Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case-control study.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Secondary prevention of stroke. A telehealth-delivered physical activity and diet pilot randomized trial (ENAbLE-pilot).

BACKGROUND: Improving physical activity levels and diet quality are important for secondary stroke prevention. AIM: To test the feasibility and safety of 6-month, co-designed telehealth-delivered interventions to increase physical activity and improve diet quality. METHODS: A 2 × 2 factorial trial (physical activity (PA); diet (DIET); PA + DIET; control) randomized, open-label, blinded endpoint trial. Primary outcomes were feasibility and safety. Secondary outcomes included stroke risk factors (blood pressure, self-report PA (International Physical Activity Questionnaire (IPAQ)) and diet quality (Australian Recommended Food Score (ARFS)), and quality of life. Between-group differences were analyzed using linear-mixed models. RESULTS: Over 23 months, 99 people were screened for participation and 40 (40%) randomized (3 months to 10 years post-stroke, mean age 59 (16) years). Six participants withdrew, and an additional five were lost to follow-up. Fifteen serious adverse events were reported, but none were deemed definitely or probably related to the intervention. Median attendance was 32 (of 36) PA sessions and 9 (of 10) DIET sessions. The proportion of missing primary outcome data (blood pressure) was 3% at 3 months, 11% at 6 months, and 14% at 12 months. Between-group 95% confidence intervals showed promising, clinically relevant differences in support of the interventions across the range of PA, diet quality, and blood pressure outcomes. CONCLUSION: Our telehealth PA and diet interventions were safe and feasible and may have led to significant behavior change. TRIAL REGISTRATION: ACTRN12620000189921.

Exposure to low-level ambient air pollution and the relationship with lung and bladder cancer in older men, in Perth, Western Australia.

BACKGROUND: Air pollution is a cause of lung cancer and is associated with bladder cancer. However, the relationship between air pollution and these cancers in regions of low pollution is unclear. We investigated associations between fine particulate matter (PM2.5), nitrogen dioxide, and black carbon (BC), and both these cancers in a low-pollution city. METHODS: A cohort of 11,679 men ≥65 years old in Perth (Western Australia) were followed from 1996-1999 until 2018. Pollutant concentrations, as a time-varying variable, were estimated at participants' residential addresses using land use regression models. Incident lung and bladder cancer were identified through the Western Australian Cancer Registry. Risks were estimated using Cox proportional-hazard models (age as the timescale), adjusting for smoking, socioeconomic status, and co-pollutants. RESULTS: Lung cancer was associated with PM2.5 and BC in the adjusted single-pollutant models. A weak positive association was observed between ambient air pollution and squamous cell lung carcinoma but not lung adenocarcinoma. Positive associations were observed with bladder cancer, although these were not statistically significant. Associations were attenuated in two-pollutant models. CONCLUSION: Low-level ambient air pollution is associated with lung, and possibly bladder, cancer among older men, suggesting there is no known safe level for air pollution as a carcinogen.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

Direct oral anticoagulants or vitamin K antagonists in emergencies: comparison of management in an observational study.

Background: Restoring hemostasis in patients on oral anticoagulants presenting with major hemorrhage (MH) or before surgical intervention has changed, with the replacement of vitamin K antagonist (VKA) with direct oral anticoagulants (DOACs). Objectives: To observe the difference in urgent hemostatic management between patients on VKA and those on DOACs. Methods: A multicenter observational study evaluated the variation in laboratory testing, hemostatic management, mortality, and hospital length of stay (LOS) in patients on VKA or DOACs presenting with MH or urgent hemostatic restoration. Results: Of the 1194 patients analyzed, 783 had MH (61% VKA) and 411 required urgent hemostatic restoration before surgery (56% VKA). Compared to the international normalized ratio (97.6%), plasma DOAC levels were measured less frequently (<45%), and the time taken from admission for the coagulation sample to reach the laboratory varied widely (median, 52.3 minutes; IQR, 24.8-206.7). No significant plasma DOAC level (<50 ng/mL) was found in up to 19% of patients. There was a poor relationship between plasma DOAC level and the usage of a hemostatic agent. When compared with patients receiving VKA (96.5%) or dabigatran (93.7%), fewer patients prescribed a factor Xa inhibitor (75.5%) received a prohemostatic reversal agent. The overall 30-day mortality for MH (mean: 17.8%) and length of stay (LOS) (median: 8.7 days) was similar between VKA and DOAC patients. Conclusion: In DOAC patients, when compared to those receiving VKA, plasma DOAC levels were measured less frequently than the international normalized ratio and had a poor relationship with administering a hemostatic reversal agent. In addition, following MH, mortality and LOS were similar between VKA and DOAC patients.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Rebleeding following aneurysmal subarachnoid hemorrhage before 'endovascular first' treatment: a retrospective case-control study of published scoring systems.

BACKGROUND: Pre-treatment re-bleeding following aneurysmal subarachnoid hemorrhage (aSAH) affects up to 7.2% of patients even with ultra-early treatment within 24 hours. We retrospectively compared the utility of three published re-bleed prediction models and individual predictors between cases who re-bled matched to controls using size and parent vessel location from a cohort of patients treated in an ultra-early, 'endovascular first' manner. METHODS: On retrospective analysis of our 9-year cohort of 707 patients suffering 710 episodes of aSAH, there were 53 episodes of pre-treatment re-bleeding (7.5%). Forty-seven cases who had a single culprit aneurysm were matched to 141 controls. Demographic, clinical and radiological data were extracted and predictive scores calculated. Univariate, multivariate, area under the receiver operator characteristic curve (AUROCC) and Kaplan-Meier (KM) survival curve analyses were performed. RESULTS: The majority of patients (84%) were treated using endovascular techniques at a median 14.5 hours post-diagnosis. On AUROCC analysis the score of Liu et al. had minimal utility (C-statistic 0.553, 95% confidence interval (CI) 0.463 to 0.643) while the risk score of Oppong et al. (C-statistic 0.645 95% CI 0.558 to 0.732) and the ARISE-extended score of van Lieshout et al. (C-statistic 0.53 95% CI 0.562 to 0.744) had moderate utility. On multivariate modeling, the World Federation of Neurosurgical Societies (WFNS) grade was the most parsimonious predictor of re-bleeding (C-statistic 0.740, 95% CI 0.664 to 0.816). CONCLUSIONS: For aSAH patients treated in an ultra-early timeframe matched on size and parent vessel location, WFNS grade was superior to three published models for re-bleed prediction. Future re-bleed prediction models should incorporate the WFNS grade.

Healthy lifestyles are associated with better vitamin D status in community-dwelling older men: The Health In Men Study (HIMS).

OBJECTIVE: Older people are more prone to vitamin D deficiency than younger populations. Individual lifestyle factors have been associated with vitamin D status. We examined the influence of a combination of lifestyle factors on vitamin D status in older men. PARTICIPANTS AND MEASUREMENTS: In a population-based cohort study of older men (age ≥65 years), a lifestyle score was calculated from eight prudent health-related behaviours (smoking, exercise, alcohol, fish and meat consumption, adding salt, milk choices and obesity) collected via questionnaire at baseline. Blood samples were collected 5 years afterwards to measure plasma 25-hydroxyvitamin D (25OHD) levels. Associations between lifestyles and the likelihood of having plasma 25OHD levels of ≥75 versus <75 nmol/L and ≥50 versus <50 nmol/L were tested using logistic regression models. RESULTS: Of the 2717 men analysed, mean plasma 25OHD was 69.0 ± 23.5 nmol/L, with 20.7% having plasma 25OHD <50 nmol/L. Men engaging in ≥4 healthy lifestyle behaviours had 20% higher odds of plasma 25OHD ≥75 nmol/L (adjusted OR = 1.20, 95% CI: 1.01-1.45) compared to those with <4 healthy behaviours. No association was found for 25OHD ≥50 nmol/L. Higher physical activity was the only individual component significantly associated with vitamin D sufficiency (highest vs. lowest quintiles of physical activity, adjusted OR = 2.01, 95% CI: 1.47-2.74 for 25OHD ≥50 nmol/L, adjusted OR = 2.35, 95% CI: 1.81-3.06 for 25OHD ≥75 nmol/L). CONCLUSION: Multiple healthy lifestyle behaviours are associated with better vitamin D status in older men. Further work is needed to determine the effects of promoting healthy lifestyle behaviours, including physical activity, on vitamin D sufficiency.

Balance and Strength Measures are Associated With Mortality in Older Men.

OBJECTIVES: As people age, rates of morbidity and mortality are heterogenous. Balance and strength performance may contribute to this, offering modifiable risk factors for mortality. We aimed to compare relationships of balance and strength performance with all-cause and cause-specific mortality. DESIGN: The Health in Men Study, a cohort study, using wave 4 as baseline for analyses (2011-2013). SETTING AND PARTICIPANTS: 1335 older men (>65 years old), initially recruited April 1996-January 1999 in Western Australia, were included. METHODS: Physical tests included a strength (knee extension test) and balance measure (modified Balance Outcome Measure for Elder Rehabilitation (mBOOMER) Score), derived from baseline physical assessments. Outcome measures included all-cause, cardiovascular, and cancer mortality, ascertained via the WADLS death registry. Data were analyzed using Cox proportional hazards regression models (age as analysis time, adjusted for sociodemographic data, health behaviors, and conditions). RESULTS: Four hundred seventy-three participants died before the end of follow-up (December 17, 2017). Better performance on both the mBOOMER score and knee extension test was associated with lower likelihood of all-cause [hazard ratio (HR) 0.83, 95% CI 0.80-0.87, and HR 0.96, 95% CI 0.95-0.98, respectively] and cardiovascular mortality (HR 0.82, 95% CI 0.77-0.87, and HR 0.96, 95% CI 0.94-0.98, respectively). Better mBOOMER score performance was associated with lower likelihood of cancer mortality (HR 0.90, 95% CI 0.83-0.98) only when including participants with prior cancer. CONCLUSIONS AND IMPLICATIONS: In summary, this study demonstrates an association of poorer performance in both strength and balance with future all-cause and cardiovascular mortality. Notably, these results clarify the relationship of balance with cause-specific mortality, with balance equaling strength as a modifiable risk factor for mortality.

Is incident cancer in later life associated with lower incidence of dementia?

Cancer has been associated with lower risk of dementia, although methodological issues raise concerns about the validity of this association. We recruited 31,080 men aged 65-85 years who were free of cancer and dementia, and followed them for up to 22 years. We used health record linkage to identify incident cases of cancer and dementia, and split time span to investigate this association. 18,693 (60.1%) and 6897 (22.2%) participants developed cancer and dementia during follow-up. The hazard ratio (HR) of dementia associated with cancer was 1.13 (95% CI = 1.07, 1.20) and dropped to 0.85 (95% CI = 0.80, 0.91) when 449 participants who developed dementia within 2 years were excluded. The diagnosis of cancer seems to facilitate the early detection of dementia cases. Older participants who survive cancer for 2 or more years have lower risk of receiving the diagnosis of dementia over time. The factors that mediate this association remain unclear.

Long-term exposure to low air pollutant concentrations and hospitalisation for respiratory diseases in older men: A prospective cohort study in Perth, Australia.

Background: Acute exposure to ambient air pollution even at low concentrations has been associated with increased hospitalisation for respiratory diseases but the effects of long-term exposure are less certain. In this study, we investigated the associations between long-term exposures to PM2.5, PM2.5 absorbance and NO2 and hospitalisation for asthma, chronic obstructive pulmonary disease and pneumonia in a cohort of older men living in Perth, Western Australia, a city where the levels of air pollutants are well below the world standards. Materials and methods: The study population of 11,156 men with no prior hospitalisation for respiratory disease was drawn from the Health in Men Study (HIMS) cohort of men aged >65 years living in Perth, Western Australia between 1996-1999. PM2.5, PM2.5 absorbance (PM2.5a) and NO2 were measured across the Perth metropolitan area over three seasons in 2012. Land use regression (LUR) models were used to estimate annual concentrations of PM2.5, PM2.5 absorbance and NO2 at the residential address of each participant from inception (1996) to 2015. Hospitalisation for respiratory disease between inception and 2015 was ascertained using the Western Australian Data Linkage System. The association between exposure to air pollution with hospitalisation for respiratory disease was examined using Cox regression analysis. Results: No statistically significant associations were observed in the fully adjusted models. However, positive associations were observed with first hospitalisation for pneumonia (HR 1.08, 95% CI: 1.01-1.16) when adjusted for age, year of enrolment, smoking status, education, BMI and physical activity. Conclusions: In this longitudinal study of older men we found no evidence of associations between increased long-term exposure to low-level air pollution with increased risk of hospitalisation for respiratory diseases in Perth, Australia. More studies on respiratory morbidity associated with exposure to low levels of air pollution are needed for more comprehensive understanding of the overall risk.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Ambient air pollution and risk of incident dementia in older men living in a region with relatively low concentrations of pollutants: The Health in Men Study.

BACKGROUND: In areas with moderate to severe air pollution, pollutant concentrations are associated with dementia risk. It is unclear whether the same relationship is present in regions with lower ambient air pollution. OBJECTIVE: To determine whether exposure to air pollution is associated with risk of incident dementia in general, and Alzheimer's disease and vascular dementia in particular, in older men living in a relatively low ambient air pollution region. METHODS: The cohort comprised 11,243 men residing in Perth, Australia. Participants were aged ≥65 years and free of a dementia diagnosis at time of recruitment in 1996-1999. Incident dementia was identified from recruitment to 2018 via ICD diagnosis codes and subsequent study waves. Concentrations for three air pollutants, nitrogen dioxide (NO2), fine particulate matter less than 2.5 µm in diameter (PM2.5), and black carbon (BC) were estimated at participants' home addresses using land-use regression models. We used Cox proportional hazards regression models adjusting for smoking status, physical activity, BMI, education, and socio-economic status. RESULTS: Of 3053 (27.2%) incident cases of dementia, 1670 (54.7%) and 355 (11.6%) had documented Alzheimer's disease and vascular dementia. The average concentration of NO2 was 13.5 (SD 4.4) µg/m3, of PM2.5 was 4.54 (SD 1.6) µg/m3 and of BC was 0.97 (SD 0.29) ×10-5 m-1. None of the air pollutants were associated with incident dementia or Alzheimer's disease. In the unadjusted model, increased exposure to PM2.5 was associated with an increased risk of vascular dementia (for a 5 µg/m3 increase: HR 1.62, 95% CI 1.13, 2.31). However, this association was attenuated following adjustment for confounders (HR 1.39, 95% CI 0.93, 2.08). NO2 and BC were not associated with vascular dementia incidence. DISCUSSION: Exposure to air pollution is not associated with increased risk of incident dementia in older men living in a region with relatively low ambient air pollution.

Bone Turnover Markers Including Undercarboxylated Osteocalcin Are Associated With Mortality Risk in Older Men.

Osteocalcin in its undercarboxylated form (ucOC) may influence diabetes risk; however, its relationship with all-cause and cause-specific mortality is unclear. Whether other bone turnover markers (BTMs) are associated with mortality risk differently from ucOC also remains uncertain. Our aim was to determine associations of serum ucOC with all-cause and cause-specific mortality and compare these with the corresponding associations of serum total osteocalcin (TOC), procollagen type I N-propeptide (PINP), and collagen type 1 C-terminal cross-linked telopeptide (CTX) in older men. We conducted a prospective cohort study of 3871 community-dwelling men, aged 77.0 ± 3.6 years at baseline, followed for a median of 12.3 years. Exposure variables were ucOC, TOC, PINP, and CTX concentrations assayed in serum. Outcomes were incidence of all deaths and deaths due to cardiovascular disease (CVD) or cancer, ascertained using death registry data. Cox regression analyses adjusted for cardiovascular risk factors and prevalent CVD and for prevalent cancer in analyses of cancer-related mortality. Higher concentrations of ucOC, PINP, and CTX were associated with all-cause mortality (hazard ratio [HR] per 1 standard deviation increase: ucOC 1.12, 95% confidence interval [CI] 1.06-1.18, p < 0.001; PINP HR = 1.06, 95% CI 1.01-1.11, p = 0.009; CTX HR = 1.13, 95% CI 1.08-1.19, p < 0.001), but TOC was not associated. Similar results were found after excluding men with an incident fracture during follow-up. Higher ucOC and CTX were associated with CVD mortality (ucOC HR per 1 SD increase 1.13, 95% CI 1.05-1.22, p = 0.001; CTX HR = 1.12, 95% CI 1.04-1.20, p = 0.003), but this result was not significant in competing risks analysis. Higher CTX was also associated with cancer mortality (HR = 1.12, 95% CI 1.01-1.23, p = 0.024). In conclusion, in older men, higher bone turnover, assessed by BTMs including ucOC, is a biomarker for all-cause mortality risk. Undercarboxylated osteocalcin was a more informative biomarker for this outcome than TOC. Higher CTX was associated with all-cause and cancer-related mortality. Further evaluation of causality and potential underlying mechanisms is warranted. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Disrupted sleep and risk of depression in later life: A prospective cohort study with extended follow up and a systematic review and meta-analysis.

BACKGROUND: Sleep difficulties increase the risk of current and future depression, but it is unclear if this relationship is causal. METHODS: Prospective cohort study of a community sample of men aged 70-89 years followed for up to 17 years. Initial assessments occurred between 2001 and 2004. Participants were followed until death or 31 December 2018. Patient Health Questionnaire (PHQ-9) ≥ 10 at subsequent waves of assessments (every 2-3 years) or the recorded diagnosis of a depressive disorder in the Western Australian Data Linkage System marked the onset of depression during follow up. We excluded from follow up men with prevalent depression. The systematic review of longitudinal studies examining the association between disrupted sleep and depression in later life followed PRISMA guidelines. RESULTS: 3441 of 5547 older men reported sleep difficulties at study entry. Current or past depression affected 437 of 5547 participants. Of the 4561 older men free of depression, 2693 reported sleep difficulties. The hazard ratio (HR) of incident depression among participants with sleep problems was 1.67 (95%CI = 1.39-2.00). Statistical adjustments for age, place of birth, education, smoking and physical frailty did not change the effect-size of this association. The systematic review identified another 14 studies, and the meta-analysis yielded an overall risk ratio of depression of 1.82 (95%CI = 1.69-1.97), although the overall quality of available evidence was sub-optimal. CONCLUSIONS: Disrupted sleep increases the risk of depression in later life and this seems unlikely to be due to reverse causality. Older adults with sleep difficulties are legitimate targets of interventions to prevent depression.

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study.

Importance: Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain. Objective: To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults. Design, Setting, and Participants: This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients. Main Outcomes and Measures: Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO). Results: The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22). Conclusions and Relevance: In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population.

Mechanical thrombectomy is efficacious in patients with pre-stroke moderate disability.

INTRODUCTION: Patients with ischaemic stroke due to large vessel occlusion (LVO) can be treated successfully with mechanical thrombectomy (MT) and/or intravenous thrombolysis. In the landmark trials, MT was only performed for those with no functional disability prior to stroke (mRS 0-2). There are limited data available regarding clinical outcomes for patients with pre-stroke moderate disability (mRS ≥ 3). The aims of this study were to analyse the clinical outcomes and financial implications in regard to accommodation costs of performing MT in patients with pre-stroke mRS = 3. METHODS: An observational cohort study was performed of 802 patients with anterior circulation LVO ischaemic stroke who underwent MT between October 2016 and January 2020 at three tertiary hospitals. Patient demographics, premorbid mRS, stroke and interventional data, 90-day mRS and accommodation situation were recorded. RESULTS: Eighty-two patients with anterior circulation LVO ischaemic stroke were pre-stroke mRS 3. 38% had a good clinical outcome, as defined by mRS 3 at 90 days. Mortality rate was 38%. The majority of patients presented from home (83%) and greater than one third of those returned home during the 90 days post treatment. 81% of patients had no increase in accommodation cost at 90 days. CONCLUSION: Patients with pre-stroke moderate disability may benefit from MT if they are appropriately selected. This may result in fewer patients requiring nursing home placement and less financial burden on the public health system, indicating significant savings are possible.