (-1.39 [-1.54 to -1.25] vs -1.82 [-2.11 to -1.55] kg, p = .007) and PCS scores (-1.49 [-1.80 to -1.17] vs -2.33 [-2.93 to -1.72], p = .02) over 4 years, compared with those in the respective lowest quartile. CONCLUSIONS: Low endogenous concentrations of testosterone and dehydroepiandrosterone were associated the greatest likelihood of physical function decline in community-based women aged ≥70 years. Further studies are warranted to determine whether testosterone and dehydroepiandrosterone therapy prevent functional decline in this at-risk group using sensitive measures of muscle strength and performance.

Effect of dehydroepiandrosterone therapy on cognitive performance among postmenopausal women: a systematic review of randomized clinical trial data.

IMPORTANCE: Whether dehydroepiandrosterone (DHEA) supplementation improves cognitive performance in older women is uncertain. Nonetheless, DHEA supplements are readily available over the counter in several countries and are potentially being used to prevent cognitive decline and dementia. OBJECTIVE: This systematic review was conducted to evaluate the effect of exogenous DHEA on cognitive performance in postmenopausal women. EVIDENCE REVIEW: Ovid MEDLINE, EMBASE, PsycINFO, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials databases were searched for studies of postmenopausal women until November 30, 2022. Eligible studies were required to be randomized clinical trials, be at least single blind, have a placebo or comparator arm and published in English. Risk of bias of the included studies was assessed by the revised Cochrane risk-of-bias tool. FINDINGS: Of the 15 articles retrieved for full-text review, four met the inclusion criteria. In all studies DHEA was administered as a 50-mg oral daily dose and all were double blind with an identical placebo. Three were placebo-controlled, crossover studies and one was a parallel-group clinical trial. The only positive outcome was limited to a 4-wk cross-over study in which DHEA statistically significantly enhanced five of six tests of visual-spatial performance compared with placebo in 24 cognitively normal postmenopausal women. Improvement in cognitive performance with DHEA treatment over placebo group was not seen in any other study. Heterogeneity of design and use of multiple measures of cognitive performance was a barrier to meta-analysis and between study comparisons. The studies were limited by high risk of bias in multiple domains. CONCLUSION AND RELEVANCE: Overall, this systematic review does not support a beneficial effect of DHEA therapy on cognitive performance in postmenopausal women.

Associations between low sex hormone concentrations and depression in older women: An observational study.

OBJECTIVE: We investigated whether low sex hormone concentrations are associated with depression in older women. STUDY DESIGN: This was a cross-sectional study of Australian women, aged at least 70 years, not taking medications modulating sex hormone levels. Associations between hormones, measured by liquid chromatography-tandem mass spectrometry, and depression were examined by logistic regression adjusted for potential confounders. MAIN OUTCOME MEASURES: The primary outcome was a Center for Epidemiologic Studies Depression score >10, designated as 'depression', with an expanded definition that included anti-depressant use as a secondary outcome. RESULTS: For the 5535 participants in the analysis, median age 74.0 years (interquartile range 71.7-77.7), depression prevalence was 5.8 % (95 % CI 5.2-6.4 %). In the adjusted models, a statistically significantly greater likelihood of depression was seen for women with testosterone and oestrone blood concentrations in quartile 1 compared with quartiles 2-4 (odds ratio 1.33, 95 % CI 1.04 to 1.70, p = 0.022; and 1.37, 95 % CI 1.06 to 1.78, p = 0.017, respectively). For the expanded definition, the odds ratios for the lowest testosterone and oestrone quartile compared with other quartiles were 1.47 (95 % CI 1.24 to 1.75, p < 0.001) and 1.31 (95 % CI 1.09 to 1.58, p < 0.001), respectively. A significant association for low DHEA was seen only for the expanded definition of depression (1.36, 95 % CI 1.13 to 1.64, p = 0.001). Receiver operating characteristic curves showed that the contribution of each sex hormone to the likelihood of depression was small. CONCLUSIONS: Amongst older women not taking medications that influence sex hormone concentrations, low testosterone and oestrone levels are associated with a greater likelihood of depression, but the effects are small. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and clinicaltrials.gov (NCT01038583).

The impact of endometriosis on work ability in young Australian women.

BACKGROUND: Whereas symptomatic endometriosis may affect work performance, the impact of endometriosis in the general community is not known. AIMS: The associations between endometriosis and each of sick leave and work ability, were investigated in a large sample of non-healthcare seeking women. MATERIALS AND METHODS: This community-based, cross-sectional study recruited 6986 women, aged 18-39 years, from three eastern states of Australia between 11 November 2016 and 21 July 2017. Women were identified as having endometriosis if they had undergone a pelvic ultrasound and reported a diagnosis of endometriosis. Working women completed the Work Ability Index. RESULTS: Participants were predominantly of European ancestry (73.1%) and 46.8% were overweight or had obesity. The prevalence of endometriosis was 5.4% (95%CI 4.9-6.0%) with the highest prevalence of 7.7% (95%CI 6.5 to 9.1%) for women aged 35-39 years. Among the 4618 working women, those with endometriosis had significantly more sick days from work (33.6% reported ≥10 days vs 13.5%, overall χ2 P < 0.001). Endometriosis was associated with a greater likelihood of poor to moderate work ability, after adjusting for age, body mass index, ethnicity, relationship status, student status, insecure housing, being a carer for another person, parity, ever use of assisted reproductive technologies, and depressed mood (odds ratio 1.90, 95%CI 1.40-2.58, P < 0.001). CONCLUSIONS: This study provides new evidence that the negative impact of endometriosis on work attendance and work ability is not limited to women with prevalent symptoms and severe disease, but appears to encompass women across a broader spectrum of this condition in the community.

The association between sex hormones and the change in brain-predicted age difference in older women.

OBJECTIVE: The role of circulating sex hormones on structural brain ageing is yet to be established. This study explored whether concentrations of circulating sex hormones in older women are associated with the baseline and longitudinal changes in structural brain ageing, defined by the brain-predicted age difference (brain-PAD). DESIGN: Prospective cohort study using data from NEURO and Sex Hormones in Older Women; substudies of the ASPirin in Reducing Events in the Elderly clinical trial. PATIENTS: Community-dwelling older women (aged 70+ years). MEASUREMENTS: Oestrone, testosterone, dehydroepiandrosterone (DHEA), and sex-hormone binding globulin (SHBG) were quantified from plasma samples collected at baseline. T1-weighted magnetic resonance imaging was performed at baseline, 1 and 3 years. Brain age was derived from whole brain volume using a validated algorithm. RESULTS: The sample comprised of 207 women not taking medications known to influence sex hormone concentrations. A statistically higher baseline brain-PAD (older brain age relative to chronological age) was seen for women in the highest DHEA tertile compared with the lowest in the unadjusted analysis (p = .04). This was not significant when adjusted for chronological age, and potential confounding health and behavioural factors. Oestrone, testosterone and SHBG were not associated with brain-PAD cross-sectionally, nor were any of the examined sex hormones or SHBG associated with brain-PAD longitudinally. CONCLUSION: No strong evidence of an association between circulating sex hormones and brain-PAD. Given there is prior evidence to suggests sex hormones may be important for brain ageing, further studies of circulating sex hormones and brain health in postmenopausal women are warranted.

A systematic review of dengue outbreak prediction models: Current scenario and future directions.

Dengue is among the fastest-spreading vector-borne infectious disease, with outbreaks often overwhelm the health system and result in huge morbidity and mortality in its endemic populations in the absence of an efficient warning system. A large number of prediction models are currently in use globally. As such, this study aimed to systematically review the published literature that used quantitative models to predict dengue outbreaks and provide insights about the current practices. A systematic search was undertaken, using the Ovid MEDLINE, EMBASE, Scopus and Web of Science databases for published citations, without time or geographical restrictions. Study selection, data extraction and management process were devised in accordance with the 'Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies' ('CHARMS') framework. A total of 99 models were included in the review from 64 studies. Most models sourced climate (94.7%) and climate change (77.8%) data from agency reports and only 59.6% of the models adjusted for reporting time lag. All included models used climate predictors; 70.7% of them were built with only climate factors. Climate factors were used in combination with climate change factors (13.4%), both climate change and demographic factors (3.1%), vector factors (6.3%), and demographic factors (5.2%). Machine learning techniques were used for 39.4% of the models. Of these, random forest (15.4%), neural networks (23.1%) and ensemble models (10.3%) were notable. Among the statistical (60.6%) models, linear regression (18.3%), Poisson regression (18.3%), generalized additive models (16.7%) and time series/autoregressive models (26.7%) were notable. Around 20.2% of the models reported no validation at all and only 5.2% reported external validation. The reporting of methodology and model performance measures were inadequate in many of the existing prediction models. This review collates plausible predictors and methodological approaches, which will contribute to robust modelling in diverse settings and populations.

Endogenous dehydroepiandrosterone and depression in postmenopausal women: a systematic review of observational studies.

IMPORTANCE: The associations between endogenous dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), and depression in older women are uncertain. However, DHEA supplements are widely available over the counter in some countries, and some people may be taking DHEA with the hope of positive mood effects. OBJECTIVE: This systematic review aimed to investigate the association between endogenous DHEA/DHEAS blood concentrations and depression/depressive symptoms in community-dwelling postmenopausal women.Evidence Review: Searches were conducted in Ovid MEDLINE, EMBASE, PsycINFO, and Web of Science databases for observational studies with at least 100 community-dwelling participants until March 9, 2022. The bibliographies of retrieved articles were manually searched. The studies published in English and meeting the inclusion criteria were included in the review. The risk of bias was assessed with the modified Hoy tool for cross-sectional designs and the Joanna Briggs Institute modified critical appraisal checklist for cohort studies. FINDINGS: Of the 30 articles retrieved for full-text review, 14 met the criteria for inclusion. Seven studies were cross-sectional, six were longitudinal, and one had both cross-sectional and longitudinal data. Five of eight cross-sectional studies found no association between DHEAS and depression, whereas three studies reported an inverse association. Similarly, most of the studies (n = 4) with longitudinal data reported no association, whereas two studies reported either an inverse association or mixed results for DHEAS and depression severity. No association between DHEA and depression was found irrespective of the study design. Heterogeneity of design was a barrier to meta-analysis and between study comparison. The majority of studies were limited by high risk of bias in at least one assessed domain. CONCLUSION AND RELEVANCE: This systematic review does not support an association between endogenous DHEA/DHEAS and depression in postmenopausal women.

The association between testosterone and depression in postmenopausal women: A systematic review of observational studies.

OBJECTIVE: The contribution of testosterone to depression in older women is uncertain. This review was conducted to investigate the association between endogenous testosterone blood concentrations and depression in postmenopausal women. METHODS: We searched Ovid MEDLINE, EMBASE, PsycINFO, and Web of Science databases for observational studies with at least 100 community-dwelling participants. The results were categorised by study design, and the reporting of total, bioavailable and free testosterone findings is narrative. RESULTS: The search strategy retrieved 28 articles for full-text review, of which eight met the criteria for inclusion; these described 6 cross-sectional and 2 longitudinal studies. Testosterone was measured by immunoassay in all of the included studies. No association was seen between total testosterone or free testosterone and depression in either the cross-sectional or the longitudinal studies. A significant association between bioavailable testosterone and incident depressive symptoms was limited to women at least 21 years postmenopause in one study. Most of the cross-sectional studies were not representative of national populations and lacked random selection. CONCLUSIONS: This systematic review does not support an association between testosterone and depression in postmenopausal women. However, as the included studies had substantial methodological limitations, studies of community-based samples, employing validated instruments for depression and precise measurement of blood testosterone, are needed to address this knowledge gap.

Endogenous testosterone concentrations and muscle mass, strength and performance in women, a systematic review of observational studies.

OBJECTIVE: To explore the associations between endogenous testosterone blood concentrations and muscle mass, strength and performance in community dwelling women. DESIGN, PATIENTS AND MEASUREMENTS: Online databases, including Ovid MEDLINE, EMBASE and Web of Science, were searched for observational studies, with at least 100 female participants, reporting associations between endogenous testosterone blood concentrations and muscle mass, strength and performance. The findings were synthesized in a narrative review. Heterogeneity in study design and analysis precluded a meta-analysis. RESULTS: Of the 36 articles retrieved for full-text review, 10 met the inclusion criteria. Eight studies were cross-sectional, 1 longitudinal and 1 provided both cross-sectional and longitudinal data. Testosterone was measured by liquid chromatography-tandem mass spectrometry in two studies and by immunoassay in 8. An association between total testosterone and muscle mass, strength or performance in women was not found. The studies of calculated free or bioavailable testosterone and lean muscle mass reported a positive association, but no association was reported for muscle strength or performance. Each included study was limited by a high risk of bias in at least one assessed domain. CONCLUSIONS: This review does not support an association between testosterone and muscle mass, strength or performance in women. This, together with the reported associations between free or bioavailable testosterone and muscle mass should be interpreted cautiously due to the predominant use of immunoassay and the inaccuracy of calculated variables. Additionally, biological significance of nonprotein bound testosterone has not been established. Further studies examining the relationship between precisely measured testosterone and muscle mass and function in women are required.

Pattern of contraceptive use among reproductive-aged women with diabetes and/or hypertension: findings from Bangladesh Demographic and Health Survey.

BACKGROUND: The prevalence of chronic conditions such as diabetes and hypertension is increasing among reproductive-aged women in Bangladesh. However, the pattern of contraceptive use among this population remains unknown. We, therefore, explored the pattern of contraceptive use among reproductive-aged women with diabetes and/or hypertension in Bangladesh. METHODS: We extracted and analysed data of 3,947 women from the 2017/18 Bangladesh Demographic and Health Survey. Women's pattern of contraceptive use was our outcome variable. We first classified the contraceptive using status as no method use, traditional method use (periodic abstinence, withdrawal, other traditional) and modern method use (pill, intra-uterine device, injections, male condom, female sterilization, male sterilization). We later classified these as (i) no contraceptive use vs any contraceptive use, (ii) traditional method or no use vs modern method use, (iii) traditional method vs modern method use. The explanatory variables were diagnosis of diabetes only, hypertension only or both diabetes and hypertension. The multilevel Poisson regression with robust variance was used to explore the associations. RESULTS: The overall prevalence of contraceptive use was 68.0% (95% CI 66.3-69.7). The corresponding prevalences were 69.4% (95% CI 61.8-76.1) in women with diabetes only, 67.3% (95% CI 63.5-70.9) with hypertension only, and 62.0% (95% CI 52.8-70.4) in women having both diabetes and hypertension. The prevalence of modern methods of contraceptive use was lower (46.4%, 95% CI 37.4-55.6) and traditional methods use was higher (16.6%, 95% CI 13.8-16.8) in women who had both diabetes and hypertension than in women who did not have these conditions. The fully adjusted regression model showed that the prevalence of traditional method use was 31% (Prevalence ratio: 1.31, 95% CI 1.02-2.01) higher in women having both diabetes and hypertension compared with their counterparts who had none of these conditions. CONCLUSION: In Bangladesh, women with both diabetes and hypertension were more likely to use traditional contraception methods. These women are likely to experience increased risks of unwanted pregnancies and associated adverse maternal and child health outcomes. Targeted policies and programs should be undertaken to promote modern contraceptive use among women living with both chronic conditions.

Awareness, Treatment, and Control of Diabetes in Bangladesh: Evidence from the Bangladesh Demographic and Health Survey 2017/18.

Background: The prevalence of diabetes is increasing in Bangladesh from ∼5% in 2001 to ∼13% in 2017/18 (∼8.4 million cases). The prevalence of undiagnosed diabetes was also found to be higher at 6% in 2017/18. However, very little is known about the management of diabetes assessed by diabetes awareness, treatment, and control. We aimed to estimate the age-standardised prevalence of awareness, treatment, and control of diabetes and its associated factors. Methods: Cross-sectional data from 1,174 Bangladeshi adults aged 18 years and older available from the most recent nationally representative Bangladesh Demographic and Health Survey (BDHS) 2017-18 were analysed. Outcomes were age-standardised prevalence of awareness, treatment, and control of diabetes, estimated using the direct standardisation. Multilevel mixed-effects Poisson regression models were used to identify factors associated with awareness, treatment, and control of diabetes. Results: Of the respondents we analysed, 30.9% (95% CI, 28.2-33.6) were aware that they had the condition, and 28.2% (95% CI, 25.6-30.7) were receiving treatment. Among those treated for diabetes, 26.5% (95% CI, 19.5-33.5) had controlled diabetes. The prevalence of diabetes awareness, treatment, and control was lower in men than women. Factors positively associated with awareness and treatment were increasing age and hypertension, while factors negatively associated with awareness and treatment were being men and lower education. Factors associated with poor control were secondary education and residing in Rajshahi and Rangpur divisions. Conclusions: This study provides evidence of poor management of diabetes in Bangladesh, especially in men. Less than one-third of the people with diabetes were aware of their condition. Just over one-fourth of the people with diabetes were on treatment, and among those who were treated only one-fourth had controlled diabetes. Interventions targeting younger people, in particular men and those with lower education, are urgently needed. Government policies that address structural factors including the cost of diabetes care and that strengthen diabetes management programmes within primary healthcare in Bangladesh are urgently needed.

Medical waste management-related factors affecting health and experiences of health risks among medical waste handlers in low and middle-income countries: a systematic review protocol of qualitative studies.

INTRODUCTION: Medical waste management (MWM)-related factors affecting the health of medical waste handlers (MWHs) and their health risks in low and middle-income countries (LMICs) are an important public health concern. Although studies of MWM-related factors and health risks among MWHs in LMICs are available, literature remains undersynthesised and knowledge fragmented. This systematic review will provide a comprehensive synthesis of evidence regarding the individual, system and policy-level MWM-related factors that affect MWHs' health and their experiences of health risks in LMICs. METHODS AND ANALYSIS: All qualitative studies published in peer-reviewed journals between 1 July 2011 and 30 June 2021 with full texts available and accessible will be included in the review. Seven specific electronic databases (eg, Scopus, Ovid MEDLINE, EMBASE, Global Health, CINAHL, ProQuest and PsycINFO) will be searched. Two authors will review the citations and full texts, extract data and complete the quality appraisal independently. A third reviewer will check discrepancies when a consensus cannot be reached on differences between the two reviewers. Data extraction will be conducted using the Joanna Briggs Institute standardised data extraction form for qualitative research. The quality of articles will be assessed using a Critical Appraisal Skills Programme checklist. Results from eligible articles will be synthesised into a set of findings using the thematic framework analysis approach and will be reported according to the Enhancing Transparency in Reporting the Synthesis of Qualitative Research statement. ETHICS AND DISSEMINATION: This review is based on published articles, which does not require ethical approval because there is no collection of primary data. Findings from this review will be published in a peer-reviewed journal and presented at relevant public health conferences. This protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO). PROSPERO REGISTRATION NUMBER: CRD42020226851.

Associations between blood sex steroid concentrations and risk of major adverse cardiovascular events in healthy older women in Australia: a prospective cohort substudy of the ASPREE trial.

BACKGROUND: Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the seventh decade, after which concentrations increase and are restored to those of reproductive-aged women early in the eighth decade. We aimed to establish the association between the concentration of testosterone in the blood and risk of major adverse cardiovascular events (MACE) and all-cause mortality in healthy older women. METHODS: SHOW was a prospective cohort substudy of the longitudinal randomised ASPREE trial. Eligible participants were women aged at least 70 years from Australia with unimpaired cognition, no previous MACE, and a life expectancy of at least 5 years. Participants who were receiving hormonal or steroid therapy were ineligible for inclusion. We measured serum concentrations of sex steroids with liquid chromatography-tandem mass spectrometry and of SHBG with immunoassay. We compared lower concentrations of sex hormones with higher concentrations using four quartiles. Primary endpoints were risk of MACE and all-cause mortality, the associations of which with sex steroid concentrations were assessed using Cox proportional hazards regression that included age, body-mass index, smoking status, alcohol consumption, diabetes, hypertension, dyslipidaemia, impaired renal function, and treatment allocation in the ASPREE trial (aspirin vs placebo). ASPREE is registered with ClinicalTrials.gov, NCT01038583. FINDINGS: Of the 9180 women recruited to the ASPREE trial between March 10, 2010, and Dec 31 2014, 6358 participants provided sufficient biobank samples at baseline and 5535 were included in the final analysis. Median age at entry was 74·0 years (IQR 71·7-77·7). During a median 4·4 years of follow-up (24 553 person-years), 144 (2·6%) women had a first MACE (incidence 5·9 per 1000 person-years). During a median 4·6 years of follow-up (3·8-5·6), 200 women died (7·9 per 1000 person-years). In the fully adjusted models, higher concentrations of testosterone were associated with a lower incidence of MACE (quartile 4 vs quartile 1: hazard ratio 0·57 [95% CI 0·36-0·91]; p=0·02), as were higher concentrations of DHEA (quartile 4 vs quartile 1: 0·61 [0·38-0·97]; p=0·04). For oestrone, a lower risk of MACE was seen for concentrations in quartile 2 only, compared with quartile 1 (0·55 [0·33-0·92]; p=0·02). In fully adjusted models, no association was seen between SHBG and MACE, or between any hormone or SHBG and all-cause mortality. INTERPRETATION: Blood concentrations of testosterone and DHEA above the lowest quartile in older women were associated with a reduced risk of a first-ever MACE. Given that the physiological effects of DHEA are mediated through its steroid metabolites, if the current findings were to be replicated, trials investigating testosterone therapy for the primary prevention of ischaemic cardiovascular disease events in older women would be warranted. FUNDING: The National Health and Medical Research Council of Australia, US National Institute on Aging, the Victorian Cancer Agency, the Commonwealth Scientific and Industrial Research Organisation, and Monash University.

Prevalence of undiagnosed diabetes and the relative importance of its risk factors among adults in Bangladesh: Findings from a nationwide survey.

AIM: To estimate the prevalence of undiagnosed diabetes, and to identify the relative importance of risk factors for undiagnosed diabetes among Bangladeshi adults. METHOD: Data from 11, 421 Bangladeshi adults aged 18 years and older available from the most recent nationally representative Bangladesh Demographic and Health Survey 2017-18 were used. Anthropometric measurements and fasting blood glucose samples were taken as part of the survey. Prevalence estimates of undiagnosed diabetes was age-standardised with direct standarisation, and risk factors were identified using multilevel mix-effects Poisson regression models with robust variance. RESULTS: The overall age-standardised prevalence of undiagnosed diabetes was 6.0% (95 %CI, 5.5-6.4%) (men: 6.1%, women: 5.9%). Risk factors associated with undiagnosed diabetes were older age, elevated body mass index (BMI), highest wealth quintile, hypertension, and being male. The top two modifiable risk factors contributing over 50% to undiagnosed diabetes were BMI and wealth quintiles. CONCLUSION: Undiagnosed diabetes affects a substantial proportion of Bangladeshi adults. Since elevated BMI and the highest wealth quintile are strong risk factors, these offer an opportunity for early detection and screening to reduce undiagnosed diabetes in Bangladesh. In addition, wide-reaching awareness campaigns among the general public, clinicians, and policymakers are needed.

Health system readiness for non-communicable diseases at the primary care level: a systematic review.

OBJECTIVE: To synthesise evidence on the primary healthcare system's readiness for preventing and managing non-communicable diseases (NCDs). DESIGN: Systematic review. DATA SOURCES: Ovid MEDLINE, EMBASE, CINAHL, PsycINFO and Scopus were searched from 1 January 1984 to 30 July 2021, with hand-searching references and expert advice. ELIGIBILITY CRITERIA: Any English-language health research with evidence of readiness/preparedness of the health system at the primary healthcare level in the context of four major NCDs: diabetes mellitus, cancer, chronic respiratory diseases (CRDs) and cardiovascular diseases (CVDs). DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted data and assessed the bias. The full-text selected articles were then assessed using the Mixed Methods Appraisal Tool. Health system readiness was descriptively and thematically synthesised in line with the health system dynamics framework. RESULTS: Out of 7843 records, 23 papers were included in this review (15 quantitative, 3 qualitative and 5 mixed-method studies). The findings showed that existing literature predominantly examined health system readiness from the supply-side perspective as embedded in the WHO's health system framework. However, at the primary healthcare level, these components are insufficiently prepared for NCDs. Among NCDs, higher levels of readiness were reported for diabetes mellitus and hypertension in comparison to CRDs (asthma, chronic obstructive pulmonary disease), CVDs and cancer. There has been a dearth of research on the demand-side perspective, which is an essential component of a health system and must be addressed in the future research. CONCLUSION: The supply-side components at the primary healthcare level are inadequately ready to address the growing NCD burden. Improving supply-side factors, with a particular focus on CRDs, CVDs and cancer, and improving understanding of the demand-side components of the health system's readiness, may help to prevent and manage NCDs at the primary healthcare level.

Psychometric validation of diabetes distress scale in Bangladeshi population.

Diabetes Distress (DD)-an emotional or affective state arise from challenge of living with diabetes and the burden of self-care-negatively impact diabetes management and quality of life of T2DM patients. Early detection and management of DD is key to efficient T2DM management. The study aimed at developing a valid and reliable instrument for Bangladeshi patients as unavailability such a tool posing challenge in diabetes care. Linguistically adapted, widely used, 17-item Diabetes Distress Scale (DDS), developed through forward-backward translation from English to Bengali, was administered on 1184 T2DM patients, from four diabetes hospitals in Bangladesh. Psychometric assessment of the instrument included, construct validity using principal component factor analysis, internal consistency using Cronbach's α and discriminative validity through independent t-test and test-retest reliability using intraclass-correlation coefficient (ICC) and Kappa statistics. Factor analysis extracted 4 components similar to original DDS domains, confirms the construct validity. The scale demonstrated satisfactory internal consistency (α = 0.838), stability (test-retest ICC = 0.941) and good agreement across repeated measurements (Kappa = 0.584). Discriminative validity revealed that patients with complication (p < 0.001) and those are on insulin (p < 0.001) had significantly higher distress scores in all domains. Bengali version of DDS is a valid and reliable tool for assessing distress among Bangladeshi T2DM patients.