Safety and efficacy of satralizumab in patients with generalised myasthenia gravis (LUMINESCE): a randomised, double-blind, multicentre, placebo-controlled phase 3 trial.

Background: Evidence from preclinical studies suggests that IL-6 signalling has the potential to modulate immunopathogenic mechanisms upstream of autoantibody effector mechanisms in patients with generalised myasthenia gravis. We aimed to assess the safety and efficacy of satralizumab, a humanised monoclonal antibody targeting the IL-6 receptor, in patients with generalised myasthenia gravis.

Methods: LUMINESCE was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study at 105 sites, including hospitals and clinics, globally.

Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study.

Background: Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study.

Tuberculosis and people who use drugs: why focus on this overlooked population is important and why adapted interventions are necessary.

People who use drugs show a higher incidence and prevalence of tuberculosis than people who do not use drugs in areas where Mycobacterium tuberculosis is endemic. However, this population is largely neglected in national tuberculosis programmes. Strategies for active case finding, screening, and linkage to care designed for the general population are not adapted to the needs of people who use drugs, who are stigmatised and difficult to reach.

Crossing the blood-brain barrier: emerging therapeutic strategies for neurological disease.

The blood-brain barrier is a physiological barrier that can prevent both small and complex drugs from reaching the brain to exert a pharmacological effect. For treatment of neurological diseases, drug concentrations at the target site are a fundamental parameter for therapeutic effect; thus, the blood-brain barrier is a major obstacle to overcome. Novel strategies have been developed to circumvent the blood-brain barrier, including CSF delivery, intracranial delivery, ultrasound-based methods, membrane transporters, receptor-mediated transcytosis, and nanotherapeutics.

Hidradenitis suppurativa.

Hidradenitis suppurativa is a chronic inflammatory disease characterised by painful, deep-seated nodules, abscesses, and draining tunnels in the skin of axillary, inguinal, genitoanal, or inframammary areas. In recent years, the body of knowledge in hidradenitis suppurativa has advanced greatly. This disorder typically starts in the second or third decade of life.

Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.

More than 50% of families with suspected rare monogenic diseases remain unsolved after whole-genome analysis by short-read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare-disease cohort of 98 samples from 41 families, using nanopore sequencing, achieving per sample ∼36× average coverage and 32-kb read N50 from a single flow cell.

Structures and mRNP remodeling mechanism of the TREX-2 complex.

mRNAs are packaged with proteins into messenger ribonucleoprotein complexes (mRNPs) in the nucleus. mRNP assembly and export are of fundamental importance for all eukaryotic gene expression. Before export to the cytoplasm, mRNPs undergo dynamic remodeling governed by the DEAD-box helicase DDX39B (yeast Sub2).

Structural and functional analysis of SAM-dependent N-methyltransferases involved in ovoselenol and ovothiol biosynthesis.

Thio/selenoimidazole Nπ-methyltransferases are an emerging family of enzymes catalyzing the final step in the production of the S/Se-containing histidine-derived antioxidants ovothiol and ovoselenol. These enzymes, prevalent in prokaryotes, show minimal sequence similarity to other methyltransferases, and the structural determinants of their reactivities remain poorly understood. Herein, we report ligand-bound crystal structures of OvsM from the ovoselenol pathway as well as a member of a previously unknown clade of standalone ovothiol-biosynthetic Nπ-methyltransferases, which we have designated OvoM.

A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance.

Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo and applied this to sonic hedgehog (SHH) medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver.

Ligand interaction landscape of transcription factors and essential enzymes in E. coli.

Knowledge of protein-metabolite interactions can enhance mechanistic understanding and chemical probing of biochemical processes, but the discovery of endogenous ligands remains challenging. Here, we combined rapid affinity purification with precision mass spectrometry and high-resolution molecular docking to precisely map the physical associations of 296 chemically diverse small-molecule metabolite ligands with 69 distinct essential enzymes and 45 transcription factors in the gram-negative bacterium Escherichia coli. We then conducted systematic metabolic pathway integration, pan-microbial evolutionary projections, and independent in-depth biophysical characterization experiments to define the functional significance of ligand interfaces.

Clinical and intracranial electrophysiological signatures of post-operative and post-ictal delirium.

Objectives: (1) Gain insight into the mechanisms of postoperative delirium (POD). (2) Determine mechanistic overlap with post-ictal delirium (PID). Epilepsy patients undergoing intracranial electrophysiological monitoring can experience both POD and PID, and thus are suitable subjects for these investigations.

Oyster reef recovery: Impacts of rotational management and restoration efforts on public fishing grounds.

