Health state utilities associated with invasive pneumococcal disease, pneumonia, and recurrent acute otitis media in young children.

Purpose: Cost-utility analyses examining the value of new vaccines for pneumococcal disease will require health state utilities as inputs. Existing utilities for pneumococcal infections in young children are limited. The purpose of this study was to estimate health state utilities associated with pneumococcal infections in young children.

Corner Charge Fluctuation as an Observable for Quantum Geometry and Entanglement in Two-Dimensional Insulators.

Measuring bipartite fluctuations of a conserved charge, such as the particle number, is a powerful approach to understanding quantum systems. When the measured region has sharp corners, the bipartite fluctuation receives an additional contribution known to exhibit a universal angle dependence in 2D isotropic and uniform systems. Here we establish that, for generic lattice systems of interacting particles, the corner charge fluctuation is directly related to quantum geometry.

Exploring Restaurant Worker Mental Models of Injury and Safety Using Pathfinder Networks.

OCCUPATIONAL APPLICATIONSResults from our exploratory study of restaurant worker mental models of injury and safety emphasize the need for improved occupational safety in the culinary industry through targeted interventions for chefs and managers. The analysis we performed showed that managers possess more integrated and coherent mental models of injury and safety than chefs, reflected in network parameters showing better organization of safety concepts. Kitchen training programs should focus on bridging gaps in safety awareness and mitigating hazards such as burns, cuts, slips, and equipment-related risks.

Resolution of Neuropsychiatric Adverse Events After Switching to a Doravirine-Based Regimen in the Open-Label Extensions of the DRIVE-AHEAD and DRIVE-FORWARD Trials.

Background: Neuropsychiatric adverse events (NPAEs) are associated with several antiretrovirals. Doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor indicated for HIV-1 treatment, does not interact significantly with known neurotransmitter receptors in vitro. First-line therapy with DOR-based regimens resulted in significantly fewer NPAEs than efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) and similar rates to those of ritonavir-boosted darunavir (DRV/r) with 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) through Week 96 of the phase 3 DRIVE-AHEAD and DRIVE-FORWARD studies, respectively.

Maximizing the clinical utility and performance of cytology samples for comprehensive genetic profiling.

Comprehensive molecular profiling by next-generation sequencing has revolutionized tumor classification and biomarker evaluation. However, routine implementation is challenged by the scant nature of diagnostic material obtained through minimally invasive procedures. Here, we describe our long-term experience in profiling cytology samples with an in-depth assessment of the performance, quality metrics, biomarker identification capabilities, and potential pitfalls.

Combined endurance and resistance exercise training in heart failure with preserved ejection fraction: a randomized controlled trial.

Endurance exercise training (ET) is an effective treatment in heart failure with preserved ejection fraction (HFpEF), but the efficacy of resistance training in this patient population has been only scarcely evaluated. In this multicenter, randomized trial, we evaluated the effects of combined endurance and resistance training over 12 months in patients with HFpEF. The primary endpoint was a modified Packer score, including all-cause mortality, hospitalizations classified as potentially related to heart failure or exercise and changes in peak oxygen consumption ( ), diastolic function (E/e'), New York Heart Association (NYHA) class and global self-assessment (GSA).

The impact of common and rare genetic variants on bradyarrhythmia development.

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively.

Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.

Dysfunction of the endo-lysosomal intracellular Cholesterol transporter 2 protein (NPC2) leads to the onset of Niemann-Pick Disease Type C (NPC), a lysosomal storage disorder. Metabolic and homeostatic mechanisms are disrupted in lysosomal storage disorders (LSDs) hence we characterized a cellular model of NPC2 knock out, to assess alterations in organellar function and inter-organellar crosstalk between mitochondria and lysosomes. We performed characterization of lipid alterations and confirmed altered lysosomal morphology, but no overt changes in oxidative stress markers.

Impact Assessment Through Interrupted Time Series: Divergent Influences of Stay-at-Home Order on Socioeconomically Disadvantaged Areas in NYC Shooting Incidents.

This study examines the impact of the COVID-19 pandemic and stay-at-home (SAH) orders on gun violence in New York City (NYC), with a focus on variations across neighborhood demographic and socioeconomic characteristics. Using a 4-year longitudinal and geospatial analysis, we investigate the relationship between socioeconomic factors (e.g.

Development and optimization of dapagliflozin oral nano-bilosomes using response surface method: evaluation, evaluation.

In treating type 2 diabetes, avoiding glucose reabsorption (glucotoxicity) and managing hyperglycemia are also important. A metabolic condition known as diabetes (type-2) is characterized by high blood sugar levels in comparison to normal Bilosomes (BLs) containing Dapagliflozin (Dapa) were formulated, optimized, and tested for oral therapeutic efficacy in the current investigation. Used the Box Behnken design to optimize the Dapa-BLs, formulated via a thin-film hydration technique.

Sleep microstructure organizes memory replay.

Recently acquired memories are reactivated in the hippocampus during sleep, an initial step for their consolidation. This process is concomitant with the hippocampal reactivation of previous memories, posing the problem of how to prevent interference between older and recent, initially labile, memory traces. Theoretical work has suggested that consolidating multiple memories while minimizing interference can be achieved by randomly interleaving their reactivation.

Deciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.

Ataxin-2 is a protein containing a polyQ extension and intermediate length of polyQ extensions increases the risk of Amyotrophic Lateral Sclerosis (ALS). Down-regulation of Ataxin-2 has been shown to mitigate TDP-43 proteinopathy in ALS models. To identify alternative therapeutic targets that can mitigate TDP-43 toxicity, we examined the interaction between Ataxin-2 and TDP-43.

Clinical outcomes by baseline metastases in patients with renal cell carcinoma treated with lenvatinib plus pembrolizumab versus sunitinib: Post hoc analysis of the CLEAR trial.

Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off).

PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Type 1 diabetes genetic risk score variation across ancestries using whole genome sequencing and array-based approaches.

A Type 1 Diabetes Genetic Risk Score (T1DGRS) aids diagnosis and prediction of Type 1 Diabetes (T1D). While traditionally derived from imputed array genotypes, Whole Genome Sequencing (WGS) provides a more direct approach and is now increasingly used in clinical and research studies. We investigated the concordance between WGS-based and array-based T1DGRS across genetic ancestries in 149,265 UK Biobank participants using WGS, TOPMed-imputed, and 1000 Genomes-imputed array genotypes.

Automated 24-sector grid-map algorithm for prostate mpMRI improves precision and efficacy of prostate lesion location reporting.

Background: The Prostate Imaging-Reporting and Data System (PI-RADS) calls for reporting the prostate index lesion and the location within the transition (TZ) or peripheral zone (PZ) and location on a corresponding sector map. The aim of this study was to train a deep learning DL-based algorithm for automatic prostate sector mapping and to validate its' performance.

Methods: An automatic 24-sector grid-map (ASG) of the prostate was developed, based on an automatic zone-specific deep learning segmentation of the prostate.

Predicting sepsis mortality into an era of pandrug-resistant E. coli through modeling.

Background: Infections caused by antibiotic-resistant bacteria are increasingly frequent, burdening healthcare systems worldwide. As pathogens acquire resistance to all known antibiotics - i.e.

Predicting cisplatin tolerability in older adults with head and neck cancer - Insights for improved chemoradiation outcomes.

Purpose: Cumulative cisplatin doses of ≥ 200 mg/m improve survival in adults with head-and-neck squamous cell carcinoma (HNSCC) undergoing chemoradiation, but many older adults with HNSCC cannot receive this prognostically relevant dose due to toxicities. This study aims to develop predictive models to assess the likelihood of older adults with HNSCC receiving ≥ 200 mg/m cisplatin during chemoradiation.

Methods: 366 patients from the SENIOR database, an international cohort of adults ≥ 65 years with HNSCC, received definitive chemoradiation with single-agent cisplatin and were analyzed.

SETTING AN AGENDA FOR THE APPLICATION OF THE THOUGHT OF ARTHUR SCHOPENHAUER (1788-1860) IN CONTEMPORARY PSYCHIATRY, PSYCHOLOGY, AND PSYCHOTHERAPY.

There is a growing interest in the German thinker Arthur Schopenhauer (1788-1860), sometimes referred to as "the psychologist of the "will", but scarce empirical research has been conducted on the relevance of his philosophy for psychology and psychiatry. Following his death, philosophers, psychologists, psychiatrists, artists, writers, and natural scientists commended him. However, he was harshly criticized by others, notably by Friedrich Nietzsche and Martin Heidegger.

Prediction of metabolic subphenotypes of type 2 diabetes via continuous glucose monitoring and machine learning.

The classification of type 2 diabetes and prediabetes does not consider heterogeneity in the pathophysiology of glucose dysregulation. Here we show that prediabetes is characterized by metabolic heterogeneity, and that metabolic subphenotypes can be predicted by the shape of the glucose curve measured via a continuous glucose monitor (CGM) during standardized oral glucose-tolerance tests (OGTTs) performed in at-home settings. Gold-standard metabolic tests in 32 individuals with early glucose dysregulation revealed dominant or co-dominant subphenotypes (muscle or hepatic insulin-resistance phenotypes in 34% of the individuals, and β-cell-dysfunction or impaired-incretin-action phenotypes in 40% of them).

Identification of Polycystin 2 Missense Mutants Targeted for Endoplasmic Reticulum-Associated Degradation.

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder leading to end-stage renal disease. ADPKD arises from mutations in the and genes, which encode polycystin 1 (PC1) and polycystin 2 (PC2), respectively. PC2 is a non-selective cation channel, and disease-linked mutations disrupt normal cellular processes, including signaling and fluid secretion.

Phosphopeptide Neoantigens as Emerging Targets in Cancer Immunotherapy.

Protein post-translational modifications play a vital role in various cellular events essential for maintaining cellular physiology and homeostasis. In cancer cells, aberrant post-translational modifications such as glycosylation, acetylation, and phosphorylation on proteins can result in the generation of antigenic peptide variants presented in complex with MHC molecules. These modified peptides add to the class of tumorspecific antigens and offer promising avenues for targeted anti- cancer therapies.