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BACKGROUND Guidelines advocate multifactorial cardiovascular risk management in patients with diabetes and atherosclerotic cardiovascular disease. In hospitalised patients with diabetes following coronary artery bypass graft (CABG) we evaluated the impacts of decision-support algorithms for optimising glycaemia and lipid-lowering. We also assessed the safety of initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors near time of hospital discharge. METHODS This was a single-site, pre- and post-intervention analysis of glucose and lipid management in consecutive hospitalised patients with diabetes undergoing CABG surgery. The intervention involved education and decision-support algorithms designed by a multidisciplinary committee to guide cardiac surgery unit clinicians. RESULTS A total of 200 patients were included in the study. The pre- and post-intervention groups had similar baseline characteristics (HbA1c 7.9 ± 1.9% versus 8.1 ± 1.8%). Of 4092 blood glucose measurements the incidence of levels between 5 to 10 mmol/L was not different post-intervention (55.5% versus 57.0%, p = 0.441). Fewer endocrinology consultations occurred (59.0% versus 45.0%, p = 0.048) and rates of hypoglycaemia remained low. High-intensity statin was prescribed in >90% pre- and post-intervention although non-statin lipid-lowering agents remained

Objective To determine if hearing loss is associated with increased risk of frailty in later life. Study design Cross-sectional study of a community sample of 4,004 men aged 70 years and above living in the metropolitan region of Perth, Western Australia. Data were retrieved from the Health in Men Study (HIMS) and the Western Australian Data Linkage System (WADLS). Frailty was assessed using the FRAIL scale and the Frailty Index. Hearing loss was defined by self-report or by diagnosis recorded in the WADLS. We also collected demographic, lifestyle and social support information. Main outcome measures Frailty was assessed using the FRAIL scale and the Frailty Index. Results The prevalence of frailty in the sample population was 16.1% and 25.4% when assessed using the FRAIL scale and the Frailty Index respectively. After adjusting for participant demographic, lifestyle and social factors, hearing loss was significantly associated with the prevalence of frailty when diagnosed by either measure (FRAIL scale: odds ratio [OR] 1.59, 95 CI% 1.32 to 1.91; Frailty Index: OR 1.76, 95 CI% 1.50 to 2.05). The proportion of men with hearing loss increased with increasing severity of frailty. Conclusion Hearing loss is associated with increased prevalence of frailty in older men when assessed using the FRAIL scale and the Frailty Index. Future longitudinal studies using objective measures of hearing will be helpful in determining if this association is likely to be causal.

We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10-3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10-8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10-3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2 p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.

Context The osteoblast-derived polypeptide, osteocalcin (OC), has been associated with lower risk of type 2 diabetes and metabolic syndrome (MetS) in several epidemiological studies. Animal studies have indicated the undercarboxylated form of OC (ucOC) drives its association with metabolic outcomes. Objective We compared associations of ucOC and carboxylated OC (cOC) with MetS and its components in older men. Methods A cross-sectional analysis of 2575 men aged ≥70 years and older resident in Perth, Western Australia. ucOC was assayed using a hydroxyapatite-binding method, and cOC calculated by subtracting ucOC from total OC. Main outcome measures were MetS and its components. Results Both lower serum ucOC and cOC levels, and the proportion of cOC (%cOC) were associated with less favorable metabolic parameters (higher waist circumference, triglyceride, glucose, blood pressure, and lower high-density lipoprotein cholesterol), whereas inverse associations were found with %ucOC. Men in the lowest quintile of ucOC had higher risk of MetS compared to men in the highest quintile (Q1 ≤ 7.7 vs Q5 > 13.8 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). Men in the lowest quintile of cOC had higher risk of MetS compared to those in the highest quintile (≤ 5.8 vs > 13.0 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). Conclusion Lower concentrations of serum ucOC or cOC were associated with less favorable metabolic parameters and a higher risk of MetS. In contrast, a lower proportion of ucOC was associated with better metabolic parameters and lower MetS risk. Further research is warranted to determine whether ucOC and cOC are suitable biomarkers for cardiometabolic risk in men.

The endothelium is integral to the maintenance of vascular health in humans, and advancing age and low testosterone levels are associated with endothelial dysfunction in men. We compared the impacts of testosterone and exercise training, alone and in combination, on endothelium-dependent flow-mediated dilation % and endothelium-independent glyceryl trinitrate % responses. In this 2×2 factorial 12-week randomized controlled trial, 80 men aged 50 to 70 years with waist girth ≥95 cm and low-normal serum testosterone levels (6–14 nmol/L) were randomized to transdermal AndroForte5 (testosterone 5.0% w/v, 100 mg/2 mL; testosterone), or matching placebo; and to supervised centre-based exercise or no additional exercise. Testosterone increased serum testosterone levels (testosterone×time, P =0.003) to the extent that 62% of subjects in testosterone groups increased levels to >14 nmol/L, whereas placebo treatment had no impact on testosterone levels. Exercise training increased flow-mediated dilation % (exercise×time, P =0.033; testosterone+exercise: +0.5, placebo+exercise: +1.0 versus testosterone+no additional exercise: −0.7, placebo+no additional exercise: +0.2%), whereas testosterone did not impact flow-mediated dilation, nor was it additive to exercise (all P >0.05). There were no significant exercise or drug main effects on glyceryl trinitrate responses (all P >0.05). Exercise training improved endothelium-dependent vasodilator function, whereas administration of testosterone at therapeutic doses did not impact flow-mediated dilation % or add to the exercise benefit. Vascular smooth muscle sensitivity to nitric oxide was not modified by exercise, testosterone, or their combination. In middle-to-older-aged men with central adiposity and low/normal testosterone levels, we observed no evidence that testosterone added to the beneficial impact of exercise on vascular function and health. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368611 ; Unique identifier: ACTRN12615000600549.

Context Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. Objective We aimed to determine the effect of testosterone treatment on bone microarchitecture using high resolution–peripheral quantitative computed tomography (HR-pQCT). Methods Men ≥ 50 years of age were recruited from 6 Australian centers and were randomized to receive injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. The primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (1 center). Secondary endpoints included other HR-pQCT parameters and bone remodeling markers. Areal BMD (aBMD) was measured by dual-energy x-ray absorptiometry (DXA) in 601 men (5 centers). Using a linear mixed model for repeated measures, the mean adjusted differences (95% CI) at 12 and 24 months between groups are reported as treatment effect. Results Over 24 months, testosterone treatment, versus placebo, increased tibial cortical vBMD, 9.33 mg hydroxyapatite (HA)/cm3) (3.96, 14.71), P Conclusion In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.

