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.

Distinct effects of PTST2b and MRC on starch granule morphogenesis in potato tubers.

The molecular mechanisms underpinning the formation of the large, ellipsoidal starch granules of potato tuber are poorly understood. Here, we demonstrate the distinct effects of PROTEIN TARGETING TO STARCH2b (PTST2b) and MYOSIN RESEMBLING CHLOROPLAST PROTEIN (MRC) on tuber starch granule morphology. A gene duplication event in the Solanaceae resulted in two PTST2 paralogs (PTST2a and PTST2b).

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.

Discovery of CVN293, a Brain Permeable KCNK13 (THIK-1) Inhibitor Suitable for Clinical Assessment.

The potassium (K) ion channel KCNK13 is specifically expressed in human microglia with elevated expression observed in post-mortem human brain tissue from patients with Alzheimer's disease. Modulation of KCNK13 activity by a small-molecule inhibitor is proposed as a potential treatment for neurodegenerative diseases. Herein, we describe the evolution of a series of KCNK13 inhibitors derived from a high-throughput screening campaign, resulting in , a potent, selective, and brain permeable clinical candidate molecule.

Diabetes increases risk of lumbar spinal fusion complications: association with altered structure of newly formed bone at the fusion site.

Diabetes predisposes to spine degenerative diseases often requiring surgical intervention. However, the statistics on the prevalence of spinal fusion success and clinical indications leading to the revision surgery in diabetes are conflicting. The purpose of the presented retrospective observational study was to determine the link between diabetes and lumbar spinal fusion complications using a database of patients ( = 552, 45% male, age 54 ± 13.

Embodying loving kindness: Examining self-compassionate writing tasks and body satisfaction among transgender and non-binary people.

Using an experimental posttest-only control group design, the purpose of this study was to examine the effects of self-compassionate writing exercises on transgender and non-binary participants' body satisfaction, gender identity pride, and internalized transphobia. A total of 238 transgender people participated in this study (M = 28.27, SD = 8.

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.

Differential contribution of THIK-1 K channels and P2X7 receptors to ATP-mediated neuroinflammation by human microglia.

Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release of IL-1β. Extracellular ATP is a strong activator of NLRP3 by inducing K efflux as a key signaling event, suggesting that K-permeable ion channels could have high therapeutic potential. In microglia, these include ATP-gated THIK-1 K channels and P2X7 receptors, but their interactions and potential therapeutic role in the human brain are unknown.

Thermal Damage in Orthopaedics.

There are numerous potential sources of thermal damage encountered in orthopaedic surgery. An understanding of the preclinical mechanisms of thermal damage in tissues is necessary to minimize iatrogenic injuries and use these mechanisms therapeutically. Heat generation is a phenomenon that can be used to a surgeon's benefit, most commonly for hemostasis and local control of tumors.

A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy.

Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain.

Discovery and first-time disclosure of CVN766, an exquisitely selective orexin 1 receptor antagonist.

Modulators of orexin receptors are being developed for neurological illnesses such as sleep disorders, addictive behaviours and other psychiatric diseases. We herein describe the discovery of CVN766, a potent orexin 1 receptor antagonist that has greater than 1000-fold selectivity for the orexin 1 receptor over the orexin 2 receptor and demonstrates low off target hits in a diversity screen. In agreement with its in vitro ADME data, CVN766 demonstrated moderate in vivo clearance in rodents and displayed good brain permeability and target occupancy.

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.

Moderate sagittal plane deformity patients have similar radiographic and functional outcomes with either anterior or posterior surgery.

Purpose: This study aimed to compare the functional and radiographic outcomes of two surgical interventions for adult spinal deformity (ASD): anterior lumbar interbody fusion with anterior column realignment (ALIF-ACR) and posterior approach using Smith-Peterson osteotomy with transforaminal lumbar interbody fusion and pedicle screw fixation (TLIF-Schwab2).

Methods: A retrospective cohort study included 61 ASD patients treated surgically between 2019 and 2020 at a single tertiary orthopedic specialty hospital. Patients were divided into two groups: Group 1 (ALIF-ACR, 29 patients) and Group 2 (TLIF-Schwab2, 32 patients).