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Background Before 2012, few studies had addressed pregnancy outcomes following maternal influenza vaccination; however, the number of publications on this topic has increased recently. Objectives To review comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy. Search strategy We searched bibliographic databases from inception to April 2014. Selection criteria Experimental or observational studies assessing the relationship between influenza vaccination during pregnancy and fetal death or preterm birth. Data collection and analysis Two reviewers independently abstracted data from studies meeting the inclusion criteria. Main results We included one randomised clinical trial and 26 observational studies. Meta-analyses were not considered appropriate because of high clinical and statistical heterogeneity. Three studies of fetal death at any gestational age reported adjusted effect estimates in the range 0.56-0.79, and four of five studies of fetal death at <20 weeks reported adjusted estimates between 0.89 and 1.23, all with confidence intervals including 1.0. Adjusted effect estimates for four of five studies of fetal death at ≥20 weeks ranged from 0.44 to 0.77 (two with confidence intervals not crossing 1.0), whereas a fifth reported a non-significant effect in the opposite direction. Among 19 studies of preterm birth, there was no strong evidence suggesting any increased risk, and meta-regression did not explain the moderate between-study heterogeneity ( I2 = 57%). Authors' conclusions Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness. [ABSTRACT FROM AUTHOR]

Background: A previous study suggested a potential increased risk of cardiac arrhythmia with new use of long-acting β-agonists and ipratropium bromide in patients with COPD, although conclusions were limited by the small cohort size.Methods: We reassessed this association in a larger cohort formed from the health-care databases of the province of Quebec, Canada. We identified a cohort of patients with COPD aged ≥ 67 years who began treatment between 1990 and 1999 and followed them until December 2003. A nested case-control approach matched each subject who developed severe arrhythmia during follow-up with 20 control subjects from the cohort on age, sex, and calendar time. The rate ratio (RR) of arrhythmia associated with new use of bronchodilators was estimated using conditional logistic regression, adjusting for COPD disease severity, cardiovascular disease, and other comorbidities.Results: The cohort included 76,661 patients with COPD, of whom 5,307 developed an arrhythmia (10.3 arrhythmias per 1,000 per year), 621 of which were fatal. The rate of cardiac arrhythmias was elevated with the new use of short-acting (RR, 1.27; 95% CI, 1.03-1.57) and long-acting (RR, 1.47; 95% CI, 1.01-2.15) β-agonists. The rate was slightly elevated, although not statistically significantly, with new use of ipratropium bromide (RR, 1.23; 95% CI, 0.95-1.57) and methylxanthines (RR, 1.28; 95% CI, 0.93-1.77). These effects waned with longer-term use.Conclusions: New use of short- and long-acting β-agonists may slightly increase the risk of cardiac arrhythmia in patients with COPD. It remains unclear whether ipratropium bromide also increases this risk, despite the use of a larger study population. [ABSTRACT FROM AUTHOR]

Background: Bronchodilators are first-line therapy for COPD. There is some evidence that they may increase the risk of cardiac arrhythmias.Methods: We used the computerized health-care databases of the Province of Saskatchewan, Canada, to identify a cohort of subjects with COPD, aged ≥ 55 years, between 1990 and 1999. The subjects were followed until December 2003 for a hospital admission for, or death from, arrhythmia. A nested case-control approach was used to match each arrhythmia case on age, sex, and calendar time to 20 control subjects selected from the corresponding cohort risk set. Conditional logistic regression was used to estimate the rate ratio (RR) of arrhythmia associated with new use of bronchodilators, adjusted for disease severity and comorbidity.Results: The cohort included 6,018 patients with COPD in whom 469 arrhythmia cases occurred, including 56 deaths, for an overall rate of 1.37 arrhythmias per 100 per year. The rate of arrhythmia was elevated with the new use of ipratropium (RR, 2.4; 95% CI, 1.4-4.0) and of long-acting β-agonists (LABAs) (RR, 4.5; 95% CI, 1.4-14.4). It was not elevated with new use of short-acting β-agonists (RR, 0.9; 95% CI, 0.5-1.6) or methylxanthines (RR, 1.6; 95% CI, 0.7-3.7).Conclusions: The new use of bronchodilators, particularly ipratropium and LABAs, may increase the risk of cardiac arrhythmias in patients with COPD. Although these results raise concerns regarding LABAs, they were based on few cases and require confirmation in larger cohorts. [ABSTRACT FROM AUTHOR]

Contemporary fetal growth standards are created by using theoretical properties (percentiles) of birth weight (for gestational age) distributions. The authors used a clinically relevant, outcome-based methodology to determine if separate fetal growth standards are required for singletons and twins. All singleton and twin livebirths between 36 and 42 weeks' gestation in the United States (1995-2002) were included, after exclusions for missing information and other factors (n = 17,811,922). A birth weight range was identified, at each gestational age, over which serious neonatal morbidity and neonatal mortality rates were lowest. Among singleton males at 40 weeks, serious neonatal morbidity/mortality rates were lowest between 3,012 g (95% confidence interval (CI): 3,008, 3,018) and 3,978 g (95% CI: 3,976, 3,980). The low end of this optimal birth weight range for females was 37 g (95% CI: 21, 53) less. The low optimal birth weight was 152 g (95% CI: 121, 183) less for twins compared with singletons. No differences were observed in low optimal birth weight by period (1999-2002 vs. 1995-1998), but small differences were observed for maternal education, race, parity, age, and smoking status. Patterns of birth weight-specific serious neonatal morbidity/neonatal mortality support the need for plurality-specific fetal growth standards. [ABSTRACT FROM AUTHOR]

RATIONALE: Depression and anxiety are significant comorbid and potentially modifiable conditions in chronic obstructive pulmonary disease (COPD), but their effects on exacerbations are not clear. OBJECTIVES: To investigate the independent effect of depression and anxiety on the risk of COPD exacerbations and hospitalizations. METHODS: A multicenter prospective cohort study in 491 patients with stable COPD in China. Multivariate Poisson and linear regression analyses were used, respectively, to estimate adjusted incidence rate ratios (IRRs) and adjusted effects on duration of events. MEASUREMENTS AND MAIN RESULTS: Depression and anxiety were measured using the Hospital Anxiety and Depression Scale (HADS) at baseline. Other measurements included sociodemographic, clinical, psychosocial, and treatment characteristics. Patients were then monitored monthly for 12 months to document the occurrence and characteristics of COPD exacerbations and hospitalizations. Exacerbation was determined using both symptom-based (worsening of > or =1 key symptom) and event-based definitions (> or =1 symptom worsening plus > or =1 change in regular medications). A total of 876 symptom-based and 450 event-based exacerbations were recorded, among which 183 led to hospitalization. Probable depression (HADS depression score > or = 11) was associated with an increased risk of symptom-based exacerbations (adjusted IRR, 1.51; 95% confidence interval [CI], 1.01-2.24), event-based exacerbations (adjusted IRR, 1.56; 95% CI, 1.02-2.40), and hospitalization (adjusted IRR, 1.72; 95% CI, 1.04-2.85) compared with nondepression (score < or = 7). The duration of event-based exacerbations was 1.92 (1.04-3.54) times longer for patients with probable anxiety (HADS anxiety score > or = 11) than those with no anxiety (score < or = 7). CONCLUSIONS: This study suggests a possible causal effect of depression on COPD exacerbations and hospitalizations. Further studies are warranted to confirm this finding and to test the effectiveness of antidepressants and psychotherapies on reducing exacerbations and improving health resource utilizations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Providers need a reliable way to identify patients with chronic kidney disease (CKD) at the highest risk of progression to end-stage renal disease so they can intervene to slow progression and refer patients to nephrology for comanagement. We developed a risk score to predict the 5-year risk of renal replacement therapy (RRT) in patients with stage 3 or 4 CKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Participants were members of a health maintenance organization and met Kidney Disease Outcomes Quality Initiative criteria for stage 3 or 4 CKD during 1999 or 2000: two estimated glomerular filtration rate values of 15 to 59 mL/min/1.73 m(2). PREDICTOR: Characteristics collected during routine clinical practice. OUTCOMES & MEASUREMENTS: We ascertained the onset of RRT (dialysis or kidney transplantation) using the health maintenance organization databases. Cox regression predicted patient risk of RRT and generated a risk scoring system. RESULTS: 9,782 patients experienced a 3.3% five-year progression to RRT (95% confidence interval, 2.9 to 3.7). Using 6 characteristics (age, sex, estimated glomerular filtration rate, diabetes, anemia, and hypertension), the risk score discriminated the highest risk patients effectively: 19.0% of patients in the highest risk quintile experienced progression, and 0.2% of patients in the lowest risk quintile experienced progression. The c statistic also showed effective discrimination: 0.89 on a scale of 0.5 to 1.0. Predicted and observed risks agreed within 1.0%--effective calibration. We present a range of predicted risk cutoff values from 1% to 20% and their test properties for decision makers' consideration. LIMITATIONS: Characteristics were measured without a protocol. CONCLUSIONS: The risk score can help providers identify patients with CKD at the highest risk of progression to improve referral to nephrology for comanagement. A separate risk score for mortality also is needed. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Weight-for-gestational-age charts and definitions of 'small-for-gestational-age' based on the distribution of livebirths at a given gestational age have conventionally been used to identify infants whose fetal growth is poor. However, references based on the weights of only livebirths have serious shortcomings at preterm ages due to missing data on the weights of fetuses still in utero, and these missing data introduce considerable bias to etiologic studies of fetal growth restriction. Application of standard epidemiologic approaches for missing data is needed to help produce perinatal weight percentiles that provide unbiased assessment of fetal growth and risks of small-for-gestational-age. [ABSTRACT FROM AUTHOR]

Abstract  Secondary syringe exchange (SSE) refers to the exchange of sterile syringes between injection drug users (IDUs). To date there has been limited examination of SSE in relation to the social networks of IDUs. This study aimed to identify characteristics of drug injecting networks associated with the receipt of syringes through SSE. Active IDUs were recruited from syringe exchange and methadone treatment programs in Montreal, Canada, between April 2004 and January 2005. Information on each participant and on their drug-injecting networks was elicited using a structured, interviewer-administered questionnaire. Subjects’ network characteristics were examined in relation to SSE using regression models with generalized estimating equations. Of 218 participants, 126 were SSE recipients with 186 IDUs in their injecting networks. The 92 non-recipients reported 188 network IDUs. Networks of SSE recipients and non-recipients were similar with regard to network size and demographics of network members. In multivariate analyses adjusted for age and gender, SSE recipients were more likely than non-recipients to self-report being HIV-positive (OR = 3.56 [1.54–8.23]); require or provide help with injecting (OR = 3.74 [2.01–6.95]); have a social network member who is a sexual partner (OR = 1.90 [1.11–3.24]), who currently attends a syringe exchange or methadone program (OR = 2.33 [1.16–4.70]), injects daily (OR = 1.77 [1.11–2.84]), and shares syringes with the subject (OR = 2.24 [1.13–4.46]). SSE is associated with several injection-related risk factors that could be used to help focus public health interventions for risk reduction. Since SSE offers an opportunity for the dissemination of important prevention messages, SSE-based networks should be used to improve public health interventions. This approach can optimize the benefits of SSE while minimizing the potential risks associated with the practice of secondary exchange. [ABSTRACT FROM AUTHOR]

BACKGROUND: The evidence that breastfeeding protects against obesity and a variety of chronic diseases comes almost entirely from observational studies, which have a potential for bias due to confounding, selection bias, and selective publication. OBJECTIVE: We assessed whether an intervention designed to promote exclusive and prolonged breastfeeding affects children's height, weight, adiposity, and blood pressure at age 6.5 y. DESIGN: The Promotion of Breastfeeding Intervention Trial (PROBIT) is a cluster-randomized trial of a breastfeeding promotion intervention based on the WHO/UNICEF Baby-Friendly Hospital Initiative. A total of 17,046 healthy breastfed infants were enrolled from 31 Belarussian maternity hospitals and their affiliated clinics; of those infants, 13,889 (81.5%) were followed up at 6.5 y with duplicate measurements of anthropometric variables and blood pressure. Analysis was based on intention to treat, with statistical adjustment for clustering within hospitals or clinics to permit inferences at the individual level. RESULTS: The experimental intervention led to a much greater prevalence of exclusive breastfeeding at 3 mo in the experimental than in the control group (43.3% and 6.4%, respectively; P < 0.001) and a higher prevalence of any breastfeeding throughout infancy. No significant intervention effects were observed on height, body mass index, waist or hip circumference, triceps or subscapular skinfold thickness, or systolic or diastolic blood pressure. CONCLUSIONS: The breastfeeding promotion intervention resulted in substantial increases in the duration and exclusivity of breastfeeding, yet it did not reduce the measures of adiposity, increase stature, or reduce blood pressure at age 6.5 y in the experimental group. Previously reported beneficial effects on these outcomes may be the result of uncontrolled confounding and selection bias. [ABSTRACT FROM AUTHOR]

Objectives: To examine delirium, chronic medical problems and sociodemographic factors as predictors of activities of daily living (ADL), basic ADL (BADL) and instrumental ADL (IADL).Methods: A prospective cohort study of four groups of elderly patients examined in the emergency department (ED): those with delirium, dementia, neither, and both. All were aged 66 years or older and living at home. Delirium was assessed with the Confusion Assessment Method and dementia with the Informant Questionnaire on Cognitive Decline in the Elderly. Demographic variables and chronic medical problems were ascertained with questionnaires. Outcome was ADL at 6, 12 and 18 months, measured with the ADL subscale of the Older Americans Resources and Services instrument.Results: Univariate analyses suggested significantly poorer ADL, particularly IADL, at 18 months in the delirium versus the non-delirium group, in the absence of dementia only. Statistically significant independent predictors of poorer ADL at 18 months in the non-dementia groups were poorer initial ADL, stroke, Parkinson's disease, hypertension and female sex. Independent predictors of poorer BADL at 18 months in the non-dementia groups were poorer initial BADL, Parkinson's disease, stroke, cancer, colds/sinusitis/laryngitis, female sex and hypertension. Independent predictors of poorer IADL at 18 months in the non-dementia groups were poorer initial IADL, stroke, never-married status, colds/sinusitis/laryngitis, arthritis and hypertension, with Parkinson's disease showing a non-significant but numerically large regression coefficient.Conclusion: Rather than finding delirium to be a predictor of poorer functional outcome among survivors, we found an interaction between delirium and dementia and several plausible confounders, primarily chronic medical problems, although we cannot rule out the effect of misclassification or survivor bias. [ABSTRACT FROM AUTHOR]

Preschool children diagnosed with either global developmental delay (GDD) or developmental language impairment (DLI) were reassessed during their early school years with standardized developmental (Battelle Developmental Inventory [BDI]) and functional (Vineland Adaptive Behavior Scale [VABS]) outcome measures. Of an original cohort of 99 children with GDD and 70 children with DLI assessed and diagnosed at a mean age of 3 years 5 months (SD 1.1) and 3 years 7 months (SD 0.7) respectively, 48 children (34 [71%] males) with GDD and 43 children (36 [84%] males) with DLI were reassessed at a mean age of 7 years 4 months (SD 0.9) and 7 years 5 months (SD 0.7) respectively. The overall total mean BDI score for children with GDD was 66.4 (SD 4.3) versus 71.9 (SD 8.2) for children with DLI (p=0.002). On each subdomain of the BDI, except communication, mean scores for the GDD group were significantly lower than for the DLI group (p<0.05). Similarly, the VABS total score for the GDD group was significantly lower than for the DLI group (p<0.001). For each subdomain of the VABS, the GDD group scored significantly lower than the DLI group (p<0.001). The proportion of children falling below meaningful cut-offs on the outcome measures selected was significantly higher for those initially diagnosed with GDD. Preschool diagnosis of either GDD or DLI has later prognostic validity with regard to persisting developmental and functional deficits. [ABSTRACT FROM AUTHOR]

OBJECTIVES: This study reviewed evidence on the effect of maternal smoking on early weaning. METHODS: The following databases and journals were searched: Medline, Scientific Citation Index, Pediatrics, Journal of Pediatrics, New England Journal of Medicine, and Lancet. Analysis was restricted to studies in which infants who had never been breastfed were excluded or the prevalence of breastfeeding initiation was more than 90%. RESULTS: In smoking vs nonsmoking mothers, the random effects odds ratio for weaning before 3 months was 1.93 (95% confidence interval [CI] = 1.55, 2.40). An adjusted odds ratio of 1.50 (95% CI = 1.34, 1.68) was shown in studies that had lost-to-follow-up rates below 15% and included adequate adjustment for confounding. CONCLUSIONS: Maternal smoking increases the risk of early weaning. © 2002 by the United States Cancer Pain Relief Committee. [ABSTRACT FROM AUTHOR]

Context: The World Health Organization defines preterm birth as birth at less than 37 completed gestational weeks, but most studies have focused on very preterm infants (birth at <32 weeks) because of their high risk of mortality and serious morbidity. However, infants born at 32 through 36 weeks are more common and their public health impact has not been well studied.Objective: To assess the quantitative contribution of mild (birth at 34-36 gestational weeks) and moderate (birth at 32-33 gestational weeks) preterm birth to infant mortality.Design, Setting, and Participants: Population-based cohort study using linked singleton live birth-infant death cohort files for US birth cohorts for 1985 and 1995 and Canadian birth cohorts (excluding Ontario) for 1985-1987 and 1992-1994.Main Outcome Measures: Relative risks (RRs) and etiologic fractions (EFs) for overall and cause-specific early neonatal (age 0-6 days), late neonatal (age 7-27 days), postneonatal (age 28-364 days), and total infant death among mild and moderate preterm births vs term births (at >/=37 gestational weeks).Results: Relative risks for infant death from all causes among singletons born at 32 through 33 gestational weeks were 6.6 (95% confidence interval [CI], 6.1-7.0) in the United States in 1995 and 15.2 (95% CI, 13.2-17.5) in Canada in 1992-1994; among singletons born at 34 through 36 gestational weeks, the RRs were 2.9 (95% CI, 2.8-3.0) and 4.5 (95% CI, 4.0-5.0), respectively. Corresponding EFs were 3.2% and 4.8%, respectively, at 32 through 33 gestational weeks and 6.3% and 8.0%, respectively, at 34 through 36 gestational weeks; the sum of the EFs for births at 32 through 33 and 34 through 36 gestational weeks exceeded those for births at 28 through 31 gestational weeks. Substantial RRs were observed overall for the neonatal (eg, for early neonatal deaths, 14.6 and 33.0 for US and Canadian infants, respectively, born at 32-33 gestational weeks; EFs, 3.6% and and 6. 2% for US and Canadian infants, respectively) and postneonatal (RRs, 2.1-3.8 and 3.0-7.0 for US and Canadian infants, respectively, born at 32-36 gestational weeks; EFs, 2.7%-5.8% and 3.0%-7.0% for the same groups, respectively) periods and for death due to asphyxia, infection, sudden infant death syndrome, and external causes. Except for a reduction in the RR and EF for neonatal mortality due to infection, the patterns have changed little since 1985 in either country.Conclusions: Mild- and moderate-preterm birth infants are at high RR for death during infancy and are responsible for an important fraction of infant deaths. JAMA. 2000;284:843-849 [ABSTRACT FROM AUTHOR]

"The objective of most biomedical research is to determine an unbiased estimate of effect for an exposure on an outcome, i.e. to make causal inferences about the exposure. Recent developments in epidemiology have shown that traditional methods of identifying confounding and adjusting for confounding may be inadequate.~Background~Background~The traditional methods of adjusting for ""potential confounders"" may introduce conditional associations and bias rather than minimize it. Although previous published articles have discussed the role of the causal directed acyclic graph approach (DAGs) with respect to confounding, many clinical problems require complicated DAGs and therefore investigators may continue to use traditional practices because they do not have the tools necessary to properly use the DAG approach. The purpose of this manuscript is to demonstrate a simple 6-step approach to the use of DAGs, and also to explain why the method works from a conceptual point of view.~Discussion~Conclusions~Using the simple 6-step DAG approach to confounding and selection bias discussed is likely to reduce the degree of bias for the effect estimate in the chosen statistical model.~Summary~Conclusions" [ABSTRACT FROM AUTHOR]

Background: Interpregnancy interval (IPI), marital status, and neighborhood are independently associated with birth outcomes. The joint contribution of these exposures has not been evaluated. We tested for effect modification between IPI and marriage, controlling for neighborhood.Methods: We analyzed a cohort of 98,330 live births in Montréal, Canada from 1997-2001 to assess IPI and marital status in relation to small for gestational age (SGA) birth. Births were categorized as subsequent-born with short (<12 months), intermediate (12-35 months), or long (36+ months) IPI, or as firstborn. The data had a 2-level hierarchical structure, with births nested in 49 neighborhoods. We used multilevel logistic regression to obtain adjusted effect estimates.Results: Marital status modified the association between IPI and SGA birth. Being unmarried relative to married was associated with SGA birth for all IPI categories, particularly for subsequent births with short (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.31-1.95) and intermediate (OR 1.48, 95% CI 1.26-1.74) IPIs. Subsequent births had a lower likelihood of SGA birth than firstborns. Intermediate IPIs were more protective for married (OR 0.50, 95% CI 0.47-0.54) than unmarried mothers (OR 0.65, 95% CI 0.56-0.76).Conclusion: Being unmarried increases the likelihood of SGA birth as the IPI shortens, and the protective effect of intermediate IPIs is reduced in unmarried mothers. Marital status should be considered in recommending particular IPIs as an intervention to improve birth outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker.Background: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias.Methods: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and digoxin.Results: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31).Conclusions: This study suggests that the use of amiodarone in elderly patients with AF and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. [ABSTRACT FROM AUTHOR]

Importance: Previous studies on the comparative effectiveness between buprenorphine and methadone provided limited evidence on differences in treatment effects across key subgroups and were drawn from populations who use primarily heroin or prescription opioids, although fentanyl use is increasing across North America., Objective: To assess the risk of treatment discontinuation and mortality among individuals receiving buprenorphine/naloxone vs methadone for the treatment of opioid use disorder., Design, Setting, and Participants: Population-based retrospective cohort study using linked health administrative databases in British Columbia, Canada. The study included treatment recipients between January 1, 2010, and March 17, 2020, who were 18 years or older and not incarcerated, pregnant, or receiving palliative cancer care at initiation., Exposures: Receipt of buprenorphine/naloxone or methadone among incident (first-time) users and prevalent new users (including first and subsequent treatment attempts)., Main Outcomes and Measures: Hazard ratios (HRs) with 95% compatibility (confidence) intervals were estimated for treatment discontinuation (lasting ≥5 days for methadone and ≥6 days for buprenorphine/naloxone) and all-cause mortality within 24 months using discrete-time survival models for comparisons of medications as assigned at initiation regardless of treatment adherence ("initiator") and received according to dosing guidelines (approximating per-protocol analysis)., Results: A total of 30 891 incident users (39% receiving buprenorphine/naloxone; 66% male; median age, 33 [25th-75th, 26-43] years) were included in the initiator analysis and 25 614 in the per-protocol analysis. Incident users of buprenorphine/naloxone had a higher risk of treatment discontinuation compared with methadone in initiator analyses (88.8% vs 81.5% discontinued at 24 months; adjusted HR, 1.58 [95% CI, 1.53-1.63]), with limited change in estimates when evaluated at optimal dose in per-protocol analysis (42.1% vs 30.7%; adjusted HR, 1.67 [95% CI, 1.58-1.76]). Per-protocol analyses of mortality while receiving treatment exhibited ambiguous results among incident users (0.08% vs 0.13% mortality at 24 months; adjusted HR, 0.57 [95% CI, 0.24-1.35]) and among prevalent users (0.08% vs 0.09%; adjusted HR, 0.97 [95% CI, 0.54-1.73]). Results were consistent after the introduction of fentanyl and across patient subgroups and sensitivity analyses., Conclusions and Relevance: Receipt of methadone was associated with a lower risk of treatment discontinuation compared with buprenorphine/naloxone. The risk of mortality while receiving treatment was similar for buprenorphine/naloxone and methadone, although the CI estimate for the hazard ratio was wide.

Importance: There is uncertainty as to whether treatment of subclinical hypothyroidism (SCH) is associated with cardiovascular outcomes. Objectives: To determine whether levothyroxine replacement therapy decreases the risk of major adverse cardiovascular events (MACE) among individuals with SCH defined as having a thyrotropin (TSH) level between 5 and 10 mU/L. Design: We conducted a population-based cohort study using a prevalent new-user design. Setting: The study utilized data from the United Kingdom Clinical Practice Research Datalink. Participants: We identified a base cohort of individuals aged ≥18 years with incident SCH defined as having at least two TSH levels between 5 and 10 mU/L within one year between 1998 and 2018. We matched 76,946 levothyroxine treated to 76,946 untreated individuals based on age, sex, calendar time, duration of SCH, and time-conditional propensity score. We compared individuals with SCH treated with levothyroxine with individuals with no treatment. Exposure: Levothyroxine treatment versus no treatment. Main Outcome Measures: The primary outcome, MACE, was defined as a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, and cardiovascular-related mortality. Results: The mean age of the study cohort was 62.8 years, and 76.5% were women. During a median follow-up time of 1.6 years (interquartile range: 0.5-4.2), the incidence rate for MACE among individuals treated with levothyroxine was 12.8 per 1000 person-years; confidence interval (CI): 12.2-13.3 and 13.9 per 1000 person-years; CI: 13.4-14.3 among nontreated individuals. Levothyroxine treatment was associated with a small decreased risk of MACE (hazard ratio: 0.88; CI: 0.83-0.93). Conclusions: Levothyroxine treatment of SCH was associated with a small decreased risk of MACE. However, given the observational nature of the study, residual confounding should be considered in the interpretation of this finding.

Real-world evidence (RWE) can complement and fill knowledge gaps from randomized controlled trials to assist in health-technology assessment (HTA) for regulatory decision-making. However, the generation of RWE is an intricate process with many sequential decision points, and different methods and approaches may impact the quality and reliability of evidence. Standardization and transparency in reporting these decisions is imperative to appraise RWE and incorporate it into HTA decision-making. A partnership between Canadian health system stakeholders, namely Health Canada and Canada's Drug Agency (formerly the Canadian Agency for Drugs and Technologies in Health (CADTH)), was established to develop a guidance for standardization of reporting of RWE for regulatory and HTA decision-making in Canada. In this article, we describe the methods to develop the Guidance for Reporting Real-World Evidence document and checklist for reporting RWE for regulatory and HTA decision-making in Canada. This guidance can be adapted for other jurisdictions and will have future extensions to incorporate emerging issues with RWE and HTA decision-making., (Copyright © 2024. Published by Elsevier Inc.)

Background: Following the mass recall of valsartan products with nitrosamine impurities in July 2018, the number of patients exposed to these products, the duration of exposure, and the potential for cancer remains unknown. Therefore, we assessed the extent and duration of use of valsartan products with a nitrosamine impurity in the United States, Canada, and Denmark., Methods: We conducted a retrospective cohort study using administrative healthcare data from the US FDA Sentinel System, four Canadian provinces that contribute to the Canadian Network for Observational Drug Effect Studies (CNODES), and the Danish National Prescription Registry. Patients, 18 years and older between May 2012 and December 2020 with a valsartan dispensing were identified in each database. Patients were followed from the date of valsartan dispensing until discontinuation. We defined four valsartan exposure categories based on nitrosamine impurity status; recalled generic products with confirmed NDMA/NDEA levels (recalled-tested); recalled generic products that were not tested (recalled); non-recalled generic and non-recalled branded products. In Denmark, the recalled-tested category was not included due to absence of testing data. The proportion and duration of use of valsartan episodes stratified by nitrosamine-impurity status was calculated., Results: We identified 3.3 and 2.8 million (United States) and 51.3 and 229 thousand (Canada) recalled-tested and recalled valsartan exposures. In Denmark, where valsartan exposure was generally low, there were 10 747 recalled exposures. Immediately after the recall notices were issued, there was increased rates of switching to a non-valsartan ARB. The mean duration of use of the recalled-tested products was 167 (±223.1) and 146 (±255.8) days in the United States and Canada respectively. For the recalled products, mean cumulative duration of use was 178 (±249.6), 269 (±397.3) and 166 (±251.0) days in the United States, Canada, and Denmark, respectively., Conclusion: In this cohort study, despite widespread use of recalled generic valsartan between 2012 and 2018, the duration of use was relatively short and probably did not pose an elevated risk of nitrosamine-induced cancer. However, since products with nitrosamine impurity could have been on the market over a 6-year period, patients exposed to these products for longer durations could have a potentially different risk of cancer., (© 2024 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

External validity is an important part of epidemiologic research. To validly estimate effects in specific external target populations using a chosen effect measure (ie, "transport"), some methods require that one account for all effect measure modifiers (EMMs). However, little is known about how including other variables that are not EMMs (ie, non-EMMs) in adjustment sets affects estimates. Using simulations, we evaluated how inclusion of non-EMMs affected estimation of the transported risk difference (RD) by assessing the impacts of covariates that (1) differ (or not) between the trial and the target, (2) are associated with the outcome (or not), and (3) modify the RD (or not). We assessed variation and bias when covariates with each possible combination of these factors were used to transport RDs using outcome modeling or inverse odds weighting. Inclusion of variables that differed in distribution between the populations but were non-EMMs reduced precision, regardless of whether they were associated with the outcome. However, non-EMMs associated with selection did not amplify bias resulting from omission of necessary EMMs. Including all variables associated with the outcome may result in unnecessarily imprecise estimates when estimating treatment effects in external target populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women., Objective: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data., Methods: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI)., Results: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56)., Conclusions: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Aim: Fluoroquinolone-related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population-based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas., Materials and Methods: Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second-generation sulphonylureas (1998-2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent-to-treat exposure definition, we assessed the 30-day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin., Results: Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91-1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41-5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79-1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin., Conclusions: In patients using second-generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)