Introduction Fractures are common and disabling health events, particularly later in life. The presence of clinically significant depressive symptoms has been associated with increased risk of fractures, and we designed the present study to clarify if this association is likely to be causal or due to the confounding effect of measures associated with both fractures and depression. Method Cohort study of a community-derived sample of 4224 men aged 70 to 88 years at the start of the follow-up period of up to 17 years. Clinically significant symptoms of depression were defined as a recorded diagnosis of depressive episode in the Western Australian Data Linkage System (WADLS) or by a total score of 7 or greater on the 15-item Geriatric Depression Scale. Health contacts associated with fractures were retrieved from WADLS. Other measures included age, past history of fractures, education, smoking, frailty, poor vision, falls, medications, and the concentration of vitamin D, homocysteine, hsCRP and testosterone. Death was considered a competing risk for fractures. Results 911 (21.6%) participants had a bone fracture during follow-up. After adjustment for multiple potential confounders, past and current depression were associated with an increase in the risk of novel fractures; respective odds ratios were 1.41 (95%CI = 1.03, 1.93) and 1.64 (95%CI = 1.20, 2.25). Parsimonious competing risk regression showed that both past and current depression were associated with an increase in the risk of novel fractures: sub-hazard ratio = 1.29 (95%CI = 1.03, 1.63) and 1.27 (95%CI = 1.05, 1.55) respectively. Estimation of confounding due to unmeasured factors showed that a small additional effect could potentially dilute the association between depression and fractures. Discussion History of clinically significant symptoms of depression is associated with an increased risk of future fractures. This association may be due to multiple other associated risk factors, both measured and unmeasured, but nevertheless the presence of depression should alert clinicians to the need to develop a management plan that includes the management not only of depression but also of fracture risk.

Summary Background Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme. Methods T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50–74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8–11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. Findings Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was −0·95 mmol/L (SD 2·78) in the placebo group and −1·70 mmol/L (SD 2·47) in the testosterone group (mean difference −0·75 mmol/L, −1·10 to −0·40; p Interpretation Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated. Funding Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

Recent cardiovascular safety trials on sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists have demonstrated the significant cardiovascular and renal benefits of these medications. Diabetes organisations have revised their medication guidelines to include a focus on disease outcomes for cardiovascular disease, heart failure and renal disease. This article summarises latest evidence, guideline recommendations and current Australian Pharmaceutical Benefits Scheme requirements.

OBJECTIVE Serum testosterone concentrations are affected by factors unrelated to hypothalamo-pituitary-testicular axis pathology. We evaluated the impact of sociodemographic, lifestyle and medical factors, on serum testosterone and sex hormone-binding globulin (SHBG) in men aged 40-69 years. DESIGN Cross-sectional analysis of 208,677 community-dwelling men from the UK Biobank. MEASUREMENTS We analysed associations of different factors with serum testosterone and SHBG (immunoassays) and calculated free testosterone (cFT), using smoothed centile plots, linear mixed models and effect size estimates. RESULTS Median (interquartile range) for serum testosterone was 11.6 (9.4-14.1) nmol/L, SHBG 36.9 (27.9-48.1) nmol/L and cFT 213 (178-255) pmol/L. Age and BMI were inversely associated with testosterone and cFT, while SHBG was associated with age and inversely with BMI (all P

Sodium-glucose cotransporter 2 inhibitors can improve heart failure outcomes, however, the effects on left ventricular (LV) function remain unclear. This prospective observational study aimed to investigate whether initiating empagliflozin therapy was associated with improved LV diastolic function following an acute coronary syndrome (ACS) in patients with type 2 diabetes (T2D). Patients with ACS and T2D were identified during hospitalisation in a cardiology unit. Empagliflozin was initiated at discharge in eligible patients (i.e. HbA1c > 7%) without contraindications or precautions. Transthoracic echocardiography was performed during admission and after 3–6 months. Changes in echocardiographic parameters were compared between patients initiated on empagliflozin versus not initiated on empagliflozin (control). There were 22 patients in each group (n = 44). Baseline characteristics, medications and echocardiographic parameters were similar except HbA1c (empagliflozin: 9.8 ± 1.6% versus control: 6.6 ± 0.7%, p

The metabolic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on human blood plasma were characterized using multi-platform metabolic phenotyping with Nuclear Magnetic Resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Quantitative measurements of lipoprotein sub-fractions, alpha-1-acid glycoprotein, glucose and biogenic amines were made on samples from symptomatic coronavirus disease 19 (COVID-19) patients who had tested positive for the SARS-CoV-2 virus (n = 17) and from age and gender-matched controls (n = 25). Data were analyzed using an orthogonal-projections to latent structures (O-PLS) method and used to construct an exceptionally strong (AUROC=1) hybrid NMR-MS model that enabled detailed metabolic discrimination between the groups and their biochemical relationships. Key discriminant metabolites included markers of inflammation including elevated alpha-1 acid glycoprotein and an increased kynurenine/tryptophan ratio. There was also an abnormal lipoprotein, glucose and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides). Plus, multiple highly significant amino acid markers of liver dysfunction (including the elevated glutamine/glutamate and Fischer’s ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern. A multivariate training-test set model was validated using independent samples from additional SARS-CoV-2 positive patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidaemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems. Metabolights study reference: MTBLS2014.

Outcomes after coronary artery bypass graft (CABG) surgery have improved due to advances in surgical technique and post-operative care. We aimed to describe contemporary clinical characteristics and short-term post-operative outcomes in diabetic patients undergoing CABG surgery.A retrospective analysis of patients who underwent CABG surgery over a 4.5-year period in a Western Australian tertiary hospital was performed in September 2019. The cohort was stratified according to pre-operative diabetes status.A total of 1327 patients underwent CABG surgery, of which 572 (43.1%) had diabetes. Diabetic patients were more likely to be female (24.7% vs. 13.9%, p 0.001) and have dyslipidaemia (83.0% vs. 68.1%, p 0.001), hypertension (82.0% vs. 68.7%, p 0.001), raised body mass index (29.8 ± 5.6 vs. 28.7 ± 5.1 kg/mDiabetic patients continue to represent a higher-risk cohort, highlighting the need for further strategies to reduce short-term adverse outcomes following CABG surgery.

Purpose Whether androgens, distinct from estrogen, maintain bone health during male aging has implications for understanding osteoporosis. We assessed associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. Participants and methods Analysis of 3307 community-dwelling men aged 76.8 ± 3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analyzed probability of fracture and performed Cox regression adjusted for age, medical comorbidities, and frailty. Results Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested nonlinear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T, lower E2, higher SHBG, and higher LH. In fully adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Quartile 2 [Q2] versus Q1: fully adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] 0.51–0.94, P = .020; Q3: HR 0.59, 95% CI 0.42–0.83, P = .002) and hip fracture (Q2 versus Q1: HR 0.60, 95% CI 0.37–0.93, P = .043; Q3: HR 0.52, 95% CI 0.31–0.88, P = .015). DHT, E2, and LH were not associated with fracture. Higher SHBG was associated with hip fracture (Q4 versus Q1: HR 1.76, 95% CI 1.05–2.96, P = .033). Conclusions Midrange plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk.

This individual participant data analysis assesses the cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia., Key Points Question Is thyroid dysfunction associated with cognitive decline? Findings In this individual participant data analysis of 23 cohorts including 74 565 participants with cognitive function and/or dementia measurements, subclinical thyroid dysfunction was not associated with global cognitive function at baseline (standardized mean difference, −0.02 for subclinical hyperthyroidism and 0.05 for subclinical hypothyroidism) or annual decline (standardized mean difference, −0.02 for subclinical hyperthyroidism and −0.00 for subclinical hypothyroidism). Meaning These findings do not support the need for screening for subclinical thyroid dysfunction for prevention of cognitive decline or dementia., Importance In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism—cross-sectionally (−0.06 standardized mean difference in score; 95% CI, –0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, –0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

ObjectivesThe overall study aim is to clarify the relation of endogenous sex hormones with major health outcomes in men. This paper reports a systematic review focusing on published estimates for testosterone associations.SettingCommunity-dwelling men.Participants20 180 adult men participated in the final set of studies identified and selected from a systematic review. Eligible studies included prospective cohort studies with plasma or serum testosterone concentrations measured for adult men using mass spectrometry with at least 5 years of follow-up data and one of the specified outcome measures recorded. Only published or grey literature items written in English were considered.Primary and secondary outcome measuresPlanned prospective outcome measures: cardiovascular disease (CVD) events, CVD deaths, all-cause mortality, cancer deaths, cancer diagnoses, cognitive decline, dementia. Meta-analyses were of the most frequently reported outcomes in selected studies: CVD deaths and all-cause mortality. Succinct characterisations of testosterone associations with other outcomes are also presented.ResultsScreening of 1994 deduplicated items identified 9 suitable studies, with an additional 2 identified by colleagues (11 in total). Summary estimates of mean testosterone concentration and age at recruitment for 20 180 adult men were 15.4±0.7 nmol/L and 64.9±3.3 year. Despite considerable variation in mean testosterone, a metaregression estimated no significant dependence on mean age at recruitment among studies (slope=−0.03, 95% CI −0.11 to 0.06). Meta-analyses demonstrated negligible heterogeneity and no significant effect of a 5 nmol/L increase in testosterone on the risk of all-cause mortality (HR=0.96, 95% CI 0.89 to 1.03) or death from CVD (HR=0.95, 95% CI 0.83 to 1.08).ConclusionsAnalyses of published estimates did not demonstrate associations of endogenous testosterone with CVD deaths or with all-cause mortality. Suggested further research includes the planned individual participant data meta-analyses for selected studies, enabling the investigation of non-linear summary effects.PROSPERO registration numberPROSPERO: CRD42019139668.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Objectives The recently developed Hospital Frailty Risk Score (HFRS) allows ascertainment of frailty from administrative data. We aimed to compare the HFRS against the widely used FRAIL Scale and Frailty Index. Design Population-based cohort study linked to Western Australian Hospital Morbidity Data Collection and Death Registrations. Setting and Participants The Health in Men Study with frailty determined at wave 2 (2001/2004), mortality in the 1-year period following wave 2, and disability at wave 3 (2008). Participants were 4228 community-based men aged ≥75 years, followed until wave 3. Measurements We used multivariable regression to determine the association between each frailty measure and outcomes of length of stay (LOS), death, and disability. We also determined if the additional cases of frailty identified by one measure over the other was associated with these outcomes. Results Of 4228 men studied, the HFRS (n = 689) identified fewer men as frail than the FRAIL Scale (n = 1648) and Frailty Index (n = 1820). In the fully adjusted models, all 3 frailty measures were associated with longer LOS and mortality, whereas only the FRAIL Scale and Frailty Index were significantly associated with disability. The additional cases of frailty identified by the FRAIL Scale and Frailty Index had longer LOS and greater risks of death and disability. The fully adjusted hazard ratio for death among the additional cases of frailty identified by the FRAIL Scale (compared to being not frail on both HFRS and FRAIL Scale) was 2.14 (95% CI 1.48-3.08). Conclusions and Implications The HFRS is associated with adverse outcomes. However, it identified approximately 60% fewer men who were frail than the FRAIL Scale and Frailty Index, and the additional cases identified were also at high risks of adverse outcomes. Users of the HFRS should be aware of the differences with other frailty measures.

In this real-world study, the main barriers for not initiating SGLT2 inhibitor therapy early after an acute cardiac event are prescribing criteria around glycated haemoglobin and renal function. Initiation of SGLT2 inhibitors near to, or at, hospital discharge following the cardiac event was not associated with 30-day diabetic ketoacidosis readmissions.

Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are a unique class of oral anti‐hyperglycaemic medications that act to reduce glucose reabsorption in the renal proximal tubules, thereby enhancing urinary glucose excretion. Large randomized placebo‐controlled trials in people with diabetes at high cardiovascular risk have demonstrated that SGLT2 inhibitors reduce heart failure hospitalization within months of commencing therapy. These findings are of considerable interest, as diabetes is associated with an increased risk of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. In addition, left ventricular (LV) hypertrophy and impaired diastolic function is thought to be more prevalent in people with diabetes. Although many hypotheses have been proposed, the underlying mechanisms through which SGLT2 inhibitors reduce the risk of heart failure in people with diabetes are not fully understood. Given the rapid reduction in heart failure hospitalization, it is conceivable that the benefits of SGLT2 inhibitors are due to favourable haemodynamic and metabolic effects on LV function. Several clinical studies have been conducted to investigate the effect of SGLT2 inhibitors on LV structure and function and have found that LV mass index and diastolic function improve following SGLT2 inhibitor therapy in people with type 2 diabetes. If these findings are confirmed in future studies utilizing novel cardiac imaging modalities and large randomized controlled trials, then this will bring new hope for the prevention and management of heart failure with preserved ejection fraction, for which no current treatments have been shown to reduce mortality. At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited. The purpose of this review is to summarize current knowledge regarding the effects of SGLT2 inhibitors on LV function, particularly the findings from clinical studies, proposed biological mechanisms, and future directions.

Objectives The aim of the study was to compare the response rates and costs of phone call vs. short message service (SMS) screening reminders to prospective randomized controlled trial (RCT) participants. Study Design and Setting This study was a randomized evaluation within a large Australian diabetes prevention RCT. Participants were men aged 50–74 years, overweight or obese, without a previous type 2 diabetes diagnosis. Those eligible on a prescreening questionnaire who did not attend a further screening assessment within 4 weeks were randomized to receive an SMS or phone call reminder (N = 709). The primary outcome was attendance for further screening assessment within 8 weeks of prescreening. Results Attendance was 18% (62/354) in the SMS reminder group, and 23% (80/355) in the phone reminder group, with no statistically significant difference in response according to reminder type (relative risk = 1.29, 95% confidence interval [CI]: 0.96–1.73, P = 0.09). The lower confidence limits for response to SMS (95% CI: 14–22%) and phone reminders (95% CI: 18–27%) did not include the 8-week attendance rate before this evaluation, 12%. Phone reminders cost substantially more than SMS reminders (AU$6.21 vs. AU$0.53 per reminder). Conclusion SMS reminders were as adequate a method as phone reminders to boost RCT screening uptake and were considerably more affordable.

Context Diabetes mellitus is conventionally associated with an increased risk of cancer; however, inverse associations of diabetes with prostate cancer are well described. Mechanisms are unclear, although hormonal factors, including alterations in sex hormone and IGF1 concentrations due to metabolic disturbances, have been hypothesized to play a role. Objective To assess sex hormones, IGF1, glucose, and advanced glycation end products (AGEs) as potential mediators of the association between diabetes mellitus and prostate cancer. Design and Participants Longitudinal cohort study. The association of baseline diabetes with prostate cancer incidence was assessed using proportional hazards competing risks analysis in 3149 men followed for 12 years. Baseline hormone, glucose, and carboxymethyllysine (CML) levels were examined as potential mediators of this association. Results Diabetes was associated with a lower prostate cancer risk (fully adjusted subhazard ratio, 0.63; 95% CI, 0.43 to 0.92; P = 0.017). This association was unchanged after accounting for testosterone, DHT, estradiol, or SHBG. Similarly, the addition of IGF1 or its binding proteins 1 and 3, or glucose, did not alter this association. CML was not associated with the risk of prostate cancer, and additional correction for CML in the fully adjusted model did not alter the inverse association of diabetes and prostate cancer risk. Conclusions In this study, alterations in sex hormone, IGF1, glucose, and CML levels did not account for the inverse association of diabetes and prostate cancer risk. Further studies are required to provide more insight into underlying causes of this association.

Background: Long-term air pollution exposure has been associated with increased risk of mortality and stroke. Less is known about the risk at lower concentrations. The association of long-term exposure to PM2.5, PM2.5 absorbance, NO2, and NOx with all-cause mortality and stroke was investigated in a cohort of men aged >= 65 years who lived in metropolitan Perth, Western Australia. Methods: Land use regression models were used to estimate long-term exposure to air pollutants at participant's home address (n = 11,627) over 16 years. Different metrics of exposure were assigned: baseline; year before the outcome event; and average exposure across follow-up period. The Mortality Register and Hospital Morbidity Data from the Western Australia Data Linkage System were used to ascertain mortality and stroke cases. Hazard ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazard models, adjusting for age, smoking, education, and body mass index for all-cause mortality. For fatal and hospitalized stroke, the models included variables controlled for all-cause mortality plus hypertension. Results: Fifty-four percent of all-participants died, 3% suffered a fatal stroke, and 14% were hospitalized stroke cases. PM2.5 absorbance increased the risk of all-cause mortality with adjusted HR of 1.12 (1.02-1.23) for baseline and average exposures, and 1.14 (1.02-1.24) for past-year exposure. There were no associations between PM2.5 absorbance, NO2, and NOx and stroke outcomes. However, PM2.5 was associated with reduced risks of fatal stroke. Conclusion: Long-term exposure to PM2.5 absorbance was associated with all-cause mortality among older men exposed to low concentrations; and exposure to PM2.5 was associated with reduced risk of fatal stroke.

Background Effective interventions are required to prevent the current rapid increase in the prevalence of Type 2 diabetes. Clinical trials of large-scale interventions to prevent Type 2 diabetes are essential but recruitment is challenging and expensive, and there are limited data regarding the most cost-effective and efficient approaches to recruitment. This paper aims to evaluate the cost and effectiveness of a range of promotional strategies used to recruit men to a large Type 2 diabetes prevention trial. Methods An observational study was conducted nested within the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, a large, multi-centre randomised controlled trial (RCT) of testosterone treatment for the prevention of Type 2 diabetes in men aged 50–74 years at high risk of developing diabetes. Study participation was promoted via mainstream media—television, newspaper and radio; direct marketing using mass mail-outs, publicly displayed posters and attendance at local events; digital platforms, including Facebook and Google; and online promotions by community organisations and businesses. For each strategy, the resulting number of participants and the direct cost involved were recorded. The staff effort required for each strategy was estimated based on feedback from staff. Results Of 19,022 men screened for the study, 1007 (5%) were enrolled. The most effective recruitment strategies were targeted radio advertising (accounting for 42% of participants), television news coverage (20%) and mass mail-outs (17%). Other strategies, including radio news, publicly displayed posters, attendance at local events, newspaper advertising, online promotions and Google and Facebook advertising, each accounted for no more than 4% of enrolled participants. Recruitment promotions cost an average of AU$594 per randomised participant. The most cost-effective paid strategy was mass mail-outs by a government health agency (AU$745 per participant). Other paid strategies were more expensive: mail-out by general practitioners (GPs) (AU$1104 per participant), radio advertising (AU$1081) and newspaper advertising (AU$1941). Conclusion Radio advertising, television news coverage and mass mail-outs by a government health agency were the most effective recruitment strategies. Close monitoring of recruitment outcomes and ongoing enhancement of recruitment activities played a central role in recruitment to this RCT. Trial registration ANZCTR, ID: ACTRN12612000287831. Registered on 12 March 2012. Electronic supplementary material The online version of this article (10.1186/s13063-019-3485-2) contains supplementary material, which is available to authorized users.

Context: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men. Participants and methods: We used cross‐sectional data from 2913 men aged 76.7 ± 3.2 years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone‐binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history. Results: Average difference per decade of age was T −0.46 nmol/L, DHT −0.11 nmol/L, E2 −7.5 pmol/L, SHBG +10.2 nmol/L and LTL (T/S ratio) −0.065. E2 correlated with T/S ratio (r = 0.038, P = 0.039) and SHBG was inversely correlated (r = −0.053, P = 0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, P = 0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P = 0.014) and SHBG inversely (coefficient −0.013, P = 0.037) associated with T/S ratio. Conclusions: In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.

The aim of this study was to investigate the effect of a single dose of prednisolone on (A) high-intensity interval cycling performance and (B) post-exercise metabolic, hormonal and haematological responses. Nine young men participated in this double-blind, randomised, cross-over study. The participants completed exercise sessions (4 × 4 min cycling bouts at 90–95% of peak heart rate), 12 h after ingesting prednisolone (20 mg) or placebo. Work load was adjusted to maintain the same relative heart rate between the sessions. Exercise performance was measured as total work performed. Blood samples were taken at rest, immediately post exercise and up to 3 h post exercise. Prednisolone ingestion decreased total work performed by 5% (P P P > 0.05). Prednisolone suppressed the increase in blood lactate immediately post exercise (P P P

Insulin‐like growth factor‐I (IGF‐I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full‐cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF‐I, sex hormone‐binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable‐adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two‐sample Mendelian randomisation (MR) analysis of IGF‐I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis‐ and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow‐up 6.9 years). Higher circulating IGF‐I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05‐1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02‐1.29). MR analyses also supported the role of IGF‐I in prostate cancer diagnosis (cis‐MR odds ratio per 5 nmol/L increment = 1.34, 1.07‐1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05‐1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94‐0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF‐I and free testosterone in prostate cancer development and/or progression., What's new? Testosterone, insulin‐like growth factor‐I (IGF‐I), and sex hormone‐binding globulin (SHBG) all have been associated with prostate‐cancer risk. In this large, prospective study, the authors analyzed how these circulating hormones might impact mortality as well as risk. They found that men with higher IGF‐I had a higher risk of both prostate‐cancer diagnosis and mortality. Men with higher free testosterone had an increased risk of prostate cancer, while men with higher SHBG had a decreased risk. These results support the roles of IGF‐I and testosterone in prostate cancer development.

Management of diabetes-related foot ulceration (DFU) includes pressure offloading resulting in a period of reduced activity. The metabolic effects of this are unknown. This study aims to investigate changes in bone mineral density (BMD) and body composition 12 weeks after hospitalisation for DFU. A longitudinal, prospective, observational study of 22 people hospitalised for DFU was conducted. Total body, lumbar spine, hip and forearm BMD, and total lean and fat mass were measured by dual-energy X-ray absorptiometry (DXA) during and 12 weeks after hospitalisation for DFU. Significant losses in total hip BMD of the ipsilateral limb (− 1.7%, p p = 0.005), femoral neck BMD of the ipsilateral limb (− 2.8%, p p = 0.008) were observed after 12 weeks. Lumbar spine and forearm BMD were unchanged. HbA1c improved from 75 mmol/mol (9.2%) to 64 mmol/mol (8.0%) (p = 0.002). No significant changes to lean and fat mass were demonstrated. Total hip and femoral neck BMD decreased bilaterally 12 weeks after hospitalisation for DFU. Future research is required to confirm the persistence and clinical implications of these losses.

The global prevalence of diabetic kidney disease is rapidly accelerating due to an increasing number of people living with type 2 diabetes. It has become a significant global problem, increasing human and financial pressures on already overburdened healthcare systems. Interest in diabetic kidney disease has increased over the last decade and progress has been made in determining the pathogenic mechanisms and patient-related factors involved in the development and pathogenesis of this disease. A greater understanding of these factors will catalyse the development of novel treatments and influence current practice. This review summarises the latest evidence for the factors involved in the development and progression of diabetic kidney disease, which will inform better management strategies targeting such factors to improve therapeutic outcomes in patients living with diabetes.

We illustrate that exercise training generates superior outcomes to testosterone treatment for improving aerobic fitness, muscular strength, and total and visceral fat mass in men 50–70 yr with low-normal serum testosterone concentrations. Adding testosterone treatment to exercise did not provide any additive benefit for these variables. Testosterone treatment alone and exercise alone had similar impacts on lean mass. Therefore, men unable to exercise may obtain benefit from testosterone treatment alone to improve lean mass.

Context An association was recently reported between genetic markers related to high testosterone and increased risk of thromboembolism in men, but a possible causal role of estradiol for risk of thromboembolism in men remains unknown. Objective This work aimed to determine whether endogenous estradiol has a causal role in thromboembolism in men. Methods A 2-sample mendelian randomization study using gene-based genetic instruments assessed the association between endogenous estradiol genetically predicted by 22 variants in the aromatase CYP19A1 gene region and the risk of thromboembolism (5815 cases) in 170 593 unrelated men of White ancestry in the UK Biobank. The main outcome measure included thromboembolism based on self-reports, hospital episodes, and death. Results Endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of thromboembolism (odds ratio per SD increase in estradiol 0.74; 95% CI, 0.62-0.90). In contrast, genetic variants in the JMJD1C gene, used as a predictor of high endogenous testosterone, were associated with an increased risk of thromboembolism (odds ratio per SD increase in testosterone 1.39; 95% CI, 1.12-1.72). Subsequent explorative analyses evaluating potential repercussions of thromboembolism revealed that endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of ischemic stroke (0.68; 95% CI, 0.49-0.95) but not myocardial infarction (0.97; 95% CI, 0.84-1.13). Conclusion Genetically predicted estradiol was inversely associated with the risk of thromboembolism and ischemic stroke in men. The ratio between testosterone and estradiol, determined by CYP19A1 activity, may contribute to the overall impact of sex steroids on thromboembolism in men.

BACKGROUND Diabetes distress, self-efficacy and health literacy are associated with diabetes self-management and health outcomes. Measures of coping styles and their impact on diabetes self-management and diabetes-related distress may add value in identifying those at risk of poorer health outcomes. Current evidence of associations between psychological flexibility/inflexibility and diabetes related health outcomes is limited. AIMS To measure associations of psychological flexibility, self-efficacy and health literacy with diabetes distress and HbA1c, in adults with type 1 diabetes. METHODS We surveyed 105 adults with type 1 diabetes attending a tertiary diabetes outpatient clinic (mean age 27±7.1 years, 53% men, duration of diabetes 12.6±8.5 years, HbA1c 72±22 mmol/mol, 8.7± 2.0 %, 34% using insulin pumps). We assessed psychological flexibility, self-efficacy, health literacy and diabetes distress. Regression models explored the relative contributions of different factors to diabetes distress and HbA1c. RESULTS The majority of health literacy scores were in the low risk range. Those with greater psychological flexibility had higher self-efficacy (r=0.34, p

Context Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. Objective To analyze associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men. Design, Setting, and Participants The UK Biobank prospective cohort study of community-dwelling men aged 40–69 years old, followed for 11 years. Main Outcome Measures All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa. Results In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06–1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09–1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63–0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59–0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72–0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results. Conclusions Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.

Refereed/Peer-reviewed Objective Low endogenous sex hormones and low physical activity (PA) levels have been associated with CVD risk. Whether these interact to influence CVD outcomes remains unclear. We assessed whether sex hormone concentrations and PA were additively associated with lower central adiposity and CVD risk. Patients 3351 community-dwelling men, mean age 77 years. Measurements Baseline testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Levels of PA were ascertained by questionnaire. Men were stratified using median splits into high hormone + high PA (H/H), high hormone + low PA (H/L); low hormone + high PA (L/H) and low hormone + low PA (L/L) groups. Results A total of 865 CVD events and 499 CVD deaths occurred during 10-year mean follow-up. Men with higher T, DHT or SHBG and higher PA had the lowest BMI, waist circumference and risk of metabolic syndrome. Men with higher T had the lowest risk of incident CVD events, irrespective of PA level. Men with higher T or DHT and higher PA had the lowest risk of dying from CVD (eg, hazard ratios for T/PA H/H 0.76 P = 0.031; H/L 0.85 P = 0.222; L/H 0.80 P = 0.075; L/L 1.00). Conclusion Higher circulating androgens and higher PA were associated with less central adiposity at baseline and fewer CVD deaths during follow-up. These findings are consistent with a potential additive effect of androgens and PA on cardiometabolic outcomes in older men.

Background Testosterone prescriptions have increased dramatically in recent decades, with increasing usage in men. Despite epidemiological associations reported high circulating concentrations of endogenous androgens and low risk of cardiovascular events and mortality, the effects of exogenous androgens in the form of testosterone therapy for maintaining physiological circulating androgen concentrations on the cardiovascular system remain uncertain with no published meta-analysis on this topic. Objective The aim of this study was to investigate the effects of prescribed testosterone treatment, in all forms and durations, from well-developed randomized controlled trials, on cardiovascular events in men aged 18 years or older. Methods Peer-reviewed journal articles published from 1980 to 2019 will be searched from databases (ie CINAHL [Cumulated Index to Nursing and Allied Health Literature], Embase, Medline, Scopus, Cochrane Controlled Register of Trials as well as the Clinical Trial Registry). Randomized controlled trials or cluster randomized controlled trials with at least one intervention arm of testosterone and a control group of usual care or no testosterone treatment will be included in this review and meta-analysis. Studies on men with previous cardiovascular events or cardiac vascularization (coronary bypass surgery or percutaneous coronary intervention) will be excluded. Data related to primary outcomes such as clinical events of any type of stroke or transient ischemic attack, nonfatal myocardial infarction or acute coronary syndrome, emergency coronary artery revascularization, carotid surgery, cardiac mortality, and all-cause mortality will be extracted for analysis. The criteria for PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) will be followed in the evaluation of evidence. Results Search terms have been piloted and finalized. This study will be completed by the end of 2020. Conclusions This protocol will guide a systematic literature review of the evidence around prescribed testosterone and its effect on cardiovascular events in men aged 18 years or older. The findings will inform clinical management of hypogonadal men. Trial Registration PROSPERO International Prospective Register of Systematic Reviews CRD42019134278; https://tinyurl.com/y6t7ggge International Registered Report Identifier (IRRID) PRR1-10.2196/15163

The pathophysiology and time course of impairment in cutaneous microcirculatory function and structure remain poorly understood in people with diabetes, partly due to the lack of investigational tools capable of directly imaging and quantifying the microvasculature in vivo. We applied a new optical coherence tomography (OCT) technique, at rest and during reactive hyperemia (RH), to assess the skin microvasculature in people with diabetes with foot ulcers (DFU, n = 13), those with diabetes without ulcers (DNU, n = 9), and matched healthy controls (CON, n = 13). OCT images were obtained from the dorsal part of the foot at rest and following 5 min of local ischemia induced by inflating a cuff around the thigh at suprasystolic level (220 mmHg). One-way ANOVA was used to compare the OCT-derived parameters (diameter, speed, flow rate, and density) at rest and in response to RH, with repeated-measures two-way ANOVA performed to analyze main and interaction effects between groups. Data are means ± SD. At rest, microvascular diameter in the DFU (84.89 ± 14.84 µm) group was higher than CON (71.25 ± 7.6 µm, P = 0.012) and DNU (71.33 ± 12.04 µm, P = 0.019) group. Speed in DFU (65.56 ± 4.80 µm/s, P = 0.002) and DNU (63.22 ± 4.35 µm/s, P = 0.050) were higher than CON (59.58 ± 3.02 µm/s). Microvascular density in DFU (22.23 ± 13.8%) was higher than in CON (9.83 ± 2.94%, P = 0.008), but not than in the DNU group (14.8 ± 10.98%, P = 0.119). All OCT-derived parameters were significantly increased in response to RH in the CON group (all P < 0.01) and DNU group (all P < 0.05). Significant increase in the DFU group was observed in speed ( P = 0.031) and density ( P = 0.018). The change in density was lowest in the DFU group (44 ± 34.1%) compared with CON (199.2 ± 117.5%, P = 0.005) and DNU (148.1 ± 98.4, P = 0.054). This study proves that noninvasive OCT microvascular imaging is feasible in people with diabetes, provides powerful new physiological insights, and can distinguish between healthy individuals and patients with diabetes with distinct disease severity.

Osteocalcin, the osteoblast-derived protein, has been shown to be modulated in patients with problematic glucose metabolism. Our systematic review and meta-analysis found that in humans, higher blood osteocalcin level is associated with lower body indices of fat. Osteocalcin (OC) was found to be inversely correlated with measures of glucose and energy metabolism, with some groups suggesting the undercarboxylated form (ucOC) to be metabolically active, although the link is not clear, especially in humans. Given obesity is a major risk factor for metabolic disorders, we aimed to assess the correlation between OC and two measures of body weight: body mass index (BMI) and percentage body fat (%BF). MEDLINE and EMBASE were searched to identify observational studies in adult populations that reported the crude correlation coefficients (r) between OC and BMI and %BF. Pool r were obtained using random-effects models. Fifty-one publications were included in this analysis. Both total OC (TOC) (pooled r = − 0.151, 95% CI – 0.17, − 0.130; I2 = 52%) and ucOC (pooled r = − 0.060, 95% CI – 0.103, − 0.016; I2 = 54%) were inversely correlated with BMI. The pooled r between TOC and BMI in Caucasian-and-other-regions (r = − 0.187) were stronger than those in Asian populations (r = − 0.126; intra-group p = 0.002; R2 = 0.21). The mean/median BMI of the reported cohort was the major contributor to between-study heterogeneity in correlation between TOC/ucOC and BMI (R2 = 0.28 and 0.77, respectively). Both TOC and ucOC were also inversely correlated with %BF (TOC: pooled r = − 0.185, 95% CI – 0.257 to − 0.112; ucOC: pooled r = − 0.181, 95% CI – 0.258 to − 0.101). Higher OC and ucOC were correlated with lower BMI and %BF. The inverse correlations between TOC/ucOC and BMI appear to be affected by ethnicity and obesity status.

CONTEXT: Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. OBJECTIVE: To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). DESIGN: Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. SETTING: General community. PARTICIPANTS: 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. EXPOSURE: Plasma sex hormone levels were measured at visit 4 (1996-1998). MAIN OUTCOME MEASURES: Incident HF events were identified through hospital discharge codes and death certificates. RESULTS: The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. CONCLUSION: In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.

We previously showed that implementing algorithms for managing diabetes in acute coronary syndrome was associated with improved inpatient glycaemic control and increased sodium-glucose cotransporter 2 (SGLT2) inhibitor prescriptions. The present study performed 1 year later found that inpatient hyperglycaemia had relapsed to pre-intervention rates, although SGLT2 inhibitor prescriptions remained increased. We discuss the challenges of improving inpatient glycaemic control.

In men with obesity and IGT, serum testosterone (T) is inversely associated with incident T2D. Hypothesizing that T treatment prevents or reverses T2D beyond the effects of a lifestyle program alone, we conducted a multi-center, double-blinded placebo-controlled trial. Men (N=1007), aged 50-74 yrs., waist circumference (WC)>95cm, serum T≤14nmol/L (chemiluminescent assay), and IGT or newly diagnosed T2D, established by an OGTT, were randomized to receive, on a 1:1 basis, either IM T undecanoate (Reandron, Bayer) (1000mg/4ml) or vehicle (V) at baseline, 6 weeks and then 3-monthly for 2 yrs. All participants were enrolled in a lifestyle program (Weight Watchers® (WW)). Co-primary 2-yr outcomes: (1) OGTT 2-hr glucose ≥11 mmol/L: 55/443 (12.4%) in the T and 87/413 (21.1%) in V groups; RR (95% CI) 0.59 (0.43-0.80), P Disclosure G.A. Wittert: Research Support; Self; Bayer Inc., Lawley Pharmaceuticals, Lilly, Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins. K.P. Robledo: None. M. Grossmann: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Novartis Pharmaceuticals Canada Inc., Otsuka Pharmaceutical Co., Ltd., Weight Watchers International, Inc. Speaker’s Bureau; Self; Besins Healthcare, Otsuka Pharmaceutical Co., Ltd. K. Bracken: None. B.B. Yeap: Advisory Panel; Self; Sanofi. Research Support; Self; Bayer AG, Lawley Pharmaceuticals. Speaker’s Bureau; Self; Besins, Sanofi. B.G.A. Stuckey: None. R.I. McLachlan: None. D.J. Handelsman: None. C. Allan: Advisory Panel; Self; Ferring Pharmaceuticals. Speaker’s Bureau; Self; Besins. W. Inder: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc. Speaker’s Bureau; Self; Amgen, Novo Nordisk Inc., Pfizer Inc. D. Jesudason: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. A.C. Keech: Advisory Panel; Self; Amgen, Kowa Research Institute, Inc. Consultant; Self; Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Amgen. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. M. Ng Tang Fui: None. M. Daniel: None. Funding National Health and Medical Council of Australia (1030123); Eli Lilly and Company; Bayer AG; Weight Watchers; University of Adelaide

Lipoprotein(a) [Lp(a)] and diabetes are independently associated with premature coronary artery disease (pCAD). However, there is an inverse relationship between Lp(a) concentration and type 2 diabetes (T2D) risk. We examine whether Lp(a) distribution in patients with pCAD differs between those with or without T2D, and whether elevated Lp(a) is associated with pCAD in patients with T2D.Lp(a) concentration was measured in consecutive acute coronary syndrome (ACS) patients in two coronary care units (study one: ACS with or without diabetes, study two: ACS and diabetes). Elevated Lp(a) mass concentration was defined as ≥0.5 g/L and pCAD where CAD was diagnosed age60 years. The association between elevated Lp(a) and pCAD was assessed using logistic regression.Of 449 patients, 233 (51.9%) had pCAD and 278 (61.9%) had T2D. In patients with pCAD, those with T2D had a significantly lower median Lp(a) concentration (0.13 g/L versus 0.27 g/L, p=0.004). In patients with T2D, elevated Lp(a) was significantly associated with pCAD (OR 2.419, 95% CI 1.513-3.867, p0.001). After adjusting for gender, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, elevated Lp(a) remained significantly associated with pCAD (OR 2.895, 95% CI 1.427-5.876, p=0.003) in patients with T2D.In coronary care patients with pCAD, patients with T2D had lower Lp(a) concentrations than those without T2D. Despite this, elevated Lp(a) remained predictive of pCAD in patients with T2D. Measurement of Lp(a) should be considered in younger adults with T2D to identify who may benefit from earlier preventative therapies to reduce pCAD burden.

IntroductionThe pathophysiology of microvascular disease is poorly understood, partly due to the lack of tools to directly image microvessels in vivo.Research design and methodsIn this study, we deployed a novel optical coherence tomography (OCT) technique during local skin heating to assess microvascular structure and function in diabetics with (DFU group, n=13) and without (DNU group, n=10) foot ulceration, and healthy controls (CON group, n=13). OCT images were obtained from the dorsal foot, at baseline (33°C) and 30 min following skin heating.ResultsAt baseline, microvascular density was higher in DFU compared with CON (21.9%±11.5% vs 14.3%±5.6%, p=0.048). Local heating induced significant increases in diameter, speed, flow rate and density in all groups (all pConclusionsThis proof of principle study indicates that it is feasible to directly visualize and quantify microvascular function in people with diabetes; and distinguish microvascular disease severity between patients.

