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Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Abstract The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare (

Abstract A decoupling between confidence and action could relate to compulsive behaviour as seen in obsessive-compulsive disorder (OCD). The link between confidence and action in OCD has been investigated in clinical case-control studies and in the general population with discrepant findings. The generalizability of findings from highly-compulsive general population samples to clinical OCD samples has been questioned. Here, we investigate action-confidence coupling for 38 OCD patients compared to 37 healthy controls (HC), using a predictive inference task. We compared those results to a comparison between matched high and low compulsive individuals from the general population. Action-updating, confidence and their coupling were compared between the groups. Moreover, computational modeling was performed to compare groups on error sensitivity and environmental parameters. OCD patients showed lower confidence and higher learning rates in reaction to (small) prediction errors than HC, signaling hyperactive error signaling and lower confidence estimation. No evidence was found for differences in action-confidence coupling between groups. In contrast high the compulsive group showed higher confidence and stronger decoupling than the low compulsive group, both of which were related to symptoms. The underlying mechanisms of obsessive-compulsive behaviour might differ between clinical and highly-compulsive general population samples, resulting in different (meta)cognitive profiles.

Contrasting pollination syndromes in closely related species suggest that floral trait divergence is associated with differences in pollination system, but empirical observations are required to confirm syndrome-based predictions. We present a comparative study of two closely related Erica species with contrasting pollination syndromes from the Cape Floristic Region of South Africa. Erica cylindrica has narrowly tubular pale and strongly scented flowers and is known to be hawkmoth-pollinated. The closely related Erica infundibuliformis has bright flower colours and appears to lack scent, traits that are suggestive of pollination by long-tongued nemestrinid flies (rhinomyiophily). Floral trait measurements revealed that both species exhibit predominantly upright flower orientation and elongated floral tubes, although tube length of E. infundibuliformis is consistently greater than that of E. cylindrica. For both species, petals are brighter than floral tube surfaces, but flowers of E. cylindrica lack the strong UV reflectance found in E. infundibuliformis. Nectar of E. infundibuliformis is more concentrated and produced in larger volumes. Scent composition, but not evening scent emission rates, differed between the species: scent of E. cylindrica is dominated by aromatic compounds, whereas scent of E. infundibuliformis is dominated by (E)-ocimene and other terpenoid compounds and is emitted at higher rates during the day than the evening. Pollinator observations contradicted trait-based predictions: although a single nemestrinid fly captured in the vicinity of E. infundibuliformis did carry Erica pollen, almost all other diurnal flower visitors were nectar-robbing Hymenoptera which did not carry Erica pollen. Contrary to predictions, at two sites and over two flowering seasons, flowers were consistently visited in the evenings by several species of settling moths and hawkmoths which carried pollen, almost exclusively of Erica, on their proboscides. Our findings thus suggest that, despite objective differences in key floral traits between the closely related hawkmoth-pollinated E. cylindrica and E. infundibuliformis, moths are also important pollinators of E. infundibuliformis. A bimodal pollination system involving predominant pollination by moths and occasional visits by long-proboscid flies could partially reconcile findings with predictions. Our study further suggests that hawkmoth pollination may be more widespread in both Erica and the broader Cape flora than has hitherto been assumed and emphasises the importance of nocturnal pollinator observations.

ObjectiveTo test associations of candidate obesity-related single nucleotide polymorphisms (SNPs) and obesity polygenic risk scores (PRS) with neural reward reactivity to food cues.MethodsAfter consuming a pre-load meal, 9–12-year-old children completed a functional magnetic resonance imaging (fMRI) paradigm with exposure to food and non-food commercials. Genetic exposures included FTO rs9939609, MC4R rs571312, and a pediatric-specific obesity PRS. A targeted region-of-interest (ROI) analysis for 7 bilateral reward regions and a whole-brain analysis were conducted. Independent associations between each genetic factor and reward responsivity to food cues in each ROI were evaluated using linear models.ResultsAnalyses included 151 children (M = 10.9 years). Each FTO rs9939609 obesity risk allele was related to a higher food-cue-related response in the right lateral hypothalamus after controlling for covariates including the current BMI Z-score (p

Abstract We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model’s performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

Abstract Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Abstract Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Abstract Background Immunoglobulin G4-related disease is an inflammatory disease affecting multiple organs including the kidney. Immunoglobulin G4-related kidney disease most commonly manifests as a tubulointerstitial nephritis and is associated with glomerular disease in a proportion of cases. Membranous nephropathy is the most frequent glomerular lesion. Herein, we report the first documented case of immunoglobulin G4-related disease presenting with nephrotic syndrome owing to minimal change disease. Case presentation A 67-year-old South Asian male presented to our service with systemic upset and leg swelling. He had heavy proteinuria (urine protein:creatinine ratio 1042 mg/mmol) and was hypoalbuminemic (17 g/L) and hypercholersterolemic (9.3 mmol/L), consistent with the nephrotic syndrome. His serum creatinine was 140 μmol/L, and he was hypocomplementemic (C3 0.59 g/L, C4

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of findings. Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important. Plain Language Summary: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on using less glucocorticoids to limit side effects. New drugs that drastically limit glucocorticoid use are not available in many countries. Studies are needed to find other ways of reducing glucocorticoid exposure to treat AAV, but it is unclear how best to achieve this. We administered a survey to doctors with experience in treating AAV and had them grade different combinations of widely available treatments with 2 or 4 weeks of glucocorticoids. We found that a combination of 2 doses cyclophosphamide with 2 doses rituximab and 4 weeks of glucocorticoids was the preferred treatment. The results will guide the development of a trial studying minimal use of glucocorticoids for the treatment of AAV.

Knowledge of the mechanical properties of brain tissue in vivo is essential to understanding the mechanisms underlying traumatic brain injury (TBI) and to creating accurate computational models of TBI and neurosurgical simulation. Brain white matter, which is composed of aligned, myelinated, axonal fibers, is structurally anisotropic. White matter in vivo also exhibits mechanical anisotropy, as measured by magnetic resonance elastography (MRE), but measurements of anisotropy obtained by mechanical testing of white matter ex vivo have been inconsistent. The minipig has a gyrencephalic brain with similar white matter and gray matter proportions to humans and therefore provides a relevant model for human brain mechanics. In this study, we compare estimates of anisotropic mechanical properties of the minipig brain obtained by identical, non-invasive methods in the live (in vivo) and dead animals (in situ). To do so, we combine wave displacement fields from MRE and fiber directions derived from diffusion tensor imaging (DTI) with a finite element-based, transversely-isotropic nonlinear inversion (TI-NLI) algorithm. Maps of anisotropic mechanical properties in the minipig brain were generated for each animal alive and at specific times post-mortem. These maps show that white matter is stiffer, more dissipative, and more anisotropic than gray matter when the minipig is alive, but that these differences largely disappear post-mortem, with the exception of tensile anisotropy. Overall, brain tissue becomes stiffer, less dissipative, and less mechanically anisotropic post-mortem. These findings emphasize the importance of testing brain tissue properties in vivo. Statement of Significance: In this study, MRE and DTI in the minipig were combined to estimate, for the first time, anisotropic mechanical properties in the living brain and in the same brain after death. Significant differences were observed in the anisotropic behavior of brain tissue post-mortem. These results demonstrate the importance of measuring brain tissue properties in vivo as well as ex vivo, and provide new quantitative data for the development of computational models of brain biomechanics.

Abstract Background PDE6H encodes PDE6γ′, the inhibitory subunit of the cGMP-specific phosphodiesterase 6 in cone photoreceptors. Inhibition of PDE6, which has been widely studied for its role in light transduction, increases cGMP levels. The purpose of this study is to characterise the role of PDE6H in cancer cell growth. Methods From an siRNA screen for 487 genes involved in metabolism, PDE6H was identified as a controller of cell cycle progression in HCT116 cells. Role of PDE6H in cancer cell growth and metabolism was studied through the effects of its depletion on levels of cell cycle controllers, mTOR effectors, metabolite levels, and metabolic energy assays. Effect of PDE6H deletion on tumour growth was also studied in a xenograft model. Results PDE6H knockout resulted in an increase of intracellular cGMP levels, as well as changes to the levels of nucleotides and key energy metabolism intermediates. PDE6H knockdown induced G1 cell cycle arrest and cell death and reduced mTORC1 signalling in cancer cell lines. Both knockdown and knockout of PDE6H resulted in the suppression of mitochondrial function. HCT116 xenografts revealed that PDE6H deletion, as well as treatment with the PDE5/6 inhibitor sildenafil, slowed down tumour growth and improved survival, while sildenafil treatment did not have an additive effect on slowing the growth of PDE6γ′-deficient tumours. Conclusions Our results indicate that the changes in cGMP and purine pools, as well as mitochondrial function which is observed upon PDE6γ′ depletion, are independent of the PKG pathway. We show that in HCT116, PDE6H deletion replicates many effects of the dark retina response and identify PDE6H as a new target in preventing cancer cell proliferation and tumour growth.

This paper describes the development and validation of the Autonomy Scale Amsterdam (ASA). We propose that a new measure of autonomy is needed and, as such, we developed and validated an autonomy scale relevant for psychiatry. Based on literature, an expert meeting and three samples of the general population (N = 298, N = 207, N = 309) we provide evidence (a) that supports a 6-factor structure model as a better fit than alternative models with a high reliability to capture the concept of autonomy consisting of: Self-integration, Engagement with life, Goal-directedness, Self-control, External constraints and Social support, (b) for the scale's convergent and discriminant validity with constructs in autonomy's nomological network and (c) for the scale's criterion validity with well-established well-being outcomes, and (d) that the measure is not redundant with a prior measure of autonomy, the autonomy-connectedness scale, and demonstrates incremental validity in the prediction of mental health over and above an existing measure of autonomy. Taken together, the results suggest that the ASA is a useful scale that shows positive evidence of psychometric quality to measure autonomy in a sample of the general population (total N = 856), accounting for a unique predictive value over and above an existing measure of autonomy concerning several mental health outcomes. The ASA can further help our understanding of the role of autonomy in mental disorders.

Abstract African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Abstract Background Whether obesity is a cause or consequence of low physical activity levels and more sedentary time has not yet been fully elucidated. Better instrumental variables and a more thorough consideration of potential confounding variables that may influence the causal inference between physical activity and obesity are needed. Methods Leveraging results from our recent genome-wide association study for leisure time moderate-to-vigorous intensity (MV) physical activity and screen time, we here disentangle the causal relationships between physical activity, sedentary behavior, education—defined by years of schooling—and body mass index (BMI), using multiple univariable and multivariable Mendelian Randomization (MR) approaches. Results Univariable MR analyses suggest bidirectional causal effects of physical activity and sedentary behavior with BMI. However, multivariable MR analyses that take years of schooling into account suggest that more MV physical activity causes a lower BMI, and a higher BMI causes more screen time, but not vice versa. In addition, more years of schooling causes higher levels of MV physical activity, less screen time, and lower BMI. Conclusions In conclusion, our results highlight the beneficial effect of education on improved health and suggest that a more physically active lifestyle leads to lower BMI, while sedentary behavior is a consequence of higher BMI.

Abstract Background The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D. Methods We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier. Results The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. Conclusions We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Current clinical diagnostic imaging methods for lung metastases are sensitive only to large tumours (1–2 mm cross-sectional diameter), and early detection can dramatically improve treatment. We have previously demonstrated that an antibody-targeted MRI contrast agent based on microparticles of iron oxide (MPIO; 1 μm diameter) enables the imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Using a mouse model of lung metastasis, upregulation of endothelial VCAM-1 expression was demonstrated in micrometastasis-associated vessels but not in normal lung tissue, and binding of VCAM-MPIO to these vessels was evident histologically. Owing to the lack of proton MRI signals in the lungs, we modified the VCAM-MPIO to include zirconium-89 (89Zr, t1/2 = 78.4 h) in order to allow the in vivo detection of lung metastases by positron emission tomography (PET). Using this new agent (89Zr-DFO-VCAM-MPIO), it was possible to detect the presence of micrometastases within the lung in vivo from ca. 140 μm in diameter. Histological analysis combined with autoradiography confirmed the specific binding of the agent to the VCAM-1 expressing vasculature at the sites of pulmonary micrometastases. By retaining the original VCAM-MPIO as the basis for this new molecular contrast agent, we have created a dual-modality (PET/MRI) agent for the concurrent detection of lung and brain micrometastases.

Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumour's response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies.

Abstract Objective: To explore the source, message, channel, and receiver effects on patient concern for antibiotic resistance, willingness to reduce antibiotic use, and expectations for an antibiotic prescription in a prepandemic sample. Methods: We used data reported from a national cross-sectional survey of adults who had visited an urgent care center within the last year. Data were collected from April 4 to April 9, 2017. The survey included an embedded experimental design to test changing effects before versus after message exposure. Participants: A national sample of adult participants (n = 610) who had used urgent care at least once in the past year were recruited through GfK’s KnowledgePanelTM. KnowledgePanel survey response rates are typically about 65%. Respondents ranged in age from 18 to 85 and were more likely to be female (377/610; 62%), White (408/610; 67%), and covered by private insurance (414/610; 68%). Results: Outcome variables were measured on 4-point scales 1–4 scale, and t-tests were conducted for measures that were collected pre and postmessaging. The majority of participants trusted their doctor and desired them as the source for information regarding antibiotic resistance, followed by field experts (eg, CDC). Direct messaging (eg, email) and targeted advertisements were least preferred. Conclusions: This study provides foundational data on patient communication preferences in terms of source, message content, and channel when receiving information on antibiotics and antibiotic resistance, as well as how these factors affect patient concern, willingness, and expectations. Follow-up work is needed to replicate these findings in a postpandemic sample.

Hispanic Immigrants (HI) have lower vaccination rates than their non-Hispanic white counterparts. Culturally appropriate interventions are more influential in evoking change among viewers; therefore, it is important to understand the cultural factors of specific ethnic groups. In this study, we identify cultural barriers to vaccination of Hispanic Immigrants. An electronic survey was administered among HI parents living in the United States. Using structural equation modeling, we found that high religious practice and positive religious beliefs towards vaccination correspond with positive vaccine attitudes (+0.20 and +0.587, respectively). Trust in institutions is strongly correlated with strong positive vaccine attitudes (+0.734). While trusting one's folk practitioner more than a medical doctor leads to negative vaccine attitudes (-0.596), the use of home remedies is associated with positive vaccine attitudes (+0.486). The cultural competence of a medical practitioner, especially regarding folk medicine, is essential to lower cultural barriers HI patients face in vaccination.

A patient was admitted for chest pain with electrocardiographic changes, and cardiac magnetic resonance showed focal myocardial hypertrophy secondary to edema. Combined positron emission tomography and computed tomography corroborated foci of myocardial hypermetabolism, as well as multiple adenopathies consistent with lymphoma in the biopsy. Hypertrophy and edema regressed with chemotherapy.

IntroductionThere are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance.MethodsWe estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method.ResultsThe results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = −0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments.DiscussionOur findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data.Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American).Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74–0.88)]. This variant was replicated in the Vanderbilt University Medical Center’s DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3.Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least 12 different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remain to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype–phenotype relationships across the UBA5 allelic series. In vivo, we observed a broad spectrum of phenotypes in viability, developmental timing, lifespan, locomotor activity, and bang sensitivity. A range of functional effects was also observed in vitro across comprehensive biochemical assays for protein stability, ATP binding, UFM1 activation, and UFM1 transthiolation. Importantly, there is a strong correlation between in vivo and in vitro phenotypes, establishing a classification of LoF variants into mild, intermediate, and severe allelic strengths. By systemically evaluating UBA5 variants across in vivo and in vitro platforms, this study provides a foundation for more basic and translational UBA5 research, as well as a basis for evaluating current and future individuals afflicted with this rare disease.

Summary: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. The Omicron spike (S) protein accumulated an unprecedented number of sequence changes relative to previous variants. In this review, we discuss how Omicron S protein structural features modulate host cell receptor binding, virus entry, and immune evasion and highlight how these structural features differentiate Omicron from previous variants. We also examine how key structural properties track across the still-evolving Omicron subvariants and the importance of continuing surveillance of the S protein sequence evolution over time.

Abstract Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations—eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.

Traumatic brain injury (TBI) is one of the leading causes of death and disability. TBI is associated with neuroinflammation, but temporal changes in immune and inflammatory signaling following TBI have not been fully elucidated. Furthermore, there have been no previous studies on changes in immune cell populations following TBI via the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). The current study aimed to determine the time course changes to inflammatory marker mRNA expression in the acute period following TBI in juvenile rats and to determine acute changes to brain and circulating immune cell populations. For this study, post-natal day (PND)-30 male Long Evans rats sustained a TBI or Sham TBI and were euthanized at 0, 3, 6, 12, 24, or 96 h post-injury. Prefrontal cortex and hippocampus samples were used to determine mRNA expression changes of inflammatory factors. The mRNA expression of the pro-inflammatory cytokine TNF-α was significantly elevated at 6 h post-injury in both regions evaluated. To evaluate immune cell populations, male Long Evans rats were euthanized at 48 h post-injury, and brain and blood samples were used for cell sorting by marker-specific antibodies. In the peripheral blood, there was an elevation in CD3+ total T cells, CD45R+ total B cells, and CD3+CD4+ helper T cells in the TBI subjects. However, there were no changes to natural killer cells or CD3+CD8+ cytotoxic T cell populations. In the brain, there was a reduction in CD11b/c+ monocytes/macrophages, but no changes in other immune cell populations. At 48 h post-injury, the TBI subjects also demonstrated expansion of the thymic medulla. These changes in the cerebral and blood immune cell populations and thymic medulla expansion may implicate the subacute recovery timeframe as a vulnerable window for the immune system in the pediatric population.

Introduction The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations.Methods Here, we examined how ancestrally diverse studies could clarify Lp(a)’s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.Results Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a ‘rule out’ for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%–99.9%) across PRS thresholds (80th–99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10−6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects.Conclusions Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.

Background The reconfiguration of specialist hospital services, with service provision concentrated in a reduced number of sites, is one example of major system change (MSC) for which there is evidence of improved patient outcomes. This paper explores the reconfiguration of specialist oesophago-gastric (OG) cancer surgery services in a large urban area of England (Greater Manchester, GM), with a focus on the role of history in this change process and how reconfiguration was achieved after previous failed attempts.Methods This study draws on qualitative research from a mixed-methods evaluation of the reconfiguration of specialist cancer surgery services in GM. Forty-six interviews with relevant stakeholders were carried out, along with ~160 hours of observations at meetings and the acquisition of ~300 pertinent documents. Thematic analysis using deductive and inductive approaches was undertaken, guided by a framework of ‘simple rules’ for MSC.Results Through an awareness of, and attention to, history, leaders developed a change process which took into account previous unsuccessful reconfiguration attempts, enabling them to reduce the impact of potentially challenging issues. Interviewees described attending to issues involving competition between provider sites, change leadership, engagement with stakeholders, and the need for a process of change resilient to challenge.Conclusion Recognition of, and response to, history, using a range of perspectives, enabled this reconfiguration. Particularly important was the way in which history influenced and informed other aspects of the change process and the influence of stakeholder power. This study provides further learning about MSC and the need for a range of perspectives to enable understanding. It shows how learning from history can be used to enable successful change.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Elevated body mass index is heritable and associated with many health conditions that impact morbidity and mortality. Here, the authors identify greater than 900 genetic loci for body mass index (BMI) and find over 300 diagnoses associated with increasing BMI.

