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Salmonella is a major zoonotic foodborne pathogen, and antimicrobial resistance (AMR) in Salmonella presents a significant public health challenge. Compared with conventional antimicrobial susceptibility testing (AST), whole-genome sequencing (WGS) provides a more rapid and comprehensive approach to AMR characterization, thereby informing antimicrobial selection and supporting public health surveillance. In this study, Oxford Nanopore Technology (ONT)-based WGS was performed on 1,490 Salmonella isolates collected through nationwide surveillance in Taiwan in 2025. Genotypic resistance inferred from WGS data was compared with phenotypic AST results to assess the performance of ONT-WGS. Overall, WGS-inferred resistance showed high concordance with phenotypic resistance for most antimicrobials. However, major genotype-phenotype discordance was observed, attributed to four categories: (i) breakpoint-dependent classification, (ii) reduced or absent phenotypic expression of resistance genes, (iii) minimum inhibitory concentration (MIC) modulation by ramAp, and (iv) absence of known AMR determinants. Notable discrepancies included tigecycline resistance without known genetic determinants, nalidixic acid resistance linked to ramAp-mediated MIC elevation, and a high prevalence of colistin resistance (35.7%) in S. Enteritidis, with most resistant isolates lacking identifiable AMR determinants. Additionally, a significant proportion of ESBL- and AmpC-producing isolates were classified as susceptible or intermediate to cefotaxime and ceftazidime under CLSI criteria, highlighting the potential for misclassification and treatment failure. These findings demonstrate that ONT-WGS enables accurate and comprehensive AMR characterization by directly identifying resistance determinants and avoiding potential misclassification associated with breakpoint-based AST interpretations. When interpreted appropriately, WGS can support better antimicrobial selection and serve as a valuable alternative to conventional susceptibility testing. Accurate prediction of antimicrobial resistance is essential for appropriate therapy and effective surveillance of Salmonella. However, discordance between genotype-based predictions and phenotypic antimicrobial susceptibility testing (AST) can complicate clinical interpretation. In this nationwide study of 1,490 Salmonella isolates, we show that Oxford Nanopore Technology-based whole-genome sequencing (ONT-WGS) provides rapid and comprehensive detection of antimicrobial resistance determinants with high concordance to phenotypic AST. We further identify four major mechanisms underlying genotype-phenotype discordance, including breakpoint-dependent classification, reduced or absent phenotypic expression of resistance genes, minimum inhibitory concentration (MIC) modulation by ramAp, and the absence of known AMR determinants. These findings demonstrate how WGS can complement conventional AST, improve interpretation of challenging susceptibility results, and strengthen genomic surveillance of emerging antimicrobial-resistant Salmonella.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a major threat to global public health. Although intensive care units (ICUs) are traditionally regarded as the main reservoirs for CRKP, CRKP has been widely reported across multiple hospital departments; however, department-specific molecular epidemiology and resistance gene dissemination remain incompletely characterized. Moreover, CRKP isolates co-harboring multiple carbapenemase genes, such as bla NDM-1 and bla OXA-232, are rare and insufficiently characterized. Twenty K. pneumoniae isolates were collected from a teaching hospital in 2024. Antimicrobial susceptibility testing was performed to determine minimum inhibitory concentrations. Conjugation assays were conducted to evaluate the transferability of bla NDM-1 Whole-genome sequencing was performed using Illumina and Oxford Nanopore platforms, followed by hybrid assembly. Resistance genes, insertion sequences, and virulence factors were identified using ABRicate with ResFinder, ISFinder, and VFDB. MLST, plasmid replicon typing, cgMLST, and comparative genomic analyses were performed using BacWGSTdb. The isolates were mainly recovered from sputum and peritoneal drainage fluid, each accounting for 25% (5/20). Most isolates originated from the Surgery department (60%, 12/20), followed by the ICU (20%, 4/20). ST11 was the predominant clone (65%, 13/20), followed by ST15 (10%, 2/20), with ST638, ST1049, ST4573, ST23, and ST3332 detected at low frequencies. Thirteen isolates carried bla KPC-2, while two harbored bla NDM-1 Conjugation assays confirmed the transferability of bla NDM-1. Genomic analysis of the ST638 isolate KP1226 identified a 173,720-bp plasmid, pKP1226-1, carrying bla NDM-1, bla OXA-232, and multiple T4SS-related genes, suggesting a conjugative structure. This study describes CRKP dissemination outside ICUs in this single tertiary hospital, driven by both ST11 clonal expansion and plasmid-mediated horizontal gene transfer. The rare bla NDM-1-positive plasmid co-harboring bla OXA-232 highlights the accumulation of resistance determinants and potential enhanced multidrug resistance transmission.
There is ongoing clinical equipoise regarding the optimal treatment strategy for symptomatic cerebral cavernous malformations (CCMs). The aim of this study was to estimate the causal effect between CCM intervention (microsurgical resection or stereotactic radiosurgery) and clinical outcomes during long-term follow-up. This population-based cohort study included patients (aged 16 years or older) newly diagnosed with CCM using brain MRI or pathology in Scotland during 1999-2003 or 2006-2010. Using Cox regression analysis, we evaluated associations between CCM intervention (as a time-dependent covariate) and a primary outcome of persistent functional impairment or death (defined as at least 2 consecutive annual Oxford Handicap Scale [OHS] scores of ≥2, with sensitivity analysis of OHS scores ≥3), a composite of symptomatic intracranial hemorrhage or new persistent/progressive nonhemorrhagic focal neurologic deficit (ICH/FND) definitely/possibly related to CCM or CCM intervention, and epileptic seizure(s) definitely/possibly related to CCM during prospective follow-up. Among 306 patients with CCM, 190 were symptomatic (89 [47%] because of ICH/FND and 101 [53%] because of epileptic seizure(s), median age 40 years [interquartile range (IQR) 31-55], and 95 [50%] women). During a median follow-up of 16 years (IQR 14-21, completeness 95%), 37 (19%) patients underwent CCM intervention (n = 35 microsurgical resection and n = 2 stereotactic radiosurgery); they were younger (median 33 [26-40] vs 43 [32-59] years, p < 0.001), had presented with ICH more often (18/37 [49%] vs 35/153 [23%], p = 0.002), and had brainstem CCM less frequently (3/37 [8%] vs 36/153 [24%], p = 0.037) than those managed conservatively. CCM intervention was not associated with persistent functional impairment or death when analyzing OHS scores of ≥2 but was associated with OHS scores ≥3 (adjusted hazard ratio [HR] 2.66 [95% CI 1.19-5.94], p = 0.017). CCM intervention was associated with ICH/FND definitely related to CCM or CCM intervention during follow-up (adjusted HR 3.59 [95% CI 1.05-12.20], p = 0.041). CCM intervention was not associated with epileptic seizure(s) during follow-up (adjusted HR 1.56 [95% CI 0.49-4.99], p = 0.45). CCM intervention for symptomatic CCM was associated with persistent functional dependence or death during long-term follow-up. This may be explained by ICH/FND definitely related to CCM or CCM intervention. These findings should be investigated in a definitive randomized controlled trial.
Welcome to the Australian and New Zealand Stroke Organisation Conference 2026 (ANZSOC 2026), marking the return of the conference to Brisbane after 10 years. As a stroke community, we have made significant advances over recent decades in reducing the incidence of stroke and improving outcomes. This conference offers a platform to build on these achievements by fostering collaborations across disciplines and sectors. It will also showcase cutting-edge research and innovations that continue to transform prevention, treatment and recovery in stroke care. At ANZSOC 2026, we will hear from internationally and nationally recognised stroke clinicians, researchers, and people with lived experience of stroke about the latest developments in stroke prevention, acute care, rehabilitation, and life after stroke. We have an exciting and diverse program planned for ANZSOC 2026. We are delighted to welcome our international and national invited speakers: Professor Gert Kwakkel (Amsterdam University Medical Centre, Netherlands), Professor Lara Boyd (University of British Columbia, Canada), Professor William Whiteley (University of Oxford, United Kingdom), and Professor Bruce Campbell (University of Melbourne, Australia). These four highly regarded stroke clinicians and researchers reflect our commitment to diversity, covering fields such as acute care, primary and secondary prevention, epidemiology, neurorehabilitation, and neuroscience. We have over 60 invited speakers from Australia, New Zealand, and beyond, participating in 26 concurrent sessions. Each session is structured to open and close with an invited speaker giving an expert update on relevant topics, with long and short abstract presentations in between. The continued use of short, "lightning" presentations on an ongoing basis with the ANZSOC conference provides many more researchers with the opportunity to present their work directly. We have also scheduled themed poster tours as part of all morning and afternoon teas, offering more opportunities for researchers to engage in scientific discussion with the broader stroke community. ANZSOC 2026 includes specific programming for people with lived experience of stroke. This includes workshop sessions and research presentations designed to be accessible to a diverse audience. For the first time at ANZSOC 2026, researchers will have the opportunity to connect directly with people with lived experience of stroke through Lived Experience Speed Consults. Delivered by the Stroke CRE Lived Experience Advisory Group, these 15- or 30-minute sessions are designed to help researchers test ideas, strengthen study design, refine participant materials and explore meaningful ways to involve lived experience in their work.
Arthur Greeves (1895-1966) was the world-famous Oxford scholar and author C.S. Lewis's (1898-1963) lifelong gay best friend. The article offers the first sustained reconstruction of Greeves's sexual self-understanding across six identifiable stages between 1917 and 1935. Drawing on Lewis's nearly three hundred published letters to Greeves, some of them censored but successfully restored, Greeves's three unpublished diaries, and related archival materials, the article argues that Greeves's homosexuality or same-sex attraction was not static but developed through discernible phases of disclosure, affirmation, psychoanalysis (conversion therapy), theological reframing, and attempted renunciation.
This systematic review and meta-analysis examined the association between intracranial pressure monitoring (ICPm) and mortality in patients with severe traumatic brain injury (sTBI), with additional focus on functional neurological outcomes and intensive care unit (ICU) and hospital length of stay (LOS). This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered with PROSPERO (CRD42025643607). MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched through August 1, 2025, for studies comparing ICP-monitored and non-ICP-monitored patients with traumatic brain injury. Eligible study designs included randomized controlled trials, prospective observational cohort studies, retrospective observational cohort studies, registry-based cohort studies, and case-control studies. Study quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist, Risk of Bias 2.0 for randomized trials, and the Oxford Centre for Evidence-Based Medicine Levels of Evidence framework. Thirty-one studies met inclusion criteria. The mortality meta-analysis included 121,799 patients. Pooled crude analysis showed lower mortality in ICP-monitored patients than in non-monitored patients (OR 0.79, 95% CI 0.68-0.91, p = 0.002), with high heterogeneity (I²=92%). Across studies with extractable group-level mortality percentages, median mortality was 28.6% in ICP-monitored patients and 33.2% in non-monitored patients. Functional neurological outcomes were inconsistently reported and did not show a consistent benefit with ICPm. ICU and hospital LOS were generally longer in ICP-monitored patients. Ten studies reported complication data, most commonly infection, hemorrhagic events, and mechanical or device-related complications; reporting was heterogeneous and precluded pooled analysis. ICPm was associated with lower crude mortality in sTBI; however, substantial heterogeneity and residual confounding limit causal interpretation. Functional outcomes did not show consistent benefit. Complication reporting was inconsistent, but reported events included infection, hemorrhage, and device-related complications. Future studies should standardize functional outcome reporting and adjust for key confounders. Systematic review and meta-analysis; Level III.
The coronavirus disease-2019 pandemic has been shaped by successive waves of variants due to the high mutational capacity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monitoring the genomic diversity and mutational profiles of these variants and their clinical impact is essential to inform public health measures as well as vaccine and treatment strategies. This study aimed to analyze clinical samples detected as SARS-CoV-2 positive by real-time reverse transcription polymerase chain reaction (rRT-PCR) during two different periods of the pandemic in Türkiye using next-generation sequencing to compare their genomic profiles, determine their phylogenetic positions and assess the relationship between mutations and clinical findings. A total of 39 rRT-PCR-positive respiratory samples (9 in September 2021 and 30 in March-April 2022) with cycle threshold <20 from our laboratory were included in the study.An amplicon-based Oxford Nanopore method was used for next-generation sequencing. The 22 high-quality sequences obtained were evaluated phylogenetically using MEGA software together with the sequences obtained from the Global Initiative on Sharing All Influenza Data and the reference genome in order to enrich the phylogenetic tree. Lineage and clade assignments were performed using Nextstrain and PANGO. According to the Nextstrain classification, nine of the sequences belonged to the 21J (Delta) clade and 30 to the 21L (Omicron) clade. In the PANGO analysis, sequences from the 2021 period mostly matched B.1.617.2 and its AY sublineages (AY.122, AY.46, AY.46.2, etc.), while sequences from the 2022 period mostly matched BA.2 and its sublineages (BA.2.9, BA.2.5). In the phylogenetic analysis, sequences from the two periods diverged significantly. The evolutionary distance between the reference genome and the Omicron variant was found to be greater than that to the Delta variant. In addition, the distance of Omicron to Delta exceeded its distance to the reference genome. In the phylogenetic tree including Alpha sequences from the previous predominant variant period, the Alpha variant clustered with Omicron. These results suggest that Omicron does not appear to have evolved from Delta. The mutational analysis revealed that the Omicron variant harbored a higher number of amino acid changes across multiple regions of the genome, particularly in the Spike protein; a substantial portion of these alterations included deletions in the NTD (L24/P25/P26), as well as point mutations such as S375F, E484A, Q493R, and N501Y in the receptor binding domain and H655Y and N679K in the fusion region, which are associated with host cell entry and immune evasion. In the Delta variant, substitutions P681R and L452R near the S1/S2 cleavage site of Spike and deletions Δ156/157 in the N-terminal domain predominated. Both variants retained common adaptive mutations that confer an infectious advantage, such as S:D614G, S:T478K, and ORF1b:P314L. Clinical evaluation showed that Omicron cases had a significantly milder course (p= 0.032), with similar age, comorbidity and vaccination profiles between the two groups. The results suggest that some Omicron-specific Spike mutations suppress membrane fusion by reducing TMPRSS2 usage, a feature that may contribute to the variant's low virulence. This study presents comprehensive regional genomic data from the Delta-Omicron transition period in Türkiye, including phylogenetic positions, Spike mutation profiles and clinical outcomes. The results emphasize that monitoring the molecular adaptations of variants in conjunction with clinical data is essential for early warning and control of rapidly evolving pathogens such as SARS-CoV-2.
Mortality from alcohol-related liver disease (ARLD) in England rose after the COVID-19 pandemic. Existing reports lack data on prior healthcare use, which is key to understanding care pathways before death. This study examined long-term trends in ARLD mortality before, during and after the pandemic and assessed changes in relation to prior inpatient care. In this population-based observational study using English national mortality records linked to NHS hospital data, all ARLD deaths in adults aged 25-84 were analysed from January 2004 to December 2024. Monthly mortality trends were examined by age, sex, deprivation, region and prior inpatient care. Interrupted time series estimated changes in mortality after the pandemic onset. Over the study period, 97 058 ARLD deaths occurred, with about one-third out-of-hospital. Following the pandemic, ARLD mortality increased by 27.7% (95% CI 23.3% to 32.3%), representing 5571 excess deaths between March 2020 and December 2024. The step-increase was greater for out-of-hospital deaths (34.9%, 95% CI 28.4% to 41.7%) than for in-hospital deaths (22.9%, 95% CI 18.2% to 27.8%), and the increase in out-of-hospital deaths was driven by deaths in people who had no recent discharge in the previous year (75.7%, 95% CI 61.7% to 90.9%). The increase in deaths from ARLD has been driven by a disproportionate increase in those without recent inpatient care. Efforts to understand ARLD mortality should increasingly be focused on the out-of-hospital setting.
Ecological data are increasingly collected by networks of collaborators using replicated designs and methods, which can significantly improve the quality and quantity of data throughout the ecological niche and geographic range of species or communities. The coordinated generation and management of data is critical for producing datasets (Standard Data Products) across multiple sites that can be used by different researchers, over extended time periods and for multiple purposes.We describe and use a Quality Assurance framework for the design, collection and production of reproducible Standard Data Products for distributed ecology projects. We identified six critical project elements of a Quality Assurance framework (QA1-6) to produce ecological Standard Data Products with high immediate and future value.We applied the Quality Assurance framework to the Plantpopnet project as a case-study. Plantpopnet is a coordinated distributed system for population macroecology using the model species Plantago lanceolata. We mapped Plantpopnet activities to the Quality Assurance Framework as follows: (QA1) Measurable objectives: research project objectives with data requirements, (QA2) Process control: governance policies, (QA3) Project specific procedures: model organism selection and data collection protocol, (QA4) Supporting production of high quality data: recruitment, retention and engagement of participants, (QA5) Data management: data management plan and reproducible data cleaning workflow, (QA6) Production and management of outputs: Standard Data Products and papers.Explicit use of Quality Assurance, project and data management tools together with standardised ecological methods facilitated the design, collection, maintenance and sustainability of high-quality data products. We provide a Quality Assurance framework together with governance documents, code and data for a reproducible Standard Data Product. This framework supports a distributed funding model which can be sustainably applied to facilitate future research and applications of coordinated distributed ecology projects.
High-throughput computational screening of polymers offers a powerful way to address the imbalance between the vast number of polymers synthesised for diverse applications and the relatively small subset that can be studied using atomistic simulations. This work presents PolyRapid: an automatic workflow designed to enable the rapid and efficient screening of an extensive polymer library. In this work it is deployed on a library of 103 homopolymers. The workflow integrates an automated annealing protocol with adaptive control, allowing for reproducible simulations with minimal human intervention and minimisation of the computational cost. To this end, we test a number of quantitative conformational and energetic convergence metrics. It achieves equilibration in 95% of systems within four 30 ns annealing cycles, and 100% within nine annealing cycles saving, for our dataset, more than 2500 hours of compute compared to a fixed equilibration protocol. The simulation results are compared with experimental data and compiled into a publicly available repository which reports polymer temperature, tacticity and crystallinity. The availability of a homogenous large set of simulations enables the adoption of machine learning approaches for a variety of tasks. We exemplify this possibility by proposing rapid machine-learning-based method to predict the (computed) polymer density (F1-score = 0.91) and (experimental) glass transition temperature (F1-score = 0.76), using both chemical fingerprint representations and physically meaningful MD-derived descriptors.
Women with systemic lupus erythematosus (SLE) are at increased risk of infertility due to disease activity and exposure to gonadotoxic therapies. Anti‑CD19 chimeric antigen receptor (CAR) T‑cell therapy has recently been shown to induce durable, drug‑free remission in refractory SLE; however, its effects on ovarian function remain unknown. We assessed longitudinal changes in reproductive endocrine markers to evaluate the impact of CAR T‑cell therapy on ovarian reserve and hypothalamic-pituitary-ovarian (HPO) axis function. Women with severe, treatment‑refractory SLE receiving autologous anti‑CD19 CAR T‑cell therapy (Miltenyi Biomedicine) in conjunction with standard lymphodepletion at two tertiary care centres were studied. Anti‑Müllerian hormone (AMH), estradiol (E2), progesterone, follicle‑stimulating hormone (FSH), luteinizing hormone (LH), and prolactin were measured at baseline and 12 months after therapy. Blood samples were obtained independent of menstrual cycle phase. Paired statistical analyses were performed. Thirteen women were included; median age at CAR T‑cell therapy was 27 years. AMH levels were stable (1.54 ng/mL [IQR 0.64-3.15] vs 2.14 ng/mL [0.63-3.26]; p = 0.886). E2 (243 pmol/L [186-346] vs 484 pmol/L [277-829]; p = 0.339) and progesterone (0.90 nmol/L [0.80-0.90] vs 1.80 nmol/L [0.90-3.40]; p = 0.054) showed substantial variability without significant longitudinal change. FSH increased modestly (6.60 IU/L [4.00-7.90] vs 7.20 IU/L [4.50-9.90]; p = 0.033) without a concomitant decline in AMH. LH (6.10 IU/L [5.10-12.90] vs 7.00 IU/L [5.00-12.90]; p = 0.946) and prolactin (10.0 µg/L [8.0-10.0] vs 8.0 µg/L [5.0-9.0]; p = 0.123) remained stable. Anti‑CD19 CAR T‑cell therapy including standard lymphodepletion showed no signal of impaired ovarian reserve, as assessed by AMH and hormone profiles. Observed hormonal changes, including FSH, should be interpreted with caution given study limitations.
Adults who survive intensive care unit (ICU) admission with sepsis (sepsis survivors) have immune impairments involving concurrent inflammation and immunosuppression that increase their long-term risk of reinfections and mortality. Vaccine immunogenicity could therefore be abnormal in sepsis survivors but has never been examined. Here, in a 1:1 randomized, placebo-controlled trial, we tested the efficacy and immunogenicity of a single intramuscular dose of 13-valent pneumococcal conjugate vaccine (PCV13) in 214 sepsis survivors at ICU discharge. The PCV13 group (n = 104) experienced 43 primary outcome events (time to first infection-related rehospitalization or death during 365 days of follow-up) among 72.5 person-years of follow-up compared with 38 events among 76.5 person-years of follow-up in the placebo group (n = 110) [hazard ratio, 1.23 (95% CI, 0.80 to 1.91)]. The PCV13 group experienced higher rates of reinfections and received earlier antibiotic prescriptions in primary care. There were no vaccine-related serious adverse events. PCV13 immunogenicity assessments included serotype-specific immunoglobulin G (IgG), immunophenotyping, and pan-leukocyte RNA sequencing measured at baseline and 10 and 30 days postrandomization. PCV13-induced serotype-specific IgG responses varied across serotypes and participants, without excessive cytokine responses. PCV-induced blood transcriptional module responses in antigen-presenting cells and helper T cells were also variable. Variations in PCV13 immunogenicity were associated with age in men, body mass index in women, and cytotoxicity-associated gene modules regardless of sex. This trial showed that PCV13 administered at ICU discharge did not benefit this sepsis survivor population and underscores the need for further research to delineate treatable molecular mechanisms of postsepsis immune dysfunction (ClinicalTrials.gov identifier NCT03565159).
Suicide is one of the leading causes of death among adolescents, yet little is understood about the biopsychosocial factors related to suicidality. The demographic, clinical, and biological characteristics of adolescents with and without psychiatric histories may help inform mechanistic approaches to treatment of mood disorders and suicidality. The 'characterizing the inflammatory profile and suicidal behavior in adolescents' and 'RAD arm of the Texas Resilience Against Depression' studies aimed to characterize the clinical and biological profiles of youth with suicidal behavior and youth at risk for mood disorders, compared to healthy adolescents (n = 75 in each group). Here, we report the descriptive baseline clinical and psychological characteristics of adolescents at risk of mood disorders and those with suicidal behavior. The adolescents with suicidal behavior reported 3.53 lifetime suicidal events on average, predominantly reported moderate to very severe depression (34.7%, 24%, to 9.3%), moderate to severe anxiety (58.6%), low optimism (91.9%), and mild (39.2%) to moderate (28.4%) degree of hopelessness. The at-risk adolescents predominantly reported no depression (60%) or anxiety (68.9%), moderate optimism (50%), and a positive outlook (85.7%). Healthy adolescents predominantly reported no depression (88.3%) or anxiety (93.2%), moderate optimism (59%), and a positive outlook (87%). The adolescents with suicidal behavior and those at risk of mood disorders exhibited significantly higher irritability and borderline personality disorder features (uncorrected p = 0.02 to p < 0.001) and lower resilience compared to healthy adolescents. Ongoing investigations using the longitudinal clinical and biological data will help identify the immune biosignatures of suicidality in youth.
Animal experimental studies and human observational data suggest that fetal inflammatory response to chorioamnionitis is associated with increased risk of neonatal encephalopathy and attenuation of fetal responses to intrapartum hypoxia-ischemia, but the effects of clinical and/or histological chorioamnionitis and fetal inflammatory response on fetal heart rate patterns during labor in the term human fetus remain undefined. To compare intrapartum fetal heart rate responses to hypoxia, assessed by fetal heart rate deceleration frequency and cumulative deceleration area, in acidemic fetuses in term labor to their peers with and without hypoxic-ischemic encephalopathy and clinical and/or histological chorioamnionitis. This retrospective cohort study included 317,126 term singleton deliveries from 7 hospitals in the Helsinki University Hospital district, Finland, between 2005-2024. Among these, 3,487 newborns with umbilical artery acidemia, defined as pH <7.10, and continuous intrapartum cardiotocographic recordings were identified. Fetal heart rate data from the final 9 hours before birth were analyzed, with hourly median values calculated for deep deceleration (decreases of ≥60 beats per minute below baseline lasting >15 seconds) and shallow deceleration (decreases of 10-15 beats per minute lasting >15 seconds) frequencies, cumulative deceleration area (all decelerations of ≥10 beats per minute lasting >15 seconds), and uterine contraction frequency. Neonatal hypoxic-ischemic encephalopathy was diagnosed according to Sarnat staging, and chorioamnionitis based on clinical criteria and/or placental histology. Acidemic cases were categorized into 4 groups: acidemia with hypoxic-ischemic encephalopathy and clinical and/or histological chorioamnionitis (N=133), acidemia with hypoxic-ischemic encephalopathy without chorioamnionitis (N=181), acidemia with clinical and/or histological chorioamnionitis without hypoxic-ischemic encephalopathy (N=436), and acidemia without hypoxic-ischemic encephalopathy or chorioamnionitis (N=2,737). Among 3,487 term fetuses with umbilical artery acidemia, clinical and/or histological chorioamnionitis was associated with an increased risk of hypoxic-ischemic encephalopathy (adjusted odds ratio, 4.61; 95% confidence interval, 3.60-5.87; p<.001), despite a shift toward less severe umbilical artery acidemia, with a greater proportion of moderate (pH 7.09-7.00) and a lower proportion of severe (pH <7.00) acidemia (p=.026). Among histological chorioamnionitis cases, funisitis, a histopathologic manifestation of the fetal inflammatory response, remained independently associated with hypoxic-ischemic encephalopathy after adjustment for acidemia severity (adjusted odds ratio, 2.21; 95% confidence interval, 1.32-4.13; p<.001). Consistent with these findings, clinical and/or histological chorioamnionitis was associated with attenuated fetal heart rate responses to intrapartum hypoxic stress. Among fetuses who developed hypoxic-ischemic encephalopathy, those with clinical and/or histological chorioamnionitis exhibited fewer deep decelerations (adjusted ratio of medians, 0.62; 95% confidence interval, 0.49-0.76), a smaller cumulative deceleration area (adjusted ratio of medians, 0.70; 95% confidence interval, 0.59-0.82), and more shallow decelerations (adjusted ratio of medians, 2.45; 95% confidence interval, 2.33-2.63; all p<.001), despite similar uterine contraction frequency, with attenuation most pronounced among fetuses with funisitis. Clinical chorioamnionitis alone remained independently associated with hypoxic-ischemic encephalopathy (adjusted odds ratio, 1.44; 95% confidence interval, 1.02-2.05; p<.001), whereas histological chorioamnionitis was associated with a 2.5-fold higher risk than clinical chorioamnionitis alone (adjusted odds ratio, 2.54; 95% confidence interval, 1.68-3.86; p<.001). Clinical and histological chorioamnionitis, particularly when accompanied by funisitis, are associated with attenuated fetal heart rate responses to intrapartum hypoxic stress and reduced fetal tolerance to hypoxia, thereby increasing the risk of hypoxic-ischemic encephalopathy at milder degrees of acidemia.
Network-based analyses of omics data are widely used and, while many of these methods have been adapted to single-cell scenarios, they often remain memory- and space-intensive. As a result, they are better suited to batch data or smaller datasets. Furthermore, the application of network-based methods in multi-omics often relies on similarity-based networks, which lack structurally discrete topologies. This limitation may reduce the effectiveness of graph-based methods that were initially designed for topologies with better defined structures. We propose Subset-Contrastive multi-Omics Network Embedding (SCONE), a method that employs contrastive learning techniques on large datasets through a scalable subgraph contrastive approach. By exploiting the pairwise similarity basis of many network-based omics methods, we transformed this characteristic into a strength, developing an approach that aims to achieve scalable and effective analysis. Our method demonstrates synergistic omics integration for cell type clustering in single-cell data. Additionally, we evaluate its performance in a bulk multi-omics integration scenario, where SCONE performs comparable with the state-of-the-art despite utilizing limited views of the original data. We anticipate that our findings will motivate further research into the use of subset contrastive methods for omics data.
Androgenetic alopecia (AGA) is a common form of hair loss with limited treatment options, driven by poorly understood molecular mechanisms. Using single-cell RNA sequencing of human scalp follicles from balding and non-balding regions, we constructed a high-resolution molecular anatomy atlas of the hair follicle and its microenvironment. We identified significant silencing of Wingless-related integration site 5A (WNT5A) signaling, which was widely known as the trigger of non-canonical WNT signaling pathway, in hair follicle stem cells (HFSCs) from balding areas, leading to downregulation of the transcription factor ATF3 and its target FOSB. Therapeutically, functional validation showed that activating the WNT5A-ATF3-FOSB axis maintained HFSC competence in AGA murine models and significantly inhibited the progression of AGA. Our findings reveal a critical molecular axis in AGA pathogenesis, highlighting its potential as a therapeutic target for hair loss disorders.
Somatotrophinomas can occasionally occur in familial settings and may be associated with known germline mutations, such as MEN1, AIP, CDKN1B, PRKAR1A, SDHx, and MAX. Recently, the CHEK2 gene has emerged as a potential pituitary tumour predisposition gene. To present a rare case of a patient with a pituitary somatotrophinoma and primary hyperparathyroidism (PHPT) associated with a likely pathogenic CHEK2 germline mutation, suggesting a novel MEN1-like phenotype. We conducted a detailed clinical, biochemical, radiological, and genetic evaluation of a 38-year-old woman presenting with features of acromegaly and PHPT. Genetic testing for known MEN1 syndrome-associated genes and broader pituitary tumour predisposition genes was performed. The patient presented with features of acromegaly of 3 years duration and a collagenoma. Laboratory evaluation revealed an elevated IGF-1. Biochemical and imaging studies also revealed PTH-dependent hypercalcaemia and bilateral inferior parathyroid adenomas. Genetic testing for a panel of genes causing hypercalcaemia - including MEN1 and CDKN1B - was negative; however, a pathogenic nonsense variant in CHEK2 (c.232C>T; p.(Gln78Ter); gnomAD frequency: 0.0006%) was detected with exome sequencing. The patient underwent transsphenoidal resection of the pituitary tumour followed by gamma-knife radiosurgery and received long-acting octreotide every four weeks. Parathyroidectomy was performed 1.5 years later. This is the first reported case of a CHEK2 germline mutation associated with somatotrophinoma, PHPT, and collagenoma, mimicking the clinical MEN1 syndrome. These findings expand the spectrum of possible CHEK2-associated neoplasia and highlight the need to consider CHEK2 as a possible candidate gene in patients with MEN1-like syndromes when common mutations have been excluded.
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To evaluate whether the risk of progression from psoriasis to psoriatic arthritis (PsA) is affected by the class of bDMARD used for treatment of psoriasis, in a real-world cohort with a large follow-up. We conducted a retrospective study in two university dermatology-rheumatology centers. Consecutive adults with psoriasis receiving bDMARDs for ≥6 months between 2008 and 2025 were included. Patients were followed until PsA diagnosis, last visit, or study end. The primary outcome was incidence of PsA. Among 393 patients, 86 (22%) developed PsA during follow-up. In the single-class bDMARD exposure analysis (n = 257), PsA occurred more frequently in patients treated with tumour necrosis factor inhibitors (TNFi) than in those receiving IL-17, IL-23, or IL-12/23 inhibitors. After adjustments, all non-TNFi bDMARDs were associated with significantly lower odds (OR range 0.16-0.25) and hazards (HR range 0.17-0.30) of PsA compared with TNFi. Similar findings were observed when patients were grouped according to the bDMARD class used for the longest duration. In patients analyzed by first bDMARD received (n = 137), PsA prevalence and adjusted hazards did not differ between bDMARD classes. In this long-term real-life cohort of patients with psoriasis, treatment with non-TNFi bDMARDs-particularly IL-17 and IL-23 inhibitors-was associated with lower risk of incident PsA compared with TNFi. These findings support PsA interception and warrant prospective studies to determine whether biologic class selection can modify disease progression.
Rotational percutaneous mechanical thrombectomy with adjunctive angioplasty, stenting or limited thrombolysis (rPMT+) has become commonplace in the treatment of acute and subacute limb ischaemia (SLI). This systematic review and proportional meta-analysis synthesises the available evidence on its safety and efficacy. MEDLINE, Embase and the Cochrane Library. We searched for studies (≥10 patients) published since January 1, 2012 (PROSPERO protocol CRD420251015846). Risk of bias was assessed using RoBANS 2. Proportional meta-analysis maximised representative sample sizes by incorporating both single-arm and comparative studies. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) evidence profiles were developed for each outcome of interest. Twenty-four studies - 7 comparative and 17 single arm - containing 2954 procedures (2697 rPMT+, 257 controls) met eligibility criteria. There were no randomised controlled trials. The pooled technical success (TS) rate for rPMT+ was 98% (95% confidence interval [CI]: 97%-100%, p < .001). Amputation-free survival (AFS) was 96% (95% CI: 93%-98%, p < .001). Twelve-month primary patency (PP) was 68% (95% CI: 55%-79%, p < .001). The pooled rate of freedom from clinically-driven target lesion revascularisation was 85% (95% CI: 80%-90%, p < .001). No significant differences existed between acute, subacute and mixed subgroups. Procedure-related mortality was 0.5% (11 deaths in 2086 procedures from 17 studies) with most deaths occurring after adjunctive catheter-directed thrombolysis. Major adverse events occurred in 4% of procedures (95% CI: 1%-8%, p < .001) and distal embolisation in 8% (95% CI: 5%-11%, p < .001). rPMT+ reduced length of stay by 1.7 days versus alternatives (95% CI: 3.3%-0.1 days, p < .05). All outcomes demonstrated heterogeneity; GRADE assessment rated evidence certainty as low to very low. The evidence available from 24 real-world observational studies of 2954 procedures supports the use of rPMT+ in acute limb ischaemia and SLI - delivering an overall pooled TS rate of 98% and AFS rate of 96% with no significant differences between acute, subacute and mixed subgroups. rPMT+ is associated with shorter hospital stays than either surgery or thrombolysis.Clinical ImpactThis systematic review and proportional meta-analysis synthesises 24 single-arm and comparative non-randomised studies encompassing nearly 3000 procedures to provide a comprehensive assessment of the safety and efficacy of rotational percutaneous mechanical thrombectomy in patients with acute and subacute lower limb ischaemia. It demonstrates that, when used for initial revascularisation prior to adjunctive angioplasty, stenting or limited thrombolysis, this endovascular approach delivers clinically valuable rates of technical success and amputation-free survival with notably high rates of freedom from clinically-driven target lesion revascularisation, acceptable primary patency, low procedural risk and significantly shorter hospital stays.