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Background: COVID-19 vaccination has been associated with anaphylaxis and hypersensitivity reactions. Infectious disease physicians and allergists in the Canadian Special Immunization Clinic (SIC) Network developed guidance for evaluating patients with adverse events following immunization (AEFI) including suspected hypersensitivity. This study evaluated management and adverse event recurrence following subsequent COVID-19 vaccinations., Methods: Individuals aged 12 years and older enrolled at participating SICs before February 28, 2023 who were referred for suspected or diagnosed hypersensitivity reaction following COVID-19 vaccination, or for prevaccination assessment of suspected allergy to a COVID-19 vaccine component were included. De-identified clinical assessments and revaccination data, captured in a centralized database, were analyzed. The Brighton Collaboration case definition (BCCD) for anaphylaxis (2023 version) was applied., Results: The analysis included 206 participants from 13 sites: 26 participants referred for pre-vaccination assessment and 180 participants referred for adverse events following COVID-19 vaccination (15/180 [8.3%] with BCCD confirmed anaphylaxis, 84 [46.7%] with immediate hypersensitivity symptoms not meeting BCCD, 33 [18.3%] with other diagnosed hypersensitivity reactions, and 48 [26.7%] participants with a final diagnosis of non-hypersensitivity AEFI). Among participants referred for AEFIs following COVID-19 vaccination, 166/180 (92.2%) were recommended for COVID-19 revaccination after risk assessment, of whom 158/166 (95.2%) were revaccinated (all with a COVID-19 mRNA vaccine). After revaccination, 1/15 (6.7%) participants with prior anaphylaxis, 1/77 (1.3%) with immediate hypersensitivity not meeting criteria for anaphylaxis and 1/24 (4.2%) with other physician diagnosed hypersensitivity developed recurrent AEFI symptoms that met the BCCD for anaphylaxis. All 26 participants referred pre-vaccination, including 9 (34.6%) with history of polyethylene glycol-asparaginase reactions, were vaccinated without occurrence of immediate hypersensitivity symptoms., Conclusions: Most individuals in this national cohort who experienced a hypersensitivity event following COVID-19 vaccination and were referred for specialist review were revaccinated without AEFI recurrence, suggesting that specialist evaluation can facilitate safe revaccination., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, and Sanofi-Pasteur; all funds have been paid to his institute, and he has not received any personal payments. VC received honoraria from Pfizer, Aralez pharmaceuticals and CSL Behring financial support for publication from CSL Behring. JEMU reports advisory board for Pfizer, clinical trials with Sanofi, and other from Novartis, all outside the current work. KZ reports honoraria from AstraZeneca and Regeneron. JMP is an investigator on projects funded by MedImmune and Merck; all funds have been paid to his institute, and he has not received any personal payments. ZA reports honoraria for speaker fees for Pfizer outside of the submitted work. AM received honoraria for presentations from Pfizer and Sanofi. ADR participated in multicentric studies with ALK for sublingual immunotherapy as investigator. AC received honoraria for presentations from Pfizer, AstraZeneca, GlaxoSmithKline and Moderna. JC received honoraria for presentations from Pfizer, AstraZeneca, and GlaxoSmithKline. KAT has received funding to her institution from the Coalition for Epidemic Preparedness Innovations for vaccine safety studies. All other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Existing evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood., Methods: Urine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples)., Results: Most phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58-60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10-0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios were observed., Conclusion: Metabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Type-H capillary endothelial cells control bone formation during embryogenesis and postnatal growth but few signalling mechanisms underpinning this influence have been characterised. Here, we identify a highly expressed type-H endothelial cell protein, Clec14a, and explore its role in coordinating osteoblast activity. Expression of Clec14a and its ligand, Mmrn2 are high in murine type-H endothelial cells but absent from osteoblasts. Clec14a -/- mice have premature condensation of the type-H vasculature and expanded distribution of osteoblasts and bone matrix, increased long-bone length and bone density indicative of accelerated skeletal development, and enhanced osteoblast maturation. Antibody-mediated blockade of the Clec14a-Mmrn2 interaction recapitulates the Clec14a -/- phenotype. Endothelial cell expression of Clec14a regulates osteoblast maturation and mineralisation activity during postnatal bone development in mice. This finding underscores the importance of type-H capillary control of osteoblast activity in bone formation and identifies a novel mechanism that mediates this vital cellular crosstalk., (© 2024. The Author(s).)

Background: The recent International Study Group for Pancreatic Surgery (ISGPS) risk classification for postoperative pancreatic fistula (grade B/C) was developed based on data from open and mixed minimally invasive pancreatoduodenectomy. The ISGPS risk classification model has not been validated specifically for POPF after robotic pancreatoduodenectomy (RPD)., Methods: We calculated the rate of POPF (ISGPS 2016 definition, grade B/C) by analyzing consecutive patients after RPD by surgeons after their learning curves (80 RPDs per surgeon). The validation of the ISGPS 4-tier and the simplified 3-tier risk classification was conducted using the area under the receiver operating curve (AUC)., Results: From 2019 to 2023, 187 patients after RPD were included. Neither the ISGPS 4-tier nor the simplified 3-tier classification model showed robust discrimination (AUC: 0.696 and 0.685, respectively). Moreover, both risk classifications failed to differentiate the rates of POPF and major complications among subgroups. Multivariate analysis suggested that soft pancreatic texture and pancreatic duct ≤ 2 mm were independent risk factors for POPF after RPD. After adjusting the duct size's cutoff from 3 to 2 mm, the revised 4-tier "2 mm" classification model showed no significant difference between risk categories B and C (6.7% vs. 9.4%, P = 0.063). The revised 3-tier "2 mm" classification model stratified patients into A (n = 54), B (n = 68), and C (n = 65) groups, with corresponding POPF rates of 0.0%, 8.8%, and 23.1% (P < 0.001), and major complication rates of 5.6, 14.7, and 24.6% (P = 0.014), respectively. Compared to the simplified 3-tier classification model, the revised 3-tier "2 mm" classification model showed improved discrimination (AUC: 0.753 vs. 0.685, P = 0.034) and clinical utility., Conclusions: The current ISGPS 4-tier and the simplified 3-tier classification models lacked sufficient discrimination in patients after RPD. We propose a revised 3-tier "2 mm" risk classification model for RPD with a robust discrimination, which requires further international validation with prospectively obtained data., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Exposure to military burn pit smoke during deployment is associated with different respiratory and non-respiratory diseases. However, information linking smoke exposure to human pulmonary health is lacking. This study examined the effects of simulated burn pit smoke condensates on human airway epithelial cells (HAECs) from twelve donors (smokers/non-smokers, biological female/male) cultured at an air-liquid interface and exposed to condensates from three simulated burn pit waste materials (cardboard, plywood, and plastic) incinerated at two combustion conditions: smoldering and flaming. Cellular gene expression was analyzed using bulk RNA sequencing, and basolateral media cytokine levels were assessed using multiplex immunoassay., Results: Flaming smoke condensates caused more significant differentially expressed genes (DEGs) with plywood flaming smoke being the most potent in altering gene expression and modulating cytokine release. Cardboard and plywood flaming condensates primarily activated detoxification pathways, whereas plastic flaming affected genes related to anti-microbial and inflammatory responses. Correlation analysis between smoke condensate chemicals and gene expression to understand the underlying mechanism revealed crucial role of oxygenated polycyclic aromatic hydrocarbons (PAHs) and aluminum, molybdenum, and silicon elements; IL6 expression was positively correlated with most PAHs. Stratification of data based on HAEC donor demographics suggests that these affect gene expression changes. Enrichment analysis indicated similarity with several deployment-related presumptive and reported diseases, including asthma, emphysema, and cancer of different organs., Conclusions: This study highlights that simulated burn pit smoke exposure of HAECs causes gene expression changes indicative of deployment-related diseases with more pronounced effects seen in smokers and females. Future studies are needed to further characterize how sex and smoking status affect deployment-related diseases., (© 2024. The Author(s).)

While highly effective at killing Gram-positive bacteria, auranofin lacks significant activity against Gram-negative species for reasons that largely remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the low susceptibility of the Gram-negative model organism Escherichia coli to auranofin when compared to the Gram-positive model organism Bacillus subtilis . The proteome response of E. coli exposed to auranofin suggests a combination of inactivation of thiol-containing enzymes and the induction of systemic oxidative stress. Susceptibility tests in E. coli mutants lacking proteins upregulated upon auranofin treatment suggested that none of them are directly involved in E. coli 's high tolerance to auranofin. E. coli cells lacking the efflux pump component TolC were more sensitive to auranofin treatment, but not to an extent that would fully explain the observed difference in susceptibility of Gram-positive and Gram-negative organisms. We thus tested whether E. coli 's thioredoxin reductase (TrxB) is inherently less sensitive to auranofin than TrxB from B. subtilis , which was not the case. However, E. coli strains lacking the low-molecular-weight thiol glutathione, but not glutathione reductase, showed a high susceptibility to auranofin. Bacterial cells expressing the genetically encoded redox probe roGFP2 allowed us to observe the oxidation of cellular protein thiols in situ . Based on our findings, we hypothesize that auranofin leads to a global disturbance in the cellular thiol redox homeostasis in bacteria, but Gram-negative bacteria are inherently more resistant due to the presence of drug export systems and high cellular concentrations of glutathione.IMPORTANCEAuranofin is an FDA-approved drug for the treatment of rheumatoid arthritis. However, it has also high antibacterial activity, in particular against Gram-positive organisms. In the current antibiotics crisis, this would make it an ideal candidate for drug repurposing. However, its much lower activity against Gram-negative organisms prevents its broad-spectrum application. Here we show that, on the level of the presumed target, there is no difference in susceptibility between Gram-negative and Gram-positive species: thioredoxin reductases from both Escherichia coli and Bacillus subtilis are equally inhibited by auranofin. In both species, auranofin treatment leads to oxidative protein modification on a systemic level, as monitored by proteomics and the genetically encoded redox probe roGFP2. The single largest contributor to E. coli 's relative resistance to auranofin seems to be the low-molecular-weight thiol glutathione, which is absent in B. subtilis and other Gram-positive species.