Abstract Background Getting knowledge from healthcare research into practice (knowledge mobilisation) remains a global challenge. One way in which researchers may attempt to do this is to develop products (such as toolkits, actionable tools, dashboards, guidance, audit tools, protocols and clinical decision aids) in addition to journal papers. Despite their increasing ubiquity, the development of such products remains under-explored in the academic literature. This study aimed to further this understanding by exploring the development of products from healthcare research and how the process of their development might influence their potential application. Methods This study compared the data generated from a prospective, longitudinal, comparative case study of four research projects which aimed to develop products from healthcare research. Qualitative methods included thematic analysis of data generated from semi-structured interviews (38), meeting observations (83 h) and project documents (300+). Cases were studied for an average of 11.5 months (range 8–19 months). Results Case comparison resulted in the identification of three main themes with the potential to affect the use of products in practice. First, aspects of the product, including the perceived need for the specific product being identified, the clarity of product aim and clarity and range of end-users. Second, aspects of development, whereby different types of stakeholder engagement appear to influence potential product application, which either needs to be ‘meaningful’, or delivered through the implicit understanding of users’ needs by the developing team. The third, overarching theme, relates to the academic context in which products are developed, highlighting how the academic context perpetuates the development of products, which may not always be useful in practice. Conclusions This study showed that aspects of products from healthcare research (need/aim/end-user) and aspects of their development (stakeholder engagement/implicit understanding of end-users) influence their potential application. It explored the motivation for product development and identifies the influence of the current academic context on product development. It shows that there is a tension between ideal ‘systems approaches’ to knowledge mobilisation and ‘linear approaches’, which appear to be more pervasive in practice currently. The development of fewer, high-quality products which fulfil the needs of specified end-users might act to counter the current cynicism felt by many stakeholders in regard to products from healthcare research.

Most genetic association studies have been done on single nucleotide polymorphisms and small indels, while other types of variants have been less studied. Here, the authors use whole genome sequencing in a diverse population to identify and provide experimental evidence for associations between structural variants and blood-cell traits.

Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.

Abstract Background Concurrent variation in adiposity and inflammation suggests potential shared functional pathways and pleiotropic disease underpinning. Yet, exploration of pleiotropy in the context of adiposity-inflammation has been scarce, and none has included self-identified Hispanic/Latino populations. Given the high level of ancestral diversity in Hispanic American population, genetic studies may reveal variants that are infrequent/monomorphic in more homogeneous populations. Methods Using multi-trait Adaptive Sum of Powered Score (aSPU) method, we examined individual and shared genetic effects underlying inflammatory (CRP) and adiposity-related traits (Body Mass Index [BMI]), and central adiposity (Waist to Hip Ratio [WHR]) in HLA participating in the Population Architecture Using Genomics and Epidemiology (PAGE) cohort (N = 35,871) with replication of effects in the Cameron County Hispanic Cohort (CCHC) which consists of Mexican American individuals. Results Of the > 16 million SNPs tested, variants representing 7 independent loci were found to illustrate significant association with multiple traits. Two out of 7 variants were replicated at statistically significant level in multi-trait analyses in CCHC. The lead variant on APOE (rs439401) and rs11208712 were found to harbor multi-trait associations with adiposity and inflammation. Conclusions Results from this study demonstrate the importance of considering pleiotropy for improving our understanding of the etiology of the various metabolic pathways that regulate cardiovascular disease development.

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.

Objectives To explore the effect of changes in national clinical recommendations in 2019 that extended provision of survival focused care to babies born at 22 weeks’ gestation in England and Wales.Design Population based cohort study.Setting England and Wales, comprising routine data for births and hospital records.Participants Babies alive at the onset of care in labour at 22 weeks+0 days to 22 weeks+6 days and at 23 weeks+0 days to 24 weeks+6 days for comparison purposes between 1 January 2018 and 31 December 2021.Main outcome measures Percentage of babies given survival focused care (active respiratory support after birth), admitted to neonatal care, and surviving to discharge in 2018-19 and 2020-21.Results For the 1001 babies alive at the onset of labour at 22 weeks' gestation, a threefold increase was noted in: survival focused care provision from 11.3% to 38.4% (risk ratio 3.41 (95% confidence interval 2.61 to 4.45)); admissions to neonatal units from 7.4% to 28.1% (3.77 (2.70 to 5.27)), and survival to discharge from neonatal care from 2.5% to 8.2% (3.29 (1.78 to 6.09)). More babies of lower birth weight and early gestational age received survival focused care in 2020-21 than 2018-19 (46% to 64% at

Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell–mediated inflammation. However, the role of CD4+ T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells’ pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.

Abstract Background African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub-Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation. Methods Using whole genome sequencing and best practice workflows, we performed a comprehensive analysis of SVs for 180 (predominantly Gleason score ≥ 8) prostate tumours derived from 115 African, 61 European and four ancestrally admixed patients. We investigated the landscape and relationship of somatic SVs in driving ethnic disparity (African versus European), with a focus on African men from southern Africa. Results Duplication events showed the greatest ethnic disparity, with a 1.6- (relative frequency) to 2.5-fold (count) increase in African-derived tumours. Furthermore, we found duplication events to be associated with CDK12 inactivation and MYC copy number gain, and deletion events associated with SPOP mutation. Overall, African-derived tumours were 2-fold more likely to present with a hyper-SV subtype. In addition to hyper-duplication and deletion subtypes, we describe a new hyper-translocation subtype. While we confirm a lower TMPRSS2-ERG fusion-positive rate in tumours from African cases (10% versus 33%), novel African-specific PCa ETS family member and TMPRSS2 fusion partners were identified, including LINC01525, FBXO7, GTF3C2, NTNG1 and YPEL5. Notably, we found 74 somatic SV hotspots impacting 18 new candidate driver genes, with CADM2, LSAMP, PTPRD, PDE4D and PACRG having therapeutic implications for African patients. Conclusions In this first African-inclusive SV study for high-risk PCa, we demonstrate the power of SV interrogation for the identification of novel subtypes, oncogenic drivers and therapeutic targets. Identifying a novel spectrum of SVs in tumours derived from African patients provides a mechanism that may contribute, at least in part, to the observed ethnic disparity in advanced PCa presentation in men of African ancestry.

Accurate classification of genetic variants is critical for research and patient care. Here, the authors report that population-based associations between rare variants and quantitative endophenotypes for monogenic diseases can provide support for variant pathogenicity.

Abstract We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Polygenic risk scores have potential to predict an individual’s risk of disease based on genetic markers. Here, the authors develop a polygenic risk score for hypertension and test it in a multi-ethnic cohort, finding that the score is associated with higher likelihood of hypertension development 4-6 years later.

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

The human ventromedial prefrontal cortex helps to determine value and confidence in certain decisions, but only in situations when there is a potential for a (monetary) reward.

Abstract Background Nod-like receptors (NLRs) are critical to innate immune activation and induction of adaptive T cell responses. Yet, their role in autoinflammatory diseases of the central nervous system (CNS) remains incompletely defined. The NLR, Nlrp12, has been reported to both inhibit and promote neuroinflammation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE), where its T cell-specific role has been investigated. Uveitis resulting from autoimmunity of the neuroretina, an extension of the CNS, involves a breach in immune privilege and entry of T cells into the eye. Here, we examined the contribution of Nlrp12 in a T cell-mediated model of uveitis, experimental autoimmune uveitis (EAU). Methods Mice were immunized with interphotoreceptor retinoid-binding protein peptide 1–20 (IRBP1–20) emulsified in Complete Freund’s adjuvant, CFA. Uveitis was evaluated by clinical and histopathological scoring, and comparisons were made in WT vs. Nlrp12−/− mice, lymphopenic Rag1−/− mice reconstituted with WT vs. Nlrp12−/− CD4+ T cells, or among bone marrow (BM) chimeric mice. Antigen-specific Th-effector responses were evaluated by ELISA and intracellular cytokine staining. Cellular composition of uveitic eyes from WT or Nlrp12−/− mice was compared using flow cytometry. Expression of Nlrp12 and of cytokines/chemokines within the neuroretina was evaluated by immunoblotting and quantitative PCR. Results Nlrp12−/− mice developed exacerbated uveitis characterized by extensive vasculitis, chorioretinal infiltrates and photoreceptor damage. Nlrp12 was dispensable for T cell priming and differentiation of peripheral Th1 or Th17 cells, and uveitis in immunodeficient mice reconstituted with either Nlrp12−/− or WT T cells was similar. Collectively, this ruled out T cells as the source of Nlrp12-mediated protection to EAU. Uveitic Nlrp12−/− eyes had more pronounced myeloid cell accumulation than uveitic WT eyes. Transplantation of Nlrp12−/− BM resulted in increased susceptibility to EAU regardless of host genotype, but interestingly, a non-hematopoietic origin for Nlrp12 function was also observed. Indeed, Nlrp12 was found to be constitutively expressed in the neuroretina, where it suppressed chemokine/cytokine induction. Conclusions Our data identify a combinatorial role for Nlrp12 in dampening autoimmunity of the neuroretina. These findings could provide a pathway for development of therapies for uveitis and potentially other autoinflammatory/autoimmune diseases of the CNS.

