The respiratory microbiome is linked to the severity of RSV infections and the persistence of symptoms in children.

Respiratory syncytial virus (RSV) is the leading cause of infant respiratory infections and hospitalizations. To investigate the relationship between the respiratory microbiome and RSV infection, we sequence nasopharyngeal samples from a birth cohort and a pediatric case-control study (Respiratory Syncytial virus Consortium in Europe [RESCEU]). 1,537 samples are collected shortly after birth ("baseline"), during RSV infection and convalescence, and from healthy controls.

Glucocorticoid treatment and new-onset hyperglycaemia and diabetes in people living with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Introduction: In people living with chronic obstructive pulmonary disease (COPD), we aimed to estimate: (1) the prevalence of glucocorticoid-induced hyperglycaemia (GIH); (2) whether the prevalence of GIH varies by age, baseline diabetes status, treatment duration, ascertainment of glycaemia, definition of hyperglycaemia, study design and year of publication; and (3) the relative risk (RR) of new-onset hyperglycaemia in exposed vs non-exposed to systemic glucocorticoids.

Methods: We searched electronic databases until 9 November 2023 for randomised controlled trials and observational studies including adults diagnosed with COPD, with or without diabetes at baseline, using systemic glucocorticoids equivalent to prednisolone ≥5 mg/day for ≥3 days if exposed. Hyperglycaemia was defined as a blood glucose above a study-specific cut-off.

Systems Immunology Approaches to Understanding Immune Responses in Acute Infection of Yellow Fever Patients.

In the 2018 yellow fever (YF) outbreak in Brazil, we generated new transcriptomic data and combined it with clinical and immunological data to decode the pathogenesis of YF. Analyzing 79 patients, we found distinct gene expression patterns between acute YF, other viral infections, and the milder YF-17D vaccine infection. We identified a critical role for low-density, immature neutrophils in severe outcomes, marked by the downregulation of genes essential for neutrophil migration and maturation, such as PADI4, CSF3R, and ICAM1, in deceased patients.

Diet quality from mid-life and body composition in older age: findings from a British birth cohort.

We investigated associations between 'healthy dietary pattern' scores, at ages 36, 43, 53 and 60-64 years, and body composition at age 60-64 among participants from the MRC National Survey of Health and Development (NSHD). Principal component analyses of dietary data (food diaries) at age 60-64 were used to calculate diet scores (healthy dietary pattern scores) at each age. Higher scores indicated healthier diets (higher consumption of fruit, vegetables and wholegrain bread).

Evidentiary basis of the first regulatory qualification of a digital primary efficacy endpoint.

Stride velocity 95th centile (SV95C) is a wearable-derived endpoint representing the 5% fastest strides taken during everyday living. In July 2023, SV95C received European Medicines Agency (EMA) qualification for use as a primary endpoint in trials of patients with Duchenne muscular dystrophy (DMD) aged ≥ 4 years-becoming the first digital endpoint to receive such qualification. We present the data supporting this qualification, providing insights into the evidentiary basis of qualification as a digital clinical outcome assessment.

Circadian clock disruption impairs immune oscillation in chronic endogenous hypercortisolism: a multi-level analysis from a multicentre clinical trial.

Background: Glucocorticoids (GC) are potent entrainers of the circadian clock. However, their effects on biological rhythms in chronic human exposure have yet to be studied. Endogenous hypercortisolism (Cushing's Syndrome, CS) is a rare condition in which circadian disruption is sustained by a tumorous source of GC excess, offering the unique opportunity to investigate GC's chronic effects in vivo.

Biomarkers of vaccine safety and efficacy in vulnerable populations: Lessons from the fourth international precision vaccines conference.

Vaccination has been a cornerstone of public health, substantially reducing the global burden of infectious diseases, notably evident during the COVID-19 pandemic caused by SARS-CoV-2. However, vulnerable populations (VPs), including those in extreme age groups and those with underlying health conditions, have borne a disproportionate burden of morbidity and mortality from infectious diseases. Understanding vaccine immunogenicity in these populations is crucial for developing effective vaccines.

Ranked Importance of Visual Function Outcome Measures in Choroideremia Clinical Trials.

Purpose: Clinical trials of novel therapies for choroideremia require robust and clinically meaningful visual function outcome measures. Best-corrected visual acuity (BCVA) is mostly insensitive to changes in disease state, until late stages, and hence also to potential therapeutic gains after gene therapies. While the insensitivity of BCVA as an effective outcome measure is common wisdom, its low importance has not been rigorously demonstrated in the literature.

Enhancing broadly neutralising antibody suppression of HIV by immune modulation and vaccination.

Although HIV infection can be managed with antiretroviral drugs, there is no cure and therapy has to be taken for life. Recent successes in animal models with HIV-specific broadly neutralising antibodies (bNAbs) have led to long-term virological remission and even possible cures in some cases. This has resulted in substantial investment in human studies to explore bNAbs as a curative intervention for HIV infection.

The risk of revision surgery after trainee-led primary total hip replacement.

Introduction: The aim of this study was to determine the impact of operating surgeon grade and level of supervision on the incidence of one-year patient mortality and all-cause revision following elective primary total hip replacement (THR).

Methods: National Joint Registry data from 2005 to 2020 for a single University Teaching Hospital were used, with analysis performed on the 15-year dataset divided into 5-year block periods (B1, 2005-2010; B2, 2010-2015; B3, 2015-2020). Outcome measures were mortality and revision surgery at one year, in relation to lead surgeon grade, and level of supervision for trainee-led (TL) operations.

Past, Present and Future of Phase 3 Vaccine Trial Design: Rethinking Statistics for the 21st Century.

Vaccines are crucial for protecting health globally; however, their widespread use relies on rigorous clinical development programmes. This includes Phase 3 randomised controlled trials (RCTs) to confirm their safety, immunogenicity, and efficacy. Traditionally, such trials used fixed designs with predetermined assumptions, lacking the flexibility to change during the trial or stop early due to overwhelming evidence of either efficacy or futility.

Single-cell integration reveals metaplasia in inflammatory gut diseases.

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood.

Learning patterns of HIV-1 resistance to broadly neutralizing antibodies with reduced subtype bias using multi-task learning.

The ability to predict HIV-1 resistance to broadly neutralizing antibodies (bnAbs) will increase bnAb therapeutic benefits. Machine learning is a powerful approach for such prediction. One challenge is that some HIV-1 subtypes in currently available training datasets are underrepresented, which likely affects models' generalizability across subtypes.

Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease.

Predicting individual patient and hospital-level discharge using machine learning.

Background: Accurately predicting hospital discharge events could help improve patient flow and the efficiency of healthcare delivery. However, using machine learning and diverse electronic health record (EHR) data for this task remains incompletely explored.

Methods: We used EHR data from February-2017 to January-2020 from Oxfordshire, UK to predict hospital discharges in the next 24 h.

Acceptability of and satisfaction with continuous glucose monitoring in pregnant women with type 2 diabetes mellitus: A service improvement project.

Background: There are limited data regarding intermittently scanned continuous glucose monitoring (isCGM) in pregnancy for women with Type 2 diabetes. We have tested the acceptability and feasibility of an isCGM method using Libre device.

Method: In a hospital-based service improvement project, 23 pregnant women (March 2022-April 2023), with Type 2 diabetes got isCGM for monitoring from 20 weeks until delivery.