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Genetic cardiomyopathies are associated with increased risk for cardiac arrhythmias and sudden cardiac death. The management of ventricular arrhythmias (VAs) in patients with these conditions can be nuanced due to particular disease-based considerations, yet data specifically addressing management in these patients are limited. Here we describe the current evidence-based approach to the management of ventricular rhythm disorders in patients with genetic forms of cardiomyopathy, namely, hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, left ventricular noncompaction, and Brugada syndrome, including recommendations from consensus guideline statements when available.

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Background: Telemedicine and commercial wearable devices capable of detecting atrial fibrillation (AF) have revolutionized arrhythmia care during coronavirus disease 2019. However, not much is known about virtual patient-provider interactions or device sharing behaviors. Objective: The purpose of this study was to characterize how participants with or at risk of AF are engaging with their providers in the context of telemedicine and using commercially wearable devices to manage their health. Methods: We developed a survey to describe participant behaviors around telemedicine encounters and commercial wearable device use. The survey was distributed to participants diagnosed with AF or those at risk of AF (as determined by being at least 65 years old and having a CHA2DS2-VASc stroke risk score of >2) in the University of Massachusetts Memorial Health Care system. Results: The survey was distributed to 23,530 patients, and there were 1222 (5.19%) participant responses. Among the participants, 327 (26.8%) had AF and 895 (73.2%) were at risk of AF. Neither device ownership nor device type use differed by AF status. After adjusting for covariates that may influence surveyed participant communication patterns, we found that participants with AF were more likely to share their wearable device-derived data with providers (adjusted odds ratio 1.87; 95% confidence interval 1.02–3.41). Rates of sharing physical activity or sleep data were low for both groups and did not differ by AF status. Conclusion: Compared with participants at risk of developing AF, those with AF were more likely to share heart rate and rhythm data from their commercial wearable devices with providers. However, both groups had similar rates of sharing physical activity and sleep data, telemedicine engagement, and technology use and ownership.

There is increasing interest in the environmental noise emissions from grain dryers and the potential impact of practical noise pollution mitigations such as barriers adjacent to dryers. Grain dryers are an essential part of grain production in many parts of the world, including Ontario, Canada. Most dryers are large, stationary units that include a burner to provide process heat and a fan or blower to move heated air through the grain being dried. This study measured sound levels at a range of distances from multiple grain drying facilities in Ontario, Canada, over two drying seasons. It was found that the sound level at a given distance varied substantially, depending on the dryer type and presence of blocking features such as grain bins or buildings. Noise emissions did not necessarily correlate to the size or drying capacity of the facility, with some smaller top dry dryers having higher noise emissions than other much larger tower dryers. Targeted investigations of the impact of practical remediations in the form of physical sound barriers showed sound level reductions were possible that were similar in magnitude to those achieved by highway sound walls along roadways, with most sound reduction being at higher frequencies.

Abstract Background All-cause mortality following atrial fibrillation (AF) has decreased over time. Data regarding temporal trends in causes of death among individuals with AF are scarce. The aim of our study was to analyze temporal trends in cause-specific mortality and predictors for cardiovascular (CVD) and non-CVD deaths among participants with incident AF in the Framingham Heart Study. Methods We categorized all newly diagnosed AF cases according to age at AF diagnosis (

Abstract This international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

This corrects the article DOI: 10.1038/ncomms15805.

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74g

BackgroundAtrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.MethodsTo determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

Background Models predicting atrial fibrillation (AF) risk, such as Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE‐AF), have not performed as well in electronic health records. Natural language processing (NLP) may improve models by using narrative electronic health record text. Methods and Results From a primary care network, we included patients aged ≥65 years with visits between 2003 and 2013 in development (n=32 960) and internal validation cohorts (n=13 992). An external validation cohort from a separate network from 2015 to 2020 included 39 051 patients. Model features were defined using electronic health record codified data and narrative data with NLP. We developed 2 models to predict 5‐year AF incidence using (1) codified+NLP data and (2) codified data only and evaluated model performance. The analysis included 2839 incident AF cases in the development cohort and 1057 and 2226 cases in internal and external validation cohorts, respectively. The C‐statistic was greater (P

Electron bifurcation is a fundamental energy conservation mechanism in nature in which two electrons from an intermediate-potential electron donor are split so that one is sent along a high-potential pathway to a high-potential acceptor and the other is sent along a low-potential pathway to a low-potential acceptor. This process allows endergonic reactions to be driven by exergonic ones and is an alternative, less recognized, mechanism of energy coupling to the well-known chemiosmotic principle. The electron-bifurcating [FeFe] hydrogenase from Thermotoga maritima (HydABC) requires both NADH and ferredoxin to reduce protons generating hydrogen. The mechanism of electron bifurcation in HydABC remains enigmatic in spite of intense research efforts over the last few years. Structural information may provide the basis for a better understanding of spectroscopic and functional information. Here, we present a 2.3 Å electron cryo-microscopy structure of HydABC. The structure shows a heterododecamer composed of two independent ‘halves’ each made of two strongly interacting HydABC heterotrimers connected via a [4Fe–4S] cluster. A central electron transfer pathway connects the active sites for NADH oxidation and for proton reduction. We identified two conformations of a flexible iron–sulfur cluster domain: a ‘closed bridge’ and an ‘open bridge’ conformation, where a Zn2+ site may act as a ‘hinge’ allowing domain movement. Based on these structural revelations, we propose a possible mechanism of electron bifurcation in HydABC where the flavin mononucleotide serves a dual role as both the electron bifurcation center and as the NAD+ reduction/NADH oxidation site.

Abstract Despite its consequences for ecological processes and population dynamics, intra‐specific variability is frequently overlooked in animal movement studies. Consequently, the necessary resolution to reveal drivers of individual movement decisions is often lost as animal movement data are aggregated to infer average or population patterns. Thus, an empirical understanding of why a given movement pattern occurs remains patchy for many taxa, especially in marine systems. Nonetheless, movement is often rationalized as being driven by basic life history requirements, such as acquiring energy (feeding), reproduction, predator‐avoidance, and remaining in suitable environmental conditions. However, these life history requirements are central to every individual within a species and thus do not sufficiently account for the high intra‐specific variability in movement behavior and hence fail to fully explain the occurrence of multiple movement strategies within a species. Animal movement appears highly context dependent as, for example, within the same location, the behavior of both resident and migratory individuals is driven by life history requirements, such as feeding or reproduction, however different movement strategies are utilized to fulfill them. A systematic taxa‐wide approach that, instead of averaging population patterns, incorporates and utilizes intra‐specific variability to enable predictions as to which movement patterns can be expected under a certain context, is needed. Here, we use intra‐specific variability in elasmobranchs as a case study to introduce a stepwise approach for studying animal movement drivers that is based on a context‐dependence framework. We examine relevant literature to illustrate how this context‐focused approach can aid in reliably identifying drivers of a specific movement pattern. Ultimately, incorporating behavioral variability in the study of movement drivers can assist in making predictions about behavioral responses to environmental change, overcoming tagging biases, and establishing more efficient conservation measures.

Background: Cardiac magnetic resonance (CMR) is the gold standard for left ventricular hypertrophy (LVH) diagnosis. CMR-derived LV mass can be estimated using proprietary algorithms (eg, InlineVF), but their accuracy and availability may be limited. Objective: To develop an open-source deep learning model to estimate CMR-derived LV mass. Methods: Within participants of the UK Biobank prospective cohort undergoing CMR, we trained 2 convolutional neural networks to estimate LV mass. The first (ML4Hreg) performed regression informed by manually labeled LV mass (available in 5065 individuals), while the second (ML4Hseg) performed LV segmentation informed by InlineVF (version D13A) contours. We compared ML4Hreg, ML4Hseg, and InlineVF against manually labeled LV mass within an independent holdout set using Pearson correlation and mean absolute error (MAE). We assessed associations between CMR-derived LVH and prevalent cardiovascular disease using logistic regression adjusted for age and sex. Results: We generated CMR-derived LV mass estimates within 38,574 individuals. Among 891 individuals in the holdout set, ML4Hseg reproduced manually labeled LV mass more accurately (r = 0.864, 95% confidence interval [CI] 0.847–0.880; MAE 10.41 g, 95% CI 9.82–10.99) than ML4Hreg (r = 0.843, 95% CI 0.823–0.861; MAE 10.51, 95% CI 9.86–11.15, P = .01) and InlineVF (r = 0.795, 95% CI 0.770–0.818; MAE 14.30, 95% CI 13.46–11.01, P < .01). LVH defined using ML4Hseg demonstrated the strongest associations with hypertension (odds ratio 2.76, 95% CI 2.51–3.04), atrial fibrillation (1.75, 95% CI 1.37–2.20), and heart failure (4.67, 95% CI 3.28–6.49). Conclusions: ML4Hseg is an open-source deep learning model providing automated quantification of CMR-derived LV mass. Deep learning models characterizing cardiac structure may facilitate broad cardiovascular discovery.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

We conducted a multi‐site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.‐1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = −0.29, P

Abstract Because single genetic variants may have pleiotropic effects, one trait can be a confounder in a genome-wide association study (GWAS) that aims to identify loci associated with another trait. A typical approach to address this issue is to perform an additional analysis adjusting for the confounder. However, obtaining conditional results can be time-consuming. We propose an approximate conditional phenotype analysis based on GWAS summary statistics, the covariance between outcome and confounder, and the variant minor allele frequency (MAF). GWAS summary statistics and MAF are taken from GWAS meta-analysis results while the traits covariance may be estimated by two strategies: (i) estimates from a subset of the phenotypic data; or (ii) estimates from published studies. We compare our two strategies with estimates using individual level data from the full GWAS sample (gold standard). A simulation study for both binary and continuous traits demonstrates that our approximate approach is accurate. We apply our method to the Framingham Heart Study (FHS) GWAS and to large-scale cardiometabolic GWAS results. We observed a high consistency of genetic effect size estimates between our method and individual level data analysis. Our approach leads to an efficient way to perform approximate conditional analysis using large-scale GWAS summary statistics.

Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, Pobesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, Pextremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, Pobesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, Pextremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 × 10-8). Eight additional gene-gene interactions were also marginally significant (P

Precise control over the energy of atomic metal sites is key to unlocking novel reaction pathways. Here, the authors achieve selective oxygen activation by the isolated copper site on ceria, due to its reduced 3d orbital energy via cerium induced electron withdrawing effect.

Background: Many digital health technologies capable of atrial fibrillation (AF) detection are directly available to patients. However, adaptation into clinical practice by heart rhythm healthcare practitioners (HCPs) is unclear. Objective: To examine HCP perspectives on use of commercial technologies for AF detection and management. Methods: We created an electronic survey for HCPs assessing practice demographics and perspectives on digital devices for AF detection and management. The survey was distributed electronically to all members of 3 heart rhythm professional societies. Results: We received 1601 responses out of 73,563 e-mails sent, with 43.6% from cardiac electrophysiologists, 12.8% from fellows, and 11.6% from advanced practice practitioners. Most respondents (62.3%) reported having recommended patient use of a digital device for AF detection. Those who did not had concerns about their accuracy (29.6%), clinical utility of results (22.8%), and integration into electronic health records (19.8%). Results from a 30-second single-lead electrocardiogram were sufficient for 42.7% of HCPs to recommend oral anticoagulation for patients at high risk for stroke. Respondents wanted more data comparing the accuracy of digital devices to conventional devices for AF monitoring (64.9%). A quarter (27.3%) of HCPs had no reservations recommending digital devices for AF detection, and most (53.4%) wanted guidelines from their professional societies providing guidance on their optimal use. Conclusion: Many HCPs have already integrated digital devices into their clinical practice. However, HCPs reported facing challenges when using digital technologies for AF detection, and professional society recommendations on their use are needed.

Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM.

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

Oxidative degradation impedes practical applications of highly active but fragile catalysts. Here the authors show that combining a protection matrix for O2 reduction and hydrogen peroxide decomposition stabilizes highly O2-sensitive hydrogenase in the harsh oxidative conditions of operating fuel cells.

Ice-nucleating particles (INPs) in the troposphere can form ice in clouds via heterogeneous ice nucleation. Yet, atmospheric number concentrations of INPs (NINP) are not well characterized, and, although there is some understanding of their sources, it is still unclear to what extend different sources contribute or if all sources are known. In this work, we examined properties of INPs at Cabo Verde (a.k.a. Cape Verde) from different environmental compartments: the oceanic sea surface microlayer (SML), underlying water (ULW), cloud water and the atmosphere close to both sea level and cloud level. Both enrichment and depletion of NINP in SML compared to ULW were observed. The enrichment factor (EF) varied from roughly 0.4 to 11, and there was no clear trend in EF with ice-nucleation temperature. NINP values in PM10 sampled at Cape Verde Atmospheric Observatory (CVAO) at any particular ice-nucleation temperature spanned around 1 order of magnitude below −15 ∘C, and about 2 orders of magnitude at warmer temperatures (>-12 ∘C). Among the 17 PM10 samples at CVAO, three PM10 filters showed elevated NINP at warm temperatures, e.g., above 0.01 L−1 at −10 ∘C. After heating samples at 95 ∘C for 1 h, the elevated NINP at the warm temperatures disappeared, indicating that these highly ice active INPs were most likely biological particles. INP number concentrations in PM1 were generally lower than those in PM10 at CVAO. About 83±22 %, 67±18 % and 77±14 % (median±standard deviation) of INPs had a diameter >1 µm at ice-nucleation temperatures of −12, −15 and −18 ∘C, respectively. PM1 at CVAO did not show such elevated NINP at warm temperatures. Consequently, the difference in NINP between PM1 and PM10 at CVAO suggests that biological ice-active particles were present in the supermicron size range. NINP in PM10 at CVAO was found to be similar to that on Monte Verde (MV, at 744 m a.s.l.) during noncloud events. During cloud events, most INPs on MV were activated to cloud droplets. When highly ice active particles were present in PM10 filters at CVAO, they were not observed in PM10 filters on MV but in cloud water samples instead. This is direct evidence that these INPs, which are likely biological, are activated to cloud droplets during cloud events. For the observed air masses, atmospheric NINP values in air fit well to the concentrations observed in cloud water. When comparing concentrations of both sea salt and INPs in both seawater and PM10 filters, it can be concluded that sea spray aerosol (SSA) only contributed a minor fraction to the atmospheric NINP. This latter conclusion still holds when accounting for an enrichment of organic carbon in supermicron particles during sea spray generation as reported in literature.

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

BackgroundBoth elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF.Method and resultsSeven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: 75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata.ConclusionsFor resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

In this study, a lumped parameter model, developed and extensively validated by the authors, is used to simulate the impact of three different dehumidification technologies (mechanical refrigeration dehumidifier, liquid desiccant dehumidifier, and a heat recovery ventilation unit), at a commercial greenhouse growing potted roses in southwestern Ontario, Canada. Typical meteorological year (TMY) data from nearby Vineland, Ontario was used to provide the external weather data used in the model. Each greenhouse bay containing a dehumidification unit was simulated for spring, fall, and winter conditions. The potential reductions in energy use (kWh), greenhouse gas emissions (kg CO2e), and operating cost were estimated for each test case. The potential energy savings from switching from high-pressure sodium (HPS) to light-emitting diode (LED) lights were also examined. The simulation results showed that switching to LED lamps could reduce the electrical energy usage by up to 60% but would increase the space heating requirements. The expected energy-savings from using dehumidification equipment and switching from HPS to LED lighting in Canadian greenhouses is underrepresented in the literature. With the industry growing in the region, this study provides insight into the expected impact that these systems will have on the energy use in commercial greenhouses.

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.

Background Atrial fibrillation (AF) commonly occurs in the setting of acute conditions. We aimed to identify the acute conditions associated with secondary AF (AF precipitants) including pneumonia/sepsis, pneumothorax, respiratory failure, myocarditis, pericarditis, alcohol intoxication, thyrotoxicosis, cardiothoracic surgery, other surgery in patients with newly diagnosed AF and determine their association with subsequent oral anticoagulant use. Methods and Results We assembled a cohort of patients in the UMass Memorial Healthcare system with a new diagnosis of AF with and without AF precipitants. We used combinations of International Classification of Diseases, Tenth Revision (ICD‐10) codes, Current Procedural Terminology codes, laboratory values, imaging reports, and physician notes including discharge summary texts to identify AF precipitants. We then manually reviewed the individual charts to validate presence of AF precipitants. The study sample consisted of 185 patients with and 172 patients without AF precipitants. Pneumonia/sepsis, myocardial infarction, respiratory failure, and cardiothoracic surgery were the most common precipitants identified. In multivariable analyses adjusting for age, sex, patient comorbidities, left atrial enlargement, left ventricular ejection fraction, and antiplatelet use, patients with AF precipitants were less likely to receive subsequent anticoagulation therapy at 30 days after the initial AF diagnosis (odds ratio, 0.31; 95% CI, 0.19–0.52). The association was persistent after excluding men with CHA2DS2‐VASc score

Background Performance of existing atrial fibrillation (AF) risk prediction models in poststroke populations is unclear. We evaluated predictive utility of an AF risk model in patients with acute stroke and assessed performance of a fully refitted model. Methods and Results Within an academic hospital, we included patients aged 46 to 94 years discharged for acute ischemic stroke between 2003 and 2018. We estimated 5‐year predicted probabilities of AF using the Cohorts for Heart and Aging Research in Genomic Epidemiology for Atrial Fibrillation (CHARGE‐AF) model, by recalibrating CHARGE‐AF to the baseline risk of the sample, and by fully refitting a Cox proportional hazards model to the stroke sample (Re‐CHARGE‐AF) model. We compared discrimination and calibration between models and used 200 bootstrap samples for optimism‐adjusted measures. Among 551 patients with acute stroke, there were 70 incident AF events over 5 years (cumulative incidence, 15.2%; 95% CI, 10.6%–19.5%). Median predicted 5‐year risk from CHARGE‐AF was 4.8% (quartile 1–quartile 3, 2.0–12.6) and from Re‐CHARGE‐AF was 16.1% (quartile 1–quartile 3, 8.0–26.2). For CHARGE‐AF, discrimination was moderate (C statistic, 0.64; 95% CI, 0.57–0.70) and calibration was poor, underestimating AF risk (Greenwood‐Nam D’Agostino chi‐square, P

