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.

Two-dimensional turbulence above topography: Vortices and potential vorticity homogenization.

The evolution of unforced and weakly damped two-dimensional turbulence over random rough topography presents two extreme states. If the initial kinetic energy [Formula: see text] is sufficiently high, then the topography is a weak perturbation, and evolution is determined by the spontaneous formation and mutual interaction of coherent axisymmetric vortices. High-energy vortices roam throughout the domain and mix the background potential vorticity (PV) to homogeneity, i.e., in the region between vortices, which is most of the domain, the relative vorticity largely cancels the topographic PV. If [Formula: see text] is low, then vortices still form but they soon become locked to topographic features: Anticyclones sit above topographic depressions and cyclones above elevated regions. In the low-energy case, with topographically locked vortices, the background PV retains some spatial variation. We develop a unified framework of topographic turbulence spanning these two extreme states of low and high energy. A main organizing concept is that PV homogenization demands a particular kinetic energy level [Formula: see text]. [Formula: see text] is the separator between high-energy evolution and low-energy evolution.

Polar vortex crystals: Emergence and structure.

Vortex crystals are quasiregular arrays of like-signed vortices in solid-body rotation embedded within a uniform background of weaker vorticity. Vortex crystals are observed at the poles of Jupiter and in laboratory experiments with magnetized electron plasmas in axisymmetric geometries. We show that vortex crystals form from the free evolution of randomly excited two-dimensional turbulence on an idealized polar cap. Once formed, the crystals are long lived and survive until the end of the simulations (300 crystal-rotation periods). We identify a fundamental length scale, Lγ=(U/γ)1/3, characterizing the size of the crystal in terms of the mean-square velocity U of the fluid and the polar parameter γ=fp/a2p, with fp the Coriolis parameter at the pole and ap the polar radius of the planet.

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.

Advocacy Connection Team-Now educational program for headache fellows and patients/caregivers: Assessment of educational objectives.

OBJECTIVE: To assess for improvement in comfort in participating in advocacy for migraine and headache disorders and knowledge needed for successful advocacy. BACKGROUND: The Advocacy Connection Team (ACT)-Now program is an educational program offered through Miles for Migraine, a non-profit advocacy organization. It is designed to teach headache fellows and patients advocacy skills. METHODS: In a cross-sectional pre-test-post-test design, the 2021 ACT-Now cohort of 98 participants were administered a set of 11 pre-course survey questions identifying their role (healthcare provider/headache fellow or patient/caregiver), baseline knowledge of migraine-related disability and stigma, and baseline engagement and comfort with advocating. The post-course survey questions were the same as the pre-course questions, with the addition of one question assessing knowledge of migraine-related disability, additional questions addressing comfort levels advocating with insurance and policymakers, as well as creating an advocacy plan. RESULTS: For the pre-course survey, 69 participants responded and for the post-course survey, 40 participants responded. Compared to the pre-course survey, participants were able to correctly identify epidemiological data about migraine following the ACT-Now course (pre-course 46% correct, post-course 58% correct, p = 0.263). There was also an increase in the comfort level of participants in advocacy activities, including the creation of an advocacy action plan (pre-course 23% were "very comfortable" advocating, post-course 63%, p < 0.05). CONCLUSION: These results demonstrate that ACT-Now is effective at improving advocacy skills in a mixed cohort of patients and headache fellows, giving them the skills to create advocacy plans and engage with other patients and physicians, payers, and policymakers to create a more understanding, equitable and compassionate world for persons with migraine and other headache diseases.

Local intraspecific aggregation in phytoplankton model communities: spatial scales of occurrence and implications for coexistence.

The coexistence of multiple phytoplankton species despite their reliance on similar resources is often explained with mean-field models assuming mixed populations. In reality, observations of phytoplankton indicate spatial aggregation at all scales, including at the scale of a few individuals. Local spatial aggregation can hinder competitive exclusion since individuals then interact mostly with other individuals of their own species, rather than competitors from different species. To evaluate how microscale spatial aggregation might explain phytoplankton diversity maintenance, an individual-based, multispecies representation of cells in a hydrodynamic environment is required. We formulate a three-dimensional and multispecies individual-based model of phytoplankton population dynamics at the Kolmogorov scale. The model is studied through both simulations and the derivation of spatial moment equations, in connection with point process theory. The spatial moment equations show a good match between theory and simulations. We parameterized the model based on phytoplankters' ecological and physical characteristics, for both large and small phytoplankton. Defining a zone of potential interactions as the overlap between nutrient depletion volumes, we show that local species composition-within the range of possible interactions-depends on the size class of phytoplankton. In small phytoplankton, individuals remain in mostly monospecific clusters. Spatial structure therefore favours intra- over inter-specific interactions for small phytoplankton, contributing to coexistence. Large phytoplankton cell neighbourhoods appear more mixed. Although some small-scale self-organizing spatial structure remains and could influence coexistence mechanisms, other factors may need to be explored to explain diversity maintenance in large phytoplankton.

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.

Adrenal and juxta-adrenal schwannomas: A single-centre study.

OBJECTIVE: Adrenal schwannomas and juxta-adrenal schwannomas are rare tumours. We aimed to summarise their clinical, biochemical and imaging characteristics. DESIGN: Single-centre retrospective study of eligible patients between 1995 and 2022. PATIENTS AND MEASUREMENTS: Patients with a histopathologic diagnosis of adrenal or juxta-adrenal schwannoma. RESULTS: Twenty-four patients were diagnosed with either primary adrenal schwannoma (8, 33%) or juxta-adrenal schwannoma (16, 67%). Most tumours (21, 88%) were discovered incidentally on imaging. All tumours were unilateral, with 15 (62%) on the left and 9 (38%) on the right. At diagnosis, the median tumour size was 4 cm (range, 2-13 cm). Adrenal schwannomas were smaller when compared to juxta-adrenal schwannomas (median of 3.1 cm [range, 2-9 cm] vs. 4.6 cm [range, 2.3-13.3 cm], p = .037). On imaging, the tumours were round or oval in shape in 16 (70%), lobulated in 7 (30%), solid in 15 (68%), solid-cystic in 7 (32%), heterogeneous in 14 (61%) and homogeneous in 9 (39%). The median unenhanced computed tomography attenuation was 30 Hounsfield units (HU) (range, 12-38 HU). Of the 20 patients who underwent complete hormonal testing, all had nonfunctioning tumours. There was no recurrence or new tumour development in our cohort. CONCLUSIONS: Adrenal and juxta-adrenal schwannomas are nonfunctioning benign tumours that present with indeterminate radiographic features, including large tumour size and increased unenhanced CT attenuation. We did not find an imaging phenotype that was diagnostic of schwannoma. The diagnosis of this rare tumour is based on biopsy or resection.

Clinical, imaging and biochemical presentation of cystic pheochromocytomas.

OBJECTIVE: Cystic adrenal mass is a rare imaging presentation of pheochromocytoma. We aimed to describe the clinical, biochemical and imaging characteristics of patients with cystic pheochromocytoma. DESIGN: Single-centre, retrospective study, 2000-2020. PATIENTS: Consecutive patients with cystic pheochromocytoma were identified from our institutional pathology and adrenal tumour database. RESULTS: Of the 638 patients with pheochromocytomas, 21 (3.2%) had cystic pheochromocytomas (median age: 57 years, 57% women). Most pheochromocytomas were discovered incidentally (57%) or due to symptoms of catecholamine excess (24%). The median tumour size was 6.4 cm. On imaging, cystic pheochromocytomas were round or oval (90%), heterogeneous lesions (86%) with a thick solid rim (median rim thickness 13.9 mm, unenhanced computed tomography (CT) attenuation 40 Hounsfield units (HU), venous-phase CT attenuation 83 HU), and a median cystic component of 40% (unenhanced CT attenuation 17.6 HU, venous-phase CT attenuation 20.4 HU), and rarely with calcifications (15%). All 20 patients with biochemical testing had functioning tumours (adrenergic in 80%, noradrenergic in 20%). Total urinary metanephrine excretion correlated with the volume of the solid component (R2 = .75, p < .0001) but not the cystic component (R2 = .04, p = .4386). All patients underwent adrenalectomy (48% laparoscopic, 52% open), and the median duration of hospital stay was 4 days. CONCLUSIONS: Cystic pheochromocytomas are rare, large tumours with a phenotypic appearance that can masquerade as other adrenal cystic lesions. The degree of biochemical abnormality in cystic pheochromocytomas is associated with the volume of the solid component. All patients with adrenal cysts that have a solid component or an unenhanced attenuation >10 HU should undergo biochemical testing for pheochromocytoma.

Adrenal venous sampling for lateralization of cortisol hypersecretion in patients with bilateral adrenal masses.

OBJECTIVE: The objective of this study was to evaluate the role of adrenal venous sampling (AVS) in guiding the management of patients with corticotropin (ACTH)-independent glucocorticoid secretory autonomy and bilateral adrenal masses. DESIGN AND PATIENTS: A cohort with 25 patients underwent AVS and surgical management. MEASUREMENTS: Cortisol was measured from the adrenal veins (AVs) and inferior vena cava (IVC). AV/IVC cortisol ratio and cortisol lateralization ratio (CLR) (dominant AV cortisol concentration divided by the nondominant AV cortisol concentration) were calculated. Posthoc receiver-operating characteristic curves were generated to determine the specificity of revised AV/IVC cortisol ratio and CLR in differentiating unilateral from bilateral disease. RESULTS: Patients underwent unilateral (n = 21) or bilateral (n = 4) adrenalectomy. The mean AV/IVC cortisol ratio for unilateral adrenalectomy was 12.1 ± 9.6 (dominant) and 4.7 ± 3.8 (contralateral) with a mean CLR of 3.6 ± 3.5. The mean AV/IVC cortisol ratio for bilateral adrenalectomy was 7.5 ± 2.1, with a mean CLR of 1.1 ± 0.6. At a mean follow-up of 22 months, one patient who underwent unilateral adrenalectomy for the predicted bilateral disease developed recurrent mild autonomous cortisol secretion. Posthoc analyses demonstrated a specificity of 95%-100% for unilateral disease with AV/IVC cortisol ratio >9 for one side, <2.0 for the opposite side and a CLR > 2.3. The specificity was 80%-90% for bilateral disease with AV/IVC cortisol ratio >5.1 bilaterally and a CLR < 1.1. CONCLUSIONS: Among patients with bilateral adrenal masses and ACTH-independent autonomous cortisol secretion, AVS can distinguish between unilateral and bilateral disease with high specificity and may guide surgical management.

The effect of mobility-related anxiety on walking across the lifespan: a virtual reality simulation study.

Older adults who report a fear of falling are more likely to subsequently fall, yet, some gait anxiety-related alterations may protect balance. We examined the effect of age on walking in anxiety-inducing virtual reality (VR) settings. We predicted a high elevation-related postural threat would impair gait in older age, and differences in cognitive and physical function would relate to the observed effects. Altogether, 24 adults (age (y) = 49.2 (18.7), 13 women) walked on a 2.2-m walkway at self-selected and fast speeds at low (ground) and high (15 m) VR elevation. Self-reported cognitive and somatic anxiety and mental effort were greater at high elevations (all p < 0.001), but age- and speed-related effects were not observed. At high VR elevations, participants walked slower, took shorter steps, and reduced turning speed (all p < 0.001). Significant interactions with age in gait speed and step length showed that relatively older adults walked slower (ß = - 0.05, p = 0.024) and took shorter steps (ß = - 0.05, p = 0.001) at self-selected speeds at high compared to low elevation settings. The effect of Age on gait speed and step length disappeared between self-selected and fast speeds and at high elevation. At self-selected speeds, older adults took shorter and slower steps at high elevation without changing step width, suggesting that in threatening settings relatively older people change gait parameters to promote stability. At fast speeds, older adults walked like relatively younger adults (or young adults walked like older adults) supporting the notion that people opt to walk faster in a way that still protects balance and stability in threatening settings.

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.

The perceived control model of falling: developing a unified framework to understand and assess maladaptive fear of falling.

BACKGROUND: fear of falling is common in older adults and can have a profound influence on a variety of behaviours that increase fall risk. However, fear of falling can also have potentially positive outcomes for certain individuals. Without progressing our understanding of mechanisms underlying these contrasting outcomes, it is difficult to clinically manage fear of falling. METHODS: this paper first summarises recent findings on the topic of fear of falling, balance and fall risk-including work highlighting the protective effects of fear. Specific focus is placed on describing how fear of falling influences perceptual, cognitive and motor process in ways that might either increase or reduce fall risk. Finally, it reports the development and validation of a new clinical tool that can be used to assess the maladaptive components of fear of falling. RESULTS: we present a new conceptual framework-the Perceived Control Model of Falling-that describes specific mechanisms through which fear of falling can influence fall risk. The key conceptual advance is the identification of perceived control over situations that threaten one's balance as the crucial factor mediating the relationship between fear and increased fall risk. The new 4-item scale that we develop-the Updated Perceived Control over Falling Scale (UP-COF)-is a valid and reliable tool to clinically assess perceived control. CONCLUSION: this new conceptualisation and tool (UP-COF) allows clinicians to identify individuals for whom fear of falling is likely to increase fall risk, and target specific underlying maladaptive processes such as low perceived control.

Unilateral Adrenalectomy for Primary Aldosteronism Due to Bilateral Adrenal Disease Can Result in Resolution of Hypokalemia and Amelioration of Hypertension.

BACKGROUND: Bilateral idiopathic hyperaldosteronism (IHA) is responsible for 60% of primary aldosteronism (PA) cases. Medical management is standard of care for IHA. Unilateral adrenalectomy (UA) with the intent of debulking total aldosterone production as a palliative measure remains controversial. METHODS: Single-center retrospective review (2010-2020) of patients undergoing UA with a diagnosis of PA due to IHA (lateralization index [LI] on adrenal venous sampling [AVS] < 4). Demographic, pre-operative, intra-operative, and post-operative variables were assessed. Hypertensive regimens were converted to the WHO Defined Daily Dose (DDD). RESULTS: Twenty-four patients were identified, 14, 58% male and mean age 52 ± 10 years. Preoperative hypokalemia was present in 22, 92% of patients. Median number of antihypertensives taken was 3 (interquartile range [IQR], 2-4) and median DDD was 4 (IQR, 3-5.3). Median lateralization index on AVS was 3.52 (range, 1.19-3.88). All operations were performed in minimally invasive fashion. There were no conversions to open procedure, ICU admissions, or post-operative complications. Median follow-up was 10.5 months (range, 1-145 months). Hypokalemia resolved in 17, 76% of patients at last follow-up. Post-operative median number of antihypertensives taken was 1 (IQR, 1-3) and median DDD was 2 (IQR, 0.5-2.75) from 4, P = 0.003. Three (%) patients required continuation of mineralocorticoid receptor antagonists post-operatively. Blood pressure control improved in 65% of patients. CONCLUSION: Unilateral adrenalectomy in the setting of bilateral hyperaldosteronism can improve blood pressure control and stabilize potassium levels in selected patients. Further prospective studies in larger cohorts will be necessary to further define the role of unilateral adrenalectomy in the setting of PA due to bilateral adrenal disease.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

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.

Stokes drift and its discontents.

The Stokes velocity [Formula: see text], defined approximately by Stokes (1847, Trans. Camb. Philos. Soc., 8, 441-455.), and exactly via the Generalized Lagrangian Mean, is divergent even in an incompressible fluid. We show that the Stokes velocity can be naturally decomposed into a solenoidal component, [Formula: see text], and a remainder that is small for waves with slowly varying amplitudes. We further show that [Formula: see text] arises as the sole Stokes velocity when the Lagrangian mean flow is suitably redefined to ensure its exact incompressibility. The construction is an application of Soward & Roberts's glm theory (2010, J. Fluid Mech., 661, 45-72. (doi:10.1017/S0022112010002867)) which we specialize to surface gravity waves and implement effectively using a Lie series expansion. We further show that the corresponding Lagrangian-mean momentum equation is formally identical to the Craik-Leibovich (CL) equation with [Formula: see text] replacing [Formula: see text], and we discuss the form of the Stokes pumping associated with both [Formula: see text] and [Formula: see text]. This article is part of the theme issue 'Mathematical problems in physical fluid dynamics (part 1)'.