Family members of survivors of critical illness are known to experience adverse outcomes in the months following the critical care admission, which can impact their physical, social and emotional health. This protocol describes the Family or Caregiver Outcomes after critical illness (FOCUS) study, which aims to develop a core outcome set (COS) for trials involving family members of critical care patients across the continuum of care. A modified Delphi consensus process with researcher, clinician and patient/caregiver stakeholder groups and consensus meetings for ratification of findings, resolving uncertainty and developing an action plan for COS implementation. The FOCUS COS will inform relevant stakeholders about important outcomes for family members of critical care patients and may enhance the future design and conduct of trials in this area. This study has been approved by the University of Cambridge Psychology Research Ethics Committee. The COS will be disseminated through peer-reviewed publications and engagement with key stakeholders. COMET database (https://comet-initiative.org/Studies/Details/1977).
Accurate health utilities are critical for health economic models, as quality-adjusted life-years (QALYs) combine health utilities and life years. Individual patient utility data are an important source of these inputs, as they are used to calculate health state utility values, yet no dedicated best practice guidance exists for analysing patient-level utility data. This research aimed to develop guidance for analysing such data and identify gaps. We conducted a scoping survey, literature and NICE technology appraisal reviews, and a modified Delphi process to generate consensus-based recommendations. The research examined key analysis considerations including utility distributions (e.g., upper bounded), data characteristics (e.g., missing data, repeated collection), and associated analytical methods (e.g., regression models). It also examined post-hoc adjustments required to address specific data properties. The derivation of individual patient utility data was out of scope. Thirty-one participants-predominantly health economists, alongside statisticians-from academia, industry, consultancies, and NICE contributed to the Delphi process. Thirteen topics were discussed, covering three stages of analysis: core methods, potential adjustments, and sensitivity analyses. While no new recommendations emerged, the panel refined wording, added clarifications, and expanded recommendations. Broad consensus across all recommendations was achieved by the end of Round 3. The research informed the development of best practice guidance for analysing individual patient utility data. Important evidence gaps remain in the published literature, particularly regarding optimal methods for responding to data characteristics. These findings support health technology assessment agencies in providing clearer, more consistent instructions for robust and transparent analysis of these data.
Natural History Collections (NHC) often contain exceptional specimens documenting unusual historical events, and these records can be valuable for detecting overlooked biological introductions. Here, we examine a striking case: a Neotropical leaf beetle, Acentroptera norrisii, labelled as collected in central Spain in 1998 by Dr J. Modolell. Given the species' native distribution in the Neotropics, this record raises the question of whether it represents a failed historical introduction or a curatorial artefact. We reconstructed the circumstances of the collection event using the collector's personal archives. We conducted scanning electron microscopy (SEM) to document microscopic particles on the specimen's cuticle. We also analysed the content of the original specimen box to evaluate the likelihood of pollen cross-contamination, considering the geographical origin and family-level identity of all co-stored specimens. Archival evidence confirms the collector's presence at the labelled locality and date. SEM revealed several pollen grains consistent with plant taxa occurring at the collection site. However, the original box also contained numerous Spanish specimens belonging to beetle families with known anthophilous habits, meaning that cross-contamination during storage cannot be fully excluded. As a result, the palynological evidence remains inconclusive. Together, the available evidence makes a failed historical introduction a plausible scenario, yet the inconclusive particle analysis prevents any confident confirmation. This case highlights both the potential and the limitations of NHC-derived data in invasion biology: while museum collections can preserve traces of otherwise "invisible" introductions, interpreting isolated and context-poor specimens remains inherently uncertain.
Autism Spectrum Disorder is a neurodevelopmental condition characterized by persistent difficulties in social interaction and communication alongside restricted, repetitive patterns of behavior, interests, or activities. Emerging evidence suggests that bi/multilingualism may enhance social interaction skills, yet prior research has largely focused on children, relied on small samples, and used oversimplified monolingual-bilingual groupings. The present study examines whether multilingual engagement predicts autism-associated social traits in adults with and without autism diagnoses. Specifically, we investigated whether childhood and/or current multilingual engagement (operationalized as entropy) predicts social interaction, communication, and overall autistic traits, measured via the Comprehensive Autistic Trait Inventory (CATI). Four hundred and fifty-nine adults (of which 132 diagnosed autistic) participated in the study. Analyses revealed that, both in the full sample and in the subsample of individuals with autism diagnoses, greater language entropy was associated with lower CATI scores in social interaction and overall. No relation between language entropy and communication traits was found. Within the autistic subgroup, the associations between current language entropy and both social interaction and overall CATI scores had large effect sizes (ηp2 = 0.14-0.18). These findings show that multilingual engagement is reliably associated with reduced social autistic traits in adulthood. Autism is a developmental condition which often involves social and behavioural difficulties. This study looked at whether speaking more than one language positively affects autistic and no‐autistic adults' social skills. We found that people who regularly use multiple languages showed fewer social difficulties linked to autism. The effect was strongest in autistic adults.
Imidazole propionate (ImP), a microbial metabolite of histidine, may impair glucose metabolism, but its relevance to coronary heart disease (CHD) risk and potential diet-microbiota regulations remain unclear. We aimed to examine prospective associations of plasma ImP levels and histidine intake with CHD risk, to identify ImP-predicting gut microbes, and to investigate diet-microbiome interactions influencing ImP levels. Associations of ImP and histidine with CHD risk were evaluated using Cox models in 7,432 participants from Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-up Study. Microbiome-diet interactions influencing ImP levels were assessed using fecal metagenome and 7-day diet record data in 296 men from the Men's Lifestyle Validation Study, with replication in the Mind-Body Study. Higher plasma ImP was associated with increased CHD risk (HR comparing extreme quintiles = 1.82; 95%CI = 1.17-2.81; p-trend = 0.002), while histidine intake showed a non-significant inverse association. Although histidine intake was not associated with ImP levels, the intake of fiber, especially pectin, emerged as a key negative predictor. We identified 17 distinct ImP-predicting species, including Clostridium and Blautia species. A parametric ImP-microbial score was constructed based on these species to represent the microbial capacity of producing ImP. Further functional characterization uncovered that the microbial urocanate reductase gene urdA was also associated with cardiovascular risk markers. No significant interaction was observed between histidine intake and the microbial score on ImP levels, but ImP levels increased with higher histidine intake and higher microbial score only under low pectin intake (p for 3-way interaction = 0.01). Similar interactions were seen for total fiber (p = 0.09), soluble fiber (p = 0.09), and insoluble fiber (p = 0.11), without statistical significance. ImP, but not its dietary precursor histidine, was associated with a higher CHD risk. The gut microbial metabolism of ImP appeared context-dependent, with ImP production from histidine associated with a higher ImP-producing microbial capacity and lower fiber intake. These findings highlight the potential role of dietary fiber and gut microbiome in modulating diet-health associations related to ImP metabolism.
On behalf of my co-authors I am pleased to present our sixth annual review highlighting articles that have been deemed as impactful in the field of drug transporter sciences. Drug transporters influence the absorption, distribution, and elimination of prescribed drugs and, as a result, it is necessary to understand their impact on new drug development programs. The articles highlighted in this review were selected based on their scientific impact, novelty, and relevance to advancing key areas of transporter research, including mechanistic understanding, translational application, and implications for drug development and regulatory science.Similar to our previous reviews, each co-author has selected peer reviewed articles and provided a brief synopsis of the article and commentary on the article's significance (Chothe et al. 2021; Chothe et al. 2022, 2023; Chothe et al. 2024; Sandoval et al. 2025). The review is divided into the following sections 1) transporter function and DDI evaluation, 2) novel in vivo models, 3) endogenous biomarkers and 4) drug transporter structure and regulation. The below synopses and commentaries are meant to provide high level highlights of the articles and readers are encouraged to review these articles for further details. While individual studies are discussed within these categories, a key objective of this review is to place these findings within broader emerging trends in transporter sciences. The synopsis and commentaries are therefore intended not only to highlight individual studies but also to provide perspective on how these advances collectively shape the field.The studies highlighted in this review collectively illustrate several important advances in drug transporter sciences in 2025. These include increasing integration of mechanistic approaches such as physiologically based pharmacokinetic (PBPK) modeling to better understand complex drug-drug interactions, the development of improved in vivo models to enhance translational predictivity, and continued progress in the identification and qualification of endogenous biomarkers for clinical application. In addition, recent structural insights are beginning to bridge molecular-level understanding with functional and clinical outcomes. Together, these advances reflect a shift toward more integrated and predictive frameworks for assessing transporter-mediated drug disposition, with important implications for drug development and regulatory science.This review provides a curated, single-source overview of these advances.
Outcome measures are essential in healthcare. This study aimed to use Think Aloud methodology to explore the face validity of three patient-reported outcome measures (PROMs)-the Subjective Norms, Self-Regulation, and Expected Illness Perception questionnaires-among individuals undergoing surgery for lumbar spinal stenosis (LSS). Twelve participants aged 59-88 verbalised their thoughts while completing the questionnaires. Content analysis revealed 96 issues across the 3 PROMs. The Expected Illness Perception and Subjective Norms questionnaires yielded the highest number of problems, particularly around phrasing and inconsistent response scales. While the Self-Regulation questionnaire was generally well understood, some items still prompted confusion. Findings highlight the importance of clear item phrasing, scale consistency, and contextual framing to reduce cognitive burden and enhance usability. Recommendations for item revision are provided to improve face validity and interpretability. Further qualitative and quantitative evaluation in a more diverse participant population is warranted before clinical or research use.
The inferiorly based dermo-glandular sling is well described for implant coverage in post-mastectomy prosthetic reconstruction and attempted restoration of upper pole fullness in (therapeutic and aesthetic) mammaplasty procedures, to variable long-term effect. We reviewed the technique modifications by a single surgeon, over 13 years, and the aesthetic outcomes achieved, when used in the context of cosmetic breast implant removal. Breast explant patients with a Wise-pattern skin incision by a single surgeon between 2011 and 2024 were identified. implant exchange, explantation only and LeJour pattern breast lift. Demographics and perioperative data were recorded. Perioperative photographs were assessed using the established Breast Cancer Conservation Treatment. Cosmetic Results (BCCT.core) software to analyse the aesthetic result. 19 patients underwent implant removal and parenchymal re-draping with an inferiorly based dermo-glandular sling. Patients were: perimenopausal women (mean=54yrs) with raised BMI (mean=27.6kg/m2). Indications (overlapping) for explantation included: disharmony between implant and breast envelope (10/19; 52.6%), discomfort/ pain (8/19; 42.1%), concerns about BIA-ALCL (5/19; 26.3%) and symptoms of "breast implant illness" (6/19; 31.6%). Others claimed their augmented breasts were simply too large (9/19; 47.4%). Bra size decreased from pre-explant size of 36E to 36C (median). Post-operative photographs were available for 18/19 patients. BCCT.core ratings were wholly favourable, with five rated Excellent and the remainder rated as Good. An inferior, de-epithelialised dermo-glandular sling can reliably rejuvenate the female breast following breast implant removal, where there is disharmony between parenchymal volume, distribution and envelope. We illustrate a reliable technique that achieves objectively good to excellent aesthetic results, with long-term efficacy. (249 words) Most common presentations for seeking explantation in our cohort were concerns about the degree of ptosis, pain, anxiety about BIA-ALCL and symptoms of breast implant illness. This technique offers a reliable and aesthetically robust option to restore some volume and uplift and reshape the explanted breast, in patients declining re-implantation or staged surgeries. Suitable patients as determined by our cohort are middle-aged women with large, previously augmented breasts (~330cc mean, 36E median), with an above-average BMI (27.6) yielding suitable inferior pole tissue for suspension. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
To investigate the expression of succinate dehydrogenase B and its potential as a therapeutic target in pleural mesothelioma (PM). The expression of succinate dehydrogenase B was examined in cell lines using PCR. The expression of succinate dehydrogenase B mRNA was subsequently examined in a series of fresh-frozen primary patient samples using reverse transcription polymerase chain reaction. The expression of succinate dehydrogenase B protein was examined by immunohistochemistry on a pleural mesothelioma tissue microarray derived from Formalin-Fixed and Paraffin-Embedded specimens to determine if succinate dehydrogenase B expression correlated with survival benefit. Using a resazurin-based assay we examined whether targeting the mitochondrial complex II (containing succinate dehydrogenase B) with a chemical inhibitor could have effects on cell proliferation. Total ribonucleic acid was isolated from a panel of mesothelial-derived cell lines (both cancerous and non-cancerous), and expression of succinate dehydrogenase B messenger RNA was assessed by RT-PCR and found to be ubiquitously expressed. Total Ribonucleic acid was isolated from a panel of fresh-frozen surgical specimens, and succinate dehydrogenase B was significantly overexpressed in mesothelioma at the messenger RNA level. Immunohistochemical staining and analysis of a mesothelioma tissue microarray showed that expression did not correlate with any survival benefit, confirmed by in silico analyses of other datasets. However, links between DNA methylation at individual residues of the succinate dehydrogenase B gene and overall survival were identified, along with correlations to immune cell infiltrates. Targeting the mitochondrial complex II with oxaloacetic acid did not show any significant potential for higher efficacy in cell lines derived from malignant tumors compared to those derived from normal mesothelial cells. Our results demonstrate that succinate dehydrogenase B is overexpressed in PM but may not be a suitable candidate for therapeutic targeting in this disease.
Two-dimensional polyaramids (2DPAs) represent an emerging class of solution-synthesized, molecularly thin polymer sheets that combine the exceptional in-plane mechanical strength and barrier performance of conventional 2D materials with the synthetic versatility of organic polymers. Despite increasing interest in 2D polymers as gas barriers and membrane materials, the long-term stability of nanometer-scale suspended films remains largely unexplored. Here, we report the first longitudinal study of 2D polyaramid (2DPA-1) nanofilm bulges monitored continuously for over 1000 days. Using a microwell bulge test platform integrated with atomic force microscopy and optical interferometry, we show that 2DPA-1 forms highly stable, gas-retaining membranes whose upward deflection persists for years under ambient environmental fluctuations. Using a single-point mechanical model with thermodynamic analysis, we show that initial bulge pressurization proceeds through transient rim seal opening, while the intact seal remains robust during thermal cycling up to 120 °C without measurable gas loss. Together, these results establish a comprehensive mechanistic framework for long-term stability, permeability assessment, and interfacial failure modes in nanofilm bulge systems. This framework enables reliable interpretation of bulge test data and provides design principles for next-generation 2D polymer membranes intended for ultrahigh-barrier, filtration, and separation technologies.
Intuitive eating, an adaptive approach to eating that involves listening to and trusting the body's internal cues, has been identified as an effective strategy for fostering a positive body image and enhancing physical and mental well-being. While body image scholars have extensively explored intuitive eating among the general population, extant theory and practice have yet to consider the neurodivergent community, specifically autistic/AuDHD people (autistic and have ADHD). To address this, we explored how autistic/AuDHD people understand and experience intuitive eating, and their perceived barriers and facilitators to eating more intuitively. Using a lived-experience-led qualitative framework, we conducted one-to-one semi-structured interviews among 20 autistic/AuDHD adults (nine female-identifying, eight male-identifying, and three identifying as non-binary; aged 21-63 years) from the United Kingdom. Through reflexive thematic analysis, we identified three superordinate themes that reflect body- and eating-related experiences: (Re)defining intuitive eating, disruptions to intuitive eating, and reframing and supporting intuitive eating. Critically, we identified four sub-themes that reflect the core components of autistic/AuDHD people's intuitive eating: (1) unconditional permission to eat; (2) eating for physical, emotional, and sensory reasons; (3) relying on internal and external cues; and (4) autistic/AuDHD body-food choice congruence. While some aspects of intuitive eating are consistent with those found in the general population, there are crucial nuances in how autistic/AuDHD people experience and adopt strategies to eat intuitively. Further research is needed to enhance the applicability of intuitive eating for promoting a healthier body image and eating well-being in the wider autistic/AuDHD population.
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While still nascent, research has yet to examine the factor structure and measurement invariance of the State Functionality Appreciation Scale (S-FAS; Longhurst et al., 2025) across demographic groups, beyond gender identity. Additionally, there is a need to explicitly examine the utility of Expand Your Horizon (EYH), a programme designed to target functionality appreciation, among underrepresented groups, including older adults and those who live in larger bodies. To this end, using secondary data from Longhurst et al. (2025), the aims of this study were two-fold: First, among a UK-based community sample (N = 861), we sought to examine the factorial stability and measurement invariance of the S-FAS across adult age groups and body size groups. Among a second UK-based community subsample (N = 293), the secondary aim was to assess the preliminary efficacy of EYH across adult age groups and body size groups. Confirmatory factor analysis supported a unidimensional structure of S-FAS baseline scores and measurement invariance (up to latent means) across adult age groups and (up to partial scalar) body size groups. Additional results demonstrated that baseline S-FAS scores were highest among older adults, while changes in state functionality appreciation following intervention were highest among emerging adults. EYH improved state functionality appreciation across all body size groups, particularly among those who live in larger bodies. Future research should assess the longitudinal measurement invariance of the S-FAS and qualitatively explore body functionality across marginalised populations.
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To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.
Machine learning (ML) has the potential to revolutionize antibody design and selection, but its success depends on access to well-curated datasets of antibody-antigen interactions. We developed a synthetic Fab yeast display library optimized for seamless integration with ML processes, focusing on sequence diversity within the complementary determining region heavy chain CDRH3 loop. The library incorporates key sequence features derived from human B cell repertoires captured in a compact antigen recognition module (ARM) format. Built with the VH1-69 heavy chain and four light chains, the library was evaluated against ten human and murine cell surface antigens, including programmed cell death ligand 1 (PD-L1), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT), and roundabout guidance receptor 1 (ROBO1). This approach yielded hundreds of antibodies with robust biophysical properties, some of which were validated by flow cytometry and immunohistochemistry. Furthermore, ML analysis identified additional antibodies for ROBO2 and PD-L2 from the aggregate sequencing data. The publicly available dataset establishes an ML-compatible framework designed to accelerate and streamline antibody discovery and development. A record of this paper's transparent peer review process is included in the supplemental information.
Major advances in Plasmodium sequencing approaches, bioinformatic pipelines, and data analysis tools have provided valuable insights into malaria epidemiology from parasite genomic data. However, translating genetic data into actionable information for decision-makers remains a challenge. Significant barriers limit the integration of these advances into a functional data analysis ecosystem that produces standardized, interpretable results for use by national malaria control programs. The Plasmodium Genomic Epidemiology network convened 18 subject matter experts across 15 institutions at the Reproducibility, Accessibility, Documentation, and Interoperability Standards Hackathon in 2023 to identify available analysis tools, evaluate software standards, improve documentation, and outline workflows. Eight use cases for genomic data were identified, and a subset was developed into analysis workflows comprising a series of connected functionalities. Software tools were then mapped against functionalities to outline a modular approach to data analysis for these use cases. In addition to outlining workflows, a set of objective criteria was developed for evaluating software standards. A total of 40 Plasmodium genomic analysis tools were identified, 22 of which were prioritized for software standards evaluation. Additional tutorials were developed for 10 tools in the form of reproducible code applied to shared datasets. These resources are available on PGEforge (mrc-ide.github.io/PGEforge), a new community resource that serves as a central, open repository for current and future resources for malaria genomic data analysis.
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Exploratory post-hoc analyses of the AEGIS-II trial suggested that the efficacy of CSL112 (apolipoprotein A-I infusion) may be greater in patients with high baseline LDL-C. This genetic study aimed to assess whether LDL-C levels modify the effect of apoA-I on cardiovascular outcomes. We conducted drug-target Mendelian randomization analyses using data from 339,210 UK Biobank participants. Genetic proxies for apoA-I elevation (cis-acting variants within APOA1 gene) were used to mimic the effect of CSL112 therapy. The primary outcome was a composite of ischemic heart disease, myocardial infarction, and stroke; secondary outcomes were the individual components. To mitigate collider bias, we stratified by residual LDL-C, derived from a model adjusting LDL-C for the genetic instrument, age, sex, genotyping array and top 40 genetic principal components. Sensitivity analyses included alternative genetic instruments and formal tests for effect modification. Genetically proxied apoA-I elevation was associated with elevated circulating apoA-I and HDL-C, but there was no concomitant association with any cardiovascular outcome. Null findings were consistent across strata of residual LDL-C. Sensitivity analyses with alternative instrument sets and formal interaction tests uniformly confirmed the absence of any association or effect modification. Genetically proxied lifelong elevation of apoA-I concentration was not associated with reduced cardiovascular risk, even among individuals with high residual LDL-C.