Purpose Osteocalcin (OC), an osteoblast-specific secreted protein expressed by mature osteoblasts, is used in clinical practice and in research as a marker of bone turnover. The carboxylated (cOC) and undercarboxylated (ucOC) forms may have a different biological function but age-specific reference ranges for these components are not established. Given the different physiological roles, development of reference ranges may help to identify people at risk for bone disease. Methods Blood was collected in the morning after an overnight fast from 236 adult men (18 to 92 years old) free of diabetes, antiresorptive, warfarin or glucocorticoid use. Serum was analyzed for total osteocalcin (tOC) and the ucOC fraction using the hydroxyapatite binding method. cOC, ucOC/tOC and cOC/tOC ratios were calculated. Reference intervals were established by polynomial quantile regression analysis. Results The normal ranges for young men (≤30 years) were: tOC 17.9–56.8 ng/mL, ucOC 7.1–22.0 ng/mL, cOC 8.51–40.3 ng/mL (2.5th to 97.5th quantiles). Aging was associated with a “U” shaped pattern for tOC, cOC and ucOC levels. ucOC/tOC ratio was higher, while cOC/tOC ratio was lower in men of advanced age. Age explained ∼31%, while body mass index explained ∼4%, of the variance in the ratios. Conclusions We have defined normal reference ranges for the OC forms in Australian men and demonstrated that the OC ratios may be better measures, than the absolute values, to identify the age-related changes on OC in men. These ratios may be incorporated into future research and clinical trials, and their associations with prediction of events, such as fracture or diabetes risk, should be determined.

Background Bipolar disorder (BD) has been associated with greater health morbidity burden, but it is unclear if this association is affected by age at the time of diagnosis and how this might impact on the use of general hospital services. Methods Cross-sectional study investigating the prevalence of common medical morbidities among participants with early (EOBD) and late onset diagnosis of BD (LOBD – age at diagnosis ≥ 60 years) derived from a community-representative sample of 37,183 men aged 65–85 years. Cohort study over a follow up period of up to 17.7 years investigating the hazard of general hospital use among older men associated with EOBD and LOBD taking into account age and prevalent medical morbidities. Results 250 older men had a recorded diagnosis of BD, 75 of whom had LOBD. Diabetes, stroke and diseases of the respiratory and digestive systems were more frequent in men with than without BD. There were no differences in the distribution of medical morbidities between men with EOBD and LOBD. The adjusted hazard ratio (HR) of contact with general hospital services was significantly higher among men with EOBD (HR = 1.33; 95%CI = 1.14, 1.54) and LOBD (HR = 1.27, 95%CI = 1.06, 1.51) compared with older men without BD. Older men with EOBD had the highest number of contacts with general hospital services during follow up, although men with EOBD and LOBD did not differ in the number of contacts due to episodes of mania or depression. The medical reasons for contact with general hospital services of men with EOBD and LOBD overlapped but were not identical. Conclusions Older men with BD experience greater health morbidity than men without BD. Older men with BD access hospital services for the management of physical morbidities earlier and more frequently than men without BD. Age at the time of diagnosis of BD has limited impact on the risk of contact with general medical services, although subtle differences in the physical morbidity of men with EOBD and LOBD warrant further investigation.

Background: Diabetes mellitus is associated with increased fracture risk despite preservation of bone density and reduced bone turnover.Aims: We tested the hypothesis that circulating advanced glycation end products (AGEs) and endogenous secretory receptor for AGEs (esRAGE) differentially modulate bone turnover and predict fracture risk in older men.Participants: A total of 3384 community-dwelling men aged 70 to 89 years.Methods: Collagen type I C-terminal cross-linked telopeptide, N-terminal propeptide of type I collagen (P1NP), and total osteocalcin (TOC) were assayed using immunoassay and undercarboxylated osteocalcin (ucOC) following hydroxyapatite binding. Plasma N-carboxymethyllysine (CML) and esRAGE were assayed using immunoassay. Methylglyoxal and glyoxal were assayed using mass spectrometry. Incident hip fractures were ascertained.Results: Median age was 76.3 years (interquartile range, 74.2 to 79.1 years). Plasma CML was measured in 3011 men, methylglyoxal and glyoxal in 766 men, and esRAGE in 748 men. Plasma CML, methylglyoxal, glyoxal, and esRAGE were similar in men without and with diabetes (all P > 0.05). CML was positively associated with fasting glucose (r = 0.06, P < 0.001), and esRAGE was inversely associated (r = -0.08, P = 0.045). esRAGE was positively associated with bone formation (P1NP, r = 0.17, P < 0.001; ucOC, r = 0.11, P = 0.008; TOC, r = 0.16, P < 0.001). Incident hip fractures occurred in 106 men during follow-up. Men with CML in the third quartile of values had reduced incidence of hip fracture compared with men in the lowest quartile (hazard ratio, 0.49; 95% CI, 0.24 to 0.99; P = 0.045).Conclusions: Glycemia associates positively with CML and reciprocally with esRAGE in older men. Circulating esRAGE modulates bone turnover in older men, whereas CML predicts incidence of hip fracture.

A decrease in the concentration of circulating testosterone in many older men is a biomarker and possibly a rectifiable contributing factor to ill health. Low circulating testosterone concentration has been associated with cardiovascular disease, reduced cognition, fracture risk, and anaemia. However, randomised placebo-controlled trials are essential to clarify the benefits and possible risks of testosterone treatment in men without hypothalamic, pituitary, or testicular disease. The Testosterone Trials (T-Trials) were a coordinated set of trials that, following a screening-to-enrolment ratio of 65:1, randomly assigned 790 men aged 65 years or older who had a baseline testosterone concentration of less than 9·54 nmol/L and symptoms consistent with hypogonadism, but no recognisable hypothalamic-pituitary-testicular axis pathology, to daily transdermal testosterone or placebo for 12 months. In the main trial, testosterone treatment resulted in a modest benefit for sexual function, whereas the other primary outcomes of vitality and physical function were not met. Data from concomitant substudies raised a possible concern over changes in coronary plaque volume, showed a neutral effect on memory and other cognitive functions, and revealed improvements in volumetric bone mineral density and anaemia. Although insufficient to alter the existing clinical equipoise, the T-Trials provided substantial new data on organ-specific outcomes for testosterone treatment in older men. Further clinical trials are necessary to determine whether testosterone treatment will translate into patient-valued health outcomes and to clarify effects on the cardiovascular system.