Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least One F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

Objective: The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers.

Study Design: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included.

Introducing the Concept of Sanctuary Sites in Ischemic Stroke.

Background: The topography of arterial territories has been defined using digital maps of supratentorial infarcts. Regions with a high probability of infarction (Pi) exist in the deep compartment due to a paucity of collaterals. However, less attention has been given to regions with a low Pi.

Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.

β-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway.

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.

Background: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF.

Dabrafenib plus Trametinib in Pediatric Glioma with V600 Mutations.

Background: Detection of the V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with V600 mutations, findings that warrant further evaluation of this combination as first-line therapy.

Methods: In this phase 2 trial, patients with pediatric low-grade glioma with V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine).

How can artificial intelligence decrease cognitive and work burden for front line practitioners?

Artificial intelligence (AI) has tremendous potential to improve the cognitive and work burden of clinicians across a range of clinical activities, which could lead to reduced burnout and better clinical care. The recent explosion of generative AI nicely illustrates this potential. Developers and organizations deploying AI have a responsibility to ensure AI is designed and implemented with end-user input, has mechanisms to identify and potentially reduce bias, and that the impact on cognitive and work burden is measured, monitored, and improved.

Levels of Fibrinogen Variants Are Altered in Severe COVID-19.

 Fibrinogen variants as a result of alternative messenger RNA splicing or protein degradation can affect fibrin(ogen) functions. The levels of these variants might be altered during coronavirus disease 2019 (COVID-19), potentially affecting disease severity or the thrombosis risk.  To investigate the levels of fibrinogen variants in plasma of patients with COVID-19.

Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance.

Enhancing the removal of aggregate-prone toxic proteins is a rational therapeutic strategy for a number of neurodegenerative diseases, especially Huntington's disease and various spinocerebellar ataxias. Ideally, such approaches should preferentially clear the mutant/misfolded species, while having minimal impact on the stability of wild-type/normally-folded proteins. Furthermore, activation of both ubiquitin-proteasome and autophagy-lysosome routes may be advantageous, as this would allow effective clearance of both monomeric and oligomeric species, the latter which are inaccessible to the proteasome.

Reengineering the specificity of the highly selective Clostridium botulinum protease via directed evolution.

The botulinum neurotoxin serotype A (BoNT/A) cuts a single peptide bond in SNAP25, an activity used to treat a wide range of diseases. Reengineering the substrate specificity of BoNT/A's protease domain (LC/A) could expand its therapeutic applications; however, LC/A's extended substrate recognition (≈ 60 residues) challenges conventional approaches. We report a directed evolution method for retargeting LC/A and retaining its exquisite specificity.

Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

Autophagy in healthy aging and disease.

Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease.

Power and sample size calculation for the win odds test: application to an ordinal endpoint in COVID-19 trials.

The win odds is a distribution-free method of comparing locations of distributions of two independent random variables. Introduced as a method for analyzing hierarchical composite endpoints, it is well suited to be used in the analysis of ordinal scale endpoints in COVID-19 clinical trials. For a single outcome, we provide power and sample size calculation formulas for the win odds test.

Autophagy in major human diseases.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies.

Personalized Piperacillin Dosing for the Critically Ill: A Retrospective Analysis of Clinical Experience with Dosing Software and Therapeutic Drug Monitoring to Optimize Antimicrobial Dosing.

Optimization of antibiotic dosing is a treatment intervention that is likely to improve outcomes in severe infections. The aim of this retrospective study was to describe the therapeutic exposure of steady state piperacillin concentrations (c) and clinical outcome in critically ill patients with sepsis or septic shock who received continuous infusion of piperacillin with dosing personalized through software-guided empiric dosing and therapeutic drug monitoring (TDM). Therapeutic drug exposure was defined as c of 32-64 mg/L (2-4× the 'MIC breakpoint' of ).

Enhanced xylene sensing performance using Ag-VO loaded mesoporous graphitic carbon nitride.

A 3-dimensional ordered cubic mesoporous Ag-V2O5 loaded graphitic carbon nitride (mpg-CN) hybrid was fabricated via a facile nanocasting technique using mesoporous silica as the hard template and its sensing response towards xylene gas was investigated in detail. The physicochemical properties of the as prepared nanocomposite were estimated by transmission electron microscopy (TEM), X-ray diffraction (XRD), scanning electron microscopy (SEM), elemental dispersive X-ray spectroscopy (EDX) and BET surface area analysis. The hybridized Ag-V2O5/mpg-CN nanocomposite prepared by template inversion of KIT-6 silica showed temperature reliant response towards the detection of common VOCs (xylene, formaldehyde, 2-propanol and benzene) usually found in our indoor environment.

Removal of organic dyes from wastewater using Eichhornia crassipes: a potential phytoremediation option.

Wastewater from textile industries is a potential source of organic dyes in natural water bodies. Environmental concerns of chemical methods for removal of dyes from wastewater are no more a viable solution, and there is growing concern to develop alternative approaches such as green chemistry and phytoremediation. This study reports the removal of organic dyes from wastewater using Eichhornia crassipes (Mart.

Comparative Effectiveness and Safety of Oral Anticoagulants Across Kidney Function in Patients With Atrial Fibrillation.

Background: Patients with atrial fibrillation and severely decreased kidney function were excluded from the pivotal non-vitamin K antagonist oral anticoagulants (NOAC) trials, thereby raising questions about comparative safety and effectiveness in patients with reduced kidney function. The study aimed to compare oral anticoagulants across the range of kidney function in patients with atrial fibrillation.

Methods And Results: Using a US administrative claims database with linked laboratory data, 34 569 new users of oral anticoagulants with atrial fibrillation and estimated glomerular filtration rate ≥15 mL/(min·1.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

Background: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.

S100A9-RAGE Axis Accelerates Formation of Macrophage-Mediated Extracellular Vesicle Microcalcification in Diabetes Mellitus.

Objective: Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. Previous work has established a role for calcification-prone extracellular vesicles in promoting vascular calcification. However, the mechanisms by which diabetes mellitus provokes cardiovascular events remain incompletely understood.