Abstract Background While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. Results Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10− 7). Conclusions Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

Background Chronic leukemia is the most common leukemia subtype seen among adults in Jos, Nigeria, with few reported isolated cases of ocular morbidity. There are no published comprehensive data on adult leukemic ophthalmopathy from this region. Aim The aim of this study was to determine the prevalence, pattern, and causes of visual impairment (VI) among adult patients with chronic leukemia in Jos, North-Central Nigeria. Patients and methods The study included adult patients diagnosed with either chronic myeloid leukemia or chronic lymphocytic leukemia, confirmed by bone marrow biopsy, in two tertiary hospitals in Jos, North-Central Nigeria, between January 2016 and June 2017. Visual acuity was assessed and categorized using the International Classification of Diseases. Detailed ocular examination was carried out and causes of vision loss were noted. Results A total of 104 eyes of 52 patients were examined within the study period. The mean age of the patients was 45±17.7 years, and 35 (67.3%) patients were males. The majority (63.4%) of the participants had chronic myeloid leukemia. Ocular disorders were present in 32 (61.5%) of all patients, and 10 (19.2%) patients were visually impaired. Of these, nine (90.0%) had moderate VI due to refractive errors, cataract, glaucoma, and disk swelling; and one (10.0%) person was bilaterally blind from exudative retinal detachment and vitreous hemorrhage. Only 27% of all causes of VI were leukemia specific and included disk swelling, exudative retinal detachment, and vitreous hemorrhage. Conclusion Although ocular disorders were frequent among adults with chronic leukemia in Jos, the magnitude of vision loss from chronic leukemia-specific ocular disorders was low.

Nearly all cases of melioidosis in the continental United States are related to international travel to areas to which Burkholderia pseudomallei, the bacterium that causes melioidosis, is endemic. We report the diagnosis and clinical course of melioidosis in a patient from the United States who had no international travel history and the public health investigation to determine the source of exposure. We tested environmental samples collected from the patient’s home for B. pseudomallei by PCR and culture. Whole-genome sequencing was conducted on PCR-positive environmental samples, and results were compared with sequences from the patient’s clinical specimen. Three PCR-positive environmental samples, all collected from a freshwater home aquarium that had contained imported tropical fish, were a genetic match to the clinical isolate from the patient. This finding suggests a novel route of exposure and a potential for importation of B. pseudomallei, a select agent, into the United States from disease-endemic areas.

Abstract Knowledge regarding preventable hospital readmissions is scarce. Our aim was to compare the clinical characteristics of potentially preventable readmissions (PPRs) with non-PPRs. Additionally, we aimed to identify risk factors for PPRs. Our study included readmissions within 30 days after discharge from 1 of 7 hospital departments. Preventability was assessed by multidisciplinary meetings. Characteristics of the readmissions were collected and 23 risk factors were analyzed. Of the 1120 readmissions, 125 (11%) were PPRs. PPRs occurred equally among different departments (p = 0.21). 29.6% of PPRs were readmitted by a practitioner of a different medical specialty than the initial admission (IA) specialist. The PPR group had more readmissions within 7 days (PPR 54% vs. non-PPR 44%, p = 0.03). The median LOS was 1 day longer for PPRs (p = 0.16). Factors associated with PPR were higher age (p = 0.004), higher socio-economic status (p = 0.049), fewer prior hospital admissions (p = 0.004), and no outpatient visit prior to readmission (p = 0.025). This study found that PPRs can occur at any department in the hospital. There is not a single type of patient that can easily be pinpointed to be at risk of a PPR, probably due to the multifactorial nature of PPRs.