Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension.

Genome-wide association studies of blood pressure (BP) have identified >1,000 loci, but the effector genes and biological pathways at these loci are mostly unknown. Using published association summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation and colocalization to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with ≥2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, and DBH) and previously unreported BP candidate genes (NRIP1 and MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, gene expression and tissue abundance data, and literature review, we provide consolidated evidence for 436 BP candidate genes for future functional validation and discover several potential drug targets.

Fine mapping of candidate effector genes for heart rate.

An elevated resting heart rate (RHR) is associated with increased cardiovascular mortality. Genome-wide association studies (GWAS) have identified > 350 loci. Uniquely, in this study we applied genetic fine-mapping leveraging tissue specific chromatin segmentation and colocalization analyses to identify causal variants and candidate effector genes for RHR. We used RHR GWAS summary statistics from 388,237 individuals of European ancestry from UK Biobank and performed fine mapping using publicly available genomic annotation datasets. High-confidence causal variants (accounting for > 75% posterior probability) were identified, and we collated candidate effector genes using a multi-omics approach that combined evidence from colocalisation with molecular quantitative trait loci (QTLs), and long-range chromatin interaction analyses. Finally, we performed druggability analyses to investigate drug repurposing opportunities. The fine mapping pipeline indicated 442 distinct RHR signals. For 90 signals, a single variant was identified as a high-confidence causal variant, of which 22 were annotated as missense. In trait-relevant tissues, 39 signals colocalised with cis-expression QTLs (eQTLs), 3 with cis-protein QTLs (pQTLs), and 75 had promoter interactions via Hi-C. In total, 262 candidate genes were highlighted (79% had promoter interactions, 15% had a colocalised eQTL, 8% had a missense variant and 1% had a colocalised pQTL), and, for the first time, enrichment in nervous system pathways. Druggability analyses highlighted ACHE, CALCRL, MYT1 and TDP1 as potential targets. Our genetic fine-mapping pipeline prioritised 262 candidate genes for RHR that warrant further investigation in functional studies, and we provide potential therapeutic targets to reduce RHR and cardiovascular mortality.

Associations of educational and marketing messages with beliefs about nicotine and reduced nicotine cigarettes.

INTRODUCTION: Widespread misperceptions about nicotine may have unintended effects on public health. We examined associations between existing messages about nicotine or tobacco and beliefs about nicotine and reduced nicotine cigarettes (RNC). METHODS: 2962 U.S. 18-45-year-olds were randomized in a May 2022 web-based survey to view one of 26 text-based messages about tobacco or nicotine from three sources: ongoing research (n = 8), messages authorized by FDA for VLN cigarettes (n = 6), and FDA's "From Plant to Product to Puff" campaign (n = 12); six messages from FDA's campaign did not reference nicotine and were treated as the reference source. Analyses examined associations between messages, grouped by source and individually, with beliefs about nicotine and RNC addictiveness and harms. RESULTS: Relative to FDA messages that did not reference nicotine, all message sources were associated with greater odds of a correct belief about nicotine (Odds Ratios [ORs] = 1.40-1.87, p's < 0.01); VLN messages were associated with greater correct beliefs about RNC addictiveness (b = 0.23, p < .05). No campaign produced greater correct beliefs about RNC harms. At the individual level, only five messages were associated with a correct belief about nicotine (ORs = 2.12-2.56, p-values < .01), and one with correct beliefs about RNC harms (b = 1.09, p < .05), vs. the reference message. CONCLUSIONS: Few existing messages improved understanding of the risks of nicotine separately from the risks of combustible products. Communication research is needed to promote greater public understanding of nicotine while minimizing unintended effects on nicotine and tobacco use.

Genomic and pleiotropic analyses of resting QT interval identifies novel loci and overlap with atrial electrical disorders.

The resting QT interval, an electrocardiographic (ECG) measure of ventricular myocardial repolarization, is a heritable risk marker of cardiovascular mortality, but the mechanisms remain incompletely understood. Previously reported candidate genes have provided insights into the regulatory mechanisms of the QT interval. However, there are still important knowledge gaps. We aimed to gain new insights by (i) providing new candidate genes, (ii) identifying pleiotropic associations with other cardiovascular traits, and (iii) scanning for sexually dimorphic genetic effects. We conducted a genome-wide association analysis for resting QT interval with ~9.8 million variants in 52 107 individuals of European ancestry without known cardiovascular disease from the UK Biobank. We identified 40 loci, 13 of which were novel, including 2 potential sex-specific loci, explaining ~11% of the trait variance. Candidate genes at novel loci were involved in myocardial structure and arrhythmogenic cardiomyopathy. Investigation of pleiotropic effects of QT interval variants using phenome-wide association analyses in 302 000 unrelated individuals from the UK Biobank and pairwise genome-wide comparisons with other ECG and cardiac imaging traits revealed genetic overlap with atrial electrical pathology. These findings provide novel insights into how abnormal myocardial repolarization and increased cardiovascular mortality may be linked.

Common Genetic Variants Modulate the Electrocardiographic Tpeak-to-Tend Interval.

Sudden cardiac death is responsible for half of all deaths from cardiovascular disease. The analysis of the electrophysiological substrate for arrhythmias is crucial for optimal risk stratification. A prolonged T-peak-to-Tend (Tpe) interval on the electrocardiogram is an independent predictor of increased arrhythmic risk, and Tpe changes with heart rate are even stronger predictors. However, our understanding of the electrophysiological mechanisms supporting these risk factors is limited. We conducted genome-wide association studies (GWASs) for resting Tpe and Tpe response to exercise and recovery in ∼30,000 individuals, followed by replication in independent samples (∼42,000 for resting Tpe and ∼22,000 for Tpe response to exercise and recovery), all from UK Biobank. Fifteen and one single-nucleotide variants for resting Tpe and Tpe response to exercise, respectively, were formally replicated. In a full dataset GWAS, 13 further loci for resting Tpe, 1 for Tpe response to exercise and 1 for Tpe response to exercise were genome-wide significant (p ≤ 5 × 10-8). Sex-specific analyses indicated seven additional loci. In total, we identify 32 loci for resting Tpe, 3 for Tpe response to exercise and 3 for Tpe response to recovery modulating ventricular repolarization, as well as cardiac conduction and contraction. Our findings shed light on the genetic basis of resting Tpe and Tpe response to exercise and recovery, unveiling plausible candidate genes and biological mechanisms underlying ventricular excitability.

Estimating Prevalence of Premium or Traditional Cigar Use and User Characteristics Based on Varying Definitions of Use.

BACKGROUND: Premium cigar use is infrequent compared with the use of other tobacco products, including other cigar types (eg, cigarillos), though current measurement methods for premium cigar use have limitations. Accordingly, prevalence estimates from existing surveillance studies likely underestimate the true prevalence of premium cigar use. AIMS AND METHODS: Using an online convenience sample of adults (ages 18-45 years) surveyed in February 2022, we examined premium or traditional cigar prevalence and characterized users based on four definitions of use: (1) past-year use, (2) past 30-day use, (3) use every day or some days, and (4) use every day, some days, or rarely, using a novel, one-item measure. We examined demographics, cigar use behaviors, and other tobacco product use for each definition and conducted sensitivity analyses using cigar brands. RESULTS: Prevalence estimates ranged from 1.8% using Definition 3 to 11.6% using Definition 1. Regardless of definition, premium or traditional cigar users were largely male, white, and aged 25-45 years. A large proportion of users based on Definition 3 were aged 25-34 years, had a regular premium cigar brand, smoked cigars on more than one day in the past month, used cannabis in the past month, and reported perceiving premium cigars as less harmful compared with cigarettes. DISCUSSION: Prevalence estimates of premium or traditional cigar use varied by more than fivefold based on the definition of use and user characteristics varied by definition. Existing national surveys are likely underestimating the prevalence and patterns of premium cigar use. IMPLICATIONS: Given that the negative health effects of premium cigars vary based on how the cigars are used (eg, frequency or duration), as well as co-use with other tobacco products and substances (eg, alcohol and cannabis), accurate measurement of these products is important for understanding patterns of use and their impact on public health.

Tobacco Treatment Knowledge and Practices Among US Psychiatrists.

This study explores the extent to which psychiatrists are familiar with, and utilize, the USPHS guidelines for treating tobacco use and dependence (i.e., the 5A's), deliver cessation treatment, and the barriers they perceive to doing so. An original, national survey of 141 psychiatrists revealed that most Ask patients if they smoke (81.6%). Fewer Advise them to stop (78.7%) and Assess their willingness to quit (73.6%). A minority Assist with a quit plan (15.9%) and Arrange for follow-up (26.4%). Just 11.9% have used the USPHS guidelines in clinical practice; 37% have never heard of them. Even among those who say they have used the USPHS guidelines, implementation of the 5A's is quite low. Time-related factors were the most common barriers to cessation delivery (51.4%). Patient factors (30%) and financial/resource factors (25%) were less common. There is a strong need for increased implementation of clinical guidelines for evidence-based tobacco treatments among psychiatrists.

Defining electrocardiographic criteria to differentiate non-type 1 Brugada ECG variants from normal incomplete RBBB patterns in the young SCD-SOS cohort.

INTRODUCTION: We assessed the prevalence of non-type 1 Brugada pattern (T1BrP) in children and young adults from the Sudden Cardiac Death-Screening Of risk factorS cohort and the diagnostic yield of nonexpert manual and automatic algorithm electrocardiogram (ECG) measurements. METHODS: Cross-sectional study. We reviewed 14 662 ECGs and identified 2226 with a rSr'-pattern in V1-V2. Among these, 115 were classified by experts in hereditary arrhythmic-syndromes as having or not non-T1BrP, and were compared with measurements of 5 ECG-derived parameters based on a triangle formed by r' -wave (d(A), d(B), d(B)/h, ß-angle) and ST-ascent, assessed both automatically and manually by nonexperts. We estimated intra- and interobserver concordance for each criterion, calculated diagnostic accuracy and defined the most appropriate cut-off values. RESULTS: A rSr'-pattern in V1-V2 was associated with higher PQ interval and QRS duration, male gender, and lower body mass index (BMI). The manual measurements of non-T1BrP criteria were moderately reproducible with high intraobserver and moderate interobserver concordance coefficients (ICC: 0.72-0.98, and 0.63-0.76). Criteria with higher discriminatory capacity were: distance d(B) (0.72; 95% confidence interval [CI]: 0.65-0.80) and ST-ascent (0.87; 95% CI: 0.82-0.92), which was superior to the 4 r'-wave criteria together (area under curve [AUC: 0.74]). We suggest new cut-offs with improved combination of sensitivity and specificity: d(B) ≥ 1.4 mm and ST-ascent ≥ 0.7 mm (sensitivity: 1%-82%; specificity: 71%-84%), that can be automatically measured to allow classification in four morphologies with increasing non-T1BrP probability. CONCLUSION: rSr'-pattern in precordial leads V1-V2 is a frequent finding and the detection of non-T1BrP by using the aforementioned five measurements is reproducible and accurate. In this study, we describe new cut-off values that may help untrained clinicians to identify young individuals who may require further work-up for a potential Brugada Syndrome diagnosis.

Clinical and echocardiographic predictors of decompensation in acute severe aortic regurgitation due to infective endocarditis.

