Multimodal data integration to predict atrial fibrillation.

Aims: Many studies have utilized data sources such as clinical variables, polygenic risk scores, electrocardiogram (ECG), and plasma proteins to predict the risk of atrial fibrillation (AF). However, few studies have integrated all four sources from a single study to comprehensively assess AF prediction.

Methods And Results: We included 8374 (Visit 3, 1993-95) and 3730 (Visit 5, 2011-13) participants from the Atherosclerosis Risk in Communities Study to predict incident AF and prevalent (but covert) AF.

Cancer associated fibroblasts drive epithelial to mesenchymal transition and classical to basal change in pancreatic ductal adenocarcinoma cells with loss of IL-8 expression.

Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, in part resulting from cellular heterogeneity that supports overall tumorigenicity. Cancer associated fibroblasts (CAF) are key determinants of PDAC biology and response to systemic therapy. While CAF subtypes have been defined, the effects of patient-specific CAF heterogeneity and plasticity on tumor cell behavior remain unclear.

Associations of Social, Behavioral, and Clinical Factors With Sex Differences in Stroke Recurrence and Poststroke Mortality.

Background: Few population-based studies have assessed sex differences in stroke recurrence. In addition, contributors to sex differences in recurrence and poststroke mortality, including social factors, are unclear. We investigated sex differences in these outcomes and the contribution of social, clinical, and behavioral factors to the sex differences.

Small molecule inhibits KCNQ channels with a non-blocking mechanism.

Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel.

Prognostic Value of LV Global Longitudinal Strain by 2D and 3D Speckle-Tracking Echocardiography in Patients With HFpEF.

Background: In patients with heart failure with preserved ejection fraction (HFpEF), the impact of type 2 diabetes (T2D) on left ventricular global longitudinal strain (LV GLS) and its prognostic implications remains unclear. We aimed to evaluate LV function using two-dimensional (2D) and three-dimensional (3D) speckle-tracking echocardiography in patients with HFpEF with and without T2D, and to investigate its prognostic significance.

Methods: A total of 335 patients with HFpEF were prospectively enrolled for echocardiographic evaluation.

Increased Risk of Patellofemoral Instability Events and Surgical Management in Patients With Joint Hypermobility Syndromes: A Matched Cohort Analysis.

Purpose: To compare the odds of patellofemoral instability events requiring subsequent surgery and revision surgical intervention in patients with joint hypermobility syndromes (JHS) to that of a matched cohort.

Methods: This is a retrospective cohort study using the PearlDiver Mariner Database. Records were queried between 2010 and 2021 with a diagnosis of JHS, including Ehlers-Danlos syndrome (EDS) and Marfan syndrome.

Safety and Efficacy of Remote Ischemic Conditioning in Patients With Intravenous Thrombolysis: The SERIC-IVT Trial.

Background: Approximately half of the patients with acute ischemic stroke who receive intravenous thrombolysis (IVT) do not achieve an excellent outcome. Remote ischemic conditioning (RIC) as a promising neuroprotective treatment may improve clinical outcomes in this population. This study aimed to assess the efficacy and safety of RIC in patients with IVT.

Single-Cell Multiomics Profiling Reveals Heterogeneity of Müller Cells in the Oxygen-Induced Retinopathy Model.

Purpose: Retinal neovascularization poses heightened risks of vision loss and blindness. Despite its clinical significance, the molecular mechanisms underlying the pathogenesis of retinal neovascularization remain elusive. This study utilized single-cell multiomics profiling in an oxygen-induced retinopathy (OIR) model to comprehensively investigate the intricate molecular landscape of retinal neovascularization.

Modeling lung adenocarcinoma metastases using patient-derived organoids.

Approximately 50% of patients with surgically resected early-stage lung cancer develop distant metastasis. At present, there is no in vivo metastasis model to investigate the biology of human lung cancer metastases. Using well-characterized lung adenocarcinoma (LUAD) patient-derived organoids (PDOs), we establish an in vivo metastasis model that preserves the biologic features of human metastases.

Ticking Brain: Circadian Rhythm as a New Target for Cerebroprotection.

Circadian rhythm is a master process observed in nearly every type of cell throughout the body, and it macroscopically regulates daily physiology. Recent clinical trials have revealed the effects of circadian variation on the incidence, pathophysiological processes, and prognosis of acute ischemic stroke. Furthermore, core clock genes, the cell-autonomous pacemakers of the circadian rhythm, affect the neurovascular unit-composing cells in a nonparallel manner after the same pathophysiological processes of ischemia/reperfusion.

NKG2A genetic deletion promotes human primary NK cell anti-tumor responses better than an anti-NKG2A monoclonal antibody.

Natural killer (NK) cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E to evade NK cell surveillance. Given the successes of immune checkpoint blockade in cancer therapy, NKG2A is an interesting novel target.

Deep repertoire mining uncovers ultra-broad coronavirus neutralizing antibodies targeting multiple spike epitopes.

The development of vaccines and therapeutics that are broadly effective against known and emergent coronaviruses is an urgent priority. We screened the circulating B cell repertoires of COVID-19 survivors and vaccinees to isolate over 9,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs), providing an expansive view of the SARS-CoV-2-specific Ab repertoire. Among the recovered antibodies was TXG-0078, an N-terminal domain (NTD)-specific neutralizing mAb that recognizes diverse alpha- and beta-coronaviruses.

Implications of Race Adjustment in Lung-Function Equations.

Background: Adjustment for race is discouraged in lung-function testing, but the implications of adopting race-neutral equations have not been comprehensively quantified.

Methods: We obtained longitudinal data from 369,077 participants in the National Health and Nutrition Examination Survey, U.K.

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people.

Background: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects.

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

Background: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain.

Methods: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group).

Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial-Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma.

Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells.

Testing multiplexed anti-ASFV CRISPR-Cas9 in reducing African swine fever virus.

Unlabelled: African swine fever (ASF) is a highly fatal viral disease that poses a significant threat to domestic pigs and wild boars globally. In our study, we aimed to explore the potential of a multiplexed CRISPR-Cas system in suppressing ASFV replication and infection. By engineering CRISPR-Cas systems to target nine specific loci within the ASFV genome, we observed a substantial reduction in viral replication .

The neutrophil to lymphocyte ratio associates with markers of Alzheimer's disease pathology in cognitively unimpaired elderly people.

Background: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects.

Early human lung immune cell development and its role in epithelial cell fate.

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry.