Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C.

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON).

Provision of inguinal hernia surgery in first-referral hospitals across low- and middle-income countries: Secondary analysis of an international cohort study.

Introduction: Surgical care in first-referral hospitals (FRHs) in low- and middle-income countries (LMICs) is poorly characterized. Inguinal hernia repair can act as a good tracer condition. This study aimed to evaluate the variation in hernia repair across different hospital types in LMICs.

National phosphorus planning for food and environmental security.

The dependence of countries on phosphorus fertilisers derived from phosphate rock to maintain crop yields and ensure food security is well established. Yet, exposure of national food systems to constrained reserves of phosphate rock and supply chain complexities still pose risks to farmers' access to this critical nutrient in many countries. Whilst phosphorus scarcity can threaten food security, suboptimal fertiliser use and poor wastewater treatment can lead to pollution of freshwaters and coasts, causing eutrophication.

Structures, processes and outcomes between first referral and referral hospitals in low-income and middle-income countries: a secondary preplanned analysis of the FALCON and ChEETAh randomised trials.

First referral hospitals, often known as district hospitals, are neglected in the discourse on universal health coverage in low-income and middle-income countries (LMICs). However, these hospitals are important for delivering safe surgery for 313 million people. This study aims to understand the structures, processes and outcomes of patients undergoing surgery in these centres in LMICs.

Smaller meat portions contribute the most to reducing meat consumption in the United Kingdom.

Reducing meat consumption can help improve environmental and health outcomes, yet the effect of specific meat-reducing strategies is context dependent. Here, using decomposition analysis of National Diet and Nutrition Survey data (2008-2009 to 2018-2019), we found that in the United Kingdom, reduced meat portions had the largest impact on total meat consumption decline (52%), followed by fewer meat-eating days (24%), fewer meat consumers (17%) and fewer meat-eating meal occasions (7%). Understanding meat consumption behaviour patterns is key for more effective policies.

Cellular and Molecular Mechanisms of Hypertrophy of Ligamentum Flavum.

Hypertrophy of the ligamentum flavum (HLF) is a common contributor to lumbar spinal stenosis (LSS). Fibrosis is a core pathological factor of HLF resulting in degenerative LSS and associated low back pain. Although progress has been made in HLF research, the specific molecular mechanisms that promote HLF remain to be defined.

Retinal detachment in Type IX collagen recessive Stickler syndrome.

Objective: Stickler Syndrome (SS) is associated with eye, joint and orofacial abnormalities. Most cases are dominantly inherited through COL2A1/COL11A1 variants encoding type-II/XI collagen, with patients having up to 78% retinal detachment (RD) risk. Rarer cases of recessive SS have also been identified, associated with pathogenic variants of genes including COL9A1, COL9A2 & COL9A3 encoding type-IX collagen, but there is limited published data on patients' phenotype or RD risk.

Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response.

Immunotherapy successfully complements traditional cancer treatment. However, primary and acquired resistance might limit efficacy. Reduced antigen presentation by MHC-I has been identified as potential resistance factor.

Microbiome-derived antimicrobial peptides show therapeutic activity against the critically important priority pathogen, Acinetobacter baumannii.

Acinetobacter baumannii is designated by the World Health Organisation as a critical priority pathogen. Previously we discovered antimicrobial peptides (AMPs), namely Lynronne-1, -2 and -3, with efficacy against bacterial pathogens, such as Staphylococcus aureus and Pseudomonas aeruginosa. Here we assessed Lynronne-1, -2 and -3 structure by circular dichroism and efficacy against clinical strains of A.

ACTION-ARC Pediatric and Adult Congenital Heart Disease Ventricular Assist Device Adverse Event Definitions-2023.

Adverse events (AEs) experienced by children and adults with congenital heart disease (CHD) on ventricular assist devices (VADs) are sometimes unique to these populations. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and the Academic Research Consortium (ARC) aimed to harmonize definitions of pediatric and CHD AEs for use in clinical trials, registries, and regulatory evaluation. Data from the ACTION registry and adjudication committee were used to adapt general mechanical circulatory support ARC definitions.

When to vaccinate for seasonal influenza? Check the peak forecast.

Background: Seasonal influenza infects 5-20% of people every year in the United States, resulting in hospitalizations, deaths, and adverse economic impacts. To mitigate these impacts, influenza vaccines are developed and distributed annually; however, growing evidence suggests that vaccine effectiveness (VE) wanes over the course of a flu season. Delaying influenza vaccination for older adults has attracted attention as a potential public health strategy.

Extracorporeal cardiopulmonary resuscitation for pediatric out-of-hospital cardiac arrest: A review of the Extracorporeal Life Support Organization Registry.

Aims: Current data are insufficient for the leading resuscitation societies to advise on the use of extracorporeal cardiopulmonary resuscitation (ECPR) for pediatric out-of-hospital cardiac arrest (OHCA). The aim of this study was to explore the current utilization of ECPR for pediatric OHCA and characterize the patient demographics, arrest features, and metabolic parameters associated with survival.

Methods: Retrospective review of the Extracorporeal Life Support Organization Registry database from January 2020 to May 2023, including children 28 days to 18 years old who received ECPR for OHCA.

Vitrectomy as an Adjunct to Treat-and-Extend Anti-VEGF Injections for Diabetic Macular Edema: The Vitrectomy in Diabetic Macular Oedema (VIDEO) Randomized Clinical Trial.

Importance: There are reported benefits from vitrectomy for diabetic macular edema (DME); however, data precede anti-vascular endothelial growth therapy (VEGF) therapy, supporting a need to assess the current role of vitrectomy.

Objective: To determine rates of recruitment and efficacy outcomes of vitrectomy plus internal limiting membrane (ILM) peeling adjunctive to treat-and-extend (T&E) anti-VEGF injections for diabetic macular edema (DME).

Design, Setting, And Participants: This was a single-masked, multicenter randomized clinical trial at 21 sites in the United Kingdom from June 2018 to January 2021, evaluating single eyes of treatment-naive patients with symptomatic vision loss from DME for less than 1 year.

Estimated effects of reductions in processed meat consumption and unprocessed red meat consumption on occurrences of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality in the USA: a microsimulation study.

Background: High consumption of processed meat and unprocessed red meat is associated with increased risk of multiple chronic diseases, although there is substantial uncertainty regarding the relationship for unprocessed red meat. We developed a microsimulation model to estimate how reductions in processed meat and unprocessed red meat consumption could affect rates of type 2 diabetes, cardiovascular disease, colorectal cancer, and mortality in the US adult population.

Methods: We used data from two versions of the US National Health and Nutrition Examination Survey, one conducted during 2015-16 and one conducted during 2017-18, to create a simulated US population.

Priorities for Clinical Research in Pediatric Extracorporeal Membrane Oxygenation Anticoagulation From the Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

Objectives: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus.

Data Sources: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children.

Study Selection: The management of ECMO anticoagulation for critically ill neonates and children.

Management of Bleeding and Thrombotic Complications During Pediatric Extracorporeal Membrane Oxygenation: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

Objectives: To derive systematic-review informed, modified Delphi consensus regarding the management of bleeding and thrombotic complications during pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE Consensus Conference.

Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021.

Study Selection: The management of bleeding and thrombotic complications of ECMO.

Management of Extracorporeal Membrane Oxygenation Anticoagulation in the Perioperative Period: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

Objectives: To derive systematic review-informed, modified Delphi consensus regarding the management of children on extracorporeal membrane oxygenation (ECMO) undergoing invasive procedures or interventions developed by the Pediatric Anticoagulation on ECMO CollaborativE (PEACE) Consensus Conference.

Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021.

Study Selection: ECMO anticoagulation and hemostasis management in the perioperative period and during procedures.

Antifibrinolytic and Adjunct Hemostatic Agents: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

Objectives: To derive systematic-review informed, modified Delphi consensus regarding antifibrinolytic and adjunct hemostatic agents in neonates and children supported with extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE consensus conference.

Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021.

Study Selection: Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs).