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Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3 mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than in adults, with an AUC of 861 ± 805 vs2629 ± 1487 μmg × h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59 ± 0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077 ± 1551 μg × h/l compared to 1795 ± 973 μg × h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These... [ABSTRACT FROM AUTHOR]

Background: Amyloid A (AA) amyloidosis is a complication of chronic inflammatory conditions that develops when proteolytic fragments of serum amyloid A protein (SAA) are deposited in tissues as amyloid fibrils. Amyloid deposition in the kidney causes progressive deterioration in renal function. Eprodisate is a member of a new class of compounds designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils and deposition of the fibrils in tissues.Methods: We performed a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of eprodisate in patients with AA amyloidosis and kidney involvement. We randomly assigned 183 patients from 27 centers to receive eprodisate or placebo for 24 months. The primary composite end point was an assessment of renal function or death. Disease was classified as worsened if any one of the following occurred: doubling of the serum creatinine level, reduction in creatinine clearance by 50% or more, progression to end-stage renal disease, or death.Results: At 24 months, disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of 94 patients given placebo (40%, P=0.06); the hazard ratio for worsening disease with eprodisate treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P=0.02). The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m(2) of body-surface area per year in the eprodisate and the placebo groups, respectively (P=0.02). The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94). The incidence of adverse events was similar in the two groups.Conclusions: Eprodisate slows the decline of renal function in AA amyloidosis. (ClinicalTrials.gov number, NCT00035334.) [ABSTRACT FROM AUTHOR]

Introduction: Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents., Methods and Analysis: Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day and escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE., Discussion: This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials., Trial Registration: CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033., Competing Interests: Lauren E Kelly is the Scientific Director for The Canadian Collaborative for Childhood Cannabinoid Therapeutics (C4T) academic research team. She holds funding from the Canadian Institutes of Health Research, Canadian Cancer Society, Research Manitoba, the Sick Kids Foundation, the Children’s Hospital Research Institute of Manitoba, the University of Manitoba and a Mitacs Accelerate award in partnership with Canopy Growth. Dr. Kelly was a member of the Scientific Advisory Board for Health Products Containing Cannabis at Health Canada and is president elect for the Board of Directors of the Canadian Consortium for the Investigation of Cannabinoids (CCIC). Richard J. Huntsmanis a clinical lead for both the Cannabinoid Research Initiative of Saskatchewan and C4T. He was the co-chair of the Scientific Advisory Committee for Health Products Containing Cannabis at Health Canada. Katelynn E Boerner’s time is supported by a fellowship from the Canadian Child Health Clinician Scientist Program, and she currently holds unrelated funding from the Society of Pediatric Psychology, BC Children’s Hospital Research Institute, Canadian Institutes of Health Research, ZonMw: The Netherlands Organization for Health Research and Development, and the CHILD-BRIGHT Network. Evan C. Lewis has received speaking honoraria from Spectrum Therapeutics, Biome Grow, MedReleaf and Miravo Healthcare. He holds a non-salaried position as the Chief Medical Advisor for the JMCC Group. He was the Vice President of Neurology Services for Numinus, a psychedelic medicine treatment and research company. He is a member of the Expert Committee of the Medical Cannabis Clinicians Society (MCCS) in the United Kingdom and sits on the Advisory Councils for Cannabis Patient Advocacy & Support Services (CPASS) and MedCan. In the last 12 months, Samantha Lee Irwin has received honoraria for authoring a chapter for the Canadian Pharmacy Association (CPhA) and for doing an online lecture for NeuroDiem. She also receives compensation for scientific consulting (Impel NeuroPharma Inc, Biohaven Pharmaceuticals and Lundbeck A/S) and has had research support from the Duke Clinical Research Institute. Manik Chhabra has been granted the 2022 Research Manitoba-George & Fay Yee Centre for Healthcare Innovation in Health Research PhD Studentship Award. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Chhabra 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.)

Asthma exhibits a distinct sex bias in the disease prevalence, severity, and response to therapy. However, sex-related differences in alterations of the lung proteome mediated by aeroallergens critical in asthma, such as house dust mites (HDM), remain unknown. In this study, we define sex-related differences in the lung proteome using an HDM-challenged mouse model by 1D LC-MS/MS. Sex-disaggregated data analysis showed that 406 proteins were uniquely altered in females, 273 proteins were uniquely altered in males, and 414 proteins were altered in both females and males in response to HDM. In a linear mixed model analysis, sex modified the HDM exposure effect for 163 proteins, i.e., a significant sex:exposure interaction was identified in 84 proteins in females and 35 proteins in males. Of these, 12 proteins showed a significant sex effect in both female and male lungs. We further selected 3 proteins Tjp1, Lamtor1, and G3BP2 for independent confirmation studies. Our findings detail the sex-specific lung proteome in response to an aeroallergen critical in asthma and demonstrate that sex is a significant effect modifier of HDM response. These results will serve as a valuable resource for delineating sex-specific mechanisms in aeroallergen-driven responses in asthma research.

Background: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score., Methods: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups., Results: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF., Conclusions: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk., (© 2024 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: Evidence suggests that prenatal air pollution exposure alters DNA methylation (DNAm), which could go on to affect long-term health. It remains unclear whether DNAm alterations present at birth persist through early life. Identifying persistent DNAm changes would provide greater insight into the molecular mechanisms contributing to the association of prenatal air pollution exposure with atopic diseases., Objectives: This study investigated DNAm differences associated with prenatal nitrogen dioxide ( NO 2 ) exposure (a surrogate measure of traffic-related air pollution) at birth and 1 y of age and examined their role in atopic disease. We focused on regions showing persistent DNAm differences from birth to 1 y of age and regions uniquely associated with postnatal NO 2 exposure., Methods: Microarrays measured DNAm at birth and at 1 y of age for an atopy-enriched subset of Canadian Health Infant Longitudinal Development (CHILD) study participants. Individual and regional DNAm differences associated with prenatal NO 2 ( n = 128 ) were identified, and their persistence at age 1 y were investigated using linear mixed effects models ( n = 124 ). Postnatal-specific DNAm differences ( n = 125 ) were isolated, and their association with NO 2 in the first year of life was examined. Causal mediation investigated whether DNAm differences mediated associations between NO 2 and age 1 y atopy or wheeze. Analyses were repeated using biological sex-stratified data., Results: At birth ( n = 128 ), 18 regions of DNAm were associated with NO 2 , with several annotated to HOX genes. Some of these regions were specifically identified in males ( n = 73 ), but not females ( n = 55 ). The effect of prenatal NO 2 across CpGs within altered regions persisted at 1 y of age. No significant mediation effects were identified. Sex-stratified analyses identified postnatal-specific DNAm alterations., Discussion: Regional cord blood DNAm differences associated with prenatal NO 2 persisted through at least the first year of life in CHILD participants. Some differences may represent sex-specific alterations, but replication in larger cohorts is needed. The early postnatal period remained a sensitive window to DNAm perturbations. https://doi.org/10.1289/EHP13034.

Background: There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19 pandemic, the Transplant Manitoba Adult Kidney Program updated its monitoring protocols for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) to a reduced frequency., Methods: This single-center nested case-control study evaluated 252 adult kidney transplant recipients transplanted from 2015 to 2021, with the updated protocols effective on March 19 th 2020. Cases included recipients transplanted after the protocol update who developed CMV, EBV, and BKV DNAemia and were matched to controls with DNAemia transplanted prior to the protocol update. The primary outcome was the difference in maximum DNA load titers between cases and matched controls. Secondary outcomes included time to initial DNAemia detection and DNAemia clearance. Safety outcomes of tissue-invasive viral disease were described., Results: There were 216 recipients transplanted preupdate and 36 recipients postupdate. There was no difference between cases and controls in maximum or first DNA load titers for EBV, CMV, or BKV. Cases experienced earlier EBV DNAemia detection (26 (IQR 8, 32) vs. 434 (IQR 96, 1184) days, p = .005). Median follow-up was significantly longer for recipients transplanted preupdate (4.3 vs. 1.3 years, p < .0001). After adjusting for follow-up time, there was no difference in DNAemia clearance or tissue-invasive viral disease., Conclusion: Our findings suggest that reduced frequency viral monitoring protocols may be safe and cost-effective. This quality assurance initiative should be extended to detect longer-term and tissue-invasive disease outcomes., (© 2024 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

De novo donor-specific antibody (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n = 949) with over 15 years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into recipient age molecular mismatch categories, we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years, 98% and 97%, respectively). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (hazard ratio [HR], 0.37; 95% CI, 0.2-0.6; P < .0001) and recipient age molecular mismatch category: intermediate versus low (HR, 2.48; 95% CI, 1.5-4.2; P = .0007), high versus intermediate (HR, 2.56; 95% CI, 1.6-4.2; P = .0002), and high versus low (HR, 6.36; 95% CI, 3.7-10.8; P < .00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A significant proportion of Canadian adults is impacted by chronic noncommunicable diseases. These conditions may be improved by peer-led health promotion interventions that target modifiable risk factors; however, to date, there is mixed evidence on the effectiveness of these interventions. Unlike other health promotion programs, Hans Kai is grounded in a holistic model of health that simultaneously addresses multiple determinants of health at different levels of human ecology. In Hans Kai, a set of informational sessions that are delivered in a group setting by healthcare professionals are followed by regular peer-led group meetings in a self-governed support group setting that is designed to promote implementation of newly learned health competences. The Hans Kai trial described here aims to evaluate the efficacy of the Hans Kai program in promoting the health and wellbeing of its participants and investigate the experiences of the Hans Kai participants and facilitators., Methods: This research will involve a mixed methods trial combining an experimental component with a qualitative component. The experimental component will involve a 6-month 2-group parallel superiority randomized controlled trial (RCT) in which 105 participants will be randomly assigned to two conditions, an intervention group (n = 70) that will participate in the Hans Kai program and a control group (n = 35) that will have access to standard care using a computer-generated random sequence; blinding will not occur. The RCT will test the impact of the program on several health outcomes and will be followed by a 12-18-month observational follow-up study that will provide data on the long-term durability of the 6-month RCT health outcomes. The qualitative component will investigate the experiences of program participants (n = 30) and facilitators (n = 15) to identify the main strengths and limitations of Hans Kai, uncover potential implementation issues, and elucidate the mechanisms through which the program works. The population of interest will include adults aged 18 + with or without chronic health conditions who self-report an interest in taking control of their own health and improving their lifestyle. In the RCT, all outcomes of interest will be measured using a multi-method approach, involving self-report questionnaires and objective indicators, and within-subject mean changes in outcomes over time between the two groups will be compared to address the RCT aims. Similarly, in the qualitative component, a multi-method approach, involving in-depth individual interviews, photovoice, and online surveys, will be used to reach a deeper and more nuanced understanding of the program strengths, how the program works, and for which people it is more effective. Adaptable components of the program will also be investigated and modified according to the feedback provided by the RCT participants. In the mixed methods integration of evidence, the qualitative findings will be used to explain the quantitative RCT results., Discussion: The RCT findings will help support the further development and use of Hans Kai as well as other peer-led health promotion interventions., Trial Registration: United Stated Clinical Trial Registry ClinicalTrials.gov (registration# NCT03949725; Protocol version 2, June 22nd, 2022)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Potassium regulation in the body is primarily done in the kidney. In addition to this, hyperkalemia, occurs in approximately 10% of individuals with chronic kidney disease (CKD) and is associated with elevated all-cause mortality. Individuals with CKD are often told to restrict dietary potassium (K), however, this recommendation is based on low quality evidence. Reduced quality of life, limited dietary choices and nutritional deficiencies are all potential negative outcomes that may occur when restricting dietary K in CKD patients. There is a need for randomized controlled trials investigating the impact of dietary K modification on serum K concentrations in people with CKD., Methods: A randomized 2-period crossover design comparing a liberalized K fruit and vegetable diet where participants will be required to consume ~ 3500 mg of dietary K daily, to a standard K restricted diet where participants will be required to consume < 2000 mg of dietary K daily. All participants will begin on a liberalized K run-in period for 2 weeks where they will receive fruit and vegetables home deliveries and for safety will have clinical chemistry, including serum potassium measurements taken after 1 week. Participants will then be randomized into either liberalized K or standard K diet for six weeks and then crossover to the other intervention for another 6 weeks after a 2-week washout period., Discussion: 30 male and female CKD outpatients, ≥ 18 years of age, who have an estimated glomerular filtration rate (eGFR) between 15 and 45 ml/min/1.73m 2 and serum K between 4.5 and 5.5 mEq/L. This design would have greater than 80% power to detect a difference of 0.35 mEq/L serum K between groups. Anthropometric measurements, clinical chemistry, dietary recalls, physical function assessments, as well as a quality of life assessments will also be measured in this trial. These findings will provide high quality evidence for, or against, recommendations for dietary K restriction in individuals living with CKD. The removal of K restriction could provide individuals living with CKD more dietary choice leading to improved dietary status and quality of life., Trial Registration: This trial has received approval from the University of Manitoba Research Ethics board (HS25191 (B2021:104))., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Individuals with chronic kidney disease (CKD) can develop metabolic acidosis which, in turn, is associated with faster progression of CKD and an increased need for dialysis. Oral sodium bicarbonate (the current standard of care therapy for metabolic acidosis) is poorly tolerated leading to low adherence. Base-producing or alkalizing Fruit and vegetables have potential as an alternative treatment for metabolic acidosis as they have been shown to reduce acid load arising from the diet., Objective: This trial will evaluate the feasibility of providing base-producing fruit and vegetables as a dietary treatment for metabolic acidosis, compared with oral sodium bicarbonate., Design: A 2-arm, open-label, dual-center, randomized controlled feasibility trial., Setting: Two Canadian sites: a nephrology clinic in Winnipeg, Manitoba, and a nephrology clinic in Halifax, Nova Scotia., Participants: Adult participants with G3-G5 CKD and metabolic acidosis., Measurements: Participants will undergo baseline measurements and attend 5 study visits over 12 months at which they will have a measurement of feasibility criteria as well as blood pressure, blood and urine biochemistry, 5-repetition chair stand test (STS5), and questionnaires to assess quality of life and symptoms. Furthermore, participants fill out Automated Self-Administered 24-hour recalls (ASA-24) in the beginning, middle, and end of trial., Methods: A total of 40 eligible participants will be randomized 1:1 to either base-producing fruit and vegetables (experimental) group or sodium bicarbonate (control) group, beginning from a daily dose of 1500 mg., Limitations: Using self-administered dietary assessments, lack of supervision over the consumption of study treatments and the possible disappointment of the control group for not receiving fruit and vegetables would be considered as limitations for this study. However, we are planning to undertake proper practices to overcome the possible limitations. These practices are discussed throughout the article in detail., Conclusions: This study will generate data on base-producing fruit and vegetables consumption as a dietary treatment for metabolic acidosis in CKD. The data will be used to design a future multi-center trial looking at slowing CKD progression in people with metabolic acidosis., Trial Registration: This study is registered on clinicaltrials.gov with the identifier NCT05113641., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is important in determining COVID-19 outcomes, with an inadequate IFN response associated with disease severity. Our objective was to examine the prophylactic potential of IFN administration to limit viral transmission., Methods: A cluster randomised open label clinical trial was undertaken to determine the effects of pegylated IFNβ-1a administration on SARS-CoV-2 household transmission between December 3rd, 2020 and June 29th, 2021. Index cases were identified from databases of confirmed SARS-CoV-2 individuals in Santiago, Chile. Households were cluster randomised (stratified by household size and age of index cases) to receive 3 doses of 125 μg subcutaneous pegylated IFNβ-1a (172 households, 607 participants), or standard care (169 households, 565 participants). The statistical team was blinded to treatment assignment until the analysis plan was finalised. Analyses were undertaken to determine effects of treatment on viral shedding and viral transmission. Safety analyses included incidence and severity of adverse events in all treatment eligible participants in the standard care arm, or in the treatment arm with at least one dose administered. Clinicaltrials.gov identifier: NCT04552379., Findings: 5154 index cases were assessed for eligibility, 1372 index cases invited to participate, and 341 index cases and their household contacts (n = 831) enrolled. 1172 participants in 341 households underwent randomisation, with 607 assigned to receive IFNβ-1a and 565 to standard care. Based on intention to treat (ITT) and per protocol (PP) analyses for the primary endpoints, IFNβ-1a treatment did not affect duration of viral shedding in index cases (absolute risk reduction = -0.2%, 95% CI = -8.46% to 8.06%) and transmission of SARS-CoV-2 to household contacts (absolute risk reduction = 3.87%, 95% CI = -3.6% to 11.3%). Treatment with IFNβ-1a resulted in significantly more treatment-related adverse events, but no increase in overall adverse events or serious adverse events., Interpretation: Based upon the primary analyses, IFNβ-1a treatment did not affect duration of viral shedding or the probability of SARS-CoV-2 transmission to uninfected contacts within a household., Funding: Biogen PTY Ltd. Supply of interferon as 'Plegridy (peginterferon beta-1a).' The study was substantially funded by BHP Holdings Pty Ltd., Competing Interests: Authors Castro-Rodriguez, Kollman, and Stick received funding from BHP Holdings Pty Ltd and Biogen Pty Ltd to conduct this study. Balshaw was paid consulting fees to advise on this study. Castro-Rodriguez received honoraria from AstraZeneca and GlaxoSmithKline to speak at symposia and Eurofarma for participation on advisory board. Kollmann has received research funding from NIH, Medical Research Future Fund, and Bill and Melinda Gates Foundation, honoraria from the Human Immunome Project to attend a conference, and holds two patents unrelated to this study. Montgomery received funding from NHMRC and TSANZ to present findings from this study at conferences. Authors Aniba, Borzutzky, Chen, Fish, Garcia-Huidobro, Gigi-Yunge, Hancock, Hartnell, Ho, Iturriaga, Karpievitch, Othman, Perret, Shannon, Tebbutt, and Urzua have no declared conflicts of interest., (© 2023 The Author(s).)

Background: Urine CXCL10 (C-X-C motif chemokine ligand 10, interferon gamma-induced protein 10 [IP10]) outperforms standard-of-care monitoring for detecting subclinical and early clinical T-cell-mediated rejection (TCMR) and may advance TCMR therapy development through biomarker-enriched trials. The goal was to perform an international multicenter validation of a CXCL10 bead-based immunoassay (Luminex) for transplant surveillance and compare with an electrochemiluminescence-based (Meso Scale Discovery [MSD]) assay used in transplant trials., Methods: Four laboratories participated in the Luminex assay development and evaluation. Urine CXCL10 was measured by Luminex and MSD in 2 independent adult kidney transplant trial cohorts (Basel and TMCT04). In an independent test and validation set, a linear mixed-effects model to predict (log 10 -transformed) MSD CXCL10 from Luminex CXCL10 was developed to determine the conversion between assays. Net reclassification was determined after mathematical conversion., Results: The Luminex assay was precise, with an intra- and interassay coefficient of variation 8.1% and 9.3%; showed modest agreement between 4 laboratories (R 0.96 to 0.99, P < 0.001); and correlated with known CXCL10 in a single- (n = 100 urines, R 0.94 to 0.98, P < 0.001) and multicenter cohort (n = 468 urines, R 0.92, P < 0.001) but the 2 assays were not equivalent by Passing-Bablok regression. Linear mixed-effects modeling demonstrated an intercept of -0.490 and coefficient of 1.028, showing Luminex CXCL10 are slightly higher than MSD CXCL10, but the agreement is close to 1.0. After conversion of the biopsy thresholds, the decision to biopsy would be changed for only 6% (5/85) patients showing acceptable reclassification., Conclusions: These data demonstrate this urine CXCL10 Luminex immunoassay is robust, reproducible, and accurate, indicating it can be readily translated into clinical HLA laboratories for serial posttransplant surveillance., Competing Interests: S.K. is the founder of Renovar, which licensed its urine chemokine patent to Thermo Fisher. S.C., J.-H.L., J.N., R.P., R.S., M.T., and J.W. work for Thermo Fisher Scientific. A.M.J. is a consultant for Hansa Biopharma and Novartis. R.C. is a consultant for Hansa Biopharma and has an investigator-initiated grant from Bristol Myers-Squibb. P.N. is a consultant for CSL Behring. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To determine what modifiable interventions used in the neonatal intensive care unit (NICU) are associated with severe necrotizing enterocolitis (NEC) requiring surgical intervention., Methods: A retrospective review of patients treated for NEC at a tertiary hospital from 1991 to 2016 was performed. Patient characteristics were used to calculate propensity scores for likelihood of exposure to seven interventions: enteral feeds, use of glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), antacids, antibiotics, or umbilical arterial (UAC) and venous catheters (UVC). Conditional logistic regression was used to compare the odds of having surgical NEC if exposed to each treatment., Results: We included 195 NEC patients: 69 severe NEC managed with surgery and 126 non-severe NEC managed medically. After propensity score matching based on birth characteristics, exposure to glucocorticoids (OR 5.21, 95%CI: 1.62, 16.70), NSAIDs (OR 4.87, 95%CI: 1.67, 14.17), UVC (OR 2.53 (95%CI: 1.19, 5.73), and UAC (OR 4.91, 95%CI: 2.12, 11.37) were associated with surgical NEC in separate conditional logistic regression analyses. Including these treatments in a second round of propensity matching and conditional logistic regression revealed that glucocorticoids (OR 2.99, 95%CI: 1.01, 8.88), NSAIDs (OR 3.97, 95%CI: 1.41, 11.19), UVC (OR 3.07, 95%CI: 1.46, 6.48), and UAC (OR 5.10, 95%CI: 2.10, 12.36) were still associated with surgical NEC., Conclusion: After controlling for birth confounders and common NICU supportive interventions, use of glucocorticoids, NSAIDs and umbilical catheters independently increased the odds of developing severe NEC requiring surgical intervention., Level-Of-Evidence Rating: Case-control, Level III evidence., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Rates of pediatric hospitalizations following an injury while riding an all-terrain vehicle (ATV) are increasing. Few studies have compared the rates of severe injuries among children, adolescents, and adults., Objectives: To investigate whether younger ATV riders are at risk for more severe ATV-related injuries., Design, Setting, and Participants: This cross-sectional study was conducted using administrative data from hospitals in 9 provinces in Canada. Participants included patients admitted to hospitals with ATV-related injuries between 2002 and 2019. Statistical analysis was performed from June 2020 to September 2021., Exposures: The primary exposure was age younger than 16 years. Comparison groups were youths aged 16 to 20 years and adults aged 21 years and older., Main Outcomes and Measures: The main outcomes of interest were death, spinal cord injury, and an Injury Severity Score (ISS) greater than 25. Secondary outcomes were less severe injuries, including head injuries, crush type injuries, and fractures., Results: Among 52 745 patients with complete data, 15% were youths younger than 16 years, 13% were youths aged 16 to 20 years, 82% were male, and 47% lived in rural areas. After adjusting for covariates, the odds of dying were higher among youths aged 16 to 20 years (adjusted odds ratio [aOR], 1.64; 95% CI, 1.04-2.60) compared with those younger than 16 years. Youths aged 16 to 20 years also had higher odds of spinal cord injury (aOR, 2.72; 95% CI, 1.80-4.20) and an injury severity score greater than 25 (aOR, 1.63; 95% CI, 1.36-1.96) compared with youths 16 years of age or less. Sex-specific analyses revealed these associations were greater for male youths aged 16 to 20 years (spinal cord injury: aOR, 3.81; 95% CI, 1.38-11.10, and dying in a hospital: aOR, 4.37; 95% CI, 1.19-21.02) than female youths aged 16 to 20 years., Conclusions and Relevance: In this cross-sectional study of patients hospitalized for ATV injuries in Canada, youths aged 16 to 20 years and adults aged 21 years and older were at an increased risk of death and severe injuries compared with youths younger than 16 years. The increased risk of death and severe injuries was most evident among male patients.

Background: Metabolomics is a potential means for biofluid-based lung cancer detection. We conducted a non-targeted, data-driven assessment of plasma from early-stage non-small cell lung cancer (ES-NSCLC) cases versus cancer-free controls (CFC) to explore and identify the classes of metabolites for further targeted metabolomics biomarker development., Methods: Plasma from 250 ES-NSCLC cases and 250 CFCs underwent ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) in positive and negative electrospray ionization (ESI) modes. Molecular feature extraction, formula generation, and find-by-ion tools annotated metabolic entities. Analysis was restricted to endogenous metabolites present in ≥ 80% of samples. Unsupervised hierarchical cluster analysis identified clusters of metabolites. The metabolites with the strongest correlation with the principal component of each cluster were included in logistic regression modeling to assess discriminatory performance with and without adjustment for clinical covariates., Results: A total of 1900 UHPLC-QTOF-MS assessments identified 1667 and 2032 endogenous metabolites in the ESI-positive and ESI-negative modes, respectively. After data filtration, 676 metabolites remained, and 12 clusters of metabolites were identified from each ESI mode. Multivariable logistic regression using the representative metabolite from each cluster revealed effective classification of cases from controls with overall diagnostic accuracy of 91% (ESI positive) and 94% (ESI negative). Metabolites of interest identified for further targeted analysis include the following: 1b, 3a, 12a-trihydroxy-5b-cholanoic acid, pyridoxamine 5'-phosphate, sphinganine 1-phosphate, gamma-CEHC, 20-carboxy-leukotriene B4, isodesmosine, and 18-hydroxycortisol., Conclusions: Plasma-based metabolomic detection of early-stage NSCLC appears feasible. Further metabolomics studies targeting phospholipid, steroid, and fatty acid metabolism are warranted to further develop noninvasive metabolomics-based detection of early-stage NSCLC., (© 2022. The Author(s).)

Background: We examined associations between NFκB1 polymorphisms and influenza A (H1N1) clinical outcomes in Canadian. Methods: A total of thirty-six Caucasian patients admitted to the intensive care unit (ICU) in hospitals in Canada were recruited during the 2009 H1N1 pandemic. Genomic DNA was extracted from the whole blood samples. The NFkB1 gene was targeted for genotyping using next-generation sequencing technology—Roche 454. Results: A total of 136 single nucleotide polymorphisms (SNPs) were discovered within the NFκB1 gene. Among them, 63 SNPs were significantly enriched in patients admitted in the ICU (p < 0.05) compared with the British Caucasian population in the 1000 Genomes study. These enriched SNPs are mainly intron variants, and only two are exon SNPs from the non-transcribing portion of the NFκB1 gene. Conclusions: Genetic variations in the NFκB1 gene could influence clinical outcomes of pandemic H1N1 infections. Our findings showed that sequence variations of the NFκB1 gene might influence patient response to influenza infection.

Purpose: The aim of this study was to assess real-world educational outcomes and developmental disorders in patients with a history of Hirschsprung disease compared to an age-matched control group., Methods: With ethics approval (H2016:014) a retrospective cohort study of all children diagnosed with Hirschsprung disease at a single centre from 1992 to 2017 was performed. A 10:1 date-of-birth matched control cohort was constructed from a population-based directory. The educational outcomes were compared using the following measures: Early Developmental Instrument, Grades 3, 7, and 8 assessments, Grade 9 completion, Grade 9 performance, and high school graduation. Fisher's exact tests were used to compare the odds of failure between cases to controls. Only children who reached 4 years of age were included., Results: A total of 75 cases with Hirschsprung disease patients were identified. Patients with Hirschsprung disease were at increased risk of failing to meet expectations on the Early Development Instrument. After entering elementary school, Hirschsprung patients were at no greater risk than their peers of failing to meet expectations on standardized testing or failing to graduate from high school., Conclusion: Using real-world measures of academic success as a surrogate for neurodevelopmental status, our study demonstrates that patients with a history of Hirschsprung disease demonstrated poor neurodevelopmental performance in pre-school, but the educational achievements of patients did not differ from controls once they started school. These promising data can be used to mitigate preconceived notions that patients with Hirschsprung disease require special education, which may be isolating and psychosocially damaging., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: It is unclear if musculoskeletal deformities observed in patients with congenital diaphragmatic hernia (CDH), congenital lung lesion (CLL) and esophageal atresia/tracheoesophageal fistula (EA/TEF) are associated with the anomaly or are a result of the surgery required to treat the anomaly. This study compared the prevalence of musculoskeletal deformities for: (1) children with congenital thoracic anomalies to controls; (2) CLL to EA/TEF both repaired via thoracotomy; and (3) CLL and EA/TEF to CDH repaired via laparotomy., Methods: We performed a retrospective study of children with CLL, CDH or EA/TEF between 1990 and 2016. Date-of-birth-matched control groups were generated from a population-based dataset. International Classification of Disease codes were used to identify scoliosis and pectus anomalies. We determined Hazard ratios (HR) for cases versus controls., Results: We included 167 cases (CDH n = 82; CLL n = 29; EA/TEF n = 56) and 1670 controls. EA/TEF had a greater risk of scoliosis (HR 5.52, 95%CI 1.49,13.73) and pectus deformities (HR 4.07, 95%CI 1.96,8.45). CDH showed more scoliosis (HR 5.03, 95%CI 1.99,12.74) but not pectus anomalies. Musculoskeletal deformities were not more common in CLL., Conclusion: Children born with CDH or EA/TEF, but not CLL, had more musculoskeletal deformities than controls. The inconsistent association between musculoskeletal deformities and the surgical approach suggested a congenital predisposition., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The benefit of elective resection of congenital lung malformations continues to be debated. Proponents of resection endorse a decreased risk of respiratory complications as one indication for surgery. Our study aimed to compare the prevalence of respiratory infections in cases, before and after resection of congenital lung malformations, to controls without a history of congenital lung malformation., Methods: We performed a retrospective cohort study of children born from 1991 to 2007 who underwent congenital lung malformation resection. Patients were identified from Winnipeg´s Surgical Database of Outcomes and Management (WiSDOM), and a 10:1 date-of-birth matched control group was generated from a population-based administrative data repository. International Classification of Disease codes were used to assess pulmonary infection outcomes. Relative rates (RR) were calculated to compare the frequency of pneumonia, respiratory infections and influenza between cases and controls., Results: We included 31 congenital lung malformation cases and 310 controls. Cases consisted of 14 (45.16%) congenital pulmonary airway malformations, 9 (29.03%) bronchopulmonary sequestrations and 8 (25.81%) hybrid lesions. Before resection, pneumonia was more common in cases than controls (RR 6.85; 95%CI 3.89, 11.9), while the risk of acute respiratory infections (RR 1.21; 95%CI 0.79, 1.79) and influenza (RR 0.46; 95%CI 0.01, 3.22) were similar to controls. Post-resection, the risk of pneumonia (RR 9.75; 5.06, 18.50) was still higher in cases than controls, and respiratory infections (RR 1.77; 95%CI 1.20, 2.53) and influenza (RR 3.98; 95%CI 1.48, 9.36) were more common in cases than controls., Conclusion: Our study demonstrated that after resection of congenital lung malformations, children experience more frequent respiratory infections compared to the general population. Resection does not eliminate the increased risk of pneumonia., Competing Interests: Conflict of Interest None of the authors have conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

The prevalence and long-term impact of T cell-mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate-based maintenance therapy. This observational study evaluated 775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for-cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow-up biopsies. Alloimmune risk categories based on the HLA-DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death-censored and all-cause graft loss when adjusted for baseline covariates and other significant time-dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA-DR/DQ molecular mismatch scores, remain under-immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: We analyzed the prevalence of pre-antiretroviral therapy (ART) drug resistance mutations (DRMs) in a Kenyan population. We also examined whether host HLA class I genes influence the development of pre-ART DRMs., Methods: The HIV-1 proviral DNAs were amplified from blood samples of 266 ART-naïve women from the Pumwani Sex Worker cohort of Nairobi, Kenya using a nested PCR method. The amplified HIV genomes were sequenced using next-generation sequencing technology. The prevalence of pre-ART DRMs was investigated. Correlation studies were performed between HLA class I alleles and HIV-1 DRMs., Results: Ninety-eight percent of participants had at least one DRM, while 38% had at least one WHO surveillance DRM. M184I was the most prevalent clinically important variant, seen in 37% of participants. The DRMs conferring resistance to one or more integrase strand transfer inhibitors were also found in up to 10% of participants. Eighteen potentially relevant ( p < 0.05) positive correlations were found between HLA class 1 alleles and HIV drug-resistant variants., Conclusions: High levels of HIV drug resistance were found in all classes of antiretroviral drugs included in the current first-line ART regimens in Africa. The development of DRMs may be influenced by host HLA class I-restricted immunity.

Objective: To assess the association between long term prescription opioid treatment medically dispensed for non-cancer pain and the initiation of injection drug use (IDU) among individuals without a history of substance use., Design: Retrospective cohort study., Setting: Large administrative data source (containing information for about 1.7 million individuals tested for hepatitis C virus or HIV in British Columbia, Canada) with linkage to administrative health databases, including dispensations from community pharmacies., Participants: Individuals age 11-65 years and without a history of substance use (except alcohol) at baseline., Main Outcome Measures: Episodes of prescription opioid use for non-cancer pain were identified based on drugs dispensed between 2000 and 2015. Episodes were classified by the increasing length and intensity of opioid use (acute (lasting <90 episode days), episodic (lasting ≥90 episode days; with <90 days' drug supply and/or <50% episode intensity), and chronic (lasting ≥90 episode days; with ≥90 days' drug supply and ≥50% episode intensity)). People with a chronic episode were matched 1:1:1:1 on socioeconomic variables to those with episodic or acute episodes and to those who were opioid naive. IDU initiation was identified by a validated administrative algorithm with high specificity. Cox models weighted by inverse probability of treatment weights assessed the association between opioid use category (chronic, episodic, acute, opioid naive) and IDU initiation., Results: 59 804 participants (14 951 people from each opioid use category) were included in the matched cohort, and followed for a median of 5.8 years. 1149 participants initiated IDU. Cumulative probability of IDU initiation at five years was highest for participants with chronic opioid use (4.0%), followed by those with episodic use (1.3%) and acute use (0.7%), and those who were opioid naive (0.4%). In the inverse probability of treatment weighted Cox model, risk of IDU initiation was 8.4 times higher for those with chronic opioid use versus those who were opioid naive (95% confidence interval 6.4 to 10.9). In a sensitivity analysis limited to individuals with a history of chronic pain, cumulative risk for those with chronic use (3.4% within five years) was lower than the primary results, but the relative risk was not (hazard ratio 9.7 (95% confidence interval 6.5 to 14.5)). IDU initiation was more frequent at higher opioid doses and younger ages., Conclusions: The rate of IDU initiation among individuals who received chronic prescription opioid treatment for non-cancer pain was infrequent overall (3-4% within five years) but about eight times higher than among opioid naive individuals. These findings could have implications for strategies to prevent IDU initiation, but should not be used as a reason to support involuntary tapering or discontinuation of long term prescription opioid treatment., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from British Columbia Centre for Disease Control and the Canadian Institutes of Health Research for the submitted work; outside of the submitted work, MK has received research grant funding via his institution from Roche Molecular Systems, Siemens Healthcare Diagnostics, and Hologic; MEK has received consulting fees from Biogen; and RCD has performed research and consulted on the over-the-counter product Tylenol for the consumer division of Johnson & Johnson. RCD is executive director of the RADARS System, which performs post-marketing surveillance of prescription drugs. This information is primarily used for regulatory purposes. Subscribers to the RADARS System include the US Food and Drug Administration and some manufacturers of prescription analgesics or treatment for opioid addiction. These companies include Collegium, Purdue Pharma, and Indivior. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. All authors report no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The online Tuberculin Skin Test/Interferon Gamma Release Assay (TST/IGRA) Interpreter V3.0 (TSTin3D), a tool for estimating the risk of active tuberculosis (TB) in individuals with latent TB infection (LTBI), has been in use for more than a decade, but its predictive performance has never been evaluated., Methods: People with a positive TST or IGRA result from 1985 to 2015 were identified using a health data linkage that involved migrants to British Columbia, Canada. Comorbid conditions at the time of LTBI testing were identified from physician claims, hospitalizations, vital statistics, outpatient prescriptions, and kidney and HIV databases. The risk of developing active TB within 2 and 5 years was estimated using TSTin3D. The discrimination and calibration of these estimates were evaluated., Results: A total of 37 163 individuals met study inclusion criteria; 10.4% were tested by IGRA. Generally, the TSTin3D algorithm assigned higher risks to demographic and clinical groups known to have higher active TB risks. Concordance estimates ranged from 0.66 to 0.68 in 2- and 5-year time frames. Comparing predicted to observed counts suggests that TSTin3D overestimates active TB risks and that overestimation increases over time (with relative bias of 3% and 12% in 2- and 5-year periods, respectively). Calibration plots also suggest that overestimation increases toward the upper end of the risk spectrum., Conclusions: TSTin3D can discriminate adequately between people who developed and did not develop active TB in this linked database of migrants with predominately positive skin tests. Further work is needed to improve TSTin3D's calibration., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: Intravenous immune globulin (IVIG) may improve survival in people with septic shock. Current utilization patterns of IVIG are unknown. We sought to characterize adult patients with septic shock requiring vasopressors who received IVIG, describes IVIG regimens, and evaluate determinants of IVIG use in patients with septic shock., Methods: We conducted a retrospective database study of adult patients with septic shock admitted to US hospitals in the Premier Healthcare Database (from July 2010 to June 2013). We described the proportion of patients with septic shock receiving IVIG, examined IVIG regimens across sites and employed random-effects multivariable regression techniques to identify predictors of IVIG use., Results: Intravenous immune globulin was administered to 0.3% (n = 685) of patients with septic shock; with a median [interquartile range (IQR)] dose of 1 [0.5-1.8] g·kg -1 for a median [IQR] of 1 [1-2] day. Receipt of IVIG was less likely for Black patients (odds ratio [OR], 0.54; 95% confidence interval [CI] 0.41 to 0.72) and patients without private insurance (Medicare OR, 0.73; 95% CI 0.59 to 0.90; Medicaid OR, 0.41; 95% CI 0.30 to 0.57) and more likely for patients with immunocompromise (OR, 6.83; 95% CI 5.47 to 8.53), necrotizing fasciitis (OR, 9.78; 95% CI 6.97 to 13.72), and toxic shock (OR, 56.9; 95% CI 38.7 to 83.7)., Conclusions: Intravenous immune globulin is used infrequently across the US in patients with septic shock. Regimens of IVIG in septic shock may be less intensive than those associated with a survival benefit in meta-analyses. Observed infrequent use supports apparent clinical equipoise, perhaps secondary to limitations of the primary literature. A clinical trial evaluating the role of IVIG in septic shock is needed., (© 2021. Canadian Anesthesiologists' Society.)

Aims: Orthopaedic surgeries are complex, frequently performed procedures associated with significant haemorrhage and perioperative blood transfusion. Given refinements in surgical techniques and changes to transfusion practices, we aim to describe contemporary transfusion practices in orthopaedic surgery in order to inform perioperative planning and blood banking requirements., Methods: We performed a retrospective cohort study of adult patients who underwent orthopaedic surgery at four Canadian hospitals between 2014 and 2016. We studied all patients admitted to hospital for nonarthroscopic joint surgeries, amputations, and fracture surgeries. For each surgery and surgical subgroup, we characterized the proportion of patients who received red blood cell (RBC) transfusion, the mean/median number of RBC units transfused, and exposure to platelets and plasma., Results: Of the 14,584 included patients, the most commonly performed surgeries were knee arthroplasty (24.8%), hip arthroplasty (24.6%), and hip fracture surgery (17.4%). A total of 10.3% of patients received RBC transfusion; the proportion of patients receiving RBC transfusions varied widely based on the surgical subgroup (0.0% to 33.1%). Primary knee arthroplasty and hip arthroplasty, the two most common surgeries, were associated with in-hospital transfusion frequencies of 2.8% and 4.5%, respectively. RBC transfusion occurred in 25.0% of hip fracture surgeries, accounting for the greatest total number of RBC units transfused in our cohort (38.0% of all transfused RBC units). Platelet and plasma transfusions were uncommon., Conclusion: Orthopaedic surgeries were associated with variable rates of transfusion. The rate of RBC transfusion is highly dependent on the surgery type. Identifying surgeries with the highest transfusion rates, and further evaluation of factors that contribute to transfusion in identified at-risk populations, can serve to inform perioperative planning and blood bank requirements, and facilitate pre-emptive transfusion mitigation strategies. Cite this article: Bone Jt Open  2021;2(10):850-857.

Background: Tranexamic acid (TXA) reduces transfusion in a wide range of surgical populations, although its real-world use in non-cardiac surgeries has not been well described. The objective of this study was to describe prophylactic TXA use in non-cardiac surgeries at high risk for transfusion., Methods: This is a retrospective cohort study of all adult patients undergoing major non-cardiac surgery at ≥5% risk of perioperative transfusion at five Canadian hospitals between January 2014 and December 2016. Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database were linked to transfusion and laboratory databases. TXA use was ascertained electronically from The Ottawa Hospital Data Warehouse and via manual chart review for Winnipeg hospitals. For each surgery, we evaluated the percentage of patients who received TXA as well as the specifics of TXA dosing and administration., Results: TXA use was evaluable in 14 300 patients. Overall, 17% of surgeries received TXA, ranging from 0% to 68% among individual surgeries. TXA use was more common in orthopaedic (n = 2043/4942; 41%) and spine surgeries (n = 239/1322; 18%) compared to other surgical domains (n = 109/8036; 1%). TXA was commonly administered as a bolus (n = 2097/2391; 88%). The median TXA dose was 1000 mg (IQR 1000-1000 mg)., Conclusion: TXA is predominantly used in orthopaedic and spine surgeries, with little uptake in other non-cardiac surgeries at high risk for red blood cell transfusion. Further studies are needed to evaluate the effectiveness and safety of TXA and to understand the barriers to TXA administration in a broad range of non-cardiac surgeries., (© 2021 British Blood Transfusion Society.)

Background: Little attention has been given to the long-term respiratory outcomes of children with gastroschisis. The purpose of this study was to determine if gastroschisis survivors have more respiratory illnesses in their first 10 years of life compared with age-matched controls., Methods: We performed a retrospective cohort study of all gastroschisis children born in Manitoba between 1991 and 2017. Gastroschisis cases were identified from a clinical database, and a date of birth-matched control cohort was constructed from a population-based data repository. International Classification of Disease codes were used to compare the risk and frequency of respiratory diagnoses for children with gastroschisis to date of birth-matched controls from 0-5 years of age and 5-10 years of age., Results: The 0-5 years of age analysis included 117 gastroschisis cases and 1205 date of birth-matched controls; children with gastroschisis had a higher risk of asthma (relative risk [RR] = 1.46; 95% confidence interval [CI]: 1.03, 2.55; p = .029), acute bronchitis/bronchiolitis (RR = 1.61; 95% CI: 1.27, 2.03; p < .001), pneumonia (RR = 1.99; 95% CI: 1.45, 2.72; p < .001), viral pneumonia (RR = 5.15; 95% CI: 1.79, 14.81; p = .007), and pneumonia due to unspecified organism (RR = 2.06; 95% CI: 1.45, 2.92; p < .001). Gastroschisis children 0-5 years of age were also diagnosed more frequently with bronchitis/bronchiolitis (RR = 2.14; 95% CI: 1.79, 2.57; p < .001) and viral pneumonia (RR = 8.10; 95% CI: 3.79, 17.31; p < .001). The 5-10 years of age analysis included 73 cases and 738 controls; no difference in the risk of respiratory illness was found for gastroschisis cases and controls in this age group. However, gastroschisis cases were more frequently diagnosed with bacterial pneumonia (RR = 3.03; 95% CI: 1.67, 5.51; p < .001) and influenza (RR = 3.03; 95% CI: 1.67, 5.51; p < .001)., Conclusion: Our study shows that children with gastroschisis have an increased risk of asthma and respiratory infections compared with children without gastroschisis, most noticeably in the first 5 years of life., (© 2021 Wiley Periodicals LLC.)

Purpose: Tranexamic acid (TXA) reduces red blood cell transfusion in various orthopedic surgeries, yet the degree of practice variation in its use among anesthesiologists and surgeons has not been described. To target future knowledge transfer and implementation strategies, and to better understand determinants of variability in prophylactic TXA use, our primary objective was to evaluate the influence of surgical team members on the variability of prophylactic TXA administration., Methods: This was a retrospective cohort study of all adult patients undergoing primary total hip arthroplasty (THA), hip fracture surgery, and spine fusion ± vertebrectomy at two Canadian hospitals between January 2014 and December 2016. We used Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database which we linked to the Ottawa Data Warehouse. We described the percentage of patients that received TXA by individual surgery, the specifics of TXA dosing, and estimated the effect of anesthesiologists and surgeons on prophylactic TXA using multivariable mixed-effects logistic regression analyses., Results: In the 3,900 patients studied, TXA was most commonly used in primary THA (85%; n = 1,344/1,582), with lower use in hip fracture (23%; n = 342/1,506) and spine fusion surgery (23%; n = 186/812). The median [interquartile range] total TXA dose was 1,000 [1,000-1,000] mg, given as a bolus in 92% of cases. Anesthesiologists and surgeons added significant variability to the odds of receiving TXA in hip fracture surgery and spine fusion, but not primary THA. Most of the variability in TXA use was attributed to patient and other factors., Conclusion: We confirmed the routine use of TXA in primary THA, while observing lower utilization with more variability in hip fracture and spine fusion surgery. Further study is warranted to understand variations in use and the barriers to TXA implementation in a broader population of orthopedic surgical patients at high risk for transfusion.

Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and "real world" CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant-ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: The unprecedented worldwide social distancing response to COVID-19 resulted in a quick reversal of escalating case numbers. Recently, local governments globally have begun to relax social distancing regulations. Using the situation in Manitoba, Canada as an example, we estimated the impact that social distancing relaxation may have on the pandemic., Methods: We fit a mathematical model to empirically estimated numbers of people infected, recovered, and died from COVID-19 in Manitoba. We then explored the impact of social distancing relaxation on: (a) time until near elimination of COVID-19 (< one case per million), (b) time until peak prevalence, (c) proportion of the population infected within one year, (d) peak prevalence, and (e) deaths within one year., Results: Assuming a closed population, near elimination of COVID-19 in Manitoba could have been achieved in 4-6 months (by July or August) if there were no relaxation of social distancing. Relaxing to 15% of pre-COVID effective contacts may extend the local epidemic for more than two years (median 2.1). Relaxation to 50% of pre-COVID effective contacts may result in a peak prevalence of 31-38% of the population, within 3-4 months of initial relaxation., Conclusion: Slight relaxation of social distancing may immensely impact the pandemic duration and expected peak prevalence. Only holding the course with respect to social distancing may have resulted in near elimination before Fall of 2020; relaxing social distancing to 15% of pre-COVID-19 contacts will flatten the epidemic curve but greatly extend the duration of the pandemic., Competing Interests: The authors have declared that no competing interests exist.

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of cerebrospinal fluid and serum samples from 111 patients with acute SCI and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at 6 months with an area under the receiver operating characteristic curve of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response and establish the cerebrospinal fluid abundance of glial fibrillary acidic protein as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Perioperative bleeding is a major indication for red blood cell (RBC) transfusion, yet transfusion data in many major noncardiac surgeries are lacking and do not reflect recent blood conservation efforts. We aim to describe transfusion practices in noncardiac surgeries at high risk for RBC transfusion. We completed a retrospective cohort study to evaluate adult patients undergoing major noncardiac surgery at 5 Canadian hospitals between January 2014 and December 2016. We used Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database, which we linked to transfusion and laboratory databases. We studied all patients undergoing a major noncardiac surgery at ≥5% risk of perioperative RBC transfusion. For each surgery, we characterized the percentage of patients exposed to an RBC transfusion, the mean/median number of RBC units transfused, and platelet and plasma exposure. We identified 85 noncardiac surgeries with an RBC transfusion rate ≥5%, representing 25,607 patient admissions. The baseline RBC transfusion rate was 16%, ranging from 5% to 49% among individual surgeries. Of those transfused, the median (Q1, Q3) number of RBCs transfused was 2 U (1, 3 U); 39% received 1 U RBC, 36% received 2 U RBC, and 8% were transfused ≥5 U RBC. Platelet and plasma transfusions were overall low. In the era of blood conservation, we described transfusion practices in major noncardiac surgeries at high risk for RBC transfusion, which has implications for patient consent, preoperative surgical planning, and blood bank inventory management., Competing Interests: Conflicts of interest None., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: When managing opioid overdose (OD) patients, the optimal naloxone regimen should rapidly reverse respiratory depression while avoiding opioid withdrawal. Published naloxone administration guidelines have not been empirically validated and most were developed before fentanyl OD was common. In this study, rates of opioid withdrawal symptoms (OW) and reversal of opioid toxicity in patients treated with two naloxone dosing regimens were evaluated., Methods: In this retrospective matched cohort study, health records of patients who experienced an opioid OD treated in two urban emergency departments (ED) during an ongoing fentanyl OD epidemic were reviewed. Definitions for OW and opioid reversal were developed a priori . Low dose naloxone (LDN; ≤0.15 mg) and high dose naloxone (HDN; >0.15 mg) patients were matched in a 1:4 ratio based upon initial respiratory rate (RR). The proportion of patients who developed OW and who met reversal criteria were compared between those treated initially with LDN or HDN. Odds ratios (OR) for OW and opioid reversal were obtained via logistic regression stratified by matched sets and adjusted for age, sex, pre-naloxone GCS, and presence of non-opioid drugs or alcohol., Results: Eighty LDN patients were matched with 299 HDN patients. After adjustment, HDN patients were more likely than LDN patients to have OW after initial dose (OR = 8.43; 95%CI: 1.96, 36.3; p  = 0.004) and after any dose (OR = 2.56; 95%CI: 1.17, 5.60; p  = 0.019). HDN patients were more likely to meet reversal criteria after initial dose (OR = 2.73; 95%CI: 1.19, 6.26; p  = 0.018) and after any dose (OR = 6.07; 95%CI: 1.81, 20.3; p  = 0.003)., Conclusions: HDN patients were more likely to have OW but also more likely to meet reversal criteria versus LDN patients.

Study Objectives: To compare delta spectral power (delta) and odds ratio product (ORP) as measures of sleep depth during sleep restriction with placebo or a drug that increases delta., Methods: This is a secondary analysis of data from a study of 41 healthy participants randomized to receive placebo or gaboxadol 15 mg during sleep restriction. Participants underwent in-laboratory sleep studies on two baseline, four sleep restriction (5-h), and two recovery nights. Relation between delta or ORP and sleep depth was operationally defined as the degree of association of each metric to the probability of arousal or awakening occurring during the next 30 s (arousability)., Results: ORP values in wake, N1, N2, N3, and REM were significantly different. Delta differed between both N2 and N3 and other sleep stages but not between wake and N1 or N1 and REM. Epoch-by-epoch and individual correlations between ORP and delta power were modest or insignificant. The relation between ORP and arousability was linear across the entire ORP range. Delta also changed with arousability but only when delta values were less than 300 μV2. Receiver-operating-characteristic analysis found the ability to predict imminent arousal to be significantly greater with ORP than with log delta power for all experimental conditions. Changes in ORP, but not log delta, across the night correlated with next-day physiologic sleep tendency., Conclusions: Compared to delta power, ORP is more discriminating among sleep stages, more sensitive to sleep restriction, and more closely associated with arousability. This evidence supports ORP as a measure of sleep depth/intensity., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objectives: Vomiting is common in children after minor head injury. In previous research, isolated vomiting was not a significant predictor of intracranial injury after minor head injury; however, the significance of recurrent vomiting is unclear. This study aimed to determine the value of recurrent vomiting in predicting intracranial injury after pediatric minor head injury., Methods: This secondary analysis of the CATCH2 prospective multicenter cohort study included participants (0-16 years) who presented to a pediatric emergency department (ED) within 24 hours of a minor head injury. ED physicians completed standardized clinical assessments. Recurrent vomiting was defined as ≥ four episodes. Intracranial injury was defined as acute intracranial injury on computed tomography scan. Predictors were examined using chi-squared tests and logistic regression models., Results: A total of 855 (21.1%) of the 4,054 CATCH2 participants had recurrent vomiting, 197 (4.9%) had intracranial injury, and 23 (0.6%) required neurosurgical intervention. Children with recurrent vomiting were significantly more likely to have intracranial injury (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.7-3.1), and require neurosurgical intervention (OR, 3.5; 95% CI, 1.5-7.9). Recurrent vomiting remained a significant predictor of intracranial injury (OR, 2.8; 95% CI, 1.9-3.9) when controlling for other CATCH2 criteria. The probability of intracranial injury increased with number of vomiting episodes, especially when accompanied by other high-risk factors, including signs of a skull fracture, or irritability and Glasgow Coma Scale score < 15 at 2 hours postinjury. Timing of first vomiting episode, and age were not significant predictors., Conclusions: Recurrent vomiting (≥ four episodes) was a significant risk factor for intracranial injury in children after minor head injury. The probability of intracranial injury increased with the number of vomiting episodes and if accompanied by other high-risk factors, such as signs of a skull fracture or altered level of consciousness.

Purpose: The VICI-trial reported that in patients with congenital diaphragmatic hernia (CDH), mortality or bronchopulmonary dysplasia (BPD) were equivalent using conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation. The purpose of this study was to determine if the mode of ventilation at the time of CDH repair affected mortality or oxygen dependence at 28 days., Methods: We performed a retrospective cohort study of infants born wih CDH from 1991 to 2015. A generalized linear model was applied to the data using a propensity score analysis., Results: Eighty patients met the inclusion criteria; at the time of surgery 39 (48.8%) patients were on HFV and 41 (51.3%) patients were on CMV. In the HFV group, 16 (47.1%) patients remained oxygen dependent and there were 5 (12.8%) deaths at 28 days. In the CMV group, 5 (12.2%) patients remained oxygen dependent at 28 days but none had died. The base model demonstrated that the HFV group had increased rates of oxygen dependence [OR = 6.40 (2.13, 22.2), p = 0.002]. However, after propensity score analysis, we found no difference between HFV and CMV., Conclusion: Our study suggests that in infants with CDH, there is no significant difference between HFV and CMV in oxygen dependency or death.

Background: Most public health datasets do not include sexual orientation measures, thereby limiting the availability of data to monitor health disparities, and evaluate tailored interventions. We therefore developed, validated, and applied a novel computable phenotype model to classify men who have sex with men (MSM) using multiple health datasets from British Columbia, Canada, 1990-2015. Methods: Three case surveillance databases, a public health laboratory database, and five administrative health databases were linked and deidentified (BC Hepatitis Testers Cohort), resulting in a retrospective cohort of 727,091 adult men. Known MSM status from the three disease case surveillance databases was used to develop a multivariable model for classifying MSM in the full cohort. Models were selected using "elastic-net" (GLMNet package) in R, and a final model optimized area under the receiver operating characteristics curve. We compared characteristics of known MSM, classified MSM, and classified heterosexual men. Findings: History of gonorrhea and syphilis diagnoses, HIV tests in the past year, history of visit to an identified gay and bisexual men's clinic, and residence in MSM-dense neighborhoods were all positively associated with being MSM. The selected model had sensitivity of 72%, specificity of 94%. Excluding those with known MSM status, a total of 85,521 men (12% of cohort) were classified as MSM. Interpretation: Computable phenotyping is a promising approach for classification of sexual minorities and investigation of health outcomes in the absence of routinely available self-report data., (Copyright © 2020 Salway, Butt, Wong, Abdia, Balshaw, Rich, Ablona, Wong, Grennan, Yu, Alvarez, Rossi, Gilbert, Krajden and Janjua.)

Background: Nine mRNA transcripts associated with acute cellular rejection (ACR) in previous microarray studies were ported to the clinically amenable NanoString nCounter platform. Here we report the diagnostic performance of the resulting blood test to exclude ACR in heart allograft recipients: HEARTBiT., Methods: Blood samples for transcriptomic profiling were collected during routine post-transplantation monitoring in 8 Canadian transplant centres participating in the Biomarkers in Transplantation initiative, a large (n = 1622) prospective observational study conducted between 2009 and 2014. All adult cardiac transplant patients were invited to participate (median age = 56 [17 to 71]). The reference standard for rejection status was histopathology grading of tissue from endomyocardial biopsy (EMB). All locally graded ISHLT ≥ 2R rejection samples were selected for analysis (n = 36). ISHLT 1R (n = 38) and 0R (n = 86) samples were randomly selected to create a cohort approximately matched for site, age, sex, and days post-transplantation, with a focus on early time points (median days post-transplant = 42 [7 to 506])., Results: ISHLT ≥ 2R rejection was confirmed by EMB in 18 and excluded in 92 samples in the test set. HEARTBiT achieved 47% specificity (95% confidence interval [CI], 36%-57%) given ≥ 90% sensitivity, with a corresponding area under the receiver operating characteristic curve of 0.69 (95% CI, 0.56-0.81)., Conclusions: HEARTBiT's diagnostic performance compares favourably to the only currently approved minimally invasive diagnostic test to rule out ACR, AlloMap (CareDx, Brisbane, CA) and may be used to inform care decisions in the first 2 months post-transplantation, when AlloMap is not approved, and most ACR episodes occur., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to determine the degree of left ventricular (LV) dysfunction and its determinants in adolescents with type 2 diabetes (T2D). We hypothesized that adolescents with T2D would display impaired LV diastolic function and that these cardiovascular complications would be exacerbated in youth exposed to maternal diabetes in utero., Methods: Left ventricular structure and function, carotid artery intima media thickness and strain, and serum metabolomic profiles were compared between adolescents with T2D (n = 121) and controls (n = 34). Sub-group analyses examined the role of exposure to maternal diabetes as a determinant of LV or carotid artery structure and function among adolescents with T2D., Results: Adolescents with T2D were 15.1 ± 2.5 years old, (65% female, 99% Indigenous), had lived with diabetes for 2.7 ± 2.2 years, had suboptimal glycemic control (HbA1c = 9.4 ± 2.6%) and 58% (n = 69) were exposed to diabetes in utero. Compared to controls, adolescents with T2D displayed lower LV diastolic filling (early diastole/atrial filling rate ratio [E/A] = 1.9 ± 0.6 vs 2.2 ± 0.6, P = 0.012), lower LV relaxation and carotid strain (0.12 ± 0.05 vs 0.17 ± 0.05, P = .03) and elevated levels of leucine, isoleucine and valine. Among adolescents with T2D, exposure to diabetes in utero was not associated with differences in LV diastolic filling, LV relaxation, carotid strain or branched chain amino acids., Conclusions: Adolescents with T2D display LV diastolic dysfunction, carotid artery stiffness, and elevated levels of select branch chain amino acids; differences were not associated with exposure to maternal diabetes in utero., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Early dietary introduction of highly allergenic foods has been associated with decreased risk of food allergy in high-risk infants., Objective: Early introduction of highly allergenic foods for lower risk infants was examined using Canadian Healthy Infant Longitudinal Development (CHILD) Study data., Methods: CHILD participants were recruited from the general population before birth. Every 6 months, caregivers reported food introduction and allergic reactions. At ages 1 and 3 years, sensitization to peanut, egg, and cow's milk was measured by skin prick testing (SPT) and atopic dermatitis diagnosed at clinical visits. Multivariable logistic regression was used to examine associations between timing of introduction to peanut, egg, and cow's milk and the presence at 3 years of sensitization (positive SPT) and probable clinical IgE-mediated allergy (sensitization with no current consumption and convincing history of allergic reaction to the specific food)., Results: Among 2669 CHILD participants at age 3 years, 101 (3.80%) showed sensitization to peanut, 59 (2.21%) to egg, and 30 (1.12%) to cow's milk; 46 (1.78%) showed probable clinical IgE-mediated allergy to peanut, 4 (0.16%) to egg, and 2 (0.08%) to cow's milk. Infants introduced to peanut after 12 months had increased odds of sensitization (odds ratio [OR]: 2.38, 95% confidence interval [CI]: 1.39-4.07) and probable clinical allergy (OR: 4.04, 95% CI: 1.66-9.85) to peanut at 3 years. Associations persisted after exclusion of high-risk infants with moderate-to-severe atopic dermatitis in the first year/egg sensitization at 1 year., Conclusions: General-population infants introduced to peanut after age 12 months were more likely to have sensitization and probable clinical allergy to peanut at 3 years., (Copyright © 2019. Published by Elsevier Inc.)

Background: Climate change is increasing the number and intensity of extreme weather events in many parts of the world. Precipitation extremes have been linked to both outbreaks and sporadic cases of waterborne illness. We have previously shown a link between heavy rain and turbidity to population-level risk of sporadic cryptosporidiosis and giardiasis in a major Canadian urban population. The risk increased with 30 or more dry days in the 60 days preceding the week of extreme rain. The goal of this study was to investigate the change in cryptosporidiosis and giardiasis risk due to climate change, primarily change in extreme precipitation., Methods: Cases of cryptosporidiosis and giardiasis were extracted from a reportable disease system (1997-2009). We used distributed lag non-linear Poisson regression models and projections of the exposure-outcome relationship to estimate future illness (2020-2099). The climate projections are derived from twelve statistically downscaled regional climate models. Relative Concentration Pathway 8.5 was used to project precipitation derived from daily gridded weather observation data (~ 6 × 10 km resolution) covering the central of three adjacent watersheds serving metropolitan Vancouver for the 2020s, 2040s, 2060s and 2080s., Results: Precipitation is predicted to steadily increase in these watersheds during the wet season (Oct. -Mar.) and decrease in other parts of the year up through the 2080s. More weeks with extreme rain (>90th percentile) are expected. These weeks are predicted to increase the annual rates of cryptosporidiosis and giardiasis by approximately 16% by the 2080s corresponding to an increase of 55-136 additional cases per year depending upon the climate model used. The predicted increase in the number of waterborne illness cases are during the wet months. The range in future projections compared to historical monthly case counts typically differed by 10-20% across climate models but the direction of change was consistent for all models., Discussion: If new water filtration measures had not been implemented in our study area in 2010-2015, the risk of cryptosporidiosis and giardiasis would have been expected to increase with climate change, particularly precipitation changes. In addition to the predicted increase in the frequency and intensity of extreme precipitation events, the frequency and length of wet and dry spells could also affect the risk of waterborne diseases as we observed in the historical period. These findings add to the growing evidence regarding the need to prepare water systems to manage and become resilient to climate change-related health risks.

Background: Latent tuberculosis infection (LTBI) screening and treatment is a key component of the World Health Organization (WHO) EndTB Strategy, but the impact of LTBI screening and treatment at a population level is unclear. We aimed to estimate the impact of LTBI screening and treatment in a population of migrants to British Columbia (BC), Canada., Methods: This retrospective cohort included all individuals (N = 1 080 908) who immigrated to Canada as permanent residents between 1985 and 2012 and were residents in BC at any time up to 2013. Multiple administrative databases were linked to identify people with risk factors who met the WHO strong recommendations for screening: people with tuberculosis (TB) contact, with human immunodeficiency virus, on dialysis, with tumor necrosis factor-alpha inhibitors, who had an organ/haematological transplant, or with silicosis. Additional TB risk factors included immunosuppressive medications, cancer, diabetes, and migration from a country with a high TB burden. We defined active TB as preventable if diagnosed ≥6 months after a risk factor diagnosis. We estimated the number of preventable TB cases, given optimal LTBI screening and treatment, based on these risk factors., Results: There were 16 085 people (1.5%) identified with WHO strong risk factors. Of the 2814 people with active TB, 118 (4.2%) were considered preventable through screening with WHO risk factors. Less than half (49.4%) were considered preventable with expanded screening to include people migrating from countries with high TB burdens, people who had been prescribed immunosuppressive medications, or people with diabetes or cancer., Conclusions: The application of WHO LTBI strong recommendations for screening would have minimally impacted the TB incidence in this population. Further high-risk groups must be identified to develop an effective LTBI screening and treatment strategy for low-incidence regions., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We validate our previously developed (DOI: 10.1101/089227) clinical prediction rule for diagnosing transient ischemic attack on the basis of presenting clinical symptoms and compare its performance with the ABCD2 score in first-contact patient settings. Two independent and prospectively collected patient validation cohorts were used: (a) referral cohort-prospectively referred emergency department and general practitioner patients ( N = 877); and (b) SpecTRA cohort-participants recruited as part of the SpecTRA biomarker project ( N = 545). Outcome measure consisted of imaging-confirmed clinical diagnosis of mild stroke/transient ischemic attack. Results showed that our clinical prediction rule demonstrated significantly higher accuracy than the ABCD2 score for both the referral cohort (70.5% vs 59.0%; p < 0.001) and SpecTRA cohort (72.8% vs 68.3%; p = 0.028). We discuss the potential of our clinical prediction rule to replace the use of the ABCD2 score in the triage of transient ischemic attack clinic referrals.

Background and Aims: The province of British Columbia (BC) Canada has experienced a rapid increase in illicit drug overdoses and deaths during the last 4 years, with a provincial emergency declared in April 2016. These deaths have been driven primarily by the introduction of synthetic opioids into the illicit opioid supply. This study aimed to measure the combined impact of large-scale opioid overdose interventions implemented in BC between April 2016 and December 2017 on the number of deaths averted., Design: We expanded on the mathematical modelling methodology of our previous study to construct a Bayesian hierarchical latent Markov process model to estimate monthly overdose and overdose-death risk, along with the impact of interventions., Setting and Cases: Overdose events and overdose-related deaths in BC from January 2012 to December 2017., Interventions: The interventions considered were take-home naloxone kits, overdose prevention/supervised consumption sites and opioid agonist therapy MEASUREMENTS: Counterfactual simulations were performed with the fitted model to estimate the number of death events averted for each intervention and in combination., Findings: Between April 2016 and December 2017, BC observed 2177 overdose deaths (77% fentanyl-detected). During the same period, an estimated 3030 (2900-3240) death events were averted by all interventions combined. In isolation, 1580 (1480-1740) were averted by take-home naloxone, 230 (160-350) by overdose prevention services and 590 (510-720) were averted by opioid agonist therapy., Conclusions: A combined intervention approach has been effective in averting overdose deaths during British Columbia's opioid overdose crisis in the period since declaration of a public health emergency (April 2016-December 2017). However, the absolute numbers of overdose deaths have not changed., (© 2019 Society for the Study of Addiction.)