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BackgroundLate outbreak identification is a common risk factor mentioned in case reports of large respiratory infection outbreaks in long-term care (LTC) homes.AimTo systematically measure the association between late SARS-CoV-2 outbreak identification and secondary SARS-CoV-2 infection and mortality in residents of LTC homes.MethodsWe studied SARS-CoV-2 outbreaks across LTC homes in Ontario, Canada from March to November 2020, before the COVID-19 vaccine rollout. Our exposure (late outbreak identification) was based on cumulative infection pressure (the number of infectious resident-days) on the outbreak identification date (early: ≤ 2 infectious resident-days, late: ≥ 3 infectious resident-days), where the infectious window was -2 to +8 days around onset. Our outcome consisted of 30-day incidence of secondary infection and mortality, based on the proportion of at-risk residents with a laboratory-confirmed SARS-CoV-2 infection with onset within 30 days of the outbreak identification date.ResultsWe identified 632 SARS-CoV-2 outbreaks across 623 LTC homes. Of these, 36.4% (230/632) outbreaks were identified late. Outbreaks identified late had more secondary infections (10.3%; 4,437/42,953) and higher mortality (3.2%; 1,374/42,953) compared with outbreaks identified early (infections: 3.3%; 2,015/61,714; p < 0.001, mortality: 0.9%; 579/61,714; p < 0.001). After adjustment for 12 LTC home covariates, the incidence of secondary infections in outbreaks identified late was 2.90-fold larger than that of outbreaks identified early (OR: 2.90; 95% CI: 2.04-4.13).ConclusionsThe timeliness of outbreak identification could be used to predict the trajectory of an outbreak, plan outbreak measures and retrospectively provide feedback for quality improvement, with the objective of reducing the impacts of respiratory infections in LTC home residents.

Objectives: In Canada, patients whose acute medical issues have been resolved but are awaiting discharge from hospital are designated as alternate level of care (ALC). We investigated short-term mortality and palliative care use following ALC designation in Ontario, Canada., Methods: We conducted a population-based retrospective cohort study of adult, acute care hospital admissions in Ontario with an ALC designation between January and December 2021. Our follow-up window was until 90 days post-ALC designation or death. Setting of discharge and death was determined using admission and discharge dates from multiple databases. We measured palliative care using physician billings, inpatient palliative care records and palliative home care records. We compared the characteristics of ALC patients by 90-day survival status and compared palliative care use across settings of discharge and death., Results: We included 54 839 ALC patients with a median age of 80 years. Nearly one-fifth (18.4%) of patients died within 90 days. Patients who died were older, had more comorbid conditions and were more likely to be male. Among those who died, 35.1% were never discharged from hospital and 20.3% were discharged but ultimately died in the hospital. The majority of people who died received palliative care following their ALC designation (68.1%)., Conclusions: A significant proportion of patients experiencing delayed discharge die within 3 months, with the majority dying in hospitals despite being identified as ready to be discharged. Future research should examine the adequacy of palliative care provision for this population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is a large body of evidence evaluating quality improvement (QI) programmes to improve care for adults living with diabetes. These programmes are often comprised of multiple QI strategies, which may be implemented in various combinations. Decision-makers planning to implement or evaluate a new QI programme, or both, need reliable evidence on the relative effectiveness of different QI strategies (individually and in combination) for different patient populations., Objectives: To update existing systematic reviews of diabetes QI programmes and apply novel meta-analytical techniques to estimate the effectiveness of QI strategies (individually and in combination) on diabetes quality of care., Search Methods: We searched databases (CENTRAL, MEDLINE, Embase and CINAHL) and trials registers (ClinicalTrials.gov and WHO ICTRP) to 4 June 2019. We conducted a top-up search to 23 September 2021; we screened these search results and 42 studies meeting our eligibility criteria are available in the awaiting classification section., Selection Criteria: We included randomised trials that assessed a QI programme to improve care in outpatient settings for people living with diabetes. QI programmes needed to evaluate at least one system- or provider-targeted QI strategy alone or in combination with a patient-targeted strategy. - System-targeted: case management (CM); team changes (TC); electronic patient registry (EPR); facilitated relay of clinical information (FR); continuous quality improvement (CQI). - Provider-targeted: audit and feedback (AF); clinician education (CE); clinician reminders (CR); financial incentives (FI). - Patient-targeted: patient education (PE); promotion of self-management (PSM); patient reminders (PR). Patient-targeted QI strategies needed to occur with a minimum of one provider or system-targeted strategy., Data Collection and Analysis: We dual-screened search results and abstracted data on study design, study population and QI strategies. We assessed the impact of the programmes on 13 measures of diabetes care, including: glycaemic control (e.g. mean glycated haemoglobin (HbA1c)); cardiovascular risk factor management (e.g. mean systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), proportion of people living with diabetes that quit smoking or receiving cardiovascular medications); and screening/prevention of microvascular complications (e.g. proportion of patients receiving retinopathy or foot screening); and harms (e.g. proportion of patients experiencing adverse hypoglycaemia or hyperglycaemia). We modelled the association of each QI strategy with outcomes using a series of hierarchical multivariable meta-regression models in a Bayesian framework. The previous version of this review identified that different strategies were more or less effective depending on baseline levels of outcomes. To explore this further, we extended the main additive model for continuous outcomes (HbA1c, SBP and LDL-C) to include an interaction term between each strategy and average baseline risk for each study (baseline thresholds were based on a data-driven approach; we used the median of all baseline values reported in the trials). Based on model diagnostics, the baseline interaction models for HbA1c, SBP and LDL-C performed better than the main model and are therefore presented as the primary analyses for these outcomes. Based on the model results, we qualitatively ordered each QI strategy within three tiers (Top, Middle, Bottom) based on its magnitude of effect relative to the other QI strategies, where 'Top' indicates that the QI strategy was likely one of the most effective strategies for that specific outcome. Secondary analyses explored the sensitivity of results to choices in model specification and priors.  Additional information about the methods and results of the review are available as Appendices in an online repository. This review will be maintained as a living systematic review; we will update our syntheses as more data become available., Main Results: We identified 553 trials (428 patient-randomised and 125 cluster-randomised trials), including a total of 412,161 participants. Of the included studies, 66% involved people living with type 2 diabetes only. Participants were 50% female and the median age of participants was 58.4 years. The mean duration of follow-up was 12.5 months. HbA1c was the commonest reported outcome; screening outcomes and outcomes related to cardiovascular medications, smoking and harms were reported infrequently. The most frequently evaluated QI strategies across all study arms were PE, PSM and CM, while the least frequently evaluated QI strategies included AF, FI and CQI. Our confidence in the evidence is limited due to a lack of information on how studies were conducted.  Four QI strategies (CM, TC, PE, PSM) were consistently identified as 'Top' across the majority of outcomes. All QI strategies were ranked as 'Top' for at least one key outcome. The majority of effects of individual QI strategies were modest, but when used in combination could result in meaningful population-level improvements across the majority of outcomes. The median number of QI strategies in multicomponent QI programmes was three.  Combinations of the three most effective QI strategies were estimated to lead to the below effects:  - PR + PSM + CE: decrease in HbA1c by 0.41% (credibility interval (CrI) -0.61 to -0.22) when baseline HbA1c < 8.3%; - CM + PE + EPR: decrease in HbA1c by 0.62% (CrI -0.84 to -0.39) when baseline HbA1c > 8.3%;  - PE + TC + PSM: reduction in SBP by 2.14 mmHg (CrI -3.80 to -0.52) when baseline SBP < 136 mmHg; - CM + TC + PSM: reduction in SBP by 4.39 mmHg (CrI -6.20 to -2.56) when baseline SBP > 136 mmHg;  - TC + PE + CM: LDL-C lowering of 5.73 mg/dL (CrI -7.93 to -3.61) when baseline LDL < 107 mg/dL; - TC + CM + CR: LDL-C lowering by 5.52 mg/dL (CrI -9.24 to -1.89) when baseline LDL > 107 mg/dL. Assuming a baseline screening rate of 50%, the three most effective QI strategies were estimated to lead to an absolute improvement of 33% in retinopathy screening (PE + PR + TC) and 38% absolute increase in foot screening (PE + TC + Other)., Authors' Conclusions: There is a significant body of evidence about QI programmes to improve the management of diabetes. Multicomponent QI programmes for diabetes care (comprised of effective QI strategies) may achieve meaningful population-level improvements across the majority of outcomes. For health system decision-makers, the evidence summarised in this review can be used to identify strategies to include in QI programmes. For researchers, this synthesis identifies higher-priority QI strategies to examine in further research regarding how to optimise their evaluation and effects. We will maintain this as a living systematic review., (Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5-10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558&#95;2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights., (© 2022. The Author(s).)

The complement system plays a crucial role in host defense, homeostasis, and tissue regeneration and bridges the innate and the adaptive immune systems. Although the genetic variants in complement C2 (c.839&#95;849+17del; p.(Met280Asnfs*5)) and C8B (c.1625C&gt;T; p.(Thr542Ile)) are known individually, here, we report on a patient carrying their combination in a heterozygous form. The patient presented with a reduced general condition and suffers from a wide variety of autoimmune diseases. While no autoimmune disease-specific autoantibodies could be detected, genetic analysis revealed abnormalities in the two complement genes C2 and C8B. Therefore, we performed a comprehensive investigation of the innate immune system on a cellular and humoral level to define the functional consequences. We found slightly impaired functionality of neutrophils and monocytes regarding phagocytosis and reactive oxygen species generation and a diminished expression of the C5aR1. An extensive complement analysis revealed a declined activation potential for the alternative and classical pathway. Reconstitution with purified C2 and C8 into patient serum failed to normalize the dysfunction, whereas the addition of C3 improved the hemolytic activity. In clinical transfer, in vitro supplementation of the patient's plasma with FFP as a complement source could fully restore full complement functionality. This study describes for the first time a combined heterozygous genetic variation in complement C2 and C8B which, however, cannot fully explain the overall dysfunctions and calls for further complement deficiency research and corresponding therapies., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole-exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with ovarian germ cell tumors in two families. Functional characterization showed these mutants retain APC/C activation activity but have impaired binding to BUBR1, a component of the SAC. Expression of L151R and N331K variants promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. Generation of mice carrying the N331K variant using CRISPR-Cas9 showed that, although homozygous N331K mice were nonviable, heterozygotes displayed accelerated oncogenicity of Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor-promoting genes., Significance: Two germline CDC20 missense variants that segregate with cancer in two families compromise the spindle assembly checkpoint and lead to aberrant mitotic progression, which could predispose cells to transformation. See related commentary by Villarroya-Beltri and Malumbres, p. 3432., (©2022 American Association for Cancer Research.)

