324139 research outputs found
Sort by
The Geology of a Small Main-belt S-class Binary Asteroid System: Dinkinesh and Its Contact Binary Satellite Selam as Observed by the Lucy Mission
Get PDFThe Lucy spacecraft flew past the ∼738 m diameter, S-class main-belt asteroid (152830) Dinkinesh on 2023 November 1, revealing a satellite named Selam. We used images acquired during the flyby to evaluate surface features on both Dinkinesh and Selam. We find a shallow crater size–frequency distribution (SFD) for Dinkinesh, consistent with crater SFDs observed on other subkilometer asteroids. We derive crater depth-to-diameter ratios near 0.1, also consistent with typical values seen on other asteroids. We calculate a cumulative boulder SFD for Dinkinesh with power-law index 3.93 ± 0.15 slightly steeper though in the range of other S-class asteroids. We find growing evidence that boulder SFDs are, on average, steeper for S-class than C-complex asteroids. Two major surface features on Dinkinesh, Sumak Fossa (a large trough) and Fab Dorsum (an equatorial ridge), are likely an outcome of YORP spinning up Dinkinesh fast enough to produce failure. A self-consistent structure for Dinkinesh that complies with the global shape, feature morphologies, and the estimated 10–20 Myr YORP spin-up timescale is a rubble-pile object with a nearly strengthless surface and an interior strength that is less than tens of Pa. Selam could have formed via YORP-driven mass shedding from Dinkinesh, though other formation mechanisms are possible. Combining a low-strength surface with the crater population and an impact model, we estimate a ∼1 Myr surface age for Dinkinesh. The presence of mass wasting and young troughs indicates that stress accumulation and release continue on Dinkinesh to the present day
Targeting community-level drivers of antimicrobial resistance in sub-Saharan Africa: the effect of a community-based intervention bundle on household transmission of extended spectrum beta-lactamase-producing E. coli in rural Burkina Faso - a cluster randomised trial
Get PDFBackground In sub-Saharan Africa (sSA), invasive antimicrobial-resistant infections often originate from community-level acquisition. We assessed whether a behavioural intervention bundle targeting sub-optimal antibiotic use and hygiene practices reduced household-level acquisition of extended-spectrum beta-lactamase–producing E. coli (ESBL-E).
Methods We conducted a cluster-randomised controlled trial in 22 village clusters in Nanoro district, Burkina Faso. We enrolled 12 randomly selected households per cluster to assess intervention impact on ESBL-E household-transmission. The intervention comprised three rounds at three-month intervals and combined WHO AWaRe–based educational feedback for formal and informal medicine providers with a community-wide WASH and antibiotic-use behaviour change campaign. Consenting household members provided stool samples before, during, and after intervention rollout, alongside a pre–post household WASH survey. We estimated intervention effects on ESBL-E acquisition using Bayesian Markov models. Cox frailty models assessed associations between WASH exposures and acquisition. ClinicalTrials.gov, NCT05378880.
Findings Between Oct 11, 2022, and Feb 19, 2024, 1203 individuals were enrolled. At baseline, 57·3% (346/604) of control and 48·6% (291/599) of intervention household members were colonised. Pre-intervention acquisition incidence was 3·8 per 100 person-days (95% credible interval [CrI] 2·0–9·9) in the intervention group and 3·5 (95% CrI 1·8–9·6) in the control group. The intervention did not change the risk of ESBL-E acquisition in months 1–6 (hazard ratio [HR] 1·02, 95% CrI 0·78–1·31), while we estimated a reduction in ESBL-E acquisition from months 6–9 (HR 0·82, 95% CrI 0·56–1·14). Acquisition risk was higher in the rainy season (peak HR 1·73, 95% CI 1·49–2·00), while improved sanitation was associated with lower risk (HR 0·77, 95% CI 0·59–1·00).
Interpretation Findings, though inconclusive, were consistent with a modest intervention-related reduction in ESBL-E incidence. Higher acquisition rates associated with the rainy season and poor sanitation highlight the need to tackle environmental drivers of AMR transmission in addition to antibiotic use in rural sSA.
Funding JPI-AMR CABU EICO grant number: JPIAMR2021-05
Leveraging malaria microscopy infrastructure to diagnose common and neglected skin diseases using direct microscopy in Sumba, Indonesia
Get PDFMultiscale modes of functional brain connectivity
Get PDFInformation processing in the brain spans from localised sensorimotor processes to higher-level cognition that integrates across multiple regions. Interactions between and within these subsystems enable multiscale information processing. Despite this multiscale characteristic, functional brain connectivity is often either estimated based on 10-30 distributed modes or parcellations with 100-1000 localised parcels, both missing across-scale functional interactions. We present Multiscale Probabilistic Functional Modes (mPFMs), a new mapping which comprises modes over various scales of granularity, thus enabling direct estimation of functional connectivity within- and across-scales. Crucially, mPFMs were not formulated, but emerged from data-driven multilevel Bayesian modelling of large functional MRI (fMRI) populations and every individual. We demonstrate that mPFMs capture both distributed brain modes and their co-existing subcomponents. In addition to validating mPFMs using simulations and real data, we show that mPFMs can predict ~900 personalised traits from UK Biobank more accurately than current standard techniques. Therefore, mPFMs can offer a new basis for functional connectivity modelling and yield enhanced fMRI biomarkers for traits and diseases
<i>In Vitro</i> and <i>In Vivo</i> Safety Evaluation of <i>Streptococcus salivarius</i> eK12, a Genetically Modified Dietary Probiotic Derived from the Oral Probiotic <i>S. salivarius</i> K12
Get PDFGroup A Streptococcus (GAS) pharyngitis is a common and recurrent childhood illness, usually treated with antibiotics. While effective, repeated antibiotic use contributes to antimicrobial resistance, disrupts host microbiota, and increases adverse effects. Streptococcus salivarius K12 is an extensively studied probiotic for oral health, particularly for reducing the incidence of GAS pharyngotonsillitis. A modified version, S. salivarius eK12, has recently been developed from the wild-type K12 through genetic modification to enhance anti-GAS activity. However, its safety and tolerability have not previously been evaluated, and this study provides the first systematic assessment of eK12 under OECD-guided toxicological frameworks. Genotoxicity was assessed through the bacterial reverse mutation assay (OECD 471, Ames test) in five Salmonella typhimurium strains, with and without metabolic activation. Acute oral toxicity was examined in female Wistar rats at a limit dose of 2,000 mg/kg (~2 × 1011 CFU/kg) (OECD 423). Sub-chronic safety was investigated in a 90-day repeated-dose oral toxicity study (OECD 408) using Sprague Dawley rats randomized to vehicle, low, mid, or high eK12 dose groups, with additional recovery cohorts (vehicle, high dose) observed for 28 days post-treatment. Results showed no mutagenic activity, no mortality, and no treatment-related abnormalities in clinical, hematological, biochemical, or histopathological parameters. Minor fluctuations were incidental and non-dose dependent. Recovery groups confirmed the absence of delayed or persistent toxicity. These findings indicate that eK12 is potentially non-mutagenic, non-toxic, and well tolerated, with a NOAEL of 2,000 mg/kg/day (~2 × 1011 CFU/kg/day), retaining the favorable safety profile of its parental strain K12 and supporting its further development
PROTOCOL: Health Visiting Interventions With 0–5 Year Olds and Their Families: An Evidence and Gap Map
Get PDFMapping the genetic landscape across 14 psychiatric disorders
Get PDFPsychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology. These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations
Validation of an algorithm for selection of SGLT2 and DPP4 inhibitor therapies in people with type 2 diabetes across major UK ethnicity groups: a retrospective cohort study
Get PDFBackgroundRoutine clinical features of individual patients can potentially be used to guide selection of type 2 diabetes treatments. We aimed to evaluate a recently proposed treatment selection model predicting differences in glycaemic responses to SGLT2-inhibitors and DPP4-inhibitors across major UK ethnicity groups.MethodsWe externally validated the SGLT2i-DPP4i model in UK primary care cohort (CPRD Aurum, 2013-2020) independent of the original model development cohort. Non-insulin treated individuals with type 2 diabetes were identified and categorised by major UK self-reported ethnicity groups: White, Black, South Asian and Mixed/Other. For each ethnicity group, we applied a closed testing procedure to assess whether model recalibration was required. After model updates, we assessed the calibration accuracy of predicted differences in glycaemic response (6-month change in HbA1c) between SGLT2i and DPP4i for each ethnicity group.FindingsSGLT2i (n = 57,749) and DPP4i (n = 87,807) initiations were identified amongst people of White (n = 114,287; 78.5%), Black (n = 6663; 4.6%), South Asian (n = 20,969; 14.4%) and Mixed/Other (n = 3637; 2.5%) ethnicities. Minor model adjustment was required to adjust for greater observed than predicted glycaemic responses to DPP4i (White-1.6 mmol/mol; Black-3.0 mmol/mol; South Asian-2.6 mmol/mol; Mixed/Other-2.6 mmol/mol). SGLT2i predictions did not require adjustment for non-White ethnicity groups. After model updates, average predicted HbA1c reduction was 3.7 mmol/mol (95% CI 3.5-3.9) greater with SGLT2i than DPP4i for those of White ethnicity; this was greater than for those of South Asian (2.1 mmol/mol (95% CI 1.6-2.6)), Black (0.6 mmol/mol (95% CI 0.5-1.7)) and Mixed/Other (2.6 mmol/mol (95% CI 1.4-3.8)) ethnicity groups. For all ethnicity groups, predicted differential glycaemic treatment effects were well calibrated.InterpretationOur model for selection of SGLT2-inhibitor and DPP4-inhibitor therapies was accurate for all major self-reported ethnicity groups in a UK primary care cohort. Simple recalibration is beneficial to optimise performance and this is recommended prior to deployment of the model in new populations and settings.FundingUK Medical Research Council, National Institute for Health and Care Research Exeter Biomedical Research Centre, and EFSD/Novo Nordisk
Hydrodynamics with multiple charges and holography
Get PDFWe establish the connection between thermodynamic and dynamical instabilities in relativistic hydrodynamics with multiple flavours of conserved U(1) charges. In theories with positive hydrodynamic entropy production, where the underlying perfect fluid has a positive speed of sound squared and satisfies the null energy condition, we show that hydrodynamic instabilities can arise only through negative diffusion coefficients associated with the U(1) charges. The onset of such instabilities is governed by the eigenvalues of the thermodynamic Hessian matrix, while the flavour-space polarisations of the unstable diffusion modes are determined by the corresponding eigenvectors. We illustrate this connection using strongly coupled = 4 supersymmetric Yang-Mills theory at finite densities of the three U(1) R-charges. In the dual holographic description, the five-dimensional STU black brane exhibits unstable quasinormal modes precisely at the onset of thermodynamic instability. We derive analytic expressions for the R-charge diffusion coefficients in several representative cases, including the configuration with three equal chemical potentials
Dynamically reconfigurable 2D polarization-agnostic image edge-detection using nonvolatile phase-change metasurfaces
Get PDFThe development of novel, compact, and reconfigurable devices for optical analog computing would pave the way for the next generation of imaging systems free from high power consumption electronics and computationally demanding processing algorithms. Recently, nonlocal metasurfaces have emerged as a powerful platform to perform analog image processing operations with low energy consumption, at the speed of light, and without the need to physically access the Fourier space, thereby providing both high computational speeds and ease of integration. However, once such devices are designed and fabricated, their effect on optical beams is fixed, constraining their performance to a singular function. Here, we show how nonlocal metasurfaces made of novel low-loss chalcogenide phase-change materials, such as Sb2Se3, offer a degree of reconfigurability, enabling switching between certain imaging modes. Specifically, we show that switching between a two-dimensional edge-detection mode and a bright-field imaging mode, or between a two-dimensional edge-detection mode and a two-dimensional image blurring mode, is possible