Coastal ecosystems are degraded worldwide and oyster reefs are among the most threatened coastal habitats. Oysters are a critical ecosystem engineer and valuable fishery species, thus effective management strategies must balance tradeoffs between protecting reef ecosystems and continued human use. Management practices for oysters commonly incorporate shell replenishment (provisioning hard substrates to increase reef relief) and spatial management (rotational harvest areas or sanctuaries); however, the impact of these practices on reef dynamics and fisheries outcomes are poorly understood, particularly on harvested reefs.

Integrative deep immune profiling of the elderly reveals systems-level signatures of aging, sex, smoking, and clinical traits.

Background: Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability.

Methods: We conducted an immune profiling study of 550 elderly participants (≥60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort.

Geographical variation in the long-arm of childhood.

Scholars have documented the lasting impact of childhood socioeconomic status (SES) on health, but few studies have considered how state contexts in childhood shape health trajectories based on childhood SES across the life course. The current project uses data from the Panel Study of Income Dynamics, 2009-2021 (N = 18,227 person-year observations of adults aged 18-41) to build on these studies by 1) examining state variation in the relationship between childhood SES and adult self-rated health, and 2) assessing the contributions of childhood state-level economic context in moderating this relationship. Logistic regression models first confirmed the expected relationship between childhood SES and adult self-rated health that parallels other literature (OR = 1.

Prolonged length of stay among individuals presenting to the emergency department with psychosis: Associations with sociodemographic and visit-level characteristics.

Introduction: Individuals experiencing psychosis commonly initiate and engage in treatment within an emergency department (ED) setting. Understanding factors contributing to adverse ED experiences is critical for improving psychosis-related treatment. Prolonged ED length of stay (LOS), which can be conversely associated with treatment quality, is not well explored among individuals experiencing psychosis.

Isolated subsegmental pulmonary embolism identification based on international classification of diseases (ICD)-10 codes and imaging reports.

Background: Isolated subsegmental pulmonary embolism (issPE) is a commonly encountered diagnosis. Although the International Classification of Diseases (ICD)-10 codes are used for research, their validity for identifying issPE is unknown. Moreover, issPE diagnosis is challenging, and the findings from radiology reports may conflict with those from expert radiologists.

Effect of surface roughness on the efficacy of Plasma Activated Mist (PAM) for inactivation of Listeria innocua and Klebsiella michiganensis.

Cold plasma generated by dielectric barrier discharge (DBD) and DBD combined with nebulized liquid microdroplets to generate plasma-activated mist (PAM) have shown the potential as a surface decontamination method for the food industry. The objective of this research was to measure the microbial inactivation caused by DBD and by PAM on tryptic soy agar (TSA) and on glass slides and to determine the efficacy of PAM on selected surfaces having different surface topographies. Tryptic soy agar in Petri dishes and on glass slides (surface roughness Pq = 0.

Characterization of senescence-associated transcripts in the human placenta.

Introduction: Fusion of mononucleated cytotrophoblasts into syncytium leads to trophoblast senescence. Yet, premature senescence is associated with preeclampsia, fetal growth restriction (FGR), and related obstetrical syndromes. A set of 28 transcripts that comprise senescence-associated secretory phenotype (SASP) was recently described in placentas from women with preeclampsia.

Health effects of occupational exposure to jet fuels used in the military: A systematic review of the epidemiologic literature.

Background: Jet fuels are a common chemical exposure in occupational settings involving aircraft. Jet fuels are heterogeneous mixtures of aromatic and aliphatic hydrocarbons, as well as non-hydrocarbon performance additives. Several components of jet fuels have been linked to adverse health outcomes.

Three-dimensional kinematics in patients with anterior shoulder instability - A systematic review with meta-analysis.

Anterior Shoulder Instability (ASI) is a common orthopedic condition often resulting in altered shoulder kinematics. Understanding the biomechanics of the unstable shoulder is critical to determine the most appropriate treatment. This study aims to conduct the first systematic review and meta-analysis of three-dimensional (3D) shoulder kinematic studies in ASI patients.

Nitrosyl factors play a vital role in the ventilatory depressant effects of fentanyl in freely moving guinea pigs.

An understanding of intracellular mechanisms by which fentanyl and other synthetic opioids exert adverse effects on breathing is needed. Using freely moving adult male guinea pigs, we administered the nitric oxide synthase (NOS) inhibitor, L-NAME (N-nitro-L-arginine methyl ester), to determine whether nitrosyl factors, such as nitric oxide and S-nitrosothiols, play a role in fentanyl-induced respiratory depression. Ventilatory parameters were recorded by whole body plethysmography to determine the effects of fentanyl (75 μg/kg, IV) in guinea pigs that had received a prior injection of vehicle (saline), L-NAME or the inactive D-isomer, D-NAME (both at 50 μmol/kg, IV), 15 min beforehand.