Background: Context is recognized as important to successful knowledge translation (KT) in health settings. What is meant by context, however, is poorly understood. The purpose of the current study was to elicit tacit knowledge about what is perceived to constitute context by conducting interviews with a variety of health system stakeholders internationally so as to compile a comprehensive list of contextual attributes and their features relevant to KT in healthcare., Methods: A descriptive qualitative study design was used. Semi-structured interviews were conducted with health system stakeholders (change agents/KT specialists and KT researchers) in four countries: Australia, Canada, the United Kingdom, and the United States. Interview transcripts were analyzed using inductive thematic content analysis in four steps: (1) selection of utterances describing context, (2) coding of features of context, (3) categorizing of features into attributes of context, (4) comparison of attributes and features by: country, KT experience, and role., Results: A total of 39 interviews were conducted. We identified 66 unique features of context, categorized into 16 attributes. One attribute, Facility Characteristics, was not represented in previously published KT frameworks. We found instances of all 16 attributes in the interviews irrespective of country, level of experience with KT, and primary role (change agent/KT specialist vs. KT researcher), revealing robustness and transferability of the attributes identified. We also identified 30 new context features (across 13 of the 16 attributes)., Conclusion: The findings from this study represent an important advancement in the KT field; we provide much needed conceptual clarity in context, which is essential to the development of common assessment tools to measure context to determine which context attributes and features are more or less important in different contexts for improving KT success., (© 2022 The Author(s); Published by Kerman University of Medical Sciences This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Background: Inappropriate health care leads to negative patient experiences, poor health outcomes and inefficient use of resources. We aimed to conduct a systematic review of inappropriately used clinical practices in Canada., Methods: We searched multiple bibliometric databases and grey literature to identify inappropriately used clinical practices in Canada between 2007 and 2021. Two team members independently screened citations, extracted data and assessed methodological quality. Findings were synthesized in 2 categories: diagnostics and therapeutics. We reported ranges of proportions of inappropriate use for all practices. Medians and interquartile ranges (IQRs), based on the percentage of patients not receiving recommended practices (underuse) or receiving practices not recommended (overuse), were calculated. All statistics are at the study summary level., Results: We included 174 studies, representing 228 clinical practices and 28 900 762 patients. The median proportion of inappropriate care, as assessed in the studies, was 30.0% (IQR 12.0%-56.6%). Underuse (median 43.9%, IQR 23.8%-66.3%) was more frequent than overuse (median 13.6%, IQR 3.2%-30.7%). The most frequently investigated diagnostics were glycated hemoglobin (underused, range 18.0%-85.7%, n = 9) and thyroid-stimulating hormone (overused, range 3.0%-35.1%, n = 5). The most frequently investigated therapeutics were statin medications (underused, range 18.5%-71.0%, n = 6) and potentially inappropriate medications (overused, range 13.5%-97.3%, n = 9)., Interpretation: We have provided a summary of inappropriately used clinical practices in Canadian health care systems. Our findings can be used to support health care professionals and quality agencies to improve patient care and safety in Canada., Competing Interests: Competing interests: Alan Katz is a member of the ICES Scientific Advisory Committee and the SAIL International Advisory Board. He is president of the Canadian Association for Health Services and Policy Research and a member of the Board of Directors of The College of Family Physicians Canada. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Introduction: Genetic obesity is rare and quite challenging for pediatricians in terms of early identification. Src-homology-2 (SH2) B adapter protein 1 (SH2B1) is an important component in the leptin-melanocortin pathway and is found to play an important role in leptin and insulin signaling and therefore in the pathogenesis of obesity and diabetes. Microdeletions in chromosome 16p11.2, encompassing the SH2B1 gene, are known to be associated with obesity, insulin resistance, hyperphagia, and developmental delay. The aim of our study is to report on a case series of young individuals with 16p11.2 microdeletions, including the SH2B1 gene, and provide detailed information on body mass index (BMI) development and obesity-associated comorbidities. In this way, we want to raise awareness of this syndromic form of obesity as a differential diagnosis of genetic obesity., Methods: We describe the phenotype of 7 children (3 male; age range: 2.8-18.0 years) with 16p11.2 microdeletions, encompassing the SH2B1 gene, and present their BMI trajectories from birth onward. Screening for obesity-associated comorbidities was performed at the time of genetic diagnosis., Results: All children presented with severe, early-onset obesity already at the age of 5 years combined with variable developmental delay. Five patients presented with elevated fasting insulin levels, 1 patient developed diabetes mellitus type 2, 4 patients had dyslipidemia, and 4 developed nonalcoholic fatty-liver disease., Discussion/conclusion: Chromosomal microdeletions in 16p11.2, including the SH2B1 gene, in children are associated with severe, early-onset obesity and comorbidities associated with insulin resistance. Early genetic testing in suspicious patients and early screening for comorbidities are recommended., (© 2021 S. Karger AG, Basel.)

Background: Despite expected initial universal susceptibility to a novel pandemic pathogen like SARS-CoV-2, the pandemic has been characterized by higher observed incidence in older persons and lower incidence in children and adolescents., Objective: To determine whether differential testing by age group explains observed variation in incidence., Design: Population-based cohort study., Setting: Ontario, Canada., Participants: Persons diagnosed with SARS-CoV-2 and those tested for SARS-CoV-2., Measurements: Test volumes from the Ontario Laboratories Information System, number of laboratory-confirmed SARS-CoV-2 cases from the Integrated Public Health Information System, and population figures from Statistics Canada. Demographic and temporal patterns in incidence, testing rates, and test positivity were explored using negative binomial regression models and standardization. Sources of variation in standardized ratios were identified and test-adjusted standardized infection ratios (SIRs) were estimated by metaregression., Results: Observed disease incidence and testing rates were highest in the oldest age group and markedly lower in those younger than 20 years; no differences in incidence were seen by sex. After adjustment for testing frequency, SIRs were lowest in children and in adults aged 70 years or older and markedly higher in adolescents and in males aged 20 to 49 years compared with the overall population. Test-adjusted SIRs were highly correlated with standardized positivity ratios (Pearson correlation coefficient, 0.87 [95% CI, 0.68 to 0.95]; P  < 0.001) and provided a case identification fraction similar to that estimated with serologic testing (26.7% vs. 17.2%)., Limitations: The novel methodology requires external validation. Case and testing data were not linkable at the individual level., Conclusion: Adjustment for testing frequency provides a different picture of SARS-CoV-2 infection risk by age, suggesting that younger males are an underrecognized group at high risk for SARS-CoV-2 infection., Primary Funding Source: Canadian Institutes of Health Research.

Uterine epithelial cells (UEC) and migrated polymorphonuclear cells (PMN) play important roles in the uterine defence against microbial infection. The aims of the present study were to investigate i) whether undiluted uterine secretions modulate the expression of genes associated with the innate immune response in UEC and PMN in vitro, ii) whether these changes differ between the two cell populations and iii) whether uterine secretions from cows with subclinical endometritis produce a different response to those from unaffected cows. Therefore, undiluted uterine secretions, cytobrush and biopsy samples were collected from bovine uteri at a local abattoir. All cows had calved at least 3 months prior to sample collection. Subclinical endometritis was diagnosed by cytology (≥5% polymorphonuclear neutrophils) and histology. The uteri were thereby retrospectively categorised as endometritis-positive (E-pos; n = 14), if either the cytology or the histology results were positive, or endometritis-negative (E-neg; n = 17), if both diagnostics were negative. Cultured UEC responded to secretions from E-pos and E-neg cows with an increased gene expression of CXC ligand (CXCL) 8 and interleukin (IL) 6 compared to incubation with control medium alone. PMN expressed significantly higher mRNA levels of CXCL5, CXCL8 and IL1B in response to supernatant from UEC incubated with secretions from both groups (E-pos and E-neg) compared to those incubated with control medium alone. Gene expression of IL10 in uterine epithelial cells remained comparable to the control in cells exposed to E-pos secretions and was 3.6 times lower in those exposed to E-neg secretions. These results demonstrate that the expression of genes associated with the innate immune response in UEC and indirectly also PMN is affected by uterine secretions in vitro. Depending on the target gene, these changes differ between the two cell populations. UEC exposed to uterine secretions from cows without subclinical endometritis produce lower levels of IL10 compared to those exposed to secretions from affected cows or control medium alone. Therefore, the model established in this study can be used as a valuable tool to further understand the contributions of the two cell populations to the coordinated immune response in the uterus., Competing Interests: Declaration of competing interest None of the authors have any competing interests to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a high-mortality global pandemic. The clinical spectrum of disease caused by this virus is broad, ranging from asymptomatic infection to organ failure and death. Risk stratification of individuals with coronavirus disease 2019 (COVID-19) is desirable for management, and prioritization for trial enrollment. We developed a prediction rule for COVID-19 mortality in a population-based cohort in Ontario, Canada., Methods: Data from Ontario's provincial iPHIS system were extracted for the period from January 23 to May 15, 2020. Logistic regression-based prediction rules and a rule derived using a Cox proportional hazards model were developed and validated using split-halves validation. Sensitivity analyses were performed, with varying approaches to missing data., Results: Of 21 922 COVID-19 cases, 1734 with complete data were included in the derivation set; 1796 were included in the validation set. Age and comorbidities (notably diabetes, renal disease, and immune compromise) were strong predictors of mortality. Four point-based prediction rules were derived (base case, smoking excluded, long-term care excluded, and Cox model-based). All displayed excellent discrimination (area under the curve for all rules > 0.92) and calibration ( P  > .50 by Hosmer-Lemeshow test) in the derivation set. All performed well in the validation set and were robust to varying approaches to replacement of missing variables., Conclusions: We used a public health case management data system to build and validate 4 accurate, well-calibrated, robust clinical prediction rules for COVID-19 mortality in Ontario, Canada. While these rules need external validation, they may be useful tools for management, risk stratification, and clinical trials., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Implementation theories, models and frameworks offer guidance when implementing and sustaining healthcare evidence-based interventions. However, selection can be challenging given the myriad of potential options. We propose to inform a decision support tool to facilitate the appropriate selection of an implementation theory, model or framework in practice. To inform tool development, this study aimed to explore barriers and facilitators to identifying and selecting implementation theories, models and frameworks in research and practice, as well as end-user preferences for features and functions of the proposed tool., Methods: We used an interpretive descriptive approach to conduct semi-structured interviews with implementation researchers and practitioners in Canada, the United States and Australia. Audio recordings were transcribed verbatim. Data were inductively coded by a single investigator with a subset of 20% coded independently by a second investigator and analyzed using thematic analysis., Results: Twenty-four individuals participated in the study. Categories of barriers/facilitators, to inform tool development, included characteristics of the individual or team conducting implementation and characteristics of the implementation theory, model or framework. Major barriers to selection included inconsistent terminology, poor fit with the implementation context and limited knowledge about and training in existing theories, models and frameworks. Major facilitators to selection included the importance of clear and concise language and evidence that the theory, model or framework was applied in a relevant health setting or context. Participants were enthusiastic about the development of a decision support tool that is user-friendly, accessible and practical. Preferences for tool features included key questions about the implementation intervention or project (e.g., purpose, stage of implementation, intended target for change) and a comprehensive list of relevant theories, models and frameworks to choose from along with a glossary of terms and the contexts in which they were applied., Conclusions: An easy to use decision support tool that addresses key barriers to selecting an implementation theory, model or framework in practice may be beneficial to individuals who facilitate implementation practice activities. Findings on end-user preferences for tool features and functions will inform tool development and design through a user-centered approach.

