Single-cell RNA seq-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma.

Background & Aims: The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit versus resistance to atezo+bev.

Meta-epidemiology and reporting characteristics of mapping reviews: a scoping review.

Objectives: To investigate the meta-epidemiology and reporting characteristics of mapping reviews.

Study Design And Setting: We conducted a scoping review of a sample of recent mapping reviews (2022-2023) by searching nine electronic databases and eleven institutional websites up to January 2024. A 28-item reporting checklist, developed by our team and based on existing guidance and methodological studies of mapping reviews, was employed to assess reporting characteristics.

Breast cancer patients with a pre-existing mental illness are less likely to receive guideline-recommended cancer treatment: A systematic review and meta-analysis.

Breast cancer is the most commonly diagnosed cancer worldwide, with early detection and advanced treatments contributing to declining mortality rates. However, managing comorbid conditions, particularly mental illness, presents significant challenges for cancer treatment. This study systematically reviews and meta-analyses the impact of having a pre-existing mental illness on breast cancer treatment utilisation, focusing on specific treatments and comparing different mental illnesses.

An expert consensus statement on biomarkers of ageing for use in intervention studies.

Biomarkers of ageing serve as important outcome measures in longevity-promoting interventions. However, there is limited consensus on which specific biomarkers are most appropriate for human intervention studies. This work aimed to address this need by establishing an expert consensus on biomarkers of ageing for use in intervention studies via the Delphi method.

Unravelling 2-oxoglutarate turnover and substrate oxidation dynamics in 5-methylcytosine-oxidising TET enzymes.

Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases use 2OG and O cofactors to catalyse substrate oxidation and yield oxidised product, succinate, and CO. Simultaneous detection of substrate and cofactors is difficult, contributing to a poor understanding of the dynamics between substrate oxidation and 2OG decarboxylation activities. Here, we profile 5-methylcytosine (C)-oxidising Ten-Eleven Translocation (TET) enzymes using MS and H NMR spectroscopy methods and reveal a high degree of substrate oxidation-independent 2OG turnover under a range of conditions.

Oncogenic PIK3CA corrupts growth factor signaling specificity.

Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations of PI3K-specific information transfer for different growth factors. This features live-cell imaging of PI3K/AKT activity reporters and multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers over time.

The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression.

Objective: To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression.

Methods: For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with psychological support.

Randomized trial investigating the utility of a liver tissue transcriptional biomarker in identifying adult liver transplant recipients not requiring maintenance immunosuppression.

The maintenance of stable allograft status in the absence of immunosuppression, known as operational tolerance, can be achieved in a small proportion of liver transplant recipients, but we lack reliable tools to predict its spontaneous development. We conducted a prospective, multi-center, biomarker-strategy design, immunosuppression withdrawal clinical trial to determine the utility of a predictive biomarker of operational tolerance. The biomarker test, originally identified in a patient cohort with high operational tolerance prevalence, consisted of a 5-gene transcriptional signature measured in liver tissue collected before initiating immunosuppression weaning.

Clinical and cost-effectiveness of parenting intervention for mothers experiencing psychosocial stress: insights from the early closure of the Mellow Babies RCT.

Background: Problems in children's early social and emotional development are likely to have major long-term consequences for the individual and society: maternal emotional well-being is associated with better outcomes. Interventions designed to improve both maternal mental health and the mother-child relationship are thus likely to benefit both maternal health and child development.

Objectives: To establish the clinical and cost-effectiveness of the Mellow Babies parenting intervention for women experiencing psychosocial stress and their 6- to 18-month-old babies.

Genetic and Genomic Approaches to the Study of Drug-Induced Liver Injury.

Idiosyncratic hepatotoxicity induced by prescribed drugs has been known since the early 20th century. Identifying risk factors, including genetic factors, that trigger this drug-induced liver injury (DILI) has been an important priority for many years, both to prevent drugs that cause liver injury being licensed and as a potential means of preventing at-risk patients being prescribed causative drugs. Improved methods for genomic analysis, particularly the development of genome-wide association studies, have facilitated the identification of genomic risk factors for DILI, but, to date, there are only two main examples, liver injury caused by amoxicillin-clavulanate (AC) and by flucloxacillin, where genetic risk factors causing the injury have been identified and replicated with understanding of the underlying mechanism.

Changes in iPSC-Astrocyte morphology reflect Alzheimer's disease patient clinical markers.

Human induced pluripotent stem cells (iPSCs) provide powerful cellular models of Alzheimer's disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms. Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimer's disease (AD) reflect clinical markers, including β-amyloid (Aβ) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets.

Comparisons of approaches to pelvic floor muscle training for urinary incontinence in women.

Background: Pelvic floor muscle training (PFMT) is a recommended treatment for female stress, urgency, and mixed urinary incontinence. Training varies in exercise type (pelvic floor muscles contracting with and without other muscles), dose, and delivery (e.g.

Can eggshells indicate stressor exposure in free-range laying hens?

Finding effective ways to monitor laying hen welfare is challenging as UK flock sizes can reach 16,000 birds. Eggs provide potential for welfare monitoring, as they are a daily output with previous evidence of links to stress. We explored the associations between stressors and eggs using two complementary studies.

Evaluating enrichment use in group-housed rhesus macaques (): A machine learning approach.

Environmental enrichment programmes are widely used to improve welfare of captive and laboratory animals, especially non-human primates. Monitoring enrichment use over time is crucial, as animals may habituate and reduce their interaction with it. In this study we aimed to monitor the interaction with enrichment items in groups of rhesus macaques (), each consisting of an average of ten individuals, living in a breeding colony.

Community-based physical and social activity for older adults with mild frailty: a rapid qualitative study of a collaborative intervention pilot.

Background: Intervening to modify frailty trajectories may be critical to maintain health and independence in later life. The Active Ageing Programme (AAP) is a 16-week community-based intervention for older people with mild frailty that combines physical activity and social interaction. The programme aims to positively impact resilience and wellbeing, changing the physical, mental and social factors that impact on frailty trajectories.

Tackling algorithmic bias and promoting transparency in health datasets: the STANDING Together consensus recommendations.

Without careful dissection of the ways in which biases can be encoded into artificial intelligence (AI) health technologies, there is a risk of perpetuating existing health inequalities at scale. One major source of bias is the data that underpins such technologies. The STANDING Together recommendations aim to encourage transparency regarding limitations of health datasets and proactive evaluation of their effect across population groups.

Longer-term survival, quality of life, and cost-effectiveness of conservative versus liberal oxygenation targets in critically ill children: a pre-specified analysis from Oxy-PICU, a multicentre, open, parallel-group, randomised controlled trial.

Background: Peripheral oxygen saturation (SpO) above 94% is typical in children in paediatric intensive critical care units (PICUs) who are receiving invasive ventilation and supplemental oxygen. In a previous report from the Oxy-PICU trial, we showed that lower (conservative) oxygenation targets (SpO 88-92%) are beneficial, showing small but statistically significant differences in duration of organ support and large but non-significant cost reductions at 30 days. In this pre-specified analysis of the Oxy-PICU trial, we compare longer-term outcomes and cost-effectiveness of conservative versus liberal (SpO >94%) oxygenation targets in children with emergency PICU admission.

Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.

The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency.

Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial.

Background: Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial.

Methods: FIREFLY-1 investigated the efficacy (arm 1, n=77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG).