Real-world evidence: state-of-the-art and future perspectives.

Recent developments in digital infrastructure, advanced analytical approaches, and regulatory settings have facilitated the broadened use of real-world evidence (RWE) in population health management and evaluation of novel health technologies. RWE has uniquely contributed to improving human health by addressing unmet clinical needs, from assessing the external validity of clinical trial data to discovery of new disease phenotypes. In this perspective, we present exemplars across various health areas that have been impacted by real-world data and RWE, and we provide insights into further opportunities afforded by RWE.

RNA Helicase DDX3 Interacts with the Capsid Protein of Hepatitis E Virus and Plays a Vital Role in the Viral Replication.

DDX3 is an ATP-dependent RNA helicase that is involved in multiple cellular activities, including RNA metabolism and innate immunity. DDX3 is known to assist the replication of some viruses while restricting others through its direct interaction with viral proteins. However, the role of DDX3 in the replication of the hepatitis E virus (HEV) is unknown.

17β-estradiol status alters NMDAR function and antipsychotic-like activity in female rats.

Low 17β-estradiol (E2) in females of reproductive age, and marked E2 decline with menopause, contributes to heightened symptom severity in schizophrenia (i.e. cognitive dysfunction) and diminished response to antipsychotic medications.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups.

We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10) variants, 184 of which were novel.

AlphaFold and Docking Approaches for Antibody-Antigen and Other Targets: Insights From CAPRI Rounds 47-55.

Accurate modeling of the structures of protein-protein complexes and other biomolecular interactions represents a longstanding and important challenge for computational biology. The Critical Assessment of PRedicted Interactions (CAPRI) experiment has served for over two decades as a key means to assess and compare current approaches and methods through blind predictive scenarios, highlighting useful strategies, and new developments. Here we describe the performance of our laboratory's team in recent CAPRI rounds, which included submissions for 10 modeling targets.

Clinical impacts of utilizing ceftriaxone and metronidazole versus piperacillin/tazobactam in patients diagnosed with complicated diverticulitis.

Background: The optimal antibiotic regimen to empirically treat complicated diverticulitis has not been well established in guidelines.

Methods: A 5-year retrospective cohort study was conducted with 322 patients admitted to Mayo Clinic hospitals for complicated diverticulitis. Outcomes for 89 patients treated with ceftriaxone and metronidazole were compared to 233 patients treated with piperacillin/tazobactam.

Reactivity of a heterobinuclear heme-peroxo-Cu complex with -substituted catechols shows a p -dependent change in mechanism.

In biological systems, heme-copper oxidase (HCO) enzymes play a crucial role in the oxygen reduction reaction (ORR), where the pivotal O-O bond cleavage of the (heme)Fe-peroxo-Cu intermediate is facilitated by active-site (peroxo core) hydrogen bonding followed by proton-coupled electron transfer (PCET) from a nearby (phenolic) tyrosine residue. A useful approach to comprehend the fundamental relationships among H-bonding/proton/H-atom donors and their abilities to induce O-O bond homolysis involves the investigation of synthetic, bioinspired model systems where the exogenous substrate properties (such as p and bond dissociation energy (BDE)) can be systematically altered. This report details the reactivity of a heme-peroxo-copper HCO model complex (LS-4DCHIm) toward a series of substituted catechol substrates that span a range of p and O-H bond BDE values, exhibiting different reaction mechanisms.

Characterization of DNA methylation clock algorithms applied to diverse tissue types.

Background: DNA methylation (DNAm) data from human samples has been leveraged to develop "epigenetic clock" algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types.

Differential DNA Methylation in the Benign and Cancerous Prostate Tissue of African American and European American Men.

Background: African American (AA) men are at increased risk of prostate cancer compared with European American (EA) men. Biological mechanisms, including epigenetics, likely contribute to this disparity, but prior studies have been limited by sample size, candidate gene approaches, or lack of epigenome-wide DNA methylation (DNAm) data.

Methods: To improve our understanding of these mechanisms, we compared DNAm features distinguishing tumor and paired histologically benign tissue from 76 AA and 75 EA patients with prostate cancer.

Alternative splicing induces sample-level variation in gene-gene correlations.

Background: The vast majority of genes in the genome are multi-exonic, and are alternatively spliced during transcription, resulting in multiple isoforms for each gene. For some genes, different mRNA isoforms may have differential expression levels or be involved in different pathways. Bulk tissue RNA-seq, as a widely used technology for transcriptome quantification, measures the total expression (TE) levels of each gene across multiple isoforms in multiple cell types for each tissue sample.

Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings.

To gain further insight into the conformational properties of small cyclic peptides that bind to the G-protein coupled receptor C5aR1, we report here for the first time the elucidation of three peptide solution conformations using residual dipolar couplings and NMR temperature coefficients. Each of these peptides varies by at least one amino acid, adopts a different intramolecular hydrogen bonding pattern, and has a different solution conformation. The solution conformations were used in combination with a homology structure of C5aR1 as a design template for increasing the potency of peptide leads for the C5a receptor.

A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV.

Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing cGMP manufacturing capability. Here we report the engineering of an anti-CD4 binding-site (CD4bs) bnAb, N49P9.

Exploring the potential of structure-based deep learning approaches for T cell receptor design.

Deep learning methods, trained on the increasing set of available protein 3D structures and sequences, have substantially impacted the protein modeling and design field. These advancements have facilitated the creation of novel proteins, or the optimization of existing ones designed for specific functions, such as binding a target protein. Despite the demonstrated potential of such approaches in designing general protein binders, their application in designing immunotherapeutics remains relatively underexplored.

TCR3d 2.0: expanding the T cell receptor structure database with new structures, tools and interactions.

Recognition of antigens by T cell receptors (TCRs) is a key component of adaptive immunity. Understanding the structures of these TCR interactions provides major insights into immune protection and diseases, and enables design of therapeutics, vaccines and predictive modeling algorithms. Previously, we released TCR3d, a database and resource for structures of TCRs and their recognition.

The influence of near-peer teaching on undergraduate health professional students' self-efficacy beliefs: A systematic integrative review.

Background: Near-peer teaching, a type of peer teaching traditionally used in medical education, has gained popularity as a way of enhancing students' learning in undergraduate health disciplines such as nursing, physiotherapy and paramedicine. Research has established the positive impact of near-peer teaching on health professional students' cognitive and psychomotor outcomes; however, little is known about its influence on students' self-efficacy beliefs, which are important predictors of future clinical performance.

Aim: To determine the influence, if any, of near-peer teaching participation on undergraduate health professional students' self-efficacy beliefs.

A Mediating Effect of Public Service Motivation on Retention Intention Among Child Welfare Students: Task Self-Efficacy.

Purpose: This study investigates the role of Public Service Motivation (PSM) in retaining highly skilled and qualified child welfare graduates within the public child welfare sector.

Materials And Methods: Three entire cohorts of child welfare student social workers over three years ( = 125) in BSW and MSW child welfare programs at seven universities in a Southern state were surveyed to examine the effects of task self-efficacy achieved through the curriculum and public service motivation on retention intention among social work students specializing in child welfare practice at both the baccalaureate and master's levels. Mediation analysis was conducted to estimate the indirect effect of self-efficacy on students' retention intention.

Real-world study of the multimorbidity and health service utilisation among individuals with non-diabetic hyperglycemia and type 2 diabetes mellitus in North West London.

Introduction: The prevalence of non-diabetic hyperglycemia (NDH) and type 2 diabetes mellitus (T2DM) is increasing. While T2DM is recognised to be associated with multimorbidity and early mortality, people with NDH are frequently thought to be devoid of such complications, potentially exposing individuals with NDH to suboptimal care. We therefore used the Discover London Secure Data Environment (SDE) dataset to appreciate the relationship of NDH/T2DM with multimorbidity, healthcare usage, and clinical outcomes.

DNA methylation correlates of chronological age in diverse human tissue types.

Background: While the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types.

Results: Here, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project.

Examining the psychometric properties of the self-efficacy in clinical teaching scale with undergraduate nursing students: A cross-sectional study.

Aim: This paper aimed to examine the psychometric properties of a modified version of the Self-Efficacy in Clinical Teaching Scale with a sample of undergraduate nursing students.

Background: Enhancing nursing students' self-efficacy in clinical teaching is important for developing their clinical teaching capabilities, which ultimately contributes to safe quality healthcare. Little is known about nursing students' self-efficacy in clinical teaching, potentially due to a lack of validated instruments to measure their self-efficacy in clinical teaching.

Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ∼50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (RNA-seq) with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1.

An integrative multi-context Mendelian randomization method for identifying risk genes across human tissues.

Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often context- or tissue-specific eQTL effects challenge the MR assumption of consistent IV effects across eQTL and GWAS data.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study.

Objective: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria.

Methods: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria.

Low risk squamous cell carcinoma and appropriate follow up.

A recent article in the BJD postulated that it may be "Time to reconsider skin cancer-related follow-up visits". In our unit, we too have been seeing too many patient's unnecessarily and we put in place measures to reduce the numbers of outpatient appointments thereby diverting the resources saved into professional development.