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BackgroundType 1 diabetes is a demanding chronic condition that requires diligent blood glucose monitoring and timely insulin administration by patients who must integrate self-management into their daily lives. ObjectiveThis study aimed to better understand what outcome measures are important to individuals living with type 1 diabetes (T1D) in Ontario, Canada, to help inform the development of type 1 diabetes virtual self-management Education and support (T1ME) trial. MethodsA qualitative approach was used, in which we conducted 6 focus groups with a total of 24 adult participants living with T1D (from age 18 to >65 years) in Ontario. Each focus group was semistructured in nature; participants were encouraged to talk openly about their experiences with T1D self-management and provide their perspectives on more focused topics such as technology and relationships with health care providers. ResultsAn interpretive analysis helped us devise a framework for our results that centered around 6 main discussion themes: (1) adapting self-management to meet evolving needs, (2) looking “beyond A1c” toward more personalized indicators of glycemic management, (3) the benefits and challenges of adopting new T1D technology, (4) establishing trusting relationships with diabetes care providers, (5) perceived benefits of peer support, and (6) pre– and post–COVID-19 perspectives on virtual care. ConclusionsOur goal is for these findings to help facilitate the development of patient-oriented outcome measures that are in line with the unique needs and preferences of T1D patients in this new, more virtual landscape of clinical care, education, and self-management support.

The hormonally active form of vitamin D, 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], has been associated with neuroprotective effects in the brain, but has been difficult to measure in human brain tissue because of its low concentration. The aim of this study was to develop and validate a sensitive method to quantify 1,25(OH)2D3 in the human brain. Prior to analysis by the LC-MS/MS, the samples were derivatized with 4-phenyl-1,2,4-triazoline-3,5-dione. The method showed good linearity of 1,25(OH)2D3 over the physiological range (R2 = 0.9998). The limit of detection was 2.5 pg/g, >10 times lower than the previously reported limit of detection. The average 1,25(OH)2D3 concentrations in 3 regions of human brain tissue samples were: anterior watershed 30.7 pg/g; mid-temporal cortex 19.2 pg/g; and cerebellum 18.5 pg/g. This validated method to quantify 1,25(OH)2D3 in human brain tissue can be applied to obtain information about its presence in various regions of the human brain associated with neurodegenerative diseases.

In recent years there has been increased interest in identifying biological signatures of food consumption for use as biomarkers. Traditional metabolomics-based biomarker discovery approaches rely on multivariate statistics which cannot differentiate between host- and food-derived compounds, thus novel approaches to biomarker discovery are required to advance the field. To this aim, we have developed a new method that combines global untargeted stable isotope traced metabolomics and a machine learning approach to identify biological signatures of cruciferous vegetable consumption. Participants consumed a single serving of broccoli (n = 16), alfalfa sprouts (n = 16) or collard greens (n = 26) which contained either control unlabeled metabolites, or that were grown in the presence of deuterium-labeled water to intrinsically label metabolites. Mass spectrometry analysis indicated 133 metabolites in broccoli sprouts and 139 metabolites in the alfalfa sprouts were labeled with deuterium isotopes. Urine and plasma were collected and analyzed using untargeted metabolomics on an AB SCIEX TripleTOF 5,600 mass spectrometer. Global untargeted stable isotope tracing was completed using openly available software and a novel random forest machine learning based classifier. Among participants who consumed labeled broccoli sprouts or collard greens, 13 deuterium-incorporated metabolomic features were detected in urine representing 8 urine metabolites. Plasma was analyzed among collard green consumers and 11 labeled features were detected representing 5 plasma metabolites. These deuterium-labeled metabolites represent potential biological signatures of cruciferous vegetables consumption. Isoleucine, indole-3-acetic acid-N-O-glucuronide, dihydrosinapic acid were annotated as labeled compounds but other labeled metabolites could not be annotated. This work presents a novel framework for identifying biological signatures of food consumption for biomarker discovery. Additionally, this work presents novel applications of metabolomics and machine learning in the life sciences.

IntroductionQuantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma. MethodsWe established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas. ResultsHere we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates. DiscussionWe describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case–control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Background & Aims: Metabolic reprogramming, in particular, glycolytic regulation, supports abnormal survival and growth of hepatocellular carcinoma (HCC) and could serve as a therapeutic target. In this study, we sought to identify glycolytic regulators in HCC that could be inhibited to prevent tumor progression and could also be monitored in vivo, with the goal of providing a theragnostic alternative to existing therapies. Methods: An orthotopic HCC rat model was used. Tumors were stimulated into a high-proliferation state by use of off-target liver ablation and were compared with lower-proliferating controls. We measured in vivo metabolic alteration in tumors before and after stimulation, and between stimulated tumors and control tumors using hyperpolarized 13C magnetic resonance imaging (MRI) (h13C MRI). We compared metabolic alterations detected by h13C MRI to metabolite levels from ex vivo mass spectrometry, mRNA levels of key glycolytic regulators, and histopathology. Results: Glycolytic lactate flux increased within HCC tumors 3 days after tumor stimulation, correlating positively with tumor proliferation as measured with Ki67. This was associated with a shift towards aerobic glycolysis and downregulation of the pentose phosphate pathway detected by mass spectrometry. MRI-measured lactate flux was most closely coupled with PFKFB3 expression and was suppressed with direct inhibition using PFK15. Conclusions: Inhibition of PFKFB3 prevents glycolytic-mediated HCC proliferation, trackable by in vivo h13C MRI.

Based on global 500 companies, this study examines whether the market incorporates the corporations' voluntary carbon emissions disclosures as part of their environmental sustainability efforts, thus increasing their market value. Proxies used to measure the corporations' ecological sustainability efforts include the choice of voluntary carbon disclosures, carbon emissions amounts, carbon intensity, and carbon disclosure quality. During the study period, those companies that chose to disclose their carbon information to the Carbon Disclosure Project (CDP), saw the market value their efforts towards environmental sustainability by increasing their market value. This study also compared the market value of disclosing and non-disclosing firms and found that non-disclosing companies had higher market value than did disclosing firms. However, this relationship was statistically insignificant. This study uses the more extensive data set, extended period, and more robust econometric approach (Difference GMM) and extends the boundaries of accounting research to incorporate environmental-related disclosures. Therefore, this most recent study can provide new insights to researchers, investors, and policymakers in the present context of environmental sustainability and business sustainability.

Abstract Background Walkability is a popular term used to describe aspects of the built and social environment that have important population-level impacts on physical activity, energy balance, and health. Although the term is widely used by researchers, practitioners, and the general public, and multiple operational definitions and walkability measurement tools exist, there are is no agreed-upon conceptual definition of walkability. Method To address this gap, researchers from Memorial University of Newfoundland hosted “The Future of Walkability Measures Workshop” in association with researchers from the Canadian Urban Environmental Health Research Consortium (CANUE) in November 2017. During the workshop, trainees, researchers, and practitioners worked together in small groups to iteratively develop and reach consensus about a conceptual definition and name for walkability. The objective of this paper was to discuss and propose a conceptual definition of walkability and related concepts. Results In discussions during the workshop, it became clear that the term walkability leads to a narrow conception of the environmental features associated with health as it inherently focuses on walking. As a result, we suggest that the term Active Living Environments, as has been previously proposed in the literature, are more appropriate. We define Active Living Environments (ALEs) as the emergent natural, built, and social properties of neighbourhoods that promote physical activity and health and allow for equitable access to health-enhancing resources. Conclusions We believe that this broader conceptualization allows for a more comprehensive understanding of how built, natural, and social environments can contribute to improved health for all members of the population.

Abstract Objective To determine if expansion of multi-use physical activity trails in an urban centre is associated with reduced rates of cardiovascular disease (CVD). Methods This was a natural experiment with a difference in differences analysis using administrative health records and trail-based cycling data in Winnipeg, Canada. Prior to the intervention, each year, 314,595 (IQR: 309,044 to 319,860) persons over 30 years without CVD were in the comparison group and 37,901 residents (IQR: 37,213 to 38,488) were in the intervention group. Following the intervention, each year, 303,853 (IQR: 302,843 to 304,465) persons were in the comparison group and 35,778 (IQR: 35,551 to 36,053) in the intervention group. The natural experiment was the construction of four multi-use trails, 4-7 km in length, between 2010 and 2012. Intervention and comparison areas were based on buffers of 400 m, 800 m and 1200 m from a new multi-use trail. Bicycle counts were obtained from electromagnetic counters embedded in the trail. The primary outcome was a composite of incident CVD events: CVD-related mortality, ischemic heart disease, cerebrovascular events and congestive heart failure. The secondary outcome was a composite of incident CVD risk factors: hypertension, diabetes and dyslipidemia. Results Between 2014 and 2018, 1,681,125 cyclists were recorded on the trails, which varied ~ 2.0-fold across the four trails (2358 vs 4264 counts/week in summer months). Between 2000 and 2018, there were 82,632 CVD events and 201,058 CVD risk events. In propensity score matched Poisson regression models, the incident rate ratio (IRR) was 1.06 (95% CI: 0.90 to 1.24) for CVD events and 0.95 (95%CI: 0.88 to 1.02) for CVD risk factors for areas within 400 m of a trail, relative to comparison areas. Sensitivity analyses indicated this effect was greatest among households adjacent to the trail with highest cycling counts (IRR = 0.85; 95% CI: 0.75 to 0.96). Conclusions The addition of multi-use trails was not associated with differences in CVD events or CVD risk factors, however the differences in CVD risk may depend on the level of trail use. Trial registration Trial registration number: NCT04057417 .

Introduction Transition from paediatric to adult care can be challenging for youth living with type 1 diabetes (T1D), as many youth feel unprepared to transfer to adult care and are at high risk for deterioration of glycaemic management and acute complications. Existing strategies to improve transition experience and outcomes are limited by cost, scalability, generalisability and youth engagement. Text messaging is an acceptable, accessible and cost-effective way of engaging youth. Together with adolescents and emerging adults and paediatric and adult T1D providers, we co-designed a text message-based intervention, Keeping in Touch (KiT), to deliver tailored transition support. Our primary objective is to test the effectiveness of KiT on diabetes self-efficacy in a randomised controlled trial.Methods and analysis We will randomise 183 adolescents with T1D aged 17–18 years within 4 months of their final paediatric diabetes visit to the intervention or usual care. KiT will deliver tailored T1D transition support via text messages over 12 months based on a transition readiness assessment. The primary outcome, self-efficacy for diabetes self-management, will be measured 12 months after enrolment. Secondary outcomes, measured at 6 and 12 months, include transition readiness, perceived T1D-related stigma, time between final paediatric and first adult diabetes visits, haemoglobin A1c, and other glycaemia measures (for continuous glucose monitor users), diabetes-related hospitalisations and emergency department visits and the cost of implementing the intervention. The analysis will be intention-to-treat comparing diabetes self-efficacy at 12 months between groups. A process evaluation will be conducted to identify elements of the intervention and individual-level factors influencing implementation and outcomes.Ethics and dissemination The study protocol version 7 July 2022 and accompanying documents were approved by Clinical Trials Ontario (Project ID: 3986) and the McGill University Health Centre (MP-37-2023-8823). Study findings will be presented at scientific conferences and in peer-reviewed publications.Trial registration number NCT05434754.

BackgroundIndividuals with type 1 diabetes (T1D) are more likely to achieve optimal glycemic management when they have frequent visits with their health care team. There is a potential benefit of frequent, telemedicine interventions as an effective strategy to lower hemoglobin A1c (HbA1c). ObjectiveThe objective is this study was to understand the provider- and system-level factors affecting the successful implementation of a virtual care intervention in type 1 diabetes (T1D) clinics. MethodsSemistructured interviews were conducted with managers and certified diabetes educators (CDEs) at diabetes clinics across Southern Ontario before the COVID-19 pandemic. Deductive analysis was carried out using the Theoretical Domains Framework, followed by mapping to behavior change techniques to inform potential implementation strategies for high-frequency virtual care for T1D. ResultsThere was considerable intention to deliver high-frequency virtual care to patients with T1D. Participants believed that this model of care could lead to improved patient outcomes and engagement but would likely increase the workload of CDEs. Some felt there were insufficient resources at their site to enable them to participate in the program. Member checking conducted during the pandemic revealed that clinics and staff had already developed strategies to overcome resource barriers to the adoption of virtual care during the pandemic. ConclusionsExisting enablers for high-frequency virtual care for T1D can be leveraged, and barriers can be overcome with targeted clinical incentives and support.

Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60–70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females.

Introduction The successful scale-up of a latent tuberculosis (TB) infection testing and treatment programme is essential to achieve TB elimination. However, poor adherence compromises its therapeutic effectiveness. Novel rifapentine-based regimens and treatment support based on behavioural science theory may improve treatment adherence and completion.Methods and analysis A pragmatic multicentre, open-label, randomised controlled trial assessing the effect of novel short-course rifapentine-based regimens for TB prevention and additional theory-based treatment support on treatment adherence against standard-of-care. Participants aged between 16 and 65 who are eligible to start TB preventive therapy will be recruited in England. 920 participants will be randomised to one of six arms with allocation ratio of 5:5:6:6:6:6: daily isoniazid +rifampicin for 3 months (3HR), routine treatment support (control); 3HR, additional treatment support; weekly isoniazid +rifapentine for 3 months (3HP), routine treatment support; weekly 3HP, additional treatment support ; daily isoniazid +rifapentine for 1 month (1HP), routine treatment support; daily 1HP, additional treatment support. Additional treatment support comprises reminders using an electronic pillbox, a short animation, and leaflets based on the perceptions and practicalities approach. The primary outcome is adequate treatment adherence, defined as taking ≥90% of allocated doses within the pre-specified treatment period, measured by electronic pillboxes. Secondary outcomes include safety and TB incidence within 12 months. We will conduct process evaluation of the trial interventions and assess intervention acceptability and fidelity and mechanisms for effect and estimate the cost-effectiveness of novel regimens. The protocol was developed with patient and public involvement, which will continue throughout the trial.Ethics and dissemination Ethics approval has been obtained from The National Health Service Health Research Authority (20/LO/1097). All participants will be required to provide written informed consent. We will share the results in peer-reviewed journals.Trial registration number EudraCT 2020-004444-29.

Abstract Background Diabetes is a chronic medical condition which demands that patients engage in self-management to achieve optimal glycemic control and avoid severe complications. Individuals who have diabetes and are experiencing homelessness are more likely to have chronic hyperglycemia and adverse outcomes. Our objective was to collaborate with individuals experiencing homelessness and care providers to understand the barriers they face in managing diabetes, as a first step in identifying solutions for enhancing diabetes management in this population. Methods We recruited individuals with lived experience of homelessness and diabetes (i.e. clients; n = 32) from Toronto and health and social care providers working in the areas of diabetes and/or homelessness (i.e. providers; n = 96) from across Canada. We used concept mapping, a participatory research method, to engage participants in brainstorming barriers to diabetes management, which were subsequently categorized into clusters, using the Concept Systems Global MAX software, and rated based on their perceived impact on diabetes management. The ratings were standardized for each participant group, and the average cluster ratings for the clients and providers were compared using t-tests. Results The brainstorming identified 43 unique barriers to diabetes management. The clients’ map featured 9 clusters of barriers: Challenges to getting healthy food, Inadequate income, Navigating services, Not having a place of your own, Relationships with professionals, Diabetes education, Emotional wellbeing, Competing priorities, and Weather-related issues. The providers’ map had 7 clusters: Access to healthy food, Dietary choices in the context of homelessness, Limited finances, Lack of stable, private housing, Navigating the health and social sectors, Emotional distress and competing priorities, and Mental health and addictions. The highest-rated clusters were Challenges to getting healthy food (clients) and Mental health and addictions (providers). Challenges to getting healthy food was rated significantly higher by clients (p = 0.01) and Competing priorities was rated significantly higher by providers (p = 0.03). Conclusions Experiencing homelessness poses numerous barriers to managing diabetes, the greatest of which according to clients, is challenges to getting healthy food. This study showed that the way clients and providers perceive these barriers differs considerably, which highlights the importance of including clients’ insights when assessing needs and designing effective solutions.

Abstract Ischemic heart disease (IHD) is one of the leading causes of death worldwide. While extreme summer surface air temperatures are thought to be a risk factor for IHD, it is unclear whether large-scale climate patterns also influence this risk. This multi-national population-based study investigated the association between summer Pacific and Atlantic sea surface temperature (SST) variability and annual acute myocardial infarction (AMI) or IHD event rates among older adults residing in North America and the United Kingdom. Overall, a shift from cool to warm phase of the El Niño Southern Oscillation (ENSO) was associated with reduced AMI admissions in western Canada (adjusted rate ratio [RR] 0.89; 95% CI, 0.80–0.99), where this climate pattern predominatly forces below-normal cloud cover and precipitation during summertime, and increased AMI deaths in western United States (RR 1.09; 95% CI, 1.04–1.15), where it forces increased cloud cover and precipitation. Whereas, the Atlantic Multidecadal Oscillation (AMO) during a strong positive phase was associated with reduced AMI admissions in eastern Canada (RR 0.93; 95% CI, 0.87–0.98) and increased IHD mortality during summer months in the United Kingdom (RR 1.08; 95% CI, 1.03–1.14). These findings suggest that SST variability can be used to predict changes in cardiovascular event rates in regions that are susceptible.

Evidence suggests there are roles for vitamin K in various chronic disease outcomes, but population-level diet and supplement recommendations are difficult to determine due to high levels of variability in measures of status and response to intake compared to other nutrients. In this preliminary investigation, a blood-based epigenome-wide association study (EWAS) comparing responders and non-responders to phylloquinone (vitamin K1) supplementation (NCT00183001) was undertaken in order to better understand the molecular underpinnings of this observed variability. Responders (n = 24) and non-responders (n = 24) were identified in a prior 3-year phylloquinone supplementation trial based on their changes in plasma phylloquinone concentrations. Differential DNA methylation was identified in multiple regions with previously unknown relationships to phylloquinone absorption and metabolism, such as at the TMEM263 locus. A hypothesis-driven analysis of lipid-related genes highlighted a site in the NPC1L1 gene, supplementing existing evidence for its role in phylloquinone absorption. Furthermore, an EWAS for baseline plasma phylloquinone concentrations revealed a strong correlation between the epigenomic signatures of phylloquinone baseline status and response to supplementation. This work can guide future epigenomic research on vitamin K and contributes to the development of more personalized dietary recommendations for vitamin K.

Intrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared with stellate cells, the role of macrophages in the development of fibrosis remains unclear. Multispectral imaging allows detection of multiple markers in situ in human formalin‐fixed, paraffin‐embedded tissue. This cutting‐edge technology is ideal for analyzing human liver tissues, as it allows spectral unmixing of fluorophore signals, subtraction of auto‐fluorescence, and preservation of hepatic architecture. We analyzed five different antibodies commonly observed on macrophage populations (CD68, MAC387, CD163, CD14, and CD16). After optimization of the monoplex stains and development of a Spectral Library, we combined all of the antibodies into a multiplex protocol and used them to stain biopsies collected from representative patients with chronic liver diseases, including chronic hepatitis C, nonalcoholic steatohepatitis, and autoimmune hepatitis. Various imaging modalities were tested, including cell phenotyping, tissue segmentation, t‐distributed stochastic neighbor embedding plots, and phenotype matrices that facilitated comparison and visualization of the identified macrophage and other cellular profiles. We then tested the feasibility of this platform to analyze numerous regions of interest from liver biopsies with multiple patients per group, using batch analysis algorithms. Five populations showed significant differences between patients positive for hepatitis C virus with advanced fibrosis when compared with controls. Three of these were significantly increased in patients with advanced fibrosis when compared to controls, and these included CD163+CD16+, CD68+, and CD68+MAC387+. Conclusion: Spectral imaging microscopy is a powerful tool that enables in situ analysis of macrophages and other cells in human liver biopsies and may lead to more personalized therapeutic approaches in the future.

Background: Car driving is a form of passive transport that is associated with an increase in physical inactivity, obesity, air pollution and noise. Built environment characteristics may influence transport mode choice, but comprehensive indices for built environment characteristics that drive car use are still lacking, while such an index could provide tangible policy entry points. Objective: We developed and validated a neighbourhood drivability index, capturing combined dimensions of the neighbourhood environment in the City of Toronto, and investigated its association with transportation choices (car, public transit or active transport), overall, by trip length, and combined for residential neighbourhood and workplace drivability. Methods: We used exploratory factor analysis to derive distinct factors (clusters of one or more environmental characteristics) that reflect the degree of car dependency in each neighbourhood, drawing from candidate variables that capture density, diversity, design, destination accessibility, distance to transit, and demand management. Area-level factor scores were then combined into a single composite score, reflecting neighbourhood drivability. Negative binomial generalized estimating equations were used to test the association between driveability quintiles (Q) and primary travel mode (>50% of trips by car, public transit, or walking/cycling) in a population-based sample of 63,766 Toronto residents enrolled in the Transportation Tomorrow Survey (TTS) wave 2016, adjusting for individual and household characteristics, and accounting for clustering of respondents within households. Results: The drivability index consisted of three factors: Urban sprawl, pedestrian facilities and parking availability. Relative to those living in the least drivable neighbourhoods (Q1), those in high drivability areas (Q5) had a significantly higher rate of car travel (adjusted Risk Ratio (RR): 1.80, 95%CI: 1.77–1.88), and lower rate of public transit use (RR: 0.90, 95%CI: 0.85–0.94) and walking/cycling (RR: 0.22, 95%CI: 0.19–0.25). Associations were strongest for short trips (

BackgroundThe Portfolio Diet, or Dietary Portfolio, is a therapeutic dietary pattern that combines cholesterol-lowering foods to manage dyslipidemia for the prevention of cardiovascular disease. To translate the Portfolio Diet for primary care, we developed the PortfolioDiet.app as a patient and physician educational and engagement tool for PCs and smartphones. The PortfolioDiet.app is currently being used as an add-on therapy to the standard of care (usual care) for the prevention of cardiovascular disease in primary care. To enhance the adoption of this tool, it is important to ensure that the PortfolioDiet.app meets the needs of its target end users. ObjectiveThe main objective of this project is to undertake user testing to inform modifications to the PortfolioDiet.app as part of ongoing engagement in quality improvement (QI). MethodsWe undertook a 2-phase QI project from February 2021 to September 2021. We recruited users by convenience sampling. Users included patients, family physicians, and dietitians, as well as nutrition and medical students. For both phases, users were asked to use the PortfolioDiet.app daily for 7 days. In phase 1, a mixed-form questionnaire was administered to evaluate the users’ perceived acceptability, knowledge acquisition, and engagement with the PortfolioDiet.app. The questionnaire collected both quantitative and qualitative data, including 2 open-ended questions. The responses were used to inform modifications to the PortfolioDiet.app. In phase 2, the System Usability Scale was used to assess the usability of the updated PortfolioDiet.app, with a score higher than 70 being considered acceptable. ResultsA total of 30 and 19 users were recruited for phase 1 and phase 2, respectively. In phase 1, the PortfolioDiet.app increased users’ perceived knowledge of the Portfolio Diet and influenced their perceived food choices. Limitations identified by users included challenges navigating to resources and profile settings, limited information on plant sterols, inaccuracies in points, timed-logout frustration, request for step-by-step pop-up windows, and request for a mobile app version; when looking at positive feedback, the recipe section was the most commonly praised feature. Between the project phases, 6 modifications were made to the PortfolioDiet.app to incorporate and address user feedback. At phase 2, the average System Usability Scale score was 85.39 (SD 11.47), with 100 being the best possible. ConclusionsBy undertaking user testing of the PortfolioDiet.app, its limitations and strengths were able to be identified, informing modifications to the application, which resulted in a clinical tool that better meets users’ needs. The PortfolioDiet.app educates users on the Portfolio Diet and is considered acceptable by users. Although further refinements to the PortfolioDiet.app will continue to be made before its evaluation in a clinical trial, the result of this QI project is an improved clinical tool.

BackgroundNeutrophil activation drives lung complications after cardiopulmonary bypass (CPB). Evidence suggests the healthy, ventilated lung may beneficially re-condition pro-inflammatory neutrophils. However, evidence in humans is lacking, due to a paucity of good models. CPB with simultaneous central venous and bilateral pulmonary vein sampling provides an opportunity to model effects of one-lung ventilation. The study's primary objectives were to establish a model of intra-operative, bilateral pulmonary vein sampling and to determine whether neutrophil function differed after passing through inflated or deflated lungs.MethodsSeventeen patients having "on pump" coronary artery bypass grafting (CABG) with one-lung ventilation (in two cohorts with tidal volume 2ml kg-1 and FiO2 0.21, or tidal volume 4 ml kg-1 and FiO2 0.5 respectively) were recruited. Cohort 1 consisted of 9 patients (7 male, median age 62.0 years) and Cohort 2 consisted of 8 male patients (median age 65.5 years). Recruitment was via prospective screening of scheduled elective and non-elective CABG procedures with cardiopulmonary bypass. Each patient had five blood samples taken-central venous blood pre-operatively; central venous blood pre-CPB; central venous blood post-CPB; pulmonary venous blood draining the ventilated lung post-CPB; and pulmonary venous blood draining the deflated lung post-CPB. Neutrophil phagocytosis and priming status were quantified. Plasma cytokines were measured.ResultsPhagocytosis and priming were not significantly different in neutrophils returning from the ventilated lung as compared to the non-ventilated lung. Plasma IL-6, IL-8 and IL-10 were significantly elevated by CPB.ConclusionsThe intra-operative, bilateral pulmonary vein sampling model provides unique opportunities to assess biological effects of interventions to one lung, with the other lung acting as an internal control. Single-lung ventilation during CPB had no significant effects on neutrophil function.

Abstract Higher vitamin K intakes have been associated with better cognitive function, suggestive of a vitamin K mechanistic effect or simply reflective of a healthy diet. To test the hypothesis that brain vitamin K is linked to cognitive decline and dementia, vitamin K concentrations were measured in four brain regions, and their associations with cognitive and neuropathological outcomes were estimated in 325 decedents of the Rush Memory and Aging Project. Menaquinone‐4 (MK4) was the main vitamin K form in the brain regions evaluated. Higher brain MK4 concentrations were associated with a 17% to 20% lower odds of dementia or mild cognitive impairment (MCI) (P‐value

Introduction The predictive utility for incident tuberculosis (TB) of the purified protein derivative tuberculin skin test and region of difference 1 (RD1)-based interferon-gamma release assays (IGRA) is comparable; and either is recommended to test for latent TB infection (LTBI). Despite associated high costs of IGRA, sites participating in LTBI screening in many high-income settings pragmatically favour IGRA due to its higher specificity and simpler logistics. A new RD1-based skin test, C-Tb, could offer an acceptable and as accurate, cheaper alternative to IGRA. Evaluating the impact of C-Tb on process and patient-related outcomes would provide important information to help guide its use in LTBI testing strategies.Methods and analysis This is a pragmatic multicentre, open-label, non-inferiority, randomised controlled trial. The trial will assess the initiation of LTBI treatment following a positive result of the randomised test as the primary outcome. Participants will be randomised to receive the C-Tb test (intervention) or IGRA (usual care, control) for initiation of treatment. We will enrol 1530 participants in England aged≥16 years who are eligible for LTBI testing and treatment according to UK guidance. In the C-Tb arm, skin induration will be assessed 2–3 days after intradermal injection and measured in millimetres of induration. Results of IGRA will be obtained in line with standard practice. Behavioural studies will explore people’s experiences, perspectives and preferences of LTBI testing and treatment. Economic analysis will estimate cost-effectiveness of changes to the diagnostic algorithm for LTBI. The protocol was developed with Patient and Public Involvement (PPI), which will continue throughout the trial.Ethics and dissemination Ethics approval has been obtained from The NHS Health Research Authority (269485). We will share results of the trial in peer-reviewed journals and conferences.Trial registration number EudraCT 2019-002592-34; ISRCTN17936038.

The room-temperature, velocity-averaged, total cross section for atom–atom and atom–molecule collisions can be approximated using a universal function depending only on the magnitude of the leading order dispersion coefficient, C _6 . This feature of the total cross section together with the universal function for the energy distribution transferred by glancing angle collisions ( $p_{\textrm{QDU6}}$ (Booth et al 2019 New J. Phys. 21 102001)) can be used to empirically determine the total collision cross section and realize a self-calibrating, vacuum pressure standard. This was previously validated for Rb+N _2 and Rb+Rb collisions. However, the post-collision energy distribution is expected to deviate from $p_{\textrm{QDU6}}$ in the limit of small C _6 and small reduced mass. Here we observe this deviation experimentally by performing a direct cross-species loss rate comparison for Rb+H _2 and Li+H _2 collisions. We measure a velocity averaged total collision cross section ratio of $R = \langle \sigma_{\textrm{tot}} \, v \rangle_{{\textrm{Li+H}}_2} : \langle \sigma_{\textrm{tot}} \, v \rangle_{{\textrm{Rb+H}}_2} = 0.83(5)$ . Based on an ab initio computation of $\langle \sigma_{\textrm{tot}} \, v \rangle_{{\textrm{Li+H}}_2} =$ $3.104 \times 10^{-15}$ m ^3 s ^−1 , we deduce $\langle \sigma_{\textrm{tot}} \, v \rangle_{{\textrm{Rb+H}}_2} = 3.6(2) \times 10^{-15}$ m ^3 s ^−1 , in agreement with a Rb+H _2 ab initio value of $\langle \sigma_{\mathrm{tot}} v \rangle_{\mathrm{Rb+H_2}} = 3.574 \times 10^{-15} \mathrm{m}^3\,\mathrm{s}^{-1}$ . By contrast, fitting the Rb+H _2 loss rate as a function of trap depth to the universal function we find $\langle \sigma_{\textrm{tot}} \, v \rangle_{{\textrm{Rb+H}}_2} =$ $5.52(9) \times 10^{-15}$ m ^3 s ^−1 . This work demonstrates the utility of sensor-atom cross-calibration experiments to check the validity of theoretical computations to extend and enhance the performance of cold atom based pressure sensors.

Abstract Background Prediabetes appears to be increasing worldwide. This study examined the incidence of prediabetes among immigrants to Canada of different ethnic origins and the age at which ethnic differences emerged. Methods We assembled a cohort of Ontario adults (≥ 20 years) with normoglycemia based on glucose testing performed between 2002 and 2011 through a single commercial laboratory database (N = 1,772,180). Immigration data were used to assign ethnicity based on country of origin, mother tongue, and surname. Individuals were followed until December 2013 for the development of prediabetes, defined using either the World Health Organization/Diabetes Canada (WHO/DC) or American Diabetes Association (ADA) thresholds. Multivariate competing risk regression models were derived to examine the effect of ethnicity and immigration status on prediabetes incidence. Results After a median follow-up of 8.0 years, 337,608 individuals developed prediabetes. Using definitions based on WHO/DC, the adjusted cumulative incidence of prediabetes was 40% (HR 1.40, CI 1.38–1.41) higher for immigrants relative to long-term Canadian residents (21.2% vs 16.0%, p

Abstract Background Diabetes is a chronic medical condition that requires patients to be actively engaged in intensive self-management to achieve optimal clinical outcomes. Unfortunately, individuals who are experiencing homelessness often struggle to manage diabetes and consequently suffer numerous and severe complications—both acute and chronic. There are many barriers to optimal diabetes self-management among this population, and this may be exacerbated by the lack of tailoring and customization of care to this unique population. Given this disconnect, it is likely that many organizations have attempted to provide specialized innovations for this population—which may or may not be reported in the formal literature. Our objective is to perform a scoping review to summarize and synthesize the experiences of those who have attempted to provide tailored interventions. Methods We propose a mixed methods scoping review that will include both a formal search of the published literature (MEDLINE, CINAHL, EMBASE, Web of Science, Scopus) and a thorough search of the grey literature. Eligible articles and documents are those that report on an intervention or guideline for the management of diabetes among those experiencing homelessness. All titles and abstracts will undergo duplicate review, as will the full article/document. We will include any report that either includes a description of an intervention or provides recommendations for the treatment of individuals who are homeless with diabetes. We will extract both qualitative and quantitative data for analysis and interpretation. Meta-analysis will not be performed. Discussion Those experiencing homelessness who also have diabetes often struggle to manage their chronic condition. When care is tailored to suit their needs, it is feasible that outcomes may be improved. By collating and synthesizing information from diverse organizations and jurisdictions, we hope to facilitate the sharing of knowledge with others who wish to provide this type of care.

The COVID-19 pandemic put most in-person pathology electives on-hold as departments adapted to changes in education and patient care. To address the subsequent void in pathology education, we created a free, virtual, modular, and high-quality pathology elective website. Website traffic from June 1, 2020, to October 1, 2020, was monitored using the built-in analyses on Squarespace. Twitter engagement was analyzed using Twitter analytics and the Symplur Social Graph Score. A voluntary satisfaction survey was sent to all PathElective users and results were analyzed. During this time, the site saw 25 467 unique visitors, over 34 988 visits, 181 302 page views, and 4449 subscriptions from 99 countries. Countries with the highest traffic are the United States (14 682), India (5210), and the Philippines (2195). PathElective’s Twitter social graph score increased from 63.59 to 89.3 with the addition of 1637 followers. Data from surveyed users (n = 177) show most to be pathology residents (41%). Most subscribers (89%) are committed to a career in pathology. The majority heard of the website via Twitter (55%). Almost half of those surveyed engaged with the PathTwitter community on Twitter and of those who participated, 99% found that interaction useful. In all survey questions surrounding satisfaction and usefulness, a large majority of the users were either satisfied or very satisfied. PathElective is a novel pathology elective that offers a unique opportunity to educate medical students and residents from around the globe and demonstrates high effectiveness and satisfaction among users.

Introduction Insulin pump access in type 1 diabetes may be inequitable. We studied the association between government funding programs for insulin pumps and rates of insulin pump use and disparities between pump users and non-users.Research design and methods Adults with type 1 diabetes were identified in the National Diabetes Repository, a primary care electronic medical record database of individuals with diabetes from five Canadian provinces. Proportions of individuals using insulin pumps were compared between provinces with and without pump funding programs. Multivariable logistic regression models were used to estimate the odds of insulin pump use adjusting for confounders. Univariate logistic regression models were used to estimate the odds of insulin pump use according to each predictor, according to pump funding program status.Results Of 1559 adults with type 1 diabetes, proportions using insulin pumps were 47.8% (95% CI 45.1% to 50.5%) and 37.7% (95% CI 31.5% to 44.1%) in provinces with and without pump funding programs (p=0.0038). Adjusting for age, sex, HbA1c, income quintile, and rural/urban location, the OR for insulin pump use was 1.45 (1.08–1.94) for provinces with pump funding programs compared with provinces without. Higher income was associated with a greater odds of insulin pump use in provinces with pump funding programs, and rural/urban location was not associated with insulin pump use.Conclusions Insulin pump use is more common in regions with government funding programs. Further research is required to best understand and comprehensively address persistent income disparities between pump users and non-users despite the availability of reimbursement programs.

Introduction Participatory research is a study method that engages patients in research programs, ideally from study design through to dissemination. It is not commonly used in diabetes health services research. Our objectives were to describe the process and challenges of conducting a participatory research project and to highlight the experiences of both patient co-researchers and academic researchers.Research design and methods We recruited people with lived experience of homelessness (PWLEH) and diabetes in Toronto, Canada to become patient co-researchers. They were asked to commit to attending biweekly meetings. We undertook two major research projects: concept mapping to choose a research focus; and photovoice to explore accessing healthy food while homeless. We used a convergent mixed-methods design to evaluate their experience.Results A diverse group of eight PWLEH had an average attendance of 82% over 21 meetings—despite this success, we encountered a number of challenges of conducting this research: funding, ethics approval and recruitment were particularly difficult. Group members reported that participation improved their ability to self-advocate in their diabetes care and provided them with tangible skills and social benefits. Group members stated that they valued being involved in all aspects of the research, in particular knowledge translation activities, including advocating for nutritious food at shelters; presenting to stakeholders; and meeting with policymakers.Conclusions The use of participatory research methods enables academic researchers to support community members in pursuing research that is pertinent to them and which has a positive impact. In our study, co-researchers contributed in meaningful ways and also valued the experience.

Vitamins have well-established roles in bacterial metabolism. Menaquinones (MKn, n = prenyl units in sidechain) are bacterially produced forms of vitamin K produced by the gut microbiota and consumed in the diet. Little is known about the influence of dietary vitamin K quinones on gut microbial composition and MKn production. Here, male and female C57BL6 mice were fed a vitamin K deficient diet or vitamin K sufficient diets containing phylloquinone (PK, plant-based vitamin K form), MK4, and/or MK9. DNA was extracted from cecal contents and 16S sequencing conducted to assess microbial composition. Cecal microbial community composition was significantly different in vitamin K deficient female mice compared to females on vitamin K sufficient diets (all p .05 but

BackgroundSevere acute post-cesarean delivery (CD) pain has been associated with an increased risk for persistent pain and postpartum depression. Identification of women at increased risk for pain can be used to optimize post-cesarean analgesia. The impact of labor prior to CD (intrapartum CD) on acute post-operative pain and opioid use is unclear. We hypothesized that intrapartum CD, which has been associated with both increased inflammation and affective distress related to an unexpected surgical procedure, would result in higher postoperative pain scores and increased opioid intake.MethodsThis is a secondary analysis of a prospective cohort study examining opioid use up to 2 weeks following CD. Women undergoing CD at six academic medical centers in the United States 9/2014-3/2016 were contacted by phone two weeks following discharge. Participants completed a structured interview that included questions about postoperative pain scores and opioid utilization. They were asked to retrospectively estimate their maximal pain score on an 11-point numeric rating scale at multiple time points, including day of surgery, during hospitalization, immediately after discharge, 1st week, and 2nd week following discharge. Pain scores over time were assessed utilizing a generalized linear mixed-effects model with the patient identifier being a random effect, adjusting for an a priori defined set of confounders. A multivariate negative binomial model was utilized to assess the association between intrapartum CD and opioid utilization after discharge, also adjusting for the same confounders. In the context of non-random prescription distribution, this model was constructed with an offset for the number of tablets dispensed.ResultsA total of 720 women were enrolled, 392 with and 328 without labor prior to CD. Patients with intrapartum CD were younger, less likely to undergo repeat CD or additional surgical procedures, and more likely to experience a complication of CD. Women with intrapartum CD consumed more opioid tablets following discharge than women without labor (median 20, IQR 10-30 versus 17, IQR 6-30; p = 0.005). This association persisted after adjustment for confounders (incidence rate ratio 1.16, 95% CI 1.05-1.29; p = 0.004). Pain scores on the day of surgery were higher in women with intrapartum CD (difference 0.91, 95% CI 0.52-1.30; adj. p = ConclusionIntrapartum CD is associated with worse pain on the day of surgery but not other time points. Opioid requirements following discharge were modestly increased following intrapartum CD.

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) particularly in the most severe form, idiopathic pulmonary fibrosis (IPF), although the underlying mechanisms remain unclear. Neutrophil function is modulated by numerous factors, including integrin activation, inflammatory cytokines and hypoxia. Hypoxia has an important role in inflammation and may also contribute to pulmonary disease. We aimed to determine how neutrophil activation occurs in ILD and the relative importance of hypoxia. Using lung biopsies and bronchoalveolar lavage (BAL) fluid from ILD patients we investigated the extent of hypoxia and neutrophil activation in ILD lungs. Then we used ex vivo neutrophils isolated from healthy volunteers and BAL from patients with ILD and non-ILD controls to further investigate aberrant neutrophil activation in hypoxia and ILD. We demonstrate for the first time using intracellular staining, HIF-1α stabilization in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous (+1.31-fold, p < 0.05) and phorbol 12-myristate 13-acetate (PMA)-induced (+1.65-fold, p < 0.001) neutrophil extracellular trap (NET) release, neutrophil adhesion (+8.8-fold,

Summary: Objective: While a role for vitamin K in maintaining joint tissue homeostasis has been proposed based on the presence of vitamin K dependent proteins in cartilage and bone, it is not clear if low vitamin K intake is causally linked to joint tissue degeneration. To address this gap, we manipulated vitamin K status in aging mice to test its effect on age-related changes in articular cartilage and sub-chondral bone. Methods: Eleven-month old male C57BL6 mice were randomly assigned to a low vitamin K diet containing 120 mcg phylloquinone/kg diet (n = 32) or a control diet containing 1.5 mg phylloquinone/kg diet (n = 30) for 6 months. Knees were evaluated histologically using Safranin O and H&E staining, as well as using micro-CT. Results: Eleven mice in the low vitamin K diet group and three mice in the control group died within the first 100 days of the experiment (p = 0.024). Mice fed the low vitamin K diet had higher Safranin-O scores, indicative of more proteoglycan loss, compared to mice fed the control diet (p ≤ 0.026). The articular cartilage structure scores did not differ between the two groups (p ≥ 0.190). The sub-chondral bone parameters measured using micro CT also did not differ between the two groups (all p ≥ 0.174). Conclusion: Our findings suggest low vitamin K status can promote joint tissue proteoglycan loss in older male mice. Future studies are needed to confirm our findings and obtain a better understanding of the molecular mechanisms underlying the role of vitamin K in joint tissue homeostasis.

The use of social media at academic conferences is expanding, and platforms such as Twitter are used to share meeting content with the world. Pathology conferences are no exception, and recently, pathology organizations have promoted social media as a way to enhance meeting exposure. A social media committee was formed ad hoc to implement strategies to enhance social media involvement and coverage at the 2018 and 2019 annual meetings of the Association of Pathology Chairs. This organized approach resulted in an 11-fold increase in social media engagement compared to the year prior to committee formation (2017). In this article, the social media committee reviews the strategies that were employed and the resultant outcome data. In addition, we categorize tweets by topic to identify the topics of greatest interest to meeting participants, and we discuss the differences between Twitter and other social media platforms. Lastly, we review the existing literature on this topic from 23 medical specialties and health care fields.

Introduction We examined whether adults living in highly walkable areas are less likely to develop pre-diabetes and if so, whether this association is consistent according to immigration status and ethnicity.Research design and methods Population-level health, immigration, and administrative databases were used to identify adults aged 20–64 (n=1 128 181) who had normoglycemia between January 2011 and December 2011 and lived in one of 15 cities in Southern Ontario, Canada. Individuals were assigned to one of ten deciles (D) of neighborhood walkability (from lowest (D1) to highest (D10)) and followed until December 2013 for the development of pre-diabetes.Results Overall, 220 225 individuals in our sample developed pre-diabetes during a median follow-up of 8.4 years. Pre-diabetes incidence was 20% higher among immigrants living in the least (D1) (adjusted HR 1.20, 95% CI 1.15 to 1.25, p

ObjectiveThe aim of this study was to compare absolute and relative rates of conversion from prediabetes to diabetes among non-European immigrants to Europeans and Canadian-born residents, overall, and by age and level of glycemia.Research design and methodsWe conducted a retrospective cohort population-based study using administrative health databases from Ontario, Canada, to identify immigrants (n=23 465) and Canadian born (n=1 11 085) aged ≥20 years with prediabetes based on laboratory tests conducted between 2002 and 2011. Individuals were followed until 31 December 2013 for the development of diabetes using a validated algorithm. Immigration data was used to assign ethnicity based on country of origin, mother tongue, and surname. Fine and Gray’s survival models were used to compare diabetes incidence across ethnic groups overall and by age and glucose category.ResultsOver a median follow-up of 5.2 years, 8186 immigrants and 39 722 Canadian-born residents developed diabetes (7.1 vs 6.1 per 100 person-years, respectively). High-risk immigrant populations such as South Asians (HR: 1.72, 95% CI 1.55 to 1.99) and Southeast Asians (HR: 1.65, 95% CI 1.46 to 1.86) had highest risk of converting to diabetes compared with Western Europeans (referent). Among immigrants aged 20–34 years, the adjusted cumulative incidence ranged from 18.4% among Eastern Europeans to 52.3% among Southeast Asians. Conversion rates increased with age in all groups but were consistently high among South Asians, Southeast Asians and Sub-Saharan African/Caribbeans after the age of 35 years. On average, South Asians converted to diabetes 3.1–4.6 years earlier than Western Europeans and at an equivalent rate of conversion to Western Europeans who had a 0.5 mmol/L higher baseline fasting glucose value.ConclusionsHigh-risk ethnic groups converted to diabetes more rapidly, at younger ages, and at lower fasting glucose values than European populations, leading to a shorter window for diabetes prevention.

Introduction We aimed to develop algorithms distinguishing type 1 diabetes (T1D) from type 2 diabetes in adults ≥18 years old using primary care electronic medical record (EMRPC) and administrative healthcare data from Ontario, Canada, and to estimate T1D prevalence and incidence.Research design and methods The reference population was a random sample of patients with diabetes in EMRPC whose charts were manually abstracted (n=5402). Algorithms were developed using classification trees, random forests, and rule-based methods, using electronic medical record (EMR) data, administrative data, or both. Algorithm performance was assessed in EMRPC. Administrative data algorithms were additionally evaluated using a diabetes clinic registry with endocrinologist-assigned diabetes type (n=29 371). Three algorithms were applied to the Ontario population to evaluate the minimum, moderate and maximum estimates of T1D prevalence and incidence rates between 2010 and 2017, and trends were analyzed using negative binomial regressions.Results Of 5402 individuals with diabetes in EMRPC, 195 had T1D. Sensitivity, specificity, positive predictive value and negative predictive value for the best performing algorithms were 80.6% (75.9–87.2), 99.8% (99.7–100), 94.9% (92.3–98.7), and 99.3% (99.1–99.5) for EMR, 51.3% (44.0–58.5), 99.5% (99.3–99.7), 79.4% (71.2–86.1), and 98.2% (97.8–98.5) for administrative data, and 87.2% (81.7–91.5), 99.9% (99.7–100), 96.6% (92.7–98.7) and 99.5% (99.3–99.7) for combined EMR and administrative data. Administrative data algorithms had similar sensitivity and specificity in the diabetes clinic registry. Of 11 499 711 adults in Ontario in 2017, there were 24 789 (0.22%, minimum estimate) to 102 140 (0.89%, maximum estimate) with T1D. Between 2010 and 2017, the age-standardized and sex-standardized prevalence rates per 1000 person-years increased (minimum estimate 1.7 to 2.56, maximum estimate 7.48 to 9.86, p

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes the vitamin K subtype menaquinone-4 (MK-4). Previous studies in cultured cells (Schumacher et al., 2015) revealed that UBIAD1 also inhibits endoplasmic reticulum (ER)-associated degradation (ERAD) of ubiquitinated HMG CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway that produces cholesterol and essential nonsterol isoprenoids. Gene knockout studies were previously attempted to explore the function of UBIAD1 in mice; however, homozygous germ-line elimination of the Ubiad1 gene caused embryonic lethality. We now report that homozygous deletion of Ubiad1 is produced in knockin mice expressing ubiquitination/ERAD-resistant HMGCR. Thus, embryonic lethality of Ubiad1 deficiency results from depletion of mevalonate-derived products owing to enhanced ERAD of HMGCR rather than from reduced synthesis of MK-4. These findings provide genetic evidence for the significance of UBIAD1 in regulation of cholesterol synthesis and offer the opportunity in future studies for the discovery of new physiological roles of MK-4.

Abstract Background Health care data allow for the study and surveillance of chronic diseases such as diabetes. The objective of this study was to identify and validate optimal algorithms for diabetes cases within health care administrative databases for different research purposes, populations, and data sources. Methods We linked health care administrative databases from Ontario, Canada to a reference standard of primary care electronic medical records (EMRs). We then identified and calculated the performance characteristics of multiple adult diabetes case definitions, using combinations of data sources and time windows. Results The best algorithm to identify diabetes cases was the presence at any time of one hospitalization or physician claim for diabetes AND either one prescription for an anti-diabetic medication or one physician claim with a diabetes-specific fee code [sensitivity 84.2%, specificity 99.2%, positive predictive value (PPV) 92.5%]. Use of physician claims alone performed almost as well: three physician claims for diabetes within one year was highly specific (sensitivity 79.9%, specificity 99.1%, PPV 91.4%) and one physician claim at any time was highly sensitive (sensitivity 93.6%, specificity 91.9%, PPV 58.5%). Conclusions This study identifies validated algorithms to capture diabetes cases within health care administrative databases for a range of purposes, populations and data availability. These findings are useful to study trends and outcomes of diabetes using routinely-collected health care data.