We present a plasmonics-enhanced spikey nanorattle-based biosensor for direct surface-enhanced Raman scattering (SERS) detection of mRNA cancer biomarkers. Early detection of cancers such as head and neck squamous cell carcinoma (HNSCC) is critical for improving patient outcomes in regions with limited access to traditional diagnostic methods. Our method targets Keratin 14 (KRT14), a promising diagnostic mRNA biomarker for HNSCC, using a sandwich hybridization approach with magnetic beads and SERS spikey nanorattles (SpNR). We synthesized SpNR with a core-gap-shell structure to enhance SERS signals, achieving a limit of detection of 90 femtomolar. A pilot study using clinical samples demonstrated the efficacy of our biosensor in distinguishing between tissue with positive or negative diagnosis for HNSCC, highlighting its potential for rapid and sensitive cancer diagnostics in low-resource settings. This plasmonic assay offers a promising avenue for portable and high-specificity detection of nucleic acid biomarkers, with implications for early cancer detection and improved patient care, especially in middle and low-resource settings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Introduction: An error grid compares measured versus reference glucose concentrations to assign clinical risk values to observed errors. Widely used error grids for blood glucose monitors (BGMs) have limited value because they do not also reflect clinical accuracy of continuous glucose monitors (CGMs)., Methods: Diabetes Technology Society (DTS) convened 89 international experts in glucose monitoring to (1) smooth the borders of the Surveillance Error Grid (SEG) zones and create a user-friendly tool-the DTS Error Grid; (2) define five risk zones of clinical point accuracy (A-E) to be identical for BGMs and CGMs; (3) determine a relationship between DTS Error Grid percent in Zone A and mean absolute relative difference (MARD) from analyzing 22 BGM and nine CGM accuracy studies; and (4) create trend risk categories (1-5) for CGM trend accuracy., Results: The DTS Error Grid for point accuracy contains five risk zones (A-E) with straight-line borders that can be applied to both BGM and CGM accuracy data. In a data set combining point accuracy data from 18 BGMs, 2.6% of total data pairs equally moved from Zones A to B and vice versa (SEG compared with DTS Error Grid). For every 1% increase in percent data in Zone A, the MARD decreased by approximately 0.33%. We also created a DTS Trend Accuracy Matrix with five trend risk categories (1-5) for CGM-reported trend indicators compared with reference trends calculated from reference glucose., Conclusion: The DTS Error Grid combines contemporary clinician input regarding clinical point accuracy for BGMs and CGMs. The DTS Trend Accuracy Matrix assesses accuracy of CGM trend indicators., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.C.K. is a consultant for Afon, Lifecare, Novo, Samsung, embecta, Glucotrack, SynchNeuro, and Thirdwayv. G.F. is CEO of IfDT. G.F./IfDT has/have received research support, speakers’ honoraria or consulting fees in the last three years from Abbott, Ascensia, Berlin Chemie, Boydsense, Dexcom, Glucoset, i-SENS, Lilly, Menarini, Novo Nordisk, Perfood, Pharmasens, Roche, Sinocare, Terumo, Ypsomed. S.P. is an employee of IfDT. B.P.K. declares patent royalties handled by UVA from: DexCom, J&J, Novo Nordisk, and Sanofi; and research support handled by UVA: Dexcom, Novo Nordisk, Tandem Diabetes Care. D.K. has received research support from Abbott Diabetes Care. M.S.D.A. is currently receiving in kind support (CGM devices) from Dexcom Inc for an investigator-initiated clinical study. K.D. receives research funding from Dexcom, Abbott, Sanofi, Viacyte, Insulet, consulting fees from Eli Lilly, Dexcom, Insulet, Oppenheimer, Elsevier, honoraria from Academy for Continued Healthcare Learning, Med Learning Group, Medscape, Impact Education, and royalties from UptoDate. S.M. is in receipt of an investigator-initiated grant from DexCom, has received speaker fees from Sanofi & Lilly, is funded by a Wellcome Trust (223024/Z/21/Z), and is supported by the NIHR Imperial Biomedical Research Centre. A.S. was supported by the NSF Engineering Research Center for Precise Advanced Technologies and Health Systems for Underserved Populations (PATHS-UP) (#1648451). V.N.S. reports receiving personal fees from Sanofi, Embecta, NovoNordisk, Dexcom, Insulet, Tandem Diabetes Care, Ascensia Diabetes Care, Genomelink and LumosFit for consulting, advising or speaking. N.K.T. is a consultant for Roche Diagnostics / Roche Molecular Systems / Radiometer. UC Davis is a Roche Diagnostics Center of Excellence. N.K.T. has received speaking honoraria for Roche Diagnostics, Nova Biomedical, Thermo Fisher, and Radiometer. N.K.T. is also Chair-Elect for the Association for Diagnostic and Laboratory Medicine (ADLM) Critical and Point-of-Care Testing Division, Co-Founder of the Machine Intelligene Learning Optimizer (MILO), Inc, and a member of the International Federation for Clinical Chemistry (IFCC) continuous glucose monitoring workgroup. T.T. is a consultant for Clinical ink. R.E.A. is a consultant for Clinical ink. D.T.A. has received speaker’s honoraria from Abbott, Ascensia Diabetes Care, Insulet, Lilly Diabetes, Mannkind, Novo Nordisk, and Xeris Pharmaceuticals. D.T.A. has received consulting fees from Ascensia Diabetes Care, Lilly Diabetes, and Senseonics. H.K.A. received research grants through University of Colorado from Dexcom, Tandem Diabetes, Medtronic, Mannkind, IM Therapeutics, IAFMS, and received honorarium through University of Colorado for consulting from Dexcom, Tandem Diabetes, and Medtronic. M.E.A.-S. has served on the advisory boards for Abbott, Medtronic, Insulet, VitalAire, Sanofi, Eli Lilly, and Dexcom; has received honoraria for speaking from Abbott, Eli Lilly, Medtronic, Novo Nordisk, Sanofi, VitalAire, and Eli Lilly; and received research support from Medtronic and Sanofi. T.S.B. has received research support from Abbott Rapid Diagnostics, Biolinq, Dexcom, Eli Lilly, Medtronic, Medtrum, Novo Nordisk, Sanofi, Senseonics, and vTv Therapeutics and consulting honoraria from Abbott Diabetes, Abbott Rapid Diagnostics, ACON, CeQur, HagarTech, Intuity Medical, Lifescan, Mannkind, Medtronic, Novo, Perspirion, Sanofi, Sequel Med Tech, and Ypsomed. M.B. currently participates on the Hospital Advisory board with Dexcom and has received research support from Dexcom. L.B. has received research/product support from Dexcom, Ypsomed, and Boehringer Ingelheim; speaker honoraria from Dexcom and Oviva; and participated in advisory boards of Dexcom, Novo Nordisk, Sanofi, Ypsomed, Oviva, and Roche Diabetes Care. Y.M.B. has received honoraria for lectures and scientific advisory from Roche and AstraZeneca in the past 12 months. J.E.B. is on the Speaker’s bureau for Insulet and on the Advisory Board for Cardinal Health and Lifescan. J.E.B. is a consultant for Embecta. J.E.B. receives research support from the Leona M. and Harry B. Helmsley Charitable Trust. E.C. is on the scientific advisory board for Novo Nordisk, Eli-Lilly, Adocia, Arecor, Proventionbio, Portal Insulin, and MannKind. D.C. was a Dexcom employee from August 2018 to May 2024. D.C. is a shareholder of Dexcom, Lilly, Abbott and Tandem. M.C. has received consulting fees from Glooko and research support from Dexcom and Abbott Diabetes Care. G.L.C. is a shareholder of BioTex, Inc., Basepair Biotechnologies Inc., Coordination Centric, Inc., and Shape Memory Medical, Inc. G.L.C. is supported by the NSF Engineering Research Center for Precise Advanced Technologies and Health Systems for Underserved Populations (PATHS-UP) (#1648451). K.K.D. has received honoraria, travel, or fees for advisory boards from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Eli Lilly, Abbott Diabetes, Menarini, and Sanofi in the last 12 months. J.E. receives federal funding from FDA, NIMHD, and NCATS and is a consultant for Sanofi. C.F. receives royalties from Dexcom and Novo Nordisk managed through her institution. G.A.F. is an advisor for 180 Life Sciences, 89bio, Adocia, Abbott, AdipoPharma, Aerami, Amolyt, Carthera, Catalyst, Cohen Global, CMC Magnetics, Diasome, Eleos, Entera Bio, Enterin, Glyscend, Hagar, Hogan Lovells, IM Therapeutics, Innoneo, Intarcia, Levicure, Lilly Asia Ventures, Lumos, Mars Symbioscience, Melior, metaLead Therapeutics, Microbiotix, MMD, Modular Medical, New Amsterdam, Northwestern, NuSirt, NuVox, Oramed, Pano, Pasithea, PhylloPharma, Pleiogenix, Recordati, Regor, Remodeless, Renaissance, RenovoRx, Rivus, RxMP, Sera Biopharma, Seraxis, Serpin, SFC Fluidics, Skinject, SROne, Stalicla, Surf Bio, TIXiMED, Veroscience, Verthermia, WaveBreak, Zealand Pharma, and Zucara. M.A.L.G. is a consultant for Abbott, Medtronic, Novonordisk, and Roche. R.J.G. received research support from Novo Nordisk, Dexcom and Eli Lilly and consulting fees/advisory fees from Abbott Diabetes Care, Aztra Zeneca, Bayer, Boehringer, Dexcom, Eli Lilly, Novo Nordisk, and Medtronic, outside of this work. R.J.G. is partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Numbers P30DK111024, K23DK123384, R03DK138255, and U2CD137135. A.M.G.-M. reports speaker fees from Novo Nordisk, Sanofi, Elli Lilly, Boehringer Ingelheim, Abbott, and Medtronic. L.H. is a consultant for a number of companies that are developing innovative solutions for the treatment of people with diabetes. N.H. reports Advisory Board member fees from Abbott Diabetes Care and Insulet as well as honoraria for lectures from Berlin-Chemie AG, Becton Dickenson, Sanofi Germany, Roche Diabetes Care, and Dexcom Germany. T.H. serves on the advisory board for Acella and Horizons Therapeutics (no financial compensation). S.H. has served on the advisory board for Tandem, Dexcom, and Medtronic, and received honoraria for nonpromotional educational and/or consultancy work from Abbott, Insulet, Dexcom, Roche, and Sanofi. P.G.J. is a shareholder of Pacific Diabetes Technologies Inc. and serves on the advisory board for Eli Lilly. P.G.J. received grant support from SFC Fluidics and research support from Eli Lilly and Dexcom. J.J. has received fees from lectures and or advisory boards from Abbott, Astra Zeneca, Boeringer Ingelheim, Eli Lilly, Medtronic, Nordic Infucare, Novo Nordisk, and Sanofi. S.R.J is a consultant for USV, Marico, Glenmark, Franco Indian, Twin Health, Biocon, and Zydus Lifesciences. S.R.J. received speaking honoraria from Abbott, Novo Nordisk, MSD, Sanofi, Boehringer Ingelheim, AstraZeneca, Lupin, Bayer Zydus, USV, DRL, Meyer Organics, Servier, Natco. R.A.L. is a consultant for Abbott Diabetes Care, Biolinq, Capillary Biomedical, Deep Valley Labs, Gluroo, PhysioLogic Devices, Portal Insulin, Sanofi, and Tidepool. R.A.L. has served on advisory boards for. ProventionBio and Lilly. R.A.L. receives research support through his institution from Insulet, Medtronic, Tandem, and Sinocare. L.A.L. has received research funding from, has provided CME on behalf of, and/or has acted as an advisor to Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Lexicon, Merck, Novo Nordisk, Pfizer, and Sanofi. M.L. has been a consultant or received honoraria from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Nordic InfuCare, and Novo Nordisk, and has received research grants from Eli Lilly and Novo Nordisk, all outside of the submitted work. J.K.M. is a member of advisory boards of Abbott Diabetes Care, Becton-Dickinson, Biomea Fusion, Eli Lilly, Embecta, Medtronic, NovoNordisk A/S, Roche Diabetes Care, Sanofi-Aventis, and Viatris and received speaker honoraria from A. Menarini Diagnostics, Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, Dexcom, Eli Lilly, Medtrust, MSD, NovoNordisk A/S, Roche Diabetes Care, Sanofi, Viatris, and Ypsomed. J.K.M. is a shareholder of decide Clinical Software GmbH and elyte Diagnostics. A.M. reports speaker fees from Novo Nordisk. M.M. has an existing research & development relationship with Scientific Bioprocessing, Inc and has been a consultant for Abbott. S.-J.M. is a consultant for Abbott, Curestream, Daewoong, EOFlow, G2e, Huons, iSense, Medtronic, Novo Nordisk, and Sanofi. D.N.O. has served on advisory boards for Abbott Laboratories, Medtronic, Merck Sharp & Dohme, Novo Nordisk, Roche, and Sanofi; received research support from Medtronic, Novo Nordisk, Roche, Eli Lilly and Company, and Sanofi; and received travel support from Novo Nordisk and Merck Sharp & Dohme. F.J.P. has received research support (to Emory University) from Dexcom, Insulet, Novo Nordisk, Tandem, and Ideal Medical Technologies, and has received consulting fees from Dexcom. A.L.P. is on the advisory board of Medscape, Vertex, and Lilly; receives research support from Insulin and Abbott; and has stock options in Omada Health. R.P.-B. receives grant support from Novo Nordisk, Lexicon Pharmaceuticals, and Medtronic and received consulting fees from Bayer, Lexicon Pharmaceuticals, Novo Nordisk, and Roche. C.M.R. has received honoraria and/or grant support from AstraZeneca, Dexcom, Fresenius, and Vifor. D.B.S. is supported by the Intramural Research Program of the National Institutes of Health. S.S. was a Novo Nordisk employee from 2022-2023. S.S. has served as advisor for Novo Nordisk and has received speaker fees from Novo Nordisk and Nordic Infucare within the past three years. G.D.S’s employer, nonprofit International Diabetes Center, HealthPartners Institute, has received educational grant funds from Abbott Diabetes Care, Medscape, and Sanofi-Aventis Groupe. G.D.S receives no personal income/honorarium from these activities. K.S. received grant supports from Arkray, Terumo, and Dexcom. E.K.S. is partly supported by the VA Merit Award (1I01CX001825) from the US Department of Veterans Affairs Clinical Sciences Research and has received unrestricted research support from Dexcom and Tandem Diabetes (to Baltimore VA Medical Center and to University of Maryland) for the conduction of clinical trials. N.L.S. received funding from Novo Nordisk for an investigator-initiated research grant unrelated to the current project. G.E.U. is partly supported by research grants from National Institutes of Health (NIH/NATS UL 3UL1TR002378-05S2) from the Clinical and Translational Science Award program, and from National Institutes of Health and National Center for Research Resources (NIH/NIDDK 2P30DK111024-06). G.E.U. has received research support (to Emory University) from Abbott, Bayer, and Dexcom; and has participated in advisory boards for Dexcom and GlyCare. E.W. has received consulting fees from Abbott Diabetes Care, Ascensia, Bayer, Boehringer, Ingelheim, Embecta, GlaxoSmithKline, Lilly, Medtronic, Renalytix, and Sanofi. E.W. has received honoraria from Abbott Diabetes Care, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Lilly, Medtronic, Renalytix, and Sanofi. E.W. is on the Speakers’ Bureau from Abbott Diabetes Care, Bayer, Boehringer, Ingelheim, GlaxoSmithKline, Lilly, Renalytix, and Sanofi. M.Z. is a consultant for DexCom, Inc. M.A.K. is Chief Medical Officer of QuesGen, Inc. C.T., C.L., B.V.H., J.S.K., W.A.L., S.Y.R., J.J.S., K.W., C.W., K.R., C.N.H., A.T.A., A.A., R.R.B., E.M.B., J.G.C., K.Y.C., A.D., N.E., S.K.K., U.M., N.M., C.M., J.H.N., A.P., P.R., S.M.S., B.S., M.V., H.W.V., J.W., A.H.B.W., and S.Y. have nothing to disclose.

