Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial.

Janus kinase (JAK) inhibitors provide limited depth and durability of response in myelofibrosis. We evaluated pelabresib-a bromodomain and extraterminal domain (BET) inhibitor-plus ruxolitinib (a JAK inhibitor) compared with placebo plus ruxolitinib as first-line therapy. In this phase 3 study (MANIFEST-2), JAK inhibitor-naive patients with myelofibrosis were randomized 1:1 to pelabresib 125 mg once daily (QD; 50-175 mg QD permitted) for 14 days followed by a 7-day break (21-day cycle), or to placebo in combination with ruxolitinib 10 or 15 mg twice daily (BID; 5 mg QD-25 mg BID permitted).

Prevalence and Burden of Chronic Spontaneous Urticaria in Japan: A Cross-Sectional Study.

: Real-world data on the prevalence and burden of patients with chronic spontaneous urticaria (CSU) are limited in Japan. This study aimed to estimate CSU prevalence and assess its humanistic and economic burden. : This analysis utilized data from Japanese adult respondents self-reporting physician-diagnosed CSU collected through the 2019 National Health and Wellness Survey.

Presence of Fragmented Intratumoral Thrombosed Microvasculature in the Necrotic and Peri-Necrotic Regions on SWI Differentiates IDH Wild-Type Glioblastoma From IDH Mutant Grade 4 Astrocytoma.

Background: Isocitrate dehydrogenase (IDH) wild-type (IDH) glioblastomas (GB) are more aggressive and have a poorer prognosis than IDH mutant (IDH) tumors, emphasizing the need for accurate preoperative differentiation. However, a distinct imaging biomarker for differentiation mostly lacking. Intratumoral thrombosis has been reported as a histopathological biomarker for GB.

Inclisiran as a siRNA Inhibitor of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); Past, Present, and Future.

Reducing low-density lipoprotein cholesterol (LDL-C) levels has been shown to reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Statins are the foundation of LDL-C lowering therapy with other non-statin agents used in circumstances where goal LDL-C levels are not reached or owing to intolerance to adverse effects of statins. In 2003, the discovery of the role of the proprotein convertase subtilisin/kexin type 9 (PCSK9) system in promoting elevated LDL-C levels led to new avenues of drug development to achieve target LDL-C.

Autoinhibition of dimeric NINJ1 prevents plasma membrane rupture.

Lytic cell death culminates in plasma membrane rupture, which releases large intracellular molecules to augment the inflammatory response. Plasma membrane rupture is mediated by the effector membrane protein ninjurin-1 (NINJ1), which polymerizes and ruptures the membrane via its hydrophilic face. How NINJ1 is restrained under steady-state conditions to ensure cell survival remains unknown.

The need for high-resolution gut microbiome characterization to design efficient strategies for sustainable aquaculture production.

Microbiome-directed dietary interventions such as microbiota-directed fibers (MDFs) have a proven track record in eliciting responses in beneficial gut microbes and are increasingly being promoted as an effective strategy to improve animal production systems. Here we used initial metataxonomic data on fish gut microbiomes as well as a wealth of a priori mammalian microbiome knowledge on α-mannooligosaccharides (MOS) and β-mannan-derived MDFs to study effects of such feed supplements in Atlantic salmon (Salmo salar) and their impact on its gut microbiome composition and functionalities. Our multi-omic analysis revealed that the investigated MDFs (two α-mannans and an acetylated β-galactoglucomannan), at a dose of 0.

Role of narrow band imaging in detecting recurrence in patients of squamous cell carcinoma larynx and hypopharynx who underwent radiotherapy/chemo-radiotherapy.

Background: Narrow band imaging (NBI) is an emerging modality that enhances the accuracy of detection of head and neck malignancies by visualisation of aberrant neoangiogenesis in malignant tissue using narrow bandwidth light in blue and green spectrum. The purpose of this study was to assess the role of NBI in detecting recurrence in patients with Squamous cell carcinoma larynx and hypopharynx who have undergone Radiotherapy/Chemoradiotherapy (RT/CTRT). The aim of the study was to (a) determine the role of NBI in follow-up of patients with carcinoma of larynx and hypopharynx previously treated with radiotherapy or chemotherapy, (b) determine the role of NBI as the initial investigatory tool of choice in detecting local recurrence and compare with other modalities like fibreoptic laryngoscopy (FOL), Magnetic Resonance Imaging (MRI) and Positron Emission Tomography- Computed Tomography (PETCT).

Evaluation of Factors Predictive of Efficacy Among Patients With Complicated Urinary Tract Infection and/or Acute Pyelonephritis.

Background: Antibiotic treatment for complicated urinary tract infections (cUTI)/acute pyelonephritis (AP) is often followed by recurrent bacteriuria in the absence of clinical symptoms. To understand factors predictive of clinical and microbiologic outcomes in patients with cUTI/AP, multivariable analyses were undertaken using pooled data from a global, phase 3 cUTI study.

Methods: Using data from 366 tebipenem pivoxil hydrobromide- and 378 ertapenem-treated patients from the Study to Assess the Efficacy, Safety and Pharmacokinetics of Orally Administered Tebipenem Pivoxil Hydrobromide (SPR994) Compared to Intravenous Ertapenem in Participants With Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) infected with Enterobacterales uropathogens, multivariable analyses for dichotomous efficacy endpoints were performed using logistic regression and pharmacokinetic-pharmacodynamic relationships were evaluated.

Endoscopic Ultrasound-Guided Rendezvous Technique Versus Precut Sphincterotomy as Salvage Technique in Patients With Benign Biliary Disease and Difficult Biliary Cannulation : A Randomized Controlled Trial.

Background: The standard salvage technique used for difficult bile duct cannulation is precut sphincterotomy, whereas endoscopic ultrasound-guided rendezvous technique (EUS-RV) is a relatively newer method. Prospective comparative data between these 2 techniques as salvage for biliary access in patients with benign biliary disease and difficult bile duct cannulation is lacking.

Objective: To compare EUS-RV and precut sphincterotomy as salvage technique for difficult bile duct cannulation in benign biliary obstruction.

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology.

Personality is influenced by both genetic and environmental factors and is associated with other psychiatric traits such as anxiety and depression. The 'big five' personality traits, which include neuroticism, extraversion, agreeableness, conscientiousness and openness, are a widely accepted and influential framework for understanding and describing human personality. Of the big five personality traits, neuroticism has most often been the focus of genetic studies and is linked to various mental illnesses, including depression, anxiety and schizophrenia.

Deep learning to quantify care manipulation activities in neonatal intensive care units.

Early-life exposure to stress results in significantly increased risk of neurodevelopmental impairments with potential long-term effects into childhood and even adulthood. As a crucial step towards monitoring neonatal stress in neonatal intensive care units (NICUs), our study aims to quantify the duration, frequency, and physiological responses of care manipulation activities, based on bedside videos and physiological signals. Leveraging 289 h of video recordings and physiological data within 330 sessions collected from 27 neonates in 2 NICUs, we develop and evaluate a deep learning method to detect manipulation activities from the video, to estimate their duration and frequency, and to further integrate physiological signals for assessing their responses.

Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression.

The regulation of red blood cell (RBC) homeostasis by erythropoietin (EPO) is critical for O2 transport and maintaining the adequate number of RBCs in vertebrates. Therefore, dysregulation in EPO synthesis results in disease conditions such as polycythemia in the case of excessive EPO production and anemia, which occurs when EPO is inadequately produced. EPO plays a crucial role in treating anemic patients; however, its overproduction can increase blood viscosity, potentially leading to fatal heart failure.

Treatment approach and outcomes of patients with accelerated/blast-phase myeloproliferative neoplasms in the current era.

Progression of myeloproliferative neoplasms (MPNs) to accelerated or blast phase is associated with poor survival outcomes. Since 2017 there have been several therapies approved for use in acute myeloid leukemia (AML); these therapies have been incorporated into the management of accelerated/blast-phase MPNs (MPN-AP/BP). We performed a multicenter analysis to investigate outcomes of patients diagnosed with MPN-AP/BP in 2017 or later.

Diagnostic Yield of CSF Testing in Infants for Disorders of Biogenic Amine Neurotransmitter Metabolism.

Background And Objectives: Biochemical testing of CSF for neurotransmitter metabolites and their cofactors is often used in the diagnostic evaluation of infants with neurologic disorders but requires an invasive, labor-intensive procedure with many potential sources of error. Our aim was to determine the diagnostic yield of CSF testing for biogenic amines (serotonin, norepinephrine, epinephrine, and dopamine) and their cofactors in identifying inborn errors of neurotransmitter metabolism among infants.

Methods: We evaluated all infants aged 1 year or younger who underwent CSF biogenic amine neurotransmitter (CSFNT) testing at Children's Hospital of Philadelphia (CHOP) and Boston Children's Hospital (BCH) between 2008 and 2017 in this cross-sectional study.

Data-driven identification of predictive risk biomarkers for subgroups of osteoarthritis using interpretable machine learning.

Osteoarthritis (OA) is increasing in prevalence and has a severe impact on patients' lives. However, our understanding of biomarkers driving OA risk remains limited. We developed a model predicting the five-year risk of OA diagnosis, integrating retrospective clinical, lifestyle and biomarker data from the UK Biobank (19,120 patients with OA, ROC-AUC: 0.

Pearls & Oy-sters: KLHL11 IgG Paraneoplastic-Associated Hearing Loss and Rhombencephalitis in a Woman With Metastatic Müllerian Tumor.

Kelch-like protein-11 (KLHL11) immunoglobulin G (IgG) is a recently reported paraneoplastic autoantibody associated with rhombencephalitis, which commonly presents with ataxia, diplopia, vertigo, hearing loss, tinnitus, and gaze palsies. The association of this high-risk paraneoplastic autoantibody with testicular germ cell tumors is widely accepted, but it has not been associated with Müllerian tumors. In this study, we report a woman without a known germ cell tumor presenting with signs and symptoms suggesting autoimmune encephalitis.

Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1.

Immunological determinants favouring emergence of broadly neutralising antibodies are crucial to the development of HIV-1 vaccination strategies. Here, we combined RNAseq and B cell cloning approaches to isolate a broadly neutralising antibody (bnAb) ELC07 from an individual living with untreated HIV-1. Using single particle cryogenic electron microscopy (cryo-EM), we show that the antibody recognises a conformational epitope at the gp120-gp41 interface.

MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA). Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation.

Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

Methods: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program.

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications.

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (n = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry.

Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review.

: Dolutegravir (DTG)-based antiretroviral therapy (ART) rarely leads to virological failure (VF) and drug resistance in integrase strand transfer inhibitor (INSTI)-naïve persons living with HIV (PLWH). As a result, limited data are available on INSTI-associated drug resistance mutations (DRMs) selected by DTG-containing ART regimens. We reviewed studies published through July 2023 to identify those reporting emergent major INSTI-associated DRMs in INSTI-naïve PLWH receiving DTG and those containing in vitro DTG susceptibility results using a standardized assay.

Improved pearl millet genomes representing the global heterotic pool offer a framework for molecular breeding applications.

High-quality reference genome assemblies, representative of global heterotic patterns, offer an ideal platform to accurately characterize and utilize genetic variation in the primary gene pool of hybrid crops. Here we report three platinum grade de-novo, near gap-free, chromosome-level reference genome assemblies from the active breeding germplasm in pearl millet with a high degree of contiguity, completeness, and accuracy. An improved Tift genome (Tift23DB-P1-P5) assembly has a contig N50 ~ 7,000-fold (126 Mb) compared to the previous version and better alignment in centromeric regions.