Influence of preoperative aortic regurgitation on long-term autograft durability and dilatation in children and adolescents undergoing the Ross procedure.

OBJECTIVE: Primary aortic insufficiency (AI) is a risk factor for autograft reintervention in adults undergoing the Ross procedure. We sought to examine the influence of preoperative AI on autograft durability in children and adolescents. METHODS: From 1993 to 2020, 125 consecutive patients between ages 1 and 18 underwent a Ross procedure. The autograft was implanted using a full-root technique in 123 (98.4%) and included in a polyethelene terephthalate graft in 2 (1.6%). Patients with aortic stenosis (aortic stenosis group) (n = 85) were retrospectively compared with those with AI or mixed disease (AI group) (n = 40). Median length of follow-up was 8.2 years (interquartile range, 3.3-15.4 years). The primary end point was the incidence of severe AI or autograft reintervention. Secondary end points included changes in autograft dimensions analyzed using mixed-effect models. RESULTS: The incidence of severe AI or autograft reintervention was 39.0% ± 13.0% in the AI group and 8.8% ± 4.4% in the aortic stenosis group at 15 years (P = .02). Annulus z scores increased in both aortic stenosis and AI groups over time (P < .001). However, the annulus dilated at a faster rate in the AI group (absolute difference, 3.8 ± 2.0 vs 2.5 ± 1.7; P = .03). Sinus of Valsalva z scores increased in both groups as well (P < .001), but at similar rates over time (P = .11). CONCLUSIONS: Children and adolescents with AI undergoing the Ross procedure have higher rates of autograft failure. Patients with preoperative AI have more pronounced dilatation at the annulus. Akin to adults, a surgical aortic annulus stabilization technique that modulates growth is needed in children.

circCsnk1g3- and circAnkib1-regulated interferon responses in sarcoma promote tumorigenesis by shaping the immune microenvironment.

Exonic circular RNAs (circRNAs) produce predominantly non-coding RNA species that have been recently profiled in many tumors. However, their functional contribution to cancer progression is still poorly understood. Here, we identify the circRNAs expressed in soft tissue sarcoma cells and explore how the circRNAs regulate sarcoma growth in vivo. We show that circCsnk1g3 and circAnkib1 promote tumor growth by shaping a pro-tumorigenic microenvironment, possibly due to their capabilities to regulate tumor-promoting elements extrinsic to the tumor cells. Accordingly, circCsnk1g3 and circAnkib1 can control the expression of interferon-related genes and pro-inflammatory factors in the sarcoma cells, thus directing immune cell recruitment into the tumor mass, and hence their activation. Mechanistically, circRNAs may repress pro-inflammatory elements by buffering activation of the pathways mediated by RIG-I, the cytosolic viral RNA sensor. The current findings suggest that the targeting of specific circRNAs could augment the efficacy of tumor and immune response to mainstay therapies.

Exon skipping induced by CRISPR-directed gene editing regulates the response to chemotherapy in non-small cell lung carcinoma cells.

We have been developing CRISPR-directed gene editing as an augmentative therapy for the treatment of non-small cell lung carcinoma (NSCLC) by genetic disruption of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2). NRF2 promotes tumor cell survival in response to therapeutic intervention and thus its disablement should restore or enhance effective drug action. Here, we report how NRF2 disruption leads to collateral damage in the form of CRISPR-mediated exon skipping. Heterogeneous populations of transcripts and truncated proteins produce a variable response to chemotherapy, dependent on which functional domain is missing. We identify and characterize predicted and unpredicted transcript populations and discover that several types of transcripts arise through exon skipping; wherein one or two NRF2 exons are missing. In one specific case, the presence or absence of a single nucleotide determines whether an exon is skipped or not by reorganizing Exonic Splicing Enhancers (ESEs). We isolate and characterize the diversity of clones induced by CRISPR activity in a NSCLC tumor cell population, a critical and often overlooked genetic byproduct of this exciting technology. Finally, gRNAs must be designed with care to avoid altering gene expression patterns that can account for variable responses to solid tumor therapy.

The Landscape of Regulatory Noncoding RNAs in Ewing's Sarcoma.

Ewing's sarcoma (ES) is a pediatric sarcoma caused by a chromosomal translocation. Unlike in most cancers, the genomes of ES patients are very stable. The translocation product of the EWS-FLI1 fusion is most often the predominant genetic driver of oncogenesis, and it is pertinent to explore the role of epigenetic alterations in the onset and progression of ES. Several types of noncoding RNAs, primarily microRNAs and long noncoding RNAs, are key epigenetic regulators that have been shown to play critical roles in various cancers. The functions of these epigenetic regulators are just beginning to be appreciated in ES. Here, we performed a comprehensive literature review to identify these noncoding RNAs. We identified clinically relevant tumor suppressor microRNAs, tumor promoter microRNAs and long noncoding RNAs. We then explored the known interplay between different classes of noncoding RNAs and described the currently unmet need for expanding the noncoding RNA repertoire of ES. We concluded the review with a discussion of epigenetic regulation of ES via regulatory noncoding RNAs. These noncoding RNAs provide new avenues of exploration to develop better therapeutics and identify novel biomarkers.

Entropy estimation within in vitro neural-astrocyte networks as a measure of development instability.

The brain demands a significant fraction of the energy budget in an organism; in humans, it accounts for 2% of the body mass, but utilizes 20% of the total energy metabolized. This is due to the large load required for information processing; spiking demands from neurons are high but are a key component to understanding brain functioning. Astrocytic brain cells contribute to the healthy functioning of brain circuits by mediating neuronal network energy and facilitating the formation and stabilization of synaptic connectivity. During development, spontaneous activity influences synaptic formation, shaping brain circuit construction, and adverse astrocyte mutations can lead to pathological processes impacting cognitive impairment due to inefficiencies in network spiking activity. We have developed a measure that quantifies information stability within in vitro networks consisting of mixed neural-astrocyte cells. Brain cells were harvested from mice with mutations to a gene associated with the strongest known genetic risk factor for Alzheimer's disease, APOE. We calculate energy states of the networks and using these states, we present an entropy-based measure to assess changes in information stability over time. We show that during development, stability profiles of spontaneous network activity are modified by exogenous astrocytes and that network stability, in terms of the rate of change of entropy, is allele dependent.

Hearing Impairment and Cognitive Decline in Older, Community-Dwelling Adults.

BACKGROUND: Hearing impairment is prevalent among older adults and has been identified as a risk factor for cognitive impairment and dementia. We evaluated the association of hearing impairment with long-term cognitive decline among community-dwelling older adults. METHODS: A population-based longitudinal study of adults not using hearing aids who had hearing acuity and cognitive function assessed in 1992-1996, and were followed for a maximum of 24 years with up to five additional cognitive assessments. Hearing acuity was categorized based on pure-tone average (PTA) thresholds: normal (PTA ≤ 25 dB), mild impairment (PTA > 25-40 dB), moderate/severe impairment (PTA > 40 dB). RESULTS: Of 1,164 participants (mean age 73.5 years, 64% women), 580 (49.8%) had mild hearing impairment and 196 (16.8%) had moderate/severe hearing impairment. In fully adjusted models, hearing impairment was associated with steeper decline on the Mini-Mental State Examination (MMSE) (mild impairment ß = -0.04, p = .01; moderate/severe impairment ß = -0.08, p = .002) and Trails B (mild impairment ß = 1.21, p = .003; moderate/severe impairment ß = 2.16, p = .003). Associations did not differ by sex or apolipoprotein E (APOE) ϵ4 status and were not influenced by social engagement. The MMSE-hearing association was modified by education: mild hearing impairment was associated with steeper decline on the MMSE among participants without college education but not among those with college education. Moderate/severe hearing impairment was associated with steeper MMSE decline regardless of education level. CONCLUSIONS: Hearing impairment is associated with accelerated cognitive decline with age, and should be screened for routinely. Higher education may provide sufficient cognitive reserve to counter effects of mild, but not more severe, hearing impairment.

Associations between novel jump test measures, grip strength, and physical performance: the Osteoporotic Fractures in Men (MrOS) Study.

BACKGROUND/AIMS: Weight-bearing jump tests measure lower extremity muscle power, velocity, and force, and may be more strongly related to physical performance than grip strength. However, these relationships are not well described in older adults. METHODS: Participants were 1242 older men (mean age 84 ± 4 years) in the Osteoporotic Fractures in Men (MrOS) Study. Jump peak power (Watts/kg body weight), force (Newton/kg body weight) at peak power, and velocity (m/s) at peak power were measured by jump tests on a force plate. Grip strength (kg/kg body weight) was assessed by hand-held dynamometry. Physical performance included 400 m walk time (s), 6 m usual gait speed (m/s), and 5-repeated chair stands speed (#/s). RESULTS: In adjusted Pearson correlations, power/kg and velocity moderately correlated with all performance measures (range r = 0.41-0.51; all p < 0.001), while correlations for force/kg and grip strength/kg were weaker (range r = 0.20-0.33; all p < 0.001). Grip strength/kg moderately correlated with power/kg (r = 0.44; p < 0.001) but not velocity or force/kg. In adjusted linear regression with standardized ßs, 1 SD lower power/kg was associated with worse: 400 m walk time (ß = 0.47), gait speed (ß = 0.42), and chair stands speed (ß = 0.43) (all p < 0.05). Associations with velocity were similar (400 m walk time: ß = 0.42; gait speed: ß = 0.38; chair stands speed: ß = 0.37; all p < 0.05). Force/kg and grip strength/kg were more weakly associated with performance (range ß = 0.18-0.28; all p < 0.05). CONCLUSIONS/DISCUSSION: Jump power and velocity had stronger associations with physical performance than jump force or grip strength. This suggests lower extremity power and velocity may be more strongly related to physical performance than lower extremity force or upper extremity strength in older men.

Individual periodic limb movements with arousal are temporally associated with nonsustained ventricular tachycardia: a case-crossover analysis.

STUDY OBJECTIVES: Both periodic limb movements during sleep (PLMS) and arousals are associated with sympathetic nervous system activation and may be arrhythmogenic. We hypothesize a temporal relationship exists between individual PLMS, particularly with arousal, and nonsustained ventricular tachycardia (NSVT) events. METHODS: A bidirectional time-stratified case-crossover design was used to assess temporal associations between PLMS and NSVT during sleep in 49 Osteoporotic Fractures in Men Sleep Study participants with NSVT in a community-based cohort (n = 2,911). Sleep time was divided into approximate 30-min segments. For each NSVT (n = 141), we selected a preceding 30-s hazard period and three randomly chosen 30-s control periods from sleep within the same segment and evaluated for PLMS, respiratory events, minimum saturation, and arousals. Odds ratios and 95% confidence intervals-OR (95% CI)-were determined by conditional logistic regression; covariates included EEG arousals, minimum saturation, and respiratory events in the same hazard/control period. RESULTS: Participants with NSVT were 79.5 ± 6.2 years with a PLMS index of 32.1 (IQR: 10.1, 61.4) and apnea-hypopnea index of 17.1 (IQR: 9.4, 26.1). PLMS without arousal were not significantly associated with NSVT (OR = 0.80, 95% CI: 0.41-1.59). PLMS with arousal were associated with NSVT in unadjusted analyses (OR = 2.50, 95% CI: 1.11-5.65) and after adjustment (OR = 2.31, 95% CI: 1.02-5.25). Arousals associated with PLMS were associated with NSVT in unadjusted (OR = 2.84, 95% CI: 1.23-6.56) and adjusted analyses (OR = 2.61, 95% CI: 1.13-6.05). CONCLUSIONS: PLMS with (but not without) arousals are temporally associated with a greater than twofold higher odds of subsequent NSVT episodes. PLMS-related arousals may be physiologically important ventricular arrhythmia triggers. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00070681.

Pregnancy history and cognitive aging among older women: the Rancho Bernardo Study.

OBJECTIVE: The aim of the study was to examine the association of pregnancy history with trajectories of cognitive function in older women. METHODS: Participants were 1,025 women (mean age = 73.1 ±â€Š9.6 y) enrolled in the Rancho Bernardo Study who attended a clinic visit between 1988 and 1992, when pregnancy history (ever pregnant, number of pregnancies, ages at first and last pregnancy) was recorded and cognitive function was assessed with a battery of four tests repeated up to 7 times through 2016. Linear mixed-effects regression models were used to examine the association between pregnancy history and longitudinal change in cognitive function. RESULTS: Overall, 77% of women had at least one pregnancy; number of pregnancies ranged from 1 to 14 (mean = 2.9 ±â€Š1.7). Ages at first and last pregnancy ranged from 16 to 44 years (mean = 24.9 ±â€Š4.7) and 16 to 49 years (mean = 30.7 ±â€Š5.5), respectively. Of 16 associations tested (4 pregnancy exposures by 4 cognitive tests), one was statistically significant without correction for multiple comparisons. Women who reported ever being pregnant recalled 0.12 fewer words on the Buschke Selective Reminding Test for every year increase in age than women who had never been pregnant (P = 0.05). No other significant associations of pregnancy history with cognitive decline were observed. CONCLUSIONS: Our results show no clinically meaningful long-term influence of pregnancy history on age-related change in cognitive function. These reassuring findings suggest childbearing decisions and timing will not affect cognitive function in older age.

Effects of APOE on cognitive aging in community-dwelling older adults.

OBJECTIVE: The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer's disease, with elevated risk for ε4-carriers and reduced risk for ε2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether ε2 and ε4 are associated with rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking). METHOD: A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years. RESULTS: ε2-carriers showed slower executive function decline with age relative to ε3 homozygotes or ε4-carriers, whereas ε4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in ε4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in ε4-carriers, and the effect of ε4 on episodic memory interacted with alcohol consumption, such that only ε4-carriers who did not drink showed more rapid memory decline than ε4 noncarriers. The influence of ε4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise. CONCLUSIONS: These findings indicate that the ε2 and ε4 alleles have differential effects on cognitive aging, and that negative effects of ε4 may be partly mitigated by behavioral choices. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cardiovascular Risk Factors Associated With Venous Thromboembolism.

Importance: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. Design, Setting, and Participants: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. Exposures: A panel of several established cardiovascular risk factors. Main Outcomes and Measures: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). Results: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. Conclusions and Relevance: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Lifetime physical activity and late-life cognitive function: the Rancho Bernardo study.

BACKGROUND: physical activity in older age has been associated with better cognitive function, but the role of earlier life physical activity is less well understood. OBJECTIVE: determine associations between physical activity throughout the lifespan and cognitive function in older age. DESIGN: cross-sectional study. SETTING: the Rancho Bernardo Study of Healthy Aging in southern California. SUBJECTS: A total of 1,826 community-dwelling men and women (60-99 years) who attended a research visit in 1988-92. METHODS: participants underwent cognitive testing at older age, and reported physical activity as a teenager, at age 30 years, 50 years and currently. For each time-point, participants were classified as regularly active (3+ times/week) or inactive. RESULTS: regular physical activity was associated with better cognitive function, with physical activity at older ages showing the strongest associations. Physical activity in older age was associated with better global cognitive function, executive function and episodic memory, regardless of intensity. Intense physical activity in teenage years was associated with better late-life global cognitive function in women. Teenage physical activity interacted with older age physical activity on executive function; those active at both periods performed better than those active at only one period. Similar patterns of associations were observed after excluding individuals with poor health. CONCLUSIONS: regular physical activity in older age, regardless of intensity, is associated with better cognitive function. Physical activity in teenage years may enhance cognitive reserve to protect against age-related decline in executive function. Further research is needed to assess the effect of physical activity across the lifespan on healthy brain ageing.

Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.

The Relationships Between Physical Performance, Activity Levels, and Falls in Older Men.

BACKGROUND: Physical performance and activity have both been linked to fall risk, but the way they are jointly associated with falls is unclear. We investigated how these two factors are related to incident falls in older men. METHODS: In 2,741 men (78.8 ± 5 years), we evaluated the associations between activity and physical performance and how they jointly contributed to incident falls. Activity was assessed by accelerometry. Physical performance was measured by gait speed, dynamic balance (narrow walk), chair stand time, grip strength, and leg power. Falls were ascertained by tri-annual questionnaires. RESULTS: Men were grouped into four categories based on activity and performance levels. The greatest number of falls (36%-43%) and the highest fall rate (4.7-5.4/y among those who fell) (depending on the performance test) occurred in men with low activity/low performance, but most falls (57%-64%) and relatively high fall rates (3.0-4.35/y) occurred in the other groups (low activity/high performance, high activity/high performance and high activity/low performance; 70% of men were in these groups). There were interactions between activity, performance (gait speed, narrow walk), and incident falls (p = .001-.02); predicted falls per year were highest in men with low activity/low performance, but there was also a peak of predicted falls in those with high activity. CONCLUSIONS: In community-dwelling older men, many falls occur in those with the lowest activity/worst physical performance but fall risk is also substantial with better activity and performance. Activity/physical performance assessments may improve identification of older men at risk of falls, and allow individualized approaches to prevention.

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.

AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

Genetic Ancestry Markers and Difference in A1c Between African American and White in the Diabetes Prevention Program.

Purpose: HbA1c levels are higher in blacks than non-Hispanic whites (NHWs). We investigated whether genetics could explain this difference in Diabetes Prevention Program (DPP) participants. Methods: We tested (i) genetic variants causing hemoglobinopathies, (ii) a genetic risk score (GRS) based on 60 variants associated with HbA1c from genome-wide association meta-analysis, and (iii) principal component (PC) factors that capture continental ancestry derived from genetic markers distributed across the genome. Results: Of 2658 eligible DPP participants, 537 (20%) self-identified as black and 1476 (56%) as NHW. Despite comparable fasting and 2-hour glucose levels, blacks had higher HbA1c (mean ± SD = 6.2 ± 0.6%) compared with NHWs (5.8 ± 0.4%; P < 0.001). In blacks, the genetic variant causing sickle cell trait was associated with higher HbA1c [ß (SE) = +0.44 (0.08)%; P = 2.1 × 10-4]. The GRS was associated with HbA1c in both blacks and NHWs. Self-identified blacks were distributed along the first PC axis, as expected in mixed ancestry populations. The first PC explained 60% of the 0.4% difference in HbA1c between blacks and NHWs, whereas the sickle cell variant explained 16% and GRS explained 14%. Conclusions: A large proportion of HbA1c difference between blacks and NHWs was associated with the first PC factor, suggesting that unidentified genetic markers influence HbA1c in blacks in addition to nongenetic factors.

Central Obesity and Visceral Adipose Tissue Are Not Associated With Incident Atherosclerotic Cardiovascular Disease Events in Older Men.

Background Visceral adipose tissue ( VAT ) and other measures of central obesity predict incident atherosclerotic cardiovascular disease ( ASCVD ) events in middle-aged individuals, but these associations are less certain in older individuals age 70 years and older. Our objective was to estimate the associations of VAT and the android-gynoid fat mass ratio, another measure of central obesity, with incident ASCVD events among a large cohort of older men. Methods and Results Two thousand eight hundred ninety-nine men (mean [ SD ] age 76.3 [5.5] years) enrolled in the Outcomes of Sleep Disorders in Older Men study had rigorous adjudication of incident ASCVD events (myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke). We used proportional hazards models to estimate the hazard ratios for incident ASCVD per SD increase of VAT or android-gynoid fat mass ratio (measured at baseline with dual-energy absorptiometry), adjusted for age, race, education, systolic blood pressure, smoking status, oxidized low-density lipoprotein level, treatment for hypertension, statin use, aspirin use, presence of diabetes mellitus, and study enrollment site. Over a mean ( SD ) follow-up period of 7.9 (3.4) years, 424 men (14.6%) had an incident ASCVD event. Neither VAT nor android-gynoid fat mass ratio were associated with incident ASCVD events, either unadjusted or after multivariable-adjustment (hazard ratios [95% confidence interval ] per SD increase 1.02 [0.92-1.13] and 1.05 [0.95-1.17], respectively). Conclusions Central adipose tissue, as measured by VAT or android-gynoid fat mass ratio, was not associated with incident ASCVD events in this study of older men.

Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials.

BACKGROUND: The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors. METHODS: The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov, number NCT00799617. FINDINGS: The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2-15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5-6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5-21·9; p=0·0004) and PF10 (4·9, 2·2-7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0-14·1; p=0·0237) and PF10 (3·6, 1·3-5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35-3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61-5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall). INTERPRETATION: Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations. FUNDING: US National Institute on Aging and AbbVie.