Cell-type-resolved genetic regulatory variation shapes inflammatory bowel disease risk.

Most genetic variants associated with complex diseases lie in non-coding regions, complicating efforts to identify effector genes and relevant cell types. Here, we map cis-eQTLs across 2.2 million single cells from blood and intestinal biopsies of 421 individuals, including 125 with inflammatory bowel disease (IBD).

Standardization of Terminology, Definitions, and Outcome Criteria for Bleeding in Hereditary Hemorrhagic Telangiectasia: International Consensus Report.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is the second most common inherited bleeding disorder worldwide, affecting approximately 1 in 5000 people. Development of disease-modifying and efficacious hemostatic agents to treat HHT has finally begun after decades without such medical therapies. However, the lack of consensus on standardized severity definitions, outcome criteria, and terminology remains a major obstacle to clinical investigation and therapeutic development in HHT.

The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types.

Metastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries.

Premature Ventricular Complexes After Ablation for Paroxysmal Atrial Fibrillation and Recurrent Atrial Arrhythmias: The admIRE Subanalysis.

Background: Premature ventricular complexes (PVCs) have been reported to independently predict incident atrial fibrillation in the general population. The prognostic importance of PVCs after catheter ablation for paroxysmal atrial fibrillation (PAF) is unknown.

Objectives: In patients undergoing catheter ablation for PAF, we assessed whether postablation PVCs influence the risk for recurrence.

Comparison of left atrial appendage closure and oral anti-coagulation after catheter ablation for atrial fibrillation: Concomitant and sequential cohorts of the OPTION randomized controlled trial.

Background: Left atrial appendage closure (LAAC) can be performed in separate procedures with cardiac ablation (sequentially) or concomitantly in the same operative session.

Objective: The OPTION trial aims to compare the efficacy and safety of LAAC with oral anticoagulation (OAC) in patients who have undergone catheter ablation for atrial fibrillation (AF). The objective of this sub-analysis is to evaluate LAAC vs OAC within concomitant and sequential ablation timings.

The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes.

The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes).

Embolotherapy for Pulmonary Arteriovenous Malformations in the Pediatric Population with Hereditary Hemorrhagic Telangiectasias-A Retrospective Case Series.

Purpose: To investigate the outcomes of embolotherapy for pulmonary arteriovenous malformation (pAVM) management and investigate factors associated with pAVM persistence after embolotherapy in pediatric patients with hereditary hemorrhagic telangiectasia (HHT).

Materials And Methods: Pediatric patients with HHT who received embolotherapy for pAVMs at the institute were retrospectively identified from January 1, 1999, to January 31, 2024. Cases with adequate clinical and imaging follow-up and without prior pAVM treatment at another institution were included.

Exome sequencing of UK birth cohorts.

Birth cohort studies involve repeated surveys of large numbers of individuals from birth and throughout their lives. They collect information useful for a wide range of life course research domains, and biological samples which can be used to derive data from an increasing collection of omic technologies. This rich source of longitudinal data, when combined with genomic data, offers the scientific community valuable insights ranging from population genetics to applications across the social sciences.

Early versus late atrial fibrillation recurrence after pulsed field ablation: insights from the admIRE trial.

Aims: Studies have shown correlations between early recurrence (ER) and late recurrence (LR) of atrial arrhythmia after ablation with thermal technologies. This admIRE trial (NCT05293639) subanalysis aims to analyse ER vs. LR in patients with paroxysmal atrial fibrillation (PAF) undergoing pulsed field ablation (PFA).

Resource Use in the Randomized Master Protocol for Immune Modulators for Treating COVID-19 (ACTIV-1 IM): A Secondary Data Analysis.

Background: Coronavirus disease 2019 (COVID-19) pneumonia requires considerable healthcare resources.

Research Objective: Examine if a single dose of infliximab or abatacept, in addition to remdesivir and steroids, decreased resource utilization among participants hospitalized with COVID-19 pneumonia.

Study Design And Methods: Accelerating COVID-19 Therapeutic Interventions and Vaccines Immunomodulator (ACTIV-1 IM) master protocol was a randomized, placebo-controlled trial examining the potential benefit in time to recovery and mortality of immunomodulators infliximab, abatacept, and cenicriviroc.

Pulsed Field Ablation to Treat Paroxysmal Atrial Fibrillation: Safety and Effectiveness in the AdmIRE Pivotal Trial.

Background: Evidence from clinical trials of early pulsed field ablation (PFA) systems in treating atrial fibrillation has demonstrated their promising potential to reduce complications associated with conventional thermal modalities while maintaining efficacy. However, the lack of a fully integrated mapping system, a staple technology of most modern electrophysiology procedures, poses limitations in lesion creation and workflow options. A novel variable-loop PFA catheter integrated with an electroanatomic mapping system has been developed that allows for real-time nonfluoroscopic procedural guidance and lesion indexing as well as feedback of tissue-to-catheter proximity.

Inhibition of angiogenesis in the management of refractory gastrointestinal bleeding in patients with LVAD support.

Background: Gastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF-LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD-associated GIAD bleeding, and now present follow-up data on patients treated with IV bevacizumab and/or low-dose oral pazopanib.

Methods: All consecutive adult patients with LVAD-associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis.

Executive summary of the 14th HHT international scientific conference.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by small, dilated clustered vessels (telangiectasias) and by larger visceral arteriovenous malformations (AVMs), which directly connect the feeding arteries with the draining veins. These lesions are fragile, prone to rupture, and lead to recurrent epistaxis and/or internal hemorrhage among other complications. Germline heterozygous loss-of-function (LOF) mutations in Bone Morphogenic Protein 9 (BMP9) and BMP10 signaling pathway genes (endoglin-ENG, activin like kinase 1 ACVRL1 aka ALK1, and SMAD4) cause different subtypes of HHT (HHT1, HHT2 and HHT-juvenile polyposis (JP)) and have a worldwide combined incidence of about 1:5000.

Digital Pulmonology Practice with Phonopulmography Leveraging Artificial Intelligence: Future Perspectives Using Dual Microwave Acoustic Sensing and Imaging.

Respiratory disorders, being one of the leading causes of disability worldwide, account for constant evolution in management technologies, resulting in the incorporation of artificial intelligence (AI) in the recording and analysis of lung sounds to aid diagnosis in clinical pulmonology practice. Although lung sound auscultation is a common clinical practice, its use in diagnosis is limited due to its high variability and subjectivity. We review the origin of lung sounds, various auscultation and processing methods over the years and their clinical applications to understand the potential for a lung sound auscultation and analysis device.

Population-based analysis of variants in a cutaneous melanoma case-control cohort.

Pathogenic germline variants in the protection of telomeres 1 gene () have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations.

Mutually exclusive genetic interactions and gene essentiality shape the genomic landscape of primary melanoma.

Melanoma is a heterogenous malignancy with an unpredictable clinical course. Most patients who present in the clinic are diagnosed with primary melanoma, yet large-scale sequencing efforts have focused primarily on metastatic disease. In this study we sequence-profiled 524 American Joint Committee on Cancer Stage I-III primary tumours.

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls.

Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.

Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1).

Predictors of seroconversion after coronavirus disease 2019 vaccination.

Background: Vaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks.

Objective: To investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: Demographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination.