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Background and Objectives: Most older widowed men and women experience elevated depressive symptoms after spousal loss, and many recover to pre-widowhood levels over time. However, not all widows return to pre-loss mental health, and recovery may differ by gender. Pre-widowhood psychological resilience (PR) has been shown to influence these effects. This study evaluates changes in depressive symptoms for older men and women to determine how PR shapes acute and long-term depressive symptom responses to spousal loss., Research Design and Methods: Using longitudinal Health and Retirement Study data, we evaluate changes in depressive symptoms from baseline PR pre-widowhood to (1) the first study wave in which individuals report widowhood (acute effects) and (2) the second wave after reporting widowhood (recovery period), for men and for women. We use inverse probability weighted regression models, comparing new widows with their continuously married counterparts., Results: Both widowed men and women experienced increased depressive symptoms in the acute period following spousal loss regardless of PR level. However, moderate to high levels of PR for men and high PR for women predicted recovery to pre-widowhood depressive symptoms two years later. High PR was also associated with fewer depressive symptoms over time among continuously married men and women., Discussion and Implications: Results suggest interventions that bolster PR preceding spousal loss could enhance likelihood of recovery following widowhood for both men and women and may also provide protective effects regarding overall depressive symptoms among married individuals over time., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The interpretation of antibodies to glutamic acid decarboxylase 65 (GAD-Abs) in neurological practice is challenging. GAD-Abs are not considered directly pathogenic and immunotherapy guidelines are lacking., Methods: We undertook a single-center retrospective service evaluation of GAD-Abs, documenting clinical features, immunotherapy responses, and outcomes of 335 patients with positive GAD-Abs measured by indirect ELISA between 2012 and 2020. The serum:CSF ratio of GAD-Ab values was used as a surrogate for intrathecal synthesis., Results: 168 (50%) patients had diagnosed neurological disorders (GAD-ND). Ninety-six had neurological disorders often or sometimes associated with GAD-Abs, i.e., stiff person syndrome spectrum disorders (SPS-SD, n = 26), cerebellar ataxia (n = 21), epilepsy (n = 19), encephalitis (n = 18), or any combination of these ("mixed", n = 12). Seventy-two had other neurological disorders (ONDs) not typically associated with GAD-Abs. We defined a cut-off of 10,000 IU/mL a priori and a posteriori for GAD-Ab associated NDs, but identified values > 10,000 IU/mL in 21% and 11% of patients with ONDs or diabetes respectively, and < 10,000 IU/mL in 39% patients with classical GAD-Ab syndromes, indicating low assay specificity and sensitivity. Low serum: CSF GAD-Ab ratios were consistent with intrathecal synthesis in 12/19 tested; 25/54 patients had oligoclonal bands. 30/50 patients given adequate immunotherapies had partial (n = 17) or good (n = 13) responses, particularly those with SPS-SD or limbic encephalitis. Within the limitations of small subgroups and routine laboratory titrations, patients with GAD-Ab values > 10,000 IU/mL, intrathecal synthesis of GAD-Abs, or oligoclonal bands, were not more likely to improve with immunotherapies than those with GAD-Ab values < 10,000 IU/mL and a non-inflammatory CSF. Rather, treatment response correlated with disease group, principally SPS-SD and encephalitis., Conclusions: These results suggest caution in over-interpreting GAD-Abs values. Better biomarkers for identifying patients with immunotherapy responsive GAD-Ab disease are needed., Competing Interests: Declarations. Conflicts of interest: MZ has received fees for lectures for the Norwegian Neurological Society; Copenhagen Neuropsychological Society, Rigshospitalet; Cygnet Healthcare; GSK; and UCB Pharma, and personal fees to attend the European Association of Neurology (EAN) meeting on autoimmune encephalitis in April 2022. MH has received consulting fees from Accenture Consulting. PG has received grants and honoraria for advisory board from Vico Therapeutics, honoraria for advisory board from Triplet Therapeutics, grants and personal fees from Reata Pharmaceutical, grants from Wave. AV and the University of Oxford receive royalties for LGI1 and CASPR2 antibodies. AV has received lecture fees from Alexion, UCB and Johnson&Johnson., (© 2025. The Author(s).)

Introduction: Disadvantaged socioeconomic status (SES) are linked with adverse cognitive outcomes in ageing and heightened dementia risk. Few studies have examined relationships between life course SES and adult structural brain changes that may be associated with cognitive decline., Aims: This systematic review assesses evidence from neuroimaging based epidemiological studies that have explored relationships between life course SES and adult structural brain changes., Methods: Embase, PsycINFO and Medline from inception to November 2020 were systematically searched according to strict search criteria which captured studies examining relationships between life course SES and adult structural neuroimaging changes. Bibliographies and citations of relevant papers were selected. Searches were limited to English language publications., Results: Amongst 8134 search results, 91 unique titles were screened and 24 studies selected. All 24 studies demonstrated at least partial relationships between disadvantaged life SES and adverse structural brain changes. Selected studies utilised diverse structural imaging techniques, neuroanatomical sites and operational definitions of life course SES. The methodological approaches and statistical analysis varied significantly between studies. We specifically discuss the neurobiological interpretation of Diffusion weighted MRI based studies and MRI volumetric studies investigating associations between life course SES and adult brain structural changes and the wider global health implications of these studies., Conclusion: Disadvantaged life course SES may have associations with structural brain changes which underlie adverse ageing outcomes. Given heterogeneity of study designs and operationalisation of SES, the cross-sectional design of studies and wide-ranging neuroimaging modalities any association should be considered with caution. Mediatory mechanisms including malnutrition, stress, markers of inflammation, hormonal changes and cognitive reserve and health behaviour are presented in selected studies. Targeting life course SES in public health-based interventions may offer approaches to maintain healthy brain structure and function in ageing., Competing Interests: Declaration of interests No potential conflict of interest was reported by the authors., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

This manuscript describes the collation of available water quality data from the freshwater reaches of surface streams within the Great Barrier Reef catchment area, northeastern Australia. This compilation represents one of the most comprehensive online datasets for historical tropical and subtropical freshwater quality around the world. We document the criteria for selection of the data and associated publications as well as the processes of data cleaning used to produce a qualitative assessment of the datasets. The final compilation includes 41 individual datasets that collectively report 466 sites and contain over 26,000 discrete water quality sample records totaling more than 350,000 unique water quality results. Finally, we outline the nuances of the data that end users need to take into account when combining them for spatial and temporal analyses. The dataset ensures that these valuable water quality data collected over the past four decades are preserved for the next generations of researchers, practitioners, management agencies and policy makers., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Human-centered design (HCD) is rooted in building trust with end users by developing empathetic understanding of key partners' needs, continuous engagement, and iterative solution creation and refinement. One of the core tenets of HCD in health care is that consistent end-user engagement will result in better health outcomes. Children with medical complexity (CMC), a subset of children and youth with special health care needs, are characterized by multiple chronic health care conditions and high health care use, including emergency department visits. To address the known challenges with providing high-quality care for CMC in emergency settings, emergency information forms are currently recommended to provide insights into existing health complexities at the point of care. However, these forms have faced significant implementation challenges that lead to limited stakeholder buy-in and lack of incorporation into current emergency care workflows. We present HCD as a strategy to aid in the creation and optimization of an emergency care action plan (ECAP) for CMC. The objectives of this communication are, therefore, as follows: (1) to demonstrate HCD as an accessible approach to delineate and address pediatric care challenges within a complex health care system and (2) to illustrate a commonly used HCD methodological approach to address implementation challenges of an emergency care planning tool through the creation of an ECAP for CMC., (Copyright © 2025 by the American Academy of Pediatrics.)

