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Background: No treatment is available to prevent brain oedema, which can occur after a large hemispheric infarction. Glibenclamide has previously been shown to improve functional outcome and reduce neurological or oedema-related death in patients younger than 70 years who were at risk of brain oedema after an acute ischaemic stroke. We aimed to assess whether intravenous glibenclamide could improve functional outcome at 90 days in patients with large hemispheric infarction., Methods: CHARM was a phase 3, double-blind, placebo-controlled, randomised trial conducted across 143 acute stroke centres in 21 countries. We included patients aged 18-85 years with a large stroke, defined either by an Alberta Stroke Program Early CT Score (ASPECTS) of 1-5 or by an ischaemic core lesion volume of 80-300 mL on CT perfusion or MRI diffusion-weighted imaging. Patients were randomly assigned in a 1:1 ratio to either intravenous glibenclamide (8·6 mg over 72 h) or placebo. The study drug was started within 10 h of stroke onset. The primary efficacy outcome was the shift in the distribution of scores on the modified Rankin Scale at day 90, as a measure of functional outcome. The primary efficacy outcome was analysed in a modified intention-to-treat population, which included all randomly assigned patients aged 18-70 years. The safety population comprised all randomly assigned patients who received a dose. This trial is registered with ClinicalTrials.gov (NCT02864953). The trial was stopped early by the sponsor for strategic and operational reasons (slow enrolment because of COVID-19), before any unblinding or knowledge of the trial results., Findings: Between Aug 29, 2018, and May 23, 2023, 535 patients were enrolled and randomly assigned, of whom 518 received a dose (safety population) and 431 were aged 18-70 years and comprised the modified intention-to-treat population (217 were assigned glibenclamide and 214 placebo). The mean age of patients was 58·7 (SD 9·0) years in the placebo group and 58·0 (9·5) years in the glibenclamide group; the median US National Institutes of Health Stroke Scale (NIHSS) score was 19 (IQR 16-23) in the placebo group and 19 (IQR 16-22) in the glibenclamide group; and the mean time from stroke onset to study drug start was 8·9 h (SD 2·1) in the placebo group and 9·2 h (2·1) in the glibenclamide group. Intravenous glibenclamide was not associated with a favourable shift in the modified Rankin scale at 90 days (common odds ratio [OR] 1·17 [95% CI 0·80-1·71], p=0·42). 90-day mortality was 29% (61 of 214) in the placebo group and 32% (70 of 217) in the glibenclamide group (hazard ratio 1·20 [0·85-1·70]; p=0·30). Serious adverse events in the prespecified safety population were consistent with the known safety profile of glibenclamide and included hypoglycaemia in 15 (6%) of 259 patients in the glibenclamide group and in four (2%) of 259 patients in the placebo group, leading to dose interruption or reduction in seven (3%) patients in the glibenclamide group and in one (<1%) in the placebo group., Interpretation: Intravenous glibenclamide did not improve functional outcome in patients aged 18-70 years after large hemispheric infarction, although the trial was underpowered to make definitive conclusions because it was stopped early. Future prospective evaluation could be warranted to identify a possible benefit of intravenous glibenclamide in specific subgroups., Funding: Biogen., Competing Interests: Declaration of interests KNS has received research support from Biogen administered as a grant to Yale University; other research support from the US National Institutes of Health (NIH), American Heart Association, and Hyperfine, received consulting fees from CSL Behring, Rhaeos, Cerevasc, Astrocyte, Bexorg, and Brain Q; owns equity in Alva Health as a co-founder; and has served on data safety and monitoring board for Zoll, Sense, and Phillips. GWA has received consulting fees from Biogen related to the conduct of the CHARM trial; consulting fees from Genentech and RapidAI; and has equity in RapidAI. JLS has received consulting fees for advising on rigorous and safe clinical trial design and conduct from Biogen, Medtronic, Phenox, and Rapid Medical. BJM has received research support from Biogen administered as a grant to their previous institution (University of Pittsburgh Medical Center); has received grant funding from the NIH; and has equity interest in Celdara Medical. HEH has received consulting fees from Biogen related to the conduct of the CHARM trial; consulting fees from RapidAI; and grant funding from the NIH. CC has received research funding from Biogen related to the conduct of the CHARM trial in France; grant funding from French Ministry of Health and Agence Nationale de la Recherche; and consulting fees from Bayer. KT has received lecture fees from Daiichi-Sankyo, Otsuka, Janssen, Bayer, and Bristol Myers Squibb. RL is an employee of Biogen. MWa, RL, JC, NL, and KD are employees and stockholders of Biogen. RGN reports consulting fees for advisory roles with Anaconda, Biogen, Cerenovus, Genentech, Philips, Hybernia, Hyperfine, Imperative Care, Medtronic, Phenox, Philips, Prolong Pharmaceuticals, Stryker Neurovascular, Shanghai Wallaby, and Synchron; and stock options for advisory roles with Astrocyte, Brainomix, Cerebrotech, Ceretrieve, Corindus Vascular Robotics, CrestecBio, Euphrates Vascular, Vesalio, Viz-AI, RapidPulse, and Perfuze. RGN is one of the Principal Investigators of the “Endovascular Therapy for Low NIHSS Ischemic Strokes (ENDOLOW)” trial; is the Principal Investigator of the “Combined Thrombectomy for Distal MediUm Vessel Occlusion StroKe (DUSK)” trial; and is an investor in Viz-AI, Perfuze, Cerebrotech, Reist/Q’Apel Medical, Truvic, Tulavi Therapeutics, Vastrax, Piraeus Medical, Brain4Care, Quantanosis AI, and Viseon. JMS has received grant funding from the NIH and US Department of Veterans Affairs; consulting fees from Biogen; and owns stocks or options from Remedy Pharmaceuticals, Martin Pharmaceuticals, and Woolsey Pharmaceuticals. WTK has received research funding from Biogen related to the conduct of the CHARM trial; grant funding from the NIH, the American Heart Association, and the Alzheimer's Association; research funding from NControl Therapeutics; research funding from Hyperfine; consulting fees from Biogen, Acasti Pharma, and Astrocyte Pharmaceuticals; and owns stocks or options from Woolsey Pharmaceuticals and Acasti Pharma. BC and MWi declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Fall injuries are the second leading cause of traumatic injury and death for all US workers and are a leading injury concern for the Department of the Air Force (DAF). Bundled interventions can improve the likelihood of injury reduction, especially in large, heterogeneous working populations. In 2013, the DAF implemented the "Air Force Fall Prevention Focus," a bundled intervention of prevention efforts designed to reduce occupational fall injury events among DAF members. The purpose of this study is to describe the burden and risk factors associated with fall injuries and evaluate the effectiveness of the Fall Prevention Focus in reducing the burden of fall injuries., Methods: The National Institute for Occupational Safety and Health (NIOSH) partnered with the US Air Force Safety Center (AFSEC) to examine the impact of the Fall Prevention Focus as a bundled intervention. Injury events included a narrative description of the injury event, demographics, work environment, job tasks, and other structured details. Descriptive statistics and pre-post longitudinal modeling were used to evaluate changes in fall injury rates., Results: The Fall Prevention Focus Implementation (2013-2018) resulted in an annual 10.4% (95% confidence interval [CI]: 8.5%, 12.2%) reduction, and a 6-year cumulative 48.3% (95% CI: 41.4%, 54.3%) reduction in fall injury event rates by 2018., Discussion: Safety in the DAF involves a comprehensive approach. Documenting the impact of the Fall Prevention Focus may help translate these findings to improve fall prevention efforts in other sectors of the military and high fall-risk industries in the private sector, such as construction., (© 2024 Wiley Periodicals LLC.)

Objectives: Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions., Methods: We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B., Results: In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine., Interpretation: Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024;96:1092-1103., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Diverse gut microorganisms present in humans and mice are essential for the prevention of microbial pathogen colonization. However, antibiotic-induced dysbiosis of the gut microbiome reduces microbial diversity and allows Clostridioides difficile ( C. difficile ) to colonize the intestine. The Oligo-Mouse-Microbiota 19.1 (OMM19.1) is a synthetic community that consists of bacteria that are taxonomically and functionally designed to mimic the specific pathogen-free mouse gut microbiota. Here, we examined the susceptibility of OMM19.1 colonized mice to C. difficile infection (CDI) at a range of infectious doses (10 3 , 10 5 , and 10 7 spores) without prior antibiotic treatment. We found that mice colonized with OMM19.1 were susceptible to CDI regardless of the dose. The clinical scores increased with increasing C. difficile dosage. Infection with C. difficile was correlated with a significant increase in Ligilactobacillus murinus and Escherichia coli , while the relative abundance of Bacteroides caecimuris, Akkermansia muciniphila, Extibacter muris, and Turicimonas muris was significantly decreased following CDI. Our results demonstrate that the OMM19.1 community requires additional bacteria to enable C. difficile colonization resistance.IMPORTANCEThe human gut microbiota consists of a wide range of microorganisms whose composition and function vary according to their location and have a significant impact on health and disease. The ability to generate and test the defined microbiota within gnotobiotic animal models is essential for determining the mechanisms responsible for colonization resistance. The exact mechanism(s) by which healthy microbiota prevents Clostridioides difficile infection is unknown, although competition for nutrients, active antagonism, production of inhibitory metabolites (such as secondary bile acids), and microbial manipulation of the immune system are all thought to play a role. Here, we colonized germ-free C57BL/6 mice with a synthetic bacterial community (OMM19.1) that mimics the specific pathogen-free mouse microbiota. Following breeding, to enable immune system development, F1 mice were infected with three different doses of C. difficile . Our research suggests that there are additional essential microbial functions that are absent from the current OMM19.1 model., Competing Interests: The authors declare no conflict of interest.

Needle-based injections currently enable the administration of a wide range of biomacromolecule therapies across the body, including the gastrointestinal tract 1-3 , through recent developments in ingestible robotic devices 4-7 . However, needles generally require training, sharps management and disposal, and pose challenges for autonomous ingestible systems. Here, inspired by the jetting systems of cephalopods, we have developed and evaluated microjet delivery systems that can deliver jets in axial and radial directions into tissue, making them suitable for tubular and globular segments of the gastrointestinal tract. Furthermore, they are implemented in both tethered and ingestible formats, facilitating endoscopic applications or patient self-dosing. Our study identified suitable pressure and nozzle dimensions for different segments of the gastrointestinal tract and applied microjets in a variety of devices that support delivery across the various anatomic segments of the gastrointestinal tract. We characterized the ability of these systems to administer macromolecules, including insulin, a glucagon-like peptide-1 (GLP1) analogue and a small interfering RNA (siRNA) in large animal models, achieving exposure levels similar to those achieved with subcutaneous delivery. This research provides key insights into jetting design parameters for gastrointestinal administration, substantially broadening the possibilities for future endoscopic and ingestible drug delivery devices., Competing Interests: Competing interests: D. Sticker, A.G., T.D., B.M., J.P.H.J., D. Schultz, E.M.D.A., M. Poulsen, C.A., H.D.P., N.E.E., C.C., A.H.U., M. Pereverzina, R.K.K., C.M.D., S.B.G., I.P., A.B., A.A., M.R.F., P.H., U.L.R., J.J.W. and S.T.B. are employees and shareholders of Novo Nordisk. G.T. has received consulting fees and grant funding from Novo Nordisk. B.M., J.P.H.J. and M.R.F. are inventors of the following patent: ‘Jensen, B. et al. Medical Device with Actuation Mechanism. WO2020157324 (6 August 2020)’. G.A., D. Sticker, A.G., Y.L., D.G., B.M., J.W., J.P.H.J., T.S.L., C.C., S.Y., A.B., N.R., J.J.W. and G.T. are inventors of the following patent: ‘Arrick, G. et al. Drug Delivery Device. WO2022034041 (17 February 2022)’. G.A., D. Sticker, A.G., D.G., J.W., J.P.H.J., M. Poulsen, C.C., J.J.W. and G.T. are inventors of the following patent: ‘Traverso, G. et al. Ingestible Drug Delivery Device. WO2022035750 (17 February 2022)’. The other authors declare no competing interests., (© 2024. The Author(s).)

Measles is vaccine-preventable extremely contagious disease caused by the measles virus. High vaccination coverage is needed to prevent outbreaks of disease. Although molecular surveillance of measles is critical to characterize outbreaks and track viral evolution, few whole-genome sequences of measles virus from West Africa are available despite continual outbreaks in the region. Using VirCapSeq-VERT, an enhanced and comprehensive metagenomic sequencing technique that allows for simultaneous identification of all vertebrate viruses, 23 wild-type near-complete genomes of measles virus from across Mali were obtained from samples collected between January 2012 to October 2022. Other febrile rash illnesses were also identified by VirCapSeq-VERT, demonstrating the advantage of using broad detection agnostic methods when the clinical diagnosis is unclear. Whereas one measles virus sequence was consistent with measles vaccine-associated rash illness (VARI), the remaining 38 were classified within the B3.1 genotype. Broad surveillance throughout Mali reveals regional measles virus transmission across West and Central Africa into Mali, while local clinical testing in Bamako shows stable sequence conservation within genotype B3.1 evolving from Nigerian sequences. The genomic information generated in this study is critical in addressing the lack of whole genome sequences available in West Africa and these findings show the importance of phylogenetically tracking measles outbreaks given recent increases in measles cases globally., Competing Interests: Declaration of competing interest Any competing interests was declared. All authors read and approved final version., (Copyright © 2024. Published by Elsevier B.V.)

Myocardial infarction (MI) results in aberrant cardiac metabolism, but no therapeutics have been designed to target cardiac metabolism to enhance heart repair. We engineer a humanized monoclonal antibody against the ectonucleotidase ENPP1 (hENPP1mAb) that targets metabolic crosstalk in the infarcted heart. In mice expressing human ENPP1, systemic administration of hENPP1mAb metabolically reprograms myocytes and non-myocytes and leads to a significant rescue of post-MI heart dysfunction. Using metabolomics, single-nuclear transcriptomics, and cellular respiration studies, we show that the administration of the hENPP1mAb induces organ-wide metabolic and transcriptional reprogramming of the heart that enhances myocyte cellular respiration and decreases cell death and fibrosis in the infarcted heart. Biodistribution and safety studies showed specific organ-wide distribution with the antibody being well tolerated. In humanized animals, with drug clearance kinetics similar to humans, we demonstrate that a single "shot" of the hENPP1mAb after MI is sufficient to rescue cardiac dysfunction., Competing Interests: Declaration of interests The intellectual property associated with hENPP1mAb is held by the Regents, University of California., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated., Background: Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults., Methods: This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (C max ), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC 0-t ), and AUC from Time 0 to infinity (AUC 0-inf ). The safety and pharmacokinetic sample sizes were 26 and 23, respectively., Results: Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC 0-inf and 110.2% (104.6%, 116.1%) for C max . LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC 0-inf and 108.8% (99.9%, 118.4%) for C max . Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%)., Conclusion: Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure., (© 2024 Pfizer Inc. and The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Background: Since 2010, all non-VA hospitals performing cardiac surgeries and percutaneous interventions in Washington State have participated in the Cardiac Care Outcomes Assessment Program (COAP), a data-driven, physician-led collaborative quality improvement (QI) collaborative. Prior literature has demonstrated QI programs such as COAP can avert avoidable utilization such as hospital readmissions. However, it is unknown whether such improvements translate into economic benefits., Hypothesis: This study compared downstream healthcare costs between patients undergoing cardiac interventions for coronary artery disease (CAD) at hospitals that were and were not participating in COAP., Methods: Post hoc analysis of Medicare administrative and claims data examined 2.5 million randomly selected deidentified beneficiaries receiving a percutaneous coronary intervention or coronary artery bypass grafting between 2013 and 2020. Total costs were defined as all reimbursements paid by Medicare for up to 5 years following cardiac intervention. Because all non-VA hospitals in Washington State participated in COAP, we compared respective groups of patients receiving intervention in Washington State with all non-Washington states, adjusting for patient demographics and comorbidity. To model costs, we applied a multipart estimator, which distinguishes the impact of QI program participation due to survival and utilization while accounting for censoring., Results: Total 5-year downstream costs were $3861 lower (95% confidence interval [CI] = $1794 to $5741) among patients receiving cardiac intervention at COAP-exposed hospitals. Lower costs were largely driven by lower utilization during calendar quarters where death was not observed., Conclusions: Participation in this state-wide cardiac quality improvement program was associated with economic benefits in patients receiving intervention for CAD., (©2024 Noridian Healthcare Solutions and The Author(s). Clinical Cardiology published by Wiley Periodicals LLC.)

Peatlands are a major store of soil carbon, due to their high concentration of carbon-rich decayed plant material. Consequently, accurate assessment of peat volumes is important for determining land-use carbon budgets, especially in the Northern hemisphere. Determination of carbon stocks at the scale of individual peat sites has principally relied on either mechanical probing or electromagnetic geophysical methods. In this study, we investigated the use of seismic nodal instrumentation for quantifying peat depth. We used Stryde™ nodes for a deployment at the Whixall moss in Shropshire, England. We measured seismic arrival times from peat-bottom reflections, as well as dispersive surface waves to invert for a model of variable peat depth along a linear cross-section. The use of very small seismic nodes (micronodes) allows for particularly rapid deployment on challenging terrain., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jack Muir reports financial support was provided by European Commission. Jack Muir reports a relationship with Fleet Space Technologies that includes: employment and equity or stocks. If there are other authors, they 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 Authors. Published by Elsevier B.V. All rights reserved.)