BACKGROUND: Patients with acute severe aortic regurgitation (AR) due to infective endocarditis can progress rapidly from the hemodynamically stable patient to pulmonary edema and cardiogenic shock. We sought to identify patients at risk of decompensation where emergent surgery should be undertaken. METHODS: We identified 90 patients with acute severe AR from the echocardiography laboratory database. Baseline clinical, hemodynamic (heart rate (HR) and blood pressure (BP)), and echocardiographic data including mitral filling, premature mitral valve closure (PMVC), and diastolic mitral regurgitation (DMR) were identified. The primary endpoint was subsequent development of pulmonary edema or severe hemodynamic instability. RESULTS: Patients who met the primary endpoint had a higher HR (98.5 bpm vs 80.5 bpm), lower diastolic BP (54 mm Hg vs 61.5 mm Hg), higher mitral E-wave velocity (113 cm/s vs 83 cm/s), higher E/e' ratio (12.4 vs 8), higher proportion of DMR (27.8% vs 7.4%), and PMVC (25% vs 9.3%) than patients who did not meet the endpoint. The proportion of patients with the primary endpoint increased as HR increased ((≤81 bpm) 3/30 (10%), (81-94 bpm) 11/31 (35.5%), (≥94 bpm) 22/29 (75.9%), P < .0001) and as the diastolic BP reduced ((≤54 mm Hg) 19/31 (61.3%), (54-63 mm Hg) 12/31 (38.7%), (≥63 mm Hg) 5/28 (17.9%), P = .003). Independent predictors were a higher HR (OR 1.08 (95% CI 1.04-1.13) P = .0003) and DMR (OR 4.71 (95% CI 1.23-18.09), P = .02). CONCLUSION: Decompensation in acute severe AR is common. Independent predictors of decompensation are increasing HR(≥94 bpm) and the presence of DMR. Those with these adverse markers should be considered for emergent surgery.

The Use of Multimode Data Collection in Random Digit Dialing Cell Phone Surveys for Young Adults: Feasibility Study.

BACKGROUND: Young adults' early adoption of new cell phone technologies have created challenges to survey recruitment but offer opportunities to combine random digit dialing (RDD) sampling with web mode data collection. The National Young Adult Health Survey was designed to test the feasibility of this methodology. OBJECTIVE: In this study, we compared response rates across the telephone mode and web mode, assessed sample representativeness, examined design effects (DEFFs), and compared cigarette smoking prevalence to a gold standard national survey. METHODS: We conducted a survey experiment where the sampling frame was randomized to single-mode telephone interviews, telephone-to-web sequential mixed mode, and single-mode web survey. A total of 831 respondents aged 18 to 34 years were recruited via RDD at baseline. A soft launch was conducted prior to main launch. We compared the web mode to the telephone modes (ie, single-mode and mixed mode) at wave 1 based on the American Association for Public Opinion Research response rate 3 for screening and extended surveys. Base-weighted demographic distributions were compared to the American Community Survey. The sample was calibrated to the US Census Bureau's American Community Survey to calculate DEFFs and to compare cigarette smoking prevalence to the National Health Interview Survey. Prevalence estimates are estimated with sampling weights and are presented with unweighted sample sizes. Consistency of estimates was judged by 95% CI. RESULTS: The American Association for Public Opinion Research response rate 3 was higher in the telephone mode than in the web mode (24% and 30% vs 6.1% and 12.5%, for soft launch and main launch, respectively), which was reflected in response rate 3 for screening and extended surveys. During the soft launch, the extended survey and eligibility rate were low for respondents pushed to the web mode. To boost productivity and survey completes for the web condition, the main launch used cell phone numbers from the sampling frame where the sample vendor matched the number to auxiliary data, which suggested that the number likely belonged to an adult in the target age range. This increased the eligibility rate, but the screener response rate was lower. Compared to population distribution from the US Census Bureau, the telephone mode overrepresented men (57.1% [unweighted n=412] vs 50.9%) and those enrolled in college (40.3% [unweighted n=269] vs 23.8%); it also underrepresented those with a Bachelor of Arts or Science (34.4% [unweighted n=239] vs 55%). The web mode overrepresented White, non-Latinos (70.7% [unweighted n=90] vs 54.4%) and those with some college education (30.4% [unweighted n=40] vs 7.6%); it also underrepresented Latinos (13.6% [unweighted n=20] vs 20.7%) and those with a high school or General Education Development diploma (15.3% [unweighted n=20] vs 29.3%). The DEFF measure was 1.28 (subpopulation range 0.96-1.93). The National Young Adult Health Survey cigarette smoking prevalence was consistent with the National Health Interview Survey overall (15%, CI 12.4%-18% [unweighted 149/831] vs 13.5%, CI 12.3%-14.7% [unweighted 823/5552]), with notable deviation among 18- to 24-year-olds (15.6%, CI 11.3%-22.2% [unweighted 51/337] vs 8.7%, CI 7.1%-10.6% [unweighted 167/1647]), and those with education levels lower than Bachelor of Arts or Science (24%, CI 19.3%-29.4% [unweighted 123/524] vs 17.1%, CI 15.6%-18.7% [unweighted 690/3493]). CONCLUSIONS: RDD sampling for a web survey is not feasible for young adults due to its low response rate. However, combining this methodology with RDD telephone surveys may have a great potential for including media and collecting autophotographic data in population surveys.

Association of Vegetation Size With Valve Destruction, Embolism and Mortality.

AIM: The mortality of patients with infective endocarditis (IE) is high. The management of patients with large vegetations is controversial. This study sought to investigate the association of vegetation size on outcomes including valve destruction, embolism and mortality. METHODS AND RESULTS: One hundred and forty-two (142) patients with definite IE and transoesophageal echocardiography (TEE) imaging available for analysis were identified and data retrospectively reviewed. Vegetation length, width and area were measured. Severe valve destruction was defined as the composite of one or more of severe valve regurgitation, abscess, pseudoaneurysm, perforation or fistula. Associations with 6-month mortality were identified by Cox regression analysis. Eighty (80) (56.3%) patients had evidence of valve destruction on TEE. Vegetation length ≥10 mm and vegetation area ≥50 mm2 were significantly associated with increased risk of valve destruction, (both odds ratio OR 1.21, p=0.03 and p=0.02 respectively). Thirty-nine (39) (72.2%) patients who had an embolic event, did so prior initiation of antibiotics. Six (6)-month mortality was 18.3%. In the surgically managed group, vegetation size was not associated with mortality. In the medically managed group, vegetation area (mm2) was associated with increased mortality (HR 1.01, p<0.01) along with age (HR 1.06, p=0.03). CONCLUSION: Vegetation length ≥10 mm or area ≥50 mm2 are associated with increased risk of valve destruction. Vegetation size may also predict mortality in medically managed but not surgically managed patients with IE. Further studies to evaluate whether surgery in patients with large vegetation size improves outcomes is warranted.

Perceived relative harm and addictiveness compared with cigarettes and intentions to use modified risk tobacco products utilizing FDA-authorized marketing claims among adults in the United States.

INTRODUCTION: We assessed adults' perceived relative harm and addictiveness of products using FDA-authorized modified risk tobacco products (MRTP) claims and associations with intentions to use MRTPs. METHODS: Data were from the May 2022 Rutgers Omnibus study among US 18-45-year-old adults (n=2964), collected by the Rutgers Institute for Nicotine and Tobacco Studies (INTS). Outcomes were perceived relative harm and addictiveness versus a typical cigarette and intentions to use a product stating a reduced harm claim (General Snus) or a reduced exposure claim (VLN King). We conducted regression analyses of associations between perceived relative harm and addictiveness and intentions to use each product, stratified by smoking status. RESULTS: The minority of participants perceived products with a reduced harm claim as much less harmful vs. cigarettes (21 %, 19 %, 7 %, and 8 % among persons who smoked daily, smoked some days, formerly smoked, and never smoked respectively) and products with a reduced exposure claim as much less addictive vs. cigarettes (24 %, 26 %, 14 %, 20 % respectively). Perceived lower relative harm and addictiveness were significantly associated with higher intentions to use products stating reduced harm or reduced exposure claim across all smoking statuses with one exception (relative addictiveness was not associated with intention to use products stating the reduced harm claim among persons who formerly smoked). CONCLUSIONS: Two current FDA-authorized MRTP claims were not effective in conveying that MRTPs were less harmful or addictive than cigarettes to most participants. Perceiving products as less harmful or addictive were significantly associated with intentions to use MRTPs.

The frequency of gene variant reclassification and its impact on clinical management in the inherited arrhythmia clinic.

BACKGROUND: Genetic testing in the inherited arrhythmia clinic informs risk stratification, clinical management, and family screening. Periodic review of variant classification is recommended as supporting evidence accrues over time. However, there is limited reporting of real-world data on the frequency and impact of variant reclassification. OBJECTIVE: The purpose of this study was to determine the burden of variant reclassification in our inherited arrhythmia clinic and the impact on clinical management. METHODS: Genetic testing reports for patients referred to our clinic from 2004-2020 were reviewed. Reported variants were reinvestigated using ClinVar, VarSome, and a literature review. Classification was updated using the American College of Medical Genetics and Genomics (ACMG) criteria and tested for association with arrhythmic events and modification of medical management. RESULTS: We identified 517 patients (median age 37 years) who underwent gene panel testing. A variant of uncertain significance (VUS) was reported for 94 patients (18.2%) and more commonly identified when using large gene panels (P <.001). A total of 28 of 87 unique VUSs (32.2%) were reclassified to pathogenic/likely pathogenic (n = 11) or benign/likely benign (n = 17). Of 138 originally reported pathogenic variants, 7 (5.1%) lacked support using ACMG criteria. Variant reclassification was not associated with arrhythmic events; however, it did impact genotype-specific counseling and future therapeutic options. CONCLUSION: In our large real-world patient cohort, we identify a clinically important proportion of both pathogenic variants and VUSs with evidence for reclassification. These findings highlight the need for informed pretest counseling, a regular structured review of variants reported in genetic testing, and the potential benefits to patients for supporting genotype-guided therapy.

T-wave morphology abnormalities in the STREAM stage 1 trial.

BACKGROUND: Shorter regimens for drug-resistant tuberculosis (DR-TB) have non-inferior efficacy compared with longer regimens, but QT prolongation is a concern. T-wave morphology abnormalities may be a predictor of QT prolongation. RESEARCH DESIGN AND METHODS: STREAM Stage 1 was a randomized controlled trial in rifampicin-resistant TB, comparing short and long regimens. All participants had regular ECGs. QT/QTcF prolongation (≥500 ms or increase in ≥60 ms from baseline) was more common on the short regimen which contained high-dose moxifloxacin and clofazimine. Blinded ECGs were selected from the baseline, early (weeks 1-4), and late (weeks 12-36) time points. T-wave morphology was categorized as normal or abnormal (notched, asymmetric, flat-wave, flat peak, or broad). Differences between groups were assessed using Chi-Square tests (paired/unpaired, as appropriate). RESULTS: Two-hundred participants with available ECGs at relevant times were analyzed (QT prolongation group n = 82; non-prolongation group n = 118). At baseline, 23% (45/200) of participants displayed abnormal T-waves, increasing to 45% (90/200, p < 0.001) at the late time point. Abnormalities were more common in participants allocated the Short regimen (75/117, 64%) than the Long (14/38, 36.8%, p = 0.003); these occurred prior to QT/QTcF ≥500 ms in 53% of the participants (Long 2/5; Short 14/25). CONCLUSIONS: T-wave abnormalities may help identify patients at risk of QT prolongation on DR-TB treatment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02409290). Current Controlled Trial number, ISRCTN78372190.

Measurement of cigarette relighting: A common but understudied behavior.

OBJECTIVE: Relighting, i.e., extinguishing, saving, and later relighting and smoking unfinished cigarettes, appears prevalent, may be associated with nicotine dependence and negative health outcomes, yet is poorly understood. We estimate the prevalence, frequency, correlates of, and reasons for, cigarette relighting. METHODS: Survey respondents (n=676) were 18-45-year-old US-based Amazon Mechanical Turk (MTurk) participants who smoked cigarettes every/some days. Items assessed frequency of and reasons for relighting. Reported smoking sessions per day were compared to calculations based on reported cigarettes per day (CPD) and relighting frequency. RESULTS: Seventy-two percent of those who smoked reported relighting cigarettes. Reasons included not having time to finish (77%), not feeling like finishing (75%), saving money or avoiding wasting (70%), and making cigarettes last longer (59%). Nearly half (44%) relight to cut down and 34% to reduce harm. Hispanic (OR=1.73, CI:1.03-2.91) and non-Hispanic Black respondents (OR= 2.23, CI:1.20-4.10) had higher odds of relighting than others, as did those who smoke within 30minutes of waking (OR=2.45, CI:1.33-4.52) or wake up at night to smoke (OR=2.40, CI:1.68-3.44) (all ps <0.05). Respondents demonstrated low consistency in reporting the number of times they smoke (first-lit and relit) compared to calculations based on CPD and relighting frequency. CONCLUSIONS: Relighting is associated with race, ethnicity, nicotine dependence, and is often done to save money, cut down smoking, and reduce harm. Among those who relight, "smoking session" frequency seemed to be underestimated. Single item smoking frequency measures may not be ideal for individuals who smoke and relight.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Right coronary artery compromise following radiofrequency catheter ablation for supraventricular tachycardia: cases reports.

Background: Coronary compromise is a serious potential complication following catheter ablation; however, procedural details in the literature are often lacking, preventing the identification of learning opportunities. Case summary: We report two cases of right coronary compromise following catheter ablation for symptomatic supraventricular tachycardia. After radiofrequency energy delivery at the coronary sinus ostium in both cases, inferior lead ST-elevation was observed. Diagnostic coronary angiography identified an occluded posterior left ventricular branch of the coronary artery, and optical coherence tomography demonstrated a high thrombus burden at this location. Electrocardiographic ST-segments settled with implantation of a drug-eluting stent. Discussion: Coronary compromise was likely secondary to energy delivery during catheter ablation. This case series highlights the need for electrophysiologist to understand coronary anatomy relative to anatomical landmarks, to anticipate the risk of vascular injury as physical distance from the site of ablation is likely important. Risk for coronary compromise, while a rare complication, needs to be discussed with patients during the consenting process. We also demonstrate the importance of an efficient multi-disciplinary team process for managing acute procedural complications.

Impact of Mode Switching on Nonresponse and Bias in a Multimode Longitudinal Study of Young Adults.

Young adults are generally hard to survey, presenting researchers with numerous difficulties. They are hard to locate and contact due to high mobility. They are hard to persuade and exhibit high levels of resistance to survey participation. As a result, they pose a greater challenge for longitudinal surveys. This paper explores the role of mode of data collection in young adults' decisions to stay in a longitudinal panel. We draw on data from the National Young Adult Health Survey (NYAHS). NYAHS is a longitudinal study (three annual waves and 2 brief between-wave follow-up surveys) of adults aged 18-34 initially recruited in 2019 through RDD sampling of cell phone numbers nationwide. All sampled cell phone numbers were randomly assigned to one of three experimental conditions; the conditions differed in mode of data collection used in subsequent interviews once screened in. In the first condition, young adults continue all rounds of interviews by telephone ("telephone only" condition). The second group of young adults completed one round of interview by web and the rest by telephone ("telephone mostly" condition). The last third was asked to complete three interviews online and two interviews by telephone ("web mostly" condition). We examined the impact of mode switching on young adults' likelihood of participating in later surveys and on nonresponse bias in key survey outcomes. We found that switching young adults from telephone to web had an immediate negative effect on their likelihood of participating in that web survey, but it did not have a continued negative effect. Switching them from web to telephone increased response rates and reduced nonresponse bias. The findings have important practical implications on how to survey young adults.