Chronic musculoskeletal pain (CMP) is highly prevalent, frequently associated with negative health outcomes, and disproportionately impacts Black Americans. Perceived racial and ethnic discrimination has emerged as a factor that may influence the experience of chronic pain in this population. Identifying modifiable psychosocial factors that influence the link between perceived discrimination and pain and that can be directly targeted in treatment is vital to reducing the disproportionate burden of CMP among Black individuals. The present study examines the moderating role of five risk factors (i.e., pain avoidance, pain fusion, experiential avoidance, pain catastrophizing, and pain anxiety) on the relationship between perceived discrimination and pain outcomes (i.e., pain intensity and interference) in a sample of 401 Black adults with CMP. We recruited 401 Black individuals (M age = 35.98, 51.9% female) with self-reported CMP and assessed their self-reported perceived discrimination, pain intensity, pain interference, and pain-related psychosocial risk factors. Results indicated that higher scores on each of the psychosocial risk factors (i.e., pain avoidance, pain fusion, experiential avoidance, pain catastrophizing, and pain anxiety) were significantly associated with greater pain intensity and pain interference (all ps < 0.01). Further, pain avoidance (B = 0.12, p = .006), pain fusion (B = 0.13, p = .002), and pain anxiety (B = 0.13, p = .002) each significantly moderated the relation between perceived discrimination and pain intensity. Greater perceived discrimination was associated with greater pain intensity at higher levels of avoidance and fusion, and was associated with less pain intensity at lower levels of avoidance and pain anxiety. In interaction models predicting pain interference, both pain fusion (B = 0.14, p = .001) and pain anxiety (B = 0.10, p = .01) significantly moderated the relation between perceived discrimination and pain interference. Perceived discrimination was associated with greater pain interference at higher levels of pain fusion and pain anxiety, and was not associated with pain interference at lower levels of pain fusion and pain anxiety. The present findings provide important insights into psychosocial risk factors that moderate the link between perceived discrimination and pain outcomes, providing important clinical implications for the treatment of Black adults with chronic musculoskeletal pain., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A thorough evaluation of the quality, reproducibility, and variability of bottom-up proteomics data is necessary at every stage of a workflow, from planning to analysis. We share vignettes applying adaptable quality control (QC) measures to assess sample preparation, system function, and quantitative analysis. System suitability samples are repeatedly measured longitudinally with targeted methods, and we share examples where they are used on three instrument platforms to identify severe system failures and track function over months to years. Internal QCs incorporated at the protein and peptide levels allow our team to assess sample preparation issues and to differentiate system failures from sample-specific issues. External QC samples prepared alongside our experimental samples are used to verify the consistency and quantitative potential of our results during batch correction and normalization before assessing biological phenotypes. We combine these controls with rapid analysis (Skyline), longitudinal QC metrics (AutoQC), and server-based data deposition (PanoramaWeb). We propose that this integrated approach to QC is a useful starting point for groups to facilitate rapid quality control assessment to ensure that valuable instrument time is used to collect the best quality data possible. Data are available on Panorama Public and ProteomeXchange under the identifier PXD051318.

The simulation of chemical reactions is an anticipated application of quantum computers. Using a Diels-Alder reaction as a test case, in this study we explore the potential applications of quantum algorithms and hardware in investigating chemical reactions. Our specific goal is to calculate the activation barrier of a reaction between ethylene and cyclopentadiene forming a transition state. To achieve this goal, we use quantum algorithms for near-term quantum hardware (entanglement forging and quantum subspace expansion) and classical post-processing (many-body perturbation theory) in concert. We conduct simulations on IBM quantum hardware using up to 8 qubits, and compute accurate activation barrier in the reaction between cyclopentadiene and ethylene by accounting for both static and dynamic electronic correlation. This work illustrates a hybrid quantum-classical computational workflow to study chemical reactions on near-term quantum devices, showcasing the potential for performing quantum chemistry simulations on quantum hardware to predict activation barriers in agreement with those predicted by CASCI.

Existing maze apparatuses used in rodents often exclusively assess spatial discriminability as a means to evaluate learning impairments. Spatial learning in such paradigms is reportedly spared by moderate prenatal alcohol exposure in rats, suggesting that spatial reinforcement alone is insufficient to delineate executive dysfunction, which consistently manifests in humans prenatally-exposed to alcohol. To address this, we designed a single-session continuous performance task in the T-maze apparatus that requires rats to discriminate within and between simultaneously-presented spatial (left or right) and tactile (sandpaper or smooth) stimuli for food reinforcement across four sequential discrimination stages: simple discrimination, intradimensional reversal 1, extradimensional shift, and intradimensional reversal 2. This design incorporates elements of working memory, attention, and goal-seeking behavior which collectively contribute to the executive function construct. Here, we found that rats prenatally-exposed to alcohol performed worse in both the tactile intradimensional reversal and extradimensional shift; alternatively, rats prenatally-exposed to alcohol acquired the extradimensional shift faster when shifting from the tactile to spatial dimension. In line with previous work, moderate prenatal alcohol exposure spared specifically spatial discrimination in this paradigm. However, when tactile stimuli were mapped into the spatial dimension, rats prenatally-exposed to alcohol required more trials to discriminate between the dimensions. We demonstrate that tactile stimuli can be operantly employed in a continuous performance T-maze task to detect discriminatory learning impairments in rats exposed to moderate prenatal alcohol. The current paradigm may be useful for assessing features of executive dysfunction in rodent models of fetal alcohol spectrum disorders., (Published by Elsevier B.V.)