A global increase in offshore windfarm development is critical to our renewable energy future. Yet, widespread construction plans have generated substantial concern for impacts to co-occurring organisms and the communities they form. Pile driving construction, prominent in offshore windfarm development, produces among the highest amplitude sounds in the ocean creating widespread concern for a diverse array of taxa. However, studies addressing ecologically key species are generally lacking and most research is disparate, failing to integrate across response types (e.g., behavior, physiology, and ecological interactions), particularly in situ. The lack of integrative field studies presents major challenges to understand or mitigate actual impacts of offshore wind development. Here, we examined critical behavioral, physiological, and antipredator impacts of actual pile driving construction on the giant sea scallop (Placopecten magellanicus). Benthic taxa including bivalves are of particular concern because they are sound-sensitive, cannot move appreciable distances away from the stressor, and support livelihoods as one of the world's most economically and socially important fisheries. Overall, pile driving sound impacted scallops across a series of behavioral and physiological assays. Sound-exposed scallops consistently reduced their valve opening (22%), resulting in lowered mantle water oxygen levels available to the gills. Repeated and rapid valve adductions led to a 56% increase in metabolic rates relative to pre-exposure baselines. Consequently, in response to predator stimuli, sound-exposed scallops displayed a suite of significantly weaker antipredator behaviors including fewer swimming events and shorter time-to-exhaustion. These results show aquatic construction activities can induce metabolic and ecologically relevant changes in a key benthic animal. As offshore windfarm construction accelerates globally, our field-based study highlights that spatial overlap with benthic taxa may cause substantial metabolic changes, alter important fisheries resources, and ultimately could lead to increased predation., 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 Elsevier Ltd. All rights reserved.)

Competing Interests: Disclosure The following authors disclosed financial relationships: R. de Latour: Consultant for Boston Scientific. S.D. Crockett: Clinical trial agreements with Guardant, Exact Sciences, and Freenome. L.V. Hernandez: Stock options in Iterative Health and Liquiglide. H. Pohl: Research support from Steris and Cosmo; advisory board for InterVenn, and The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the US government. All other authors disclosed no financial relationships.

Targeting current therapies to treat or prevent the loss of pancreatic islet β-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off-target effects. Current efforts to target the β-cell are limited by a lack of β-cell-specific targets and the inability to test multiple targeting moieties with the same delivery vehicle. Here, we fabricate a tailorable polycaprolactone nanocapsule (NC) in which multiple different targeting peptides can be interchangeably attached for β-cell-specific delivery. Incorporation of a cationic surfactant in the NC shell allows for the attachment of Exendin-4 and an antibody for ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) for β-cell-specific targeting. The average NC size ranges from 250 to 300 nm with a polydispersity index under 0.2. The NCs are nontoxic, stable in media culture, and can be lyophilized and reconstituted. NCs coated with a targeting peptide were taken up by human cadaveric islet β-cells and human stem cell-derived β-like cells (sBC) in vitro with a high level of specificity. Furthermore, NCs successfully delivered both hydrophobic and hydrophilic cargo to human β-cells. Additionally, Exendin-4-coated NCs were stable and targeted the mouse pancreatic islet β-cell in vivo. Overall, our tailorable NCs have the potential to improve cell-targeted drug delivery and can be utilized as a screening platform to test the efficacy of cell-targeting peptides.

Background: In an effort to enhance recovery after cardiac surgery, intraoperative extubation has been targeted as possibly beneficial. This multi-center cohort study aimed to assess this by evaluating the outcomes of OR extubation versus extubation within six hours of intensive care unit arrival (early ICU extubation). Furthermore, we assessed time to ICU extubation and mortality and morbidity., Methods: Patients undergoing on-pump cardiac surgery across 79 hospitals between 2011-2020 were included to 1) compare outcomes among OR extubation and early ICU extubation patients, and 2) assess time to overall ICU extubation and outcomes., Results: The overall study cohort comprised 163,982 patients, including 95,982 patients [ [ OR extubation : n= 2,529 (2.6%)and early ICU extubation : n= 93,453 (97.4%)] who underwent comparison of OR with early ICU extubation. Following overlap weighting, OR extubation patients had longer OR times (5.6 vs. 5.1 hours, p < 0.0001), and higher rates of reintubation (5.2% vs 2.9%, p=0.003), prolonged ventilation (3% vs 2%, p = 0.021), reoperation for bleeding (1.5% vs 0.7%, p < 0,01), pneumonia (1.9% vs. 1.1% , p < 0.006), and greater in-hospital mortality on multivariable regression (OR 1.34, p < 0.001). OR extubation patients at centers with low OR extubation rates (< 10%, N=60) had higher mortality (odds ratio 1.6, p = 0.001). Beyond 22 hours of postoperative ICU ventilation, the risk of morbidity and mortality increased significantly ., Conclusions: Few cardiac surgery patients are extubated in the OR, which is associated with no clinical benefit and with increased morbidity. Cardiac surgery programs should reconsider OR extubation following cardiopulmonary bypass. Additionally, increased intubation time, in particular > 22 hours, is associated with an increase in adverse outcomes., (Copyright © 2024. Published by Elsevier Inc.)

Background: Device-related thrombosis (DRT) occurs in up to 4% of patients undergoing left atrial appendage occlusion (LAAO) and is associated with substantial morbidity and mortality. However, its pathophysiology, predictors, and optimal management remain unclear., Objectives: This study aims to assess flow dynamic factors correlating to DRT., Methods: A multicenter registry of patients who underwent LAAO and had pre- and post-computed tomography imaging was used. Patient-specific 3-dimensional digital models of the left atrium were created, and finite element simulations were performed to implant an LAAO device into each model in a position that matched the clinical deployment. Computational fluid dynamic simulations were performed to quantify the following flow dynamic parameters: time averaged wall shear stress, oscillatory shear index, and endothelial cell activation potential., Results: A total of 38 patients (19 with DRT and 19 without DRT) were included. Left atrium volumes and mitral valve areas were larger in the DRT cohort compared with controls. Patients with DRT had a significantly lower time averaged wall shear stress (1.76 ± 1.24 Pa vs 2.90 ± 2.70 Pa), a higher oscillatory shear index (0.19 ± 0.11 vs 0.17 ± 0.11), and a higher endothelial cell activation potential (0.23 ± 0.58 Pa -1 vs 0.17 ± 0.30 Pa -1 ) than the controls ( P  < 0.001 for all). Thrombus locations identified from in-vivo images correlated well with the flow dynamic parameters tested., Conclusions: Flow dynamic parameters may be able to predict the risk of DRT after LAAO. Further investigation with a larger patient cohort and long-term follow-up is needed to assess the role of computational fluid dynamics in the risk stratification of patients considered for LAAO., Competing Interests: This research was partly supported by the American Heart Association (AHA) under award number 24CDA1269661. Dr De Backer has received consulting fees and institutional research grants from 10.13039/100000046Abbott and 10.13039/100008497Boston Scientific. Dr Nielsen-Kudsk has received institutional research grants from 10.13039/100000046Abbott, 10.13039/100008497Boston Scientific, and the 10.13039/501100009708Novo Nordic Foundation. Dr Bavo is an employee of FEops. Dr De Beule is a shareholder of FEops. Dr Vogl was partially supported by the 10.13039/100001502Blue Cross Blue Shield of Michigan Foundation, the DeVlieg Foundation, and the Health Research Institute fellowship at Michigan Tech. Dr Jia has received a scholarship from China Scholarship Council under the State Scholarship Fund of China. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Self-assembled networks of bottlebrush copolymers are promising materials for biomedical applications due to a unique combination of ultra-softness and strain-adaptive stiffening, characteristic of soft biological tissues. Transitioning from ABA linear-brush-linear triblock copolymers to A-g-B bottlebrush graft copolymer architectures allows significant increasing the mechanical strength of thermoplastic elastomers. Using real-time synchrotron small-angle X-ray scattering, it is shown that annealing of A-g-B elastomers in a selective solvent for the linear A blocks allows for substantial network reconfiguration, resulting in an increase of both the A domain size and the distance between the domains. The corresponding increases in the aggregation number and extension of bottlebrush strands lead to a significant increase of the strain-stiffening parameter up to 0.7, approaching values characteristic of the brain and skin tissues. Network reconfiguration without disassembly is an efficient approach to adjusting the mechanical performance of tissue-mimetic materials to meet the needs of diverse biomedical applications., (© 2024 Wiley‐VCH GmbH.)

Purpose: This study explores the lived experiences of women living with multiple sclerosis (MS) and identifies barriers to their optimal health and well-being., Methodology: Using van Manen's interpretative phenomenologic analysis, the researchers conducted semistructured interviews with 23 women diagnosed with MS in Southwestern Ontario, Canada. Data were analyzed using NVivo 12 software, and themes were validated through member checking., Results: The study revealed a key theme of "obstacles for women with MS" and subthemes related to barriers to physical, mental, and social well-being. Participants reported experiencing feelings of health despite their MS diagnosis but identified various constraints on their optimal health and well-being, including challenges with employment, financial support, and housing security., Conclusion: The findings highlight the need for healthcare professionals to advocate for equitable treatments, medication, and accessibility supports for women with MS, as well as for policies that address disability income support and affordable housing. Further research is recommended to explore power imbalances experienced by women with MS in precarious employment situations or living with episodic disabilities., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: High rates of antibiotic prescription in residential aged care are likely to promote enteric carriage of antibiotic-resistant pathogens and increase the risk of antibiotic treatment failure. Despite their importance, relationships between antibiotic exposures and patterns of enteric resistance carriage in this population remain poorly understood., Methods: We conducted a cross-sectional metagenomic cohort analysis of stool samples from residents of five long-term aged-care facilities in South Australia. Taxonomic composition was determined, and enteric carriage of antibiotic resistance genes (ARGs) was identified and quantified against the Comprehensive Antibiotic Resistance Database. Both the detection and abundance of stool taxa and ARGs were related to antibiotic exposures up to 12 months prior. Factors associated with the abundance of ARGs of high clinical concern were identified., Results: Stool samples were provided by 164 participants (median age: 88 years, IQR 81-93; 72% female). Sixty-one percent (n = 100) of participants were prescribed antibiotics at least once in the prior 12 months (median prescriptions: 4, range: 1-52), most commonly a penicillin (n = 55, 33.5%), cephalosporin (n = 53, 32.3%), diaminopyrimidine (trimethoprim) (n = 36, 22%), or tetracycline (doxycycline) (n = 21, 12.8%). More than 1100 unique ARGs, conferring resistance to 38 antibiotic classes, were identified, including 20 ARGs of high clinical concern. Multivariate logistic regression showed doxycycline exposure to be the greatest risk factor for high ARG abundance (adjusted odds ratio [aOR]=14.8, q<0.001) and a significant contributor to inter-class selection, particularly for ARGs relating to penicillins (aOR=3.1, q=0.0004) and cephalosporins (aOR=3.4, q=0.003). High enteric ARG abundance was associated with the number of separate antibiotic exposures (aOR: 6.4, q<0.001), exposures within the prior 30 days (aOR: 4.6, q=0.008) and prior 30-100 days (aOR: 2.6, q=0.008), high duration of antibiotic exposure (aOR: 7.9, q<0.001), and exposure to 3 or more antibiotic classes (aOR: 7.4, q<0.001). Carriage of one or more ARGs of high clinical concern was identified in 99% of participants (n = 162, median: 3, IQR: 2-4), involving 11 ARGs conferring resistance to aminoglycosides, four to beta-lactams, one to glycopeptides, three to fluoroquinolones, and one to oxazolidinones. Carriage of ARGs of high clinical concern was positively associated with exposure to doxycycline (aminoglycoside, fluoroquinolone, and oxazolidinone ARGs) and trimethoprim (fluoroquinolone and beta-lactam ARGs). Analysis of doxycycline impact on microbiota composition suggested that observed resistome changes arose principally through direct ARG selection, rather than through the antibiotic depletion of sensitive bacterial populations., Conclusions: The gut microbiome of aged care residents is a major reservoir of antibiotic resistance. As a critical antibiotic in medical practice, a comprehensive understanding of the impact of doxycycline exposure on the gut resistome is paramount for informed antibiotic use, particularly in an evolving landscape of prophylactic applications. Near-universal asymptomatic carriage of clinically critical resistance determinants is highly concerning and reinforces the urgent need for improved management of antibiotic use in long-term aged care., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests, nor any financial or personal relationships with other people or organisations that could bias this study., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Hematologic malignancies in women of reproductive age carry significant additional morbidity due to menstrual bleeding in conjunction with disease and treatment-associated cytopenias. Several agents for menses prophylaxis and suppression exist, but there is a paucity of data comparing these therapies, particularly in the cancer setting., Data Sources: A thorough literature review and evaluation of available data was conducted via PubMed search and combined with clinical expertise., Data Summary: The goal of prophylaxis therapy is to induce amenorrhea until it is considered safe to resume menstrual cycles. GnRH agonists remain the management of choice in achieving menses control and amenorrhea. Suppression is more likely achieved when the therapy is initiated in the late luteal phase or with the concomitant use of oral contraceptives. The effective use of oral contraceptives is achievable in appropriately selected patients. Although attractive as prophylactic agents, GnRH agonists have a slow onset of amenorrhea and can be associated with an initial increase in bleeding, thus are of limited value in immediate menorrhagia management. We recommend prioritizing estrogen therapy given its documented efficacy, and adding tranexamic acid as a secondary agent for severe or refractory bleeding., Conclusions: Thus far in the literature, this is the most comprehensive proposed pathway for the prevention and suppression of menorrhagia in hematologic cancer patients. Our protocol provides a step-wise approach for the management of menses prophylaxis and suppression to provide standardization amongst clinicians and adaptations for patient-specific needs., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Coccidioidomycosis within endemic regions is often undiagnosed because appropriate testing is not performed. A dashboard was developed to provide information about the prevalence of coccidioidomycosis throughout the year., Methods: Banner Urgent Care Service has many clinics within Maricopa County, Arizona, a highly endemic region for coccidioidomycosis. All clinic visits and subset analyses for patients with International Classification of Diseases, Tenth Revision codes for pneumonia (J18.*) or erythema nodosum (L52) during 2018-2024 were included. Tabulated were daily frequencies of visits, pneumonia and erythema nodosum coding, coccidioidal testing, and test results. Banner Urgent Care Services' counts of monthly coccidioidomycosis diagnoses were compared with those of confirmed coccidioidomycosis cases reported to Maricopa County Department of Public Health., Results: Monthly frequencies of urgent care coccidioidomycosis diagnoses strongly correlated with public health coccidioidomycosis case counts (r = 0.86). Testing frequency for coccidioidomycosis correlated with overall pneumonia frequency (r = 0.52). The proportion of pneumonia due to coccidioidomycosis varied between <5% and >45% within and between years. Coccidioidomycosis was a common cause of erythema nodosum (65%; 95% confidence interval, 45%-67%) and independent of pneumonia. Over half of Banner Urgent Care Services' coccidioidomycosis diagnoses were coded for neither pneumonia nor erythema nodosum., Conclusion: Data provided by the coccidioidomycosis dashboard can assist urgent care practitioners in knowing when coccidioidomycosis is prevalent in the community. Patients with exposure to endemic coccidioidomycosis who develop erythema nodosum or pneumonia should routinely be tested for coccidioidomycosis. Data from private health care organizations can augment surveillance of diseases important to public health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

As clinical evaluations of neuromuscular disorders such as hypertonia mostly rely on perception-based scales, the imprecise subjective ratings make it difficult to accurately monitor treatment progress. To promote objective evaluation, this work used a multi-modal sensing glove in a double-blind study to enable sensitive monitoring of medication effects across 19 participants. The biomechanical measurements from the sensing glove effectively distinguished patient cohorts receiving a baclofen treatment or a placebo with 95% confidence. Consistent monitoring over a two-month period was demonstrated, closely tracking variations in individual responses to treatment. The biomechanical changes were correlated to neural activities as recorded by electromyography, verifying the medication effects. The sensing glove is shown to be a reliable tool for point-of-care settings to facilitate precise evaluation of hypertonia, essential for tailoring individual treatment choices and timely management of chronic symptoms., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tse Nga Ng, Andrew Skalsky, Harinath Garudadri have patent #US-11123013-B2 issued to Nadi. If there are other authors, they 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 Authors. Published by Elsevier B.V. All rights reserved.)

The radiometal gallium-68 (Ga-68) has garnered significant interest due to its convenient production via compact and widely available generators and the high performance of 68 Ga-labeled compounds for positron-emission tomography (PET) imaging for cancer diagnosis and management of patients undergoing targeted radionuclide therapy. Given the short half life of Ga-68 (68 min), microfluidic-based radiosynthesis is a promising avenue to establish very rapid, efficient, and routine radiolabeling with Ga-68; however, the typical elution volume of Ga-68 from a generator (4-10 mL) is incompatible with the microliter reaction volumes of microfluidic devices. To bridge this gap, we developed a microscale cartridge-based approach to concentrate Ga-68. By optimizing cartridge design, resin type, resin mass, and eluent composition, Ga-68 was reliably concentrated from ~6 mL to ~80 µL with high recovery efficiency (>97%, n = 14). Furthermore, this method is suitable for both single- and dual-generator setups. To demonstrate suitability of the concentrated radiometal for radiolabeling, we performed microdroplet synthesis of [ 68 Ga]Ga-PSMA-11, achieving high radiochemical yield (83 ± 11%, n = 3), excellent radiochemical purity (>99%), and high apparent specific activity (255-320 MBq/μg). The entire process, including Ga-68 concentration, radiosynthesis, purification, and formulation, was completed in 12 min. Starting with activity of 0.81-0.84 GBq, 0.51-0.64 GBq of product was produced, sufficient for multiple patient doses. This work paves the way to clinical-scale production of other 68 Ga-labeled compounds using droplet microreactor methods, or high-throughput labeling optimization or compound screening of 68 Ga-labeled probes using droplet reaction arrays.

The Heisenberg uncertainty principle dictates that the position and momentum of an object cannot be simultaneously measured with arbitrary precision, giving rise to an apparent limitation known as the standard quantum limit (SQL). Gravitational-wave detectors use photons to continuously measure the positions of freely falling mirrors and so are affected by the SQL. We investigated the performance of the Laser Interferometer Gravitational-Wave Observatory (LIGO) after the experimental realization of frequency-dependent squeezing designed to surpass the SQL. For the LIGO Livingston detector, we found that the upgrade reduces quantum noise below the SQL by a maximum of three decibels between 35 and 75 hertz while achieving a broadband sensitivity improvement, increasing the overall detector sensitivity during astrophysical observations.

Robotic surgery has expanded internationally at pace. There are multiple local robotic training pathways but there is inconsistency in standardisation of core common components for curricula internationally. A framework is required to define key objectives that can be implemented across robotic training ecosystems. This Delphi consensus aimed to provide recommendations for core considerations in robotic training design across diverse training environments internationally. A literature search was performed and an international steering committee (AG, KL, JW, HM, TC) proposed key components for contemporary robotic training design and a modified Delphi approach was used to gather stakeholder opinion. The outcomes were then discussed at a face-to-face international expert consensus at the IMRA educational session at the Society of Robotic Surgery (SRS) meeting and final voting was conducted on outstanding items. Stakeholders included robotic surgeons, proctors, trainees and robotic surgical training providers. There was consensus achieved in 139 statements organised into 15 themes. There was 100% agreement that standardised themes in robotic curricula may improve patient safety. Key take-home messages include-training curricula should be multiplatform, non-technical skills are an important component of a robotic curriculum as well as console and bedside skills, clinically relevant performance metrics should be used for assessment where available, the reliance on cadaveric and live animal models should be reduced as high-fidelity synthetic models emerge, and stepwise component training is useful for advanced procedural training. These consensus recommendations are intended to guide design of fit for purpose contemporary robotic surgical curricula. Integration of these components into robotic training pathways internationally is recommended., (© 2024. The Author(s).)

Introduction: The four variable kidney failure (KF) risk equation (KFRE) is recommended to estimate KF risk (ie, need for dialysis or kidney transplantation). Earlier referral to clinical kidney services for people with high-risk of kidney failure can ensure appropriate care, education and support are in place pre-emptively. There are limited data on investigating the performance of KFRE in estimating risk of end-stage kidney disease (ESKD) in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). The primary ESKD endpoint event was defined as estimated glomerular filtration rate (eGFR) <10 mL/min/1.73 m 2 and secondary endpoint eGFR <15 mL/min/1.73 m 2 ., Research Design and Methods: We studied 7296 people (30% women, 41% African-Caribbean, 45% Caucasian) with T2DM and CKD (eGFR median (range) 48 (15-59) mL/min/1.73 m 2 ) were included at two hospitals in London (median follow-up 10.2 years). Time to ESKD event was the endpoint and Concordance index (C-index) was used to assess KFRE's discrimination of those experiencing ESKD from those who did not. Mean (integrated calibration index (ICI)) and 90th percentile (E90) of the difference between observed and predicted risks were used as calibration metrics., Results: Of the cohort 746 (10.2%) reached ESKD primary event (135 (1.9%) and 339 (4.5%) over 2 and 5 years, respectively). Similarly, 1130 (15.5%) reached the secondary endpoint (270 (3.7%) and 547 (7.5%) over 2 and 5 years, respectively). The C-index for the primary endpoint was 0.842 (95% CI 0.836 to 0.848) and 0.816 (95% CI 0.812 to 0.820) for 2 and 5 years, respectively. KFRE 'under-predicted' ESKD risk overall and by ethnic group. Likewise, the C-index for secondary endpoint was 0.843 (0.839-0.847) and 0.801 (0.798-0.804) for 2 and 5 years, respectively. KFRE performance analysis performed more optimally with the primary endpoint with 50% enhancement of the calibration metrics than with the secondary endpoint. KFRE recalibration improved ICI by 50% and E90 by more than 78%., Conclusions: Although derived for predicting KF, KFRE also demonstrated good discrimination for ESKD outcome. Further studies are needed to identify variables/biomarkers that may improve KFRE's performance/calibration and to aid the development of other predictive models to enable early identification of people at risk of advanced stages of CKD prior to onset of KF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We aim to evaluate estimated glomerular filtration rate (eGFR) patterns of progression in a multiethnic cohort of people with type I diabetes mellitus and with baseline eGFR ≥45 mL/min/1.73 m 2 ., Design: Observational cohort., Setting: People with a clinical diagnosis of type 1 diabetes, attending two university hospital-based outpatient diabetes clinics, in South London between 2004 and 2018., Participants: We studied 1495 participants (52% females, 81% white, 12% African-Caribbean and 7% others)., Primary and Secondary Outcome Measures: Clinical measures including weight and height, systolic blood pressure, diastolic blood pressure and laboratory results (such as serum creatinine, urine albumin to creatinine ratio (ACR), HbA1c were collected from electronic health records (EHRs) and eGFR was estimated by the Chronic Kidney Disease-Epidemiology Collaboration. Ethnicity was self-reported., Results: Five predominantly linear patterns/groups of eGFR trajectories were identified. Group I (8.5%) had a fast eGFR decline (>3 mL/min/1.73 m 2 year). Group II (23%) stable eGFR, group III (29.8%), groups IV (26.3%) and V (12.4%) have preserved eGFR with no significant fall. Group I had the highest proportion (27.6%) of African-Caribbeans. Significant differences between group I and the other groups were observed in age, gender, HbA1C, systolic and diastolic blood pressure, body mass index, cholesterol and urine ACR, p<0.05 for all. At 10 years of follow-up, 33% of group I had eGFR <30 and 16.5%<15 (mL/min/1.73 m 2 )., Conclusions: Distinct trajectories of eGFR were observed in people with type 1 diabetes. The group with the highest risk of eGFR decline had a greater proportion of African-Caribbeans compared with others and has higher prevalence of traditional modifiable risk factors for kidney disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

To reduce the operational friction and scale DNA engineering, we report here an in vivo DNA assembly technology platform called SCRIVENER ( S equential C onjugation and R ecombination for I n V ivo E longation of N ucleotides with low ER rors). SCRIVENER combines bacterial conjugation, in vivo DNA cutting, and in vivo homologous recombination to seamlessly stitch blocks of DNA together by mating E. coli in large arrays or pools. This workflow is simpler, cheaper, and higher throughput than current DNA assembly approaches that require DNA to be moved in and out of cells at different procedural steps. We perform over 5,000 assemblies with two to 13 DNA blocks that range from 240 bp to 8 kb and show that SCRIVENER is capable of assembling constructs as long as 23 kb at relatively high throughput and fidelity. Most SCRIVENER errors are deletions between long interspersed repeats. However, SCRIVENER can overcome these errors by enabling assembly and sequence verification at high replication at a nominal additional cost per replicate. We show that SCRIVENER can be used to build combinatorial libraries in arrays or pools, and that DNA blocks onboarded into the platform can be repurposed and reused with any other DNA block in high throughput without a PCR step. Because of these features, DNA engineering with SCRIVENER has the potential to accelerate design-build-test-learn cycles of DNA products., Competing Interests: X.L., T.M., W.L., D.M., and S.F.L filed patent applications based on the methods presented in this work (WO2022187697A1, EP4301854A4, GB202315184D0, KR20230152124A, JP2024509194A, CA3212642A1, DE112022001365T5, AU2022228362A1). S.F.L and G.S. co-founded BacStitch DNA, Inc. to commercialize methods presented in this work. T.M., P.H.H., F.L., J.C., N.W. G.S. and S.F.L have financial interest in BacStitch DNA, Inc..

Background: One major barrier to HIV cure is the persistence of virus, possibly linked to an insufficient antiretroviral drug (ARV) distribution into tissues., Objectives: To draw the whole-body distribution of three antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine and dolutegravir-in non-human primates (NHPs)., Methods: Eight uninfected NHPs received a single injection of a solution containing the three ARVs. Forty-five different tissues were sampled 24 h after injection., Results: Median tissue penetration factors (TPFs) were 45.4, 5.8 and 0.5 for tenofovir, emtricitabine and dolutegravir, respectively, and were statistically different between the three ARVs. Tissues were grouped by system, because TPFs were consistent according to these groups, and ranked in order of decreasing TPFs. The digestive system was the system with the highest tissue concentrations. Next came the two main sites of elimination, the liver and the kidney, as well as the tissues of the cardiopulmonary and urinary systems. Then, it was the whole lymphatic system. The next group included the reproductive system, the adipose tissue and the skin. The last two systems were the muscle and the CNS. The intra-tissue variability was rather low with a median coefficient of variation of the concentrations around 15% and no value greater than 80%., Conclusions: Overall, this study determines the first whole-body distribution in a validated NHP model. These data have important implications for future preclinical and clinical studies for the development of novel HIV therapies towards an HIV cure., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. 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.)

Objectives: To present a new method for displaying blood utilization data based on analysis of decision time intervals (DTIs)., Methods: Retrospective study of patients treated in a medical intensive care unit (ICU), surgical ICU, or postcardiac surgery ICU at an academic hospital between January 2018 and June 2023. Each patient's episode of care was divided into a series of DTIs. Transfusions during each time interval were recorded., Results: In total, 16,562 patients received 6980 units of plasma and 21,034 units of red blood cells during 111,557 time intervals of care. Patients had international normalized ratio (INR) values ranging from less than 1.0 to more than 4.0. Data on plasma transfusion at different INR values were displayed as the number of transfusion episodes, number of units given, or the proportion of DTIs with transfusion. Clinicians transfused plasma on 1.5% of occasions when the INR was 1.5 or less and on 2.2% of occasions when the INR was less than 2.0. Plasma was transfused without red blood cells in only 0.75% of DTIs. Transfusion practice was statistically different among the 3 ICUs., Conclusions: Compared with traditional methods of displaying the results of blood audits, DTI analysis displays information regarding the decision both to transfuse and to not transfuse. Utilization reviews that display data based on decision time analysis reveal clinical practice patterns very different from those suggested by traditional displays of plasma audit data., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. 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.)

In type 1 diabetes (T1D), autoreactive immune cells infiltrate the pancreas and secrete proinflammatory cytokines that initiate cell death in insulin producing islet β-cells. Protein kinase C δ (PKCδ) plays a role in mediating cytokine-induced β-cell death; however, the exact mechanisms are not well understood. To address this, we used an inducible β-cell specific PKCδ KO mouse as well as a small peptide inhibitor of PKCδ. We identified a role for PKCδ in mediating cytokine-induced β-cell death and have shown that inhibiting PKCδ protects pancreatic β-cells from cytokine-induced apoptosis in both mouse and human islets. We determined that cytokines induced nuclear translocation and activity of PKCδ and that caspase-3 cleavage of PKCδ may be required for cytokine-mediated islet apoptosis. Further, cytokine activated PKCδ increases activity both of proapoptotic Bax with acute treatment and C-Jun N-terminal kinase with prolonged treatment. Overall, our results suggest that PKCδ mediates cytokine-induced apoptosis via nuclear translocation, cleavage by caspase-3, and upregulation of proapoptotic signaling in pancreatic β-cells. Combined with the protective effects of PKCδ inhibition with δV1-1, the results of this study will aid in the development of novel therapies to prevent or delay β-cell death and preserve β-cell function in T1D., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To develop and implement a pilot online data collection tool to help local health departments with their COVID-19 pandemic response efforts and inform health department actions., Design: The COVID-19 Outbreak Public Evaluation (COPE) was an online survey and was distributed by participating sites to individuals who recently tested positive for SARS-CoV-2. Surveys recorded participant demographics and assessed recent infection risk behaviors (eg, mask use, air travel), vaccination status, sleep and exercise habits, social behaviors and beliefs, and physical and mental health., Setting: Seven health departments participated in the initiative, which took place during May 1 to September 30, 2022. Identical items were administered to demographically representative samples of adults nationally in the United States within a similar timeframe., Participants: A total of 38 555 participants completed surveys. Responses from participants with recent SARS-CoV-2 infections were compared with respondents from the national surveys who did not have evidence or awareness of prior SARS-CoV-2 infections., Main Outcome Measure: To implement of a process that allows health departments to receive data from local cases and compare this information to national controls during the COVID-19 pandemic., Results: Fifty-four biweekly reports were provided to public health departments between May and September 2022. Information and comparisons within the reports were updated in response to evolving public health priorities for the pandemic response. The initiative helped to guide public health response efforts during the COVID-19 pandemic. Moreover, the receptiveness by local health departments and participants provides evidence to support this data collection and reporting model as a component of the public health response to future emergencies., Conclusion: This project demonstrates the feasibility of a centralized, rapid, and adaptive data collection system for local health departments and provides evidence to advocate for data collection methods to help guide local health departments to respond in a timely and effective manner to future public health emergencies., Competing Interests: L.A.B., M.É.C., R.I.L., P.V., S.M.W.R., M.E.H., C.A.C., and M.D.W. report institutional grants from CDC Foundation and the US Centers for Disease Control and Prevention. M.É.C. reports institutional gifts or grants from WHOOP, Inc., HopeLab Foundation, consulting fees from Vanda Pharmaceuticals, Inc., and Nychthemeron, LLC, and equity interest in With Deep, Inc. M.D.W. reports institutional grants from Brigham and Women’s Hospital Physician’s Organization, Brigham Research Institute, and the National Heart, Lung, and Blood Institute; and consulting fees from the Fred Hutchinson Cancer Center, the National Sleep Foundation, and the University of Pittsburgh. S.M.W.R. reports institutional grants from Cooperative Research Centre for Alertness, Safety and Productivity, National Health and Medical Research Council, CSIRO, the Australian Research Council, Australasian Sleep Association, Wellcome Trust, Collingwood Football Club, Vanda Pharmaceuticals, Department of Defense, WHOOP, Inc. HopeLab Foundation; institutional consultancy fees from Teva Pharma Australia, Circadian Therapeutics, BHP, Roche, Avecho, Vanda Pharmaceuticals; institutional and personal consulting fees from Cooperative Research Centre for Alertness, Safety and Productivity; payment for expert testimony from Herbert Smith Freehills and Maurice Blackburn; Patent for Systems and Methods for Monitoring and Control of Sleep Patterns; and service as chair for the Sleep Health Foundation Board of Directors. M.E.H. reports participation on the ResApp Health Advisory Board, and honorary board membership for the Institute for Breathing and Sleep. C.A.C. serves as the incumbent of an endowed professorship provided to Harvard Medical School by Cephalon, Inc. and as chair of the Sleep Timing and Variability Consensus Panel, National Sleep Foundation; and reports institutional support for the Quality Improvement Initiative from Delta Airlines and Puget Sound Pilots; education support to Harvard Medical School Division of Sleep Medicine; support to Brigham and Women’s Hospital from Jazz Pharmaceuticals PLC, Inc. and Philips Respironics, Inc; support to Brigham and Women’s Hospital from Axome Therapeutics, Inc., Regeneron Pharmaceuticals, and Sanofi SA; educational funding to the Sleep and Health Education of the Harvard Medical School Division of Sleep Medicine from ResMed, Teva Pharmaceuticals Industries, Ltd., and Vanda Pharmaceuticals; royalty payments on sales of the Actiwatch-2 and Actiwatch-Spectrum devices from Philips Respironics, Inc.; personal consulting fees from With Deep, Inc. and Vanda Pharmaceuticals; honoraria for Thomas Roth Lecture of Excellence at SLEEP 2022 annual meeting and from the Massachusetts Medical Society for writing a Perspective article in the New England Journal of Medicine; payment for expert testimony from Puget Sound Pilots, Amtrak, Enterprise Rent-A-Car, Dallas Police Association, FedEx, PAR Electrical Contractors, Inc., Schlumberger Technology Corp., Union Pacific Railroad, United Parcel Service, Vanda Pharmaceuticals, and the San Francisco Sheriff’s Department; travel support from the Stanley Ho Medical Development Foundation for travel to Macao and Hong Kong; advisory board membership for the Institute of Digital Media and Child Development, Klarman Family Foundation, and the UK Biotechnology and Biological Sciences Research Council; equity interest in Vanda Pharmaceuticals, With Deep, Inc., and Signos, Inc.; and institutional receipt of educational gifts to Brigham and Women’s Hospital from Johnson & Johnson, Mary Ann and Stanley Snider via Combined Jewish Philanthropies, Alexandra Drane, DR Capital, Harmony Biosciences, LLC, and to Harvard University from ResMed, Inc. No other potential conflicts of interest were disclosed., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Genomic regions sometimes show patterns of genetic variation distinct from the genome-wide population structure. Such deviations have often been interpreted to represent effects of selection. However, systematic investigation of whether and how non-selective factors, such as recombination rates, can affect distinct patterns has been limited. Here, we associate distinct patterns of genetic variation with reduced recombination rates in a songbird, the Eurasian blackcap (Sylvia atricapilla), using a new reference genome assembly, whole-genome resequenc- ing data and recombination maps. We find that distinct patterns of genetic variation reflect haplotype structure at genomic regions with different prevalence of reduced recombination rate across populations. At low-recombining regions shared in most populations, distinct patterns reflect conspicuous haplotypes segregating in multiple populations. At low-recombining regions found only in a few populations, distinct patterns represent variance among cryptic haplotypes within the low-recombining populations. With simulations, we confirm that these distinct patterns evolve neutrally by reduced recombination rate, on which the effects of selection can be overlaid. Our results highlight that distinct patterns of genetic variation can emerge through evolutionary reduction of local recombination rate. The recombination landscape as an evolvable trait therefore plays an important role determining the heterogeneous distribution of genetic variation along the genome., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE).)

Reconstructing rainfall variability and moisture sources is a critical aspect to understand past and future hydroclimate dynamics. Here, we use changes in the deuterium content of land-plant leaf waxes from two marine sediment cores located off Chile to reconstruct changes in rainfall amount and variation in moisture sources over the last ~50 ka. The records indicate increased moisture in central Chile during precession maxima, but an obliquity modulation is evident in southern Chile. While the southern westerly winds are the dominant factor of precipitation in southern Chile by bringing moisture and perturbations from the extratropics, the subtropics represent an additional moisture source during precession maxima due to a stronger subtropical jet increasing moisture transport from the tropics to the mid-latitudes. These findings imply that a combination of orbital modulation of moisture sources and rainfall amount explains the last glacial moisture maximum and early Holocene moisture minimum in south-central Chile., (© 2024. The Author(s).)

Diverse gut microorganisms present in humans and mice are essential for the prevention of microbial pathogen colonization. However, antibiotic-induced dysbiosis of the gut microbiome reduces microbial diversity and allows C. difficile to colonize the intestine. The Oligo Mouse Microbiota 19.1 (OMM19.1) is a synthetic community that consists of bacteria that are taxonomically and functionally designed to mimic the specific pathogen-free (SPF) mouse gut microbiota. Here, we examined the susceptibility of OMM19.1 colonized mice to C. difficile infection at a range of infectious doses (10 3 , 10 5 , and 10 7 spores) without prior antibiotic treatment. We found that mice colonized with OMM19.1 were susceptible to C. difficile infection regardless of the dose. The clinical scores increased with increasing C. difficile dosage. Infection with C. difficile was correlated with a significant increase in Ligilactobacillus murinus and Escherichia coli , while the abundance of Bacteroides caecimuris, Akkermansia muciniphila, Extibacter muris, and Turicimonas muris significantly decreased following C. difficile infection. Our results demonstrate that the OMM19.1 community requires additional bacteria to enable colonization resistance.

In May 2023, the Detroit Health Department was notified of four cases of invasive nontypeable Haemophilus influenzae (Hi) disease among students attending the same elementary school and grade, all with illness onsets within 7 days. Three patients were hospitalized, and one died. Most U.S. cases of invasive Hi disease are caused by nontypeable strains. No vaccines against nontypeable or non-type b Hi strains are currently available. Chemoprophylaxis is not typically recommended in response to nontypeable Hi cases; however, because of the high attack rate (four cases among 46 students; 8.7%), rifampin prophylaxis was recommended for household contacts of patients with confirmed cases and for all students and staff members in the school wing where confirmed cases occurred. Only 10.8% of students for whom chemoprophylaxis was recommended took it, highlighting gaps in understanding among caregivers and health care providers about persons for whom chemoprophylaxis was recommended. Public health authorities subsequently enhanced communication and education to the school community, improved coordination with health care partners, and established mass prophylaxis clinics at the school. This outbreak highlights the potential for nontypeable Hi to cause serious illness and outbreaks and the need for chemoprophylaxis guidance for nontypeable Hi disease. Achieving high chemoprophylaxis coverage requires education, communication, and coordination with community and health care partners., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: With population aging and advances in surgical and anesthetic procedures, the incidence of surgery in patients over the age of 65 years is increasing. One post-operative complication often encountered by older surgical patients is post-operative cognitive dysfunction (POCD). Preoperative exercise training can improve the overall physiological resilience of older surgical patients, yet its impact on post-operative cognition is less well-established., Methods: Six databases (Medline (OVID); EMBASE (OVID); EMCARE (OVID); CINAHL (EBSCOHost), the Cochrane Library, and PubMed) were searched for studies reporting the effect of pre-operative physical training on post-operative cognition. The quality of evidence was assessed using the Mixed Methods Assessment Tool., Results: A total of 3983 studies were initially identified, three of which met the inclusion criteria for this review. Two studies were pilot randomized trials, and one was a prospective randomized trial. Two of the studies were high-quality. Each study used a different type of physical exercise and cognition assessment tool. Across the studies, post-operative cognition (p = 0.005) and attention (p = 0.04) were found to be better in the intervention groups compared to control, with one study reporting no difference between the groups., Conclusion: Preoperative physical training may improve post-operative cognitive function, although more research with a consistent endpoint is required. Future studies should focus on patients at high risk of POCD, such as older adults, and explore the impact of different exercise regimes, including frequency, intensity, time, and type., (© 2024. The Author(s).)

Aims: The aims of this study were to: (1) synthesize existing evidence regarding the integration of students with osteogenesis imperfecta (OI) into the school setting, (2) tabulate existing school integration tools for OI, and (3) create an individualized school plan to facilitate school integration., Methods: Guided by the process of developing evidence-informed guidelines, an international, interprofessional, expert task force was convened. The process entailed: (1) reviewing of the literature, (2) developing recommendations, and (3) creating a clinically meaningful, person-focused plan to facilitate the integration and promotion of school inclusivity. The 13-member task force relied on empirical studies, grey literature, and their experiential knowledge (from clinical, teaching or patient experiences) to devise the plan., Results: Over a series of eight meetings and five drafts, the Task Force prioritized 14 core items for inclusion. These items consisted of general student information, fracture response protocol, student inclusion recommendations, mobility considerations, transfer considerations, toileting protocol, physical education recommendations, fieldtrip information, transportation considerations, evacuation plan, environmental and scholarly considerations, consent and authorization, and an annual renewal document., Conclusion: Further research is recommended to pilot the plan, solicit ongoing feedback, implement and evaluate the plan into routine education and health care practices.

There has been an increasing, and welcome, open hardware trend towards science teams building and sharing their designs for new instruments. These devices, often built upon low-cost microprocessors and microcontrollers, can be readily connected to enable complex, automated and smart experiments. When designed to use open communication web standards, devices from different laboratories and manufacturers can be controlled using a single protocol and even communicate with each other. However, science labs still have a majority of old, perfectly functional equipment which tends to use older, and sometimes proprietary, standards for communications. In order to encourage the continued and integrated use of this equipment in modern automated experiments, we develop and demonstrate LabThings Retro. This allows us to retrofit old instruments to use modern Web-of-Things standards, which we demonstrate with closed-loop feedback involving an optical microscope, digital imaging and fluid pumping., Competing Interests: At the time of writing, P.C. is a Board Member of Royal Society Open Science but had no involvement in the review or assessment of the paper., (© 2024 The Authors.)

The US Environmental Protection Agency (USEPA) considers sediment toxicity tests as conditional registration requirements for pesticides with soil Kd ≥50 L/kg-solid, Koc ≥1000 L/kg-organic carbon, or log Kow ≥3. The hydrophobicity of these compounds often necessitates use of solvents to ensure accurate and homogeneous dosing of spiked-sediment studies. For sediment tests, a volatile solvent (e.g., acetone) is generally used as a transient carrier. Due to low water solubility, test material is dissolved in a volatile solvent to create stock solutions. A measured aliquot of stock solution is then mixed with sand substrate, after which the solvent is evaporated. This spiking process results in negligible solvent exposure to organisms. In 2016, USEPA released final ecotoxicity test guidelines for subchronic freshwater (850.1735) and marine (850.1740) sediment test. These methods provide an option for conducting experiments with only a solvent control and no negative control. To adopt this testing strategy, functional equivalency between the negative and solvent control must be demonstrated. These test guidelines describe specific factors that should be considered for evaluating functional equivalency, including (a) the concentration of solvent in the test sediment after evaporation, (b) the levels of solvent that are known to affect organism health, (c) the known impurities in the solvent and their potential impact on organism health, and (d) the historical organism performance of solvent versus negative controls. Our analysis considers these factors and overall supports the elimination of the negative control requirement because this change is unlikely to impact the robustness or interpretability of spiked-sediment toxicity tests. Environ Toxicol Chem 2024;43:1740-1746. © 2023 CropLife America. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2023 CropLife America. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Polymeric composites with boron nitride nanosheets (BNNs), which are thermally conductive yet electrically insulating, have been pursued for a variety of technological applications, especially those for thermal management in electronic devices and systems. Highlighted in this review are recent advances in the effort to improve in-plane thermal transport performance in polymer/BNNs composites and also the growing research activities aimed at composites of enhanced cross-plane or isotropic thermal conductivity, for which various filler alignment strategies during composite fabrication have been explored. Also highlighted and discussed are some significant challenges and major opportunities for further advances in the development of thermally conductive composite materials and their mechanistic understandings.

Targeting of current therapies to treat or prevent loss of pancreatic islet β-cells in Type 1 Diabetes (T1D) may provide improved efficacy and reduce off target effects. Current efforts to target the β-cell are limited by a lack of β-cell specific targets and the inability to test multiple targeting moieties with the same delivery vehicle. Here we fabricate a novel tailorable polycaprolactone nanocapsule (NC) where multiple different targeting peptides can be interchangeably attached for β-cell specific delivery. Incorporation of a cationic surfactant in the NC shell allows for the attachment of Exendin-4 and an antibody for ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) for β-cell specific targeting. The average NC size ranges from 250-300nm with a polydispersity index under 0.2. The NCs are non-toxic, stable in media culture, and can be lyophilized and reconstituted. NCs coated with targeting peptide were taken up by human cadaveric islet β-cells and human stem cell-derived β-like cells (sBC) in vitro with a high level of specificity. Furthermore, NCs successfully delivered both hydrophobic and hydrophilic cargo to human β-cells. Finally, Exendin-4 coated NCs were stable and targeted the mouse pancreatic islet β-cell in vivo . Our unique NC design allows for the interchangeable coating of targeting peptides for future screening of targets with improved cell specificity. The ability to target and deliver thera-peutics to human pancreatic β-cells opens avenues for improved therapies and treatments to help the delay onset, prevent, or reverse T1D.

Numerous large scale genomic studies have uncovered rare but recurrent pathogenetic variants in a significant number of genes encoding epigenetic machinery in cases with neurodevelopmental disorders (NDD) especially autism spectrum disorder (ASD). These findings provide strong support for the functional importance of epigenetic regulators in neurodevelopment. After the clinical genomics evaluation of the patients using exome sequencing, we have identified, three novel protein-truncating variants (PTVs) in the MSL2 gene (OMIM: 614802) which encodes a chromatin modifying enzyme. MSL2 modifies chromatin through both mono-ubiquitination of histone 2B on lysine 34 (K34) and acetylation of histone H4 on lysine 16 (K16). We reported first time the detailed clinical features associated with 3 MSL2 PTVs. There are 15 PTVs (13 de novo) reported from the large genomics studies (12 cases) or ClinVar (3 cases) of NDD, ASD, and developmental disorders (DD) but the specific clinical features for these cases are not described. Taken together, our descriptions of dysmorphic face and other features support the causal role of MSL2 in a likely syndromic neurodevelopmental disorder and add MSL2 to a growing list of epigenetic genes implicated in ASD., (© 2024. The Author(s).)

Purpose: A national additional risk minimization measures (aRMMs) program was implemented to train pharmacists for safe supply of non-prescription Viagra Connect ® (VC) to erectile dysfunction (ED) patients in United Kingdom (UK). A survey aimed to evaluate the effectiveness of aRMMs., Methods: A cross-sectional, web-based survey enrolled ED patients who purchased at least 1 supply of VC in UK, using a structured self-administered questionnaire. Patients were assessed for the suitability of VC and received appropriate advice from pharmacists. Descriptive statistics were used., Results: The final sample had 297 patients, who reported that pharmacists inquired about blood pressure and heart comorbidities (91.9%), relevant illnesses (87.9%), medications (86.5%), ED diagnosis (82.2%), and were advised to consult their doctor regarding ED (51.2%). Furthermore, 85.5% of patients were advised on how to take VC correctly, 82.2% on possible side effects for which they might have to discontinue taking VC and consult their doctor, 80.1% on being informed that ED could be caused by underlying conditions. About 65.0% reported that they had visited (19.2%) or planned to visit (45.8%) their doctor. A majority (68.7%) also indicated that they had received advice on lifestyle modifications to manage their ED-related health risks., Conclusion: This survey provided a reasonable confirmation of the effectiveness of the VC aRMMs program and assurance that ED patients, when requesting and purchasing VC in UK pharmacies, are assessed appropriately for suitability of VC and receive the appropriate advice from pharmacists., Competing Interests: Shaantanu S. Donde, and Kelly H. Zou are employees of Viatris who may own stocks/shares, merged between the Upjohn Division of Pfizer Inc and Mylan. Jim Z Li is a former employee of Viatris Inc. Joanna Lem is a former employee of Pfizer Inc. Muhammad Younus is an employee of Pfizer Inc. Janine Collins is an employee of UBC. The authors report no other conflicts of interest in this work., (© 2024 Li et al.)

Candida auris is an opportunistic fungal pathogen with high mortality rates which presents a clear threat to public health. The risk of C. auris infection is high because it can colonize the body, resist antifungal treatment, and evade the immune system. The genetic mechanisms for these traits are not well known. Identifying them could lead to new targets for new treatments. To this end, we present an analysis of the genetics and gene expression patterns of C. auris carbon metabolism, drug resistance, and macrophage interaction. We chose to study two C. auris isolates simultaneously, one drug sensitive (B11220 from Clade II) and one drug resistant (B11221 from Clade III). Comparing the genomes, we confirm the previously reported finding that B11220 was missing a 12.8 kb region on chromosome VI. This region contains a gene cluster encoding proteins related to alternative sugar utilization. We show that B11221, which has the gene cluster, readily assimilates and utilizes D-galactose and L-rhamnose as compared to B11220, which harbors the deletion. B11221 exhibits increased adherence and drug resistance compared to B11220 when grown in these sugars. Transcriptomic analysis of both isolates grown on glucose or galactose showed that the gene cluster was upregulated when grown on D-galactose. These findings reinforce growing evidence of a link between metabolism and drug tolerance. B11221 resists phagocytosis by macrophages and exhibits decreased β-1,3-glucan exposure, a key determinant that allows Candida to evade the host immune system, as compared to B11220. In a transcriptomic analysis of both isolates co-cultured with macrophages, we find upregulation of genes associated with transport and transcription factors in B11221. Our studies show a positive correlation between membrane composition and immune evasion, alternate sugar utilization, and drug tolerance in C. auris ., Competing Interests: The authors declare no conflict of interest.

Carbon monoxide poisoning can occur as part of smoke exposure in the burn population. Here we report the case of a 32-year-old, previously healthy male, with carbon monoxide-related blindness after smoke exposure in an apartment fire. Cerebral hypoperfusion was diagnosed using magnetic resonance imaging of the brain, and the patient was diagnosed with cortical visual impairment. He was treated with hyperbaric oxygen therapy following which he had partial recovery of his vision. There is a paucity of information regarding this phenomenon and its treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association. 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.)

Vancomycin-resistant enterococci (VRE) pose a serious threat to public health because of their limited treatment options. Therefore, there is an increasing need to identify novel targets to develop new drugs. Here, we examined the roles of the universal PTS components, PtsI and PtsH, in Enterococcus faecium to determine their roles in carbon metabolism, biofilm formation, stress response, and the ability to compete in the gastrointestinal tract. Clean deletion of ptsHI resulted in a significant reduction in the ability to import and metabolize simple sugars, attenuated growth rate, reduced biofilm formation, and decreased competitive fitness both in vitro and in vivo . However, no significant difference in stress survival was observed when compared with the wild type. These results suggest that targeting universal or specific PTS may provide a novel treatment strategy by reducing the fitness of E. faecium ., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Objective: Nontyphoidal Salmonella infection is one of the most common foodborne illnesses, and its oncogenic potential has been documented in animal models. The primary goal of this study was to examine whether individuals who were exposed to enteric Salmonella infection are more likely to develop colorectal cancer (CRC) than the general population through the linkage of 2 statewide public health surveillance databases., Materials and Methods: We designed a 2-stage probabilistic linkage, starting with 17,587 records of enteric salmonellosis reported to Michigan Department of Health and Human Services between 1992 and 2020. These records did not include unique identifiers (such as Social Security number [SSN]). The initial linkage to LexisNexis address history was conducted to obtain information to calculate each person's time in Michigan as well as SSN for the second linkage. The linkage to the state cancer registry was performed to obtain the observed number of CRC cases, while the expected number of CRC cases was calculated according to corresponding state CRC incidence by age, sex, and calendar year., Results: Ninety-three percent of the initially identified salmonellosis records were sent to LexisNexis linkage, which returned address history, death, and SSN for 97% of the records. Further linkage to the statewide cancer registry identified 98 incident CRC cases. Overall, the observed-to-expected (O/E) ratio was not different from unity (0.833; 95% CI, 0.627-1.003)., Conclusions: While the new linkage strategy was found effective and should be applicable to other health conditions, we cannot rule out bias due to incomplete or underreporting of the infection in estimating the risk of CRC., (© 2024 National Cancer Registrars Association.)

Background: The US Environmental Protection Agency Food Recovery Hierarchy suggests methods for diverting food waste from landfill. Knowledge of how hospital foodservices implement food waste management strategies could help modernize food waste practices., Objective: The aim of this study was to explore hospital staff members' experiences of implementing a food waste management strategy to divert food waste from landfill in their hospital foodservice, including the journey, challenges, and facilitators of this practice change., Design: A qualitative study was conducted in 2022-2023 using semi-structured interviews., Participants/setting: Eighteen participants were staff members with knowledge of the food waste management strategy from 14 exemplar hospitals in United States, Spain, Scotland, and Australia using strategies to divert food waste from landfill within the last 10 years., Analyses Performed: Mapping and thematic analysis were undertaken to code and identify themes from the interviews that described staff members' experiences of the journey to implement the strategy., Results: Six hospitals donated food, 1 transferred food waste for animal feed, 4 used an industrial solution, and 3 sent food waste for composting. A common journey pathway for successful implementation was identified from participants' experiences. It features the following 6 phases: idea, preparation, roll out, maintenance, established practice, and evolution. Facilitators included legislation, enthusiastic staff members, executive support, and "luck." Challenges were smells, occasions when food waste was not collected, equipment breakage, and funding depletion., Conclusions: This study identified a common journey pathway for implementing a food waste management strategy in hospital foodservices that can be used to anticipate and prepare for the steps in the implementation process., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None disclosed.