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Background Tuberculosis (TB) is a major cause of death worldwide. TB research draws heavily on clinical cohorts which can be generated using electronic health records (EHR), but granular information extracted from unstructured EHR data is limited. The St. Michael’s Hospital TB database (SMH-TB) was established to address gaps in EHR-derived TB clinical cohorts and provide researchers and clinicians with detailed, granular data related to TB management and treatment. Methods We collected and validated multiple layers of EHR data from the TB outpatient clinic at St. Michael’s Hospital, Toronto, Ontario, Canada to generate the SMH-TB database. SMH-TB contains structured data directly from the EHR, and variables generated using natural language processing (NLP) by extracting relevant information from free-text within clinic, radiology, and other notes. NLP performance was assessed using recall, precision and F1 score averaged across variable labels. We present characteristics of the cohort population using binomial proportions and 95% confidence intervals (CI), with and without adjusting for NLP misclassification errors. Results SMH-TB currently contains retrospective patient data spanning 2011 to 2018, for a total of 3298 patients (N = 3237 with at least 1 associated dictation). Performance of TB diagnosis and medication NLP rulesets surpasses 93% in recall, precision and F1 metrics, indicating good generalizability. We estimated 20% (95% CI: 18.4–21.2%) were diagnosed with active TB and 46% (95% CI: 43.8–47.2%) were diagnosed with latent TB. After adjusting for potential misclassification, the proportion of patients diagnosed with active and latent TB was 18% (95% CI: 16.8–19.7%) and 40% (95% CI: 37.8–41.6%) respectively Conclusion SMH-TB is a unique database that includes a breadth of structured data derived from structured and unstructured EHR data by using NLP rulesets. The data are available for a variety of research applications, such as clinical epidemiology, quality improvement and mathematical modeling studies.

BackgroundAttention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.MethodsWe searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.ResultsEighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.ConclusionsOverall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.RegistrationPROSPERO no. CRD 42015026049.

BACKGROUND: Smoking remains a serious public health concern. Pharmacotherapy for smoking cessation, including bupropion and varenicline, are proven means to increase quit rates. Post-marketing reports describing suicidal behaviours have raised concerns about the safety of varenicline. However, whether varenicline imparts a higher risk of suicide relative to bupropion remains uncertain. METHODS: A population-based nested case-control study in Ontario, Canada, from April 1, 2011 to March 31, 2015 was conducted. Subjects were residents of Ontario aged 18 years and older with publicly funded drug coverage receiving either bupropion or varenicline for smoking cessation. We defined cases were those with a hospitalization or emergency department visit for suicide or non-fatal self-harm within 90 days of treatment. For each case, we identified up to fifty controls from the same cohort matched on age, sex, history of self-harm, use of selected psychotropic medications, alcohol abuse and prior admission to a mental health unit. Adjusted odds ratio were used to compare the risk of suicide/self-harm of varenicline to bupropion. RESULTS: We identified 331 cases and 5,346 matched-controls. Following adjustment for potential confounders, we found that varenicline was not associated with an increased risk of suicide/self-harm relative to bupropion (adjusted odds ratio 1.15; 95% confidence interval 0.71 to 1.87). INTERPRETATION: Treatment with varenicline does not appear to significantly increase the risk of suicide or self-harm relative to bupropion. Language: en

Background Surgeon-dependent factors such as experience and volume are associated with patient outcomes. However, it is unknown whether a surgeon’s research productivity could be related to outcomes. The main aim of this study is to investigate the association between the surgeon’s academic productivity and clinical outcomes following neurosurgical clipping of ruptured aneurysms. Methods We performed a post-hoc analysis of 3567 patients who underwent clipping of ruptured intracranial aneurysms in the randomized trials of tirilazad mesylate from 1990 to 1997. These trials included 162 centers and 156 surgeons from 21 countries. Primary and secondary outcomes were: Glasgow outcome scale score and mortality, respectively. Total publications, H-index, and graduate degrees were used as academic indicators for each surgeon. The association between outcomes and academic factors were assessed using a hierarchical logistic regression analysis, adjusting for patient covariates. Results Academic profiles were available for 147 surgeons, treating a total of 3307 patients. Most surgeons were from the USA (62, 42%), Canada (18, 12%), and Germany (15, 10%). On univariate analysis, the H-index correlated with better functional outcomes and lower mortality rates. In the multivariate model, patients under the care of surgeons with higher H-indices demonstrated improved neurological outcomes (p = 0.01) compared to surgeons with lower H-indices, without any significant difference in mortality. None of the other academic indicators were significantly associated with outcomes. Conclusion Although prognostication following surgery for ruptured intracranial aneurysms primarily depends on clinical and radiological factors, the academic impact of the operating neurosurgeon may explain some heterogeneity in surgical outcomes.

Background Carpal tunnel release (CTR) is among the most common hand surgeries, although little is known about its pattern. In this study, we aimed to investigate temporal trends, age and gender variation and current practice patterns in CTR surgeries. Methods We conducted a population-based time series analysis among over 13 million residents of Ontario, who underwent operative management for carpal tunnel syndrome (CTS) from April 1, 1992 to March 31, 2010 using administrative claims data. Results The primary analysis revealed a fairly stable procedure rate of approximately 10 patients per 10,000 population per year receiving CTRs without any significant, consistent temporal trend (p = 0.94). Secondary analyses revealed different trends in procedure rates according to age. The annual procedure rate among those age >75 years increased from 22 per 10,000 population at the beginning of the study period to over 26 patients per 10,000 population (p

Background Recent evidence suggests that proton pump inhibitors (PPIs) might be linked with adverse cardiac events, but a causal relationship is unproven. Methods We applied the self-matched case series method to two studies using population-based health care data from Ontario, Canada between 1996 and 2008. The first included subjects aged 66 years or older hospitalized for acute myocardial infarction within 12 weeks following initiation of PPI, while the second included subjects hospitalized for heart failure. In both studies we designated the primary risk interval as the initial 4 weeks of therapy and the control interval as the final 4 weeks. To test the specificity of our findings we examined use of histamine H2 receptor antagonists and benzodiazepines, drugs with no plausible causal link to adverse cardiac events. Results During the 13-year study period, we identified 5550 hospital admissions for acute myocardial infarction and 6003 admissions for heart failure within 12 weeks of commencing PPI therapy. In the main analyses, we found that initiation of a PPI was associated with a higher risk of acute myocardial infarction (odds ratio 1.8; 95% confidence interval 1.7 to 1.9) and heart failure (odds ratio 1.8; 95% confidence interval 1.7 to 1.9). However, secondary analyses revealed similar risk estimates histamine H2 receptor antagonists and benzodiazepines, drugs with no known or suspected association with adverse cardiac events. Conclusion PPIs are associated with a short-term risk of adverse cardiac events, but similar associations are seen with other drugs exhibiting no known cardiac toxicity. Collectively these observations suggest that the association between PPIs and adverse cardiac events does not represent reflect cause-and-effect.

Background Diabetes is a chronic disease commonly managed by family physicians, with the most prevalent complication being cardiovascular disease (CVD). Clinical practice guidelines have been developed to support clinicians in the care of diabetic patients. We conducted a pragmatic cluster randomized controlled trial (RCT) of a printed educational toolkit aimed at improving CVD management in diabetes in primary care, and found no effect, and indeed, the possibility of some harm. We conducted a qualitative evaluation to study the strategy for guideline implementation employed in this trial, and to understand its effects. This paper focuses solely on the qualitative findings, as the RCT’s quantitative results have already been reported elsewhere. Methods and Findings All family practices in the province of Ontario had been randomized to receive the educational toolkit by mail, in either the summer of 2009 (intervention arm) or the spring of 2010 (control arm).A subset of 80 family physicians (representing approximately 10% of the practices randomized and approached, with records on 1,592 randomly selected patients with diabetes at high risk for CVD) then took part in a chart audit and reflective feedback exercise related to their own practice in comparison to the guideline recommendations. They were asked to complete two forms (one pre- and one post-audit) in order to understand their awareness of the guidelines pre-trial, their expectations regarding their individual performance pre-audit, and their reflections on their audit results. In addition, individual interviews with thirteen other family physicians were conducted. Textual data from interview transcripts and written commentary from the pre- and post-audit forms underwent qualitative descriptive analysis to identify common themes and patterns. Analysis revealed four main themes: impressions of the toolkit, awareness was not the issue, ‘it’s not me it’s my patients’, and chart audit as a more effective intervention than the toolkit. Participants saw neither the toolkit content nor its dissemination strategy to be effective, indicating they perceived themselves to be aware of the guidelines pre-trial. However, their accounts also indicated that they may be struggling to prioritize CVD management in the midst of competing demands for their attention. Upon receiving their chart audit results, many participants expressed surprise that they had not performed better. They reported that the audit results would be an important motivator for behaviour change. Conclusions The qualitative findings outlined in this paper offer important insights into why the intervention was not effective. They also demonstrate that physicians have unperceived needs relative to CVD management and that the chart audit served to identify shortcomings in their practice of which they had been hitherto unaware. The findings also indicate that new methods of intervention development and implementation should be explored. This is important given the high prevalence of diabetes worldwide; appropriate CVD management is critical to addressing the morbidity and mortality associated with the disease.

Aims To examine the impact of national clinical practice guidelines and provincial drug policy interventions on prevalence of high-dose opioid prescribing and rates of hospitalization for opioid toxicity. Design Interventional time-series analysis. Setting Ontario, Canada, from 2003 to 2014. Participants Ontario Drug Benefit (ODB) beneficiaries aged 15 to 64 years from 2003 to 2014. Interventions Publication of Canadian clinical practice guidelines for use of opioids in chronic non-cancer pain (May 2010) and implementation of Ontario’s Narcotics Safety and Awareness Act (NSAA; November 2011). Measurements Three outcomes were explored: the rate of opioid use among ODB beneficiaries, the prevalence of opioid prescriptions exceeding 200 mg and 400 mg morphine equivalents per day, and rates of opioid-related emergency department visits and hospital admissions. Findings Over the 12 year study period, the rate of opioid use declined 15.2%, from 2764 to 2342 users per 10,000 ODB eligible persons. The rate of opioid use was significantly impacted by the Canadian clinical practice guidelines (p-value = .03) which led to a decline in use, but no impact was observed by the enactment of the NSAA (p-value = .43). Among opioid users, the prevalence of high-dose prescribing doubled (from 4.2% to 8.7%) over the study period. By 2014, 40.9% of recipients of long-acting opioids exceeded daily doses of 200 mg morphine or equivalent, including 55.8% of long-acting oxycodone users and 76.3% of transdermal fentanyl users. Moreover, in the last period, 18.7% of long-acting opioid users exceeded daily doses of 400 mg morphine or equivalent. Rates of opioid-related emergency department visits and hospital admissions increased 55.0% over the study period from 9.0 to 14.0 per 10,000 ODB beneficiaries from 2003 to 2013. This rate was not significantly impacted by the Canadian clinical practice guidelines (p-value = .68) or enactment of the NSAA (p-value = .59). Conclusions Although the Canadian clinical practice guidelines for use of opioids in chronic non-cancer pain led to a decline in opioid prescribing rates among ODB beneficiaries these guidelines and subsequent Ontario legislation did not result in a significant change in rates of opioid-related hospitalizations. Given the prevalence of high dose opioid prescribing in this population, this suggests that improved strategies and programs for the safe prescribing of long-acting opioids are needed.

Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated.