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Background: The Clinical Classification Software Refined (CCSR) is a tool that groups many thousands of International Classification of Diseases 10th Revision (ICD-10) diagnosis codes into approximately 500 clinically meaningful categories, simplifying analyses. However, CCSR was developed for use in the United States and may not work well with other country-specific ICD-10 coding systems., Method: We developed an algorithm for semi-automated matching of Canadian ICD-10 codes (ICD-10-CA) to CCSR categories using discharge diagnoses from adult admissions at 7 hospitals between Apr 1, 2010 and Dec 31, 2020, and manually validated the results. We then externally validated our approach using inpatient hospital encounters in Denmark from 2017 to 2018., Key Results: There were 383,972 Canadian hospital admissions with 5,186 distinct ICD-10-CA diagnosis codes and 1,855,837 Danish encounters with 4,612 ICD-10 diagnosis codes. Only 46.6% of Canadian codes and 49.4% of Danish codes could be directly categorized using the official CCSR tool. Our algorithm facilitated the mapping of 98.5% of all Canadian codes and 97.7% of Danish codes. Validation of our algorithm by clinicians demonstrated excellent accuracy (97.1% and 97.0% in Canadian and Danish data, respectively). Without our algorithm, many common conditions did not match directly to a CCSR category, such as 96.6% of hospital admissions for heart failure., Conclusion: The GEMINI CCSR matching algorithm (available as an open-source package at https://github.com/GEMINI-Medicine/gemini-ccsr) improves the categorization of Canadian and Danish ICD-10 codes into clinically coherent categories compared to the original CCSR tool. We expect this approach to generalize well to other countries and enable a wide range of research and quality measurement applications., Competing Interests: Declaration of competing interest Mike Fralick was a consultant for ProofDx, a start-up company creating a point of care diagnostic test for COVID-19. Mike Fralick is an advisor for SIGNAL1, a start-up company deploying machine learned models to improve inpatient care. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This paper outlines the methodological approaches to a multi-site Circumpolar case study exploring the impacts of COVID-19 on Indigenous and remote communities in 7 of 8 Arctic countries. Researchers involved with the project implemented a three-phase multi-site case study to assess the positive and negative societal outcomes associated with the COVID-19 pandemic in Arctic communities from 2020 to 2023. The goal of the multi-site case study was to identify community-driven models and evidence-based promising practices and recommendations that can help inform cohesive and coordinated public health responses and protocols related to future public health emergencies in the Arctic. Research sites included a minimum of 1 one community each from Canada (Nunavut,) United States of America (Alaska), Greenland, Iceland, Norway, Sweden, Finland. The approaches used for our multi-site case study provide a comprehensive, evidence-based account of the complex health challenges facing Arctic communities, offering insights into the effectiveness of interventions, while also privileging Indigenous local knowledge and voices. The mixed method multi-site case study approach enriched the understanding of unique regional health disparities and strengths during the pandemic. These methodological approaches serve as a valuable resource for policymakers, researchers, and healthcare professionals, informing future strategies and interventions.

While its etiology is not fully elucidated, preterm birth represents a major public health concern as it is the leading cause of child mortality and morbidity. Stress is one of the most common perinatal conditions and may increase the risk of preterm birth. In this paper we aimed to investigate the association of maternal perceived stress and anxiety with length of gestation. We used harmonized data from five birth cohorts from Canada, France, and Norway. A total of 5297 pregnancies of singletons were included in the analysis of perceived stress and gestational duration, and 55,775 pregnancies for anxiety. Federated analyses were performed through the DataSHIELD platform using Cox regression models within intervals of gestational age. The models were fit for each cohort separately, and the cohort-specific results were combined using random effects study-level meta-analysis. Moderate and high levels of perceived stress during pregnancy were associated with a shorter length of gestation in the very/moderately preterm interval [moderate: hazard ratio (HR) 1.92 (95%CI 0.83, 4.48); high: 2.04 (95%CI 0.77, 5.37)], albeit not statistically significant. No association was found for the other intervals. Anxiety was associated with gestational duration in the very/moderately preterm interval [1.66 (95%CI 1.32, 2.08)], and in the early term interval [1.15 (95%CI 1.08, 1.23)]. Our findings suggest that perceived stress and anxiety are associated with an increased risk of earlier birth, but only in the earliest gestational ages. We also found an association in the early term period for anxiety, but the result was only driven by the largest cohort, which collected information the latest in pregnancy. This raised a potential issue of reverse causality as anxiety later in pregnancy could be due to concerns about early signs of a possible preterm birth., (© 2024. The Author(s).)

Objective: To train and test a super learner strategy for risk prediction of kidney failure and mortality in people with incident moderate to severe chronic kidney disease (stage G3b to G4)., Design: Multinational, longitudinal, population based, cohort study., Settings: Linked population health data from Canada (training and temporal testing), and Denmark and Scotland (geographical testing)., Participants: People with newly recorded chronic kidney disease at stage G3b-G4, estimated glomerular filtration rate (eGFR) 15-44 mL/min/1.73 m 2 ., Modelling: The super learner algorithm selected the best performing regression models or machine learning algorithms (learners) based on their ability to predict kidney failure and mortality with minimised cross-validated prediction error (Brier score, the lower the better). Prespecified learners included age, sex, eGFR, albuminuria, with or without diabetes, and cardiovascular disease. The index of prediction accuracy, a measure of calibration and discrimination calculated from the Brier score (the higher the better) was used to compare KDpredict with the benchmark, kidney failure risk equation, which does not account for the competing risk of death, and to evaluate the performance of KDpredict mortality models., Results: 67 942 Canadians, 17 528 Danish, and 7740 Scottish residents with chronic kidney disease at stage G3b to G4 were included (median age 77-80 years; median eGFR 39 mL/min/1.73 m 2 ). Median follow-up times were five to six years in all cohorts. Rates were 0.8-1.1 per 100 person years for kidney failure and 10-12 per 100 person years for death. KDpredict was more accurate than kidney failure risk equation in prediction of kidney failure risk: five year index of prediction accuracy 27.8% (95% confidence interval 25.2% to 30.6%) versus 18.1% (15.7% to 20.4%) in Denmark and 30.5% (27.8% to 33.5%) versus 14.2% (12.0% to 16.5%) in Scotland. Predictions from kidney failure risk equation and KDpredict differed substantially, potentially leading to diverging treatment decisions. An 80-year-old man with an eGFR of 30 mL/min/1.73 m 2 and an albumin-to-creatinine ratio of 100 mg/g (11 mg/mmol) would receive a five year kidney failure risk prediction of 10% from kidney failure risk equation (above the current nephrology referral threshold of 5%). The same man would receive five year risk predictions of 2% for kidney failure and 57% for mortality from KDpredict. Individual risk predictions from KDpredict with four or six variables were accurate for both outcomes. The KDpredict models retrained using older data provided accurate predictions when tested in temporally distinct, more recent data., Conclusions: KDpredict could be incorporated into electronic medical records or accessed online to accurately predict the risks of kidney failure and death in people with moderate to severe CKD. The KDpredict learning strategy is designed to be adapted to local needs and regularly revised over time to account for changes in the underlying health system and care processes., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest and declare: no support from any organisation for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. RQ has received speaker fees, attended advisory boards, and received research support from Baxter Corporation. RQ co-owns a Canadian patent for the Dialysis Measurement Analysis and Reporting System., (© 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: Hemodynamic assessment for cardiogenic shock (CS) phenotyping in patients has led to renewed interest in the use of pulmonary artery catheters (PACs)., Methods: We included patients admitted with CS from January 2014 to December 2020 and compared clinical outcomes among patients who received PACs and those who did not. The primary outcome was the rate of in-hospital mortality. Secondary outcomes included use of advanced heart failure therapies and coronary intensive care unit (CICU) and hospital lengths of stay., Results: A total of 1043 patients were analysed and 47% received PACs. Patients selected for PAC-guided management were younger and had lower left ventricular function. They also had higher use of vasopressor and inotropes, and 15.2% of them were already supported with temporary mechanical circulatory support (MCS). In-hospital mortality was lower in patients who received PACs (29.3% vs 36.2%; P = 0.02), mainly driven by a reduction in mortality among those in Society for Cardiovascular Angiography and Interventions (SCAI) stages D and E CS. Patients who received PACs were more likely to receive temporary MCS with Impella, durable ventricular assist devices (VADs), or orthotopic heart transplantation (OHT) (P < 0.001 for all analyses). CICU and hospital lengths of stay were longer in patients who used PACs., Conclusions: Among patients with CS, the use of PACs was associated with lower in-hospital mortality, especially among those in SCAI stages D and E. Patients who received PACs were also more frequently rescued with temporary MCS or received advanced heart failure therapies, such as durable VADs or OHT., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term complications. To address this challenge, we employed a supervised machine learning technique, specifically random survival forests, to predict the risk of relapse and mortality using array-based DNA methylation data from a cohort of 763 pediatric ALL patients treated in Nordic countries. The relapse risk predictor (RRP) was constructed based on 16 CpG sites, demonstrating c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The mortality risk predictor (MRP), comprising 53 CpG sites, exhibited c-indexes of 0.751 and 0.754 in the training and test sets, respectively. To validate the prognostic value of the predictors, we further analyzed two independent cohorts of Canadian (n = 42) and Nordic (n = 384) ALL patients. The external validation confirmed our findings, with the RRP achieving a c-index of 0.667 in the Canadian cohort, and the RRP and MRP achieving c-indexes of 0.529 and 0.621, respectively, in an independent Nordic cohort. The precision of the RRP and MRP models improved when incorporating traditional risk group data, underscoring the potential for synergistic integration of clinical prognostic factors. The MRP model also enabled the definition of a risk group with high rates of relapse and mortality. Our results demonstrate the potential of DNA methylation as a prognostic factor and a tool to refine risk stratification in pediatric ALL. This may lead to personalized treatment strategies based on epigenetic profiling., (© 2024. The Author(s).)

Background: The Spondyloarthritis Research Consortium of Canada (SPARCC) developers have created web-based calibration modules for the SPARCC MRI sacroiliac joint (SIJ) scoring methods. We aimed to test the impact of applying these e-modules on the feasibility and reliability of these methods., Methods: The SPARCC-SIJ RETIC e-modules contain cases with baseline and follow-up scans and an online scoring interface. Visual real-time feedback regarding concordance/discordance of scoring with expert readers is provided by a colour-coding scheme. Reliability is assessed in real time by intraclass correlation coefficient (ICC), cases being scored until ICC targets are attained. Participating readers (n=17) from the EuroSpA Imaging project were randomised to one of two reader calibration strategies that each comprised three stages. Baseline and follow-up scans from 25 cases were scored after each stage was completed. Reliability was compared with a SPARCC developer, and the System Usability Scale (SUS) assessed feasibility., Results: The reliability of readers for scoring bone marrow oedema was high after the first stage of calibration, and only minor improvement was noted following the use of the inflammation module. Greater enhancement of reader reliability was evident after the use of the structural module and was most consistently evident for the scoring of erosion (ICC status/change: stage 1 (0.42/0.20) to stage 3 (0.50/0.38)) and backfill (ICC status/change: stage 1 (0.51/0.19) to stage 3 (0.69/0.41)). The feasibility of both e-modules was evident by high SUS scores., Conclusion: The SPARCC-SIJ RETIC e-modules are feasible, effective knowledge transfer tools, and their use is recommended before using the SPARCC methods for clinical research and tria., Competing Interests: Competing interests: WM has received honoraria/consulting fees from AbbVie, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma; research grants from AbbVie, Pfizer and UCB Pharma; and educational grants from AbbVie, Janssen, Novartis and Pfizer. WM is the Chief Medical Officer for CARE ARTHRITIS. MØ has received research grants from AbbVie, BMS, Merck, Novartis and UCB and speaker and/or consultancy fees from AbbVie, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB. RM received honoraria for lectures or presentations from AbbVie, Eli Lilly, Janssen, Gilead and Pfizer. BM received travel expenditures, honoraria for lectures or presentations from AbbVie, Janssen, Novartis and Pfizer. MJN has received honoraria for travel expenditures, lectures or presentations from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer and UCB. MdH received honoraria for presentations from UCB. RM received honoraria for presentations from UCB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Beginning January of 2020, COVID-19 cases detected in Arctic countries triggered government policy responses to stop transmission and limit caseloads beneath levels that would overwhelm existing healthcare systems. This review details the various restrictions, health mandates, and transmission mitigation strategies imposed by governments in eight Arctic countries (the United States, Canada, Greenland, Norway, Finland, Sweden, Iceland, and Russia) during the first year of the COVID-19 pandemic, through 31 January 2021s31 January 2021. We highlight formal protocols and informal initiatives adopted by local communities in each country, beyond what was mandated by regional or national governments. This review documents travel restrictions, communications, testing strategies, and use of health technology to track and monitor COVID-19 cases. We provide geographical and sociocultural background and draw on local media and communications to contextualise the impact of COVID-19 emergence and prevention measures in Indigenous communities in the Arctic. Countries saw varied case rates associated with local protocols, governance, and population. Still, almost all regions maintained low COVID-19 case rates until November of 2020. This review was produced as part of an international collaboration to identify community-driven, evidence-based promising practices and recommendations to inform pan-Arctic collaboration and decision making in public health during global emergencies.

Background: Studies across the globe generally reported increased mortality risks associated with particulate matter with aerodynamic diameter ≤ 2.5 μ m ( PM 2.5 ) exposure with large heterogeneity in the magnitude of reported associations and the shape of concentration-response functions (CRFs). We aimed to evaluate the impact of key study design factors (including confounders, applied exposure model, population age, and outcome definition) on PM 2.5 effect estimates by harmonizing analyses on three previously published large studies in Canada [Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE), 1991-2016], the United States (Medicare, 2000-2016), and Europe [Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), 2000-2016] as much as possible., Methods: We harmonized the study populations to individuals 65 + years of age, applied the same satellite-derived PM 2.5 exposure estimates, and selected the same sets of potential confounders and the same outcome. We evaluated whether differences in previously published effect estimates across cohorts were reduced after harmonization among these factors. Additional analyses were conducted to assess the influence of key design features on estimated risks, including adjusted covariates and exposure assessment method. A combined CRF was assessed with meta-analysis based on the extended shape-constrained health impact function (eSCHIF)., Results: More than 81 million participants were included, contributing 692 million person-years of follow-up. Hazard ratios and 95% confidence intervals (CIs) for all-cause mortality associated with a 5 - μ g / m 3 increase in PM 2.5 were 1.039 (1.032, 1.046) in MAPLE, 1.025 (1.021, 1.029) in Medicare, and 1.041 (1.014, 1.069) in ELAPSE. Applying a harmonized analytical approach marginally reduced difference in the observed associations across the three studies. Magnitude of the association was affected by the adjusted covariates, exposure assessment methodology, age of the population, and marginally by outcome definition. Shape of the CRFs differed across cohorts but generally showed associations down to the lowest observed PM 2.5 levels. A common CRF suggested a monotonically increased risk down to the lowest exposure level. https://doi.org/10.1289/EHP12141.

The Earth's polar regions are low rates of inter- and intraspecific diversification. An extreme mammalian example is the Arctic ringed seal (Pusa hispida hispida), which is assumed to be panmictic across its circumpolar Arctic range. Yet, local Inuit communities in Greenland and Canada recognize several regional variants; a finding supported by scientific studies of body size variation. It is however unclear whether this phenotypic variation reflects plasticity, morphs or distinct ecotypes. Here, we combine genomic, biologging and survey data, to document the existence of a unique ringed seal ecotype in the Ilulissat Icefjord (locally 'Kangia'), Greenland; a UNESCO World Heritage site, which is home to the most productive marine-terminating glacier in the Arctic. Genomic analyses reveal a divergence of Kangia ringed seals from other Arctic ringed seals about 240 kya, followed by secondary contact since the Last Glacial Maximum. Despite ongoing gene flow, multiple genomic regions appear under strong selection in Kangia ringed seals, including candidate genes associated with pelage coloration, growth and osmoregulation, potentially explaining the Kangia seal's phenotypic and behavioural uniqueness. The description of 'hidden' diversity and adaptations in yet another Arctic species merits a reassessment of the evolutionary processes that have shaped Arctic diversity and the traditional view of this region as an evolutionary freezer. Our study highlights the value of indigenous knowledge in guiding science and calls for efforts to identify distinct populations or ecotypes to understand how these might respond differently to environmental change., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Background and Aim: Little is known about the cardioprotective potential of a healthy lifestyle in familial hypercholesterolemia (FH). The objective of this study was to evaluate the relationship between lifestyle and cardiovascular risk factors in adults with FH., Methods and Results: This cross-sectional study leveraged data from the CARTaGENE Quebec population-based cohort (Canada). Participants with FH were identified using the validated Simplified Canadian Definition for FH. A healthy lifestyle score (HLS), ranging from 0 to 5, was calculated per adherence to 5 lifestyle habits: 1) not smoking; 2) being physically active (≥150 min/week of moderate or vigorous physical activity); 3) eating a healthy diet (Alternate Healthy Eating Index ≥50%); 4) having a light to moderate alcohol consumption (men: 1-30 g/day; women: 1-15 g/day); and 5) sleeping 7-8 h/day. Among the 122 included individuals (women, n = 78; men, n = 44; mean age ± SD: 57.3 ± 6.7 years), 92 (75.4%) had a HLS ≤3/5, while only 5 (4.1%) had a HLS of 5/5. After adjustments for sex, age, body mass index, and lipid-lowering medication use, we found no evidence of an association between the HLS and concentrations of LDL-cholesterol (β = 0.04, 95% CI = -0.08, 0.15 mmol/L; P = 0.54). However, the HLS was favorably associated with HbA1c levels (β = -0.07, 95% CI = -0.13, -0.01%; P = 0.02), and statistical trends suggested favorable associations with HDL-cholesterol (β = 0.06, 95% CI = -0.02, 0.14 mmol/L; P = 0.06) and waist circumference (β = -2.22, 95% CI = -4.62, 0.17 cm; P = 0.07)., Conclusion: This study suggests that a healthy lifestyle is favorably associated with CVD risk factors in adults with FH., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: In this study, we aimed to evaluate the efficacy, safety, and tolerability of atogepant for the preventive treatment of chronic migraine., Methods: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 142 clinical research sites across the USA, the UK, Canada, China, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Poland, Russia, Spain, Sweden, and Taiwan. Adults aged 18-80 years with a 1-year or longer history of chronic migraine were randomly assigned (1:1:1) to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. The primary analysis was done in the modified intent-to-treat population and included all randomly assigned participants who received at least one dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had at least one evaluable post-baseline 4-week period (weeks 1-4, 5-8, and 9-12) of eDiary data during the double-blind period. The safety population consisted of all participants who received at least one dose of study intervention. This trial is registered with ClinicalTrials.gov (NCT03855137)., Findings: Between March 11, 2019 and Jan 20, 2022, 1489 participants were assessed for eligibility. 711 were excluded, and 778 participants were randomly assigned to atogepant 30 mg twice a day (n=257), atogepant 60 mg once a day (n=262), or placebo (n=259). Participants in the safety population were aged 18-74 years (mean 42·1 years). 459 (59%) of 773 patients were White, 677 (88%) patients were female, and 96 (12%) were male. 84 participants discontinued treatment during the trial, and 755 comprised the modified intent-to-treat population (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246). Baseline mean number of MMDs were 18·6 (SE 5·1) with atogepant 30 mg twice a day, 19·2 (5·3) with atogepant 60 mg once a day, and 18·9 (4·8) with placebo. Change from baseline in mean MMDs across 12 weeks was -7·5 (SE 0·4) with atogepant 30 mg twice a day, -6·9 (0·4) with atogepant 60 mg once a day, and -5·1 (0·4) with placebo. Least squares mean difference from placebo was -2·4 with atogepant 30 mg twice a day (95% CI -3·5 to -1·3; adjusted p<0·0001) and -1·8 with atogepant 60 mg once a day (-2·9 to -0·8; adjusted p=0·0009). Most common adverse events for atogepant were constipation (30 mg twice a day 28 [10·9%]; 60 mg once a day 26 [10%]; and placebo 8 [3%]) and nausea (30 mg twice a day 20 [8%]; 60 mg once a day 25 [10%]; and placebo 9 [4%]). Potentially clinically significant weight decrease (≥7% reduction at any time post-baseline) was observed in each treatment group (atogepant 30 mg twice a day 14 [6%]; atogepant 60 mg once a day 15 [6%]; and placebo 5 [2%])., Interpretation: Atogepant 30 mg twice a day and 60 mg once a day showed clinically relevant reductions in MMDs across 12 weeks in chronic migraine patients. Both atogepant doses were well tolerated, consistent with the known safety profile of atogepant., Funding: Allergan (now AbbVie)., Competing Interests: Declaration of interests PPR reports support for the present study from AbbVie, personal fees from AbbVie, Biohaven, Chiesi, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, and Teva, and grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigación Carlos III, International Headache Society, Novartis, and Teva. JA reports support for the present study from AbbVie, personal fees from AbbVie, Aeon, Amgen, Axsome, Biohaven, BioDelivery Sciences International, Eli Lilly, GlaxoSmithKline, Impel, Linpharma, Lundbeck, Miravio, Neso, Neurolief, Satsuma, Teva, and Theranica, clinical trial support from AbbVie, Biohaven, Eli Lilly, Satsuma, and Zosano, and stock options from CtrlM. She has provided editorial services to Current Pain and Headache Reports, Medscape, NeurologyLive, and SELF magazine. MA reports support for the present study from AbbVie, personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals, and grants paid to his institution from the Lundbeck Foundation, Novartis, and Novo Nordisk Foundation. PJG reports support for the present study and personal fees during the conduct of the study from AbbVie, a grant from Celgene, and personal fees from Aeon Biopharma, Amgen, BioDelivery Sciences International, CoolTech LLC, Dr Reddy's Laboratories, Eli Lilly and Company, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma, Shiratronics, Teva Pharmaceuticals, and Tremeau, personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric, fees for educational materials from CME Outfitters and WebMD, and fees for publishing from Massachusetts Medical Society and Oxford University Press and for medicolegal advice in headache. He has a patent for magnetic stimulation for headache, which is licensed to eNeura without fee. RBL reports support for the present study from AbbVie, research support paid to his institution for the present study from the National Institutes of Health/National Institute on Aging (2PO1 AG003949, Einstein Aging Study), the S&L Marx Foundation, the Czap Foundation, the National Headache Foundation, the Migraine Research Foundation, and the US Food and Drug Administration, and personal fees from AbbVie/Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven, Biovision, Boston, Dr. Reddy's Laboratories (Promius), electroCore, Eli Lilly, eNeura, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Teva, Vector, and Vedanta Research. He holds stock or options in Biohaven and Manistee. UR reports support for the present study paid to his institution from AbbVie, grants from BMBF (German Ministry for Research) and Novartis, and personal and institutional fees from AbbVie, Allergan, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer, StreaMedUp, and Teva. HG, BS, RB, RDAF, EM, and JMT are employees of AbbVie and may hold AbbVie stock. KL, RM, SYY, LS, and MF are former employees of AbbVie and may hold AbbVie stock., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background Prior chest CT provides valuable temporal information (eg, changes in nodule size or appearance) to accurately estimate malignancy risk. Purpose To develop a deep learning (DL) algorithm that uses a current and prior low-dose CT examination to estimate 3-year malignancy risk of pulmonary nodules. Materials and Methods In this retrospective study, the algorithm was trained using National Lung Screening Trial data (collected from 2002 to 2004), wherein patients were imaged at most 2 years apart, and evaluated with two external test sets from the Danish Lung Cancer Screening Trial (DLCST) and the Multicentric Italian Lung Detection Trial (MILD), collected in 2004-2010 and 2005-2014, respectively. Performance was evaluated using area under the receiver operating characteristic curve (AUC) on cancer-enriched subsets with size-matched benign nodules imaged 1 and 2 years apart from DLCST and MILD, respectively. The algorithm was compared with a validated DL algorithm that only processed a single CT examination and the Pan-Canadian Early Lung Cancer Detection Study (PanCan) model. Results The training set included 10 508 nodules (422 malignant) in 4902 trial participants (mean age, 64 years ± 5 [SD]; 2778 men). The size-matched external test sets included 129 nodules (43 malignant) and 126 nodules (42 malignant). The algorithm achieved AUCs of 0.91 (95% CI: 0.85, 0.97) and 0.94 (95% CI: 0.89, 0.98). It significantly outperformed the DL algorithm that only processed a single CT examination (AUC, 0.85 [95% CI: 0.78, 0.92; P = .002]; and AUC, 0.89 [95% CI: 0.84, 0.95; P = .01]) and the PanCan model (AUC, 0.64 [95% CI: 0.53, 0.74; P < .001]; and AUC, 0.63 [95% CI: 0.52, 0.74; P < .001]). Conclusion A DL algorithm using current and prior low-dose CT examinations was more effective at estimating 3-year malignancy risk of pulmonary nodules than established models that only use a single CT examination. Clinical trial registration nos. NCT00047385, NCT00496977, NCT02837809 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Horst and Nishino in this issue.

Background: Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively., Objective: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery., Design: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723)., Setting: 110 hospitals in 22 countries., Patients: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications., Intervention: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80 mm Hg or greater; before and for 2 days after surgery, renin-angiotensin-aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130 mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60 mm Hg or greater; all antihypertensive medications were continued before and after surgery., Measurements: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment., Results: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P  = 0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term., Limitation: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels., Conclusion: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications., Primary Funding Source: Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and Research Grant Council of Hong Kong., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3157.

Objectives: There is little research examining transnational prenatal care (TPC) (i.e., prenatal care in more than one country) among migrant women. Using data from the Migrant-Friendly Maternity Care (MFMC) - Montreal project, we aimed to: (1) Estimate the prevalence of TPC, including TPC-arrived during pregnancy and TPC-arrived pre-pregnancy, among recently-arrived migrant women from low- and middle-income countries (LMICs) who gave birth in Montreal, Canada; (2) Describe and compare the socio-demographic, migration and health profiles and perceptions of care during pregnancy in Canada between these two groups and migrant women who received no TPC (i.e., only received prenatal care in Canada); and (3) Identify predictors of TPC-arrived pre-pregnancy vs. No-TPC., Methods: The MFMC study used a cross-sectional design. Data were gathered from recently-arrived (< 8 years) migrant women from LMICs via medical record review and interview-administration of the MFMC questionnaire postpartum during the period of March 2014-January 2015 in three hospitals, and February-June 2015 in one hospital. We conducted a secondary analysis (n = 2595 women); descriptive analyses (objectives 1 & 2) and multivariable logistic regression (objective 3)., Results: Ten percent of women received TPC; 6% arrived during pregnancy and 4% were in Canada pre-pregnancy. The women who received TPC and arrived during pregnancy were disadvantaged compared to women in the other two groups (TPC-arrived pre-pregnancy and No-TPC women), in terms of income level, migration status, French and English language abilities, access barriers to care and healthcare coverage. However, they also had a higher proportion of economic migrants and they were generally healthier compared to No-TPC women. Predictors of TPC-arrived pre-pregnancy included: 'Not living with the father of the baby' (AOR = 4.8, 95%CI 2.4, 9.8), 'having negative perceptions of pregnancy care in Canada (general experiences)' (AOR = 1.2, 95%CI 1.1, 1.3) and younger maternal age (AOR = 1.1, 95%CI 1.0, 1.1)., Conclusion: Women with more capacity may self-select to migrate during pregnancy which results in TPC; these women, however, are disadvantaged upon arrival, and may need additional care. Already-migrated women may use TPC due to a need for family and social support and/or because they prefer the healthcare in their home country., (© 2023. The Author(s).)

Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardiovascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel K V 7.1/KCNE1, which is the most frequently mutated ion channel in LQTS., Methods: We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts., Findings: We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate K V 7.1/KCNE1. Using the endocannabinoid ARA-S as a prototype, we show that the effect is not dependent on the KCNE1 subunit or the phosphorylation state of the channel. In guinea pig hearts, ARA-S was found to reverse the E4031-prolonged action potential duration and QT interval., Interpretation: We consider the endocannabinoids as an interesting class of hK V 7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts., Funding: ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing., Competing Interests: Declaration of interests A patent application (#62/032,739) including a description of the interaction of charged lipophilic compounds with the K(V)7.1 channel has been submitted by the University of Miami with S.I.L. identified as one of the inventors. The other authors have no conflict of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

This pilot study was designed to investigate the effects of a holistic lighting intervention on the quality of life for individuals with low vision. Sixty participants (44 women; median age 69 years) with visual impairment received lighting interventions, including a home visit and consultation in a lighting lab. Assisted by low vision consultants, participants evaluated their performance using the Canadian Occupational Performance Measure (COPM) before and after the intervention. Improvements in visual functioning and quality of life were evaluated using the 39-item National Eye Institute Visual Function Questionnaire (NEI VFQ-39), the Groffman Visual Tracing Test , and the Farnsworth Dichotomous Test (D15). Following the lighting intervention, scores improved for all activities in the COPM ( p  < 0.01), for near activities and vision-specific role difficulties in the VFQ-39 ( p  < 0.05), and overall in the D15 test ( p  < 0.05). These results suggest the intervention provided an effective method for improving the participants' quality of life and performance.

Introduction: Comprehensive data capture systems such as the Operating Room Black Box (OR Black Box) are becoming more widely implemented to access quality data in the complex environment of the OR. Prior to installing an OR Black Box, we assessed perceptions on safety attitudes, impostor phenomenon and privacy concerns around digital information sharing among healthcare professionals in the OR. A parallel survey was conducted in Canada, hence, this study also discusses cultural and international differences when implementing new technology in healthcare., Methods: A cross-sectional survey using three previously validated questionnaires (Safety Attitudes Questionnaire (SAQ), Clance Impostor Phenomenon Scale, Dispositional Privacy Concern) was distributed through Research Electronic Data Capture to 145 healthcare professionals from the OR (July to December 2019). Analysis of variance and analysis of covariance were used to test for differences., Results: 124 responded (86%): 100 completed the survey (69%) (38 nurses, 10 anaesthesiologists, 36 obstetricians/gynaecologists, 16 residents). Significant variability in all six SAQ domains, safety climate and teamwork being the lowest ranked and job satisfaction ranked highest for all groups. The SAQ varied in all domains in Canada. Moderate to frequent impostor phenomenon was experienced by 71% predominantly among residents (p=0.003). 72% in the Canadian study. Residents were most comfortable with digital information sharing (p<0.001), only 13% of all healthcare professionals were concerned/heavy concerned compared with 45% in Canada., Conclusions: The different healthcare professional groups had diverse perceptions about safety culture, but were mainly concerned about safety climate and teamwork in the OR. Impostor phenomenon decreased with age. All groups were unconcerned about digital information sharing. The Canadian study had similar findings in terms of impostor phenomenon, but a variety within the SAQ and were more concerned about data safety, which could be due to medical litigation per se and is not widespread in Scandinavia compared with North America., Competing Interests: Competing interests: TG is the founder and Director of Surgical Safety Technologies and equity holder of Surgical Safety Technologies, Inc., Toronto, Canada., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mercury has become a ubiquitous hazardous element even ending up in pristine areas such as the Arctic, where it biomagnifies and leaves especially top predators vulnerable to potential health effects. Here we investigate total mercury (THg) concentrations and dietary proxies for trophic position and habitat foraging (δ 15 N and δ 13 C, respectively) in fur of 30 Arctic wolves collected during 1869-1998 in the Canadian High Arctic and Greenland. Fur THg concentrations (mean ± SD) of 1.46 ± 1.39 μg g -1 dry weight are within the range of earlier reported values for other Arctic terrestrial species. Based on putative thresholds for Hg-mediated toxic health effects, the studied Arctic wolves have most likely not been at compromised health. Dietary proxies show high dietary plasticity among Arctic wolves deriving nutrition from both marine and terrestrial food sources at various trophic positions. Variability in THg concentrations seem to be related to the wolves' trophic position rather than to different carbon sources or regional differences (East Greenland, the Foxe Basin and Baffin Bay area, respectively). Although the present study remains limited due to the scarce, yet unique historic study material and small sample size, it provides novel information on temporal and spatial variation in Hg pollution of remote Arctic species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The United States, the EU and Canada established a trilateral working group on the ecosystem approach to ocean health and stressors under the Atlantic Ocean Research Alliance. Recognizing the Atlantic Ocean as a shared resource and responsibility, the working group sought to advance understanding of the Atlantic Ocean and its dynamic systems to improve ocean health, enhance ocean stewardship and promote the sustainable use and management of its resources. This included consideration of multiple ocean-use sectors such as fishing, shipping, tourism and offshore energy. The working group met for 4 years and worked through eight steps that covered the development of common language as a basis for collaboration, challenges of stakeholder engagement, review of the governance mandates, exploring the links between sectors and ecosystems effects, identifying gaps in knowledge and uptake of science, identification of tools for ecosystem-based management, customary best practice for tool development and communication of key research priorities. The key findings were that ecosystem-based management enables new benefits and opportunities, and that we need to make the business case. Further findings were that adequate mandates and effective tools exist for ecosystem-based management, and that ecosystem-based management urgently requires integration of human dimensions, so we must diversify the conversation. In addition, it was found that stakeholders do not see their stake in ecosystem-based management, so greater engagement with stakeholders and targeting of ocean literacy is required and a sustainable future requires a sustained investment in ecosystem-based management, so long-term commitment is key., (© 2022 Fisheries Society of the British Isles.)

Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Regulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories., Methods: We conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013-March 2016) as well as in a BC advisory cohort (June 2014-May 2017)., Results: This study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66-0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors., Conclusion: Hydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP., (© 2022. The Author(s).)

Background: Greater understanding of international cancer survival differences is needed. We aimed to identify predictors and consequences of cancer diagnosis through emergency presentation in different international jurisdictions in six high-income countries., Methods: Using a federated analysis model, in this cross-sectional population-based study, we analysed cancer registration and linked hospital admissions data from 14 jurisdictions in six countries (Australia, Canada, Denmark, New Zealand, Norway, and the UK), including patients with primary diagnosis of invasive oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer during study periods from Jan 1, 2012, to Dec 31, 2017. Data were collected on cancer site, age group, sex, year of diagnosis, and stage at diagnosis. Emergency presentation was defined as diagnosis of cancer within 30 days after an emergency hospital admission. Using logistic regression, we examined variables associated with emergency presentation and associations between emergency presentation and short-term mortality. We meta-analysed estimates across jurisdictions and explored jurisdiction-level associations between cancer survival and the percentage of patients diagnosed as emergencies., Findings: In 857 068 patients across 14 jurisdictions, considering all of the eight cancer sites together, the percentage of diagnoses through emergency presentation ranged from 24·0% (9165 of 38 212 patients) to 42·5% (12 238 of 28 794 patients). There was consistently large variation in the percentage of emergency presentations by cancer site across jurisdictions. Pancreatic cancer diagnoses had the highest percentage of emergency presentations on average overall (46·1% [30 972 of 67 173 patients]), with the jurisdictional range being 34·1% (1083 of 3172 patients) to 60·4% (1317 of 2182 patients). Rectal cancer had the lowest percentage of emergency presentations on average overall (12·1% [10 051 of 83 325 patients]), with a jurisdictional range of 9·1% (403 of 4438 patients) to 19·8% (643 of 3247 patients). Across the jurisdictions, older age (ie, 75-84 years and 85 years or older, compared with younger patients) and advanced stage at diagnosis compared with non-advanced stage were consistently associated with increased emergency presentation risk, with the percentage of emergency presentations being highest in the oldest age group (85 years or older) for 110 (98%) of 112 jurisdiction-cancer site strata, and in the most advanced (distant spread) stage category for 98 (97%) of 101 jurisdiction-cancer site strata with available information. Across the jurisdictions, and despite heterogeneity in association size (I 2 =93%), emergency presenters consistently had substantially greater risk of 12-month mortality than non-emergency presenters (odds ratio >1·9 for 112 [100%] of 112 jurisdiction-cancer site strata, with the minimum lower bound of the related 95% CIs being 1·26). There were negative associations between jurisdiction-level percentage of emergency presentations and jurisdiction-level 1-year survival for colon, stomach, lung, liver, pancreatic, and ovarian cancer, with a 10% increase in percentage of emergency presentations in a jurisdiction being associated with a decrease in 1-year net survival of between 2·5% (95% CI 0·28-4·7) and 7·0% (1·2-13·0)., Interpretation: Internationally, notable proportions of patients with cancer are diagnosed through emergency presentation. Specific types of cancer, older age, and advanced stage at diagnosis are consistently associated with an increased risk of emergency presentation, which strongly predicts worse prognosis and probably contributes to international differences in cancer survival. Monitoring emergency presentations, and identifying and acting on contributing behavioural and health-care factors, is a global priority for cancer control., Funding: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; the Scottish Government; Western Australia Department of Health; and Wales Cancer Network., Competing Interests: Declarations of interests OB and GM declare salary compensation for analysis of trial data in preparation for review by the Data Safety Monitoring Board for the POWERRANGER trial (NCT01404156), unrelated to this project. BD declares project funding from the Velux Foundation (Velux Fonden) and the Nordic Collaboration Cancer Care Pathways, for the Danish Cancer Society. ATG reports support to her employer (Queen's University Belfast) from the Public Health Agency for Northern Ireland. DWD declares support to his employer (Northern Ireland Cancer Registry) from the Public Health Agency for Northern Ireland. DWH declares project support from Public Health Wales NHS Trust and Macmillan Cancer Support, and personal payment for research consultancy fees from Pfizer for work done by Swansea University concerning value-based health care, unrelated to this work. CGCAJ declares past part-employment by the Cancer Society of New Zealand, who co-sponsors the project. HJ declares research grant funding from the Velux Foundation (Velux Fonden). BM and YN declare research grant funding to the Cancer Registry of Norway from the Norwegian Cancer Society. RST declares project support to Public Health Wales NHS Trust from the NHS Wales Cancer Network and Macmillan Cancer Support. RRW reports research grant funding from the Michael Smith Foundation for Health Research, and the First Nations Health Authority and Canadian Partnership Against Cancer. GL declares research grant funding from the study sponsors to his employer (University College London)., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Shiga toxin (Stx) is the definitive virulence factor of Shiga toxin-producing Escherichia coli (STEC). Stx variants are currently organized into a taxonomic system of three Stx1 (a, c, and d) and seven Stx2 (a, b, c, d, e, f, and g) subtypes. In this study, seven STEC isolates from food and clinical samples possessing stx2 sequences that do not fit current Shiga toxin taxonomy were identified. Genome assemblies of the STEC strains were created from Oxford Nanopore and Illumina sequence data. The presence of atypical stx2 sequences was confirmed by Sanger sequencing, as were Stx2 expression and cytotoxicity. A strain of O157:H7 was found to possess stx1a and a truncated stx2a , which were originally misidentified as an atypical stx 2 . Two strains possessed unreported variants of Stx2a (O8:H28) and Stx2b (O146:H21). In four of the strains, we found three Stx subtypes that are not included in the current taxonomy. Stx2h (O170:H18) was identified in a Canadian sprout isolate; this subtype has only previously been reported in STEC from Tibetan Marmots. Stx2o (O85:H1) was identified in a clinical isolate. Finally, Stx2j (O158:H23 and O33:H14) was found in lettuce and clinical isolates. The results of this study expand the number of known Stx subtypes, the range of STEC serotypes, and isolation sources in which they may be found. The presence of the Stx2j and Stx2o in clinical isolates of STEC indicates that strains carrying these variants are potential human pathogens.

The harbour seal (Phoca vitulina) is the most widely distributed pinniped, occupying a wide variety of habitats and climatic zones across the Northern Hemisphere. Intriguingly, the harbour seal is also one of the most philopatric seals, raising questions as to how it colonized its current range. To shed light on the origin, remarkable range expansion, population structure and genetic diversity of this species, we used genotyping-by-sequencing to analyse ~13,500 biallelic single nucleotide polymorphisms from 286 individuals sampled from 22 localities across the species' range. Our results point to a Northeast Pacific origin of the harbour seal, colonization of the North Atlantic via the Canadian Arctic, and subsequent stepping-stone range expansions across the North Atlantic from North America to Europe, accompanied by a successive loss of genetic diversity. Our analyses further revealed a deep divergence between modern North Pacific and North Atlantic harbour seals, with finer-scale genetic structure at regional and local scales consistent with strong philopatry. The study provides new insights into the harbour seal's remarkable ability to colonize and adapt to a wide range of habitats. Furthermore, it has implications for current harbour seal subspecies delineations and highlights the need for international and national red lists and management plans to ensure the protection of genetically and demographically isolated populations., (© 2022 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Objective: To evaluate the association between regulatory drug safety advisories and changes in drug utilisation., Design: We conducted controlled, interrupted times series analyses with administrative prescription claims data to estimate changes in drug utilisation following advisories. We used random-effects meta-analysis with inverse-variance weighting to estimate the average postadvisory change in drug utilisation across advisories., Study Population: We included advisories issued in Canada, Denmark, the UK and the USA during 2009-2015, mainly concerning drugs in common use in primary care. We excluded advisories related to over-the-counter drugs, drug-drug interactions, vaccines, drugs used primarily in hospital and advisories with co-interventions within ±6 months., Main Outcome Measures: Change in drug utilisation, defined as actual versus predicted percentage change in the number of prescriptions (for advisories without dose-related advice), or in the number of defined daily doses (for dose-related advisories), per 100 000 population., Results: Among advisories without dose-related advice (n=20), the average change in drug utilisation was -5.83% (95% CI -10.93 to -0.73; p=0.03). Advisories with dose-related advice (n=4) were not associated with a statistically significant change in drug utilisation (-1.93%; 95% CI -17.10 to 13.23; p=0.80). In a post hoc subgroup analysis of advisories without dose-related advice, we observed no statistically significant difference between the change in drug utilisation following advisories with explicit prescribing advice, such as a recommendation to consider the risk of a drug when prescribing, and the change in drug utilisation following advisories without such advice., Conclusions: Among safety advisories issued on a wide range of drugs during 2009-2015 in 4 countries (Canada, Denmark, the UK and the USA), the association of advisories with changes in drug utilisation was variable, and the average association was modest., Competing Interests: Competing interests: MLDB declares PhD grants from Novo Nordisk, Lundbeck, Ferring Pharmaceuticals and LEO Pharma to the Copenhagen Centre for Regulatory Science; CH declares grants or contracts from Novo Nordisk A/S and H. Lundbeck A/S paid to her institution; BM is acting as an expert witness for Health Canada on a legal case and anticipates future payment for doing so; S-AP declares the Centre for Big Data Research in Health received funding for postmarket surveillance research, unrelated to the current study; LP has received a Michael Smith Foundation for Health Research Reach Grant; AS declares grants or contracts from Arnold Ventures and the FDA paid to his institution, consulting fees from West Health and payment for expert testimony from the ACLU; IS has received a CIHR Canadian Network for Observational Drug Effect Studies grant and a Drug Evaluation Alliance of Nova Scotia grant, and payment for serving as a member of the Patented Medicine Prices Review Board., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The Management of Myocardial Injury after Non-Cardiac Surgery (MANAGE) trial demonstrated that dabigatran 110 mg twice daily was more effective than placebo in preventing the primary composite outcome of vascular mortality, non-fatal myocardial infarction, non-hemorrhagic stroke, peripheral arterial thrombosis, amputation and symptomatic venous thromboembolism in patients with myocardial injury after non-cardiac surgery (MINS). The cost implications of dabigatran for this population are unknown but are important given the significant clinical implications., Methods: Hospitalized events, procedures, and study and non-study medications were documented. We applied Canadian unit costs to healthcare resources consumed for all patients in the trial, and calculated the average cost per patient in Canadian dollars for the duration of the study (median follow-up of 16 months). A sensitivity analysis was performed using only Canadian patients, and subgroup analyses were also conducted., Results: The total study cost for the dabigatran group was $9985 per patient, compared with $10,082 for placebo, a difference of - $97 (95% confidence interval [CI] - $2128 to $3672). Savings arising from fewer clinical events and procedures in the dabigatran 110 mg twice-daily group were enough to offset the cost of the study drug. In Canadian patients, the difference was $250 (95% CI -$2848 to $4840). Both differences were considered cost neutral. Dabigatran 110 mg twice daily was cost saving or cost neutral in many subgroups that were considered., Conclusion: Dabigatran 110 mg twice daily was cost neutral for patients in the MANAGE trial. Our cost findings support the use of dabigatran 110 mg twice daily in patients with MINS., Trial Registration: ClinicalTrials.gov identifier number NCT01661101., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Aims: Guideline-recommended use of risk calculators to select for statin therapy in primary prevention has never been tested in a randomized controlled trial (RCT). We determined the extent to which guideline-based statin recommendations from the American College of Cardiology/American Heart Association (ACC/AHA), Canadian Cardiovascular Society(CCS), UK National Institute for Health and Care Excellence (NICE), and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) is supported by available evidence from RCTs., Methods: 79,171 individuals from the Copenhagen General Population Study who were free of ASCVD and statin use at baseline were included. RCT evidence supporting guideline-recommended statin allocation and the estimated number needed to treat (NNT) to prevent one ASCVD event were assessed., Results: During 8.2 years of follow-up, 4031 ASCVD events occurred. Of individuals eligible for statin therapy with the ACC/AHA, CCS, NICE and ESC/EAS guidelines, 86%, 88%, 88% and 84% had direct RCT evidence of statin efficacy, respectively (guideline-positive&RCT-positive). This group represented 26-37% of all 79,171 individuals, while guideline-positive&RCT-negative individuals represented 5-7%, guideline-negative&RCT-positive individuals 28-39%, and guideline-negative&RCT-negative individuals represented 30-31%. The ASCVD events per 1000 person-years were 11.4-12.7 (guideline-positive&RCT-positive), 6.3-8.0 (guideline-positive&RCT-negative), 4.2-5.2 (guideline-negative&RCT-positive), and 2.3-2.5 (guideline-negative&RCT-negative), respectively, while the corresponding NNT to prevent one event in 10 years using high-intensity statin were 19-21, 30-32, 48-60, and 105-125, respectively., Conclusions: The far majority of individuals eligible for guideline-recommended primary prevention with statins have direct RCT evidence supporting statin use. Allocating statins based on guideline-criteria is more efficient with lower NNT for preventing ASCVD events than allocating statin therapy based solely on RCT evidence., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for adults. We aimed to assess and compare trends over time in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Joinpoint regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (-2.9; 95% confidence interval = -4.0 to -1.7) compared to AYAs (-1.8; -2.1 to -1.5) and adults aged >40 years (-1.5; -1.6 to -1.4). This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children -4.6 (-6.1 to -3.1) vs AYAs -3.2 (-4.2 to -2.1) and over 40s -1.1 (-1.3 to -0.8). AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged 0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients., (© 2021 UICC.)

International comparison of liver cancer survival has been hampered due to varying standards and degrees for morphological verification and differences in coding practices. This article aims to compare liver cancer survival across the International Cancer Benchmarking Partnership's (ICBP) jurisdictions whilst trying to ensure that the estimates are comparable through a range of sensitivity analyses. Liver cancer incidence data from 21 jurisdictions in 7 countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom) were obtained from population-based registries for 1995-2014. Cases were categorised based on histological classification, age-groups, basis of diagnosis and calendar period. Age-standardised incidence rate (ASR) per 100 000 and net survival at 1 and 3 years after diagnosis were estimated. Liver cancer incidence rates increased over time across all ICBP jurisdictions, particularly for hepatocellular carcinoma (HCC) with the largest relative increase in the United Kingdom, increasing from 1.3 to 4.4 per 100 000 person-years between 1995 and 2014. Australia had the highest age-standardised 1-year and 3-year net survival for all liver cancers combined (48.7% and 28.1%, respectively) in the most recent calendar period, which was still true for morphologically verified tumours when making restrictions to ensure consistent coding and classification. Survival from liver cancers is poor in all countries. The incidence of HCC is increasing alongside the proportion of nonmicroscopically verified cases over time. Survival estimates for all liver tumours combined should be interpreted in this context. Care is needed to ensure that international comparisons are performed on appropriately comparable patients, with careful consideration of coding practice variations., (© 2021 UICC.)

Background: The aim of this study was to translate the Canadian Assessment of Physical Literacy, second edition (CAPL-2) into Danish language, adapt it to Danish context and to test the measurement properties on a sample of Danish school children., Methods: The CAPL-2 measurement tool was translated into Danish language and adapted for the Danish context. This Danish version of the CAPL-2 was then tested on 891 Danish school children from 50 classes in 12 different schools., Results: Confirmatory factor analysis using the four-factor model, as suggested by the CAPL-2 original developers, showed an acceptable model fit for the Danish version (CFI = .973; TLI = .957; RMSEA = 0.040 (90% CI 0.033-0.054); SRMR = 0.040). Positive significant correlations between the domains were found. The domains as well as the total CAPL-2 score were found to be positively associated with physical education teachers' assessment of their pupil's in four central aspects of PL (i.e. enjoyment, confidence, motor skills, and diversity) indicating predictive validity. High internal consistency of the instrument used to measure motivation and confidence domain were found., Conclusion: The translated and context-adapted Danish version of CAPL-2 is a valid and reliable measurement tool ready to use in Danish research studies., (© 2021. The Author(s).)

The factors that influence patient healthcare experiences are complex and connected to place. In northern Canada, the socio-historical context and the inequitable distribution of health services are unique influences on patients. The objective of this study was to examine the characteristics of patient healthcare experiences as reported through news media in the Northwest Territories. We used a case series design to examine patient healthcare experiences reported in news media articles. We conducted a systematic search for articles published between 2008 and 2017 in the online database of a media outlet in the Northwest Territories. We used descriptive statistics to summarise the article characteristics and thematic analysis to understand patient experiences in 128 articles related to 71 cases. Most often, cases involved women, concerned mental health, suicidality, or chronic diseases, and were predominantly negative. Patient experiences included problems associated with medical travel, communication difficulties with providers, lack of cultural safety, and barriers in accessing care resulting in poor-quality care, particularly for Indigenous patients. Broadly, these experiences are rooted in the colonial history in the North. Understanding patient experiences and including Indigenous patients in health system decision-making can help focus policies and clinical care on cultural safety and equity.

Aim: Quantifying the ratio describing the difference between "true route" and "straight-line" distances from out-of-hospital cardiac arrests (OHCAs) to the closest accessible automated external defibrillator (AED) can help correct likely overestimations in AED coverage. Furthermore, we aimed to examine to what extent the closest AED based on true route distance differed from the closest AED using "straight-line"., Methods: OHCAs (1994-2016) and AEDs (2016) in Copenhagen, Denmark and in Toronto, Canada (2007-2015 and 2015, respectively) were identified. Three distances were calculated between OHCA and target AED: 1) the straight-line distance ("straight-line") to the closest AED, 2) the corresponding true route distance to the same AED ("true route"), and 3) the closest AED based only on true route distance ("shortest true route"). The ratio between "true route" and "straight-line" distance was calculated and differences in AED coverage (an OHCA ≤ 100 m of an accessible AED) were examined., Results: The "straight-line" AED coverage of 100 m was 24.2% (n = 2008/8295) in Copenhagen and 6.9% (n = 964/13916) in Toronto. The corresponding "true route" distance reduced coverage to 9.5% (n = 786) and 3.8% (n = 529), respectively. The median ratio between "true route" and "straight-line" distance was 1.6 in Copenhagen and 1.4 in Toronto. In 26.1% (n = 2167) and 22.9% (n = 3181) of all Copenhagen and Toronto OHCAs respectively, the closest AED in "shortest true route" was different than the closest AED initially found by "straight-line"., Conclusions: Straight-line distance is not an accurate measure of distance and overestimates the actual AED coverage compared to a more realistic true route distance by a factor 1.4-1.6., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Epidemiological cohort studies have consistently found associations between long-term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that these associations may be nonlinear and may persist at very low concentrations. Studies conducted in North America in particular have suggested that associations with mortality persisted at concentrations of particulate matter with an aerodynamic diameter of less than 2.5 μm (PM 2.5 ) well below current air quality standards and guidelines. The uncertainty about the shape of the concentration-response function at the low end of the concentration distribution, related to the scarcity of observations in the lowest range, was the basis of the current project. Previous studies have focused on PM 2.5 , but increasingly associations with nitrogen dioxide (NO 2 ) are being reported, particularly in studies that accounted for the fine spatial scale variation of NO 2 . Very few studies have evaluated the effects of long-term exposure to low concentrations of ozone (O 3 ). Health effects of black carbon (BC), representing primary combustion particles, have not been studied in most large cohort studies of PM 2.5 . Cohort studies assessing health effects of particle composition, including elements from nontailpipe traffic emissions (iron, copper, and zinc) and secondary aerosol (sulfur) have been few in number and reported inconsistent results. The overall objective of our study was to investigate the shape of the relationship between long-term exposure to four pollutants (PM 2.5 , NO 2 , BC, and O 3 ) and four broad health effect categories using a number of different methods to characterize the concentration-response function (i.e., linear, nonlinear, or threshold). The four health effect categories were (1) natural- and cause-specific mortality including cardiovascular and nonmalignant as well as malignant respiratory and diabetes mortality; and morbidity measured as (2) coronary and cerebrovascular events; (3) lung cancer incidence; and (4) asthma and chronic obstructive pulmonary disease (COPD) incidence. We additionally assessed health effects of PM 2.5 composition, specifically the copper, iron, zinc, and sulfur content of PM 2,5 ., Methods: We focused on analyses of health effects of air pollutants at low concentrations, defined as less than current European Union (EU) Limit Values, U.S. Environmental Protection Agency (U.S. EPA), National Ambient Air Quality Standards (NAAQS), and/or World Health Organization (WHO) Air Quality Guideline values for PM 2.5 , NO 2 , and O 3 . We address the health effects at low air pollution levels by performing new analyses within selected cohorts of the ESCAPE study (European Study of Cohorts for Air Pollution Effects; Beelen et al. 2014a) and within seven very large European administrative cohorts. By combining well-characterized ESCAPE cohorts and large administrative cohorts in one study the strengths and weaknesses of each approach can be addressed. The large administrative cohorts are more representative of national or citywide populations, have higher statistical power, and can efficiently control for area-level confounders, but have fewer possibilities to control for individual-level confounders. The ESCAPE cohorts have detailed information on individual confounders, as well as country-specific information on area-level confounding. The data from the seven included ESCAPE cohorts and one additional non-ESCAPE cohort have been pooled and analyzed centrally. More than 300,000 adults were included in the pooled cohort from existing cohorts in Sweden, Denmark, Germany, the Netherlands, Austria, France, and Italy. Data from the administrative cohorts have been analyzed locally, without transfer to a central database. Privacy regulations prevented transfer of data from administrative cohorts to a central database. More than 28 million adults were included from national administrative cohorts in Belgium, Denmark, England, the Netherlands, Norway, and Switzerland as well as an administrative cohort in Rome, Italy. We developed central exposure assessment using Europewide hybrid land use regression (LUR) models, which incorporated European routine monitoring data for PM 2.5 , NO 2 , and O 3 , and ESCAPE monitoring data for BC and PM 2.5 composition, land use, and traffic data supplemented with satellite observations and chemical transport model estimates. For all pollutants, we assessed exposure at a fine spatial scale, 100 × 100 m grids. These models have been applied to individual addresses of all cohorts including the administrative cohorts. In sensitivity analyses, we applied the PM 2.5 models developed within the companion HEI-funded Canadian MAPLE study (Brauer et al. 2019) and O 3 exposures on a larger spatial scale for comparison with previous studies. Identification of outcomes included linkage with mortality, cancer incidence, hospital discharge registries, and physician-based adjudication of cases. We analyzed natural-cause, cardiovascular, ischemic heart disease, stroke, diabetes, cardiometabolic, respiratory, and COPD mortality. We also analyzed lung cancer incidence, incidence of coronary and cerebrovascular events, and incidence of asthma and COPD (pooled cohort only). We applied the Cox proportional hazard model with increasing control for individual- and area-level covariates to analyze the associations between air pollution and mortality and/or morbidity for both the pooled cohort and the individual administrative cohorts. Age was used as the timescale because of evidence that this results in better adjustment for potential confounding by age. Censoring occurred at the time of the event of interest, death from other causes, emigration, loss to follow-up for other reasons, or at the end of follow-up, whichever came first. A priori we specified three confounder models, following the modeling methods of the ESCAPE study. Model 1 included only age (time axis), sex (as strata), and calendar year of enrollment. Model 2 added individual-level variables that were consistently available in the cohorts contributing to the pooled cohort or all variables available in the administrative cohorts, respectively. Model 3 further added area-level socioeconomic status (SES) variables. A priori model 3 was selected as the main model. All analyses in the pooled cohort were stratified by subcohort. All analyses in the administrative cohorts accounted for clustering of the data in neighborhoods by adjusting the variance of the effect estimates. The main exposure variable we analyzed was derived from the Europewide hybrid models based on 2010 monitoring data. Sensitivity analyses were conducted using earlier time periods, time-varying exposure analyses, local exposure models, and the PM 2.5 models from the Canadian MAPLE project. We first specified linear single-pollutant models. Two-pollutant models were specified for all combinations of the four main pollutants. Two-pollutant models for particle composition were analyzed with PM 2.5 and NO 2 as the second pollutant. We then investigated the shape of the concentration-response function using natural splines with two, three, and four degrees of freedom; penalized splines with the degrees of freedom determined by the algorithm and shape-constrained health impact functions (SCHIF) using confounder model 3. Additionally, we specified linear models in subsets of the concentration range, defined by removing concentrations above a certain value from the analysis, such as for PM 2.5 25 μg/m 3 (EU limit value), 20, 15, 12 μg/m 3 (U.S. EPA National Ambient Air Quality Standard), and 10 μg/m 3 (WHO Air Quality Guideline value). Finally, threshold models were evaluated to investigate whether the associations persisted below specific concentration values. For PM 2.5 , we evaluated 10, 7.5, and 5 μg/m 3 as potential thresholds. Performance of threshold models versus the corresponding no-threshold linear model were evaluated using the Akaike information criterion (AIC)., Results: In the pooled cohort, virtually all subjects in 2010 had PM 2.5 and NO 2 annual average exposures below the EU limit values (25 μg/m 3 and 40 μg/m 3 , respectively). More than 50,000 had a residential PM 2.5 exposure below the U.S. EPA NAAQS (12 μg/m 3 ). More than 25,000 subjects had a residential PM 2.5 exposure below the WHO guideline (10 μg/m 3 ). We found significant positive associations between PM 2.5 , NO 2 , and BC and natural-cause, respiratory, cardiovascular, and diabetes mortality. In our main model, the hazard ratios (HRs) (95% [confidence interval] CI) were 1.13 (CI = 1.11, 1.16) for an increase of 5 μg/m 3 PM 2.5 , 1.09 (CI = 1.07, 1.10) for an increase of 10 μg/m 3 NO 2 , and 1.08 (CI = 1.06, 1.10) for an increase of 0.5 × 10 -5 /m BC for natural-cause mortality. The highest HRs were found for diabetes mortality. Associations with O 3 were negative, both in the fine spatial scale of the main ELAPSE model and in large spatial scale exposure models. For PM 2.5 , NO 2 , and BC, we generally observed a supralinear association with steeper slopes at low exposures and no evidence of a concentration below which no association was found. Subset analyses further confirmed that these associations remained at low levels: below 10 μg/m 3 for PM 2.5 and 20 μg/m 3 for NO 2 . HRs were similar to the full cohort HRs for subjects with exposures below the EU limit values for PM 2.5 and NO 2 , the U.S. NAAQS values for PM 2.5 , and the WHO guidelines for PM 2.5 and NO 2 . The mortality associations were robust to alternative specifications of exposure, including different time periods, PM 2.5 from the MAPLE project, and estimates from the local ESCAPE model. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. HRs in two-pollutant models were attenuated but remained elevated and statistically significant for PM 2.5 and NO 2 . In two-pollutant models of PM 2.5 and NO 2 HRs for natural-cause mortality were 1.08 (CI = 1.05, 1.11) for PM 2.5 and 1.05 (CI = 1.03, 1.07) for NO 2 . Associations with O 3 were attenuated but remained negative in two-pollutant models with NO 2 , BC, and PM 2.5 . We found significant positive associations between PM 2.5 , NO 2 , and BC and incidence of stroke and asthma and COPD hospital admissions. Furthermore, NO 2 was significantly related to acute coronary heart disease and PM 2.5 was significantly related to lung cancer incidence. We generally observed linear to supralinear associations with no evidence of a threshold, with the exception of the association between NO 2 and acute coronary heart disease, which was sublinear. Subset analyses documented that associations remained even with PM 2.5 below 20 μg/m 3 and possibly 12 μg/m 3 . Associations remained even when NO 2 was below 30 μg/m 3 and in some cases 20 μg/m 3 . In two-pollutant models, NO 2 was most consistently associated with acute coronary heart disease, stroke, asthma, and COPD hospital admissions. PM 2.5 was not associated with these outcomes in two-pollutant models with NO 2 . PM 2.5 was the only pollutant that was associated with lung cancer incidence in two-pollutant models. Associations with O 3 were negative though generally not statistically significant. In the administrative cohorts, virtually all subjects in 2010 had PM 2.5 and NO 2 annual average exposures below the EU limit values. More than 3.9 million subjects had a residential PM 2.5 exposure below the U.S. EPA NAAQS (12 μg/m 3 ) and more than 1.9 million had residential PM 2.5 exposures below the WHO guideline (10 μg/m 3 ). We found significant positive associations between PM 2.5 , NO 2 , and BC and natural-cause, respiratory, cardiovascular, and lung cancer mortality, with moderate to high heterogeneity between cohorts. We found positive but statistically nonsignificant associations with diabetes mortality. In our main model meta-analysis, the HRs (95% CI) for natural-cause mortality were 1.05 (CI = 1.02, 1.09) for an increase of 5 μg/m 3 PM 2.5 , 1.04 (CI = 1.02, 1.07) for an increase of 10 μg/m 3 NO 2 , and 1.04 (CI = 1.02, 1.06) for an increase of 0.5 × 10 -5 /m BC, and 0.95 (CI = 0.93, 0.98) for an increase of 10 μg/m 3 O 3 . The shape of the concentration-response functions differed between cohorts, though the associations were generally linear to supralinear, with no indication of a level below which no associations were found. Subset analyses documented that these associations remained at low levels: below 10 μg/m 3 for PM 2.5 and 20 μg/m 3 for NO 2 . BC and NO 2 remained significantly associated with mortality in two-pollutant models with PM 2.5 and O 3 . The PM 2.5 HR attenuated to unity in a two-pollutant model with NO 2 . The negative O 3 association was attenuated to unity and became nonsignificant. The mortality associations were robust to alternative specifications of exposure, including time-varying exposure analyses. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. Effect estimates in the youngest participants (<65 years at baseline) were much larger than in the elderly (>65 years at baseline). Effect estimates obtained with the ELAPSE PM 2.5 model did not differ from the MAPLE PM 2.5 model on average, but in individual cohorts, substantial differences were found., Conclusions: Long-term exposure to PM 2.5 , NO 2 , and BC was positively associated with natural-cause and cause-specific mortality in the pooled cohort and the administrative cohorts. Associations were found well below current limit values and guidelines for PM 2.5 and NO 2 . Associations tended to be supralinear, with steeper slopes at low exposures with no indication of a threshold. Two-pollutant models documented the importance of characterizing the ambient mixture with both NO 2 and PM 2.5 . We mostly found negative associations with O 3 . In two-pollutant models with NO 2 , the negative associations with O 3 were attenuated to essentially unity in the mortality analysis of the administrative cohorts and the incidence analyses in the pooled cohort. In the mortality analysis of the pooled cohort, significant negative associations with O 3 remained in two-pollutant models. Long-term exposure to PM 2.5 , NO 2 , and BC was also positively associated with morbidity outcomes in the pooled cohort. For stroke, asthma, and COPD, positive associations were found for PM 2.5 , NO 2 , and BC. For acute coronary heart disease, an increased HR was observed for NO 2 . For lung cancer, an increased HR was found only for PM 2.5 . Associations mostly showed steeper slopes at low exposures with no indication of a threshold., (© 2021 Health Effects Institute. All rights reserved.)

Aim: Standards for health care quality, access and evaluation of early intervention in psychosis services are required to assess implementation, provide accountability to service users and funders and support quality assurance. The aim of this article is to review the application of standards in Europe and North America., Methods: Descriptive methods will be used to illustrate the organizational context in which standards are being applied and used, specific measures being applied and results so far., Results: Both fidelity scales and quality indicators of health care are being used. Fidelity scales are being applied in Australia, Canada, Denmark, Italy and United States. In England, quality indicators derived from the National Institute for Health and Care Excellence guidance are being used., Conclusion: In the last 4 years, significant progress has been made in the development and application of measures that assess quality and access to evidence-based practices for early intervention in psychosis services. This represents an important step towards providing accountability, improving outcomes and service user experience. The methods used allow for comparison between the services that are assessed with the same methods, but there is a need to compare the different methods. Further research is also required to explore links between quality of care and outcomes for community mental health services that deliver early intervention in psychotic disorders., (© 2020 John Wiley & Sons Australia, Ltd.)

In the wake of the withdrawal of the nonsteroidal anti-inflammatory drug rofecoxib, regulators worldwide reconsidered their approach to postmarket safety. Many have since adopted a "life cycle" approach to regulation of medicines, facilitating faster approval of new medicines while planning for potential postmarket safety issues. A crucial aspect of postmarket safety is the effective and timely communication of emerging risk information using postmarket safety advisories, commonly issued as letters to healthcare professionals, drug safety bulletins, media alerts, and website announcements. Yet regulators differ in their use of postmarket safety advisories. We examined the capacity of regulators in the United States, Europe, Canada, and Australia to warn about postmarket safety issues through safety advisories by assessing their governance, legislative authority, risk communication capabilities, and transparency., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Background: Stomach cancer incidence and mortality rates are declining across circumpolar nations, but the burden may not be distributed equally across subpopulations, including Indigenous peoples. Our objective was to examine stomach cancer incidence and mortality trends across circumpolar populations., Methods: Cancer incidence and mortality data from 1999-2016 were obtained from the Canadian Cancer Registry, Canadian Vital Statistics, CDC WONDER, NORDCAN, Northwestern Russian cancer registries, and National Cancer Reports. The direct method was used to calculate 10-year rolling age-standardized incidence and mortality rates to the world (WHO 2000-2025) and 2011 Canadian standard populations. Standardized incidence rate ratios (SRR) were calculated. Data were stratified by sex, year, and region. U.S. data were broken down by race [White; American Indian/Alaska Native (AIAN)]. Race data were not available from non-U.S. cancer registries., Results: Most populations showed declining incidence and mortality rates over time. Incidence rates among Greenland males and females, Alaska AIAN males and females, and Northern Canadian both sexes were elevated compared with regional counterparts and remained stable. The largest male SRR was observed among Alaska AIAN versus Alaska Whites [SRR = 3.82; 95% confidence interval (95% CI), 2.71-5.37]. The largest female SRR was observed among Alaska AIAN versus Alaska Whites (SRR = 4.10; 95% CI, 2.62-6.43)., Conclusions: Despite stomach cancer incidence and mortality rates declining overall, some northern and Indigenous populations experience elevated and stable incidence and mortality rates., Impact: There is a need to address disparities observed among circumpolar subpopulations. Given similarities in incidence, mortality, and risk factor prevalence across circumpolar regions, addressing disparities could benefit from coordinated international action., (©2021 American Association for Cancer Research.)

Background: Early in the COVID-19 pandemic, it was noted that males seemed to have higher case-fatality rates than females. We examined the magnitude and consistency of the sex differences in age-specific case-fatality rates (CFRs) in seven countries., Methods: Data on the cases and deaths from COVID-19, by sex and age group, were extracted from the national official agencies from Denmark, England, Israel, Italy, Spain, Canada and Mexico. Age-specific CFRs were computed for males and females separately. The ratio of the male to female CFRs were computed and meta-analytic methods were used to obtained pooled estimates of the male to female ratio of the CFRs over the seven countries, for all age-groups. Meta-regression and sensitivity analysis were conducted to evaluate the age and country contribution to differences., Results: The CFRs were consistently higher in males at all ages. The pooled M:F CFR ratios were 1.71, 1.88, 2.11, 2.11, 1.84, 1.78 and 1.49, for ages 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80+ respectively. In meta-regression, age group and country were associated with the heterogeneity in the CFR ratios., Conclusions: The sex differences in the age-specific CFRs are intriguing. Sex differences in the incidence and mortality have been found in many infectious diseases. For COVID-19, factors such as sex differences in the prevalence of underlying diseases may play a part in the CFR differences. However, the consistently greater case-fatality rates in males at all ages suggests that sex-related factors impact on the natural history of the disease. This could provide important clues as to the mechanisms underlying the severity of COVID-19 in some patients., Competing Interests: No competing interests.

Background: The Canadian Occupational Performance Measure (COPM) is intended to help clients identify and evaluate their occupational performance issues. As it enhances client-centred practice (CCP), more frequent use of the COPM might fulfill the political agenda of patient involvement in Denmark. However, in a study translating the COPM into Danish, challenges were found highlighting the need to study its clinical utility., Aim: To examine the clinical utility of the Danish version of the COPM (COPM-DK) and help determine whether to recommend a more routinely use., Methods: Data gathered during qualitative interviews with 16 occupational therapists (OTs) from various settings were subjected to a qualitative content analysis., Results: The COPM-DK appeared to have clinical utility, especially regarding the meaning and relevance of the information obtained, and seemed to facilitate an occupational lens and CCP. The OTs' difficulties and concerns when using the COPM and their personal and environmental commitment to the COPM seemed associated with how they performed the COPM. Thus, training was recommended to facilitate a valid and reliable use., Conclusion: Given the benefits and the perceived utility of the COPM-DK, a more routinely use, to place OTs and CCP in the center of Danish healthcare system, is recommended.Key MessagesThe utility of the Danish version of the Canadian Occupational Performance Measure is supported, according to Danish occupational therapists in various rehabilitation settings and hospitals.Using the Canadian Occupational Performance Measure seems to enhance a client-centred practice with collaborative goals and helps to establish partnership, being of value to the interdisciplinary team, too.The utility and acceptability of the Canadian Occupational Performance Measure seemed to be linked to the occupational therapists' experience and understanding of the Canadian Occupational Performance Measure's content and form, thus an introduction course is recommended to avoid a use that affects the assessment's validity and reliability.

We sought to understand the role of stage at diagnosis in observed age disparities in colon cancer survival among people aged 50 to 99 years using population-based cancer registry data from seven high-income countries: Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom. We used colon cancer incidence data for the period 2010 to 2014. We estimated the 3-year net survival, as well as the 3-year net survival conditional on surviving at least 6 months and 1 year after diagnosis, by country and stage at diagnosis (categorised as localised, regional or distant) using flexible parametric excess hazard regression models. In all countries, increasing age was associated with lower net survival. For example, 3-year net survival (95% confidence interval) was 81% (80-82) for 50 to 64 year olds and 58% (56-60) for 85 to 99 year olds in Australia, and 74% (73-74) and 39% (39-40) in the United Kingdom, respectively. Those with distant stage colon cancer had the largest difference in colon cancer survival between the youngest and the oldest patients. Excess mortality for the oldest patients with localised or regional cancers was observed during the first 6 months after diagnosis. Older patients diagnosed with localised (and in some countries regional) stage colon cancer who survived 6 months after diagnosis experienced the same survival as their younger counterparts. Further studies examining other prognostic clinical factors such as comorbidities and treatment, and socioeconomic factors are warranted to gain further understanding of the age disparities in colon cancer survival., (© 2020 Union for International Cancer Control.)

The indigenous people of the United States and Canada long have used forest fungi for food, tinder, medicine, paint, and many other cultural uses. New information about historical uses of fungi continues to be discovered from museums as accessions of fungi and objects made from fungi collected over the last 150+ years are examined and identified. Two textiles thought to be made from fungal mats are located in the Hood Museum of Art, Dartmouth College, and the Oakland Museum of California. Scanning electron microscopy and DNA sequencing were used to attempt to identify the fungus that produced the mats. Although DNA sequencing failed to yield a taxonomic identification, microscopy and characteristics of the mycelial mats suggest that the mats were produced by Laricifomes officinalis . This first report of fungal mats used for textile by indigenous people of North America will help to alert museum curators and conservators as well as mycological researchers to their existence and hopefully lead to more items being discovered that have been made from fungal fabric.

[Figure: see text].