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Background Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs. Methods We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea's healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1-30 day (hazard) and 61-90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratio (OR) with 95% confidence intervals (CI), where the relative difference in OR among the two settings was calculated to quantify the IMTB. Results The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27, 95% CI 1.12-1.44; pseudo-outpatient setting 1.21, 1.06-1.39; magnitude 0.05), case-time-control (1.18, 0.98-1.44; 1.13, 0.92-1.38; 0.04), and case-case-time-control analyses (0.99, 0.80-1.23; 0.94, 0.75-1.18; 0.05). In the mortality example, IMTB had significant impacts in the case-crossover (1.44, 1.36-1.52; 0.72, 0.67-0.78; 1.00), case-time-control (1.38, 1.26-1.51; 0.68, 0.61-0.76; 1.03), and case-case-time-control analyses (1.27, 1.15-1.40; 0.62, 0.55-0.69; 1.05). Conclusions Although IMTB had negligible impacts on the drug's effect on acute events as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug's effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.

Background. Opioids contribute to more than 60 000 deaths annually in North America. While the expansion of overdose education and naloxone distribution (OEND) programs has been recommended in response to the opioid crisis, their effectiveness remains unclear. Objectives. To conduct an umbrella review of systematic reviews to provide a broad-based conceptual scheme of the effect and feasibility of OEND and to identify areas for possible optimization. Search Methods. We conducted the umbrella review of systematic reviews by searching PubMed, Embase, PsycINFO, Epistemonikos, the Cochrane Database of Systematic Reviews, and the reference lists of relevant articles. Briefly, an academic librarian used a 2-concept search, which included opioid subject headings and relevant keywords with a modified PubMed systematic review filter. Selection Criteria. Eligible systematic reviews described comprehensive search strategies and inclusion and exclusion criteria, evaluated the quality or risk of bias of included studies, were published in English or French, and reported data relevant to either the safety or effectiveness of OEND programs, or optimal strategies for the management of opioid overdose with naloxone in out-of-hospital settings. Data Collection and Analysis. Two reviewers independently extracted study characteristics and the quality of included reviews was assessed in duplicate with AMSTAR-2, a critical appraisal tool for systematic reviews. Review quality was rated critically low, low, moderate, or high based on 7 domains: protocol registration, literature search adequacy, exclusion criteria, risk of bias assessment, meta-analytical methods, result interpretation, and presence of publication bias. Summary tables were constructed, and confidence ratings were provided for each outcome by using a previously modified version of the Royal College of General Practitioners’ clinical guidelines. Main Results. Six systematic reviews containing 87 unique studies were included. We found that OEND programs produce long-term knowledge improvement regarding opioid overdose, improve participants’ attitudes toward naloxone, provide sufficient training for participants to safely and effectively manage overdoses, and effectively reduce opioid-related mortality. High-concentration intranasal naloxone (> 2 mg/mL) was as effective as intramuscular naloxone at the same dose, whereas lower-concentration intranasal naloxone was less effective. Evidence was limited for other naloxone formulations, as well as the need for hospital transport after overdose reversal. The preponderance of evidence pertained persons who use heroin. Author’s Conclusions. Evidence suggests that OEND programs are effective for reducing opioid-related mortality; however, additional high-quality research is required to optimize program delivery. Public Health Implications. Community-based OEND programs should be implemented widely in high-risk populations.

Big data have become readily available to explore patterns in large-scale disease ecology. However, the rate at which these public databases are exploited remains unknown. We highlight trends in big data usage in disease ecology during the past decade and encourage researchers to integrate big data into their study framework.

Evidence-Based Medicine is built on the premise that clinicians can be more confident when their decisions are grounded in high-quality evidence. Furthermore, evidence from studies involving patient-oriented outcomes is preferred when making decisions about tests or treatments. Ideally, the findings of relevant and valid trials should be stable over time, that is, unlikely to be reversed in subsequent research.To evaluate the stability of evidence from trials relevant to primary healthcare and to identify study characteristics associated with their reversal.We studied synopses of randomized controlled trials (RCTs) published from 2002 to 2005 as "Daily POEMs" (Patient Oriented Evidence that Matters). The initial evidence (E1) from these POEMs (2002-2005) was compared with the updated evidence (E2) on that same topic in a summary resource (DynaMed 2019). Two physician-raters independently categorized each POEM-RCT as (i) reversed when E1 ≠ E2, or as (ii) not reversed, when E1 = E2. For all "Evidence Reversals" (E1 ≠ E2), we assessed the direction of change in the evidence.We evaluated 408 POEMs on RCTs. Of those, 35 (9%; 95% confidence interval [6-12]) were identified as reversed, 359 (88%) were identified as not reversed, and 14 (3%) were indeterminate. On average, this represents about 2 evidence reversals per annum for POEMs about RCTs.Over 12-17 years, 9% of RCTs summarized as POEMs are reversed. Information alerting services that apply strict criteria for relevance and validity of clinical information are likely to identify RCTs whose findings are stable over time.We studied the extent to which evidence from randomized controlled trials (RCTs) relevant to primary care is contradicted in subsequent research. When it was, we identified this event as an evidence reversal. In addition, we sought to identify characteristics of RCTs associated with their reversal. From 408 RCTs published during the period 2002–2005, study characteristics such as sample size were identified and extracted. Subsequently, we compared the evidence reported in each of these RCTs with the evidence on that same topic in an online summary resource in 2019. This allowed us to classify each RCT in one of the following 3 categories: evidence confirmed, reversed, or uncertain if this evidence is confirmed or reversed. Over 12–17 years of follow-up time, the findings of about 9 in 10 RCTs summarized as POEMs are stable. We found no statistically significant associations between trial characteristics and their subsequent reversal. This low rate of evidence reversal is good news for the RCTs that are used to inform decision-making.

BACKGROUND Several antihypertensive drugs are available for the primary prevention of cardiovascular disease (CVD). However, existing evidence on prescription patterns was primarily generated among patients at high CVD risk with short-term follow-up, and failed to capture impacts of time and patient characteristics. Our objective was therefore to describe longitudinal prescription patterns for antihypertensive drugs for the primary prevention of CVD among patients with arterial hypertension in the United Kingdom. METHODS This population-based cohort study used data from the Clinical Practice Research Datalink, included 660,545 patients with hypertension who initiated an antihypertensive drug between 1998 and 2018. Antihypertensive treatments were measured by drug class and described overall and in subgroups, focusing on first-line therapy (first antihypertensive drug(s) recorded after a diagnosis of hypertension) and second-line therapy (antihypertensive drug(s) prescribed as part of a treatment change following first-line therapy). RESULTS Angiotensin-converting enzyme (ACE) inhibitors (29.0%), thiazide diuretics (22.1%), and calcium-channel blockers (CCBs) (21.0%) were the most prescribed first-line therapies. ACE inhibitors have been increasingly prescribed as first-line therapy since 2001. Men were more likely to be prescribed ACE inhibitors than women (43.5% vs. 32.1%; difference: 11.4%; 95% confidence interval [CI], 11.0%–11.8%), and Black patients were more likely to be prescribed CCBs than White patients (63.6% vs. 37.0%; difference: 26.6%; 95% CI, 24.8%–28.4%). CONCLUSIONS Antihypertensive prescription patterns for the primary prevention of CVD among patients with hypertension are consistent with treatment guidelines that were in place during the study period, providing reassurance regarding the use of evidence-based prescribing.

Aims To determine whether adiposity modified the effect on the cardiovascular safety of sulfonylureas as a first-line therapy compared with metformin among patients with type 2 diabetes. Materials and methods Using the UK Clinical Practice Research Datalink, we conducted a cohort study among 13 862 new sulfonylurea users matched on body mass index (BMI) and propensity score, in a 1:1 ratio, to new metformin users between April 1, 1998 and December 31, 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), individual components of MACE (myocardial infarction, ischemic stroke, cardiovascular mortality), and all-cause mortality, comparing use of sulfonylureas with use of metformin overall, and within BMI categories (≤ 24.9 kg/m2 , 25.0-29.9 kg/m2 , ≥ 30 kg/m2 ). Results Compared with metformin, sulfonylureas were not associated with an increased risk of MACE either overall (HR: 1.08; 95% CI: 0.94-1.23) or by BMI categories. Similar findings were observed for myocardial infarction and ischemic stroke. In contrast, sulfonylureas were associated with an increased risk of cardiovascular mortality (HR: 1.24; 95% CI: 1.04-1.48), primarily among obese patients (HR: 1.52; 95% CI: 1.08-2.13), and not among normal-weight patients (HR: 1.00; 95% CI: 0.72-1.39; p-interaction: 0.21). Similar results were observed for all-cause mortality (HR: 1.47; 95% CI: 1.32-1.62), where an increased risk was observed among obese patients (HR: 1.83; 95% CI: 1.49-2.25), but not normal-weight patients (HR: 1.18; 95% CI: 0.99-1.42; p-interaction: 0.006). Conclusion The findings of this study suggest that adiposity may have a modifying effect on the association between sulfonylureas and cardiovascular and all-cause mortality compared with metformin. This article is protected by copyright. All rights reserved.

Every internet search query made out of curiosity by anyone who observed something in nature, as well as every photo uploaded to the internet, constitutes a data point of potential use to scientists. Researchers have now begun to exploit the vast online data accumulated through passive crowdsourcing for studies in ecology and epidemiology. Here, we demonstrate the usefulness of iParasitology, i.e. the use of internet data for tests of parasitological hypotheses, using hairworms (phylum Nematomorpha) as examples. These large worms are easily noticeable by people in general, and thus likely to generate interest on the internet. First, we show that internet search queries (collated with Google Trends) and photos uploaded to the internet (specifically, to the iNaturalist platform) point to parts of North America with many sightings of hairworms by the public, but few to no records in the scientific literature. Second, we demonstrate that internet searches predict seasonal peaks in hairworm abundance that accurately match scientific data. Finally, photos uploaded to the internet by non-scientists can provide reliable data on the host taxa that hairworms most frequently parasitize, and also identify hosts that appear to have been neglected by scientific studies. Our findings suggest that for any parasite group likely to be noticeable by non-scientists, information accumulating through internet search activity, photo uploads, social media or any other format available online, represents a valuable source of data that can complement traditional scientific data sources in parasitology.

Background Trends in off-label postpartum use of domperidone and the impact of safety advisories on its use remain unknown. Our objectives were to describe postpartum use of domperidone in Canada, to evaluate the impact of Health Canada advisories on prescribing patterns, and to describe the association between domperidone use and a composite end point of sudden cardiac death or ventricular tachycardia (VT) among postpartum patients. Methods We conducted a multidatabase cohort study involving pregnant patients with live births between 2004 and 2017 using administrative health databases from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario). We excluded patients with less than 1 year of prepregnancy database history and with approved indications for domperidone. We assessed domperidone use in the 6 months postpartum and the impact of the 2012 and 2015 Health Canada advisories on prescribing via interrupted time series analysis. We estimated crude rates of VT and sudden cardiac death. Results We included 1 190 987 live births. Mean maternal age was 28.6 (standard error 0.6) years. Domperidone use increased over time, from 7% in 2003-2005 to 12% in 2009-2011, when it plateaued. The 2012 advisory was followed by a drop in use and a reduction in slope, and the 2015 advisory had a more modest impact. Crude analysis suggests that domperidone may be associated with increased VT or sudden cardiac death (0.74 v. 0.37 per 10 000 person-years; difference per 10 000 person-years: 0.37, 95% confidence interval -0.67 to 1.41). Interpretation Postpartum domperidone use increased between 2004 and 2017, with prescribing attenuated after Health Canada advisories and a very low absolute rate of VT or sudden cardiac death. These findings suggest that Health Canada advisories affected prescribing; any potential increase in VT or sudden cardiac death with use of domperidone is small and could not be confirmed in this large study STUDY REGISTRATION: ClinicalTrials.gov, no. NCT04024865.

Sedation with chloral hydrate or anesthesia using propofol allow ocular examination and testing in young children, but these drugs may affect electrophysiologic recordings. We compared the flash and pattern ERGs and VEPs recorded with each drug in a cohort of young children enrolled in a prospective study of optic nerve hypoplasia (ONH) syndrome. ERGs and VEPs to light-adapted, standard, full-field flashes, to standard and steady-state pattern-reversal (PR) were recorded with cycloplegia in 9 participants. Age range at the first session, with chloral hydrate was 8–23 mo; at the second session with propofol it was 20–29 mo. Examiners masked to the drug and clinical conditions measured the waveforms for longitudinal, paired comparisons between the sessions. Flash ERG amplitudes did not differ between sessions; peak times were longer at the second session (propofol) by clinically insignificant amounts ( 10 mo between sessions (n = 5, 10 eyes) but not for those with a shorter inter-test interval ( 0.05, n = 4). Magnitudes of the steady-state PERGs did not differ between tests but the waveforms had earlier peaks at the second test with propofol. Flash VEP waveforms were present in 10/18 eyes and showed 72% agreement for recordability between sessions. Standard pattern VEPs were recordable in only a few eyes in this cohort with ONH. Light-adapted flash ERG waveforms were generally similar with chloral hydrate and with propofol. Larger PERGs with later peaks, found in the second session (propofol) could reflect maturation of the PERG generators, as the differences found were associated with a greater age difference between the sessions, but we do not rule out that small differences in the waveforms may be drug-related. There are insufficient VEP data from these children with ONH to identify drug-related or maturational effects on VEPs.

Prepulse inhibition (PPI) of the acoustic startle response can index automatic and attention-modulated aspects of sensorimotor gating. Automatic sensorimotor gating is typically assessed by a no-task PPI protocol in which participants are presented with discrete white noise prepulse and startle stimuli over continuous background broadband noise at brief short-lead intervals (e.g., 60–120 ms). In contrast, attention-modulated sensorimotor gating is typically assessed through a task-based PPI protocol using continuous format pure tone prepulses and white noise startle stimuli presented over an ambient background at a lead interval of 120 ms. The present study sought to test the extent that the assessment of attention-modulated PPI is dependent on prepulse type and lead interval across two experiments. Experiment 1 assessed attention effects on PPI produced by discrete prepulses at lead intervals of 60 and 120 ms. Experiment 2 examined attention effects on PPI with matched stimulus conditions apart from continuous prepulses. Results indicated that the use of discrete prepulses failed to elicit attentional-modulation of PPI and that assessment therein was dependent on the use of continuous prepulses at a lead interval of 120 ms. These results highlight additional methods to concurrently assess automatic and attention-modulated PPI in a single testing session using a task-based tone counting task.

The literature has identified an “immigrant effect” in commuting modal shares, accounting for higher reliance on public transit. Few studies have, however, studied the immigrant effect at the intra...

Introduction The cardiovascular safety of testosterone replacement therapy (TRT) is controversial. While several studies have investigated the association between TRT and the risk of arterial thrombosis, limited information is available regarding its risk of venous thromboembolism (VTE). We aimed to compare the risk of VTE in men randomized to TRT versus placebo or active-comparator in a systematic review. Methods We searched Medline, EMBASE, CINAHL, CENTRAL, and clinical trial registries to identify randomized controlled trials (RCTs) comparing TRT to placebo in men aged ≥18 years. We assessed study quality using the Cochrane Risk of Bias assessment tool and the overall quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were pooled across RCTs using random-effects models. Results A total of 13 RCTs (n = 5050) were included in our meta-analysis. In all, 2636 men were randomized to testosterone, and 2414 men to placebo. Sample sizes ranged from 101 to 790 men, and TRT duration from 3 to 36 months. Five studies had a high risk of bias, largely driven by unclear randomization and outcome assessment. When data were pooled across RCTs, testosterone therapy was not associated with VTE compared with placebo (RR: 1.03, 95% CI: 0.49–2.14; I2: 0%; low-quality evidence). Similar estimates were obtained for deep vein thrombosis and pulmonary embolism outcomes. Conclusions Our systematic review suggests that TRT is not associated with an increased risk of VTE. However, estimates were accompanied by a wide 95% CIs, and a clinically important increased risk cannot be ruled out.

Objectives The objective of this study was to assess approaches to reduce immeasurable time bias in case-crossover (CCO), case-time-control (CTC), and case-case-time-control (CCTC) designs. Study Design and Setting We used Korea's health care database that has inpatient and outpatient prescriptions and an empirical example of benzodiazepines and mortality among the elderly. We defined our unbiased exposure setting using all prescriptions and a pseudo-outpatient setting using outpatient records only. In the pseudo-outpatient setting, we assessed 10 approaches of restricting, adjusting, stratifying, or weighting on hospitalization-related factors. We conducted conditional logistic regression to estimate odds ratio (OR) with 95% confidence intervals (CI), where an approach was considered effective when its OR was within the unbiased exposure setting OR's 95% CI. Results Immeasurable time bias negatively biased the unbiased exposure setting's OR in all three case-only designs, overestimating the protective effect of benzodiazepines on mortality. Of the 10 approaches examined, stratifying the proportion of hospitalized time in 0.01 intervals most effectively repaired the bias in the CCO (OR 1.25, 95% CI 1.10–1.43) and CTC analyses (1.11, 0.95–1.30); no approach was effective in the CCTC analysis. Conclusion Stratifying the proportion of hospitalized time in 0.01 intervals best approximated the unbiased exposure setting estimate by overcoming the significant impact of immeasurable time bias in CCO and CTC designs.

BackgroundLevothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine.MethodsA systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers.ResultsSeven RCTs and six observational studies met our inclusion criteria. A total of 7342 individuals were included in these studies. RCTs demonstrated several sources of bias, with lack of blinding of the participants or research personnel; only one study was fully blinded. In the observational studies, there was moderate to serious risk of bias due to lack of adjustment for certain confounding variables, participant selection, and selective reporting of results. Pooled analyses showed decreased risk of pregnancy loss (RR: 0.79; 95% CI: 0.67 to 0.93) and neonatal death (RR: 0.35; 95% CI: 0.17 to 0.72) associated with levothyroxine treatment during pregnancy among women with SCH. There were no associations between levothyroxine treatment and outcomes during labour and delivery, or cognitive status in children at 3 or 5 years of age.ConclusionTreatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.

Purpose Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have been associated with an increased risk of genitourinary tract infections. Through similar biological mechanisms, they may also increase the risk of community-acquired pneumonia. Our objective was to compare the rate of hospitalization for community-acquired pneumonia (HCAP) with SGLT-2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) among patients with type 2 diabetes. Methods We used the United Kingdom's Clinical Practice Research Datalink Gold, linked to hospitalization data, to construct a cohort of patients with type 2 diabetes. Using a time-dependent Cox proportional hazards model, we estimated the adjusted hazard ratio (HR) for HCAP with current use of SGLT-2i versus DPP-4i. Results Among 29 896 patients, 705 HCAPs occurred over a mean follow-up of 1.7 years (standard deviation: 1.2). Incidence rates for SGLT-2i and DPP-4i users were 6.2 (95% confidence interval [CI]: 3.7, 10.2) and 17.8 (95% CI: 15.3, 20.7) per 1000 person-years, respectively. Current use of SGLT-2i was associated with a decreased risk of HCAP compared to current use of DPP-4i (adjusted HR: 0.48, 95% CI: 0.28, 0.82). However, a comparison of SGLT-2i versus glucagon-like peptide-1 receptor agonists (GLP-1 RA) found no difference in risk of HCAP (adjusted HR: 0.94, 95% CI: 0.44, 1.89). Conclusions SGLT-2i are associated with a decreased rate of HCAP compared to DPP-4i, but not when compared to GLP-1 RA, among patients with type 2 diabetes.

The paper complements the visual observation and ethnographic emphasis of much of the literature on ethnoburbs by offering a spatial analysis of suburban immigrant settlements. The research focuses on the Greater Toronto and Hamilton Area (GTHA), Canada’s most populous urban region. The region is especially well suited to an investigation of the suburban distribution of immigrants because of its exceptionally large and diversified influx of immigrants. The study concentrates on the two largest recent GTHA immigrant groups, Chinese and South Asians, and assesses their spatial evolution between 2006 and 2016. It demonstrates that immigrant suburban spatial patterning can take different spatial forms according to the ethnic groups under consideration—clustering in the case of the Chinese and a blending of clustering and dispersion for the South Asians. It also shows that ethnoburbs come in different guises reflecting the size and composition of different ethnic groups. Another finding concerns the evolution of ethnoburbs. The paper identifies different ethnoburb growth trajectories, but also acknowledges the possibility of a reduced presence of ethnoburbs in the future. Finally, by drawing findings from prior research on ethnoburbs, it elaborates on the gravity effect exerted by large clusters of ethnic retailing, services, and institutions on the different settlements of a given ethnic group.

Background Immeasurable time bias exaggerates drug benefits in pharmacoepidemiological studies due to exposure misclassification arising from the inability to measure in-hospital medications in many health care databases. Methods To compare the ability of different methodological approaches to minimize immeasurable time bias, we conducted a cohort study of β-blocker use and all-cause mortality among patients with heart failure (HF), using a nationwide health care database which contains both in- and outpatient prescriptions. In our gold-standard analysis, we assessed exposure using a time-varying approach involving both in- and outpatient prescriptions. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality, with exposure to β-blockers defined as a time-varying variable. To estimate the magnitude of the immeasurable time bias, we repeated the analyses using outpatient prescriptions only and compared 10 approaches to minimize the bias, which are categorized as restriction, adjustment, assumption and weighting. Results The HR for β-blocker use versus non-use was 0.76 (95% CI: 0.71 to 0.80) in our gold-standard analysis. When exposure assessment was restricted to outpatient prescriptions only, β-blocker use was substantially more protective (HR 0.43, 95% CI: 0.40 to 0.46). Of the 10 approaches examined, adjusting for hospitalization as a time-varying variable successfully minimized the bias (HR 0.75, 95% CI: 0.68 to 0.82). Conclusions The immeasurable time bias can result in substantial bias in pharmacoepidemiological studies. Time-varying adjustment for hospitalization appears to reduce the immeasurable time bias in the absence of inpatient medication data.

Background Recent interest has been geared towards the potential therapeutic and chemopreventive benefit of androgen deprivation therapy (ADT) for bladder cancer. As a result, several observational studies have investigated this potential association. Given the important side effects associated with ADT treatment, understanding the methodological strengths and weaknesses of the current evidence is warranted. Objectives The objective of this systematic review was to examine the heterogeneity of the current observational studies on the association between ADT and bladder cancer by assessing the methodological strengths and limitations of these studies. Material and methods We systematically searched Medline, EMBASE, Healthstar, Cochrane Library Online, Science Citation Index, and Dissertation Abstracts Online, from inception to August 2019 to identify all observational studies investigating the association between ADT and bladder cancer. We assessed overall study quality using the ROBINS-I tool and evaluated the presence of other key pharmacoepidemiologic biases. Results Overall, our systematic review included 7 observational studies. Five studies reported a decreased risk of bladder cancer with ADT use, 1 study reported no association, and 1 study reported an increased risk. All studies had time-related biases, did not consider a lag period, and had potential residual confounding. Moreover, 1 study had potential detection bias, 6 included prevalent users, 3 had inadequate follow-up durations, 6 had exposure misclassification, and 5 used an inappropriate comparator. Conclusion Taken together, future methodologically-rigorous studies addressing the limitations underlined in this systematic review are needed to evaluate the important potential association between ADT and bladder cancer.

Large technology firms pose new challenges for local economic development in the 21st century. They are attractive targets for local economic developers because they have the potential of providing permanent, well-paying jobs. This article examines two mega-economic development deals. Amazon’s proposed second headquarters in Queens and Sidewalk Labs’ Quayside proposal for the Toronto waterfront pit large and prosperous Big Tech firms against local governments with healthy economies. Amazon abandoned the New York City site it had chosen, rather than open new negotiations with local officials and citizens. Sidewalk Labs withdrew from the Quayside proposal after two and a half years of negotiation focusing mostly on the size of the proposed development. Although the potential benefits may be substantial, incentivizing Big Tech’s location decisions may be well beyond the means of most cities, especially those with distressed economies.

Background Sodium-glucose cotransporter-2 (SGLT-2) inhibitors could increase the risk for diabetic ketoacidosis (DKA). Objective To assess whether SGLT-2 inhibitors, compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk for DKA in patients with type 2 diabetes. Design Population-based cohort study; prevalent new-user design between 2013 and 2018. (ClinicalTrials.gov: NCT04017221). Setting Electronic health care databases from 7 Canadian provinces and the United Kingdom. Patients 208 757 new users of SGLT-2 inhibitors were matched by using time-conditional propensity scores to 208 757 recipients of DPP-4 inhibitors. Measurements Cox proportional hazards models estimated site-specific hazard ratios (HRs) with 95% CIs of DKA comparing receipt of SGLT-2 inhibitors with receipt of DPP-4 inhibitors, which were pooled by using random-effects models. Secondary analyses were stratified by molecule, age, sex, and prior receipt of insulin. Results Overall, 521 patients were diagnosed with DKA during 370 454 person-years of follow-up (incidence rate per 1000 person-years, 1.40 [95% CI, 1.29 to 1.53]). Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an increased risk for DKA (incidence rate, 2.03 [CI, 1.83 to 2.25] versus 0.75 [CI, 0.63 to 0.89], respectively; HR, 2.85 [CI, 1.99 to 4.08]). Molecule-specific HRs were 1.86 (CI, 1.11 to 3.10) for dapagliflozin, 2.52 (CI, 1.23 to 5.14) for empagliflozin, and 3.58 (CI, 2.13 to 6.03) for canagliflozin. Age and sex did not modify the association; prior receipt of insulin appeared to decrease the risk. Limitations There was unmeasured confounding and no laboratory data were available for the majority of patients, and molecule-specific analyses were conducted at a limited number of sites. Conclusion SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect. Primary funding source Canadian Institutes of Health Research.

To describe trends in the pharmacological treatment of BPH in the United Kingdom (UK) from 1998 to 2016. We created a cohort of men with a diagnosis of BPH between 1998 and 2016 using the Clinical Practice Research Datalink. Using Poisson regression, we estimated annual prescription rates of 5αRIs, α-blockers, and combination therapy (5αRIs + α-blockers). Adherence was defined by a proportion of days covered > 80%. Our cohort included 192,640 men with BPH who generated 1,176,264 person-years (PYs) of follow-up. The mean age was 68.0 (standard deviation: 10.7) years. The prescription rate of all BPH medications during the study period was 347.6 per 100 PYs (95% CI 347.2–347.9). α-Blockers had the highest prescription rate (222.9 per 100 PYs, 95% CI 222.7–223.2); prescription rates of 5αRIs and combination therapy were 69.1 per 100 PYs (95% CI 69.0–69.3) and 55.5 per 100 PYs (95% CI 55.4–55.7), respectively. The prescription rate for combination therapy was 19 times greater in 2013–2016 than in 1998–2000 (rate ratio: 19.2, 95% CI 18.6–19.7), while the prescription rates for 5αRIs and α-blockers each doubled during this period (rate ratio: 1.86, 95% CI 1.84–1.88 and rate ratio: 2.02, 95% CI 2.01–2.04, respectively). The proportion of patients who were adherent at 1 year to 5αRIs (32.3%), α-blockers (44.0%), and combination therapy (45.6%) was low. The prescription rate of BPH medications increased substantially between 1998 and 2016 in the UK, with the greatest relative increase observed with combination therapy. Adherence to BPH medications was low in this population-based study.

Purpose To assess cancer control and patient-reported outcomes (PROs) after de-intensified intensity-modulated radiotherapy (IMRT) in lateralized p16-associated oropharyngeal cancer (p16-OPC). Methods Lateralized p16-OPC treated with radiotherapy and concurrent Carboplatin/5-fluorouracil between 2011 and 2014 were enrolled. De-intensified IMRT consisted in elective neck dose of 43.2 Gy/24 fractions and omission of contralateral retropharyngeal/level IV nodes. PROs were assessed using the EORTC QLC-C30 and QLQ-HN35 scales. Results Twenty-nine patients were included. Median follow-up was 44 months. As per AJCC 7th Ed, 7%, 83% and 10% of patients had stage III, IVa and IVb. 5-year locoregional control and overall survival rates were 100% and 100%, respectively. Rates of acute were 52% and 35%, respectively. At 2 years post-treatment, 50% and 14% of patients had grade 1 xerostomia and dysgueusia, respectively. Most PROs scores returned to baseline within 8 months post-treatment. Conclusion De-intensified IMRT was associated with excellent cancer outcomes, and rapid recovery of PROs in lateralized p16-OPC.

OBJECTIVE Reports of amputations associated with sodium–glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. RESULTS The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71–1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. CONCLUSIONS In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.

Background Nonsteroidal antiinflammatory drugs (NSAIDs) may exacerbate coronavirus disease 2019 (COVID-19) and worsen associated outcomes by upregulating the enzyme that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to in order to enter cells. Methods We conducted a cohort study using South Korea’s nationwide healthcare database, which contains data for all individuals who received a COVID-19 test (n = 69 793) as of 8 April 2020. We identified adults hospitalized with COVID-19, where cohort entry was the date of hospitalization. NSAID users were those prescribed NSAIDs in the 7 days before and including cohort entry, and nonusers were those not prescribed NSAIDs during this period. Our primary outcome was a composite of in-hospital death, intensive care unit admission, mechanical ventilation use, and sepsis; our secondary outcomes were cardiovascular complications and acute renal failure. We conducted logistic regression analysis to estimate odds ratio (OR) with 95% confidence intervals (CIs) using inverse probability of treatment weighting to minimize confounding. Results Of 1824 adults hospitalized with COVID-19 (mean age, 49.0 years; female, 59%), 354 were NSAID users and 1470 were nonusers. Compared with nonuse, NSAID use was associated with increased risks of the primary composite outcome (OR, 1.54; 95% CI, 1.13–2.11) but insignificantly associated with cardiovascular complications (OR, 1.54; 95% CI, 0.96–2.48) or acute renal failure (OR, 1.45; 95% CI, 0.49–4.14). Conclusions While awaiting the results of confirmatory studies, we suggest NSAIDs be used with caution for COVID-19 patients as the harms associated with their use may outweigh their benefits.

There is often a delay between the time when a water efficiency campaign is introduced and the time of its adoption. Municipalities want to know how long it will take to reach adoption targets to p...

Purpose For nonoperable stage I non-small cell lung cancer, stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option. We aimed to compare the clinical outcomes of lung SBRT between patients with versus without pathologic cancer diagnosis. Methods and Materials We included patients treated by SBRT for a single pulmonary lesion between July 2009 and July 2017. Patients in the clinical diagnosis group had a positron emission tomography/computed tomography scan showing hypermetabolism, growth of the mass on sequential computed tomography, and were not eligible for biopsy, refused biopsy, or had an inconclusive biopsy. For each of those patients, a matched pair in the pathologic diagnosis group was identified by matching for patient, treatment, and tumoral characteristics. We performed a power calculation to estimate the sample size required to detect a difference arising from a 5% or 15% rate of benign processes in the group without pathology. Results A total of 924 lung SBRT treatments were performed among 878 patients from 2009 to 2017. Within this population, 131 patients were treated based on clinical findings. They were matched with 131 patients with a pathologic diagnosis who received treatment. At 3 years, no significant differences were observed in overall survival (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.7-2.1), local control (HR, 0.9; 95% CI, 0.4-2), or regional (HR, 0.5; 95% CI, 0.2-1.4) or distant recurrence (HR, 0.6; 95% CI, 0.3-1.1). Conclusions In our population, we found no clinically significant difference in patterns of recurrence or survival after lung SBRT for patients who had received clinical versus pathological diagnoses. There was, however, a trend toward more distant recurrences in the pathologic diagnosis group. Our power calculation suggests that data from multiple institutions would be required to rule out a difference in outcomes due to 5% to 15% of clinically diagnosed cases being treated for benign processes.

The association between use of aromatase inhibitors (AIs) and cardiovascular outcomes is controversial. While some observational studies have assessed the cardiovascular safety of AIs as upfront treatments, their cardiotoxicity as sequential treatments with tamoxifen remains unknown. Thus, we conducted a population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. We employed a prevalent new-user design to propensity-score match, in a 1:2 ratio, patients switching from tamoxifen to AIs with patients continuing tamoxifen between 1998 and 2016. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Overall, 1,962 patients switching to AIs were matched to 3,874 patients continuing tamoxifen. Compared with tamoxifen, AIs were associated with an increased risk of myocardial infarction (hazard ratio (HR) = 2.08, 95% confidence interval (CI): 1.02, 4.27). The hazard ratios were elevated for ischemic stroke (HR = 1.58, 95% CI: 0.85, 2.93) and heart failure (HR = 1.69, 95% CI: 0.79, 3.62) but not cardiovascular mortality (HR = 0.87, 95% CI: 0.49, 1.54), with confidence intervals including the null value. The elevated hazard ratios observed for the cardiovascular outcomes should be corroborated in future large observational studies.

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Chronic inflammatory conditions, including inflammatory bowel diseases (IBD), psoriasis, and psoriatic arthritis, are prevalent among women of reproductive age; patients with active disease during pregnancy may be at an increased risk of adverse birth outcomes. For this reason, physicians are focused on approaches to controlling disease activity prior to and during pregnancy. The safety profile of many therapies used for these conditions has been relatively well established, though evidence on newer therapies is lacking. Ustekinumab is a relatively new interleukin-12/23 inhibitor approved for IBD, psoriasis, and psoriatic arthritis, whose safety in pregnancy is not yet fully understood. In this comprehensive review, we critically assess the available evidence on ustekinumab in pregnancy across animal studies and human case reports, case series, observational studies, and clinical practice guidelines. We show that, to date, studies have not identified an excess risk of adverse pregnancy outcomes among women exposed to ustekinumab in pregnancy, with few exposed pregnancies and potential for some bias. Clinical guidelines are conflicted regarding whether they recommend continuing or discontinuing ustekinumab, highlighting the paucity of data and need for more research on this issue.

Robert Bilodeau passed away on 27 July 2020, at the age of 85. Many of you knew him as a pioneer of Canadian entrepreneurship.Robert’s family ran a small business in Shawinigan. He became involved ...

In this study, the authors assessed the long-term impact of the Mental Health Treatment Study (MHTS), a randomized controlled trial testing the effects of providing 2 years of employment services based on the evidence-based individualized placement and support model to Social Security Disability Insurance (SSDI) recipients with serious mental illness. Treatment recipients also received systematic medication management, supplemental health care supports, and short-term relief from medical continuing disability review by the Social Security Administration (SSA).MHTS site data for 2,160 participants were linked to SSA administrative data from 2011 to 2015, 1 to 5 years after the original study concluded. Univariate and multivariate models were used to assess the MHTS effects on employment, earnings, and disability benefit suspension-termination up to 7 years after services ended.The analyses showed that the treatment group was more likely than the control group to work, and average earnings among the treatment group increased more over time than earnings among the control group. Disability benefit suspension/termination did not differ between groups.Providing the demonstration's package of services and support to SSDI beneficiaries with psychiatric disabilities for up to 2 years may have a long-term impact on employment and earnings. Under the SSDI program as currently structured, however, even after receiving 2 years of evidence-based supported employment and high-quality mental health services, SSDI beneficiaries with psychiatric conditions are unlikely to achieve economic independence within 5 years.

Background and Purpose Previous literature suggests that the dose proximally outside the PTV could have an impact on the incidence of distant metastasis (DM) after SBRT in stage I NSCLC patients. We investigated this observation (along with local failure) in deliveries made by different treatment modalities: robotic mounted linac SBRT (CyberKnife) vs conventional SBRT (VMAT/CRT). Materials and methods This study included 422 stage I NSCLC patients from 2 institutions who received SBRT: 217 treated conventionally and 205 with CyberKnife. The dose behavior outside the PTV of both sub-cohorts were compared by analyzing the mean dose in continuous shells extending 1, 2, 3, …, 100 mm from the PTV. Kaplan-Meier analysis was performed between the two sub-cohorts with respect to DM-free survival and local progression-free survival. A multivariable Cox proportional hazards model was fitted to the combined cohort (n = 422) with respect to DM incidence and local failure. Results The shell-averaged dose fall-off beyond the PTV was found to be significantly more modest in CyberKnife plans than in conventional SBRT plans. In a 30 mm shell around the PTV, the mean dose delivered with CyberKnife (38.1 Gy) is significantly larger than with VMAT/CRT (22.8 Gy, p 10 - 8 ). For 95% of CyberKnife plans, this region receives a mean dose larger than the 21 Gy threshold dose discovered in our previous study. In contrast, this occurs for only 75% of VMAT/CRT plans. The DM-free survival of the entire CyberKnife cohort is superior to that of the 25% of VMAT/CRT patients receiving less than the threshold dose ( VMAT / CRT 21 Gy ), with a hazard ratio of 5.3 (95% CI: 3.0–9.3, p 10 - 8 ). The 2 year DM-free survival rates were 87% (95% CI: 81%–91%) and 44% (95% CI: 28%–58%) for CyberKnife and the below-threshold dose conventional cohorts, respectively. A multivariable analysis of the combined cohort resulted in the confirmation that threshold dose was a significant predictor of DM(HR = 0.28, 95% CI: 0.15–0.55, p 10 - 3 ) when adjusted for other clinical factors. CyberKnife was also found to be superior to the entire VMAT/CRT with respect to local control (HR = 3.44, CI: 1.6–7.3). The 2-year local progression-free survival rates for the CyberKnife cohort and the VMAT/CRT cohort were 96% (95% CI: 92%–98%) and 88% (95% CI: 82%–92%) respectively. Conclusions In standard-of-care CyberKnife treatments, dose distributions that aid distant control are achieved 95% of the time. Although similar doses could be physically achieved by conventional SBRT, this is not always the case with current prescription practices, resulting in worse DM outcomes for 25% of conventional SBRT patients. Furthermore, CyberKnife was found to provide superior local control compared to VMAT/CRT.

Background: The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern. Methods: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Results: The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14–3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11–2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88–2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82–1.72]). Conclusions: In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.

IntroductionIn patients with optic nerve hypoplasia (ONH), the visualisation of the optic disc can be challenging and the definitive diagnosis difficult to ascertain without fundus photography. The use of MRI for diagnosis has been reported as a diagnostic alternative with conflicting results. We retrospectively analysed a disease registry to determine the reliability of orbital MRI measurements of the optic nerve diameter to diagnose ONH, and the correlation with vision outcomes.Materials and methodsFrom a cohort of 140 patients with ONH (13% unilateral) that had reached age 5 years, we identified 43 subjects who had orbital MRI in addition to fundus photography performed prior to 2 years of age. We compared measurements of the optic nerve diameter from orbital MRI scans to the standard relative optic disc size (disc diameter/disc-macula (DD/DM) distance) by fundus photography. All patients had visual acuity tested at age 5 years. Spearman’s correlation coefficient was used to determine the correlation of orbital MRI measurements and fundus photography with the diagnosis of ONH, and with vision outcomes.ResultsRelative disc size (DD/DM)s=0.471; ps=−0.869; ps=−0.635; pDiscussionOrbital optic nerve diameter from MRI scans has moderate reliability in diagnosing ONH and predicting vision outcomes. Fundus photography for measurements of the optic nerve size should remain the reference for diagnostic confirmation of ONH. These data further support the prognostic value of fundus photography for eventual vision outcomes in this population.

Background: Cholesteryl ester transfer protein (CETP) inhibitors increase serum high-density lipoprotein cholesterol (HDL-c) concentration; however, their impact on cardiovascular outcomes is not clear. This systematic review examines the effect of CETP inhibitors on serum lipid profiles, cardiovascular events, and all-cause mortality. Methods: We searched MEDLINE, Embase, and the Cochrane Library of Clinical Trials for placebo-controlled randomized controlled trials (RCTs) that examined the effect of a CETP inhibitor (dalcetrapib, anacetrapib, evacetrapib, or TA-8995) on all-cause mortality, major adverse cardiovascular events (MACE), or the components of MACE at ≥6 months. Data were pooled using random-effects models. Results: A total of 11 RCTs (n = 62,431) were included in our systematic review; 4 examined dalcetrapib (n = 16,612), 6 anacetrapib (n = 33,682), and 1 evacetrapib (n = 12,092). Compared to dalcetrapib, ana­cetrapib and evacetrapib were more efficacious at raising HDL-c levels (∼100–130 vs. ∼30%). Anacetrapib and evacetrapib also decreased low-density lipoprotein cholesterol (LDL-c) by approximately 30% while dalcetrapib did not affect the LDL-c level. Overall, CETP inhibitors were not associated with the incidence of MACE (pooled relative risk [RR]: 0.97; 95% confidence interval [CI]: 0.91–1.04). CETP inhibitors may decrease the risks of nonfatal myocardial infarction (MI) (RR: 0.93; 95% CI: 0.87–1.00) and cardiovascular death (RR: 0.92; 95% CI: 0.83–1.01), though these trends did not reach statistical significance. Conclusions: CETP inhibitors are not associated with an increased risk of MACE or all-cause mortality. There is a trend towards small reductions in nonfatal MI and cardiovascular death, though the clinical im­portance of such reductions is likely modest.

Pediatric CKD management focuses on limiting kidney injury, including avoiding nephrotoxic medications. Nephrotoxic medication prescription practices for children with CKD are unknown. Our objective was to determine the prevalence and rates of primary care prescriptions for potentially nephrotoxic medications in children with CKD versus without CKD.We conducted a retrospective, matched population-based cohort study of patients aged18 years, registered at a general practice participating in the UK Clinical Practice Research Datalink (CPRD) from 1997 to 2017. Children with a clinical code indicating an incident diagnosis of CKD were matched 1:4 to patients without CKD on CKD diagnosis date, sex, age, CPRD practice, and number of general practitioner visits in the year before cohort entry. We calculated the prevalence and the rate of potentially nephrotoxic medication prescriptions throughout the follow-up period in patients with versus without CKD. Primary analyses included the following medication classes: aminoglycosides, antivirals, nonsteroidal anti-inflammatory drugs, salicylates, proton pump inhibitors, and immunomodulators. Secondary analyses used an expanded nephrotoxicity definition that also included, among others, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Adjusted prescription rates were calculated using multivariable binomial regression.From 1,535,816 eligible patients, we identified 1018 incident CKD and 4072 non-CKD matches (mean age, 9.8 years [range, 1.1-17.9 years]; 52% male; mean follow-up time, 3.3 years). Overall, 26% of patients with and 15% of patients without CKD were prescribed one or more potentially nephrotoxic medication during follow-up. The overall rate of nephrotoxic medication prescriptions was 71 (95% confidence interval [95% CI], 55 to 93) prescriptions per 100 person-years in patients with CKD and eight (95% CI, 7 to 9) prescriptions per 100 person-years in patients without CKD (adjusted rate ratio, 4.1; 95% CI, 2.7 to 6.1).Potentially nephrotoxic medications are prescribed at high rates to children with CKD.

The US Sentinel System and the Canadian Network for Observational Drug Effect Studies (CNODES) are two medical product safety surveillance networks. Using Sentinel's preprogrammed, parameterizable analytic tools, we reproduced two protocol-based studies conducted by CNODES to assess the risks of acute pancreatitis and heart failure (HF) associated with the use of incretin-based drugs, compared with use of ≥ 2 oral hypoglycemic agents. Results from the replication new-user cohort analyses aligned with those from the CNODES nested case-control studies. The adjusted hazard ratios were 0.95 (0.81-1.12; vs. 1.03 (0.87-1.22) in CNODES) for acute pancreatitis and 0.91 (0.84-1.00; vs. 0.82 (0.67-1.00) in CNODES) for HF among patients without HF history. The CNODES's common protocol approach allows studies tailored to specific safety questions, whereas the Sentinel's common data model plus pretested program approach enables more rapid analysis. Despite these differences, it is possible to obtain comparable results using both approaches.

Background With expanding recreational cannabis legalisation, pregnant women and their offspring are at risk of potentially harmful consequences. Objectives To assess the prevalence of recreational cannabis use among pregnant women, health outcomes associated with prenatal recreational cannabis use, and the potential impact of recreational cannabis legalisation on this population. Search strategy Five databases and the grey literature were systematically searched (2000-2019). Selection criteria Human studies published in English or French reporting on the prevalence of prenatal recreational cannabis use in high-income countries. Data collection and analysis Data on study characteristics, prenatal substance use, and health outcomes were extracted and qualitatively synthesised. Main results Forty-one publications met our inclusion criteria. The overall prevalence of prenatal cannabis use varied substantially (min-max: 0.24-22.6%), with the greatest use in the first trimester. In the three studies with temporal data available, rates of prenatal cannabis use increased across years. Only 7/41 and 5/41 studies provided information on gestational age of exposure and frequency of use, respectively. The concomitant use of alcohol, illicit drugs, and tobacco was higher among cannabis users than nonusers. Prenatal cannabis use was associated with select neonatal, but not maternal, health outcomes. There were insufficient data to compare prenatal cannabis use between the pre- and post-legalisation periods. Conclusion Cannabis use among pregnant women is prevalent and may be associated with adverse neonatal outcomes. Future studies should assess the gestational age and frequency of cannabis exposure, and usage patterns prior to and following legalisation. Tweetable abstract Women who consume cannabis during pregnancy could risk predisposing their newborns to poor birth outcomes.

The youthification hypothesis posits that young adult geographies are highly centralized, particularly in metropolitan regions with gentrified, amenity-rich downtowns successful in the knowledge economy. While prior studies have empirically substantiated centralized young adult geographies, none have considered intra-urban variations and linked these empirically to metropolitan-specific characteristics. Focusing on young adults aged 25 to 34 across 57 metropolitan regions in the United States and Canada with populations over one million, this study investigates how the residential geographies of young adults vary within and between metropolitan regions. Young adult geographies are analyzed via generalized additive models with cubic spline smoothing. Economic, housing, urban form, and demographic characteristics are compared between regions with different types of young adult geographies. Results show youthification to be widespread; young adult clusters exist in the downtowns of 56 metropolitan regions, with 31 regions having one downtown-focused young adult cluster and 25 regions having a multi-cluster profile. Only one region had a scattered profile with no clusters. Regions with a single centrally-located young adult profile had greater employment in the quaternary sector, higher public transit mode shares, fewer single-detached homes, and lower employment in manufacturing than those with multiple clusters. The study contributes to understanding the ways in which the residential geographies of specific age groups are shaped by aggregate characteristics of cohorts and the existing urban structures.

Purpose Little information is available on the performance of high-dimensional propensity scores (HDPS) in settings with more than two exposure levels. Our objective was to adapt the HDPS algorithm to allow for the inclusion of multilevel treatments and compare estimates obtained via this approach with those obtained via pairwise comparisons in a case study using real-world data. Methods We conducted a retrospective cohort study of cardiovascular events associated with three smoking cessation drugs (varenicline, bupropion, nicotine replacement therapy [NRT]) using the Clinical Practice Research Datalink. We applied the binary HDPS algorithm adjusted for pre-specified and empirically-selected covariates to cohorts formed by each treatment pair. We then constructed multinomial HDPS models on a cohort of new users of any of the three drugs, adjusting for predefined covariates and different combinations of empirically-selected covariates. After trimming the area of non-overlap of the HDPS distributions, the effects of the study drugs on cardiovascular events were estimated with the Cox proportional hazards models adjusted for propensity score category. Results Outcome models adjusted for multinomial HDPS estimated treatment effects that were slightly more protective than those estimated in pairwise comparisons (varenicline vs NRT: HRMultinomial = 0.60-0.62, HRPairwise = 0.64; bupropion vs NRT: HRMultinomial = 0.70-0.72, HRPairwise = 0.76). Trimming rates were similar between the two approaches. Conclusions The extension of HDPS to multilevel exposures is a valid and practical approach to confounder control that may be useful when comparing different classes of drugs prescribed for the same indication or different molecules within a given drug class.

Purpose To use the Canadian Network for Observational Drug Effect Studies (CNODES) to describe drug utilization of antidiabetic medications in four Canadian provinces. Methods With the use of data from CNODES, we constructed cohorts of patients with type 2 diabetes in four Canadian provinces (Manitoba, Ontario, Quebec, and Saskatchewan) who received their first-ever prescription for a noninsulin antidiabetic medication during the study period, defined as the earliest date of data availability in each province (range: 1993-1998) to the latest date of the data extraction in each province (range: 2013-2014). Prescriptions rates were calculated for all prescriptions by class and described over time. Results Across provinces, we identified 650 830 patients who initiated antidiabetic medications during the study period. In most provinces, the overall prescription rate of antidiabetic medications increased during the last two decades. Metformin particularly increased in popularity, surpassing sulfonylureas in all provinces as the most widely prescribed antidiabetic medication by the early 2000s. Thiazolidinediones grew in popularity from the onset of their availability until 2006 to 2007, at which point they rapidly declined. Dipeptidyl peptidase-4 inhibitors saw substantial growth in several provinces following their addition to provincial formularies in 2008 to 2012, while glucagon-like peptide-1 agonists experienced modest growth. Insulin prescription rates remained constant or steadily increased over the last two decades. Conclusions CNODES can be used for cross-jurisdictional drug utilization studies. In Canada, trends in antidiabetic medication prescriptions followed changing guidelines reflecting up-to-date knowledge of drug effectiveness and safety.

Aims Sulfonylureas are recommended as second-line treatment in the management of type 2 diabetes. However, they are still commonly used also as first-line treatment instead of metformin. Given the controversial cardiovascular safety of sulfonylureas, we aimed to determine if their use as first-line treatment is associated with adverse cardiovascular events among patients with newly treated type 2 diabetes compared with metformin. Methods We conducted a population-based cohort study of patients with newly treated type 2 diabetes using the UK's Clinical Practice Research Datalink. Initiators of metformin and sulfonylurea monotherapy were matched on high-dimensional propensity score, and Cox proportional hazards models were used to compare the rate of cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular death, and all-cause mortality) with sulfonylureas vs metformin. Results Our cohort included 94 750 patients initiating treatment for type 2 diabetes, 17 612 on a sulfonylurea and 77 138 on metformin. After matching, sulfonylurea monotherapy, compared with metformin monotherapy, was not associated with an increased risk of myocardial infarction (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 0.85-1.25) but was associated with increased risks of ischaemic stroke (HR: 1.25, 95% CI: 1.002-1.56), cardiovascular death (HR: 1.25, 95% CI: 1.06-1.47), and all-cause mortality (HR: 1.60, 95% CI: 1.45-1.76). This represents an additional 2.0 ischaemic strokes, 3.5 cardiovascular deaths, and 21.4 all-cause deaths per 1,000 patients per year with sulfonylureas. Conclusions Initiating treatment of type 2 diabetes with a sulfonylurea rather than metformin is associated with higher rates of ischaemic stroke, cardiovascular death, and all-cause mortality.

OBJECTIVE There are uncertainties regarding the association between dipeptidyl peptidase 4 (DPP-4) inhibitors and bullous pemphigoid (BP), a potentially severe autoimmune skin disease. Thus, we conducted a population-based study to determine whether use of DPP-4 inhibitors, when compared with other second- to third-line antidiabetic drugs, is associated with an increased risk of BP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Using the U.K. Clinical Practice Research Datalink, we conducted a cohort study among 168,774 patients initiating antidiabetic drugs between January 2007 and March 2018. Using time-dependent Cox proportional hazards models, we estimated adjusted hazard ratios (HRs) with 95% CIs of incident BP associated with current use of DPP-4 inhibitors, compared with current use of other second- to third-line antidiabetic drugs. We also conducted a propensity score–matched analysis to assess the impact of residual confounding. RESULTS During 711,311 person-years of follow-up, 150 patients were newly diagnosed with BP (crude incidence rate, 21.1 per 100,000 person-years). Current use of DPP-4 inhibitors was associated with an increased risk of BP (47.3 vs. 20.0 per 100,000 person-years; HR 2.21 [95% CI 1.45–3.38]). HRs gradually increased with longer durations of use, reaching a peak after 20 months (HR 3.60 [95% CI 2.11–6.16]). Similar results were obtained in the propensity score–matched analysis (HR 2.40 [95% CI 1.13–4.66]). CONCLUSIONS In this large population-based study, use of DPP-4 inhibitors was associated with an at least doubling of the risk of BP in patients with type 2 diabetes, albeit the absolute risk was low.

There are no head-to-head randomized controlled trials comparing different direct oral anticoagulants (DOACs). Thus, we systematically reviewed and meta-analyzed observational studies assessing the comparative effectiveness and safety of DOACs for stroke prevention in patients with atrial fibrillation (AF). We systematically searched MEDLINE and EMBASE up to February 2019 for observational studies comparing different DOACs head-to-head in patients with AF. Two independent reviewers identified studies, extracted data, and assessed the risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Random-effects models were used to meta-analyze data across higher-quality studies. We identified 25 cohort studies including 1,079,565 patients with AF treated with DOACs. Meta-analysis of the 19 studies at moderate risk of bias yielded a similar risk of ischemic stroke for rivaroxaban versus dabigatran (six studies; hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.83–1.04; I2: 0%), apixaban versus dabigatran (five studies; HR 0.94; 95% CI 0.82–1.09; I2: 0%), and apixaban versus rivaroxaban (four studies; HR 1.07; 95% CI 0.93–1.23; I2: 0%). Regarding major bleeding, there was an increased risk for rivaroxaban versus dabigatran (six studies; HR 1.33; 95% CI 1.20–1.47; I2: 22%) and decreased risks for apixaban versus either dabigatran (eight studies; HR 0.71; 95% CI 0.64–0.78; I2: 0%) or rivaroxaban (eight studies; HR 0.56; 95% CI 0.48–0.65; I2: 69%). As head-to-head trials comparing different DOACs do not exist, available evidence derives exclusively from observational studies. These data suggest that while dabigatran, rivaroxaban, and apixaban have a similar effect on the risk of ischemic stroke, apixaban may be associated with a decreased risk of major bleeding compared with either dabigatran or rivaroxaban.

Background Chronic kidney disease (CKD) management focuses on limiting further renal injury, including avoiding nephrotoxic medications such as non-steroidal anti-inflammatory drugs (NSAIDs). We performed a systematic review to evaluate the prevalence of primary care NSAID prescribing in this population. Methods We systematically searched MEDLINE and Embase from inception to October 2017 for observational studies examining NSAID prescribing practices or use in CKD patients in a primary care setting. The methodological quality of included studies was assessed independently by two authors using a modified version of the Agency for Healthcare Research and Quality’s Methodological Evaluation of Observational Research checklist. Results Our search generated 8055 potentially relevant publications, 304 of which were retrieved for full-text review. A total of 14 studies from 13 publications met our inclusion criteria. There were eight cohort and three cross-sectional studies, two quality improvement intervention studies and one prospective survey, representing a total of 49 209 CKD patients. Cross-sectional point prevalence of NSAID use in CKD patients ranged from 8 to 21%. Annual period prevalence rates ranged from 3 to 33%. Meta-analysis was not performed due to important clinical heterogeneity across study populations. Conclusions Evidence suggests that NSAID prescriptions/use in primary care among patients with CKD is variable and relatively high. Future research should explore reasons for this to better focus knowledge translation interventions aimed at reducing NSAID use in this patient population.

Postoperative ileus (POI) is regarded as the most clinically significant morbidity following loop ileostomy closure; however, its incidence remains poorly understood. Our objective was therefore to determine the pooled incidence of POI after loop ileostomy closure and identify risk factors associated with its development. We systematically searched MEDLINE (via Ovid and PubMed), Embase, the Cochrane Library, Biosis Previews, and Scopus to identify studies reporting the incidence of POI in patients who underwent loop ileostomy closure. Two independent reviewers extracted data and appraised study quality. Cumulative incidence proportions were pooled across studies using a random-effects meta-analytic model. Sixty-seven studies, including 9528 patients, met our inclusion criteria. The pooled estimate of POI was 8.0% (95% CI 6.9–9.3%; I2 = 74%). The estimated incidence varied by POI definition: studies with a robust definition of POI (n = 8) demonstrated the highest estimate of POI (12.4%, 95% CI 9.2–16.5%; I2 = 79%) while studies that did not report an explicit POI definition (n = 38) demonstrated the lowest estimate (6.7%, 95% CI 5.3–8.3%; I2 = 61%). Small bowel anastomosis technique (hand-sewn) and interval time from ileostomy creation to closure (longer time) were the factors most commonly associated with POI after loop ileostomy closure. However, most comparative studies were not powered to examine risk factors for POI. POI is an important complication after loop ileostomy closure, and its incidence is dependent on its definition. More research aimed at studying this complication is required to better understand risk factors for POI after loop ileostomy closure.

Our study aimed to describe levothyroxine prescription patterns and trends over time among pregnant women with subclinical hypothyroidism (SCH) in the United Kingdom. We used data from the Clinical Practice Research Datalink linked to its Pregnancy Register and the Hospital Episode Statistics database from 1998 to 2017. The study population included women with a diagnosis of SCH or an abnormal thyroid‐simulated hormone (TSH) level one year prior to or during pregnancy. We compared characteristics between women who received a prescription for levothyroxine during pregnancy and those who did not. We further described the timing, dose, duration, and temporal trends of levothyroxine prescriptions. Our cohort included 6,757 pregnancies from 6,287 women with SCH, of whom 10% received levothyroxine during pregnancy. Among women who received levothyroxine, most received their first prescription during the first trimester (median gestational age: 7 weeks; interquartile range [IQR]: 0, 16) with a median daily dosage of 50 mcg (IQR: 50, 73). Levothyroxine prescription varied over time, decreasing from 23% of pregnant women in 1998 to 7.5% in 2003, remaining stable until 2014, and increasing to 12.5% in 2016. Smoking, diabetes, polycystic ovary syndrome, infertility, timing of SCH diagnosis, age, TSH level at diagnosis, and general practice regions were associated with prescription. Few women with SCH received levothyroxine during pregnancy, and treatment varied by patient characteristics and geographical regions. These results highlight the need to increase awareness among healthcare providers and will guide future studies that explore barriers to initiating levothyroxine treatment for women with SCH during pregnancy., Our study found that a low proportion of women with SCH were prescribed levothyroxine during pregnancy and that prescriptions varied by patient characteristics and geographical region.