Background: Although COVID-19 is predominantly a respiratory tract infection, current antibody treatments are administered by systemic dosing. We hypothesize that inhaled delivery of a monoclonal antibody may be a more effective and convenient route. We investigated the safety, tolerability, and pharmacokinetics of IN-006, a reformulation of regdanvimab for nebulized delivery by a handheld nebulizer., Methods: A Phase 1 study was conducted in healthy volunteers aged 18-55 a Phase 1 unit in Melbourne, Australia (ACTRN12621001235897). Study staff and participants were blinded to treatment assignment, except for pharmacy staff preparing the study drug. The ratio of active:placebo randomization to each cohort was set at 3:1. The primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetics of IN-006 in nasal fluid and serum., Findings: Twenty-three participants were enrolled and randomized across two single dose and one multiple dose cohorts (30 mg or 90 mg single nebulized dose, or seven daily 90 mg doses). There were no serious adverse events. All enrolled participants completed the study without treatment interruption or discontinuation. All treatment-emergent adverse events were transient, non-dose dependent, and graded mild to moderate in severity. Nebulization was well-tolerated and completed in an average of 6 min. Geometric mean nasal fluid concentrations of IN-006 in the multiple dose cohort were 739.8 μg/mL at 30 min after dosing and 1.2 μg/mL at 22 h. Geometric mean serum levels in the multiple dose cohort peaked at 0.51 μg/mL 3 days after the final dose., Interpretation: IN-006 was well-tolerated and achieved concentrations in the respiratory tract orders of magnitude above the IC 50 range typical of antiviral mAbs. These data support further development of nebulized delivery of antiviral mAbs for respiratory infectious disease., Funding: This work was funded by the U.S. Army Medical Research and Development Command (W81XWH-15-9-0001) and regdanvimab was provided by Celltrion, Inc., Competing Interests: Declaration of interests TM, LB, BF, MH, MB, MM, ZR, JW, FF, and JH are employees of Inhalon Biopharma/Mucommune and may hold shares in Inhalon Biopharma, Inc. HK, YP, CK, JMC, and SYL are employees of Celltrion, Inc, which received funding from the government of Korea to advance Regdanvimab, which was used to cover salary for their work on this project. JL received partial salary support for his work on this project. SKL is founder of Mucommune, LLC and currently serves as its interim CEO. SKL is also founder of Inhalon Biopharma, Inc, and currently serves as its CSO as well as on its Board of Director and Scientific Advisory Board. S.K.L has equity interests in both Mucommune and Inhalon Biopharma; S.K.L's relationships with Mucommune and Inhalon are subject to certain restrictions under University policy. The terms of these arrangements are managed by UNC-CH in accordance with its conflict of interest policies., (Copyright © 2025. Published by Elsevier B.V.)

Introduction: There are limited data comparing the contamination rates of reusable and novel duodenoscopes with disposable components. The clinical implications of novel duodenoscope bacterial contamination are also unknown. This study aimed to evaluate the rate of pathogenic bacterial contamination of novel and reusable duodenoscopes and assess the clinical implications for patients exposed to contaminated duodenoscopes., Methods: We conducted an observational study of the bacterial contamination of reusable duodenoscopes and novel duodenoscopes with disposable caps (which do not have disposable elevators). Following identification of positive cultures from duodenoscopes, corresponding patient charts were reviewed for blood culture data or evidence of sepsis by quick sequential organ failure assessment (qSOFA) and systemic inflammatory response syndrome (SIRS) criteria., Results: The contamination rate of reusable duodenoscopes was 0.80% (95% CI -0.05, 1.65%). The contamination rate of novel duodenoscopes was 0.0%.The contamination rates were not significantly different (p = 0.141). In reusable duodenoscopes, > 1 colony-forming unit (CFU) of gram-negative rods was identified in 4 positive cultures. None of the patients exposed to a positive culture had an existing infection nor developed bacteremia or sepsis after ERCP., Discussion: Our data suggest bacterial contamination rates of novel duodenoscopes with disposable caps and reusable duodenoscopes are similar. The low contamination rates in this study support consistent high-level disinfection practices regardless of duodenoscope generation., (Copyright © 2025 by The American College of Gastroenterology.)

Background and Aims: Corticosteroids are widely used in managing inflammatory bowel disease (IBD). While adverse events (AEs) of corticosteroids are well recognized, current understanding of corticosteroid-related AE burden in IBD remains incomplete., Methods: AE reports for prednisone/prednisolone and budesonide were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) and VigiBase databases. Total and frequently reported AEs were tabulated, and AEs of special interest were compared with reports for all drugs using proportional reporting ratio criteria. Database reports were compared with AEs reported in a patient survey capturing corticosteroid exposure and AE recall., Results: In FAERS and VigiBase, 344 140 and 42 836 AEs were reported, respectively, in patients with IBD; among these, 10 157 (3.0%) and 11 391 (26.6%), respectively, were related to prednisone/prednisolone or budesonide. AEs associated with corticosteroid use in IBD increased over time. Adrenal insufficiency, Cushingoid complications, osteonecrosis, osteoporosis, diabetes, and pancreatitis were disproportionately reported for corticosteroids. Among 9229 patients who responded to the survey, 6434 (69.7%) reported corticosteroid exposure. AEs were more frequently recalled by patients exposed to prednisone (61.9%) vs budesonide (27.4%; p = 0.0001). The most commonly recalled AEs differed from those reported in the pharmacovigilance databases and included weight gain, sleep problems, mood disturbance, and skin changes. Younger patients and those with mental health disorders were more likely to recall suicidal thoughts/attempts., Conclusions: Adverse events associated with IBD-related corticosteroid use were frequent. Patients reported AEs affecting quality of life, while clinicians disproportionately reported AEs based on objective diagnostic criteria., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Competing Interests: AH is supported by the National Institute for Health (NIHR) Applied Research Collaboration (ARC) South London at King’s College Hospital NHS Foundation Trust. AH is also a member of King’s Improvement Science, which offers co-funding to the NIHR ARC South London and comprises a specialist team of improvement scientists and senior researchers based at King’s College London. Its work is funded by King’s Health Partners (Guy’s and St Thomas’ NHS Foundation Trust, King’s College Hospital NHS Foundation Trust, King’s College London and South London and Maudsley NHS Foundation Trust), Guy’s and St Thomas’ Charity and the Maudsley Charity.

Background and Aims: Microstructural disturbances underlie dysfunctional contraction and adverse left ventricular (LV) remodelling after ST-elevation myocardial infarction (STEMI). Biphasic diffusion tensor cardiovascular magnetic resonance (DT-CMR) quantifies dynamic reorientation of sheetlets (E2A) from diastole to systole during myocardial thickening, and markers of tissue integrity [mean diffusivity (MD) and fractional anisotropy (FA)]. This study investigated whether microstructural alterations identified by biphasic DT-CMR: (i) enable contrast-free detection of acute myocardial infarction (MI); (ii) associate with severity of myocardial injury and contractile dysfunction; and (iii) predict adverse LV remodelling., Methods: Biphasic DT-CMR was acquired 4 days (n = 70) and 4 months (n = 66) after reperfused STEMI and in healthy volunteers (HVOLs) (n = 22). Adverse LV remodelling was defined as an increase in LV end-diastolic volume ≥ 20% at 4 months. MD and FA maps were compared with late gadolinium enhancement images., Results: Widespread microstructural disturbances were detected post-STEMI. In the acute MI zone, diastolic E2A was raised and systolic E2A reduced, resulting in reduced E2A mobility (all P < .001 vs. adjacent and remote zones and HVOLs). Acute global E2A mobility was the only independent predictor of adverse LV remodelling (odds ratio .77; 95% confidence interval .63-.94; P = .010). MD and FA maps had excellent sensitivity and specificity (all > 90%) and interobserver agreement for detecting MI presence and location., Conclusions: Biphasic DT-CMR identifies microstructural alterations in both diastole and systole after STEMI, enabling detection of MI presence and location as well as predicting adverse LV remodelling. DT-CMR has potential to provide a single contrast-free modality for MI detection and prognostication of patients after acute STEMI., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objective: The majority of small testicular masses (STMs) are benign and therefore radical orchidectomy (RO) may represent overtreatment. In appropriately selected patients, surveillance or testis-sparing surgery (TSS) is an alternative option to preserve testicular function. Since there are no clear guidelines, we aimed to develop consensus recommendations on the management of STMs., Methods: A four-round Delphi study was conducted by 24 experts representing multiple subspecialties to reach consensus. Consensus was defined as ≥75% of the participants scoring within the same 3-point grouping (1-3, disagree; 4-6, uncertain; 7-9, agree.). The first two rounds were survey based, the third round was an online meeting to discuss uncertainties from the first two rounds, and the fourth round was a review of the final consensus statements from rounds 1-3., Key Findings and Limitations: The initial survey consisted of 126 statements. Following the four rounds of assessment, a list of 96 statements were produced, which focused on clinical and biochemical assessment, colour Doppler ultrasound (CDUS) characteristics, and management options including surveillance, RO, and TSS. Management should be personalised according to risk factors for testicular cancer, fertility status, uni- or bilateral tumours, status of the contralateral testis, and CDUS characteristics, with solid lesions displaying vascularity and hypoechogenicity being more suspicious for malignancy. The consensus statements are prone to a bias, and some may not reflect robust, randomised evidence., Conclusions and Clinical Implications: The expert panel has produced consensus recommendations on the management of STMs, and TSS should be considered in patients with an STM. The recommendations could aid in the dissemination of best practice., Patient Summary: There are no clear guidelines on the management of small testicular masses. Excising the whole testicle (radical orchidectomy) with a small or an indeterminate mass may affect fertility and hormonal function. A panel of experts was formed, and consensus recommendations were developed on how to deal with small and indeterminate testicular masses, which include surveillance or testis-sparing surgery., (Copyright © 2024 European Association of Urology. All rights reserved.)

Competing Interests: Competing interests: The authors declare no competing interests. Consent for publication: The patient has provided written informed consent to allow the publication of their clinical information and photographs.

Background: The aging population is a growing challenge for healthcare services and as such multimorbidity and associated aging are the focus of research programs. Chronic limb-threatening ischemia (CLTI) in the older patient is perceived to be associated with high morbidity and mortality but a potentially contentious area with limited evidence., Methods: Retrospective review of all consecutive CLTI admissions to a UK tertiary vascular during 2020. Analysis included descriptive statistics and comparisons by age. The primary outcome was survival (by Kaplan-Meier) with secondary outcomes being major adverse limb and cardiovascular events., Results: One hundred eighty-three patients with a median age of 72 of which 55 (30%) were octogenarians. Fewer octogenarians were diabetic (38.2% vs. 58.6%, P = 0.015), but comorbidities such as previous stroke (25.5% vs. 10.9%, P = 0.015) and atrial fibrillation (36.4% vs. 16.4%, P = 0.004) were increasingly common. 87.3% of octogenarians had moderate or severe frailty compared to 57.8% in those <80 (P = 0.001) (by electronic frailty index). Median survival time was 30 months with no significant difference between groups (P = 0.406). Major adverse cardiovascular event (10.9% vs. 7.81%, P = 0.504) and major adverse limb event (34.5% vs. 24.2% P = 0.261) were comparable between groups. Octogenarians were less likely to have open surgery (10.9% vs. 25.8%, P = 0.024)., Conclusions: Octogenarians have similar cardiovascular, limb, and survival outcomes following intervention despite being increasingly frail and comorbid. Holistic assessment, perioperative optimization, and risk stratification are important in this group., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None.

Introduction: Focal therapy is an emerging treatment for localized prostate cancer (PCa). The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada., Methods: Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up to 2020. We focused on studies reporting functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrials.gov., Results: FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation, or transurethral ultrasound ablation., Conclusions: Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.

Objectives: To assess the impact on patient outcomes of the spondyloarthritis (SpA) and inflammatory bowel disease (IBD) multidisciplinary team (MDT) meetings in a large university hospital., Methods: A single-centre retrospective observational case-note review was conducted assessing the outcome of all 226 cases discussed at the SpA-IBD MDT meetings in a large UK university hospital between 2017 and 2022., Results: A total of 226 patients were discussed. It was deemed that 97% of MDT meetings helped to improve communication between teams, and 100% were educational. A total of 57% of discussions led to an instant change of disease management, while 40% of discussions resulted in a treatment plan that avoided the use of dual advanced therapy. This improved patient safety by reducing immunosuppression. The MDT meetings were highly cost and time efficient; 125 referrals between specialists were avoided, and in 51 cases there was a significant chance of reducing future drug costs. A timely investigation or appointment was arranged following 50% of MDT discussions, helping to clarify the diagnosis and optimize patient care. Nine percent of meetings enabled drugs to be prescribed to patients that are not yet licensed for the other speciality, thereby improving treatment options available in the management of complex cases., Conclusion: The MDT meetings have been beneficial for patients, the clinical team and the institution. This approach might be considered by other rheumatology and gastroenterology departments., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Macromastia can limit a woman's ability to exercise. Reduction mammaplasty has been reported to subjectively improve exercise capability and stimulate weight loss. Considering the lack of published quantitative data, the authors sought to examine change in weight and body mass index (BMI) in adolescent women following reduction mammaplasty., Methods: Retrospective chart review was performed of patients younger than 21 years who underwent reduction mammaplasty at the authors' institution from 2015 through 2019., Results: Fifty-six patients with follow-up weight measurements were included in the analysis. The median follow-up time was 46.0 months. Only 22 patients (39.3%) experienced a decrease in BMI at final follow-up compared with baseline. Patients classified as having a healthy weight preoperatively (BMI, 18.5 to 24.9 kg/m 2 ) experienced a significant increase in BMI at 2-year, 3-year, 5-year, and final postoperative follow-up visits, compared with baseline. Patients classified as overweight (BMI, 25.0 to 29.99 kg/m 2 ) or obese (≥30 kg/m 2 ) did not experience significant BMI change at final postoperative follow-up., Conclusions: BMI and weight trended upward postoperatively regardless of BMI classification. Reduction mammaplasty alone is not sufficient to stimulate weight loss. Healthy lifestyle changes should be encouraged to help prevent weight gain in adolescent women following reduction mammaplasty., Clinical Question/level of Evidence: Therapeutic, IV., (Copyright © 2024 by the American Society of Plastic Surgeons.)

A multiplexed, lentivirus-based pseudovirus neutralisation assay (pVNT) was developed for high-throughput measurement of neutralising antibodies (nAbs) against three distinct SARS-CoV-2 spike variants. Intra-assay variability was minimised by optimising the plate layout and determining an optimal percentage transduction for the pseudovirus inoculum. Comparison of EC 50 titres between single and multiplexed pVNT assays showed no significant differences, indicating reliability of the multiplexed assay. Evaluation of convalescent human sera confirmed assay robustness, with consistent EC 50 titres for variant pseudoviruses relative to the ancestral strain observed across single and multiplexed assays. This multiplexed pVNT provides a reliable tool for assessing nAb responses against SARS-CoV-2 variants and could be used to accelerate preclinical vaccine assessment in preparation for the next coronavirus pandemic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) are prevalent comorbidities related to a greater likelihood of poor treatment outcomes and prolonged treatment for Reward Deficiency Syndrome (RDS) behaviors. The current exploratory case study of a small cohort (n=3; f=2 m=1) used novel neurotechnology to treat co-occurring MDD and GAD with a multifaceted intervention that combines the novel bio-resonance neurotechnology (BRNT) referred to as NuCalm ® , to restore autonomic nervous system balance and dual hemispheric repetitive transcranial magnetic stimulation (rTMS) of the ipsilateral Dorsal Lateral Prefrontal Cortex (DLPFC) to treat the disrupted structural components of the brain. Neuroacoustic brainwave entrainment, electromagnetic frequency bio-resonance, and light-blocking combine to place patients into a parasympathetic dominant state. The paired t -tests indicated a significant decrease in comparing before and after the intervention. The Patient Health Questionnaire PHQ-9 scores from the first to the last time-point (mean difference = 20, t(2) = 6.55, p = 0.0226), with a 95% confidence interval of mean difference ranging from 6.86 to 33.14. Similarly, there was a significant decrease in General Anxiety Disorder GAD-7 questionnaire scores from the first to the last time point (mean difference = 18.67, t(2) = 12.85, p = 0.0060), with a 95% confidence interval of the mean difference ranging from 12.42 to 24.92. After applying the Bonferroni correction, the corrected p-values for PHQ-9 and GAD-7 are 0.0452 and 0.0120, respectively. Cohen's d standardized effect size indicated that the main effect size was 5.47 and 13.8 times the noise (variability), respectively, for the initial versus final PHQ-9 and GAD-7. Further, more extensive, much larger sham-controlled and blinded studies are required to confirm these encouraging results and explore this multifaceted intervention., Competing Interests: Prof. Dr. Milan Makale reports consulted for PeakLogic Inc. Dr. Blum is a paid consultant of Sunder Foundation and PEAK LOGIC; received personal fees, license on KB220 from VNI. The author(s) report no other conflicts of interest in this work., (© 2025 Sunder et al.)

Background: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation ('flash freezing') limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions., Methods: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene)., Findings: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions., Interpretation: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples., Funding: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255)., Competing Interests: Declaration of interests None to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess tumour factors that reduce primary technical efficacy (PTE) from CT-guided renal cryoablation., Methods: Patients were taken from the EuRECA registry between December 2014 and November 2020. To focus on tumour factors rather than individual technique, this study was limited to cases using CT and excluded procedures using cone beam, US, MRI, or laparoscopy. PTE was assessed per tumour and defined as complete ablation of the target on enhanced CT or MRI by 90 days. Residual unablated tumour (RUT) was defined as focal persistent tumour enhancement within 90 days., Results: A total of 1,424 tumours from 11 different centres were eligible; 38 episodes of RUT were detected giving an overall PTE of 97.3%. The factors most likely to be associated with RUT were as follows and persisted in multivariate logistic regression. Tumour contact with a central artery or vein; increased OR of 5.29 (CI 2.59-10.81 p < 0.001), PTE was 89.8% in this group. Tumours size; T1b vs T1a increased OR of 2.31 (CI 1.10-4.87 p = 0.0276), T1b PTE was 94.1% vs T1a PTE 97.9%. Close proximity to the collecting system (< 4 mm) was significant at univariate logistic regression (OR 2.87, P = 0.028), as was a RENAL complexity score of 10 or above (OR 2.71, p = 0.0147), but neither was significant in the multivariate analysis., Conclusions: Overall, CT-guided percutaneous renal cryoablation has a high PTE at 97.3%. In this analysis, the most significant risk factor for RUT is central renal vessel contact. T1b tumours are also noted to have an increased risk of RUT compared to T1a., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical Approval: For this type of study formal consent is not required. The local Institutional Review Board (IRB) approved the study. Consent for Publication: For this type of study consent for publication is not required. Informed Consent: For this type of study informed consent is not required., (© 2025. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

The local arrangement of microbes can profoundly impact community assembly, function and stability. However, our understanding of the spatial organization of the human gut microbiome at the micron scale is limited. Here we describe a high-throughput and streamlined method called Split-And-pool Metagenomic Plot-sampling sequencing (SAMPL-seq) to capture spatial co-localization in a complex microbial consortium. The method obtains microbial composition of micron-scale subcommunities through split-and-pool barcoding. SAMPL-seq analysis of the healthy human gut microbiome identified bacterial taxa pairs that consistently co-occurred both over time and across multiple individuals. These co-localized microbes organize into spatially distinct groups or 'spatial hubs' dominated by Bacteroidaceae, Ruminococcaceae and Lachnospiraceae families. Using inulin as a dietary perturbation, we observed reversible spatial rearrangement of the gut microbiome where specific taxa form new local partnerships. Spatial metagenomics using SAMPL-seq can unlock insights into microbiomes at the micron scale., Competing Interests: Competing interests: H.H.W. is a scientific advisor of SNIPR Biome, Kingdom Supercultures, Fitbiomics, VecX Biomedicines, Genus PLC, and a scientific co-founder of Aclid and Foli Bio, all of which are not involved in the study. R.U.S. is a co-founder of Kingdom Supercultures. The remaining authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Articular cartilage lines bones in synovial joints, and its main structural element, collagen, has an arcade-like arrangement formed from an initially random network in a process called postnatal maturation. This reshaping of the extracellular matrix is similar across all species and is critical for the lifelong strength and durability of cartilage. Collagen remodelling during maturation is difficult to study because it spans a period of time between birth and puberty, and in larger animals this can be months or years. In this study, we show that growth factor bone morphogenetic protein-9 (BMP9) induces collagen remodelling in intact immature articular cartilage explants within 21 days, generating the characteristic arcade-like structure and zonal anisotropic architecture of adult cartilage. In explants exposed to BMP9, collagen fibrils underwent angular displacement from 19° to 78° with respect to the surface, cell density decreased 1.77-fold, and chondrons were significantly larger. The absence of labelling with anti-COL2¾m, a marker of collagen turnover, showed that the existing fibril network was restructured. We found that stromelysin-1 (metalloproteinase-3, MMP3) gene expression was consistently upregulated, whilst other MMP transcript levels were unchanged or reduced. Remodelling was dependent on proteoglycan turnover and could be inhibited using PD166973. These data suggest a possible mechanism whereby MMP3 induces proteoglycan turnover and depolymerises collagen fibrils enabling them to undergo spatial reorganisation. This process may be driven by tissue swelling, which generates directional strain to align fibrils into an arcade-like pattern. The ability to induce tissue maturation advances the potential for engineering durable and functional cartilage for patients requiring joint repair due to diseases such as osteoarthritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Anderson-Watters and Khan.)

The construction has always been a large economic sector that is very hazarous to work in. Over the past 40 years there have been major improvements in safety and health practices driven by increased research and more rapid adoption of best practices, not just in the developed countries but also in emerging economices. This special issue aims to showcase a specturm of perspectives from research to practice, about the current state of construction safety and health., (© 2025 Wiley Periodicals LLC.)

Bacterial vaginosis (BV), characterized by an imbalance in the vaginal microbiota, is a prevalent condition among women of reproductive age and a risk factor for human immunodeficiency virus, sexually transmitted infections, and preterm birth. BV is generally considered to induce mucosal inflammation, but the specific pathways and cell types involved are not well characterized. This prospective study aimed to assess associations between microbial changes and mucosal immune responses in BV patients. Therefore, samples from 20 premenopausal women with BV and treated with metronidazole were analyzed. Vaginal swabs, menstrual cup, and endocervical cytobrush samples were collected before treatment, weekly for four weeks, and at 2, 4, and 6 months for Nugent scoring, immune cell populations and cytokine analysis. Of 105 study intervals, 27 (25.7%) showed improvement in Nugent category, 61 (58.1%) remained unchanged, and 17 (16.2%) worsened. Improvement correlated with decreased monocytes (p = 0.005), while worsening was linked to increased monocytes (p < 0.001) and dendritic cells (p = 0.02). B cells (p = 0.02) and IFN-γ-induced chemokines - IP-10 (p = 0.007), MIG (p = 0.049), and ITAC (p = 0.005) - were associated with improvement. In conclusion, although the T-cell-associated chemokines IP-10, ITAC, and MIG were strongly associated with improvements in Nugent category, our findings indicate that antigen-presenting cells, particularly monocytes, show the most dynamic response to shifts in the vaginal microbiota in patients with BV., Competing Interests: Declarations. Competing interests: Dr. Mitchell serves on the scientific advisory board of Concerto Bio, and Ancilia Biosciences, and receives royalties from Up to Date. The remaining authors declare no conflict of interest., (© 2025. The Author(s).)

Lead (Pb) and cadmium (Cd) are metals that occur naturally in the environment and are present in biomass fuels, such as wood. When these fuels are burned, they can release Pb and Cd into the air, leading to exposure through inhalation. Studies of exposure to metals and health outcomes suggest harmful impacts, including cardiovascular diseases. We assessed baseline associations between Pb and Cd concentrations in dried blood spots with systolic and diastolic blood pressure (SBP, DBP) among women in the Household Air Pollution Intervention Network (HAPIN) trial. We analyzed data from three of the four HAPIN randomized controlled trial sites (Guatemala, Peru, and Rwanda), focusing on women aged 40 to 79 years living in households reliant on biomass cooking. Dried blood spots were collected, processed, and analyzed for Pb and Cd exposure; SBP and DBP were measured following international guidelines. Demographic, socioeconomic, and dietary variables were collected via standardized questionnaires administered by local field staff. Statistical analyses included multivariable linear regression to examine associations between Pb and Cd, separately, and BP, adjusting for covariates informed by a Directed Acyclic Graph. Additional analyses assessed effect modification by age and research site. There was regional variation in BP levels among women, with median SBP and DBP values higher in Rwanda (116.3 mmHg, 73.0 mmHg) and Guatemala (113.3 mmHg, 68.3 mmHg) compared to Peru (106.0 mmHg, 63.3 mmHg). Pb exposure showed positive associations with both SBP and DBP. For each log-unit increase in Pb concentration, we observed increases of 2.36 mmHg SBP (95% CI 0.51, 4.20) and 1.42 mmHg DBP (95% CI 0.16, 2.67). Cd was not associated with SBP or DBP in this analysis. Pb exposure may be an important risk factor for increased SBP and DBP, markers of cardiovascular disease risk.

Single-cell spatial transcriptomics reveals how cells organize in healthy and diseased tissues. From these data, tissue segmentation analysis defines discrete compartments that organize cells into functional multicellular units. Existing methods for automated tissue segmentation rely on spatial smoothing to define spatially coherent regions but often blur the boundaries between adjacent tissue compartments. We describe Tessera, an algorithm that approaches tissue segmentation through a novel approach, dividing the tissue into small multicellular tiles whose edges track with natural tissue boundaries. Tessera achieves this by incorporating successful tools from edge-preserving smoothing, topological data analysis, and morphology-aware agglomerative spatial clustering. We show that Tessera identifies a range of known anatomical structures, in healthy mouse brain and human lymph nodes, and novel disease-associated niches, in human brain and in lung cancer. Tessera is a general-purpose tool that returns spatially coherent spatial structures with accurate boundaries across a range of spatial transcriptomics and proteomics technologies.

Background/Objectives : The management of inflammatory bowel disease (IBD) varies due to differences in healthcare systems, treatment costs, access to diagnostics, and diverse clinical practices between specialists. Despite the frequent advocacy of a treat-to-target (T2T) approach, there is insufficient clarity on how clinicians implement T2T in real-world settings. We aim to conduct a large, global survey among IBD experts to identify current practices in management. Methods : A prospective, cross-sectional study was conducted using a 16-item survey divided into two sections-for ulcerative colitis (UC) and Crohn's disease (CD)-and distributed to practicing IBD clinicians. Results : A total of 261 respondents from 88 countries participated in the survey, with the majority (253/261) being physicians and eight being IBD nurse specialists. Despite global guidance, only a quarter of the respondents routinely perform an endoscopy to assess the response after starting an advanced therapy (28.4% in UC vs. 23.5% in CD). Moreover, despite an increasing academic focus on intestinal ultrasound (IUS), 171 (66%) of respondents in UC and 132 (51%) in CD reported that they do not routinely undertake IUS to guide treatment decisions. Faecal calprotectin for monitoring treatment response was routinely used by 87% (90% in UC and 84% in CD) of the respondents. Forty-five percent reported use of therapeutic drug monitoring (TDM) both proactively and reactively and 35% reported only using TDM reactively. Conclusions : Our study shows considerable variation in IBD management across different countries and interpretation of the T2T approach. This highlights the need for standardised and pragmatic guidelines to help improve outcomes for patients with IBD globally.

Investigation and management of hypotonic polyuria is a common challenge in clinical endocrinology. The 3 main causes, recently renamed to arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus), arginine vasopressin resistance (AVP-R, formerly nephrogenic diabetes insipidus), and primary polydipsia (PP) require accurate diagnosis, as management differs for each. This new nomenclature more accurately reflects pathophysiology and has now been adopted by the Systemized Nomenclature of Medicine (SNOMED). Advances in diagnosis over the last few years have centered around the use of copeptin measurement. Here, we use 3 patient case histories to highlight the use of this approach, and to demonstrate how it can succeed where other approaches, such as the water deprivation test, sometimes fail. We discuss the overall approach to each type of patient and the strengths and limitations of diagnostic strategies, illustrating the use of the new nomenclature., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background and Objective: Asthma-COPD overlap (ACO) is characterized by patients exhibiting features of both asthma and COPD. Currently, there is no specific treatment for ACO. This study aimed to investigate the therapeutic potential of targeting CD131, a shared receptor subunit for IL-3, IL-5 and GM-CSF, in ACO development and in preventing acute viral exacerbations., Methods: A two-hit mouse model of ACO was established by house dust mite (HDM) allergen sensitization to model asthma, and elastase treatment to model emphysema. In a separate model, human rhinovirus 1b (RV1b) was used to induce an acute asthma exacerbation. A neutralizing antibody against CD131 was used to block CD131 in vivo signalling., Results: Mice exposed to HDM and elastase developed cardinal features for asthma and COPD, including airway hyperreactivity (AHR) and emphysema. A mixed granulocytic inflammatory profile was identified in the lungs, including expansion of monocyte-derived macrophages, neutrophils and eosinophils. RT-qPCR analysis detected heightened gene expression of Mmp12, Il5 and Il13. Transcriptomic analysis further revealed pathway enrichment for type 2 inflammation and macrophage activation. Blockade of CD131 effectively reduced the lung inflammation and prevented the development of AHR, airway fibrosis and emphysema. Interestingly, pathway enrichment for Th1 response and interferon production detected in the model was not affected by the treatment. Consistently, CD131 antagonism prevented RV1b-induced asthma exacerbation without compromising RV1b clearance., Conclusion: CD131 signalling coordinates multiple pathological pathways that drive airway inflammation and lung remodelling in ACO. Hence, CD131 antagonism represents a novel approach to combating the immunopathology in the complex ACO setting., (© 2025 Asian Pacific Society of Respirology.)

Background: Studies in the UK and North America have suggested a distinct disease profile in South Asians compared to that of White populations. Disparities in the medical and surgical management of IBD in minority ethnic groups (including Black Americans and Asians) in the US have been shown, while data from Europe, including the UK, have been lacking. This study sought to evaluate South Asian (SA) and White (WH) inflammatory bowel disease (IBD) phenotypes, and to explore treatment approach variations between these cohorts in the UK using the IBD BioResource database., Design: Differences between WH and SA IBD patients were analysed using demographic, phenotypic and outcome data. Drug utilisation patterns and surgical outcomes were assessed in propensity score-matched (PSM) cohorts with multivariable logistic regression, Cox regression and Kaplan-Meier analysis., Results: 30,997 eligible patients were included. UC was the predominant disease subtype in SA (p<0.001). SA were younger at diagnosis (p<0.001), had a male preponderance (p<0.001), and were less likely to have a smoking history at diagnosis. The SA CD phenotype differed from WH, with less ileal (SA 30.3%, WH 38.4%, p=0.008) and stricturing (SA 16.9%, WH 25.6%, p<0.001) disease, but more perianal disease (SA 38.5%, WH 32.2%, p=0.009). More SA UC patients had extensive disease (SA 41.7%, WH 34.1%, p<0.001). In PSM cohorts, comparing treatments, there were no differences in 5-aminosalicylate, corticosteroid, thiopurine, anti-TNF or vedolizumab use. Survival analysis in matched cohorts showed no difference in time to surgery (CD) or colectomy (UC), and SA ethnicity was not associated with a difference in risk of surgery/colectomy., Conclusion: Demographic and phenotypic differences exist between UK SA and WH IBD patients, highlighting distinct ethnicity-related variance, and the need for a research focus on under-represented populations. In comparing matched SA and WH patients, no disparity in medical and surgical IBD therapy in UK healthcare has been demonstrated: treatment is consistent regardless of ethnicity., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Lymphatic leaks are associated with significant mortality and morbidity. Intranodal lymphangiography (ILAG) involves the direct injection of ethiodised lipid into the hilum of lymph nodes. It is diagnostic procedure that can have therapeutic effects secondary to a local sclerosant effect. The aim of the study is to describe the technical and clinical success of ILAG and adjunctive lymphatic interventions performed as first line interventional techniques for lymphatic leaks refractory to conservative and medical management in a multicentre cohort of patients with symptomatic large volume lymphatic leaks., Methods: Multicentre retrospective study of all lymphatic interventions performed between 2017-2023 in patients with large volume lymphatic leaks (> 500 ml a day). Intranodal lymphangiography was performed initially with technical success defined as opacification of the lymphatics at the aortic bifurcation and demonstration of lymphatic leak on the index ILAG procedure or immediate post procedural CT was recorded. Lymphatic embolisation was performed with a combination of direct puncture or transvenous cannulation with glue and or coil embolisation of the thoracic duct or leak point and in cases with refractory leak. Clinical success was defined as reduction in drain output to less than 20 mL per 24 h, or no further insensible lymph leak. Time to clinical success after ILAG and adjunctive embolisation was recorded., Results: ILAG alone lead to clinical success in 14 of 32 (44%) patients after a median of 14 days. Subsequent embolisation was performed in 12 refractory cases; this was successful in 8 (67%) at median of 8 days. Overall clinical success of all lymphatic interventions was 69% (22 of 32 patients) at a median of 11 days (IQR 5-34). No statistically significant correlation between the site of leakage, aetiology or embolisation technique correlated with clinical success. Decision to proceed to repeat ILAG or an adjunct procedure was made on a clinical basis, following multidisciplinary discussion., Conclusions: ILAG can be employed a first line interventional therapeutic technique to treat clinically significant lymphatic leaks that are refractory to conservative and medical management. Adjunctive procedures, including embolisation, can be considered as part of clinical decision making after a period of 1-2 weeks' watchful waiting in continuingly refractory cases., Competing Interests: Declarations. Ethics approval and consent to participate: Based on local ethics committee policies, formal review and approval of this retrospective observational study of anonymised patient data was considered not necessary. Consent for publication: No patient identifiable information is included in this manuscript. Competing interests: None to declare., (© 2025. The Author(s).)

Postoperative delirium is the most common postsurgical complication in older adults and is associated with an increased risk of long-term cognitive decline and Alzheimer's disease (AD) and related dementias (ADRD). However, the neurological basis of this increased risk-whether postoperative delirium unmasks latent preoperative pathology or leads to AD-relevant pathology after perioperative brain injury-remains unclear. Recent advancements in neuroimaging techniques now enable the detection of subtle brain features or damage that may underlie clinical symptoms. Among these, Neurite Orientation Dispersion and Density Imaging (NODDI) can help identify microstructural brain damage, even in the absence of visible macro-anatomical abnormalities. To investigate potential brain microstructural abnormalities associated with postoperative delirium and cognitive function, we analyzed pre- and post-operative diffusion MRI data from 111 patients aged ≥60 years who underwent non-cardiac/non-intracranial surgery. Specifically, we investigated preoperative variation in diffusion metrics within the posterior cingulate cortex (PCC), a region in which prior work has identified glucose metabolism alterations in the delirious brain, and a key region in the early accumulation of amyloid beta (Aβ) in preclinical AD. We also examined the relationship of preoperative PCC NODDI abnormalities with preoperative cognitive function. Compared to patients who did not develop postoperative delirium (n=99), we found increased free water (FISO) and neurite density index (NDI) and decreased orientation dispersion index (ODI) in the dorsal PCC before surgery among those who later developed postoperative delirium (n=12). These FISO differences before surgery remained present at six weeks postoperatively, while these NDI and ODI differences did not. Preoperative dorsal PCC NDI and ODI values were also positively associated with preoperative attention/concentration performance, independent of age, education level, and global brain atrophy. Yet, these diffusion metrics were not correlated with cerebrospinal fluid Aβ positivity or levels. These results suggest that preoperative latent brain abnormalities within the dorsal PCC may underlie susceptibility to postoperative delirium, independent of AD-related (i.e., Aβ) neuropathology. Furthermore, these preoperative microstructural differences in the dorsal PCC were linked to preoperative deficits in attention/concentration, a core feature of postoperative delirium. Our findings highlight microstructural vulnerability within the PCC, a key region of the default mode network, as a neuroanatomic locus that can help explain the link between preoperative attention/concentration deficits and increased postoperative delirium risk among vulnerable older surgical patients., Competing Interests: Competing interests MB has received material support (i.e. EEG monitors) for a postoperative recovery study in older adults from Masimo, unrelated to this manuscript. MB and JB have also received legal consulting fees related to postoperative neurocognitive function in older adults. JB acknowledges receiving funding from Claret Medical, Inc. and CardioGard, Inc., both unrelated to this manuscript. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). The other authors have no relevant conflicts to disclose.

Background: Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios., Methods: Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses., Results: By modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression., Conclusions: This work highlights the complexity of combining immunotherapies within the tumor microenvironment (TME) and further defines the immune and non-immune components of the TME as an intrinsic feature of immune suppression., Competing Interests: Competing interests: SDK receives clinical funding from Genentech and Ionis that does not relate to this work. She receives clinical trial funding from AstraZeneca and Genentech, none of which is related to this work. SDK receives preclinical funding from Amgen none of which is applied for this work. SDK receives preclinical research funding from Roche Pharmaceuticals, which was used as funding for much of this work in the form of drug supply. MPincha, CK, and MA declare the following conflicts: employment, patents, stock ownership with Roche. The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objectives: To assess the contemporary malignancy rate in isolated de novo red patches in the bladder and associated risk factors for better selection of red patch biopsy., Patients: Patients from the IDENTIFY dataset; Patients referred to secondary care with suspected urinary tract cancer and found to have isolated de novo red patches on cystoscopy., Methods: We reported the unadjusted cancer prevalence in isolated de novo red patches that were biopsied; multivariable logistic regression was used to explore cancer-associated risk factors including age, sex, smoking, type of haematuria, LUTS, UTIs and a suspicious-looking red patch (as reported by the cystoscopist). Sub-analysis of these by clinical role and experience was performed., Results: A total of 1110 patients with isolated de novo red patches were included. 41.5% (n = 461) were biopsied, with a malignancy rate of 12.8% (59/461), which was significantly higher in suspicious versus non-suspicious red patches (19.1% vs. 2.81%, p < 0.01). There was a significant association between bladder cancer and age (OR 1.04, 95% CI 1.01-1.07, p = 0.01), smoking history (OR 2.62, 95% CI 1.09-6.27, p = 0.03) and suspicious-looking patch (OR 6.50, 95% CI 2.47-17.1, p < 0.01). The majority of malignancies were in over 60-year-olds. Malignancy rates in suspicious versus non-suspicious red patches did not differ significantly between clinical roles or experiences.Limitations included subjectivity in classifying a suspicious patch and selection bias as not all patches were biopsied., Conclusions: Many patients still undergo unnecessary biopsies under general anaesthetic for isolated de novo red patches. Clinicians should consider the patient's age, smoking status and how suspicious-looking the patch is, before deciding on surveillance versus biopsy to improve cancer diagnostic yield., Competing Interests: None to declare., (© 2024 The Author(s). BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Study Objectives: Trauma nightmares are a core feature of PTSD, with potentially devastating implications for mental health outcomes. Treatments remain unsatisfactory and nightmares are poorly understood, both biologically and phenomenologically; measurement methods are limited. The aims of the current analyses were to (1) characterize distressing dreams in trauma survivors, (2) examine the relationships of dream features to next-day symptoms and to suicidal ideation, and (3) validate sleep diary mobile app items for the measurement of clinically relevant dream characteristics., Methods: Adult male and female veterans and nonveterans with a history of PTSD criterion trauma and at least 1 nightmare weekly were enrolled. Participants completed 3 weeks of sleep diary, including bedtime and morning surveys and weekly assessments. They also completed a Clinician-Administered PTSD Scale (CAPS)-5 PTSD assessment. Multivariable mixed models with repeated measures and standard regression were utilized to examine relationships between dream features and next-day symptoms and suicidal ideation., Results: Dream features and dream distress independently predict clinically relevant outcomes; no single feature was sufficient for predicting all outcomes of interest. In particular, the replicative quality of trauma nightmares stood out in terms of associations with next-day symptoms, CAPS severity, and suicidal ideation. Subjective dream duration, extent of postdream arousal, and subjective distress severity also independently predicted daytime symptoms., Conclusions: Results underscore the importance of examining dream characteristics to understand nightmare effects and associations with suicidal ideation. These findings also underscore the utility of mobile app technology for obtaining informative data with high temporal resolution in an appealing and user-friendly manner., (Published by Oxford University Press on behalf of Sleep Research Society 2025.)

Background: Obstructive sleep apnea is associated with increased dementia risk, yet its role in postoperative neurocognitive disorders is unclear. Here, we studied whether the severity of untreated obstructive sleep apnea is associated with the severity of postoperative neurocognitive disorder., Methods: In this single-center prospective cohort study, older noncardiac surgery patients aged 60 years and above underwent preoperative home sleep apnea testing, and pre- and postoperative delirium assessments and cognitive testing. Sleep apnea severity was determined using the measured respiratory event index (REI). Global cognitive change from before to 6 weeks (and 1 year) after surgery was used to measure postoperative neurocognitive disorder severity. Postoperative changes in individual cognitive domain performance along with subjective cognitive complaints and/or deficits in instrumental activities of daily living were used to measure postoperative neurocognitive disorder incidence., Results: Of 96 subjects who completed home sleep apnea testing, 58 tested positive for sleep apnea. In univariable analyses, sleep apnea severity was not associated with increased postoperative neurocognitive disorder severity at 6 weeks (global cognitive change ; [95% confidence interval [CI], -0.02 to 0.03]; P = .79) or 1-year after surgery (; [95% CI, -0.02 to 0.03]; P = .70). Adjusting for age, sex, baseline cognition, and surgery duration, sleep apnea severity remained not associated with increased postoperative neurocognitive disorder severity at 6 weeks (; [95% CI, -0.02 to 0.04]; P = .40) or 1-year after surgery (; [95% CI, -0.02 to 0.04]; P = .55). In a multivariable analysis, sleep apnea severity was not associated with postoperative neurocognitive disorder (either mild or major) incidence at 6 weeks (odds ratio [OR] = 0.89, [95% CI, 0.59-1.14]; P = .45) or 1-year postoperatively (OR = 1.01, [95% CI, 0.81-1.24]; P = .90). Sleep apnea severity was also not associated with postoperative delirium in univariable analyses (delirium incidence OR = 0.88, [95% CI, 0.59-1.10]; P = .37; delirium severity ; [95% CI, -0.02 to 0.03]; P = .79) or in multivariable analyses (delirium incidence OR = 1.07, [95% CI, 0.81-1.38]; P = .74; delirium severity OR = 0.95, [95% CI, 0.81-1.10]; P = .48)., Conclusions: In this older noncardiac surgery cohort, untreated sleep apnea was not associated with increased incidence or severity of postoperative neurocognitive disorder or delirium., Competing Interests: Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article., (Copyright © 2024 International Anesthesia Research Society.)

Introduction: Trauma-informed care has been posited as a framework for creating ideal and safe environments for patients to participate in treatment. However, there are limited studies that demonstrate the impact of a focused trauma-informed care training on ED staff. We implemented a 4-hour trauma-informed care training in a general emergency department. We aimed to measure changes in knowledge, opinions, self-rated competency, barriers, and recent practices before and after implementing trauma-informed care training. We hypothesized that the training would result in significant self-reported improvement in all domains., Methods: We performed a pre/post interventional study with the intervention being a trauma-informed care training adapted for ED clinical care staff. A validated, publicly available survey tool (Center for Pediatric Stress Trauma-Informed Care [TIC] Provider Survey) was used to assess knowledge, opinions, competency, and utilization of and perceived barriers to trauma-informed care. Pre- and post-training surveys were collected. Responses were stratified by role. Continuous variables were compared using analysis of variance; categorical variables compared using Pearson's chi-square., Results: Participants demonstrated a high level of perceived knowledge and opinions of trauma-informed care before and after training. We observed significant increases in self-reported competence for all ED staff, some increase in utilization of trauma-informed care in recent practice, and significant decreases in perceived barriers to providing trauma-informed care., Discussion: Trauma-informed care training is an effective means to improving ED staff self-perceived competence and practice of trauma-informed care even among those with high self-perceived knowledge and opinions of trauma-informed care before the training. Future study should explore the patient-level impact of trauma-informed care training, as well as how to continue to reduce barriers to system-wide implementation of trauma-informed care practices., (Copyright © 2025 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Hydrocephalus presents a diagnostic and therapeutic challenge due to its diverse clinical manifestations and underlying causes. Symptoms can vary from feelings of unsteadiness to focal symptoms such as weakness, difficulty ambulating, or urinary incontinence. Due to the wide variety of symptoms, hydrocephalus can present a difficult diagnosis for any physician and may require different interventions depending on the underlying cause., Case Report: This case report highlights a 69-year-old female with altered mental status, initially diagnosed with communicating hydrocephalus and sepsis. The patient's symptoms, including confusion, urinary dysfunction, and gait ataxia, initially masked the hydrocephalus, emphasizing the importance of considering this condition in patients with prolonged progression of neurological deficits. Brain imaging, including magnetic resonance imaging (MRI) and computed tomography (CT), facilitated the diagnosis, suggesting hydrocephalus with downward tonsillar herniation. The acute management involved empirical antibiotic therapy for associated sepsis, followed by the placement of an external ventricular drain for cerebrospinal fluid diversion and sampling, including cytology and cell counts, given the concern for tonsillar herniation with a lumbar puncture. Cine MRI and CT cisternogram demonstrated a cyst filling the volume of the fourth ventricle. Subsequent surgical fenestration of the cyst using a suboccipital craniotomy for cyst resection alleviated symptoms and stabilized ventricular size., Conclusion: Hydrocephalus can present with unique and varying symptoms, and it can have a variety of underlying causes. This case underscores the necessity for individualized treatment approaches tailored to the underlying etiology of hydrocephalus, including temporizing measures and more aggressive approaches once infection has improved.

Roman writers found the relative empowerment of Celtic women remarkable 1 . In southern Britain, the Late Iron Age Durotriges tribe often buried women with substantial grave goods 2 . Here we analyse 57 ancient genomes from Durotrigian burial sites and find an extended kin group centred around a single maternal lineage, with unrelated (presumably inward migrating) burials being predominantly male. Such a matrilocal pattern is undescribed in European prehistory, but when we compare mitochondrial haplotype variation among European archaeological sites spanning six millennia, British Iron Age cemeteries stand out as having marked reductions in diversity driven by the presence of dominant matrilines. Patterns of haplotype sharing reveal that British Iron Age populations form fine-grained geographical clusters with southern links extending across the channel to the continent. Indeed, whereas most of Britain shows majority genomic continuity from the Early Bronze Age to the Iron Age, this is markedly reduced in a southern coastal core region with persistent cross-channel cultural exchange 3 . This southern core has evidence of population influx in the Middle Bronze Age but also during the Iron Age. This is asynchronous with the rest of the island and points towards a staged, geographically granular absorption of continental influence, possibly including the acquisition of Celtic languages., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Air pollution may impair child growth and cognitive development, with potential markers including birth length and head circumference., Methods: The Household Air Pollution Intervention Network (HAPIN) trial was an open label multi-country-randomized controlled trial, with 3200 pregnant women aged 18-34 years (9-19 weeks of gestation) randomly assigned in a 1:1 ratio to receive liquefied petroleum gas (LPG) stove intervention compared to women continuing to cook with solid fuels for 18 months. Particulate matter ≤ 2.5 μm (PM2.5), black carbon (BC) and carbon monoxide (CO) 24-hour personal exposures were measured three times during pregnancy. Head circumference and length were measured < 24 h of birth. We conducted intention-to-treat and exposure-response analyses to determine the intervention effects and associations between household air pollution (HAP) exposure during pregnancy and head circumference, head circumference-for-gestational age Z-score, length, and length-for-gestational age Z-scores at birth., Clinicaltrials: gov., Results: Between May 2018, and Feb 2020, 3200 pregnant women were randomly assigned to intervention (n = 1593) and control groups (n = 1607) with 3060 births included in the analysis. There was a 71.9 % reduction in PM2.5 in the intervention group with similar reductions for BC and CO. Intention-to-treat analysis showed that the intervention did not affect head circumference (β = -0.01 cm, 95 %CI -0.11, 0.09), head circumference-for-gestational age Z-score (β = -0.01, 95 %CI -0.08, 0.07), or birth length (β = 0.14 cm, 95 %CI -0.01, 0.29) but did increase birth length-for-gestational age Z-score (β = 0.09, 95 %CI 0.01, 0.16). After covariate adjustment, exposure-response analysis revealed that each log-unit increase in BC was associated with a decrease in birth length-for-gestational age Z-score (β = -0.07, 95 %CI -0.13, -0.005). There was no evidence of hypothesized associations with PM2.5 or CO., Conclusion: An LPG intervention reduced HAP exposure during pregnancy but had minor effects on birth length-for-gestational age Z-score. Birth length-for-gestational age was only associated with BC., Clinical Trial Registration: The study has been registered with ClinicalTrials.gov (Identifier NCT02944682)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Advancements in imaging modalities have increased the frequency of renal mass discovery. Imaging has typically been considered sufficient to guide management for a large proportion of these tumours, but renal mass biopsies (RMBs) have an increasing role in determining malignancy and can be a valuable tool for preventing unnecessary surgery in patients with benign tumours. A structured approach should be used to help to navigate the expanding repertoire of renal tumours, many of which are molecularly defined. In terms of tumour subtyping, the pathologist's strategy should focus on stratifying patients into clinically different prognostic groups according to our current knowledge of tumour behaviour, including benign, low-grade or indolent, intermediate malignant or highly aggressive. Crucial pathological features and morphological mimicry of tumours can alter the tumour's prognostic group. Thus, pathologists and urologists can use RMB to select patients with tumours at a reduced risk of progression, which can be safely managed with active surveillance within a tailored imaging schedule, versus tumours for which ablation or surgical intervention is indicated. RMB is also crucial in the oncological setting to distinguish between different high-grade tumours and guide tailored management strategies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Crown.)

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL., Competing Interests: Competing interests: D.T.T. received research funding from BEAM Therapeutics and NeoImmune Tech and serves on advisory boards for BEAM Therapeutics, Janssen, Servier, Sobi and Jazz. D.T.T. has multiple patents pending on chimeric antigen receptor T cell therapy. The other authors declare no competing interests., (© 2024. The Author(s).)

Background & Aims: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable., Methods: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age., Results: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported., Conclusions: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified., (Copyright © 2025 AGA Institute. All rights reserved.)

Objectives: To summarize the delirium treatment trial literature, identify the unique challenges in delirium treatment trials, and formulate recommendations to address each in older adults., Design: A 39-member interprofessional and international expert working group of clinicians (physicians, nurses, and pharmacists) and nonclinicians (biostatisticians, epidemiologists, and trial methodologists) was convened. Four expert panels were assembled to explore key subtopics (pharmacological/nonpharmacologic treatment, methodological challenges, and novel research designs)., Methods: To provide background and context, a review of delirium treatment randomized controlled trials (RCTs) published between 2003 and 2023 was conducted and evidence gaps were identified. The four panels addressed the identified subtopics. For each subtopic, research challenges were identified and recommendations to address each were proposed through virtual discussion before a live, full-day, and in-person conference. General agreement was reached for each proposed recommendation across the entire working group via moderated conference discussion. Recommendations were synthesized across panels and iteratively discussed through rounds of virtual meetings and draft reviews., Results: We identified key evidence gaps through a systematic literature review, yielding 43 RCTs of delirium treatments. From this review, eight unique challenges for delirium treatment trials were identified, and recommendations to address each were made based on panel input. The recommendations start with design of interventions that consider the multifactorial nature of delirium, include both pharmacological and nonpharmacologic approaches, and target pathophysiologic pathways where possible. Selecting appropriate at-risk patients with moderate vulnerability to delirium may maximize effectiveness. Targeting patients with at least moderate delirium severity and duration will include those most likely to experience adverse outcomes. Delirium severity should be the primary outcome of choice; measurement of short- and long-term clinical outcomes will maximize clinical relevance. Finally, plans for handling informative censoring and missing data are key., Conclusions: By addressing key delirium treatment challenges and research gaps, our recommendations may serve as a roadmap for advancing delirium treatment research in older adults., Competing Interests: Dr. Devlin received research funding from the National Institutes on Aging (NIA), the Agency for Healthcare Research and Quality, Sedana Medical, and BioXcel Therapeutics; he disclosed he has served as a consultant to Ceribell. Dr. Sieber disclosed he has received unrelated grant support from the NIA and the Claude D. Pepper Odler Americans Independence Center. Drs. Devlin, Sieber, Akeju, Khan, Marcantonio, Girard, Jones, Travison, and Inouye received support for article research from the National Institutes of Health (NIH). Drs. Khan’s and Girard’s institutions received funding from the NIH. Dr. Khan’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI), Centers for Disease Control and Prevention, Gilead Sciences, and the Showalter Trust. Dr. Marcantonio disclosed he has received unrelated grant support from the NIA. Dr. Agar disclosed she has received unrelated grant support from the National Health and Medical Research Council and National Breast Cancer Foundation and Cancer Australia. Dr. Berger disclosed he has received unrelated grant support from the NIA and the Alzheimer’s Drug Discovery Foundation; he has received private legal consulting fees related to postoperative neurocognitive function. Dr. Han has disclosed funding that he receives funding from the NIA, NHLBI, and Patient-Centered Outcomes Research Institute (PCORI). Dr. Girard’s institution received funding from the Department of Defense (DoD) and Ceribell; he received funding from the NIH, the DoD, and Ceribell; and he disclosed he served previously on an advisory board for Lungpacer Medical. Dr. Hosie’s institution received funding from the National Health and Medical Research Council; she received funding from the University of Notre Dame Australia. Dr. Hughes received funding from the NIH and Sedana Medical. Dr. Subramanian’s institution received funding from Masimo; they received funding from Masimo. Dr. Inouye’s institution received funding from the NIA; she received unrelated funding from the NIH and PCORI. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)