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The ethics of wegovy for children: the argument from too many unknowns
Get PDFSemaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) marketed as Wegovy, has gained international attention for its appetite-suppressing and weight-loss effects. Approved by the U.S. FDA in 2022 for paediatric use in children aged 12 and older, Wegovy has since received similar approvals in several countries. Despite this, uptake among youth has been limited. While some clinicians advocate for broader paediatric use of Wegovy as an underutilised tool to address obesity, others urge caution citing concerns regarding its long-term safety, efficacy, and appropriateness in growing children. When prescribing medication to children there are many ethical dimensions to consider. This paper focuses on the risks, side-effects, and unknowns of Wegovy as a barrier to use in paediatric care. We argue that, while long-term effects remain uncertain, this uncertainty alone should not preclude its use in children
Single‐Cell RNAseq Identifies Heterogeneity in Myoblasts From Older Adults With Differences Related to Muscle Mass and Function
Get PDFBackground: Ageing is associated with the loss of muscle mass and function, with consequences for metabolic health, frailty and independence in later life. The aim of this study was to investigate the transcriptional heterogeneity of human proliferating muscle satellite/stem cells (myoblasts) from older adults and how this heterogeneity may vary between healthy individuals and those with low muscle mass and function. Methods: Single‐cell transcriptomic analysis was carried out on proliferating myoblasts isolated from vastus lateralis biopsies from 132 participants (34 male, 98 female) aged 72–83 years from the Hertfordshire Sarcopenia Study extension. Uniform Manifold Approximation and Projection (UMAP) clustering was applied to identify clusters of myoblasts with distinct transcriptional profiles, Gene Ontology analysis was used to identify pathways enriched among the clusters, and pseudotime trajectory analysis was used to identify inferred cell lineages. Differential gene expression within cell clusters, together with the proportions of cells within each cluster and lineage, were assessed with respect to participant appendicular lean‐mass index (ALMi), grip strength, and gait speed. Results: Thirteen distinct cell clusters based on the transcriptional heterogeneity of the myoblasts were identified. Clusters 0–6 contained the majority (94.6%) of cells. Marker genes were enriched for cytoplasmic translation (Cluster 0, false discovery rate [FDR] = 7.21 × 10−63), muscle development (Cluster 1, FDR = 2.25 × 10−13), cell proliferation (Clusters 2, 4 and 6, all FDR ≤ 0.05), extracellular matrix organisation (Cluster 3, FDR = 1.92 × 10−45) and RNA processing (Cluster 5, FDR = 1.89 × 10−08). Individuals with the highest grip strength and ALMi had a greater proportion of Cluster 1 and Cluster 5 cells. Gene expression analysis (FDR ≤ 0.05) within the clusters identified 22 differentially expressed transcripts with respect to ALMi in Cluster 2 and 13 with respect to grip strength in Cluster 1. Inferred lineage analysis identified cells transitioning along five trajectories (L1–L5), including cells in L1, L3 and L4 progressing towards a stressed pre‐senescent/senescent (L1) or fibrogenic (L3 and L4) state, with cells in these lineages being more likely to originate from individuals with low ALMi (χ2 p = 1.11 × 10−146) and grip strength (χ2 p = 1.31 × 10−269). Conclusion: Our findings demonstrate considerable transcriptional heterogeneity in skeletal muscle myoblasts from older adults. This heterogeneity includes myoblasts from individuals with low muscle mass and strength progressing towards a fibrogenic or stressed state
The dose–response effects of nitrate-rich beetroot ingestion on cardiovascular and endothelial function: a randomised controlled trial
Get PDFDietary nitrate (NO3−) supplementation has been reported to improve cardiovascular health, but beyond its effects on brachial artery blood pressure (BP), dose–response effects on other cardiovascular variables are unclear. This study assessed the effects of three acute NO3− doses (200 mg, 400 mg, 800 mg NO3--rich beetroot powder) on brachial and aortic BP, arterial stiffness and macrovascular endothelial function, in a double-blind, randomised, crossover design. Cardiovascular variables and venous blood samples were measured prior to (control) and 2.5 h post supplement ingestion. Dietary NO3− supplementation increased plasma [NO3−] and plasma [nitrite] but had no effect on cyclic guanosine monophosphate (cGMP) concentration. Arterial stiffness markers improved following all NO3− doses, with no between-dose differences. However, endothelial function only improved following 400 mg (+3.07% compared to control) and aortic systolic BP only improved following 800 mg (−4 mmHg compared to control) dietary NO3− supplementation. Acute NO3− ingestion improved some cardiovascular risk factors, including arterial stiffness, macrovascular endothelial function and aortic systolic BP with different dose–response effects, but had no effect on brachial BP or plasma [cGMP]. These findings improve our understanding of NO3− supplementation and cardiovascular function in healthy adults
MKRN1 as a prioritized drug target for postpartum depression: evidence from druggable proteome profiling and multi-layer validation
Get PDFPostpartum depression (PPD) is a significant global health concern affecting women, yet effective and innovative therapeutic targets remain limited. Although genome-wide association studies (GWAS) have identified genetic risk loci, their underlying mechanisms and translational potential remain poorly understood. Therefore, we integrated PPD GWAS data with protein quantitative trait loci from two independent datasets to identify risk genes through proteome-wide association studies (PWAS). Validation was performed using colocalization analysis and Mendelian randomization (MR). To assess the safety of genes as drug targets, phenome-wide MR (Phe-MR) was conducted using the UK Biobank disease data. Finally, we performed gene methylation analysis in PPD patients, alongside validation of expression in key brain regions including anterior cingulate gyrus (AnCg), dorsolateral prefrontal cortex, and nucleus accumbens, as well as in peripheral blood (whole blood and leukocytes), across depressive patients and chronic mild stress mice. Co-expression enrichment was used to identify biological pathways associated with risk genes. PWAS and colocalization analysis identified MKRN1 and CCDC92 as overlapping risk genes, with MKRN1 validated in MR. Phe-MR showed non-significant association between MKRN1 dysregulation and disease beyond depression and mood disorders, suggesting minimal off-target effects. Methylation analysis in PPD patients’ blood revealed significant hypomethylation of MKRN1, consistent with expression analysis that confirmed its upregulation in AnCg and as a biomarker in blood. Enrichment analysis indicated MKRN1 involvement in immune–inflammatory pathways. Our study identified MKRN1 as a therapeutic target for PPD, integrating multi-omics evidence from genomics, proteomics, and druggable proteome profiling, and offering a promising path for targeted treatments
MIRI spectrophotometry of GN-z11: Detection and nature of an optical red continuum component
Get PDFWe present new MIRI F560W, F770W, and F1000W imaging of the galaxy GN-z11 at a redshift of 10.603. We report a significant detection (14 σ ) in the F560W and F770W images, and a marginal detection (3.2 σ ) in the F1000W filter. The new MIRI observations cover the optical-red spectral range and significantly extend previous NIRCam wavelength coverage from rest-frame 0.38 μm up to 0.86 μm. In this work, we analyse the spectral energy distribution (SED) combining this new MIRI imaging data with archival NIRSpec/Prism and MRS spectroscopy, and NIRCam imaging, i.e. covering the rest-frame 0.12–0.86 μm. New constraints such as the equivalent widths of the strong optical lines ([O III ] λ 5008, H β and H α ) and the continuum emission at rest-frame 0.48 μm, 0.66 μm, and 0.86 μm, free of emission line contributions, are presented. The continuum emission shows a flat energy distribution, in f ν , up to 0.5 μm, compatible with the presence of a mixed stellar population of young (4 ± 1 Myr) and mature (63 ± 23 Myr) stars that also account for the [O III ], H β , and H α emission lines. The continuum at rest-frame 0.66 μm shows a 36 ± 3% flux excess above the predicted flux for a mixed stellar population, pointing to the presence of an additional source contributing at these wavelengths. This excess increases to 91 ± 28% at rest-frame 0.86 μm, although with a large uncertainty due to the marginal detection in the F1000W filter. We consider that hot dust emission in the dusty torus around a type 2 active galactic nucleus (AGN) could be responsible for the observed excess. Alternatively, this excess could be due to hot dust emission or a photoluminiscence dust process (Extended Red Emission, ERE) under the extreme UV radiation field, as is observed in local metal-poor galaxies and in young compact starbursts. The presence of a type 1 AGN is not supported by the observed SED as the hot dust emission in luminous high- z quasi-stellar objects (QSOs) contributes at wavelengths above rest-frame 1 μm, and an additional ad hoc red source would be required to explain the observed flux excess at 0.66 and 0.86 μm. Additional deep MIRI imaging covering the rest-frame near-IR is needed to confirm the flux detection at 10 μm, and to discriminate between the different hot dust emission in the extreme starburst and AGN scenarios
QBOi El Niño Southern Oscillation experiments: assessing relationships between ENSO, MJO, and QBO
Get PDFAbstract. This study uses an ensemble of climate model experiments coordinated by the Quasi-Biennial Oscillation initiative (QBOi) to analyze the Madden-Julian Oscillation (MJO) in the presence of either perpetual El Niño or La Niña sea surface temperatures during boreal winter. In addition to the prescribed El Niño Southern Oscillation (ENSO) conditions, the nine models internally generate QBOs, meaning each may influence the MJO. Objectives of our analyses are to assess the response of the MJO to strong idealized ENSO forcing and look for evidence of a QBO influence on the MJO in a multi-model context. The diagnostics used include wavenumber-frequency spectra of tropical convective and dynamical fields, measures of MJO lifetime, an evaluation of MJO diversity and visualization of MJO vertical structure, as well as an assessment of QBO morphology and the QBO's impact on tropical convection. Kelvin wave spectral power increases in the El Niño simulations whereas equatorial Rossby waves power is stronger in the La Niña simulations. All models simulate faster MJO propagation under El Niño conditions. This change in speed is corroborated by the MJO diversity analysis, which reveals that models better reproduce the observed “fast propagating” and “standing” MJO archetypes given perpetual El Niño and La Niña, respectively. Regardless of ENSO, QBO descent into the lower stratosphere is underestimated and we detect little QBO influence on tropical tropopause stability and MJO activity. With little influence from the QBO on the MJO activity in these runs, we can be confident that the aforementioned changes in the MJO indeed arise from the different ENSO boundary conditions
Lessons from COVID-19: the 100 Days Mission and antimicrobial resistance
Get PDFThe COVID-19 pandemic demonstrated the capacity of the world to rapidly mobilize resources and political will when faced with an immediate, visible global threat. The accelerated development of effective vaccines inspired the Coalition for Epidemic Preparedness Innovations to promote the 100 Days Mission (100DM), an initiative to enable deployment of medical countermeasures within 100 days of identifying a pandemic threat. The success of the 100DM in uniting stakeholders highlights the power of framing challenges to inspire collective action. On the other hand, antimicrobial resistance (AMR) has had insufficient visibility and urgency to galvanize similar levels of political action. Framing AMR in a way that highlights the urgency, aligns incentives and builds multisectoral coalitions can help overcome some of these barriers. Ultimately, pandemic preparedness and AMR are both collective action problems, requiring sustained political will and systemic change. The AMR community must build systems that are agile and resilient and, by creating a unifying vision for AMR analogous to the 100DM, may promote global commitment to combating this slow-moving but devastating health crisis. This article is part of the Royal Society Science+ meeting issue ‘Vaccines and antimicrobial resistance: from science to policy’
A multi‐centre qualitative study of experiences of managing diabetes mellitus among adults while hospitalised
Get PDFAims: One in six hospital beds across England is occupied by someone with diabetes. While guidance on inpatient diabetes care is available, national audit data demonstrate that people still experience significant and avoidable diabetes‐related harms. This study is unique in exploring how people with diabetes admitted to hospital for any medical reason experienced diabetes care from admission to discharge. It is part of a bigger project aiming to develop and test a Patient Reported Experience Measure for inpatients with diabetes. Methods: A qualitative approach was used to explore experiences of inpatient diabetes care. Twenty‐seven participants with type 1 or type 2 diabetes, hospitalised for any reason, were recruited using purposive sampling across four acute NHS Trusts in the South of England. Data collected in semi‐structured interviews were analysed with reflexive thematic analysis. Results: In diabetes care, the emphasis is on supporting people with self management of their diabetes. The inpatient care setting compromises this by limiting self management behaviours. These restrictions may apply to those who want to and can be actively involved in their diabetes care and may contribute to less effective diabetes management and poorer outcomes. For some participants in this study, diabetes self management was discouraged in three ways. First, their knowledge of their diabetes and willingness to self‐manage were not taken into account on admission or in planning their inpatient diabetes care. Second, their involvement in decisions about their ongoing diabetes care was limited. Third, their needs related to diabetes management were not met because of the lack of flexibility in hospital practices and schedules. Conclusions: Inpatient care is not always conducive to diabetes self management. Understanding the patient experience in the inpatient setting related to self management is important in reducing harm to patients while they are in hospital. Our findings emphasise the importance of involving people with diabetes in planning and managing their care while hospitalised. Further work needs to be done to ensure that the knowledge, involvement and flexibility of care of people with diabetes are incorporated into an inpatient setting