The Association Between the Long-Term Change in Directly Measured Cardiorespiratory Fitness and Mortality Risk

Introduction: There is a strong inverse association between cardiorespiratory fitness (CRF) and mortality outcomes. This relationship has predominantly been assessed cross-sectionally, however low CRF is a modifiable risk factor, thus assessing this association using a single baseline measure may be sub-optimal. Purpose: To examine the association of the long-term change in CRF, measured using cardiopulmonary exercise testing (CPX) with all-cause and disease-specific mortality. Methods: Participants included 833 apparently healthy men and women (42.9±10.8 years) who underwent two maximal CPXs, the second CPX being ≥ 1 year following the baseline assessment. Participants were followed for 17.7 ± 11.8 years for allcause, cardiovascular disease (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (V1) peak oxygen consumption (VO2peak (ml·kg-1·min-1)) – visit 2 (V2) VO2peak, and mortality outcomes. Results: During follow-up, 172 participants died. Overall, the change in CPX-derived CRF was inversely related to all-cause, CVD, and cancer mortality (p\u3c0.05). Each 1 ml·kg-1·min-1 increase was associated with a 10.8, 14.7, and 15.9% reductions in allcause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality remained significant (p\u3c0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO2peak, and age. Conclusion: Long-term changes in CRF were inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent examination than baseline CRF. These findings support the recent American Heart Association scientific statement advocating CRF as a clinical vital sign that should be assessed routinely in clinical practice, as well as support regular participation in physical activity to maintain adequate CRF levels across the lifespan

Hypomethylation of CYP2E1 and DUSP22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients.

OBJECTIVE:Epigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients. METHODS:Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti-cyclic citrullinated protein). Fluorescence-activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome-wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators. RESULTS:Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type-specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified. CONCLUSION:Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity

Cardiorespiratory Fitness and Mortality in Healthy Men and Women

Background There is a well-established inverse relationship between cardiorespiratory fitness (CRF) and mortality. However, this relationship has almost exclusively been studied using estimated CRF. Objectives This study aimed to assess the association of directly measured CRF, obtained using cardiopulmonary exercise (CPX) testing with all-cause, cardiovascular disease (CVD), and cancer mortality in apparently healthy men and women. Methods Participants included 4,137 self-referred apparently healthy adults (2,326 men, 1,811 women; mean age: 42.8 ± 12.2 years) who underwent CPX testing to determine baseline CRF. Participants were followed for 24.2 ± 11.7 years (1.1 to 49.3 years) for mortality. Cox-proportional hazard models were performed to determine the relationship of CRF (ml·kg-1·min-1) and CRF level (low, moderate, and high) with mortality outcomes. Results During follow-up, 727 participants died (524 men, 203 women). CPX-derived CRF was inversely related to all-cause, CVD, and cancer mortality. Low CRF was associated with higher risk for all-cause (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.20 to 3.50), CVD (HR: 2.27; 95% CI: 1.20 to 3.49), and cancer (HR: 2.07; 95% CI: 1.18 to 3.36) mortality compared with high CRF. Further, each metabolic equivalent increment increase in CRF was associated with a 11.6%, 16.1%, and 14.0% reductions in all-cause, CVD, and cancer mortality, respectively. Conclusions Given the prognostic ability of CPX-derived CRF for all-cause and disease-specific mortality outcomes, its use should be highly considered for apparently healthy populations as it may help to improve the efficacy of the individualized patient risk assessment and guide clinical decisions

The Association between the Change in Directly Measured Cardiorespiratory Fitness across Time and Mortality Risk

Background The relationship between cardiorespiratory fitness (CRF) and mortality risk has typically been assessed using a single measurement, though some evidence suggests the change in CRF over time influences risk. This evidence is predominantly based on studies using estimated CRF (CRFe). The strength of this relationship using change in directly measured CRF over time in apparently healthy men and women is not well understood. Purpose To examine the association of change in CRF over time, measured using cardiopulmonary exercise testing (CPX), with all-cause and disease-specific mortality and to compare baseline and subsequent CRF measurements as predictors of all-cause mortality. Methods Participants included 833 apparently healthy men and women (42.9 ± 10.8 years) who underwent two maximal CPXs, the second CPX being ≥1 year following the baseline assessment (mean 8.6 years, range 1.0 to 40.3 years). Participants were followed for up to 17.7 (SD 11.8) years for all-cause-, cardiovascular disease- (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (CPX1) peak oxygen consumption (VO2peak [mL·kg−1·min−1]) – visit 2 (CPX2) VO2peak, and mortality outcomes. A Wald-Chi square test of equality was used to compare the strength of CPX1 to CPX2 VO2peak in predicting mortality. Results During follow-up, 172 participants died. Overall, the change in CPX-CRF was inversely related to all-cause, CVD, and cancer mortality (p < 0.05). Each 1 mL·kg−1·min−1 increase was associated with a ~11, 15, and 16% (all p < 0.001) reduction in all-cause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality was significant (p < 0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO2peak, and age. Further, the Wald Chi-square test of equality found CPX2 VO2peak to be a significantly stronger predictor of all-cause mortality than CPX1 VO2peak (p < 0.05). Conclusion The change in CRF over time was inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent test than CPX1 CRF. These findings emphasize the importance of adopting lifestyle behaviors that promote CRF, as well as support the need for routine assessment of CRF in clinical practice to better assess risk

Normalizing Cardiorespiratory Fitness To Fat-free Mass Improves Mortality Risk Prediction In Overweight Adults From The Ball St Cohort: 2361 Board #280 May 28 3:00 PM - 4:30 PM

Cardiorespiratory fitness(CRF) is a significant predictor of mortality outcomes in various populations, including overweight and obese adults. However, CRF is commonly expressed normalized to total body weight (VO2peakTBW) which may weaken the relationship in obese adults as fat-free mass (FFM) is directly related to CRF, and increased body fat is associated with lower CRF in adults. Therefore, this study aimed to assess the relationship between CRF normalized for FFM(VO2peakFFM) and all-cause mortality, as well as compare the predictive ability of VO2peakFFM and VO2peakTBW in a cohort of self-referred overweight and obese adults

Cardiorespiratory Fitness Normalized to Fat-Free Mass and Mortality Risk

Cardiorespiratory Fitness Normalized to Fat-Free Mass and Mortality Risk. Med. Sci. Sports Exerc., Vol. 52, No. 7, pp. 1532–1537, 2020. Purpose: Cardiorespiratory fitness (CRF) is known to be directly related to fat-free mass (FFM), therefore, it has been suggested that normalizing CRF to FFM (V˙O2peakFFM) may be the most accurate expression of CRF as related to exercise performance and cardiorespiratory function. However, the influence of ˙O2peakFFM (mL·kg FFM−1·min−1) on predicting mortality has been largely unexplored. This study aimeVd to primarily assess the relationship between V˙O2peakFFM and all-cause and disease-specific mortality risk in apparently healthy adults. Further, this study sought to compare the predictive ability of V˙O2peakFFM to V˙O2peak normalized to total body weight (V˙ O2peakTBW) for mortality out-comes. Methods: Participants included 2905 adults (1555 men, 1350 women) who completed a cardiopulmonary exercise test between 1970 and 2016 to determine CRF. Body composition was assessed using the skinfold method to estimate FFM. Cardiorespiratory fitness was expressed as V˙ O2peakTBW and V˙O2peakFFM. Participants were followed for 19.0 ± 11.7 yr after their cardiopulmonary exercise test for mortality outcomes. Cox-proportional hazard models were performed to determine the relationship of V˙O2peakFFM with mortality outcomes. Parameter estimates were assessed to compare the predictive ability of CRF expressed as V˙O2peakTBW and V˙O2peakFFM. Results: Overall, VO2peakFFM was inversely related to all-cause, cardiovascular disease, and cancer mortality, with a 16.2%, 8.4%, and 8.0% lower risk per 1 mL·kg FFM−1·min−1 improvement, respectively (P \u3c 0.01). Further, assessment of the parameter estimates showed V˙O2peakFFM to be a significantly stronger predictor of all-cause mortality than V˙ O2peakTBW (parameter estimates, −0.49 vs −0.16). Conclusions: Body composition is an important factor when considering the relationship between CRF and mortality risk. Clinicians should consider normalizing CRF to FFM when feasible, because it will strengthen the predictive power of the measure

Polycrystalline diamond micro‐hotplates

Micro‐hotplate structures are increasingly being investigated for use in a host of applications ranging from broadband infra‐red sources within absorption‐based gas sensors to in situ heater stages for ultra‐high‐resolution imaging. With devices usually fabricated from a conductive electrode placed on top of a freestanding radiator element, coefficient of thermal expansion (CTE) mismatches between layers and electro‐migration within the heating element typically lead to failure upon exceeding temperatures of 1600 K. In an attempt to mitigate such issues, a series of hotplates of varying geometry have been fabricated from a single layer of mechanically robust, high thermal conductivity, and low CTE boron‐doped polycrystalline diamond. Upon testing under high vacuum conditions and characterization of the emission spectra, the resulting devices are shown to exhibit a grey‐body like emission response and reach temperatures vastly in excess of conventional geometries of up to 2731 K at applied powers of ⩽100 mW. Characterization of the thermalization time meanwhile demonstrates rapid millisecond response times, while Raman spectroscopy reveals the performance of the devices is dictated by cumulative graphitization at elevated temperatures. As such, both diamond and sp2 carbon are shown to be promising materials for the fabrication of next‐generation micro‐hotplates

Executable network of SARS-CoV-2-host interaction predicts drug combination treatments

The COVID-19 pandemic has pushed healthcare systems globally to a breaking point. The urgent need for effective and affordable COVID-19 treatments calls for repurposing combinations of approved drugs. The challenge is to identify which combinations are likely to be most effective and at what stages of the disease. Here, we present the first disease-stage executable signalling network model of SARS-CoV-2-host interactions used to predict effective repurposed drug combinations for treating early- and late stage severe disease. Using our executable model, we performed in silico screening of 9870 pairs of 140 potential targets and have identified nine new drug combinations. Camostat and Apilimod were predicted to be the most promising combination in effectively supressing viral replication in the early stages of severe disease and were validated experimentally in human Caco-2 cells. Our study further demonstrates the power of executable mechanistic modelling to enable rapid pre-clinical evaluation of combination therapies tailored to disease progression. It also presents a novel resource and expandable model system that can respond to further needs in the pandemic

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis