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Abstract Objective To determine whether there were improvements in rheumatology care for rheumatoid arthritis (RA) between 2002 and 2019 in Ontario, Canada, and to evaluate the impact of rheumatologist regional supply on access. Methods We conducted a population-based retrospective study of all individuals diagnosed with RA between January 1, 2002 and December 31, 2019. Performance measures evaluated were: (i) percentage of RA patients seen by a rheumatologist within one year of diagnosis; and (ii) percentage of individuals with RA aged 66 years and older (whose prescription drugs are publicly funded) dispensed a disease modifying anti-rheumatic drug (DMARD) within 30 days after initial rheumatologist visit. Logistic regression was used to assess whether performance improved over time and whether the improvements differed by rheumatology supply, dichotomized as

Objective Development of new systemic lupus erythematosus (SLE) treatments requires an effective responder index. Toward this end, we have recently developed a new Lupus Multivariable Outcome Score (LuMOS) to optimize discrimination between actively treated patients and those on placebo. We now report on external validation of LuMOS in two independent clinical trials. Methods Validation was performed with the Illuminate data sets that evaluated tabalumab (TB) in SLE. To accommodate laboratory results assessed on different platforms, we developed a standardized LuMOS 2.0 model that uses z score transformations of biomarker values. For validation, we calculated LuMOS 2.0 scores at week 52 for all participants. Effect size (ES), with 95% confidence intervals (CIs), compared the ability of LuMOS and the SLE Responder Index‐5 (SRI‐5) to discriminate between outcomes in patients randomized to TB dosage and outcomes in those randomized to a placebo. Results Mean LuMOS 2.0 scores were significantly higher (P 0.4) in contrast to weak SRI‐5 effects (

Background PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) suggested a potential benefit of sacubitril–valsartan in women with preserved ejection fraction. Among patients with heart failure previously treated with angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), we studied whether effectiveness of treatment with sacubitril–valsartan compared with ACEI/ARB monotherapy differed between men and women for both preserved and reduced ejection fraction. Methods and Results Data were derived from the Truven Health MarketScan Databases between January 1, 2011, and December 31, 2018. We included patients with a primary diagnosis of heart failure on treatment with ACEIs, ARBs, or sacubitril–valsartan on the basis of the first prescription after diagnosis. A total of 7181 patients treated with sacubitril–valsartan, 25 408 patients using an ACEI, and 16 177 patients treated with ARBs were included. A total of 790 readmissions or deaths occurred among 7181 patients in the sacubitril–valsartan group and 11 901 events in 41 585 patients treated with an ACEI/ARB. Adjusted for covariates, the hazard ratio (HR) for treatment with sacubitril–valsartan compared with an ACEI or ARB was 0.74 (95% CI, 0.68–0.80). The protective effect of sacubitril–valsartan was evident for men and women (women: HR, 0.75 [95% CI, 0.66–0.86]; P

Objective The study objective was to assess adherence to system‐level performance measures measuring retention in rheumatology care and disease modifying anti‐rheumatic drug (DMARD) treatment in rheumatoid arthritis (RA). Methods We used a validated health administrative data case definition to identify individuals with RA in Ontario, Canada, between 2002 and 2014 who had at least 5 years of potential follow‐up prior to 2019. During the first 5 years following diagnosis, we assessed whether patients were seen by a rheumatologist yearly and the proportion dispensed a DMARD yearly (in those aged ≥66 for whom medication data were available). Multivariable logistic regression analyses were used to estimate the odds of remaining under rheumatologist care. Results The cohort included 50,883 patients with RA (26.1% aged 66 years and older). Over half (57.7%) saw a rheumatologist yearly in all 5 years of follow‐up. Sharp declines in the percentage of patients with an annual visit were observed in each subsequent year after diagnosis, although a linear trend to improved retention in rheumatology care was seen over the study period (P

Abstract Influenza immunization protects seniors against influenza and its potentially serious complications. It is uncertain whether standard-dose (SD) quadrivalent vaccine offers better protection over other formulations in the elderly. In this study, we compared the effectiveness of SD-trivalent, high-dose (HD) trivalent, SD-quadrivalent, and adjuvanted trivalent vaccines in seniors (≥65 years) in a real-world setting. We selected over 200,000 individuals in each of 6 influenza seasons from 2012 to 2018 using MarketScan® databases. The two outcomes were hospitalization or emergency room (ER) visit due to (1) influenza or (2) pneumonia. Here, SD-quadrivalent was associated with higher risk of influenza-related hospitalization/ER visit (adjusted hazard ratio (aHR) 1.14 and 95% confidence interval (95% CI) 1.05–1.24) and of pneumonia-related hospitalization/ER visit (aHR 1.04 and 95% CI 1.01–1.07) vs. HD-trivalent. SD-trivalent followed similar trends compared to HD-trivalent (aHR 1.16 and 95% CI 1.06–1.27 for hospitalized/ER visit influenza; aHR 1.07 and 95% CI 1.05–1.10 for hospitalized/ER visit pneumonia). We could not demonstrate risk differences between SD vaccine formulations and between adjuvanted trivalent and one of the other three vaccines. Risk estimates slightly varied across seasons. These findings suggest that SD vaccine formulations vs. HD-trivalent were associated with higher risk of hospitalization/ER visit for influenza and pneumonia in seniors.

Abstract Background As cancer treatment, biotherapies can be as effective as chemotherapy while reducing the risk of secondary effects, so that they can be taken over longer periods than conventional chemotherapy. Thus, some trials aimed at assessing the benefit of maintaining biotherapies during chemotherapy-free intervals (CFI). For example, the recent PRODIGE9 trial assessed the effect of maintaining bevacizumab during CFI in metastatic colorectal cancer (mCRC) patients. However, its analysis was hindered by a small difference of exposure to the treatment between the randomized groups and by a large proportion of early drop outs, leading to a potentially unbalanced distribution of confounding factors among the trial completers. To address these limitations, we re-analyzed the PRODIGE9 data to assess the effects of different exposure metrics on all-cause mortality of patients with mCRC using methods originally developed for observational studies. Methods To account for the actual patterns of drug use by individual patients and for possible cumulative effects, we used five alternative time-varying exposure metrics: (i) cumulative dose, (ii) quantiles of the cumulative dose, (iii) standardized cumulative dose, (iv) Theoretical Blood Concentration (TBC), and (v) Weighted Cumulative Exposure (WCE). The last two metrics account for the timing of drug use. Treatment effects were estimated using adjusted Hazard Ratio from multivariable Cox proportional hazards models. Results After excluding 112 patients who died during the induction period, we analyzed data on 382 patients, among whom 320 (83.8%) died. All time-varying exposures improved substantially the model’s fit to data, relative to using only the time-invariant randomization group. All exposures indicated a protective effect for higher cumulative bevacizumab doses. The best-fitting WCE and TBC models accounted for both the cumulative effects and the different impact of doses taken at different times. Conclusions All time-varying analyses, regardless of the exposure metric used, consistently suggested protective effects of higher cumulative bevacizumab doses. However, the results may partly reflect the presence of a confusion bias. Complementing the main ITT analysis of maintenance trials with an analysis of potential cumulative effects of treatment actually taken can provide new insights, but the results must be interpreted with caution because they do not benefit from the randomization. Trial registration clinicaltrials.gov, NCT00952029 . Registered 8 August 2009.

Background: Current guidelines are relatively general regarding the type of patient with heart failure (HF) who should be considered for catheter ablation (CA) of atrial fibrillation (AF). The aim of the present study was to identify clinical predictors and sex differences for treatment with CA in the AF-HF population. Methods: A population-based AF-HF cohort was created using the Quebec administrative data (2000-2017). Patients were followed from the date of diagnosis of both diseases to the date of CA or death. Predictors for CA, represented by time-varying covariates, were assessed in a multivariable Cox model that accounted for the competing risk of death. Results: Among 101,931 patients with AF-HF with medication information (median age, 80.7 years; interquartile range [IQR], 73.9-86.3; 51.4% were female, median CHA2DS2-VASc, 4; IQR, 3-4), only 432 (0.4%) underwent CA after a median of 0.8 years (IQR, 0.1-2.7). Independent of multiple comorbidities and advanced age, which were associated with a lower likelihood of CA, women were approximately half as likely to undergo a CA (26% were women; adjusted hazard ratio, 0.6; 95% confidence interval, 0.4-0.7). Prior use of direct-acting oral anticoagulants and antiarrhythmics, and the presence of an implantable cardioverter-defibrillator were also predictors for CA treatment (P < 0.05 for all). Conclusion: In a real-world population, CA was infrequently used to treat AF among patients with HF, and the likelihood of CA was further reduced in women. Because patients with CA had few comorbidities, future studies need to be conducted to determine whether CA can be beneficial in subjects whose clinical characteristics are more representative of the AF-HF population. Résumé: Contexte: Les lignes directrices actuelles abordent de façon relativement générale les cas d’insuffisance cardiaque (IC) où les patients devraient être considérés comme des candidats à l’ablation par cathéter (AC) pour le traitement de la fibrillation auriculaire (FA). La présente étude visait à cerner les prédicteurs cliniques et les différences entre les sexes dans le contexte de l’AC au sein de la population atteinte de FA et d’IC. Méthodologie: Une cohorte populationnelle de patients atteints de FA et d’IC a été constituée à partir de données administratives du Québec (2000-2017). Le suivi des patients allait de la date du diagnostic des deux affections à la date de l’AC ou du décès. Les prédicteurs d’AC, représentés par des covariables temporalisées, ont été évalués dans un modèle de Cox multivarié tenant compte du risque concurrent de décès. Résultats: Sur 101 931 patients atteints de FA et d’IC dont la médication était documentée (âge médian : 80,7 ans; intervalle interquartile [IIQ] : 73,9-86,3; proportion de patients de sexe féminin : 51,4 %; score CHA2DS2-VASc médian : 4; IIQ : 3-4), seulement 432 (0,4 %) ont subi une AC au bout d’un laps de temps médian de 0,8 an (IIQ : 0,1-2,7). Indépendamment des maladies concomitantes multiples et de l’âge avancé, associés à une moindre probabilité d’AC, les femmes étaient environ deux fois moins susceptibles de subir une AC (proportion de patients de sexe féminin : 26 %; rapport des risques instantanés corrigé : 0,6; intervalle de confiance à 95 % : de 0,4 à 0,7). Les antécédents de traitement par des anticoagulants oraux à action directe et des antiarythmiques, ainsi que la présence d’un défibrillateur cardioverteur implantable étaient également des prédicteurs d’AC (p < 0,05 dans tous les cas). Conclusion: Au sein d’une population en contexte réel, l’AC a été rarement pratiquée pour traiter la FA chez des patients atteints d’IC. En outre, la probabilité d’une AC était moindre chez les femmes. Étant donné que les patients ayant subi une AC présentaient peu de maladies concomitantes, d’autres études devront être menées pour déterminer si l’AC peut être salutaire chez les personnes présentant des caractéristiques cliniques plus représentatives de la population atteinte de FA et d’IC.

Abstract Background How to select variables and identify functional forms for continuous variables is a key concern when creating a multivariable model. Ad hoc ‘traditional’ approaches to variable selection have been in use for at least 50 years. Similarly, methods for determining functional forms for continuous variables were first suggested many years ago. More recently, many alternative approaches to address these two challenges have been proposed, but knowledge of their properties and meaningful comparisons between them are scarce. To define a state of the art and to provide evidence-supported guidance to researchers who have only a basic level of statistical knowledge, many outstanding issues in multivariable modelling remain. Our main aims are to identify and illustrate such gaps in the literature and present them at a moderate technical level to the wide community of practitioners, researchers and students of statistics. Methods We briefly discuss general issues in building descriptive regression models, strategies for variable selection, different ways of choosing functional forms for continuous variables and methods for combining the selection of variables and functions. We discuss two examples, taken from the medical literature, to illustrate problems in the practice of modelling. Results Our overview revealed that there is not yet enough evidence on which to base recommendations for the selection of variables and functional forms in multivariable analysis. Such evidence may come from comparisons between alternative methods. In particular, we highlight seven important topics that require further investigation and make suggestions for the direction of further research. Conclusions Selection of variables and of functional forms are important topics in multivariable analysis. To define a state of the art and to provide evidence-supported guidance to researchers who have only a basic level of statistical knowledge, further comparative research is required.

Summary: Background: Wildfires emit many carcinogenic pollutants that contaminate air, water, terrestrial, and indoor environments. However, little is known about the relationship between exposure to wildfires and cancer risk. We aimed to assess the associations between residential exposure to wildfires and the incidence of several cancer outcomes (lung cancer, brain cancer, non-Hodgkin lymphoma, multiple myeloma, and leukaemia) in Canada. Methods: We did a population-based observational cohort study of participants in the 1996 Canadian Census Health and Environment Cohort. The 1996 Canadian Census Health and Environment Cohort is a nationally representative sample of Canadian adults, followed up for cancer incidence and mortality from 1996 to 2015. For this analysis, we excluded participants who lived in major Canadian cities (with a population size greater than 1·5 million people), recent immigrants, and individuals younger than 25 years or 90 years of age or older at baseline. Exposures to wildfires were assigned on the basis of area burned within a 20 km or 50 km radius of residential locations and updated for annual residential mobility. Multivariable Cox proportional hazards models were used to estimate associations between exposure to wildfires and specific cancers associated with carcinogenic compounds released by wildfires, including lung and brain cancer, non-Hodgkin lymphoma, multiple myeloma, and leukaemia, adjusted for many personal and neighbourhood-level covariates. Findings: Our analyses included more than 2 million people followed up for a median of 20 years, for a total of 34 million person-years. Wildfire exposure was associated with slightly increased incidence of lung cancer and brain tumours. For example, cohort members exposed to a wildfire within 50 km of residential locations in the past 10 years had a 4·9% relatively higher incidence (adjusted hazard ratio [HR] 1·049, 95% CI 1·028–1·071) of lung cancer than unexposed populations, and a 10% relatively higher incidence (adjusted HR 1·100, 1·026–1·179) of brain tumours. Similar associations were observed for the 20 km buffer size. Wildfires were not associated with haematological cancers in this study, and concentration-response trends were not readily apparent when area burned was modelled as a continuous variable. Interpretation: Long-term exposure to wildfires might increase the risk of lung cancer and brain tumours. Further work is needed to develop long-term estimates of wildfire exposures that capture the complex mixture of environmental pollutants released during these events. Funding: Canadian Institute for Health Research and Fonds de recherche du Quebec.

Background Long-term opioid use is an increasingly important problem related to the ongoing opioid epidemic. The purpose of this study was to identify patient, hospitalization and system-level determinants of long term opioid therapy (LTOT) among patients recently discharged from hospital. Design To be eligible for this study, patient needed to have filled at least one opioid prescription three-months post-discharge. We retrieved data from the provincial health insurance agency to measure medical service and prescription drug use in the year prior to and after hospitalization. A multivariable Cox Proportional Hazards model was utilized to determine factors associated with time to the first LTOT occurrence, defined as time-varying cumulative opioid duration of ≥ 60 days. Results Overall, 22.4% of the 1,551 study patients were classified as LTOT, who had a mean age of 66.3 years (SD = 14.3). Having no drug copay status (adjusted hazard ratio (aHR) 1.91, 95% CI: 1.40–2.60), being a LTOT user before the index hospitalization (aHR 6.05, 95% CI: 4.22–8.68) or having history of benzodiazepine use (aHR 1.43, 95% CI: 1.12–1.83) were all associated with an increased likelihood of LTOT. Cardiothoracic surgical patients had a 40% lower LTOT risk (aHR 0.55, 95% CI: 0.31–0.96) as compared to medical patients. Initial opioid dispensation of > 90 milligram morphine equivalents (MME) was also associated with higher likelihood of LTOT (aHR 2.08, 95% CI: 1.17–3.69). Conclusions and relevance Several patient-level characteristics associated with an increased risk of ≥ 60 days of cumulative opioid use. The results could be used to help identify patients who are at high-risk of continuing opioids beyond guideline recommendations and inform policies to curb excessive opioid prescribing.

BackgroundGiven that pregnant women taking medications are excluded from clinical trials, real-world evidence is essential. We aimed to build a Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO) and compare frequency of prematurity, low-birth-weight (LBW), major malformations, multiplicity, and gestational medication use across four provinces.MethodsCAMCCO is a collaborative research infrastructure that uses real-world data from large provincial health care databases in Canada; developed with standardized methods to similarly construct population-based pregnancy/child cohorts with longitudinal follow-up by linking administrative/hospital/birth databases. CAMCCO also includes a common repository to i) share algorithms and case definitions based on diagnostic and procedural codes for research/training purpose, and ii) download aggregate data relevant to primary care providers, researchers, and decision makers. For this study, data from Quebec (1998-2015), Manitoba (1995-2019), Saskatchewan (1996-2020), and Alberta (2005-2018) are compared (Chi-square tests, p-values), and trends are calculated using Cochran-Armitage trend tests.ResultsAlmost two-thirds (61%) of women took medications during pregnancy, mostly antibiotics (26%), asthma drugs (8%), and antidepressants (4%). Differences in the prevalence of prematurity (5.9-6.8%), LBW (4.0-5.2%), and multiplicity (1.0-2.5%) were statistically significant between provinces (pInterpretationMedications are often used among Canadian pregnancies but adverse pregnancy outcomes vary across provinces. Digitized health data may help researchers and care providers understand the risk-benefit ratios related to gestational medication use, as well as province-specific trends.

Introduction The main harm reduction interventions for people who inject drugs (PWID) are supervised injection facilities, needle and syringe programmes and opioid agonist treatment. Current evidence supporting their implementation and operation underestimates their usefulness by excluding skin, soft tissue and vascular infections (SSTVIs) and anoxic/toxicity-related brain injury from cost-effectiveness analyses (CEA). Our goal is to conduct a comprehensive CEA of harm reduction interventions in a setting with a large, dispersed, heterogeneous population of PWID, and include prevention of SSTVIs and anoxic/toxicity-related brain injury as measures of benefit in addition to HIV, hepatitis C and overdose morbidity and mortalities averted.Methods and analysis This protocol describes how we will develop an open, retrospective cohort of adult PWID living in Québec between 1 January 2009 and 31 December 2020 using administrative health record data. By complementing this data with non-linkable paramedic dispatch records, regional monthly needle and syringe dispensation counts and repeated cross-sectional biobehavioural surveys, we will estimate the hazards of occurrence and the impact of Montréal’s harm reduction interventions on the incidence of drug-use-related injuries, infections and deaths. We will synthesise results from our empirical analyses with published evidence to simulate infections and injuries in a hypothetical population of PWID in Montréal under different intervention scenarios including current levels of use and scale-up, and assess the cost-effectiveness of each intervention from the public healthcare payer’s perspective.Ethics and dissemination This study was approved by McGill University’s Institutional Review Board (Study Number: A08-E53-19B). We will work with community partners to disseminate results to the public and scientific community via scientific conferences, a publicly accessible report, op-ed articles and open access peer-reviewed journals.

Objectives There are increasing requirements to make research data, especially clinical trial data, more broadly available for secondary analyses. However, data availability remains a challenge due to complex privacy requirements. This challenge can potentially be addressed using synthetic data.Setting Replication of a published stage III colon cancer trial secondary analysis using synthetic data generated by a machine learning method.Participants There were 1543 patients in the control arm that were included in our analysis.Primary and secondary outcome measures Analyses from a study published on the real dataset were replicated on synthetic data to investigate the relationship between bowel obstruction and event-free survival. Information theoretic metrics were used to compare the univariate distributions between real and synthetic data. Percentage CI overlap was used to assess the similarity in the size of the bivariate relationships, and similarly for the multivariate Cox models derived from the two datasets.Results Analysis results were similar between the real and synthetic datasets. The univariate distributions were within 1% of difference on an information theoretic metric. All of the bivariate relationships had CI overlap on the tau statistic above 50%. The main conclusion from the published study, that lack of bowel obstruction has a strong impact on survival, was replicated directionally and the HR CI overlap between the real and synthetic data was 61% for overall survival (real data: HR 1.56, 95% CI 1.11 to 2.2; synthetic data: HR 2.03, 95% CI 1.44 to 2.87) and 86% for disease-free survival (real data: HR 1.51, 95% CI 1.18 to 1.95; synthetic data: HR 1.63, 95% CI 1.26 to 2.1).Conclusions The high concordance between the analytical results and conclusions from synthetic and real data suggests that synthetic data can be used as a reasonable proxy for real clinical trial datasets.Trial registration number NCT00079274.

Gender refers to the socially constructed roles, behaviours, expressions and identities of girls, women, boys, men and gender diverse people. Gender-related factors are seldom assessed as determinants of health outcomes, despite their powerful contribution. The Gender Outcomes INternational Group: to Further Well-being Development (GOING-FWD) project developed a standard five-step methodology applicable to retrospectively identify gender-related factors and assess their relationship to outcomes across selected cohorts of non-communicable chronic diseases from Austria, Canada, Spain, Sweden. Step 1 (identification of gender-related variables): Based on the gender framework of the Women Health Research Network (ie, identity, role, relations and institutionalised gender), and available literature for a certain disease, an optimal ‘wish-list’ of gender-related variables was created and discussed by experts. Step 2 (definition of outcomes): Data dictionaries were screened for clinical and patient-relevant outcomes, using the International Consortium for Health Outcome Measurement framework. Step 3 (building of feasible final list): a cross-validation between variables per database and the ‘wish-list’ was performed. Step 4 (retrospective data harmonisation): The harmonisation potential of variables was evaluated. Step 5 (definition of data structure and analysis): The following analytic strategies were identified: (1) local analysis of data not transferable followed by a meta-analysis combining study-level estimates; (2) centrally performed federated analysis of data, with the individual-level participant data remaining on local servers; (3) synthesising the data locally and performing a pooled analysis on the synthetic data and (4) central analysis of pooled transferable data. The application of the GOING-FWD multistep approach can help guide investigators to analyse gender and its impact on outcomes in previously collected data.

In health research, statistical methods are frequently used to address a wide variety of research questions. For almost every analytical challenge, different methods are available. But how do we choose between different methods and how do we judge whether the chosen method is appropriate for our specific study? Like in any science, in statistics, experiments can be run to find out which methods should be used under which circumstances. The main objective of this paper is to demonstrate that simulation studies, that is, experiments investigating synthetic data with known properties, are an invaluable tool for addressing these questions. We aim to provide a first introduction to simulation studies for data analysts or, more generally, for researchers involved at different levels in the analyses of health data, who (1) may rely on simulation studies published in statistical literature to choose their statistical methods and who, thus, need to understand the criteria of assessing the validity and relevance of simulation results and their interpretation; and/or (2) need to understand the basic principles of designing statistical simulations in order to efficiently collaborate with more experienced colleagues or start learning to conduct their own simulations. We illustrate the implementation of a simulation study and the interpretation of its results through a simple example inspired by recent literature, which is completely reproducible using the R-script available from online supplemental file 1.

Abstract Background With progress on both the theoretical and the computational fronts the use of spline modelling has become an established tool in statistical regression analysis. An important issue in spline modelling is the availability of user friendly, well documented software packages. Following the idea of the STRengthening Analytical Thinking for Observational Studies initiative to provide users with guidance documents on the application of statistical methods in observational research, the aim of this article is to provide an overview of the most widely used spline-based techniques and their implementation in R. Methods In this work, we focus on the R Language for Statistical Computing which has become a hugely popular statistics software. We identified a set of packages that include functions for spline modelling within a regression framework. Using simulated and real data we provide an introduction to spline modelling and an overview of the most popular spline functions. Results We present a series of simple scenarios of univariate data, where different basis functions are used to identify the correct functional form of an independent variable. Even in simple data, using routines from different packages would lead to different results. Conclusions This work illustrate challenges that an analyst faces when working with data. Most differences can be attributed to the choice of hyper-parameters rather than the basis used. In fact an experienced user will know how to obtain a reasonable outcome, regardless of the type of spline used. However, many analysts do not have sufficient knowledge to use these powerful tools adequately and will need more guidance.

Abstract Background Tofacitinib is the first oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA). We compared the effectiveness and safety of tofacitinib, disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor inhibitors (TNFi), and non-TNF biologics in patients with RA previously treated with methotrexate. Methods We used MarketScan® databases (2011–2014) to study methotrexate-exposed patients with RA who were newly prescribed tofacitinib, DMARDs other than methotrexate, and biologics. The date of first prescription was defined as the cohort entry. The therapy was considered effective if all of the following criteria from a claims-based algorithm were achieved at the first year of follow-up: high adherence, no biologic or tofacitinib switch or addition, no DMARD switch or addition, no increase in dose or frequency of index drug, no more than one glucocorticoid joint injection, and no new/increased oral glucocorticoid dose. The safety outcome was serious infections requiring hospitalization. Non-TNF biologics comprised the reference group. Results We included 21,832 patients with RA, including 0.8% treated with tofacitinib, 24.7% treated with other DMARDs, 61.2% who had started therapy with TNFi, and 13.3% treated with non-TNF biologics. The rates of therapy effectiveness were 15.4% for tofacitinib, 11.1% for DMARDs, 18.6% for TNFi, and 19.8% for non-TNF biologics. In adjusted analyses, tofacitinib and non-TNF biologics appeared to have similar effectiveness rates, whereas DMARD initiators were less effective than non-TNF biologics. We could not clearly establish if tofacitinib was associated with a higher rate of serious infections. Conclusions In patients with RA previously treated with methotrexate, our comparisons of tofacitinib with non-TNF biologics, though not definitive, did not demonstrate differences with respect to hospitalized infections or effectiveness.

Abstract Background Urinary incontinence (UI), one of the most prevalent health concerns confronting women aged over 60 years, affects up to 55% of older community-dwelling women—20–25% with severe symptoms. Clinical practice guidelines recommend individualized pelvic floor muscle training (PFMT) as a first-line treatment for stress or mixed UI in women, although lack of human and financial resources limits delivery of this first-line treatment. Preliminary data suggest that group-based treatments may provide the answer. To date, no adequately powered trials have evaluated the effectiveness or cost-effectiveness of group compared to individual PFMT for UI in older women. Given demographic projections, high prevalence of UI in older women, costly barriers, and group PFMT promising results, there is a clear need to rigorously compare the short- and long-term effectiveness and cost-effectiveness of group vs individual PFMT. Methods/Design The study is designed as a non-inferiority randomized controlled trial, conducted in two facilities (Montreal and Sherbrooke) in the Canadian province of Quebec. Participants include 364 ambulatory, community-dwelling women, aged 60 years and older, with stress or mixed UI. Randomly assigned participants will follow a 12-week PFMT, either in one-on-one sessions or as part of a group, under the supervision of a physiotherapist. Blinded assessments at baseline, immediately post intervention, and at one year will include the seven-day bladder diary, the 24-h pad test, symptoms and quality of life questionnaires, adherence and self-efficacy questionnaire, pelvic floor muscle function, and cost assessments. Primary analysis will test our main hypothesis that group-based treatment is not inferior to individualized treatment with respect to the primary outcome: relative (%) reduction in the number of leakages. Discussion Should this study find that a group-based approach is not less effective than individual PFMT, and more cost-effective, this trial will impact positively continence-care accessibility and warrant a change in clinical practice. Trial registration ClinicalTrials.gov, NCT02039830 . Registered on 12 December 2013; Study protocol version 2; 21 November 2013.

Abstract Background With potent antiretroviral drugs, HIV infection is becoming a chronic disease. Emergence of comorbidities, particularly cardiovascular disease (CVD) has become a leading concern for patients living with the infection. We hypothesized that the chronic and persistent inflammation and immune activation associated with HIV disease leads to accelerated aging, characterized by CVD. This will translate into higher incidence rates of CVD in HIV infected participants, when compared to HIV negative participants, after adjustment for traditional CVD risk factors. When characterized further using cardiovascular imaging, biomarkers, immunological and genetic profiles, CVD associated with HIV will show different characteristics compared to CVD in HIV-negative individuals. Methods/design The Canadian HIV and Aging cohort is a prospective, controlled cohort study funded by the Canadian Institutes of Health Research. It will recruit patients living with HIV who are aged 40 years or older or have lived with HIV for 15 years or more. A control population, frequency matched for age, sex, and smoking status, will be recruited from the general population. Patients will attend study visits at baseline, year 1, 2, 5 and 8. At each study visit, data on complete medical and pharmaceutical history will be captured, along with anthropometric measures, a complete physical examination, routine blood tests and electrocardiogram. Consenting participants will also contribute blood samples to a research biobank. The primary outcome is incidence of a composite of: myocardial infarction, coronary revascularization, stroke, hospitalization for angina or congestive heart failure, revascularization or amputation for peripheral artery disease, or cardiovascular death. Preplanned secondary outcomes are all-cause mortality, incidence of the metabolic syndrome, incidence of type 2 diabetes, incidence of renal failure, incidence of abnormal bone mineral density and body fat distribution. Patients participating to the cohort will be eligible to be enrolled in four pre-planned sub-studies of cardiovascular imaging, glucose metabolism, immunological and genetic risk profile. Discussion The Canadian HIV and Aging Cohort will provide insights on pathophysiological pathways leading to premature CVD for patients living with HIV.

Background Randomized controlled trials showed that newer glucose‐lowering agents are cardioprotective, but most participants were men. It is unknown whether benefits are similar in women. Methods and Results Among adults with type 2 diabetes mellitus not controlled with metformin with no prior use of insulin, we assessed for sex differences in the cardiovascular effectiveness and safety of sodium‐glucose‐like transport‐2 inhibitors (SGLT‐2i), glucagon‐like peptide‐1 receptor agonists (GLP‐1RA), dipeptidyl peptidase‐4 inhibitors, initiated as second‐line agents relative to sulfonylureas (reference‐group). We studied type 2 diabetes mellitus American adults with newly dispensed sulfonylureas, SGLT‐2i, GLP‐1RA, or dipeptidyl peptidase‐4 inhibitors (Marketscan‐Database: 2011–2017). We used multivariable Cox proportional hazards models with time‐varying exposure to compare time to first nonfatal cardiovascular event (myocardial infarction/unstable angina, stroke, and heart failure), and safety outcomes between drugs users, and tested for sex–drug interactions. Among 167 254 type 2 diabetes mellitus metformin users (46% women, median age 59 years, at low cardiovascular risk), during a median 4.5‐year follow‐up, cardiovascular events incidence was lower in women than men (14.7 versus 16.7 per 1000‐person‐year). Compared with sulfonylureas, hazard ratios (HRs) for cardiovascular events were lower with GLP‐1RA (adjusted HR‐women: 0.57, 95% CI: 0.48–0.68; aHR‐men: 0.82, 0.71–0.95), dipeptidyl peptidase‐4 inhibitors (aHR‐women: 0.83, 0.77–0.89; aHR‐men: 0.85, 0.79–0.91) and SGLT‐2i (aHR‐women: 0.58, 0.46–0.74; aHR‐men: 0.69, 0.57–0.83). A sex‐by‐drug interaction was statistically significant only for GLP‐1RA (P=0.002), suggesting greater cardiovascular effectiveness in women. Compared with sulfonylureas, risks of adverse events were similarly lower in both sexes for GLP‐1RA (aHR‐women: 0.81, 0.73–0.89; aHR‐men: 0.80, 0.71–0.89), dipeptidyl peptidase‐4 inhibitors (aHR‐women: 0.82, 0.78–0.87; aHR‐men: 0.83, 0.78–0.87) and SGLT‐2i (aHR‐women: 0.68, 0.59–0.78; aHR‐men: 0.67, 0.59–0.78) (all sex–drug interactions for adverse events P>0.05). Conclusions Newer glucose‐lowering drugs were associated with lower risk of cardiovascular events than sulfonylureas, with greater effectiveness of GLP‐1RA in women than men. Overall, they appeared safe, with a better safety profile for SGLT‐2i than for GLP‐1RA regardless of sex.

Introduction Identifying strategies to prevent hospital readmissions remains elusive since the reasons for returning to hospital can include a number of interlinked patient, health provider and system level factors. The impact of patient medications are of significant interest since a large proportion of re-admissions are related to adverse drug events. Objectives and Approach The objective was to determine which factors are associated with non-adherence to in-hospital medications and the impact of non-adherence on re-hospitalization, emergency department visits and death in the 30-days post discharge for patients admitted at two tertiary care academic hospitals in Montreal, Quebec between October 2014 and May 2016. Non-adherence to in-hospital changes was measured by comparing patient discharge prescriptions (patient chart) to medications filled in community 30-days post-discharge (dispensing data) and included i) community medications stopped in-hospital and filled post-discharge, ii) community medications modified in-hospital but not filled at the modified daily-dose, and iii) new medications not filled post-discharge. Results Among 2,895 included patients, mean age was 70 (SD 15) and 58% were males. A median of 4 in-hospital medication changes were made (IQR:3-6) and 54% of patients were non-adherent to at least one change. Multivariable Poisson models suggested that the most important factor associated with the number of new medications not filled post discharge was out of pocket cost; for each additional $10 increase in costs there was a 20% increase in the number of new medications not filled. Multivariable time-varying Cox models suggested that in patients who filled medications post-discharge, selective non-adherence to new and discontinued medications reduced the risk adverse health outcomes in 30-days, while not filling any medications post discharge more than doubled the risk of an adverse event in 30-days. Conclusion/Implications Not only did the majority of patients not follow all medication changes that were made during hospitalization, the extent to which this occurred significantly impacted the risk of hospital re-admissions and ED visits. Policy and patient level interventions should be developed specifically targeting barriers for adherence to medication changes.

Objective. To compare dipeptidyl peptidase-4 (DPP-4) inhibitors with neutral protamine Hagedorn (NPH) insulin, in terms of effectiveness and safety for the management of patients with type 2 diabetes mellitus (DM2) not controlled on metformin and sulfonylureas. Methods. A retrospective cohort study of individuals with DM2 newly dispensed with either DPP-4 inhibitors or NPH as third-line therapy, after metformin and sulfonylurea. Treatment discontinuation, macrovascular outcomes, and hypoglycemia were compared using multivariable Cox regression models, adjusted for sex, age, year of cohort entry, place of residence, hypertension, past history of hypoglycemia, diabetic ketoacidosis, comorbidities, and number of visits to emergency departments, outpatient physician, and hospitalizations. Results. Treatment discontinuation and hypoglycemia occurred more frequently with NPH than with DPP-4 inhibitor users. In the adjusted Cox model, the use of NPH compared to that of DPP-4 inhibitors was associated with a higher risk of discontinuation (HR: 1.33; 95% CI 1.27–1.40) and hypoglycemia (HR: 2.98; 95% CI 2.72–3.28). Risk of cardiovascular events was similar across groups. Conclusions. This real-world analysis suggests that DM2 patients initiating third-line therapy with NPH have poorer control of diabetes when compared to DPP-4 inhibitor initiators.

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence. CYP17A1 is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12–18 years) who were recruited from a genetic founder population. Our results showed that the variant of CYP17A1 rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P=8.3×10-6). Resting BP was not associated with the CYP17A1 variant in either sex. These results suggest that, in adolescent males but not females, CYP17A1 enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined.