Detailed Study of the Formation of Soot Precursors and Soot in Highly Controlled Ethylene(/Toluene) Counterflow Diffusion Flames.

We perform spatially resolved measurements of temperature, gaseous species up to three-ring Polycyclic Aromatic Hydrocarbons (PAHs), and soot in atmospheric pressure counterflow diffusion flames. First, we characterize fully a baseline ethylene flame and then a toluene-seeded flame in which an aliquot of ethylene in the feed stream is replaced with 3500 ppm of prevaporized toluene. The goal is twofold: to investigate the impact of a common reference fuel component of surrogates of transportation fuels and bypass the main bottleneck to soot formation from aliphatic fuels, that is, the formation of the first aromatic ring. The composition of the fuel and oxidizer streams are adjusted to maintain a constant stoichiometric mixture fraction and global strain rate, thereby ensuring invariance of the temperature-time history in the comparison between the two flames and decoupling the chemical effects of the fuel substitution from other factors. Major combustion products and critical radicals are fixed by the baseline flame, and profiles of critical C2-C5 species precursors to aromatic formation are invariant in both flames. On the other hand, doping with toluene boosts the aromatic content and soot volume fraction, increasing the mole fraction of benzenoid structures and soot volume fraction by a factor of 2 or 3, relative to the baseline ethylene flame. This finding is consistent with the expectation that the formation of the first aromatic ring is no longer a bottleneck to soot formation in the doped flame. In addition, toluene bypasses completely benzene formation, opening a radical recombination pathway to soot precursors through the production of C14H14 (via dimerization of benzyl radical) and pyrene (through dimerization of indenyl radical).

A robust two-sample transcriptome-wide Mendelian randomization method integrating GWAS with multi-tissue eQTL summary statistics.

By treating genetic variants as instrumental variables (IVs), two-sample Mendelian randomization (MR) methods detect genetically regulated risk exposures for complex diseases using only summary statistics. When considering gene expression as exposure in transcriptome-wide MR (TWMR) analyses, the eQTLs (expression-quantitative-trait-loci) may have pleiotropic effects or be correlated with variants that have effects on disease not via expression, and the presence of those invalid IVs would lead to biased inference. Moreover, the number of eQTLs as IVs for a gene is generally limited, making the detection of invalid IVs challenging. We propose a method, "MR-MtRobin," for accurate TWMR inference in the presence of invalid IVs. By leveraging multi-tissue eQTL data in a mixed model, the proposed method makes identifiable the IV-specific random effects due to pleiotropy from estimation errors of eQTL summary statistics, and can provide accurate inference on the dependence (fixed effects) between eQTL and GWAS (genome-wide association study) effects in the presence of invalid IVs. Moreover, our method can improve power and precision in inference by selecting cross-tissue eQTLs as IVs that have improved consistency of effects across eQTL and GWAS data. We applied MR-MtRobin to detect genes associated with schizophrenia risk by integrating summary-level data from the Psychiatric Genomics Consortium and the Genotype-Tissue Expression project (V8).

CCmed: cross-condition mediation analysis for identifying replicable trans-associations mediated by cis-gene expression.

MOTIVATION: Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cis-gene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and trans-associations mediated by cis-gene expression also have effects shared across relevant conditions. RESULTS: We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmedmost and CCmedspec for detecting cross-tissue and tissue-specific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated trans-associations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues. AVAILABILITY AND IMPLEMENTATION: CCmed software is available at http://github.com/kjgleason/CCmed. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Insights into Impact of DNA Copy Number Alteration and Methylation on the Proteogenomic Landscape of Human Ovarian Cancer via a Multi-omics Integrative Analysis.

In this work, we propose iProFun, an integrative analysis tool to screen for proteogenomic functional traits perturbed by DNA copy number alterations (CNAs) and DNA methylations. The goal is to characterize functional consequences of DNA copy number and methylation alterations in tumors and to facilitate screening for cancer drivers contributing to tumor initiation and progression. Specifically, we consider three functional molecular quantitative traits: mRNA expression levels, global protein abundances, and phosphoprotein abundances. We aim to identify those genes whose CNAs and/or DNA methylations have cis-associations with either some or all three types of molecular traits. Compared with analyzing each molecular trait separately, the joint modeling of multi-omics data enjoys several benefits: iProFun experienced enhanced power for detecting significant cis-associations shared across different omics data types, and it also achieved better accuracy in inferring cis-associations unique to certain type(s) of molecular trait(s). For example, unique associations of CNAs/methylations to global/phospho protein abundances may imply posttranslational regulations.We applied iProFun to ovarian high-grade serous carcinoma tumor data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium and identified CNAs and methylations of 500 and 121 genes, respectively, affecting the cis-functional molecular quantitative traits of the corresponding genes. We observed substantial power gain via the joint analysis of iProFun. For example, iProFun identified 117 genes whose CNAs were associated with phosphoprotein abundances by leveraging mRNA expression levels and global protein abundances. By comparison, analyses based on phosphoprotein data alone identified none. A network analysis of these 117 genes revealed the known oncogene AKT1 as a key hub node interacting with many of the rest. In addition, iProFun identified one gene, BIN2, whose DNA methylation has cis-associations with its mRNA expression, global protein, and phosphoprotein abundances. These and other genes identified by iProFun could serve as potential drug targets for ovarian cancer.

The contribution of parent-to-offspring transmission of telomeres to the heritability of telomere length in humans.

Leukocyte telomere length (LTL) is a heritable trait with two potential sources of heritability (h2): inherited variation in non-telomeric regions (e.g., SNPs that influence telomere maintenance) and variability in the lengths of telomeres in gametes that produce offspring zygotes (i.e., "direct" inheritance). Prior studies of LTL h2 have not attempted to disentangle these two sources. Here, we use a novel approach for detecting the direct inheritance of telomeres by studying the association between identity-by-descent (IBD) sharing at chromosome ends and phenotypic similarity in LTL. We measured genome-wide SNPs and LTL for a sample of 5069 Bangladeshi adults with substantial relatedness. For each of the 6318 relative pairs identified, we used SNPs near the telomeres to estimate the number of chromosome ends shared IBD, a proxy for the number of telomeres shared IBD (Tshared). We then estimated the association between Tshared and the squared pairwise difference in LTL ((ΔLTL)2) within various classes of relatives (siblings, avuncular, cousins, and distant), adjusting for overall genetic relatedness (ϕ). The association between Tshared and (ΔLTL)2 was inverse among all relative pair types. In a meta-analysis including all relative pairs (ϕ > 0.05), the association between Tshared and (ΔLTL)2 (P = 0.01) was stronger than the association between ϕ and (ΔLTL)2 (P = 0.43). Our results provide strong evidence that telomere length (TL) in parental germ cells impacts TL in offspring cells and contributes to LTL h2 despite telomere "reprogramming" during embryonic development. Applying our method to larger studies will enable robust estimation of LTL h2 attributable to direct transmission of telomeres.

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level.

Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD = 4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P = 8 × 10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P = 1.29 × 10-4), which was associated with SaO2 (P = 0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.

Comparison of Heritability Estimation and Linkage Analysis for Multiple Traits Using Principal Component Analyses.

A disease trait often can be characterized by multiple phenotypic measurements that can provide complementary information on disease etiology, physiology, or clinical manifestations. Given that multiple phenotypes may be correlated and reflect common underlying genetic mechanisms, the use of multivariate analysis of multiple traits may improve statistical power to detect genes and variants underlying complex traits. The literature, however, has been unclear as to the optimal approach for analyzing multiple correlated traits. In this study, heritability and linkage analysis was performed for six obstructive sleep apnea hypopnea syndrome (OSAHS) related phenotypes, as well as principal components of the phenotypes and principal components of the heritability (PCHs) using the data from Cleveland Family Study, which include both African and European American families. Our study demonstrates that principal components generally result in higher heritability and linkage evidence than individual traits. Furthermore, the PCHs can be transferred across populations, strongly suggesting that these PCHs reflect traits with common underlying genetic mechanisms for OSAHS across populations. Thus, PCHs can provide useful traits for using data on multiple phenotypes and for genetic studies of trans-ethnic populations.

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans.

RATIONALE: Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability. OBJECTIVES: To define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts. METHODS: Genome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration. MEASUREMENTS AND MAIN RESULTS: Two novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 × 10-8 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 × 10-8 for respiratory event duration) and seven additional loci were identified with suggestive significance (P < 5 × 10-7). Secondary sex-stratified analyses also identified one significant and several suggestive associations. Multiple loci overlapped genes with biologic plausibility. CONCLUSIONS: These are the first genome-level significant findings reported for obstructive sleep apnea-related physiologic traits in any population. These findings identify novel associations in inflammatory, hypoxia signaling, and sleep pathways.

Association Between Low Temperature During Winter Season and Hospitalizations for Ischemic Heart Diseases in New York State.

Most prior research investigating the health effects of extreme cold has been limited to temperature alone. Only a few studies have assessed population vulnerability and compared various weather indicators. The study described in this article intended to evaluate the effects of cold weather on hospital admissions due to ischemic heart disease, especially acute myocardial infarction (AMI), and to examine the potential interactive effects between weather factors and demographics on AMI. The authors found that extremely low universal apparent temperature in winter was associated with increased risk of AMI, especially during lag4-lag6. Certain demographic groups such as the elderly, males, people with Medicaid insurance, people living in warmer areas, and areas with high PM2.5 concentration showed higher vulnerabilities to cold-AMI effects than other groups.

Current Concepts in the Diagnosis and Treatment of Sleep Disorders in the Elderly.

Sleep disorders are a pervasive problem throughout all patient populations but represent an especially important health problem for the elderly. Alterations in sleep architecture that occur as a part of normal aging will contribute to sleep problems as we grow older. Other contributing factors-including comorbid medical conditions, changes in lifestyle and schedule, altered circadian rhythm, among a host of others-can have detrimental effects on the health of the elderly. Coupled with a number of sleep disorders that either emerge or exacerbate with age, the effects of poor sleep often result in an overall worsening of quality of life. Treatment options can be unique in this population and often more difficult due to the effects of normal aging, as well as polypharmacy and possible medication interactions. The following article will focus on the common sleep disorders that can besiege this population, symptoms to aid in diagnosis, and specific treatment options to help improve quality of life in the elderly.

Microdroplet evaporation with a forced pinned contact line.

Experimental and numerical investigations of water microdroplet evaporation on heated, laser patterned polymer substrates are reported. The study is focused on both (i) controlling a droplet's contact line dynamics during evaporation to identifying how the contact line influences evaporative heat transfer and (ii) validating numerical simulations with experimental data. Droplets are formed on the polymer surface using a bottom-up methodology, where a computer-controlled syringe pump feeds water through a 200 µm diameter fluid channel within the heated polymer substrate. This methodology facilitates precise control of the droplet's growth rate, size, and inlet temperature. In addition to this microchannel supply line, the substrate surfaces are laser patterned with a moatlike trench around the fluid-channel outlet, adding additional control of the droplet's contact line motion, area, and contact angle. In comparison to evaporation on a nonpatterned polymer surface, the laser patterned trench increases contact line pinning time by ∼60% of the droplet's lifetime. Numerical simulations of diffusion controlled evaporation are compared the experimental data with a pinned contact line. These diffusion based simulations consistently over predict the droplet's evaporation rate. In efforts to improve this model, a temperature distribution along the droplet's liquid-vapor interface is imposed to account for the concentration distribution of saturated vapor along the interface, which yields improved predictions within 2-4% of the experimental data throughout the droplet's lifetime on heated substrates.

The Impact of Inherited Genetic Variation on DNA Methylation in Prostate Cancer and Benign Tissues of African American and European American Men.

BACKGROUND: American men of African ancestry (AA) have higher prostate cancer incidence and mortality rates compared with American men of European ancestry (EA). Differences in genetic susceptibility mechanisms may contribute to this disparity. METHODS: To gain insights into the regulatory mechanisms of prostate cancer susceptibility variants, we tested the association between SNPs and DNA methylation (DNAm) at nearby CpG sites across the genome in benign and cancer prostate tissue from 74 AA and 74 EA men. Genome-wide SNP data (from benign tissue) and DNAm were generated using Illumina arrays. RESULTS: Among AA men, we identified 6,298 and 2,641 cis-methylation QTLs (meQTL; FDR of 0.05) in benign and tumor tissue, respectively, with 6,960 and 1,700 detected in EA men. We leveraged genome-wide association study (GWAS) summary statistics to identify previously reported prostate cancer GWAS signals likely to share a common causal variant with a detected meQTL. We identified nine GWAS-meQTL pairs with strong evidence of colocalization (four in EA benign, three in EA tumor, two in AA benign, and three in AA tumor). Among these colocalized GWAS-meQTL pairs, we identified colocalizing expression quantitative trait loci (eQTL) impacting four eGenes with known roles in tumorigenesis. CONCLUSIONS: These findings highlight epigenetic regulatory mechanisms by which prostate cancer-risk SNPs can modify local DNAm and/or gene expression in prostate tissue. IMPACT: Overall, our findings showed general consistency in the meQTL landscape of AA and EA men, but meQTLs often differ by tissue type (normal vs. cancer). Ancestry-based linkage disequilibrium differences and lack of AA representation in GWAS decrease statistical power to detect colocalization for some regions.

Efficacy and Safety of Botulinum Toxin Type A for the Prevention of Postoperative Atrial Fibrillation.

BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with increased morbidity and mortality. Epicardial injection of botulinum toxin may suppress POAF. OBJECTIVES: This study sought to assess the safety and efficacy of AGN-151607 for the prevention of POAF after cardiac surgery. METHODS: This phase 2, randomized, placebo-controlled trial assessed the safety and efficacy of AGN-151607, 125 U and 250 U vs placebo (1:1:1), for the prevention of POAF after cardiac surgery. Randomization was stratified by age (<65, ≥65 years) and type of surgery (nonvalvular/valve surgery). The primary endpoint was the occurrence of continuous AF ≥30 seconds. RESULTS: Among 312 modified intention-to-treat participants (placebo, n = 102; 125 U, n = 104; and 250 U, n = 106), the mean age was 66.9 ± 6.8 years; 17% were female; and 64% had coronary artery bypass graft (CABG) only, 12% had CABG + valve, and 24% had valve surgery. The primary endpoint occurred in 46.1% of the placebo group, 36.5% of the 125-U group (relative risk [RR] vs placebo: 0.80; 95% CI: 0.58-1.10; P = 0.16), and 47.2% of the 250-U group (RR vs placebo: 1.04; 95% CI: 0.79-1.37; P = 0.78). The primary endpoint was reduced in the 125-U group in those ≥65 years of age (RR: 0.64; 95% CI: 0.43-0.94; P = 0.02) with a greater reduction in CABG-only participants ≥65 years of age (RR: 0.49; 95% CI: 0.27-0.87; P = 0.01). Rehospitalization and rates of adverse events were similar across the 3 groups. CONCLUSIONS: There were no significant differences in the rate of POAF with either dose compared with placebo; however, there was a lower rate of POAF in participants ≥65 years undergoing CABG only and receiving 125 U of AGN-151607. These hypothesis-generating findings require investigation in a larger, adequately powered randomized clinical trial. (Botulinum Toxin Type A [AGN-151607] for the Prevention of Post-operative Atrial Fibrillation in Adult Participants Undergoing Open-chest Cardiac Surgery [NOVA]; NCT03779841); A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy and Safety of Botulinum Toxin Type A [AGN 151607] Injections into the Epicardial Fat Pads to Prevent Post-Operative Atrial Fibrillation in Patients Undergoing Open-Chest Cardiac Surgery; 2017-004399-68).

Handling death as an intercurrent event in time to recovery analysis in COVID-19 treatment clinical trials.

In clinical trials with the objective to evaluate the treatment effect on time to recovery, such as investigational trials on therapies for COVID-19 hospitalized patients, the patients may face a mortality risk that competes with the opportunity to recover (e.g., be discharged from the hospital). Therefore, an appropriate analytical strategy to account for death is particularly important due to its potential impact on the estimation of the treatment effect. To address this challenge, we conducted a thorough evaluation and comparison of nine survival analysis methods with different strategies to account for death, including standard survival analysis methods with different censoring strategies and competing risk analysis methods. We report results of a comprehensive simulation study that employed design parameters commonly seen in COVID-19 trials and case studies using reconstructed data from a published COVID-19 clinical trial. Our research results demonstrate that, when there is a moderate to large proportion of patients who died before observing their recovery, competing risk analyses and survival analyses with the strategy to censor death at the maximum follow-up timepoint would be able to better detect a treatment effect on recovery than the standard survival analysis that treat death as a non-informative censoring event. The aim of this research is to raise awareness of the importance of handling death appropriately in the time-to-recovery analysis when planning current and future COVID-19 treatment trials.

Effect of continuous positive airway pressure treatment on ambulatory blood pressures in high-risk sleep apnea patients: a randomized controlled trial.

STUDY OBJECTIVES: The long-term effect of continuous positive airway pressure (CPAP) on 24-hour blood pressure (BP) in patients at high risk with obstructive sleep apnea (OSA) is uncertain. We aimed to determine the effect of CPAP treatment on ambulatory BP in individuals with moderate or severe OSA and cardiovascular disease or multiple cardiovascular disease risk factors without severe sleepiness. METHODS: In this randomized, controlled, parallel group study, 169 participants were randomly assigned to CPAP treatment or the control group. The primary outcome was the change in mean 24-hour systolic BP between groups from baseline to the average of 6- and 12-month measurements using mixed-effect linear regression models. RESULTS: The 24-hour systolic BP did not significantly differ by group, although there was a trend of decrease in the CPAP group (treatment effect -2.7 mm Hg [95% confidence interval -5.9 to 0.6]; P = .105) compared with control. CPAP had the greatest effect on nighttime systolic BP (treatment effect -5.9 mm Hg [95% confidence interval -9.9 to -1.9]; P = .004). Similar improvements in other nocturnal BP indices were observed. CONCLUSIONS: In patients at high risk with moderate-severe OSA without severe sleepiness, CPAP resulted in modest BP improvements over 6 to 12 months of follow-up, with possibly larger effects for nocturnal BP. Use of office blood pressure may underestimate the effect of CPAP on BP profile in patients with OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Sleep Apnea Intervention for Cardiovascular Disease Reduction; Identifier: NCT01261390; URL: https://clinicaltrials.gov/ct2/show/NCT01261390. CITATION: Zhao YY, Wang R, Gleason KJ, et al. Effect of continuous positive airway pressure treatment on ambulatory blood pressures in high-risk sleep apnea patients: a randomized controlled trial. J Clin Sleep Med. 2022;18(8):1899-1907.

Effects of vehicle safety design on road traffic deaths, injuries, and public health burden in the Latin American region: a modelling study.

BACKGROUND: The Sustainable Development Goals (SDGs), which aim to halve global traffic deaths by 2020, will not be met by most low-income and middle-income countries (LMICs). In Latin America and the Caribbean (LAC) region, traffic deaths have remained stable at a high-level despite strong progress in other health domains. We evaluated the effects of road safety interventions in LAC and estimated the benefits that vehicle design improvements would have in this region. METHODS: In our study done in October, 2018, we used a counterfactual analysis to assess the reduction in deaths and disability-adjusted life years (DALYs) lost if eight proven vehicle safety technologies were made more widely available in LAC countries. We estimated: (1) country-level incidence of traffic injuries, (2) the effectiveness of technologies through a systematic literature review, (3) the prevalence of car safety technologies, and (4) the lives saved and DALYs averted if all cars had these technologies. We characterised uncertainty in estimates by reporting the sensitivity of the results to alternative modelling assumptions. FINDINGS: Increasing availability of electronic stability control, which includes antilock-brake systems, would have the largest benefits in the LAC region, estimated at 19·4% (sensitivity analysis range 8·6-31·1) fewer deaths and 17·0% (5·7-29·2) fewer DALYs. Increasing use of seatbelts would reduce deaths by 12·1% (9·1-15·5) and DALYs by 12·6% (9·4-16·3). Optimisation for side-impacts would result in 6·3% (3·1-6·5) fewer deaths, and improvements to vehicle front-end design would result in 6·0% (2·2-10·4) fewer deaths. The overall effect of improved vehicle design in the region would be 28·1% (12·8-39·2) fewer deaths, and 29·1% (13·5-39·8) fewer DALYs. Other safety technologies modelled, including airbag (front and side), side door beam, and side structure and padding, have smaller benefits. INTERPRETATION: Regulating and encouraging the use of proven vehicle safety technologies in LMICs would have large gains and needs to be prioritised in the SDG agenda for 2030. FUNDING: Inter-American Development Bank.

Primo: integration of multiple GWAS and omics QTL summary statistics for elucidation of molecular mechanisms of trait-associated SNPs and detection of pleiotropy in complex traits.

To provide a comprehensive mechanistic interpretation of how known trait-associated SNPs affect complex traits, we propose a method, Primo, for integrative analysis of GWAS summary statistics with multiple sets of omics QTL summary statistics from different cellular conditions or studies. Primo examines association patterns of SNPs to complex and omics traits. In gene regions harboring known susceptibility loci, Primo performs conditional association analysis to account for linkage disequilibrium. Primo allows for unknown study heterogeneity and sample correlations. We show two applications using Primo to examine the molecular mechanisms of known susceptibility loci and to detect and interpret pleiotropic effects.

The role of sham continuous positive airway pressure as a placebo in controlled trials: Best Apnea Interventions for Research Trial.

STUDY OBJECTIVES: The main objective of this study was to evaluate the role of sham continuous positive airway pressure (CPAP) compared to conservative medical therapy (CMT) as a control arm in the Best Apnea Interventions for Research (BestAIR) study by assessing differences in subjectively and objectively measured outcomes, adverse events, adherence, and retention rates. METHODS: BestAIR is a clinical trial aimed to identify important design features for future randomized controlled trials of CPAP. Participants with obstructive sleep apnea were randomized to one of four groups; two control arms (CMT, sham-CPAP) and two active CPAP arms (with and without behavioral interventions). Blood pressure and health-related quality of life outcomes were assessed at baseline, 6 and 12 months. Study outcomes, retention, and adverse event rates were compared between the two control arms. Sham-CPAP adherence and self-efficacy were also compared to active-CPAP adherence (without behavioral intervention). RESULTS: Our sample included 86 individuals in the control arms and 42 participants in the active-CPAP arm. There were no differences in longitudinal profiles in blood pressure, health-related quality of life outcomes, dropout rates, or adverse events in sham-CPAP group compared to CMT-only group (all ps > 0.05); standardized differences were generally small and with inconsistent directionality across measurements. When compared to active-CPAP, sham-CPAP was associated with 93 fewer minutes/night of usage over 12 months (p = 0.007) and lower outcome expectations (p < 0.05). CONCLUSION: We observed no evidence of differences in objectively or subjectively measured outcomes with the use of sham-CPAP compared to CMT group. The lower adherence on sham-CPAP and poorer self-efficacy compared to active-CPAP may suggest differences in perceived benefit. REGISTRATION: NCT01261390 Best Apnea Interventions for Research (BestAIR) www.clinicaltrials.gov.