Tumour Mutational Burden and Immune Checkpoint Inhibitor Response in Non-small Cell Lung Cancer: A Continuous Modelling Approach.

Background: Tumour mutational burden (TMB) is an established biomarker for patients treated with immune checkpoint inhibitors (ICIs). The optimal TMB cut-off is uncertain. It is also uncertain whether there is a sharp TMB threshold or a more graduated change in clinical outcomes as TMB increases.

Ritonavir may prolong sedation but is unlikely to increase the risk of respiratory arrest in patients requiring intravenous midazolam for procedural sedation.

Intravenous midazolam is frequently used for procedural sedation. Use of ritonavir containing antivirals in patients requiring procedural sedation with intravenous midazolam is postulated to increase the risk or prolong the consequences of exposure related adverse events. The primary objective of this study was to characterize interaction of ritonavir with IV midazolam.

Gender Representation of Health Care Professionals in Large Language Model-Generated Stories.

Importance: With the growing use of large language models (LLMs) in education and health care settings, it is important to ensure that the information they generate is diverse and equitable, to avoid reinforcing or creating stereotypes that may influence the aspirations of upcoming generations.

Objective: To evaluate the gender representation of LLM-generated stories involving medical doctors, surgeons, and nurses and to investigate the association of varying personality and professional seniority descriptors with the gender proportions for these professions.

Design, Setting, And Participants: This is a cross-sectional simulation study of publicly accessible LLMs, accessed from December 2023 to January 2024.

Establishing the capacity to monitor proteins relevant to the study of drug exposure and response using liver-derived extracellular vesicles.

Aims: Drug exposure and response is determined by pharmacokinetic (PK) and pharmacodynamic (PD) profiles. Interindividual differences in abundance of drug metabolizing enzymes (DMEs) and drug target proteins underpin PK and PD variability and impact treatment efficacy and tolerability. Extracellular vesicles (EVs) carry protein cargo inherited from originating cells and may be useful for defining differences in key proteins related to hepatic drug metabolism and the treatment of metabolic-associated fatty liver disease (MAFLD).

The Impact of COVID-19 on Children, Young People, and Families in Sihanoukville, Cambodia: The Mitigating Work of M'Lop Tapang.

Globally, children have been adversely affected by the wide variety of impacts of SARS-CoV-2 (Coronavirus | COVID-19). Vulnerable children who depend on the support of education and health and social care systems were left unprotected as these systems were weakened by the pandemic. COVID-19 has exposed the already fragile situations in which many children and young people live and that thousands of children and young people would need ongoing support but remained invisible to statutory authorities.

Clinical Study Report and Individual Participant Data Transparency for US Food and Drug Administration-Approved Anticancer Drugs: A Call for Systematic Data Availability.

Unlocking the full potential of clinical trials through comprehensive CSR and IPD sharing can revolutionize cancer care, enhance safety evaluations, and reduce bias in systematic reviews. It is time for all stakeholders to embrace transparency and advance patient-centered outcomes.

A lack of association between BMI and chemoimmunotherapy efficacy in advanced non-small cell lung cancer: Secondary analysis of the IMpower150 and IMpower130 clinical trials.

Background: Multiple studies have indicated that patients with high body mass index (BMI) may have favourable survival outcomes following treatment with an immune checkpoint inhibitor (ICI). However, this evidence is limited by several factors, notably the minimal evidence from randomised controlled trials (RCTs), the use of categorised BMI with inconsistent cut point definitions, and minimal investigation of contemporary combination ICI therapy. Moreover, whether overweight and obese patients gain a larger benefit from contemporary frontline chemoimmunotherapy in non-small cell lung cancer (NSCLC) is unclear.

Current safeguards, risk mitigation, and transparency measures of large language models against the generation of health disinformation: repeated cross sectional analysis.

Objectives: To evaluate the effectiveness of safeguards to prevent large language models (LLMs) from being misused to generate health disinformation, and to evaluate the transparency of artificial intelligence (AI) developers regarding their risk mitigation processes against observed vulnerabilities.

Design: Repeated cross sectional analysis.

Setting: Publicly accessible LLMs.

Accessibility of clinical study reports supporting medicine approvals: a cross-sectional evaluation.

Objectives: Clinical study reports (CSRs) are highly detailed documents that play a pivotal role in medicine approval processes. Though not historically publicly available, in recent years, major entities including the European Medicines Agency (EMA), Health Canada, and the US Food and Drug Administration (FDA) have highlighted the importance of CSR accessibility. The primary objective herein was to determine the proportion of CSRs that support medicine approvals available for public download as well as the proportion eligible for independent researcher request via the study sponsor.

Study of the ketohexokinase inhibitor PF-06835919 as a clinical cytochrome P450 3A inducer: Integrated use of oral midazolam and liquid biopsy.

PF-06835919, a ketohexokinase inhibitor, presented as an inducer of cytochrome P450 3A4 (CYP3A4) in vitro (human primary hepatocytes), and static mechanistic modeling exercises predicted significant induction in vivo (oral midazolam area under the plasma concentration-time curve [AUC] ratio [AUCR] = 0.23-0.79).

Interfacial Assembly of Bacterial Microcompartment Shell Proteins in Aqueous Multiphase Systems.

Compartments are a fundamental feature of life, based variously on lipid membranes, protein shells, or biopolymer phase separation. Here, this combines self-assembling bacterial microcompartment (BMC) shell proteins and liquid-liquid phase separation (LLPS) to develop new forms of compartmentalization. It is found that BMC shell proteins assemble at the liquid-liquid interfaces between either 1) the dextran-rich droplets and PEG-rich continuous phase of a poly(ethyleneglycol)(PEG)/dextran aqueous two-phase system, or 2) the polypeptide-rich coacervate droplets and continuous dilute phase of a polylysine/polyaspartate complex coacervate system.

Proteomic profiling of paired human liver homogenate and tissue derived extracellular vesicles.

Advances in technologies to isolate extracellular vesicles (EVs) and detect/quantify their cargo underpin the novel potential of these circulating particles as a liquid biopsy to understand physiology and disease. One organ of particular interest in terms of utilizing EVs as a liquid biopsy is the liver. The extent to which EVs originating from the liver reflect the functional status of this organ remains unknown.

A 10-year update to the principles for clinical trial data sharing by pharmaceutical companies: perspectives based on a decade of literature and policies.

Data sharing is essential for promoting scientific discoveries and informed decision-making in clinical practice. In 2013, PhRMA/EFPIA recognised the importance of data sharing and supported initiatives to enhance clinical trial data transparency and promote scientific advancements. However, despite these commitments, recent investigations indicate significant scope for improvements in data sharing by the pharmaceutical industry.

Heterogeneity and Utility of Pharmaceutical Company Sharing of Individual-Participant Data Packages.

Importance: The pharmaceutical industry has made substantial investments in developing processes for sharing individual-participant data (IPD) from clinical trials. However, the utility and completeness of shared IPD and supporting documents must be evaluated to ensure the potential for scientific advancements from the data sharing ecosystem can be realized.

Objective: To assess the utility and completeness of IPD and supporting documents provided from industry-sponsored clinical trials.

Developing rights-based standards for children having tests, treatments, examinations and interventions: using a collaborative, multi-phased, multi-method and multi-stakeholder approach to build consensus.

Children continue to experience harm when undergoing clinical procedures despite increased evidence of the need to improve the provision of child-centred care. The international ISupport collaboration aimed to develop standards to outline and explain good procedural practice and the rights of children within the context of a clinical procedure. The rights-based standards for children undergoing tests, treatments, investigations, examinations and interventions were developed using an iterative, multi-phased, multi-method and multi-stakeholder consensus building approach.

Kinetic control of shape deformations and membrane phase separation inside giant vesicles.

A variety of cellular processes use liquid-liquid phase separation (LLPS) to create functional levels of organization, but the kinetic pathways by which it proceeds remain incompletely understood. Here in real time, we monitor the dynamics of LLPS of mixtures of segregatively phase-separating polymers inside all-synthetic, giant unilamellar vesicles. After dynamically triggering phase separation, we find that the ensuing relaxation-en route to the new equilibrium-is non-trivially modulated by a dynamic interplay between the coarsening of the evolving droplet phase and the interactive membrane boundary.

Drug-drug interactions that alter the exposure of glucuronidated drugs: Scope, UDP-glucuronosyltransferase (UGT) enzyme selectivity, mechanisms (inhibition and induction), and clinical significance.

Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs.

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution.

Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported.

Understanding the Risk of Drug Interactions Between Ritonavir-Containing COVID-19 Therapies and Small-Molecule Kinase Inhibitors in Patients With Cancer.

Purpose: The introduction of COVID-19 therapies containing ritonavir has markedly expanded the scope of use for this medicine. As a strong cytochrome P450 3A4 inhibitor, the use of ritonavir is associated with a high drug interaction risk. There are currently no data to inform clinician regarding the likely magnitude and duration of interaction between ritonavir-containing COVID-19 therapies and small-molecule kinase inhibitors (KIs) in patients with cancer.

Analysis of Extracellular Vesicle and Contaminant Markers in Blood Derivatives Using Multiple Reaction Monitoring.

Extracellular vesicles (EVs) are naturally occurring membranous particles that can be isolated from blood and other biofluids. EVs have drawn considerable attention for their potential as a minimally invasive biomarker source for a range of conditions, based on tissue-specific expression of proteins and other molecular information. To promote robust characterization of EV isolates, the International Society for Extracellular Vesicles (ISEV) has established consensus minimal requirements for the study of extracellular vesicles (MISEV) reporting guidelines.

Time to change the reference ranges of children's physiological observations in emergency care? A prospective study.

Aim: High heart and respiratory rates are key indicators in many published guidelines to identify and treat serious bacterial infection and sepsis in children, but the credibility of evidence underpinning what is considered abnormal is questionable. This study established the distribution of heart and respiratory rates of children using a large data set to inform debate on what the 'normal' range of these should look like. The primary aim was to compare the distribution of heart and respiratory rates measured in children recruited from non-tertiary emergency care settings with those published by Advanced Paediatric Life Support (APLS).