Aims: To conduct a concept analysis of clinical practice contexts (work environments) in health care., Background: Context is increasingly recognized as important to the development, delivery, and understanding of implementation strategies; however, conceptual clarity about what comprises context is lacking., Design: Modified Walker and Avant concept analysis comprised of five steps: (1) concept selection; (2) determination of aims; (3) identification of uses of context; (4) determination of its defining attributes; and (5) definition of its empirical referents., Methods: A wide range of databases were systematically searched from inception to August 2014. Empirical articles were included if a definition and/or attributes of context were reported. Theoretical articles were included if they reported a model, theory, or framework of context or where context was a component. Double independent screening and data extraction were conducted. Analysis was iterative, involving organizing and reorganizing until a framework of domains, attributes. and features of context emerged., Result: We identified 15,972 references, of which 70 satisfied our inclusion criteria. In total, 201 unique features of context were identified, of these 89 were shared (reported in two or more studies). The 89 shared features were grouped into 21 attributes of context which were further categorized into six domains of context., Conclusion: This study resulted in a framework of domains, attributes and features of context. These attributes and features, if assessed and used to tailor implementation activities, hold promise for improved research implementation in clinical practice., (© 2019 John Wiley & Sons Ltd.)

Background: To increase the likelihood of successful implementation of evidence-based practices, researchers, knowledge users, and healthcare professionals must consider aspects of context that promote and hinder implementation in their setting. The purpose of the current study was to identify contextual attributes and their features relevant to implementation by healthcare professionals and compare and contrast these attributes and features across different clinical settings and healthcare professional roles., Methods: We conducted a secondary analysis of 145 semi-structured interviews comprising 11 studies (10 from Canada and one from Australia) investigating healthcare professionals' perceived barriers and enablers to their use of research evidence in clinical practice. The data was collected using semi-structured interview guides informed by the Theoretical Domains Framework across different healthcare professional roles, settings, and practices. We analyzed these data inductively, using constant comparative analysis, to identify attributes of context and their features reported in the interviews. We compared these data by (1) setting (primary care, hospital-medical/surgical, hospital-emergency room, hospital-critical care) and (2) professional role (physicians and residents, nurses and organ donor coordinators)., Results: We identified 62 unique features of context, which we categorized under 14 broader attributes of context. The 14 attributes were resource access, work structure, patient characteristics, professional role, culture, facility characteristics, system features, healthcare professional characteristics, financial, collaboration, leadership, evaluation, regulatory or legislative standards, and societal influences. We found instances of the majority (n = 12, 86%) of attributes of context across multiple (n = 6 or more) clinical behaviors. We also found little variation in the 14 attributes of context by setting (primary care and hospitals) and professional role (physicians and residents, and nurses and organ donor coordinators)., Conclusions: There was considerable consistency in the 14 attributes identified irrespective of the clinical behavior, setting, or professional role, supporting broad utility of the attributes of context identified in this study. There was more variation in the finer-grained features of these attributes with the most substantial variation being by setting.

Background: There is increasing recognition in Canada and globally that a substantial proportion of health care delivered is inappropriate as evidenced by (1) harmful and/or ineffective practices being overused, (2) effective clinical practices being underused, and (3) other clinical practices being misused. Inappropriate health care leads to negative patient experiences, poor health outcomes, and inefficient use of scarce health care resources. The purpose of this study is to conduct a systematic review of inappropriate health care in Canada. Our specific objectives are to (1) systematically search and critically review published and grey literature for studies on inappropriate health care in Canada; (2) estimate the nature and magnitude of inappropriate health care in Canada and its provincial and territorial jurisdictions., Methods: We will include all quantitative study designs reporting objective or subjective measurements of inappropriate health care in Canada over the last 10 years. We will search the following online databases: MEDLINE, Cochrane Central Register of Controlled Trials, EconLit, and ISI-Web of Knowledge, which contains Web of Science Core Collection-Citation Indexes, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and Conference Proceedings Citation Index-Social Science & Humanities. We will also search grey literature sources to identify provincial and national audits of inappropriate health care. Two authors will independently screen, assess data quality, and extract data for synthesis. Study findings will be synthesized narratively. We will organize our data into three care categorizations: preventive care, acute care, and chronic care. We will provide a compendium of inappropriate health care for each care category for Canada and each Canadian province and territory, where sufficient data exists, by calculating (1) overall medians of underuse, overuse, and misuse of clinical practices and (2) the range of medians of underuse, overuse, and misuse for each clinical practice investigated., Discussion: This review will result in the first-ever evidence-based compendium of inappropriate health care in Canada. We will also develop detailed reports of inappropriate health care for each Canadian province and territory., Systematic Review Registration: PROSPERO CRD42018093495.

Background: Systematic reviews are infrequently used by health care managers (HCMs) and policy-makers (PMs) in decision-making. HCMs and PMs co-developed and tested novel systematic review of effects formats to increase their use., Methods: A three-phased approach was used to evaluate the determinants to uptake of systematic reviews of effects and the usability of an innovative and a traditional systematic review of effects format. In phase 1, survey and interviews were conducted with HCMs and PMs in four Canadian provinces to determine perceptions of a traditional systematic review format. In phase 2, systematic review format prototypes were created by HCMs and PMs via Conceptboard©. In phase 3, prototypes underwent usability testing by HCMs and PMs., Results: Two hundred two participants (80 HCMs, 122 PMs) completed the phase 1 survey. Respondents reported that inadequate format (Mdn = 4; IQR = 4; range = 1-7) and content (Mdn = 4; IQR = 3; range = 1-7) influenced their use of systematic reviews. Most respondents (76%; n = 136/180) reported they would be more likely to use systematic reviews if the format was modified. Findings from 11 interviews (5 HCMs, 6 PMs) revealed that participants preferred systematic reviews of effects that were easy to access and read and provided more information on intervention effectiveness and less information on review methodology. The mean System Usability Scale (SUS) score was 55.7 (standard deviation [SD] 17.2) for the traditional format; a SUS score < 68 is below average usability. In phase 2, 14 HCMs and 20 PMs co-created prototypes, one for HCMs and one for PMs. HCMs preferred a traditional information order (i.e., methods, study flow diagram, forest plots) whereas PMs preferred an alternative order (i.e., background and key messages on one page; methods and limitations on another). In phase 3, the prototypes underwent usability testing with 5 HCMs and 7 PMs, 11 out of 12 participants co-created the prototypes (mean SUS score 86 [SD 9.3])., Conclusions: HCMs and PMs co-created prototypes for systematic review of effects formats based on their needs. The prototypes will be compared to a traditional format in a randomized trial.

Precise characterization of nonallelic homologous recombination (NAHR) breakpoints is key to identifying those features that influence NAHR frequency. Until now, analysis of NAHR-mediated rearrangements has generally been performed by comparison of the breakpoint-spanning sequences with the human genome reference sequence. We show here that the haplotype diversity of NAHR hotspots may interfere with breakpoint-mapping. We studied the transmitting parents of individuals with germline type-1 NF1 deletions mediated by NAHR within the paralogous recombination site 1 (PRS1) or paralogous recombination site 2 (PRS2) hotspots. Several parental wild-type PRS1 and PRS2 haplotypes were identified that exhibited considerable sequence differences with respect to the reference sequence, which also affected the number of predicted PRDM9-binding sites. Sequence comparisons between the parental wild-type PRS1 or PRS2 haplotypes and the deletion breakpoint-spanning sequences from the patients (method #2) turned out to be an accurate means to assign NF1 deletion breakpoints and proved superior to crude reference sequence comparisons that neglect to consider haplotype diversity (method #1). The mean length of the deletion breakpoint regions assigned by method #2 was 269-bp in contrast to 502-bp by method #1. Our findings imply that paralog-specific haplotype diversity of NAHR hotspots (such as PRS2) and population-specific haplotype diversity must be taken into account in order to accurately ascertain NAHR-mediated rearrangement breakpoints., (© 2017 Wiley Periodicals, Inc.)

Objectives: Lifestyle interventions can reduce type 2 diabetes risk. The Primary Care Diabetes Prevention Program (PCDPP) was implemented by the Government of Ontario to lower diabetes risk. This study first evaluated the program, and second used a validated tool to estimate a potential population impact if the program were implemented more broadly in the province., Methods: PCDPP was implemented in six primary care settings serving communities with high mortality risk due to chronic diseases. In total, 1916 adults with prediabetes or metabolic syndrome were enrolled from January 2011 to December 2012. Body weight was the primary outcome variable, and was modeled using four time periods (i.e., baseline, 3rd, 6th and 9th month). The intervention effect was estimated using multilevel mixed-effects linear regression, and was stratified by gender and age. In the population impact analysis, a number needed to treat (NNT) for the intervention to prevent one case of diabetes and an absolute number of diabetes cases averted were estimated., Results: Weight loss over 9 months was 7.5% (or 6.8 kg), with 7.4% (or 6.4 kg) in females and 8.6% (or 8.6 kg) in males. When modeled, changes in weight were all statistically significant. The models for male participants predicted, however, some gains in weight in the last 3 months of the program. Dropout rates were 26.8%, 46.8% and 63.0% at 3rd, 6th and 9th month respectively. Scaling up the program would produce an NNT of approximately 36 and would avert 6401 cases of diabetes in five years., Conclusion: PCDPP may represent a potentially effective tool for population-level diabetes risk reduction.

Background: Tens of thousands of cardiac and vascular surgeries (CaVS) are performed on seniors in Canada and the United Kingdom each year to improve survival, relieve disease symptoms, and improve health-related quality of life (HRQL). However, chronic postsurgical pain (CPSP), undetected or delayed detection of hemodynamic compromise, complications, and related poor functional status are major problems for substantial numbers of patients during the recovery process. To tackle this problem, we aim to refine and test the effectiveness of an eHealth-enabled service delivery intervention, TecHnology-Enabled remote monitoring and Self-MAnagemenT-VIsion for patient EmpoWerment following Cardiac and VasculaR surgery (THE SMArTVIEW, CoVeRed), which combines remote monitoring, education, and self-management training to optimize recovery outcomes and experience of seniors undergoing CaVS in Canada and the United Kingdom., Objective: Our objectives are to (1) refine SMArTVIEW via high-fidelity user testing and (2) examine the effectiveness of SMArTVIEW via a randomized controlled trial (RCT)., Methods: CaVS patients and clinicians will engage in two cycles of focus groups and usability testing at each site; feedback will be elicited about expectations and experience of SMArTVIEW, in context. The data will be used to refine the SMArTVIEW eHealth delivery program. Upon transfer to the surgical ward (ie, post-intensive care unit [ICU]), 256 CaVS patients will be reassessed postoperatively and randomly allocated via an interactive Web randomization system to the intervention group or usual care. The SMArTVIEW intervention will run from surgical ward day 2 until 8 weeks following surgery. Outcome assessments will occur on postoperative day 30; at week 8; and at 3, 6, 9, and 12 months. The primary outcome is worst postop pain intensity upon movement in the previous 24 hours (Brief Pain Inventory-Short Form), averaged across the previous 14 days. Secondary outcomes include a composite of postoperative complications related to hemodynamic compromise-death, myocardial infarction, and nonfatal stroke- all-cause mortality and surgical site infections, functional status (Medical Outcomes Study Short Form-12), depressive symptoms (Geriatric Depression Scale), health service utilization-related costs (health service utilization data from the Institute for Clinical Evaluative Sciences data repository), and patient-level cost of recovery (Ambulatory Home Care Record). A linear mixed model will be used to assess the effects of the intervention on the primary outcome, with an a priori contrast of weekly average worst pain intensity upon movement to evaluate the primary endpoint of pain at 8 weeks postoperation. We will also examine the incremental cost of the intervention compared to usual care using a regression model to estimate the difference in expected health care costs between groups., Results: Study start-up is underway and usability testing is scheduled to begin in the fall of 2016., Conclusions: Given our experience, dedicated industry partners, and related RCT infrastructure, we are confident we can make a lasting contribution to improving the care of seniors who undergo CaVS., Competing Interests: In-kind industry support is provided by the following industry partners: Philips, QoC Health, XAHIVE, and mPath. The following authors are employed by Philips: Karsten Russell Wood, Michael Weber, Jolene McNeil, and Robyn Alpert. Sarah Sharpe is Co-Founder and shareholder, QoC Health; Sue Bhella is employed by QoC Health. David Mohajer is Co-Founder, Chief Executive Officer, and Vice President, XAHIVE; Sem Ponnambalem is Co-Founder, Chief Operating Officer, and President, XAHIVE. Naeem Lakhani and Rabia Khan are Co-Founders, mPath.

Large deletions encompassing the NF1 gene and its flanking regions belong to the group of genomic disorders caused by copy number changes that are mediated by the local genomic architecture. Although nonallelic homologous recombination (NAHR) is known to be a major mutational mechanism underlying such genomic copy number changes, the sequence determinants of NAHR location and frequency are still poorly understood since few high-resolution mapping studies of NAHR hotspots have been performed to date. Here, we have characterized two NAHR hotspots, PRS1 and PRS2, separated by 20 kb and located within the low-copy repeats NF1-REPa and NF1-REPc, which flank the human NF1 gene region. High-resolution mapping of the crossover sites identified in 78 type 1 NF1 deletions mediated by NAHR indicated that PRS2 is a much stronger NAHR hotspot than PRS1 since 80% of these deletions exhibited crossovers within PRS2, whereas 20% had crossovers within PRS1. The identification of the most common strand exchange regions of these 78 deletions served to demarcate the cores of the PRS1 and PRS2 hotspots encompassing 1026 and 1976 bp, respectively. Several sequence features were identified that may influence hotspot intensity and direct the positional preference of NAHR to the hotspot cores. These features include regions of perfect sequence identity encompassing 700 bp at the hotspot core, the presence of PRDM9 binding sites perfectly matching the consensus motif for the most common PRDM9 variant, specific pre-existing patterns of histone modification and open chromatin conformations that are likely to facilitate PRDM9 binding., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events., (© 2014 WILEY PERIODICALS, INC.)

Background: To improve quality of care and patient outcomes, health system decision-makers need to identify and implement effective interventions. An increasing number of systematic reviews document the effects of quality improvement programs to assist decision-makers in developing new initiatives. However, limitations in the reporting of primary studies and current meta-analysis methods (including approaches for exploring heterogeneity) reduce the utility of existing syntheses for health system decision-makers. This study will explore the role of innovative meta-analysis approaches and the added value of enriched and updated data for increasing the utility of systematic reviews of complex interventions., Methods/design: We will use the dataset from our recent systematic review of 142 randomized trials of diabetes quality improvement programs to evaluate novel approaches for exploring heterogeneity. These will include exploratory methods, such as multivariate meta-regression analyses and all-subsets combinatorial meta-analysis. We will then update our systematic review to include new trials and enrich the dataset by surveying authors of all included trials. In doing so, we will explore the impact of variables not, reported in previous publications, such as details of study context, on the effectiveness of the intervention. We will use innovative analytical methods on the enriched and updated dataset to identify key success factors in the implementation of quality improvement interventions for diabetes. Decision-makers will be involved throughout to help identify and prioritize variables to be explored and to aid in the interpretation and dissemination of results., Discussion: This study will inform future systematic reviews of complex interventions and describe the value of enriching and updating data for exploring heterogeneity in meta-analysis. It will also result in an updated comprehensive systematic review of diabetes quality improvement interventions that will be useful to health system decision-makers in developing interventions to improve outcomes for people with diabetes., Systematic Review Registration: PROSPERO registration no. CRD42013005165.

The corn smut Ustilago maydis establishes a biotrophic interaction with its host plant maize. This interaction requires efficient suppression of plant immune responses, which is attributed to secreted effector proteins. Previously we identified Pep1 (Protein essential during penetration-1) as a secreted effector with an essential role for U. maydis virulence. pep1 deletion mutants induce strong defense responses leading to an early block in pathogenic development of the fungus. Using cytological and functional assays we show that Pep1 functions as an inhibitor of plant peroxidases. At sites of Δpep1 mutant penetrations, H₂O₂ strongly accumulated in the cell walls, coinciding with a transcriptional induction of the secreted maize peroxidase POX12. Pep1 protein effectively inhibited the peroxidase driven oxidative burst and thereby suppresses the early immune responses of maize. Moreover, Pep1 directly inhibits peroxidases in vitro in a concentration-dependent manner. Using fluorescence complementation assays, we observed a direct interaction of Pep1 and the maize peroxidase POX12 in vivo. Functional relevance of this interaction was demonstrated by partial complementation of the Δpep1 mutant defect by virus induced gene silencing of maize POX12. We conclude that Pep1 acts as a potent suppressor of early plant defenses by inhibition of peroxidase activity. Thus, it represents a novel strategy for establishing a biotrophic interaction.

Privacy laws are intended to preserve human well-being and improve medical outcomes. We used the Sportstats website, a repository of competitive athletic data, to test how easily these laws can be circumvented. We designed a haphazard, unrepresentative case-series analysis and applied unscientific methods based on an Internet connection and idle time. We found it both feasible and titillating to breach anonymity, stockpile personal information and generate misquotations. We extended our methods to snoop on celebrities, link to outside databases and uncover refusal to participate. Throughout our study, we evaded capture and public humiliation despite violating these 6 privacy fundamentals. We suggest that the legitimate principle of safeguarding personal privacy is undermined by the natural human tendency toward showing off.

Background: Excessive prescribing of antipsychotic therapy is a concern owing to their potential to cause serious adverse events. We explored variation in the use of antipsychotic therapy across nursing homes in Ontario, Canada, and determined if prescribing decisions were based on clinical indications., Methods: A point-prevalence study of antipsychotic therapy use in 47 322 residents of 485 provincially regulated nursing homes in December 2003. Facilities were classified into quintiles according to their mean antipsychotic prescribing rates. Residents were grouped into those with a potential clinical indication or no identified clinical indication for antipsychotic therapy., Results: A total of 15 317 residents (32.4%) were dispensed an antipsychotic agent. The mean rate of antipsychotic prescribing by home ranged from 20.9% in the quintile of facilities with the lowest mean prescribing rates (quintile 1) to 44.3% in facilities with the highest mean prescribing rates (quintile 5). Compared with individuals residing in nursing homes with the lowest mean antipsychotic prescribing rates, those residing in facilities with the highest rates were 3 times more likely to be dispensed an antipsychotic agent (adjusted odds ratio [AOR], 3.0; 95% confidence interval [CI], 2.74-3.19). Similar rates were observed among residents with psychoses with or without dementia (AOR, 2.7; 95% CI, 2.35-3.09) and residents without psychoses or dementia (AOR, 2.9; 95% CI, 2.19-3.81) who had no identifiable indication for an antipsychotic therapy., Conclusion: Residents in facilities with high antipsychotic prescribing rates were about 3 times more likely than those in facilities with low prescribing rates to be dispensed an antipsychotic agent, irrespective of their clinical indication.

In this commentary, we offer evidence about the burden of chronic conditions and use diabetes as a case study to reveal the gap between recommended and actual care in Canada. What we found through our research is cause for concern - namely, that the care that Canadians with diabetes receive is simply not good enough (an inconvenient truth) and that the country has tremendous untapped potential to prevent chronic illness and improve the quality of care (a convenient truth). Our work and the work of others help Canadians understand the benefits that will accrue to them from investments to close the gap between what we know and what we do. Given the extent of recent initiatives highlighted in this commentary - initiatives that align with evidence regarding optimal prevention and chronic illness care - we should expect governments to simultaneously invest in assessing the degree to which progress is being attained. Without better data, more transparency and comprehensive reporting, Canadians will not be kept fully informed about the results of critical healthcare investments and governments will find it increasingly difficult to demonstrate that they are meeting their commitments.

Objective: To describe Canadian family physicians' prescribing practices with regard to Alzheimer disease (AD)., Design: Cross-sectional survey administered by facsimile., Setting: Four regions in Canada (British Columbia, the Prairie Provinces, Ontario, and the Atlantic Provinces)., Participants: A stratified random sample of 1000 Canadian family physicians (250 per region) chosen from the Canadian Medical Directory; 81 of whom were excluded as ineligible., Main Outcome Measures: Prescribing practices regarding cholinesterase inhibitors (ChIs) for patients with AD., Results: Response rate was 36.3%. About 27% of respondents reported that ChIs were prescribed for less than 10% of their AD patients, while 12.5% reported that ChIs were prescribed for more than 90% of their AD patients. More physicians prescribed ChIs in the two regions with provincial formulary coverage (Prairie Provinces and Ontario) than in the two regions without coverage (British Columbia and Atlantic Provinces). Factors that significantly predicted lower prescribing rates included female sex, perception of ChIs' effectiveness, and self-reported knowledge of ChIs., Conclusion: Canadian physicians' prescribing patterns for ChIs vary; the optimal prescribing rate is unclear. Provincial coverage of these drugs along with physicians' sex, knowledge of ChIs, and perception of the effectiveness of ChIs appear to influence prescribing rates.