Background Atrial fibrillation (AF) screening is endorsed by certain guidelines for individuals aged ≥65 years. Yet many AF screening strategies exist, including the use of wrist‐worn wearable devices, and their comparative effectiveness is not well‐understood. Methods and Results We developed a decision‐analytic model simulating 50 million individuals with an age, sex, and comorbidity profile matching the United States population aged ≥65 years (ie, with a guideline‐based AF screening indication). We modeled no screening, in addition to 45 distinct AF screening strategies (comprising different modalities and screening intervals), each initiated at a clinical encounter. The primary effectiveness measure was quality‐adjusted life‐years, with incident stroke and major bleeding as secondary measures. We defined continuous or nearly continuous modalities as those capable of monitoring beyond a single time‐point (eg, patch monitor), and discrete modalities as those capable of only instantaneous AF detection (eg, 12‐lead ECG). In total, 10 AF screening strategies were effective compared with no screening (300–1500 quality‐adjusted life‐years gained/100 000 individuals screened). Nine (90%) effective strategies involved use of a continuous or nearly continuous modality such as patch monitor or wrist‐worn wearable device, whereas 1 (10%) relied on discrete modalities alone. Effective strategies reduced stroke incidence (number needed to screen to prevent a stroke: 3087–4445) but increased major bleeding (number needed to screen to cause a major bleed: 1815–4049) and intracranial hemorrhage (number needed to screen to cause intracranial hemorrhage: 7693–16 950). The test specificity was a highly influential model parameter on screening effectiveness. Conclusions When modeled from a clinician‐directed perspective, the comparative effectiveness of population‐based AF screening varies substantially upon the specific strategy used. Future screening interventions and guidelines should consider the relative effectiveness of specific AF screening strategies.

Combining therapeutic with diagnostic agents (theranostics) can revolutionize the course of malignant diseases. Chemotherapy, hyperthermia, or radiation are used together with diagnostic methods such as magnetic resonance imaging (MRI). In contrast to conventional contrast agents (CAs), which only enable non-specific visualization of tissues and organs, the theranostic probe offers targeted diagnostic imaging and therapy simultaneously. Methods: Novel salinomycin (Sal)-based theranostic probes comprising two different paramagnetic metal ions, gadolinium(III) (Gd(III)) or manganese(II) (Mn(II)), as signal emitting motifs for MRI were synthesized and characterized by elemental analysis, infrared spectral analysis (IR), electroparamagnetic resonance (EPR), thermogravimetry (TG) differential scanning calorimetry (DSC) and electrospray ionization mass spectrometry (ESI-MS). To overcome the water insolubility of the two Sal-complexes, they were loaded into empty bacterial ghosts (BGs) cells as transport devices. The potential of the free and BGs-loaded metal complexes as theranostics was evaluated by in vitro relaxivity measurements in a high-field MR scanner and in cell culture studies. Results: Both the free Sal-complexes (Gd(III) salinomycinate (Sal-Gd(III) and Mn(II) salinomycinate (Sal-Mn(II)) and loaded into BGs demonstrated enhanced cytotoxic efficacy against three human tumor cell lines (A549, SW480, CH1/PA-1) relative to the free salinomycinic acid (Sal-H) and its sodium complex (Sal-Na) applied as controls with IC50 in a submicromolar concentration range. Moreover, Sal-H, Sal-Gd(III), and Sal-Mn(II) were able to induce perturbations in the cell cycle of treated colorectal and breast human cancer cell lines (SW480 and MCF-7, respectively). The relaxivity (r1) values of both complexes as well as of the loaded BGs, were higher or comparable to the relaxivity values of the clinically applied contrast agents gadopentetate dimeglumine and gadoteridol. Conclusion: This research is the first assessment that demonstrates the potential of Gd(III) and Mn(II) complexes of Sal as theranostic agents for MRI. Due to the remarkable selectivity and mode of action of Sal as part of the compounds, they could revolutionize cancer therapy and allow for early diagnosis and monitoring of therapeutic follow-up.