Therapeutic development for skeletal muscle diseases is challenged by a lack of ex vivo models that recapitulate human muscle physiology. Here, we engineered 3D human skeletal muscle tissue in the Biowire II platform that could be maintained and electrically stimulated long-term. Increasing differentiation time enhanced myotube formation, modulated myogenic gene expression, and increased twitch and tetanic forces. When we mimicked exercise training by applying chronic electrical stimulation, the "exercised" skeletal muscle tissues showed increased myotube size and a contractility profile, fatigue resistance, and gene expression changes comparable to in vivo models of exercise training. Additionally, tissues also responded with expected physiological changes to known pharmacological treatment. To our knowledge, this is the first evidence of a human engineered 3D skeletal muscle tissue that recapitulates in vivo models of exercise. By recapitulating key features of human skeletal muscle, we demonstrated that the Biowire II platform may be used by the pharmaceutical industry as a model for identifying and optimizing therapeutic drug candidates that modulate skeletal muscle function., (© 2024 Valo Health, Inc and Regeneron Pharmaceuticals, Inc. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Globally, illegal sport hunting can threaten prey populations when unregulated. Due to its covert nature, illegal sport hunting poses challenges for data collection, hindering efforts to understand the full extent of its impacts. We gathered social media data to analyze patterns of illegal sport hunting and wildlife depletion across Brazil. We collected data for 2 years (2018-2020) across 5 Facebook groups containing posts depicting pictures of illegal sport hunting events of native fauna. We described and mapped these hunting events by detailing the number of hunters involved, the number of species, the mean body mass of individuals, and the number and biomass of individuals hunted per unit area, stratified by Brazilian biome. We also examined the effects of defaunation on hunting yield and composition via regression models, rank-abundance curves, and spatial interpolation. We detected 2046 illegal sport hunting posts portraying the hunting of 4658 animals (∼29 t of undressed meat) across all 27 states and 6 natural biomes of Brazil. Of 157 native species targeted by hunters, 19 are currently threatened with extinction. We estimated that 1414 hunters extracted 3251 kg/million km 2 . Some areas exhibited more pronounced wildlife depletion, in particular the Atlantic Forest and Caatinga biomes. In these areas, there was a shift from large mammals and reptiles to small birds as the main targeted taxa, and biomass extracted per hunting event and mean body mass across all taxonomic groups were lower than in other areas. Our results highlight that illegal sport hunting adds to the pressures of subsistence hunting and the wild meat trade on Brazil's wildlife populations. Enhanced surveillance efforts are needed to reduce illegal sport hunting levels and to develop well-managed sustainable sport hunting programs. These can support wildlife conservation and offer incentives for local communities to oversee designated sport hunting areas., (© 2024 The Author(s). Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Background: Motion-sparing scoliosis surgeries such as the posterior dynamic distraction device (PDDD) are slowly increasing in use. However, there is limited clinical data documenting postoperative motion across the PDDD construct. With this cohort study, we aim to measure sagittal and coronal motion following PDDD. We hypothesize coronal and sagittal spinal motion will be partially preserved across the construct., Methods: Retrospective review of prospectively collected data. Preoperative and minimum 1-year postoperative coronal range of motion across the instrumented levels was compared. Available flexion/extension radiographs were evaluated postoperatively to assess sagittal arc of motion. Radiographs from latest follow-up were used., Results: At a mean of 1.9 years (1 to 5 y), flexibility radiographs were available on 29 patients treated with PDDD (17 thoracic, 12 lumbar). Mean age at surgery was 16 years (12 to 25). Postoperative coronal arc of motion in PDDD patients was 11 degrees (3 to 19 degrees) in the thoracic spine and 10 degrees (0 to 28 degrees) in the lumbar spine. Compared with preoperative motion, the thoracic arc of motion was maintained by 33% (35 to 11 degrees) and lumbar motion was maintained by 30% (34 to 10 degrees). Flexion-extension radiographs were available on 7 patients. Sagittal arc for the upper instrumented vertebral end plate to the lower instrumented vertebral endplate of the cohort was 10 degrees in the thoracic spine (6 to 18) and 14 degrees in the lumbar spine (5 to 21). Sagittal measurements for the changes in the arc of the upper and lower screws on the construct were 4 degrees in the thoracic group (2 to 8) and 9 degrees in the lumbar group (2 to 17). By latest follow-up 11 patients (38%) underwent reoperation, with most cases due to implant breakage (N=4, 14%), extender misalignment (N=2, 7%), and screw misplacement (N=2, 7%)., Conclusion: At mean 1.9 years postoperatively, PDDD preserves measurable spinal motion over the construct both in the coronal and the sagittal plane without evidence for autofusion. Coronal arc of motion averages 10 to 12 degrees and sagittal arc of motion ranged from 4 to 14 degrees, although this varies by patient. This study confirms that PDDD for pediatric scoliosis preserves a measurable degree of postoperative flexibility both in the sagittal and coronal planes., Level of Evidence: Level II-therapeutic study., Competing Interests: A.N.L. is a consultant for ZimVie, Orthopediatrics, DePuy Synthes, Medtronic, and Pacira with all funds directed to Mayo Clinic. A.N.L. and Mayo Clinic receive royalties from Globus. T.A.M. is a consultant to Medtronic with all funds directed to Mayo Clinic. Mayo Clinic has received research funding from Orthopediatrics and Medtronic. M.A. is a consultant for Orthopediatrics and receives royalties from OrthoPediatrics. R.E.-H. has received grants/research support from Depuy Synthes, Medtronic, Orthopediatrics, and ZimVie. R.E.-H. is a consultant for Depuy Synthes, Medtronic, and Orthopediatrics. R.E.-H. is a shareholder for Orthopediatrics, and is on the advisory board or panel for Orthopediatrics, Scoliosis Research Society, and Pediatric Spine Foundation. G.H. is a consultant for Orthopediatrics. Sanford Health has received research funding from Orthopediatrics. The remaining authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Tesamorelin is the only FDA-approved therapy to treat abdominal fat accumulation in people with HIV (PWH). Phase III clinical trials were conducted prior to the introduction of integrase inhibitors (INSTIs), which are now a mainstay of HIV antiretroviral therapy., Design: We leveraged a randomized double-blind trial of 61 PWH and metabolic dysfunction-associated steatotic liver disease to evaluate the efficacy and safety of tesamorelin 2 mg once daily vs. identical placebo among participants on INSTI-based regimens at baseline., Methods: In the parent clinical trial, visceral fat cross-sectional area, hepatic fat fraction, and trunk-to-appendicular fat ratio were quantified using magnetic resonance imaging, proton magnetic resonance spectroscopy, and dual-energy x-ray absorptiometry, respectively, at baseline and 12 months. Metabolic and safety outcomes were compared between treatment arms., Results: Among 38 participants on INSTI-based regimens at baseline, 15 individuals on tesamorelin and 16 individuals on placebo completed the 12-month study. Tesamorelin led to significant declines in visceral fat (median [interquartile range]: -25 [-93, -2] vs. 14 [3, 41] cm 2 , P  = 0.001), hepatic fat (-4.2% [-12.3%, -2.7%] vs. -0.5% [-3.9%, 2.7%], P  = 0.01), and trunk-to-appendicular fat ratio (-0.1 [-0.3, 0.0] vs. 0.0 [-0.1, 0.1], P  = 0.03). Tesamorelin was well tolerated with a similar frequency of adverse events, including hyperglycemia, between groups., Conclusions: The current analysis provides the first dedicated data on the efficacy and safety of tesamorelin among PWH on INSTI-based regimens. Despite the association of INSTI use with weight gain and adipose tissue dysfunction, tesamorelin had beneficial effects on body composition with no exacerbation of glycemic control., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The mental health of youth with chronic kidney disease (CKD) has been increasingly recognized as an area of clinical need. The development of mental health concerns is influenced by a range of physiological, psychological, and environmental factors. Some of these factors are common across child development, but some are more unique to youth with CKD. Mental health concerns are associated with increased risk for a range of poor medical outcomes (e.g., adherence, risk of transplant rejection) and quality of life concerns. In this educational review, we discuss the current evidence base regarding the development of mental health concerns in youth with CKD. The review covers multiple domains including mood and anxiety disorders, traumatic stress, and neurodevelopmental disorders. Estimated prevalence and hypothesized risk factors are outlined, and the potential impact of mental health on medical care and functional outcomes are reviewed. Finally, we introduce options for intervention to support positive mental health and offer recommendations for building access to mental health care and improving the mental health education/training of medical professionals., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Objectives: The aim is to assess the level of stigmatization and knowledge of dementia among university students of medical, rehabilitation and social faculties in Poland. Possible correlates of these concepts and group differences are also investigated., Methods: We applied quantitative methods using an online questionnaire comprising sociodemographics, the Alzheimer's Disease Knowledge Scale, a vignette of a person with dementia and the modified Family Stigma in Alzheimer's Disease Scale., Results: Students had low levels of dementia knowledge and moderate levels of stigma. Medical science students had significantly better knowledge than the other groups but did not differ in their level of stigma. Relationships between the main variables were complex. Emotional and cognitive stigmatizing attributions were negatively correlated with knowledge about communication and behaviors of people with dementia. Better knowledge on causes and characteristics, as well as on risks and health promotion of the disease also triggered fewer negative attributions toward people with dementia., Conclusions: If health-related programs are to be effective, they should provide opportunities for the acquisition of relevant knowledge and skills that also address the stigmatization of people living with dementia. Well-established biomedical knowledge on dementia must be supplemented with a person-centered approach and proper communication skills.

Randomized clinical trials (RCTs) often suffer from a lack of representation from historically marginalized populations, and it is uncertain whether virtual RCTs (vRCTs) enhance representativeness or if elements of their consent and enrollment processes may instead contribute to underrepresentation of these groups. In this study, we aimed to identify disparities in enrollment demographics in a vRCT, the BE ACTIVE study, which recruited patients within a single health system. We discovered that the proportions of eligible patients who were randomized differed significantly by gender and race/ethnicity (men 1.2%, women 2.0%, P < .001; White 1.8%, Black 1.3%, Hispanic 0.7%, Asian 0.9%; P < .001), and compared with White patients, non-White patients were less likely to have a valid email address on file and were less likely to click on the email link to the study webpage and begin enrollment., Competing Interests: Conflict of Interest Dr. Volpp is a co-owner of a behavioral economics consulting firm, VAL Health. All other authors report no relevant conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: A previous prospective multicenter study revealed the change of the oncologists' chemotherapy advice due to the 70-Gene signature (GS) test result in half of the estrogen receptor-positive (ER+) invasive early-stage breast cancer patients with disputable chemotherapy indication. This resulted in less patients receiving chemotherapy. This study aims to complement these results by the 7-year oncological outcomes according to the 70-GS test result and the oncologists' pre-test advice., Methods: Patients operated for early-stage ER+ breast cancer with disputable chemotherapy indication, had been prospectively included between 2013 and 2015. Oncologists were asked whether they intended to administer adjuvant chemotherapy before deployment of the 70-GS test. Information on adjuvant systemic treatment and oncological outcome was obtained through active follow-up by data managers of the Netherlands Cancer Registry. The primary endpoint of this study was distant metastasis-free survival (DMFS) according to the genomic risk. Exploratory analyses were done to evaluate DMFS in relation to the oncologists' pre-test advice., Results: After a median follow-up of 7 years, distant metastases were diagnosed in 23 of the 606 patients (3.8%) and 36 (5.9%) patients had died. The DMFS rate for the 357 70-GS genomic low-risk patients was 94.2% (95% CI 91.2-96.2) and 89.1% for the 249 genomic high-risk patients (95% CI 84.3-92.4). Of the low-risk patients 3% had received chemotherapy compared to 80% of the high-risk patients. For the subgroups based on the pre-test oncologists' advice (no chemotherapy/chemotherapy/unsure) there were no clinically relevant differences in DMFS (89.8, 93.2 and 92.0%, respectively), while comparable proportions of patients had received chemotherapy., Conclusions: In patients with early-stage ER+ breast cancer with a disputable chemotherapy indication it is sensible to deploy the 70-GS to better select patients for adjuvant chemotherapy., (© 2024. The Author(s).)

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.

Introduction: Non-modular dual-mobility (DM) acetabular bearing constructs are becoming more popular due to their potential advantages for addressing range of motion (ROM) and stability. The objective of this post-market clinical study was to assess clinical outcomes, including patient satisfaction, pain and function, survivorship, and component positioning, in patients ⩾2 years after primary THA using non-modular DM acetabular components., Methods: This retrospective, multicentre study evaluated complications and functional outcomes in recipients of non-modular DM acetabular constructs at least 2 years post-THA. Our primary outcomes included the dislocation rate and mean Hip disability and Osteoarthritis Outcomes Score (HOOS). Secondary outcomes included radiographic measurements, patient satisfaction, Forgotten Joint Score (FJS), Harris Hip Score (HHS), and survivorship., Results: 316 eligible patients enrolled in this study across 3 sites, including 168 men (53%) and 148 women (47%). The cohort averaged 5.37 years post-THA (range 2.2-10.1 years) at the study visit. The mean FJS, HHS, and HOOS were good to excellent, with values of 82.3, 90.7, and 92.0, respectively. Patient satisfaction averaged 4.68, between "Very Good" (4) and "Excellent" (5). Minimal radiolucent lines (RLL) surrounded the acetabulum. More RLL surrounded the femur, but most lines were less than 1 mm (4.7% of the study population). There were few adverse events (4 events, 1.3%). Three revisions were performed (0.9%), with one patient requiring removal of the acetabular cup., Discussion: The high mid- to long-term survivorship and low to no dislocation and reoperation rates indicate this acetabular DM device is a viable option for THA patients. The patient metrics reflect satisfaction, alleviated pain, and restored function with a low risk of adverse outcomes., Competing Interests: Declaration of conflicting interestsDr. David Scott reports work with Medacta international as a paid consultant, presenter/speaker, and research support. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Peanut allergy is among the most severe and common food allergies. The diagnosis has a significant impact on the quality of life for patients and their families. An effective management approach depends on accurate, safe, and easily implementable diagnostic methods. We previously developed a cell-based assay using Hoxb8 mast cells (Hoxb8 MCs) aimed at improving clinical allergy diagnosis. In this study, we assessed its diagnostic performance by measuring blinded sera from a prospectively enrolled and pre-validated peanut allergy cohort., Methods: Hoxb8 MCs were passively sensitized with sera from peanut-allergic and peanut tolerant children and adolescents (n = 112). Degranulation of Hoxb8 MCs was quantified upon stimulation with dose-titrated peanut extract by means of flow cytometry, using CD107a as activation marker. The results from the Hoxb8 mast cell activation test (Hoxb8 MAT) were compared to established diagnostic assays such as the skin prick test (SPT), specific IgE (sIgE) levels, and the basophil activation test (BAT). Additionally, serum samples from BAT nonresponders were assessed with the Hoxb8 MAT., Results: Hoxb8 MAT displayed a robust dose-dependent activation to peanut extract, with a cutoff value of ≤5.2% CD107a positive cells. The diagnostic accuracy was highest at allergen concentrations ≥100 ng/mL, with an area under the receiver operating characteristic curve (AUROC) of 0.97, 93% sensitivity, and 96% specificity, outperforming traditional SPT and sIgE tests. When compared to BAT, Hoxb8 MAT exhibited comparable diagnostic efficacy. Moreover, sera from BAT nonresponders were accurately classified into allergics and nonallergics by the Hoxb8 MAT., Conclusions: The Hoxb8 MAT demonstrated a very good diagnostic precision in patients prospectively assessed for peanut allergy comparable to the fresh whole blood-based BAT. Additionally, it demonstrated its value for accurate classification of BAT nonresponders into allergic and nonallergic individuals. Further investigations into its utility in the routine clinical setting are warranted., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time., Purpose: The purpose of this review is to describe important considerations with local antimicrobial therapies such as locks, beads, and cement for adjunctive infection management or prevention., Summary: Local delivery of antimicrobials with locks, beads, and cement has been used for infection management with retained devices in an effort to improve clinical success. However, their use has been controversial due to conflicting clinical data and logistical issues. Antimicrobial lock therapy (ALT) has been used for both adjunctive treatment and prevention of catheter-related bloodstream infections for certain pathogens and based on patient-specific scenarios. ALT has been a controversial method for sterilizing the catheter lumen by delivering high concentrations of antibiotics with or without heparin into the catheter for prolonged durations. Studies differ regarding the selection and concentrations of antibiotics, dwell duration, presence of heparin in the ALT, clinical outcomes/definitions, and use for prevention or treatment of catheter-related bloodstream infections. Antibiotic beads and cement have been used for various surgical procedures but are predominately considered in orthopedic surgeries. Despite the widespread use of the antibiotic-loaded bone cement in orthopedics, studies differ regarding the selection and concentrations of antibiotics, clinical outcomes/definitions, and use for prevention or treatment of infections., Conclusion: Although antimicrobial locks, beads, and cement are commonly used for adjunctive treatment or prevention of infections, more data are needed to support their use to provide clinical efficacy and safety with consistent antimicrobial selection and logistics., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Gram-negative bloodstream infections (GNBSIs) more commonly occur in children with comorbidities and are increasingly associated with antimicrobial resistance. There are few large studies of GNBSIs in children that relate the clinical presentation, pathogen characteristics, and outcomes., Methods: A 3-year prospective study of GNBSIs in children aged <18 years was conducted in 5 Australian children's hospitals between 2019 and 2021. The clinical characteristics, disease severity, and outcomes were recorded. Causative pathogens underwent antibiotic susceptibility testing and whole genome sequencing., Results: There were 931 GNBSI episodes involving 818 children. Median age was 3 years (interquartile range, 0.6-8.5). A total of 576/931 episodes (62%) were community onset, though 661/931 (71%) occurred in children with comorbidities and a central venous catheter was present in 558/931 (60%). Central venous catheter (145/931) and urinary tract (149/931) were the most common sources (16% each). One hundred of 931 (11%) children required intensive care unit admission and a further 11% (105/931) developed GNBSIs in intensive care unit. A total of 659/927 (71%) isolates were Enterobacterales, of which 22% (138/630) were third-generation cephalosporin resistant (3GCR). Extended spectrum beta-lactamase genes were confirmed in 65/138 (47%) 3GCR Enterobacterales. Most common extended spectrum beta-lactamase genes were blaCTX-M-15 (34/94, 36%) and blaSHV-12 (10/94, 11%). There were 48 deaths overall and 30-day in-hospital mortality was 3% (32/931). Infections with 3GCR Enterobacterales were independently associated with higher mortality (adjusted odds ratio, 3.2; 95% confidence interval, 1.6-6.4)., Conclusions: GNBSIs in children are frequently healthcare associated and affect children younger than age 5 years. Infections with 3GCR Enterobacterales were associated with worse outcomes. These findings will inform optimal management guidelines and help prioritize future antimicrobial clinical trials., Competing Interests: Potential conflicts of interest . D. L. P. reports research grants from Shionogi, Pfizer, Merck, bioMérieux, BioVersys, Gilead, and consultancies with AMR Action Fund, CARB-X, Innoviva, Pfizer, Merck, bioMérieux, Cepheid, Aurobac, Arrepath, Spero, Shionogi. P. N. A. H. reports research grants from Gilead, has served on advisory boards for OpGen, Merck, and Sandoz, and has received honoraria from OpGen, Sandoz, Pfizer, and BioMérieux. S. C. H. W. has received honoraria for participation in MSD expert forum for pneumococcal disease, which was paid to Children's Health Queensland. U. W. received travel and accommodation support for meeting attendances by Pfizer and Moderna. A. D. I. has received honoraria for lectures from BioMérieux and Gilead that were paid to the University of Queensland. L. J. S. is a recipient of grants from Swiss National Science Foundation, Swiss Personalized Health Network (SPHN), NHMRC, NIH, NOMIS Foundation, Doris and Thomas Ammann Foundation. L. J. S. is also on the advisory board for the Lancet Child Adolescent Health Journal. HC receives grants from NIH and NIAID and payment from Merck for participation in Molnupiravir clinical trial. H. C. receives payment as senior editor for Sanford Guide to Antimicrobial Therapy and holds stocks in Moderna and Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Many preoperative urine cultures are of low value and may even lead to patient harms. This study sought to understand practices around ordering preoperative urine cultures and prescribing antibiotic treatment., Design: Open-ended, semi-structured qualitative interviews., Setting: 5 Veterans Affairs hospitals., Participants: Interviews with 14 surgeons (9 surgeons, 5 surgical leaders), 7 infectious disease physicians, 8 surgical advanced practice providers (APPs), 1 surgical nurse manager, 3 infectious disease pharmacists, 1 hospitalist, and 1 lab manager., Methods: We interviewed participants using a qualitative semi-structured interview guide. Collected data was coded inductively and with the Dual Process Model (DPM) using MAXQDA software. Data in the "Testing Decision-Making" code was further reviewed using the concept of perceived risk as a sensitizing concept., Results: We identified themes relating to surgeons' concerns about de-implementing preoperative urine cultures to detect asymptomatic bacteriuria (ASB) in patients undergoing non-urological procedures: (1) anxiety and uncertainty surrounding missing infection signs spanned surgical specialties, (2) there were perceived risks of negative consequences associated with omitting urine cultures and treatment prior to specific procedure sites and types, and additionally, (3) participants suggested potential routes for adjusting these perceived risks to facilitate de-implementation acceptance. Notably, participants suggested that leadership support and peer engagement could help improve surgeon buy-in., Conclusions: Concerns about perceived risks sometimes outweigh the evidence against routine preoperative urine cultures to detect ASB. Evidence from trusted peers may improve openness to de-implementing preoperative urine cultures.

Background: Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated., Objective: To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years., Methods: We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. Spike and nucleocapsid seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework., Results: Blood was collected from 2,046 participants (median age: 6.6 years). The overall adjusted seroprevalence of spike-antibody was 92.1% (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence was similar across geographic remoteness index and socioeconomic quintiles. Nucleocapsid antibody seroprevalence increased with age while the point seroprevalence of the spike antibody seroprevalence decreased in the first year of life and then increased to 97.8 (95% Crl 96.1-99.2) by 12-15 years of age., Conclusion: Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia., Competing Interests: All authors have no financial interests/personal relationships that may be considered as potential competing interests with this study. Some authors have received institutional research grants and travel funding from the Australian Government, non-government or private organisations for other bodies of work. Dr Archana Koirala, Professor Kristine Macartney and Professor Nicholas Wood declare funding support from the Australian Government Department of Health and Aged Care (DoHAC) to the institution National Centre for Immunisation Research and Surveillance (NCIRS). Dr Archana Koirala has received a travel and accommodation grant to present and attend the World Society of Paediatric Infectious Diseases scientific meeting in 2023. Professor Kristine Macartney received payment as an expert witness for Australian Health Departments against proceedings against COVID-19 health regulations in 2021-2022. Professor Kristine Macartney declares institutional directed funding support from the WHO and GAVI the Vaccine Alliance, Welcome Trust and the Australian NHMR, to NCIRS and the University of Sydney; payment as an expert witness for Australian health departments against proceedings against COVID-19 health regulations in 2021-2022, payment less than USD $5,000 for international travel for expert speaking engagements, non-pharmaceutical company sources. Professor Nicholas Wood, Professor Britta S von Ungern-Sternberg and Dr Brendan McMullan declare funding from the National Health and Medical Research Council (NHMRC) grants. Professor Britta S von Ungern-Sternberg declared funding support from Stan Perron Charitable Foundation. Professor Helen S Marshall declares a research grant from Pfizer to Women’s and Children’s Health Network (WCHN), no personal remuneration, for meningococcal research. Professor Peter Richmond declares research grants from Merck Sharpe & Dohme, GlaxoSmithKline (GSK) directed at the Telethon Kids Institute (TKI), no personal remuneration, on RSV, pneumococcal disease, varicella, meningococcal research and a COVID-19 vaccine study to assess immunogenicity and safety of homologous or heterologous vaccine schedules. Professor Peter Richmond, Professor Helen S Marshall and Professor Nicholas Wood declare a research grant from the Australian Government Department of Health and Aged Care to WCHN, TKI and University of Sydney for a COVID-19 DNA vaccine clinical trial Ms Alissa McMinn declares funding support from Pfizer provided support for flights/accommodation to attend the Public Health Association Australia Communicable Diseases & Immunisation Conference in 2023. Dr Ushma Wadia declares funding from Pfizer for flights and accommodation to attend Meningococcal Disease Vaccine Education in 2023. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Koirala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Emergency Medical Services patients who survive overdose are at high risk for subsequent overdose and death. Programs that seek to link overdose survivors to harm reduction and treatment services are increasingly common, though they vary in design and measured effect. Public Health - Seattle & King County (PHSKC) used a continuous quality improvement (CQI) process to assess and improve a phone-based model for post-overdose outreach in King County, Washington., Methods: King County Emergency Medical Services (KC-EMS) health records are queried weekly to identify suspected opioid overdose and other drug-related encounters. Patients treated by KC-EMS that met outreach eligibility criteria were contacted by phone and offered referrals to local services. Three Plan-Do-Study-Act (PDSA) cycles were sequentially implemented to iteratively assess program indicators and implement program adaptations. The PDSA cycles varied in terms of eligibility criteria, outreach modality, and level of resources devoted to phone number searches. Program indicators and corresponding costs were measured for each phase and calculated per month, per eligible patient, and per patient referred to services., Results: During the initial call-based outreach pilot, the fewest number of patients met eligibility criteria (monthly average =39) and were referred to services (monthly average =2). In Phase Two, outreach shifted to automated texting and eligibility criteria expanded, resulting in an increase in the monthly average number of eligible patients (monthly average =137) and patients referred to services (monthly average =3). Phase Three adaptations expanded eligibility criteria further but limited outreach to patients with a phone number documented in their KC-EMS record, resulting in an average of 405 eligible patients per month and four patients that were referred to services. The costs per patient referred to services changed from $454 in Phase one to $589 in Phase Two to $279 in Phase Three., Conclusions: The PDSA process helped PHSKC's post-overdose outreach team identify adaptations to improve the efficiency of the post-overdose outreach program. The number of people referred to services was modest, reflecting the challenges of post-incident phone-based outreach. Our experience highlights the value of incorporating CQI processes in ongoing program operations and the need for a multi-pronged overdose prevention strategy.

Background: Communication is considered an inherent element of nearly every implementation strategy. Often it is seen as a means for imparting new information between stakeholders, representing a Transaction orientation to communication. From a Process orientation, communication is more than information-exchange and is acknowledged as being shaped by (and shaping) the individuals involved and their relationships with one another. As the field of Implementation Science (IS) works to strengthen theoretical integration, we encourage an interdisciplinary approach that engages communication theory to develop richer understanding of strategies and determinants of practice., Methods: We interviewed 28 evaluators, 12 implementors, and 12 administrators from 21 Enterprise-Wide Initiatives funded by the Department of Veteran Affairs Office of Rural Health. Semi-structured interviews focused on experiences with implementation and evaluation strategies. We analyzed the interviews using thematic analysis identifying a range of IS constructs. Then we deductively classified those segments based on a Transaction or Process orientation to communication., Results: We organized findings using the two IS constructs most commonly discussed in interviews: Collaboration and Leadership Buy-in. The majority of segments coded as Collaboration (n = 34, 74%) and Leadership Buy-in (n = 31, 70%) discussed communication from a Transaction orientation and referred to communication as synonymous with information exchange, which emphasizes the task over the relationships between the individuals performing the tasks. Conversely, when participants discussed Collaboration and Leadership Buy-in from a Process orientation, they acknowledged both constructs as the result of long-term efforts to develop positive relationships based on trust and respect, and emphasized the time costliness of such strategies. Our findings demonstrate that participants who discussed communication from a Process orientation recognized the nuance and complexity of interpersonal interactions, particularly in the context of IS., Conclusions: Efficient, reliable information exchange is a critical but often overemphasized element of implementation. Practitioners and researchers must recognize and incorporate the larger role of communication in IS. Two suggestions for engaging a Process orientation to communication are to: (a) use interview probes to learn how communication is enacted, and (b) use process-oriented communication theories to develop interventions and evaluation tools., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Advances in antibody technologies have resulted in the development of potent antibody-based therapeutics with proven clinical efficacy against infectious diseases. Several monoclonal antibodies (mAbs), mainly against viruses such as SARS-CoV-2, HIV-1, Ebola virus, influenza virus, and hepatitis B virus, are currently undergoing clinical testing or are already in use. Although these mAbs exhibit potent neutralizing activity that effectively blocks host cell infection, their antiviral activity results not only from Fab-mediated virus neutralization, but also from the protective effector functions mediated through the interaction of their Fc domains with Fcγ receptors (FcγRs) on effector leukocytes. Fc-FcγR interactions confer pleiotropic protective activities, including the clearance of opsonized virions and infected cells, as well as the induction of antiviral T-cell responses. However, excessive or inappropriate activation of specific FcγR pathways can lead to disease enhancement and exacerbated pathology, as seen in the context of dengue virus infections. A comprehensive understanding of the diversity of Fc effector functions during infection has guided the development of engineered antiviral antibodies optimized for maximal effector activity, as well as the design of targeted therapeutic approaches to prevent antibody-dependent enhancement of disease., (© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.)

Background: Invasive fungal disease (IFD) is a significant complication for children receiving treatment for leukaemia, contributing to morbidity and mortality. Recent regional paediatric epidemiological IFD data are lacking. Additionally uncertainty remains regarding the optimal prophylactic approach in this context., Methods: In a multi-centre Australian cohort study of children diagnosed with de novo acute leukaemia between 1st January 2017 and 30th June 2020, we characterised antifungal prophylaxis prescribing and IFD prevalence. Impact of antifungal prophylaxis was assessed using Kaplan Meier curves and Cox-proportional hazards regression adjusting for known IFD risk factors., Findings: A total of 434 children were included (47.2% female; median age 5.0 years, median follow-up 240 days). This cohort included 351 children with ALL (214 high-risk [HR-ALL]; 137 standard-risk [SR-ALL]), and 73 with AML. The prevalence of proven/probable IFD was 6.8% for AML, 14.0% for HR-ALL and 4.4% for SR-ALL. A mould was implicated as the causative pathogen in almost two thirds of cases. Antifungal prophylaxis was prescribed in 98.7% of chemotherapy cycles for AML, 56.7% for HR-ALL and 14.9% for SR-ALL. A mould-active agent was used in 77.4% of AML cycles and 21.2% of HR-ALL cycles. Mould-active prophylaxis was associated with a lower risk of IFD overall and increased IFD-free survival in AML., Interpretation: These data demonstrate the persistent high regional burden of IFD in children with HR-ALL, and the potential for mould-active prophylaxis to ameliorate this. Strategies to increase uptake of appropriate prophylaxis are required in this cohort., Funding: This study was supported by a Perth Children's Hospital Foundation grant (PCHF9973)., Competing Interests: All authors declare no conflicts of interest associated with this publication. MS has received honoraria from Gilead and F2G, outside of this work and participates on a Data Safety and Monitoring Board for Basilea, Pfizer, Roche and Merck. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd.)

Neutrophils orchestrate a coordinated attack on bacteria, combining phagocytosis with a potent cocktail of oxidants, including the highly toxic hypochlorous acid (HOCl), renowned for its deleterious effects on proteins. Here, we examined the occurrence of lipid N-chloramines in vivo, their biological activity, and their neutralization. Using a chemical probe for N-chloramines, we demonstrate their formation in the membranes of bacteria and monocytic cells exposed to physiologically relevant concentrations of HOCl. N-chlorinated model membranes composed of phosphatidylethanolamine, the major membrane lipid in Escherichia coli and an important component of eukaryotic membranes, exhibited oxidative activity towards the redox-sensitive protein roGFP2, suggesting a role for lipid N-chloramines in protein oxidation. Conversely, glutathione a cellular antioxidant neutralized lipid N-chloramines by removing the chlorine moiety. In line with that, N-chloramine stability was drastically decreased in bacterial cells compared to model membranes. We propose that lipid N-chloramines, like protein N-chloramines, are involved in inflammation and accelerate the host immune response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Vancomycin is a crucial last-resort antibiotic for tackling Gram-positive bacterial infections. However, its potency fails against the more difficult-to-treat Gram-negative bacteria (GNB). Vancomycin derivatives have shown promise as broad-spectrum antibacterials, but are still underexplored. Toward this, we present a novel strategy wherein we substitute the sugar moiety of vancomycin with a dipicolyl amine group, yielding VanNHdipi. This novel glycopeptide enhances its efficacy against vancomycin-resistant bacteria by up to 100-fold. A comprehensive approach involving microbiological assays, biochemical analyses, proteomics, and computational studies unraveled the impact of this design on biological activity. Our investigations reveal that VanNHdipi, like vancomycin, disrupts membrane-bound steps of cell wall synthesis inducing envelope stress, while also interfering with the structural integrity of the cytoplasmic membrane, setting it apart from vancomycin. Most noteworthy is its potency against critical GNB producing metallo-β-lactamases (MBLs). VanNHdipi effectively inactivates various MBLs with IC 50 in the range of 0.2-10 μM resulting in resensitization of MBL-producing bacteria to carbapenems. Molecular docking and molecular dynamics (MD) studies indicate that H-bonding interactions between the sugar moiety of the vancomycin derivative with the amino acids on the surface of NDM-1 facilitate enhanced binding affinity for the enzyme. This work expands the scope of vancomycin derivatives and offers a promising new avenue for combating antibiotic resistance., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Zinc finger (ZnF) domains appear in a pool of structural contexts and despite their small size achieve varying target specificities, covering single-stranded and double-stranded DNA and RNA as well as proteins. Combined with other RNA-binding domains, ZnFs enhance affinity and specificity of RNA-binding proteins (RBPs). The ZnF-containing immunoregulatory RBP Roquin initiates mRNA decay, thereby controlling the adaptive immune system. Its unique ROQ domain shape-specifically recognizes stem-looped cis-elements in mRNA 3'-untranslated regions (UTR). The N-terminus of Roquin contains a RING domain for protein-protein interactions and a ZnF, which was suggested to play an essential role in RNA decay by Roquin. The ZnF domain boundaries, its RNA motif preference and its interplay with the ROQ domain have remained elusive, also driven by the lack of high-resolution data of the challenging protein. We provide the solution structure of the Roquin-1 ZnF and use an RBNS-NMR pipeline to show that the ZnF recognizes AU-rich RNAs. We systematically refine the contributions of adenines in a poly(U)-background to specific complex formation. With the simultaneous binding of ROQ and ZnF to a natural target transcript of Roquin, our study for the first time suggests how Roquin integrates RNA shape and sequence features through the ROQ-ZnF tandem., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The amount of time available in a day is fixed, and consequently, sleep is often sacrificed for waking activities. For college students, daily activities, comprised of scheduled classes, work, study, social, and other extracurricular events, are major contributors to insufficient and poor-quality sleep. We investigated the impact of daily schedules on sleep-wake timing in 223 undergraduate students (age: 18-27 years, 37% females) from a United States university, who were monitored for ~30 days. Sleep-wake timing and daily recorded activities (attendance at academic, studying, exercise-based, and/or extracurricular activities) were captured by a twice-daily internet-based diary. Wrist-worn actigraphy was conducted to confirm sleep-wake timing. Linear mixed models were used to quantify associations between daily schedule and sleep-wake timing at between-person and within-person levels. Later scheduled start time predicted later sleep onset (between and within: p < .001), longer sleep duration on the previous night (within: p < .001), and later wake time (between and within: p < .001). Later schedule end time predicted later sleep onset (within: p < .001) and shorter sleep duration that night (within: p < .001). For every 1 hour that activities extended beyond 10 pm, sleep onset was delayed by 15 minutes at the within-person level and 40 minutes at the between-person level, and sleep duration was shortened by 6 and 23 minutes, respectively. Increased daily documented total activity time predicted earlier wake (between and within: p < .001), later sleep onset that night (within: p < .05), and shorter sleep duration (within: p < .001). These results indicate that daily schedules are an important factor in sleep timing and duration in college students. Clinical Trial: Multi-scale Modeling of Sleep Behaviors in Social Networks; URL: https://clinicaltrials.gov/study/NCT02846077; Registration:NCT02846077., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Objective: To use a practical approach to examining the use of Expert Recommendations for Implementing Change (ERIC) strategies by Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) dimensions for rural health innovations using annual reports on a diverse array of initiatives., Data Sources and Study Setting: The Veterans Affairs (VA) Office of Rural Health (ORH) funds initiatives designed to support the implementation and spread of innovations and evidence-based programs and practices to improve the health of rural Veterans. This study draws on the annual evaluation reports submitted for fiscal years 2020-2022 from 30 of these enterprise-wide initiatives (EWIs)., Study Design: Content analysis was guided by the RE-AIM framework conducted by the Center for the Evaluation of Enterprise-Wide Initiatives (CEEWI), a Quality Enhancement Research Initiative (QUERI)-ORH partnered evaluation initiative., Data Collection and Extraction Methods: CEEWI analysts conducted a content analysis of EWI annual evaluation reports submitted to ORH. Analysis included cataloguing reported implementation strategies by Reach, Adoption, Implementation, and Maintenance (RE-AIM) dimensions (i.e., identifying strategies that were used to support each dimension) and labeling strategies using ERIC taxonomy. Descriptive statistics were conducted to summarize data., Principal Findings: A total of 875 implementation strategies were catalogued in 73 reports. Across these strategies, 66 unique ERIC strategies were reported. EWIs applied an average of 12 implementation strategies (range 3-22). The top three ERIC clusters across all 3 years were Develop stakeholder relationships (21%), Use evaluative/iterative strategies (20%), and Train/educate stakeholders (19%). Most strategies were reported within the Implementation dimension. Strategy use among EWIs meeting the rurality benchmark were also compared., Conclusions: Combining the dimensions from the RE-AIM framework and the ERIC strategies allows for understanding the use of implementation strategies across each RE-AIM dimension. This analysis will support ORH efforts to spread and sustain rural health innovations and evidence-based programs and practices through targeted implementation strategies., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Toxicogenomics measures molecular features, such as transcripts, proteins, metabolites and epigenomic modifications, to understand and predict the toxicological effects of environmental and pharmaceutical exposures. Transcriptomics has become an integral tool in contemporary toxicology research owing to innovations in gene expression profiling that can provide mechanistic and quantitative information at scale. These data can be used to predict toxicological hazards through the use of transcriptomic biomarkers, network inference analyses, pattern-matching approaches and artificial intelligence. Furthermore, emerging approaches, such as high-throughput dose-response modelling, can leverage toxicogenomic data for human health protection even in the absence of predicting specific hazards. Finally, single-cell transcriptomics and multi-omics provide detailed insights into toxicological mechanisms. Here, we review the progress since the inception of toxicogenomics in applying transcriptomics towards toxicology testing and highlight advances that are transforming risk assessment., (© 2024. Springer Nature Limited.)

Background: Care management programs for chronic lung disease attempt to reduce hospitalizations, yet have not reliably achieved this goal. A key limitation of many programs is that they target patients with characteristics associated with hospitalization risk, but do not specifically modify the mechanisms that lead to hospitalization., Research Question: What are the common mechanisms underlying known patient-level risk characteristics leading to hospitalizations for acute exacerbations of chronic lung disease?, Study Design and Methods: We conducted a qualitative study of patients admitted to the University of Pennsylvania Health System with acute exacerbations of chronic lung disease between January and September 2019. We interviewed patients, their family caregivers, and their inpatient and outpatient clinicians about experiences leading up to the hospitalization. We analyzed the interview transcripts using triangulation and abductive analytic methods., Results: We conducted 69 interviews focused on the admission of 22 patients with a median age of 66 years (interquartile range, 60-70 years), of whom 16 patients (73%) were female and 14 patients (64%) were Black. We interviewed 22 patients, 14 caregivers, 19 inpatient clinicians, and 14 outpatient clinicians. We triangulated the available interview data for each patient admission and identified the underlying mechanisms of how several known patient characteristics associated with risk actually led to hospitalization. These mechanisms included limited capacity for home management of acute symptom changes, barriers to accessing care, chronic functional limitations, and comorbid behavioral health disorders. Importantly, many of the clinical, social, and behavioral mechanisms underlying hospitalizations were present for months or years before the symptoms that prompted inpatient care., Interpretation: Care management programs should be built to target specific clinical, social, and behavioral mechanisms that directly lead to hospitalization. Upstream interventions that reduce hospitalization risk are possible given that many contributory mechanisms are present for months or years before the onset of acute exacerbations.

Calcium (Ca 2+ ) functions as a universal signal messenger in eukaryotes but in bacteria, the physiological roles for Ca 2+ are limited. Here, we examine the role of Ca 2+ in Streptococcus pneumoniae during manganese (Mn 2+ ) intoxication. S. pneumoniae mntE mutants, lacking the Mn 2+ efflux transporter, exhibit impaired growth due to accumulation of Mn 2+ when exposed to elevated exogenous Mn 2+ . This Mn 2+ -sensitive growth defect is restored to wild-type growth level by exogenous Ca 2+ , in a Ca 2+ -dependent manner. Despite growth restoration of the mntE mutant to wild-type levels, cellular Mn 2+ remains elevated in this strain. Bacterial capsule production is also increased for the mntE mutant, resulting in reduced adherence capacity to surfaces and poor biofilm formation, which is consistent with it experiencing Mn 2+ intoxication. Ca 2+ presence did not significantly impact bacterial capsule production or biofilm formation. Further analysis of the cell morphology demonstrates that Ca 2+ contributes to cell division and reduces cell chain lengths. Together, these data describe the first role of Ca in S. pneumoniae that has potential implications in bacterial virulence since Ca affects cell division and likely Mn 2+ -associated cellular processes.

Results from studies investigating the association between maternal or child epilepsy, use of anticonvulsants in pregnancy, and childhood cancer are inconsistent and at times contradictory. Linking Danish national databases, we obtained epilepsy and childhood cancer diagnoses, and anticonvulsant use data. We estimated adjusted odds ratios of all or specific childhood cancers in relation to maternal or child epilepsy and anticonvulsant therapies using conditional logistic regression. Maternal epilepsy was positively associated with all childhood cancers in offspring, specifically, with acute lymphoblastic leukemia (Odds Ratio (OR) = 1.68, 95% Confidence Interval (CI) = 1.16, 2.43) and Wilms tumor (OR = 2.13, 95% CI = 0.97, 4.68). When considering maternal ever (lifetime) ingestion of anticonvulsants, a positive association was found with all cancers (OR = 1.14, 95% CI = 1.00, 1.30), and central nervous system tumors (CNS) (OR = 1.36, 95% CI = 1.04, 1.76) as well as neuroblastoma (OR = 1.76, 95% CI = 1.06, 2.90) among offspring. Maternal anticonvulsant use before or during the index pregnancy was related to CNS tumors in offspring (OR = 1.99, 95% CI = 0.99, 4.00)., (© 2024. Springer Nature B.V.)

Background and Objective: Systemic corticosteroids have a long history of use in the treatment of autoimmune and inflammatory diseases. Both efficacy and safety show large interindividual variability (IIV), suggesting that corticosteroids may have the potential for individualised dosing strategies to optimise therapy. This systematic review aims to provide an overview of current evidence on the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of systemic corticosteroids in patients with autoimmune and inflammatory diseases., Methods: A systematic literature search was conducted in PubMed and Embase for PK/PD studies of systemic corticosteroids in autoimmune and inflammatory diseases in humans published until December 2023. Studies were scored from 1 to 5 according to criteria for the levels of evidence, as inspired by the Oxford Centre for Evidence-Based Medicine., Results: Twelve studies (1981-2016) were included. The majority of these studies had a small sample size. The corticosteroids involved were prednisone, prednisolone, methylprednisolone and budesonide. Substantial IIV of corticosteroid PK was described in all studies. Evidence for a relationship between the PK of corticosteroids and efficacy was inconclusive and limited. However, there was some evidence for a relationship between the PK of prednisolone and the severity of Cushingoid features., Conclusion: There is insufficient evidence to draw firm conclusions on the potential associations between PK and clinical outcome of systemic corticosteroid treatment in autoimmune and inflammatory diseases. This is remarkable given the many decades that steroid drugs have been used in clinical care. Prospective research is recommended with robust and well-defined cohorts to fully quantify the PK/PD associations of corticosteroids., (© 2024. The Author(s).)

Multiple external stressors are known to have adverse impacts on health and development. Certain groups are more vulnerable and/or more likely to be exposed toenvironmental, psychological, and social stressors simultaneously. Yet, few studies have examined combined exposure to environmental toxicants and psychosocial stress. Here, we integrated environmental chemical exposure data collected using silicone wristbands and self-report social stressor data within the Brain and Early Experience (BEE) perinatal cohort to understand co-exposure to environmental chemicals and social stress. Silicone wristbands were worn for one week by mothers throughout central North Carolina who were 6 months postpartum (n = 97). Exposure to 110 environmental chemicals across eight chemical classes was quantified on silicone wristbands using gas chromatography mass spectrometry. Social stress was evaluated using eight established self-report questionnaires (e.g., Brief Symptom Inventory, Perceived Stress Scale), quantifying experiences such as race-related stress, economic strain, and relationship conflict. Hair cortisol levels were measured as an additional metric of stress. The chemical exposure landscape and associations among chemical exposure, demographic characteristics, and social stress were characterized through individual variable analyses, cluster and data reduction, and compiled scoring approaches to comprehensively evaluate chemical and social stress burdens. We found that chemicals contain co-occurring patterns largely based on chemical class, with phthalates representing the chemical class with highest exposure and polychlorinated biphenyls the lowest. Chemicals showed differential exposure across racial groups, with diethyl phthalate, triphenyl phosphate, and tris(3,5-dimethyl phenyl) phosphate at higher levels in Black participants compared with White participants. Integrating social stressor profiling with chemical exposure data identified one particularly vulnerable subset of participants in which high chemical exposure burden coincided with high experiences of racism and economic stress. These findings demonstrate co-occurring chemical and social stress, warranting further investigation to better understand how these combined stressors may contribute to disparities in maternal and child health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The study investigated maternal exposure to heavy metals from industrial sources during pregnancy as potential risk factors for childhood cancer., Methods: Cases ages 0-19 were identified from California Cancer Registry. Controls (20:1 ratio) were randomly selected from California Birth Registry, frequency-matched by birth year (1998-2016). We estimated maternal exposure to lead, nickel, and cobalt in ambient air from the Toxics Release Inventory. We examined "ever/never" and "high/low" exposures categorized by median exposure. Models were adjusted for maternal age, race/ethnicity, method of payment for prenatal care, neighborhood socioeconomic status, and urban/rural residence., Results: Among highly exposed persons, lead was associated with an increased teratoma risk (adjusted odds ratio [aOR]: 1.52; 95% confidence interval [CI]: 0.97, 2.37), whereas nickel was associated with an increased rhabdomyosarcoma risk (aOR: 1.45; 95% CI: 1.03, 2.04). Cobalt was associated with an increased glioma risk (aOR: 2.25; 95% CI: 1.39, 3.65) among ever-exposed persons. Inverse associations were found between Wilms tumor and nickel among the ever exposed and highly exposed (ever: aOR: 0.75; 95% CI: 0.59, 0.96; high: aOR: 0.64; 95% CI: 0.45, 0.93)., Conclusions: Findings suggest that air pollution from heavy metals released by industrial sources may elevate childhood cancer risk., Competing Interests: Heck, Chen, Van Deventer, Nianogo, Vinceti, Kang, Cockburn, and Federman have no relationships/conditions/circumstances that present potential conflict of interest., (Copyright © 2024 American College of Occupational and Environmental Medicine.)

Background and Objective: Inpatient subspecialty consultation is often medically necessary but in some cases may represent overuse. While pediatric consultation patterns have been described using observational data, qualitative methods may generate knowledge about contextual determinants of consultation behavior. Our objective was to understand how pediatric hospitalists make decisions about subspecialty consultation., Methods: This qualitative study took place at a large academic children's hospital as part of an explanatory sequential mixed-methods design (QUAN → qual). We conducted semistructured interviews with a purposive sample of previously identified high-consulting (top quartile) and low-consulting (bottom quartile) pediatric hospitalists. Interviews were conducted virtually, and audio recordings were transcribed. Two analysts coded transcripts using an integrated approach and established high interrater reliability (κ > 0.75). We organized findings using the Social Ecological Model., Results: Participants (n = 12) included high-(n = 6) and low-(n = 6) consulting hospitalists. Our respondents identified considerations including patient characteristics, confidence in their own competence and that of their team, and perceived helpfulness of consultants. Participants viewed consultation requests as being strongly influenced by a desire to maintain relationships with families. Specific to this context, the hospital's elite reputation was believed to influence families to expect consultations. Other considerations included medicolegal risk, clinical pathways, and availability of secure text messaging to facilitate informal "curbside" conversations with subspecialists., Conclusions: Decision-making around pediatric subspecialty consultation is complex and influenced by factors unrelated to a patient's clinical need. Efforts to reduce low-value consultation must account for the social and organizational dynamics that promote consultation., (Copyright © 2024 by the American Academy of Pediatrics.)

Purpose: Bone marrow stimulation is a common treatment for full-thickness cartilage defects in the hip joint. However, common procedures may result in poor fibrous repair tissue and changes to the subchondral anatomy. This study investigated the clinical outcome of a cohort of International Cartilage Repair Society (ICRS) grades 3 and 4 cartilage defects treated with bone marrow stimulation compared to those who received simple debridement/chondroplasty., Methods: In this retrospective registry study, 236 patients with uni-focal acetabular chondral lesions of the hip up to 400 mm² (mean 177.4 ± 113.4 mm²) and of ICRS grade ≥3 with follow-up of at least 12 months (mean 33.2 ± 15.3 months) were included. Eighty-one patients underwent bone marrow stimulation (microfracture: n = 44, abrasion: n = 37) besides treatment of the underlying pathology, 155 patients underwent defect debridement/chondroplasty. The patient-reported outcome was measured using the International Hip Outcome Tool 33 (iHOT33) score and the Visual Analogue Scale (VAS) for pain., Results: iHOT33 and VAS both improved highly statistically significantly (p < 0.001) in the debridement group after 6, 12, 24, 36 and 60 months compared to the preoperative scores, whereas iHOT33 and VAS after microfracture or abrasion did not show statistically significant changes over time. Twenty-four and sixty months postsurgery the debridement group revealed significant higher scores in the iHOT33 compared to the bone marrow stimulation groups., Conclusion: Patients with chondral lesions of the hip ≤400 mm 2 sustainably benefit from arthroscopic debridement under preservation of the subchondral bone plate in terms of functional outcome and pain in contrast to patients treated with bone marrow stimulation. These findings discourage the currently recommended use of microfracture in the hip joint., Level of Evidence: Level III., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Robotic suturing training is in increasing demand and can be done using suture-pads or robotic simulation training. Robotic simulation is less cumbersome, whereas a robotic suture-pad approach could be more effective but is more costly. A training curriculum with crossover between both approaches may be a practical solution. However, studies assessing the impact of starting with robotic simulation or suture-pads in robotic suturing training are lacking., Methods: This was a randomized controlled crossover trial conducted with 20 robotic novices from 3 countries who underwent robotic suturing training using an Intuitive Surgical ® X and Xi system with the SimNow (robotic simulation) and suture-pads (dry-lab). Participants were randomized to start with robotic simulation (intervention group, n = 10) or suture-pads (control group, n = 10). After the first and second training, all participants completed a robotic hepaticojejunostomy (HJ) in biotissue. Primary endpoint was the objective structured assessment of technical skill (OSATS) score during HJ, scored by two blinded raters. Secondary endpoints were force measurements and a qualitative analysis. After training, participants were surveyed regarding their preferences., Results: Overall, 20 robotic novices completed both training sessions and performed 40 robotic HJs. After both trainings, OSATS was scored higher in the robotic simulation-first group (3.3 ± 0.9 vs 2.5 ± 0.8; p = 0.049), whereas the median maximum force (N) (5.0 [3.2-8.0] vs 3.8 [2.3-12.8]; p = 0.739) did not differ significantly between the groups. In the survey, 17/20 (85%) participants recommended to include robotic simulation training, 14/20 (70%) participants preferred to start with robotic simulation, and 20/20 (100%) to include suture-pad training., Conclusion: Surgical performance during robotic HJ in robotic novices was significantly better after robotic simulation-first training followed by suture-pad training. A robotic suturing curriculum including both robotic simulation and dry-lab suturing should ideally start with robotic simulation., (© 2024. The Author(s).)

Plastic ingestion by seabirds is an increasing issue worldwide, yet species can vary in ingestion based on ecological and morphological differences. This provokes the ecological question of which species are better suited to monitor plastic ingestion across regions and time. In Canada, we examined plastic ingestion in sympatric northern fulmars (Fulmarus glacialis), black-legged kittiwakes (Rissa tridactyla), thick-billed murres (Uria lomvia), and black guillemots (Cepphus grylle). Here, we present new data and compare to historical work to inform plastic pollution monitoring in Canada. In 2021, 51 % of fulmars, 7 % of kittiwakes and 7 % of murres contained plastic, whereas guillemots had no pieces >1 mm. Regardless of the methods used to collect and process samples, fulmars continue to have low levels of ingestion compared to the European Arctic, but high levels compared to other species in the Canadian Arctic, emphasizing their continued utility as a monitoring tool for plastic pollution in Canada., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mark Mallory reports financial support was provided by Natural Sciences and Engineering Research Council of Canada. Jennifer Provencher reports financial support was provided by Natural Resources Canada (Polar Continental Shelf Program). Jennifer Provencher reports was provided by Crown-Indigenous Relations and Northern Affairs Canada (Northern Contaminants Program). 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., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)