Chromatin State Maps of Blood Pressure-Relevant Renal Segments Reveal Potential Regulatory Role for SNPs.

Background: Hypertension or elevated blood pressure (BP) is a worldwide clinical challenge and the leading primary risk factor for kidney dysfunctions, heart failure, and cerebrovascular disease. The kidney is a central regulator of BP by maintaining sodium-water balance. Multiple genome-wide association studies revealed that BP is a heritable quantitative trait, modulated by several genetic, epigenetic, and environmental factors.

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4, and mediate potent PTPN2/N1 degradation in cells and mice.

Cardiac intravoxel incoherent motion diffusion-weighted imaging to assess myocardial microcirculation dysfunction in hypertension.

Background: Myocardial microcirculation dysfunction is the most potent predictor of adverse cardiovascular events in hypertension. The current study aimed to apply intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) to assess hypertension-related microcirculation dysfunction.

Methods: In this prospective study, 102 participants were recruited from our hospital and underwent cardiac magnetic resonance (CMR) examination on a 3T scanning system.

Symbolic recording of signalling and cis-regulatory element activity to DNA.

Measurements of gene expression or signal transduction activity are conventionally performed using methods that require either the destruction or live imaging of a biological sample within the timeframe of interest. Here we demonstrate an alternative paradigm in which such biological activities are stably recorded to the genome. Enhancer-driven genomic recording of transcriptional activity in multiplex (ENGRAM) is based on the signal-dependent production of prime editing guide RNAs that mediate the insertion of signal-specific barcodes (symbols) into a genomically encoded recording unit.

Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo.

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples ( = 1,384) of medication-free individuals with first-episode and recurrent MDD ( = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls ( = 699).

Positive Associations of Perfluoroalkyl and Polyfluoroalkyl Substances With Hypertension May Be Attenuated by Endogenous Sex Hormones: A Nationally Representative Cross-Sectional Study.

Background: Perfluoroalkyl and polyfluoroalkyl substance (PFAS) has endocrine-disrupting properties and may affect blood pressure. Endogenous hormones also play a crucial role in the progression of hypertension. However, their interaction with hypertension remains to be explored.

IV Flat Detector CT Angiography in Flat Detector CT Image-Guided Minimally Invasive Surgery for the Treatment of Intracerebral Hypertensive Hemorrhage.

Background And Purpose: Spontaneous intracerebral hemorrhage is a serious stroke subtype with high mortality and morbidity. Minimally invasive surgery plus thrombolysis is a promising treatment option, but it requires accurate catheter placement and real-time monitoring. The authors introduced IV flat detector CT angiography (ivFDCTA) into the minimally invasive surgery procedure for the first time, to provide vascular information and guidance for hematoma evacuation.

Deciphering cell states and genealogies of human haematopoiesis.

The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs). Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems, simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging.

A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity.

Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. We evaluated the efficacy and safety of 24-week treatment of mazdutide up to 6 mg in Chinese overweight adults or adults with obesity, as an interim analysis of a randomised, two-part (low doses up to 6 mg and high dose of 9 mg), double-blind, placebo-controlled phase 2 trial (ClinicalTrials.gov, NCT04904913).

Comprehensive split TEV based protein-protein interaction screening reveals TAOK2 as a key modulator of Hippo signalling to limit growth.

The conserved Hippo signalling pathway plays a crucial role in tumour formation by limiting tissue growth and proliferation. At the core of this pathway are tumour suppressor kinases STK3/4 and LATS1/2, which limit the activity of the oncogene YAP1, the primary downstream effector. Here, we employed a split TEV-based protein-protein interaction screen to assess the physical interactions among 28 key Hippo pathway components and potential upstream modulators.

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable.

Individualized tumor-informed circulating tumor DNA analysis for postoperative monitoring of non-small cell lung cancer.

We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients.

Impact of Neighborhood Social Deprivation on Health Care Costs Associated With TAVR.

Background: Cumulative costs of transcatheter aortic valve replacement (TAVR) differ in the referral, procedural and postprocedural phases depending on patient comorbidities, type of procedure, and procedural complications. Our goal was to determine the association between neighborhood measures of social deprivation and TAVR costs in each of the 3 phases.

Methods: Demographics, patient comorbidities, procedural details, in-hospital complications, and costs for adults undergoing TAVR between 2017 and 2020 in Ontario, Canada were obtained from administrative databases and linked to social deprivation data using the Ontario Marginalization Index.

Effect of Imaging Selection Paradigms on Endovascular Thrombectomy Outcomes in Patients With Acute Ischemic Stroke.

Background: The effect of imaging selection paradigms on endovascular thrombectomy outcomes in patients with acute ischemic stroke with large vessel occlusion remains uncertain. The study aimed to assess the effect of basic imaging (noncontrast computed tomography with or without computed tomographic angiography) versus advanced imaging (magnetic resonance imaging or computed tomography perfusion) on clinical outcomes following thrombectomy in patients with stroke with large vessel occlusion in the early and extended windows using a pooled analysis of patient-level data from 2 pivotal randomized clinical trials done in China.

Methods: This post hoc analysis used data from 1182 patients included in 2 multicenter, randomized controlled trials in China that evaluated adjunct therapies to endovascular treatment for acute ischemic stroke (Direct Endovascular Treatment for Large Artery Anterior Circulation Stroke performed from May 20, 2018, through May 2, 2020, and Intravenous Tirofiban Before Endovascular Treatment in Stroke from October 10, 2018, through October 31, 2021).

Peptide Vaccine Against ADAMTS-7 Ameliorates Atherosclerosis and Postinjury Neointima Hyperplasia.

Background: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents.

Methods: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant.

On-demand cell-autonomous gene therapy for brain circuit disorders.

Several neurodevelopmental and neuropsychiatric disorders are characterized by intermittent episodes of pathological activity. Although genetic therapies offer the ability to modulate neuronal excitability, a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and "healthy" surrounding or intermingled neurons. We describe a gene therapy strategy that down-regulates the excitability of overactive neurons in closed loop, which we tested in models of epilepsy.

Genetic deconvolution of fetal and maternal cell-free DNA in maternal plasma enables next-generation non-invasive prenatal screening.

Current non-invasive prenatal screening (NIPS) analyzes circulating fetal cell-free DNA (cfDNA) in maternal peripheral blood for selected aneuploidies or microdeletion/duplication syndromes. Many genetic disorders are refractory to NIPS largely because the maternal genetic material constitutes most of the total cfDNA present in the maternal plasma, which hinders the detection of fetus-specific genetic variants. Here, we developed an innovative sequencing method, termed coordinative allele-aware target enrichment sequencing (COATE-seq), followed by multidimensional genomic analyses of sequencing read depth, allelic fraction, and linked single nucleotide polymorphisms, to accurately separate the fetal genome from the maternal background.

Age and Blood Pressure Contribute to Aortic Cell and Tissue Stiffness Through Distinct Mechanisms.

Background: Aortic stiffening is strongly associated with both aging and hypertension, but the underlying mechanisms remain unclear. We hypothesized that aging-induced aortic stiffness is mediated by a mechanism differing from hypertension.

Methods: We conducted comprehensive in vivo and in vitro experiments using multiple rat models to dissect the different mechanisms of aortic stiffening mediated by aging and hypertension.

Canadian Multicenter Chronic Total Occlusion Registry: Ten-Year Follow-Up Results of Chronic Total Occlusion Revascularization.

Background: Chronic total occlusions (CTO) occur in nearly 20% of coronary angiograms. CTO revascularization, either by percutaneous coronary intervention (PCI) or coronary artery bypass grafting surgery (CABG), is infrequently performed, approximately one-third of cases. Long-term outcomes are unknown.

New Model for Estimation of the Age at Onset in Spinocerebellar Ataxia Type 3.

Objectives: The aim of this study was to develop an appropriate parametric survival model to predict patient's age at onset (AAO) for spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) populations from mainland China.

Methods: We compared the efficiency and performance of 6 parametric survival analysis methods (exponential, weibull, log-gaussian, gaussian, log-logistic, and logistic) based on cytosine-adenine-guanine (CAG) repeat length at to predict the probability of AAO in the largest cohort of patients with SCA3/MJD. A set of evaluation criteria, including -2 log-likelihood statistic, Akaike information criterion (AIC), bayesian information criterion (BIC), Nagelkerke R-squared (Nagelkerke R^2), and Cox-Snell residual plot, were used to identify the best model.

Global Impact of COVID-19 on Stroke Care and IV Thrombolysis.

Objective: To measure the global impact of COVID-19 pandemic on volumes of IV thrombolysis (IVT), IVT transfers, and stroke hospitalizations over 4 months at the height of the pandemic (March 1 to June 30, 2020) compared with 2 control 4-month periods.

Methods: We conducted a cross-sectional, observational, retrospective study across 6 continents, 70 countries, and 457 stroke centers. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.

Values of Baseline Posterior Circulation Acute Stroke Prognosis Early Computed Tomography Score for Treatment Decision of Acute Basilar Artery Occlusion.

Background And Purpose: This study aimed to analyze the impact of baseline posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) on the efficacy and safety of endovascular therapy (EVT) for patients with acute basilar artery occlusion.

Methods: The BASILAR was a nationwide prospective registry of consecutive patients with a symptomatic and radiologically confirmed acute basilar artery occlusion within 24 hours of symptom onset. We estimated the effect of standard medical therapy alone (SMT group) versus SMT plus EVT (EVT group) for patients with documented pc-ASPECTS on noncontrast CT, both as a categorical (0-4 versus 5-7 versus 8-10) and as a continuous variable.

Increasing Wait-Time Mortality for Severe Aortic Stenosis: A Population-Level Study of the Transition in Practice From Surgical Aortic Valve Replacement to Transcatheter Aortic Valve Replacement.

Background: Transcatheter aortic valve replacement (TAVR) has emerged as a reasonable alternative to surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis (AS). There is limited data on temporal trends in wait-times and access to care for patients with AS, irrespective of treatment modality. We sought to investigate the trends in wait-times for the treatment (either SAVR or TAVR) of AS in Ontario, Canada, and to understand the drivers of wait-list mortality and hospitalization due to heart failure.