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1.
Europace ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227165

RESUMO

AIMS: Randomized trials suggest reductions in all-cause mortality and heart failure (HF) rehospitalizations with catheter ablation (CA) in patients with atrial fibrillation (AF) and HF. Whether these results can be replicated in a real-world population with long-term follow-up or varies over time is unknown. We sought to evaluate the long-term effectiveness of CA in reducing the incidence of all-cause mortality, HF hospitalizations, stroke, and major bleeding in AF-HF patients. METHODS AND RESULTS: In a cohort of patients newly diagnosed with AF-HF in Quebec, Canada (2000-2017), CA patients were matched 1:2 to controls on time and frequency of hospitalizations. Confounders were controlled for using inverse probability of treatment weighting. Multivariable Cox models adjusted for the presence of cardiac electronic implantable devices and medication use during follow-up, and the effect of time since CA was modelled with B-splines. For non-fatal outcomes, the Lunn-McNeil approach was used to account for the competing risk of death. Among 101 933 AF-HF patients, 451 underwent CA and were matched to 899 controls. Over a median follow-up of 3.8 years, CA was associated with a statistically significant reduction in all-cause mortality [hazard ratio 0.4 (95% confidence interval 0.2-0.7)], but no difference in stroke or major bleeding. The hazard of HF rehospitalization for CA patients, relative to non-CA patients, varied with time since CA (P = 0.01), with a reduction in HF rehospitalizations until approximately 3 years post-CA. CONCLUSION: Compared with matched non-CA patients, CA was associated with a long-term reduction in all-cause mortality and a reduction in HF rehospitalizations until 3 years post-CA.

3.
Biom J ; 62(2): 492-515, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32022299

RESUMO

Many flexible extensions of the Cox proportional hazards model incorporate time-dependent (TD) and/or nonlinear (NL) effects of time-invariant covariates. In contrast, little attention has been given to the assessment of such effects for continuous time-varying covariates (TVCs). We propose a flexible regression B-spline-based model for TD and NL effects of a TVC. To account for sparse TVC measurements, we added to this model the effect of time elapsed since last observation (TEL), which acts as an effect modifier. TD, NL, and TEL effects are estimated with the iterative alternative conditional estimation algorithm. Furthermore, a simulation extrapolation (SIMEX)-like procedure was adapted to correct the estimated effects for random measurement errors in the observed TVC values. In simulations, TD and NL estimates were unbiased if the TVC was measured with a high frequency. With sparse measurements, the strength of the effects was underestimated but the TEL estimate helped reduce the bias, whereas SIMEX helped further to correct for bias toward the null due to "white noise" measurement errors. We reassessed the effects of systolic blood pressure (SBP) and total cholesterol, measured at two-year intervals, on cardiovascular risks in women participating in the Framingham Heart Study. Accounting for TD effects of SBP, cholesterol and age, the NL effect of cholesterol, and the TEL effect of SBP improved substantially the model's fit to data. Flexible estimates yielded clinically important insights regarding the role of these risk factors. These results illustrate the advantages of flexible modeling of TVC effects.

4.
J Am Heart Assoc ; 9(1): e012940, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31902326

RESUMO

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

5.
Int J Cancer ; 146(7): 1800-1809, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199510

RESUMO

Results of epidemiologic studies of physical activity and ovarian cancer risk are inconsistent. Few have attempted to measure physical activity over the lifetime or in specific age windows, which may better capture etiologically relevant exposures. We examined participation in moderate-to-vigorous recreational physical activity (MVPA) in relation to ovarian cancer risk. In a population-based case-control study conducted in Montreal, Canada from 2011 to 2016 (485 cases and 887 controls), information was collected on lifetime participation in various recreational physical activities, which was used to estimate MVPA for each participant. MVPA was represented as average energy expenditure over the lifetime and in specific age-periods in units of metabolic equivalents (METs)-hours per week. Odds ratios (OR) and 95% confidence intervals (CI) for the relation between average MVPA and ovarian cancer risk were estimated using multivariable logistic regression models. Confounding was assessed using directed acyclic graphs combined with a change-in-estimate approach. The adjusted OR (95% CI) for each 28.5 MET-hr/week increment of lifetime recreational MVPA was 1.11 (0.99-1.24) for ovarian cancer overall. ORs for individual age-periods were weaker. When examined by menopausal status, the OR (95% CI) for lifetime MVPA was 1.21 (1.00-1.45) for those diagnosed before menopause and 1.04 (0.89-1.21) for those diagnosed postmenopausally. The suggestive positive associations were stronger for invasive ovarian cancers and more specifically for high-grade serous carcinomas. These results do not support a reduced ovarian cancer risk associated with MVPA.


Assuntos
Exercício , Atividades de Lazer , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco , Fatores de Risco , Adulto Jovem
6.
J Cardiovasc Electrophysiol ; 30(12): 2678-2685, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31578788

RESUMO

INTRODUCTION: Catheter ablation (CA) has been increasingly used to treat atrial fibrillation (AF) in patients with heart failure (HF), however, its safety at the population-level has not yet been evaluated. To assess the safety of CA in AF-HF patients, the frequency and potential risk factors for adverse events (AEs) within 30 days post-CA were determined. METHODS: A population-based cohort of AF-HF patients who underwent CA in Quebec, Canada (2000-2017) was constructed using administrative databases. Major AEs included all-cause mortality, cerebrovascular accident (CVA), pericardial effusion requiring drainage (PERD), vascular AEs, hemorrhage/hematoma, and pulmonary embolism. Univariate logistic regression models were employed to assess potential risk factors for major AEs. RESULTS: Of 700 AF-HF patients who underwent CA (median age 64.5 years [interquartile range, IQR, 56.2-71.0], 22.0% female, and median CHA2 DS2 -Vasc 3 [IQR, 2-4]), 14 (2.0%) patients developed 16 major AEs within 30 days of CA. Hemorrhage/hematoma was the most frequent major AE (four patients; 0.6%) followed by all-cause mortality, CVA/TIA, PERD, and vascular AEs (three patients each; 0.4%). Coronary artery disease (odds ratio [OR], 3.9 [95% confidence interval, CI, 1.2-12.3]) and age ≥65 years (OR, 3.1 [95% CI, 1.1-9.8]) were identified predictors for the composite outcome of major AEs. More than half of the patients (57.2%) underwent a second CA within a median of 0.8 (IQR, 0.2-2.2) years from the date of first CA. CONCLUSION: CA performed in the AF-HF population portends a relatively low incidence of major AEs. A larger study is required to determine whether certain patient factors are independently associated with a higher risk of post-CA AEs.

7.
JAMA Netw Open ; 2(9): e1910756, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539073

RESUMO

Importance: Adverse drug events (ADEs) account for up to 16% of emergency department (ED) visits and 7% of hospital admissions. Medication reconciliation is required for hospital accreditation because it can reduce medication discrepancies, but there is no evidence that reducing discrepancies reduces ADEs or other adverse outcomes. Objective: To evaluate whether electronic medication reconciliation reduces ADEs, medication discrepancies, and other adverse outcomes compared with usual care. Design, Setting, and Participants: This cluster randomized trial involved 3491 patients who were discharged from 2 medical units and 2 surgical units at the McGill University Health Centre, Montreal, Quebec, Canada, between October 2014 and November 2016. Data analysis took place from July 2017 to July 2019. Intervention: The RightRx intervention electronically retrieved community drugs from the provincial insurer and aligned them with in-hospital drugs to facilitate reconciliation and communication at care transitions. Main Outcomes and Measures: The primary outcome was ADEs in 30 days after discharge. Secondary outcomes included medication discrepancies, ED visits, hospital readmissions, and a composite outcome of ED visits, readmissions, and death up to 90 days after discharge. Results: Of 4656 eligible patients, 3567 (76.6%) consented to participate (2060 [57.8%] men; mean [SD] age, 69.8 [14.9] years). Overall, 76 patients died during the hospital stay, so 3491 patients were included in the analysis. There was no significant difference in the risk of ADEs between intervention and control groups (76 [4.6%] vs 73 [4.0%]; OR, 0.97; 95% CI, 0.33-1.48), ED visits (433 [26.2%] vs 488 [26.6%]; OR, 0.83; 95% CI, 0.36-1.42), hospital readmission (170 [10.3%] vs 261 [14.2%]; OR, 0.22; 95% CI, 0.06-1.14), or the composite outcome (447 [27.0%] vs 506 [27.6%]; OR, 0.75; 95% CI, 0.34-1.27) at 30 days. Medication discrepancies were significantly reduced in the intervention group compared with the control group (437 [26.4%] vs 1029 [56.0%]; OR, 0.24; 95% CI, 0.12-0.57). Changes made to community medications (OR, 1.05; 95% CI, 1.01-1.10) and new medications (OR, 1.09; 95% CI, 1.01-1.18) were significant risk factors for ADEs. Conclusions and Relevance: Electronic medication reconciliation reduced medication discrepancies but did not reduce ADEs or other adverse outcomes. Hospital accreditation should focus on interventions that reduce the risk of adverse events for patients with multiple changes to community medications. Trial Registration: ClinicalTrials.gov identifier: NCT01179867.

8.
Am J Epidemiol ; 188(8): 1552-1562, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31107497

RESUMO

Adults with congenital heart disease are increasingly being exposed to low-dose ionizing radiation (LDIR) from cardiac procedures. In a recent study, Cohen et al. (Circulation. 2018;137(13):1334-1345) reported an association between increased LDIR exposure and cancer incidence but did not explore temporal relationships. Yet, the impact of past exposures probably accumulates over years, and its strength may depend on the amount of time elapsed since exposure. Furthermore, LDIR procedures performed shortly before a cancer diagnosis may have been ordered because of early symptoms of cancer, raising concerns about reversal causality bias. To address these challenges, we combined flexible modeling of cumulative exposures with competing-risks methodology to estimate separate associations of time-varying LDIR exposure with cancer incidence and all-cause mortality. Among 24,833 patients from the Quebec Congenital Heart Disease Database, 602 had incident cancer and 500 died during a follow-up period of up to 15 years (1995-2010). Initial results suggested a strong association of cancer incidence with very recent LDIR exposures, likely reflecting reverse causality bias. When exposure was lagged by 2 years, an increased cumulative LDIR dose from the previous 2-6 years was associated with increased cancer incidence, with a stronger association for women. These results illustrate the importance of accurate modeling of temporal relationships between time-varying exposures and health outcomes.

9.
J Manag Care Spec Pharm ; 25(6): 697-704, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31134863

RESUMO

BACKGROUND: The treatment for hepatitis C virus (HCV) infection has evolved over time, and direct-acting antivirals (DAA) have revolutionized HCV therapy. OBJECTIVES: To (a) assess early treatment discontinuation and (b) identify predictors of early discontinuation in a cohort of patients receiving second-generation DAAs. METHODS: We identified HCV patients newly prescribed simeprevir/sofosbuvir (SIM/SOF), ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD), sofosbuvir/velpatasvir (SOF/VEL), elbasvir/grazoprevir (EBR/GZR), and glecaprevir/pibrentasvir (GLE/PIB) between 2014 and 2017. Early discontinuation was defined as duration of therapy less than 8 weeks. Multivariable logistic regression was performed to evaluate the association of drug regimens and potential predictive factors to early discontinuation. RESULTS: We identified 26,098 DAA-treated patients: 67.8% with LDV/SOF, 9.9% with OPrD, 8.5% with SIM/SOF, 7.8% with SOF/VEL, 5.2% with EBR/GZR, and 0.8% with GLE/PIB. With approval of new therapies in 2016 and 2017, use of OPrD, LDV/SOF, and SIM/SOF declined substantially. At baseline, there was some heterogeneity of past HCV drug use and comorbidity across groups; patients on SIM/SOF had the highest frequency of previous interferon, cirrhosis, and decompensated cirrhosis. Most HCV patients received therapy for 8-12 weeks; fewer patients went through 16-week and 24-week therapy courses. Early discontinuation rates (95% CI) were 7.1% (6.0-8.2) for SIM/SOF, 3.2% (2.9-3.5) for LDV/SOF, 9.6% (8.5-10.7) for OPrD, 3.1% (2.3-3.8) for SOF/VEL, 4.2% (3.1-5.3) for EBR/GZR, and 2.5% (0.3-4.7) for GLE/PIB. In multivariable analyses, versus OPrD, patients starting other drug regimens were less likely to discontinue therapy early. Early discontinuation was more common in women, patients with baseline anemia, and Medicare and Medicaid patients. CONCLUSIONS: These real-world data confirm low rates of early discontinuation in users of second-generation DAAs. Future research focusing on socio-economic and sex/gender issues may help further optimize care for patients with HCV. DISCLOSURES: This study was funded by the Canadian Institutes of Health Research. Klein has received grants for investigator-initiated trials from ViiV Healthcare, Janssen, Gilead, and Merck, as well as consulting fees from ViiV Healthcare, Merck, and AbbVie. Feld has received research support and/or scientific consulting fees from AbbVie, Contravir, Enanta, Gilead, Janssen, Merck, and Wako. All other authors have no conflicts of interest to declare. Results from this study were presented as a poster at the 34th International Conference of Phamacoepidemiology and Therapeutic Risk Management; August 22-26, 2018; Prague, Czech Republic.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Antivirais/farmacologia , Canadá , Combinação de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resposta Viral Sustentada
10.
Am J Med ; 132(10): 1216-1224.e5, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31145881

RESUMO

BACKGROUND: In-hospital medication reconciliation has not demonstrated reductions in adverse health outcomes, possibly because patients do not follow the changes made to their preadmission medications. Our objective was to determine the incidence of and variables associated with failure to follow newly prescribed therapies, discontinued medications, and dose changes. METHODS: A prospective cohort study of patients admitted to hospitals in Montreal, Quebec between 2014 and 2016 was conducted. Failure to follow medication changes 30 days post discharge was measured by comparing prescribed and dispensed medications. Multivariable logistic regression was used to determine characteristics associated with failure to follow changes. RESULTS: Among 2655 patients, mean age was 69.5 years (SD 14.7), and 1581 (60%) were males. There were 10,068 medication changes made at hospital discharge and 24% were not followed in the 30 days post discharge. Thirty percent of dose modifications were filled at the incorrect dose, 27% of new medications were not filled, and 12% of discontinued medications were filled. A number of factors increased the risk of failure to follow medication changes, including increasing out-of-pocket medication costs (adjusted odds ratio [aOR] 1.12; 95% confidence interval [CI], 1.07-1.18), discharge to long-term care facility (aOR 2.29; 95% CI, 1.63-3.08), and not having medications dispensed prior to admission (aOR 4.67; 95% CI, 3.75-5.90). CONCLUSION: One in 4 hospital medication changes was not followed post discharge. Health policy aimed at eliminating out-of-pocket medication costs and investigation of factors influencing failure to follow changes for those not dispensed medications prior to admission and for long-term care residents are important next steps to address this issue.

11.
Epidemiology ; 30(4): 521-531, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30985529

RESUMO

BACKGROUND: Super learning is an ensemble machine learning approach used increasingly as an alternative to classical prediction techniques. When implementing super learning, however, not tuning the hyperparameters of the algorithms in it may adversely affect the performance of the super learner. METHODS: In this case study, we used data from a Canadian electronic prescribing system to predict when primary care physicians prescribed antidepressants for indications other than depression. The analysis included 73,576 antidepressant prescriptions and 373 candidate predictors. We derived two super learners: one using tuned hyperparameter values for each machine learning algorithm identified through an iterative grid search procedure and the other using the default values. We compared the performance of the tuned super learner to that of the super learner using default values ("untuned") and a carefully constructed logistic regression model from a previous analysis. RESULTS: The tuned super learner had a scaled Brier score (R) of 0.322 (95% [confidence interval] CI = 0.267, 0.362). In comparison, the untuned super learner had a scaled Brier score of 0.309 (95% CI = 0.256, 0.353), corresponding to an efficiency loss of 4% (relative efficiency 0.96; 95% CI = 0.93, 0.99). The previously-derived logistic regression model had a scaled Brier score of 0.307 (95% CI = 0.245, 0.360), corresponding to an efficiency loss of 5% relative to the tuned super learner (relative efficiency 0.95; 95% CI = 0.88, 1.01). CONCLUSIONS: In this case study, hyperparameter tuning produced a super learner that performed slightly better than an untuned super learner. Tuning the hyperparameters of individual algorithms in a super learner may help optimize performance.

12.
Blood Cancer J ; 9(3): 28, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30820024

RESUMO

Since the publication of the original article the authors noticed the the affiliation details for Paresh Vyas are incorrect. The correct affiliation details for this author are given below.

13.
J Affect Disord ; 249: 371-377, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30818245

RESUMO

BACKGROUND: Recent studies show that paternal depression negatively impacts children's behavioral and emotional development. This study determined the prevalence of depressed mood in first-time fathers at 2 and 6 months postpartum and identified associated risk factors. METHODS: A prospective cohort study with 622 men who completed sociodemographic and psychosocial questionnaires during their partner's third trimester of pregnancy. Fathers completed measures again at 2 and 6 months postpartum and partners completed the depressed mood measure at all three timepoints. A cutoff of ≥10 for the Edinburgh Postnatal Depression Scale identified depressed mood status. RESULTS: The prevalence of depressive symptoms in fathers was 13.76% at 2 months and 13.60% at 6 months postpartum. Men who were depressed during their partner's pregnancy were 7 times more likely to be depressed at 2 months postpartum. Depressed mood status at both the antenatal and 2 month postpartum assessment was associated with increased risk of depressed mood at 6 months postpartum. Older age, poor sleep quality at study entry, worse couple adjustment, having a partner experiencing antenatal depressive symptoms and elevated parental stress were associated with depressive symptoms at 2 months postpartum. Poor sleep quality, financial stress and a decline in couple adjustment were independently associated to depressive symptoms at 6 months postpartum. LIMITATIONS: This sample was fairly well-educated and predominately middle-class. Depressive symptoms were assessed using a self-report questionnaire. CONCLUSIONS: The psychosocial risk factors identified provide opportunities for early screening and targeted prevention strategies for fathers at risk for depression during the transition to parenthood.


Assuntos
Depressão Pós-Parto/psicologia , Depressão/psicologia , Relações Pai-Filho , Pai/psicologia , Poder Familiar/psicologia , Período Pós-Parto/psicologia , Adulto , Emoções , Feminino , Humanos , Masculino , Gravidez , Prevalência , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Fatores de Risco , Autorrelato , Inquéritos e Questionários
14.
BMC Med Res Methodol ; 19(1): 46, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841848

RESUMO

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


Assuntos
Algoritmos , Bioestatística/métodos , Modelos Teóricos , Linguagens de Programação , Projetos de Pesquisa , Interpretação Estatística de Dados , Humanos , Computação Matemática
15.
CMAJ ; 191(7): E179-E187, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782643

RESUMO

BACKGROUND: While topical azoles are the first-line treatment for fungal infections, oral fluconazole is frequently used during pregnancy. We aimed to assess the effect of exposure to low and high doses of fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. METHODS: Within the Quebec Pregnancy Cohort (1998-2015), we identified women exposed to low- (≤ 150 mg) and high-dose (> 150 mg) fluconazole, and women who were not exposed. For each case of spontaneous abortion or stillbirth, up to 5 controls were randomly selected using an incidence density sampling method matched on gestational age at diagnosis of spontaneous abortion or stillbirth (index date) and the year of the last menstrual period. For cases of major congenital malformation, we considered all liveborn babies as controls. Generalized estimation equation models were used to analyze the 3 main outcomes separately. RESULTS: Within a cohort of 441 949 pregnancies, 320 868 pregnancies were included in the analyses of spontaneous abortions, 226 599 of major congenital malformations and 7832 of stillbirths. Most (69.5%) women exposed to fluconazole in pregnancy received the common single therapeutic dose of 150 mg (low dose); the remainder received a dose of > 150 mg (high dose). Use of oral fluconazole during early pregnancy was associated with an increased risk of spontaneous abortion compared with no exposure (adjusted odds ratio [OR] for 345 cases exposed to low-dose treatment 2.23, 95% confidence interval [CI] 1.96-2.54; adjusted OR for 249 cases exposed to high-dose treatment 3.20, 95% CI 2.73-3.75). Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR 1.81, 95% CI 1.04-3.14; 13 exposed cases) compared with no exposure. No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth. INTERPRETATION: Any maternal exposure to fluconazole during pregnancy may increase risk of spontaneous abortion and doses higher than 150 mg during the first trimester may increase risk of cardiac septal closure anomalies.


Assuntos
Aborto Espontâneo/induzido quimicamente , Antifúngicos/efeitos adversos , Fluconazol/efeitos adversos , Defeitos dos Septos Cardíacos/induzido quimicamente , Exposição Materna/efeitos adversos , Natimorto/epidemiologia , Aborto Espontâneo/epidemiologia , Administração Oral , Adolescente , Adulto , Antifúngicos/administração & dosagem , Candidíase Vulvovaginal/tratamento farmacológico , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Fluconazol/administração & dosagem , Idade Gestacional , Defeitos dos Septos Cardíacos/epidemiologia , Humanos , Modelos Logísticos , Análise Multivariada , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Primeiro Trimestre da Gravidez , Quebeque/epidemiologia , Adulto Jovem
16.
Am J Epidemiol ; 188(6): 1181-1191, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649165

RESUMO

Correct specification of the exposure model is essential for unbiased estimation in marginal structural models with inverse-probability-of-treatment weights. However, although flexible modeling is commonplace when estimating effects of continuous covariates in outcome models, its use is less frequent in estimation of inverse probability weights. Using simulations, we assess the accuracy of the treatment effect estimates and covariate balance obtained with different exposure model specifications when the true relationship between a continuous, possibly time-varying covariate Lt and the logit of the probability of exposure is nonlinear. Specifically, we compare 4 approaches to modeling the effect of Lt when estimating inverse probability weights: a linear function, the covariate-balancing propensity score, and 2 easy-to-implement flexible methods that relax the assumption of linearity: cubic regression splines and fractional polynomials. Using data from 2 empirical studies, we compare linear exposure models with flexible exposure models to estimate the effect of sustained virological response to hepatitis C virus treatment on the progression of liver fibrosis. Our simulation results demonstrate that ignoring important nonlinear relationships when fitting the exposure model may provide poorer covariate balance and induce substantial bias in the estimated exposure-outcome associations. Analysts should routinely consider flexible modeling of continuous covariates when estimating inverse-probability-of-treatment weights.


Assuntos
Interpretação Estatística de Dados , Métodos Epidemiológicos , Modelos Estatísticos , Causalidade , Simulação por Computador , Progressão da Doença , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Cirrose Hepática/etiologia , Estudos Longitudinais
17.
J Rheumatol ; 46(2): 166-175, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30219771

RESUMO

OBJECTIVE: Persistent systemic lupus erythematosus (SLE) disease activity is associated with increased morbidity and mortality. In a multicenter cohort of patients with prevalent SLE, we described persistence, patterns, and predictors of change in disease activity over time. METHODS: Based on SLE Disease Activity Index (SLEDAI)-2K scores at cohort entry, patients were classified into 4 groups: low (score < 4; LOW), moderate (4 to < 6; MOD), moderately high (6 to ≤ 10; MHIGH), and very high (> 10; VHIGH). Multivariable linear and longitudinal mixed linear regression models were used to identify predictors of change over time in SLEDAI-2K. RESULTS: There were 2019 participants, with declining followup data over 5 years (1326, 580, 274, 186, and 148 patients, respectively). At cohort entry, mean (± SD) age was 42 (± 17) years, disease duration 11 (± 10) years, and 90% were female. The 4 groups included 44% LOW (n = 891), 20% MOD (n = 400), 22% MHIGH (n = 442), and 14% VHIGH (n = 286); therefore, 36% had clinically important SLE activity. The proportion of patients in the LOW group at entry who moved to a higher activity level varied from 30% (167/557) at 1 year, to 49% (41/83) at 3 years, and 54% (30/56) at 5 years. Among 181 patients with MOD to VHIGH entry activity and 3 years of followup, 116 (64.1%) remained active. In all analyses, only higher SLEDAI-2K at cohort entry remained a significant predictor of higher SLEDAI-2K in subsequent years. CONCLUSION: Higher SLEDAI-2K at study entry was the single major independent predictor of higher SLEDAI-2K over time, reflecting frequent persistence of active disease, even in patients with longstanding disease. This highlights gaps in the optimal treatment of SLE.

18.
Int J Obes (Lond) ; 43(6): 1223-1230, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30206338

RESUMO

OBJECTIVE: Life-long maintenance of brain health is important for the prevention of cognitive impairment in older age. Low-grade peripheral inflammation associated with excess visceral fat (VF) may influence brain structure and function. Here we examined (i) if this type of inflammation is associated with altered white-matter (WM) microstructure and lower cognitive functioning in adolescents, and (ii) if recently identified circulating glycerophosphocholines (GPCs) can index this type of inflammation and associated variations in WM microstructure and cognitive functioning. SUBJECTS: We studied a community-based sample of 872 adolescents (12-18 years, 48% males) in whom we assessed VF and WM microstructure with magnetic resonance imaging, processing speed with cognitive testing, serum C-reactive protein (CRP, a common marker of peripheral inflammation) with a high-sensitivity assay, and serum levels of a panel of 64 GPCs with advanced mass spectrometry. RESULTS: VF was associated with CRP, and CRP in turn was associated with "altered" WM microstructure and lower processing speed (all p < 0.003). Further, "altered" WM microstructure was associated with lower processing speed (p < 0.0001). Of all 64 tested GPCs, 4 were associated with both VF and CRP (at Bonferroni corrected p < 0.0004). One of them, PC16:0/2:0, was also associated with WM microstructure (p < 0.0001) and processing speed (p = 0.0003), and mediated the directed associations between VF and both WM microstructure (p < 0.0001) and processing speed (p = 0.02). As a mediator, PC16:0/2:0 explained 21% of shared variance between VF and WM microstructure, and 22% of shared variance between VF and processing speed. Similar associations were observed in an auxiliary study of 80 middle-aged adults. CONCLUSIONS: Our results show that VF-related peripheral inflammation is associated with "altered" WM microstructure and lower cognitive functioning already in adolescents, and a specific circulating GPC may be a new molecule indexing this VF-related peripheral inflammation and its influences on brain structure and function.

19.
Pharmacoepidemiol Drug Saf ; 28(2): 179-186, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30264875

RESUMO

PURPOSE: To quantify misclassification in glucocorticoid (GC) exposure defined using UK primary care prescription data. METHODS: A cross-sectional study including patients with rheumatoid arthritis prescribed oral GCs in the past 2 years. Glucocorticoid exposure based on electronic prescription records was compared with participant-reported GC use captured using a paper diary. Prescription data (containing information about prescriptions issued but no dispensing information) was provided by the Clinical Practice Research Datalink. The following variables were defined: current use and dose of oral GCs and if (and when) participants had received a GC injection. For oral GCs, self-reported use was taken to represent "true" exposure. A dataset representing a hypothetical population was generated to assess the impact of the misclassification found for current use. RESULTS: A total of 67 of 78 study participants (86%) were correctly classified as currently on/off oral GCs; 32/38 (84.2%) participants reporting current GC use and 35/40 (87.5%) participants not reporting current use were correctly classified. Estimated values of current dose were imprecise (correlation coefficient 0.46). Concordance between reported and prescribed GC injections was poor (kappa statistic 0.14). Misclassification bias was demonstrated in the hypothetical population: For "true" relative risks of 1.5, 4, and 9, the "observed" relative risks were 1.33, 2.48, and 3.58, respectively. CONCLUSIONS: Misclassification of current use of oral GCs was low but sufficient to lead to significant bias. Researchers should take care to assess the likely impact of exposure misclassification on their analyses.

20.
Arthritis Care Res (Hoboken) ; 71(5): 602-610, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29047218

RESUMO

OBJECTIVE: Studies have demonstrated a link between chronic obstructive pulmonary disease (COPD) and inflammation, raising the question whether chronic inflammatory conditions, such as rheumatoid arthritis (RA), predispose to COPD. Our objective was to evaluate the risk of incident COPD hospitalization in RA compared to the general population. METHODS: We studied a population-based incident RA cohort with matched general population controls, using administrative health data. All incident RA cases in British Columbia who first met RA definition between January 1996 and December 2006 were selected using previously published criteria. General population controls were randomly selected, matched 1:1 to RA cases on birth year, sex, and index year. COPD outcome was defined as hospitalization with a primary COPD code. Incidence rates, 95% confidence intervals (95% CIs), and incidence rate ratios (IRRs) were calculated for RA and controls. Multivariable Cox proportional hazards models estimated the risk of COPD in RA compared to the general population after adjusting for potential confounders. Sensitivity analyses were performed to test the robustness of the results to the possible confounding effect of smoking, unavailable in administrative data, and to COPD outcome definitions. RESULTS: The cohorts included 24,625 RA individuals and 25,396 controls. The incidence of COPD hospitalization was greater in RA than controls (IRR 1.58, 95% CI 1.34-1.87). After adjusting for potential confounders, RA cases had a 47% greater risk of COPD hospitalization than controls. The increased risk remained significant after modeling for smoking and with varying COPD definitions. CONCLUSION: In our population-based cohort, individuals with RA had a 47% greater risk of COPD hospitalization compared to the general population.


Assuntos
Artrite Reumatoide/complicações , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Colúmbia Britânica/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologia , Estudos Retrospectivos , Medição de Risco
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