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.
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.
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.
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.
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.
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.
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.
This document is written on behalf of the two professional bodies in the UK that represent genetic counsellors (the Association of Genetic Nurses and Counsellors (AGNC)) and clinical geneticists (the Clinical Genetics Society). The delivery of genomic medicine in the UK continues to evolve in response to technological advancements, increasing demand and national strategic priorities. This paper presents an updated framework describing the professional roles within specialist genomic services, refining responsibilities across key domains of clinical care, education, research and mainstreaming.Building on previous role descriptors, through focused workshops with specific expertise, we integrated national consultation, emerging service models and policy alignment. A new colour-coded matrix delineates role-specific scope of practice for different roles as described in the AGNC career structure.A key development is the formal inclusion of the genomic practitioner role, reflecting workforce diversification. Expanded emphasis is placed on mainstreaming genomic services and involvement in clinical and psychosocial research.This updated framework provides a structured and transparent tool for workforce planning, interprofessional collaboration and service development across genomic medicine. The framework remains aspirational and adaptable, acknowledging regional variability and anticipating future service developments.
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The role of locoregional treatment in oligometastatic oesophago-gastric (OG) cancer remains uncertain, with conflicting trial evidence and limited guidance for clinical practice. This study aimed to evaluate clinician and patient attitudes toward locoregional management, assess clinical equipoise, and explore trade-offs between survival gain and quality of life (QOL) reduction in response to locoregional therapies. A cross-sectional survey of clinicians involved in multidisciplinary management of OG cancer was conducted between August and December 2025. Scenario-based questions assessed acceptability of combined survival gain (6-15 months) and QOL reduction (5%-20%) as a modified discrete choice experiment. A clustered logistic regression model evaluated the independent effects of survival gain and QOL reduction on clinician acceptability. Patient and public involvement workshops were undertaken to understand patient preferences in potential future trial design. Thirty clinicians from 24 centres participated. Sixty percent reported offering locoregional treatment following stability on systemic therapy. Approximately 93% of respondents indicated willingness to participate in a randomised controlled trial (RCT). Acceptability of treatment strategies increased with greater survival gain and decreased with increasing QOL reduction. In clustered regression analysis, each additional 3 months of survival gain increased the odds of acceptability by ∼75%, whereas each additional 5% QOL reduction decreased the odds by ∼45%. There is substantial variation in clinician attitudes toward locoregional treatment of oligometastatic OG cancer, but marked equipoise and high trial willingness exist. Acceptability is strongly influenced by the balance between survival benefit and QOL impact. These findings support the design of prospective RCTs incorporating patient-centred outcomes.
Gla proteins are a vitamin K-dependent family long studied for their roles in blood clotting and vascular calcification. This review examines their broader involvement in cardiovascular disease, particularly cardiac fibrosis. We highlight that their functions are context-dependent, varying with disease stage and cellular environment, and that several occur independently of γ-carboxylation, challenging the view that this modification is universally required for their function. By comparing fibrosis across the heart, lung, liver, and kidney, we distinguish shared from organ-specific mechanisms. Finally, we discuss prospective therapies, from vitamin K supplementation to receptor-targeted approaches, and the questions that remain before clinical translation.
Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that recognizes bacterial-derived antigens presented on MR1. Upon TCR triggering, MAIT cells respond rapidly, producing a range of effector molecules which facilitate host-protective responses in the context of microbial infections. In contrast, MAIT cell responses to viral infection are instead triggered by the recognition of cytokines, and occur independently of TCR engagement. The molecular and metabolic regulation of MAIT cell TCR responses is rapidly emerging, but there is a paucity of data on cytokine driven responses. Here, using high-resolution, quantitative proteomic analysis, we map the downstream proteome of innate cytokine (IL-18/IFNα)-activated MAIT cells, highlighting robust cytokine-driven remodeling and a signature that is distinct from the TCR-driven response. MAIT cells significantly increase protein biosynthesis in response to innate cytokine stimulation and rapidly upregulate the production of IFNγ, granzyme B, and IFN-stimulated gene 15. We demonstrate the metabolic kinetics of MAIT cell responses to cytokine stimulation and highlight a rapid but transient glycolytic burst that is uncoupled from mitochondrial remodeling and contrasts the robust metabolic profile elicited downstream of TCR engagement. Finally, we demonstrate differential contributions from both glycogen and glucose in supporting MAIT cell responses to innate cytokines and further highlight the importance of nutrient availability as a governing signal for MAIT cell fitness and effector functioning.
Quackery remains a significant yet under-recognized public health threat in Pakistan. The term "quack" varies in definition across regions but commonly refers to individuals lacking formal training, legal registration, and authorization to provide healthcare services. As per Section 2(XXIX) of the Sindh Health Care Commission (SHCC) Act, 2013, a quack is defined as a pretender delivering healthcare services without registration with the Pakistan Medical Commission (PMC), National Council for Tibb (NCT), National Council for Homeopathy (NCH), or Pakistan Nursing Council (PNC). This narrative review aims to explore the historical background, current prevalence, and contributing factors sustaining the practice of quackery in Pakistan, as well as to propose potential strategies for its control and eradication. A narrative literature search was conducted across various databases, including PubMed, Science Direct, Embase, Google Scholar, and Scopus, along with official government documents from the Pakistan Medical and Dental Commission (PMDC), Provincial Health Commissions of Pakistan, the World Health Organization (WHO), and news outlets. Quackery continues to flourish in both rural and urban areas, largely due to systemic challenges such as poverty, illiteracy, lack of access to qualified medical services, and public mistrust of formal healthcare systems. While some quacks may provide short-term symptom relief, the long-term consequences often result in severe health complications or fatalities. Addressing the widespread menace of quackery in Pakistan requires a multifaceted and coordinated strategy. This includes stricter policy enforcement, expanded health education programs, strengthened primary healthcare infrastructure, and strategic media engagement for public awareness.
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.
Three-dimensional (3D) organoids have emerged as powerful models for studying human development, disease, and drug response in vitro. Yet, their analysis remains constrained by standard imaging and characterization techniques, which are invasive, require exogenous labeling, and offer limited multiplexing. Here, we present a noninvasive, label-free imaging platform that integrates Raman microspectroscopy with deep learning-based hyperspectral unmixing for unsupervised, spatially resolved biochemical analysis of neural organoids. Our approach enables 2D and 3D mapping of cellular and subcellular structures in both cryosectioned and intact organoids, achieving improved imaging accuracy and robustness compared to conventional methods for hyperspectral analysis. Using our platform, we demonstrate volumetric imaging of a neural rosette within a neural organoid and interrogate changes in biochemical composition during early developmental stages in intact neural organoids, revealing spatiotemporal variations in lipids, proteins, and nucleic acids. This work establishes a versatile framework for high-content, label-free (bio)chemical phenotyping with broad applications in organoid research and beyond.
There remains an unmet need for additional treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable, or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma whose tumors are claudin 18 isoform 2 (CLDN18.2)-positive and programmed death-ligand 1 (PD-L1)-positive. The phase 2 ILUSTRO trial previously demonstrated promising clinical activity with the combination of zolbetuximab plus chemotherapy and checkpoint inhibitor therapy in patients with HER2-negative, LA unresectable, or mG/GEJ adenocarcinoma whose tumors were CLDN18.2-positive, warranting further exploration. In LUCERNA, a multicenter, double-blind, phase III trial, patients with HER2-negative, LA unresectable, or mG/GEJ adenocarcinoma whose tumors are CLDN18.2-positive and PD-L1-positive will be randomly assigned 1:1 to either first-line zolbetuximab plus pembrolizumab and chemotherapy (a capecitabine and oxaliplatin regimen, CAPOX; or a modified folinic acid, fluorouracil, and oxaliplatin regimen, mFOLFOX6) or placebo plus pembrolizumab and chemotherapy. The primary endpoint is overall survival. Key secondary endpoints are progression-free survival and objective response rate. Additional secondary endpoints include duration of response and safety. The results of this trial have the potential to support a new standard-of-care option in this patient population.
Orientia tsutsugamushi (Ot) is a cytoplasmic, gram-negative, obligate intracellular bacterium that causes the human disease scrub typhus. It has a highly repetitive genome, whereby approximately 50% is composed of multiple copies of a proliferated integrative and conjugative element, the Rickettsial amplified Genetic Element (RAGE). Previous RNA sequencing analysis revealed a high level of antisense transcription in Ot, particularly from RAGE-encoded genes, with 18% of all genes having a sense:antisense ratio <1 and 5% with a ratio <0.1. In our current study, we have confirmed the earlier RNA sequencing findings via polymerase chain reaction (PCR)-based methods and established that this antisense transcription is a consistent feature across eight distinct Ot strains. Furthermore, we have utilized PCR to monitor differences in sense and antisense expression between intracellular and extracellular bacteria. Our findings lend weight to the hypothesis that antisense transcription in Ot is a regulated mechanism, possibly playing a crucial role in the pathogen's lifecycle during infection.IMPORTANCEOrientia tsutsugamushi (Ot) is an obligate intracellular bacterium with a highly repetitive genome and an unusual abundance of antisense RNA transcripts. Antisense transcription has been proposed to regulate gene expression, yet its biological significance in intracellular bacteria remains unclear. By confirming high and conserved levels of antisense transcription in specific genes across multiple O. tsutsugamushi strains and showing that antisense expression decreases in extracellular forms, this study provides new evidence that antisense transcription is a regulated process rather than transcriptional noise. These findings suggest that antisense RNAs may play a role in controlling gene activity during the bacterial life cycle, offering insights into gene regulation in organisms with reduced and repetitive genomes.
To describe contemporary trends in kidney stone disease (KSD)-related inpatient episodes, procedures, and costs in England and Scotland, with emphasis on post-coronavirus disease 2019 (COVID-19) service recovery, socioeconomic variation in Scotland, comparison with other urological procedures, and 10-year healthcare demand and cost projections. Retrospective descriptive analyses were conducted using English Hospital Episode Statistics (2020-2025) and Public Health Scotland data (2019-2024). KSD-related finished consultant inpatient episodes and procedures were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision and Operation and Procedures fourth edition codes, respectively. Procedures were categorised as extracorporeal shockwave lithotripsy, ureterorenoscopy (URS), percutaneous nephrolithotomy, or open. Trends were compared with uro-oncological resections and benign prostate obstruction procedures. Socioeconomic variation was assessed using the Scottish Index of Multiple Deprivation. The 10-year healthcare demand and cost projections, accounting for National Health Service (NHS) cost uplift factors, were modelled using historical data. The COVID-19 pandemic disproportionately reduced KSD-associated activity compared with procedures for bladder and kidney cancer. Although volumes now exceed pre-pandemic levels, inpatient episodes remain below baseline and waiting times remain prolonged. Between 2020 and 2025, inpatient episodes increased by 27.4% in England and 17% in Scotland, with URS accounting for >50% of interventions. KSD procedural volumes are comparable to the combined volume of uro-oncological resections and benign prostatic obstruction procedures. In Scotland, 44% of procedures were performed in the two most deprived socioeconomic quintiles versus 37% in the two least deprived. In England, KSD-associated episodes are projected to increase by 33% to 111 907 (95% confidence interval 96 057-130 373) by 2034-2035, with an estimated cumulative NHS cost of £1.82 billion over the next decade. Kidney stone disease exacts a growing burden on healthcare services with incomplete recovery of inpatient care following the COVID-19 pandemic, socioeconomic disparities, and rising healthcare demand. These findings can inform service planning and prioritise evaluation of strategies to improve efficiency, equity, and prevention.
Fibromuscular dysplasia (FMD) is an under-recognized, non-atherosclerotic, and non-inflammatory arteriopathy that predominantly affects women and can involve multiple vascular territories. It commonly presents with hypertension, cerebrovascular events, or arterial dissections in otherwise low-risk individuals, yet diagnostic delays and management variability remain frequent. This ten tips review provides practical guidance for clinicians to improve recognition, diagnosis, and management of FMD in everyday practice. Key recommendations emphasize maintaining a high index of suspicion in patients with early-onset or resistant hypertension, pre-eclampsia, pulsatile tinnitus, or unexplained headaches. High-quality imaging with computed tomographic angiography or magnetic resonance angiography is central to diagnosis, alongside a one-time head-to-pelvis vascular assessment to detect multivessel involvement. The review highlights the importance of recognizing atypical presentations-usually unexplained vascular events-and the limited role of routine genetic screening, while advocating selective evaluation of at-risk relatives. Management strategies, including percutaneous transluminal angioplasty, focus on individualized care. Medical management prioritizes strict blood pressure control, smoking cessation, and selective use of antiplatelet therapy, while statins are not routinely indicated. Lifestyle guidance supports regular physical activity with avoidance of high-risk activities that may predispose to dissection. Special considerations include pregnancy, which is generally safe with appropriate monitoring, and migraine management, which requires balancing efficacy with vascular safety. Finally, this review underscores the importance of multidisciplinary care, patient education, and participation in registries and support networks to advance knowledge and improve outcomes in this rare disease.
Human milk banks (HMBs) are an essential clinical service, providing safe, screened donor human milk (DHM) to clinically vulnerable infants, which can enable mothers to establish their own milk supply. While HMB processes share similarities with other medical products of human origin (e.g., blood, platelets), HMBs remain marginalised services with limited resilience to external or internal pressures. As demand for DHM increases, understanding how to mitigate these vulnerabilities is essential. In November 2022, a workshop organised by the Human Milk Foundation brought together UK milk bank leaders, academics, and planners. The workshop aimed to understand existing pressures faced by UK HMBs and create a network to support strategic, evidence-based responses. Emergent themes highlighted that HMBs are stretched, facilitated largely by goodwill. Most services are reliant on limited workforces with limitations in service continuity, training, and succession planning. COVID-19 exacerbated pressures, but led to HMBs cooperating more. Proposed responses included investment in staffing, training and IT resources, greater public awareness and inter-HMB cooperation, and a national HMB Risk Register. Service continuity needs to be urgently addressed through external multiagency engagement, operational support, and research prioritization (including qualitative, technological and implementation science), defining optimal service design and financial resourcing to meet nationally agreed needs. Without intervention, the UK milk bank network may be unable to respond to future significant pressures, including specialist infant feed or infant formula shortages. With appropriate investment, a comprehensive National Service can be created to provide equitable services underpinned by robust research and innovation.