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From 19 to 22 June 2013, intense rainfall and concurrent snowmelt led to devastating floods in the Canadian Rockies, foothills and downstream areas of southern Alberta and southeastern British Columbia, Canada. Such an event is typical of late-spring floods in cold-region mountain headwater, combining intense precipitation with rapid melting of late-lying snowpack, and represents a challenge for hydrological forecasting systems. This study investigated the factors governing the ability to predict such an event. Three sources of uncertainty, other than the hydrological model processes and parameters, were considered: (i) the resolution of the atmospheric forcings, (ii) the snow and soil moisture initial conditions (ICs) and (iii) the representation of the soil texture. The Global Environmental Multiscale hydrological modeling platform (GEM-Hydro), running at a 1 km grid spacing, was used to simulate hydrometeorological conditions in the main headwater basins of southern Alberta during this event. The GEM atmospheric model and the Canadian Precipitation Analysis (CaPA) system were combined to generate atmospheric forcing at 10, 2.5 and 1 km over southern Alberta. Gridded estimates of snow water equivalent (SWE) from the Snow Data Assimilation System (SNODAS) were used to replace the model SWE at peak snow accumulation and generate alternative snow and soil moisture ICs before the event. Two global soil texture datasets were also used. Overall 12 simulations of the flooding event were carried out. Results show that the resolution of the atmospheric forcing affected primarily the flood volume and peak flow in all river basins due to a more accurate estimation of intensity and total amount of precipitation during the flooding event provided by CaPA analysis at convection-permitting scales (2.5 and 1 km). Basin-averaged snowmelt also changed with the resolution due to changes in near-surface wind and resulting turbulent fluxes contributing to snowmelt. Snow ICs were the main sources of uncertainty for half of the headwater basins. Finally, the soil texture had less impact and only affected peak flow magnitude and timing for some stations. These results highlight the need to combine atmospheric forcing at convection-permitting scales with high-quality snow ICs to provide accurate streamflow predictions during late-spring floods in cold-region mountain river basins. The predictive improvement by inclusion of high-elevation weather stations in the precipitation analysis and the need for accurate mountain snow information suggest the necessity of integrated observation and prediction systems for forecasting extreme events in mountain river basins.

Abstract Background Few epidemiologic findings are as well established as the association between smoking and lung cancer. It is therefore somewhat surprising that there is not yet a clear consensus about the exposure-response relationships between various metrics of smoking and lung cancer risk. In part this is due to heterogeneity of how exposure-response results have been presented and the relative paucity of published results using any particular metric of exposure. The purposes of this study are: to provide new data on smoking-lung cancer associations and to explore the relative impact of different dimensions of smoking history on lung cancer risk. Methods Based on a large lung cancer case-control study (1203 cases and 1513 controls) conducted in Montreal in 1996–2000, we estimated the lifetime prevalence of smoking and odds ratios in relation to several smoking metrics, both categorical and continuous based on multivariable unconditional logistic regression. Results Odds ratios (ORs) for ever vs never smoking were 7.82 among males and 11.76 among females. ORs increased sharply with every metric of smoking examined, more so for duration than for daily intensity. In models using continuous smoking variables, all metrics had strong effects on OR and mutual adjustment among smoking metrics did not noticeably attenuate the OR estimates, indicating that each metric carries some independent risk-related information. Among all the models tested, the one based on a smoking index that integrates several smoking dimensions, provided the best fitting model. Similar patterns were observed for the different histologic types of lung cancer. Conclusions This study provides many estimates of exposure-response relationships between smoking and lung cancer; these can be used in future meta-analyses. Irrespective of the histologic type of lung cancer and the smoking metric examined, high levels of smoking led to high levels of risk, for both men and women.

This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents.

Background. The aim of the study was to assess the accuracy of the colorectal-cancer incidence estimated from administrative data. Methods. We selected potential incident colorectal-cancer cases in 2004-2005 French administrative data, using two alternative algorithms. The first was based only on diagnostic and procedure codes, whereas the second considered the past history of the patient. Results of both methods were assessed against two corresponding local cancer registries, acting as “gold standards.” We then constructed a multivariable regression model to estimate the corrected total number of incident colorectal-cancer cases from the whole national administrative database. Results. The first algorithm provided an estimated local incidence very close to that given by the regional registries (646 versus 645 incident cases) and had good sensitivity and positive predictive values (about 75% for both). The second algorithm overestimated the incidence by about 50% and had a poor positive predictive value of about 60%. The estimation of national incidence obtained by the first algorithm differed from that observed in 14 registries by only 2.34%. Conclusion. This study shows the usefulness of administrative databases for countries with no national cancer registry and suggests a method for correcting the estimates provided by these data.

Information on the distribution of lag duration between exposure or intervention and the subsequent changes in risk can help in assessing the impact of exposure, predicting cost-effectiveness of intervention, and understanding the underlying biological mechanisms. Previous approaches focused more on optimizing the strength of the exposure–disease association than on directly estimating lag duration. We propose an alternative approach applicable to the analysis of the lagged effects of binary exposure variables. The density function of the distribution of lags is estimated based on flexible modelling of changes in hazard ratio of exposed versus unexposed subjects. The methodology is evaluated in a simulation study and is applied to the Framingham data to investigate the lagged effect of smoking cessation on coronary heart disease risk. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Excess body fatness in late adulthood has been observed to increase ovarian cancer risk, but the association is relatively weak. Body fatness can change over time, and timing may differently influence risk. We used a life course epidemiology approach to identify whether the relation between body fatness and ovarian cancer risk is best described by a critical period, accumulation or sensitive period hypothesis. In a population-based case-control study of ovarian cancer in Montreal, Canada (2011-16), data on body mass index (BMI) at each decade starting at age 20 was available. Among 363 cases and 707 controls aged ≥ 50 years, we used a Bayesian relevant life course exposure model to estimate the relative importance of BMI for three pre-specified periods across the adult life course, i.e., early childbearing years, late childbearing years, and peri/postmenopause, on ovarian cancer risk. The accumulation hypothesis best described BMI in relation to ovarian cancer overall, with an odds ratio (OR) for the lifetime effect of BMI (per 5 kg/m 2 increase) of 1.10 (95% credible interval [CrI]: 0.90-1.35). For invasive ovarian cancer, the OR (95% CrI) for the lifetime effect was 1.16 (0.92-1.48), with BMI during early childbearing years showing the highest relative importance, suggesting this may be a sensitive period. For borderline cancer, the lifetime effect OR was not strongly supportive of an association (OR: 0.90, 95% CrI: 0.53-1.32). The results suggest that a sensitive period of early childbearing years is a candidate hypothesis for further investigation., (© 2024. Springer Nature B.V.)

The evidence from previous studies of serum 25-hydroxyvitamin D (25(OH)D) and ovarian cancer risk is not conclusive. However, the 25(OH)D levels were generally only measured in late adulthood, which may not capture the etiologically relevant exposure periods. We investigated predicted 25(OH)D over the adult lifetime in relation to ovarian cancer risk in a population-based case-control study conducted from 2011 to 2016 in Montreal, Canada (n = 490 cases and 896 controls). Predicted 25(OH)D was computed using previously validated regression models. Unconditional multivariable logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% CIs for average predicted 25(OH)D over the adult lifetime and ovarian cancer risk. In addition, the relative importance of different periods of past 25(OH)D exposure was explored using a weighted cumulative exposure (WCE) model. For each 20-nmol/L increase in average predicted 25(OH)D over the adult lifetime, the aOR (95% CI) was 0.73 (0.55-0.96). In WCE analyses, the inverse association was strongest for exposures 5 to 20 years and 35 to 55 years prior to diagnosis, with aORs (95% CIs) of 0.82 (0.69-0.94) and 0.79 (0.66-1.02), respectively, for each 20-nmol/L increase in predicted 25(OH)D. These results support an inverse association between 25(OH)D levels in adulthood and ovarian cancer risk. This article is part of a Special Collection on Gynecological Cancers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality., Methods: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality., Results: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results., Conclusion: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Quantitative bias analysis (QBA) permits assessment of the expected impact of various imperfections of the available data on the results and conclusions of a particular real-world study. This article extends QBA methodology to multivariable time-to-event analyses with right-censored endpoints, possibly including time-varying exposures or covariates. The proposed approach employs data-driven simulations, which preserve important features of the data at hand while offering flexibility in controlling the parameters and assumptions that may affect the results. First, the steps required to perform data-driven simulations are described, and then two examples of real-world time-to-event analyses illustrate their implementation and the insights they may offer. The first example focuses on the omission of an important time-invariant predictor of the outcome in a prognostic study of cancer mortality, and permits separating the expected impact of confounding bias from non-collapsibility. The second example assesses how imprecise timing of an interval-censored event - ascertained only at sparse times of clinic visits - affects its estimated association with a time-varying drug exposure. The simulation results also provide a basis for comparing the performance of two alternative strategies for imputing the unknown event times in this setting. The R scripts that permit the reproduction of our examples are provided., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the association between childhood body fatness and epithelial ovarian cancer (EOC), and whether this association differs by type of EOC., Methods: Using data from a population-based case-control study (497 cases and 902 controls) in Montreal, Canada conducted 2011-2016, we examined the association between childhood body fatness and EOC, overall and separately for invasive vs. borderline EOCs. A figure rating scale was used to measure body fatness at ages 5 and 10. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Quantitative bias analyses were conducted to assess the impact of exposure misclassification and non-participation., Results: The aOR (95% CI) of overall EOC for high vs. low body fatness was 1.07 (0.85-1.34) at age 5 and 1.28 (0.98-1.68) at age 10. The associations were stronger for invasive EOC, specifically the endometrioid histological type. For borderline cancers, the aORs were below the null value with wide confidence intervals. Bias analyses did not reveal a strong influence of non-participation. Non-differential exposure misclassification may have biased aORs towards the null for invasive cancers but did not appear to have an appreciable influence on the aORs for borderline cancers., Conclusions: Childhood body fatness may be a risk factor for invasive EOC in later adult life. Our study highlights the potential importance of examining early life factors for a comprehensive understanding of EOC development., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Hydrochlorothiazide (HCTZ), a widely prescribed antihypertensive drug with photosensitising properties, has been linked with non-melanoma skin cancer (NMSC) risk. However, previous analyses did not fully explore if and how the impact of past HCTZ exposures accumulates with prolonged use and/or depends on time elapsed since exposures. Therefore, we used different models to more comprehensively assess how NMSC risk vary with HCTZ exposure, and explore how the results may depend on modeling strategies., Methods: We used different parametric models with alternative time-varying exposure metrics, and the flexible weighted cumulative exposure model (WCE) to estimate associations between HCTZ exposures and NMSC risk in a population-based cohort of HCTZ users over 65 years old, in the province of Ontario, Canada., Results: Among 3844 HCTZ users, 273 developed NMSC during up to 8 years of follow-up. In parametric models, based on all exposures, increased duration of past HCTZ use was associated with an increase of NMSC risk but cumulative dose showed no systematic association. Yet, WCE results suggested that only exposures taken 2.5-4 years in the past were associated with the current NMSC hazard. This finding led us to re-define the parametric models, which also confirmed that any HCTZ dose taken outside this time-window were not systematically associated with NMSC incidence., Conclusions: Our analyses illustrate how flexible modeling may yield new insights into complex temporal relationships between a time-varying drug exposure and risks of adverse events. Duration and recency of antihypertensive agents exposures must be taken into account in evaluating risk and benefits., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Both inadequate and excessive maternal weight gain are correlated with preterm delivery in singleton pregnancies, yet this relationship has not been adequately studied in twins. We investigated the relationship between time-varying maternal weight gain and gestational age at delivery in twin pregnancies and compared it with that in singletons delivered in the same study population. We used serial weight measurements abstracted from charts for twin and singleton pregnancies delivered during 1998-2013 in Pittsburgh, Pennsylvania. Our exposure was time-varying weight gain z score, calculated using gestational age-standardized and prepregnancy body mass index-stratified twin- and singleton-specific charts, and our outcome was gestational age at delivery. Our analyses used a flexible extension of the Cox proportional hazards model that allowed for nonlinear and time-dependent effects. We found a U-shaped relationship between weight gain z score and gestational age at delivery among twin pregnancies (lowest hazard of delivery observed at z score = 1.2), which we attributed to increased hazard of early preterm spontaneous delivery among pregnancies with low weight gain and increased hazard of late preterm delivery without labor among pregnancies with high weight gain. Our findings may be useful for updating provisional guidelines for maternal weight gain in twin pregnancies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hydrochlorothiazide, a common antihypertensive, has photosensitive properties, potentially increasing skin cancer risk. We evaluated melanoma and nonmelanoma skin cancer among hydrochlorothiazide users with 3 different cohorts as each allows assessment of different potential cofounders/effect modifiers, including race/ethnicity., Methods: We built 3 cohorts using IBM MarketScan Research Databases: Commercial and Encounters (>3.5 million individuals, 2010-2018), a subcohort with health risk assessment respondents (415, 330), and Medicaid (509, 767, 2011-2017). Adults (aged 18+ years) entered the respective cohort with a first-filled prescription (cohort entry) for hydrochlorothiazide (the exposure of interest) or angiotensin-converting enzyme (ACE) inhibitors (the active comparator), with ≥12 months of continuous enrollment with medical/pharmacy coverage at baseline. We excluded those who used hydrochlorothiazide/ACE inhibitor (including fixed-dose combination products) 12 months before cohort entry and those with prior skin cancer, HIV, or organ transplant. We compared the risk for hydrochlorothiazide versus ACE inhibitor using multivariate proportional hazards regression., Results: Baseline characteristics were similar, aside from more Black individuals among hydrochlorothiazide users (43.3% [95% CI, 43.0%-43.6%]) than ACE inhibitor users (28.1% [95% CI, 27.9%-28.3%]). The hazard ratio (95% CI) for nonmelanoma skin cancer related to hydrochlorothiazide (versus ACE inhibitor) was 0.96 (0.91-1.00) in the Commercial cohort, 1.01 (0.77-1.32) for the health risk assessment subcohort, and 1.33 (0.77-2.29) for Medicaid. For melanoma, the respective hazard ratios were 1.07 (0.95-1.20), 0.85 (0.43-1.67), and 0.93 (0.51-1.67), respectively., Conclusions: Our evaluation using 3 different approaches, including adjustment for race/ethnicity, did not establish a clear difference between hydrochlorothiazide and ACE inhibitor in terms of skin cancer risk., Competing Interests: Disclosures None.

Previous research linking opioid prescribing to adverse drug events has failed to properly account for the time-varying nature of opioid exposure. This study aimed to explore how the risk of opioid-related emergency department visits, readmissions, or deaths (composite outcome) varies with opioid dose and duration, comparing different novel modeling techniques. A prospective cohort of 1,511 hospitalized patients discharged from 2 McGill-affiliated hospitals in Montreal, 2014-2016, was followed from the first postdischarge opioid dispensation until 1 year after discharge. Marginal structural Cox proportional hazards models and their flexible extensions were used to explore the association between time-varying opioid use and the composite outcome. Weighted cumulative exposure models assessed cumulative effects of past use and explored how its impact depends on the recency of exposure. The patient mean age was 69.6 (standard deviation = 14.9) years; 57.7% were male. In marginal structural model analyses, current opioid use was associated with a 71% increase in the hazard of opioid-related adverse events (adjusted hazard ratio = 1.71, 95% confidence interval: 1.21, 2.43). The weighted cumulative exposure results suggested that the risk cumulates over the previous 50 days of opioid consumption. Flexible modeling techniques helped assess how the risk of opioid-related adverse events may be associated with time-varying opioid exposures while accounting for nonlinear relationships and the recency of past use., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Cohort and nested case-control (NCC) designs are frequently used in pharmacoepidemiology to assess the associations of drug exposure that can vary over time with the risk of an adverse event. Although it is typically expected that estimates from NCC analyses are similar to those from the full cohort analysis, with moderate loss of precision, only few studies have actually compared their respective performance for estimating the effects of time-varying exposures (TVE). We used simulations to compare the properties of the resulting estimators of these designs for both time-invariant exposure and TVE. We varied exposure prevalence, proportion of subjects experiencing the event, hazard ratio, and control-to-case ratio and considered matching on confounders. Using both designs, we also estimated the real-world associations of time-invariant ever use of menopausal hormone therapy (MHT) at baseline and updated, time-varying MHT use with breast cancer incidence. In all simulated scenarios, the cohort-based estimates had small relative bias and greater precision than the NCC design. NCC estimates displayed bias to the null that decreased with a greater number of controls per case. This bias markedly increased with higher proportion of events. Bias was seen with Breslow's and Efron's approximations for handling tied event times but was greatly reduced with the exact method or when NCC analyses were matched on confounders. When analyzing the MHT-breast cancer association, differences between the two designs were consistent with simulated data. Once ties were taken correctly into account, NCC estimates were very similar to those of the full cohort analysis., (© 2023 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Background PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) suggested a potential benefit of sacubitril-valsartan in women with preserved ejection fraction. Among patients with heart failure previously treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), we studied whether effectiveness of treatment with sacubitril-valsartan compared with ACEI/ARB monotherapy differed between men and women for both preserved and reduced ejection fraction. Methods and Results Data were derived from the Truven Health MarketScan Databases between January 1, 2011, and December 31, 2018. We included patients with a primary diagnosis of heart failure on treatment with ACEIs, ARBs, or sacubitril-valsartan on the basis of the first prescription after diagnosis. A total of 7181 patients treated with sacubitril-valsartan, 25 408 patients using an ACEI, and 16 177 patients treated with ARBs were included. A total of 790 readmissions or deaths occurred among 7181 patients in the sacubitril-valsartan group and 11 901 events in 41 585 patients treated with an ACEI/ARB. Adjusted for covariates, the hazard ratio (HR) for treatment with sacubitril-valsartan compared with an ACEI or ARB was 0.74 (95% CI, 0.68-0.80). The protective effect of sacubitril-valsartan was evident for men and women (women: HR, 0.75 [95% CI, 0.66-0.86]; P <0.01; men: HR, 0.71 [95% CI, 0.64-0.79]; P <0.01; P interaction 0.03). A protective effect for both sexes was seen only among those with systolic dysfunction. Conclusions Treatment with sacubitril-valsartan is more effective at reducing death and admission to the hospital for heart failure compared with ACEIs/ARBs similarly among men and women with systolic dysfunction; sex differences in the effectiveness of sacubitril-valsartan in diastolic dysfunction requires further investigation.

Purpose: To investigate the association between alcohol intake over the lifetime and the risk of overall, borderline, and invasive ovarian cancer., Methods: In a population-based case-control study of 495 cases and 902 controls, conducted in Montreal, Canada, average alcohol intake over the lifetime and during specific age periods were computed from a detailed assessment of the intake of beer, red wine, white wine and spirits. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between alcohol intake and ovarian cancer risk., Results: For each one drink/week increment in average alcohol intake over the lifetime, the adjusted OR (95% CI) was 1.06 (1.01-1.10) for ovarian cancer overall, 1.13 (1.06-1.20) for borderline ovarian cancers and 1.02 (0.97-1.08) for invasive ovarian cancers. This pattern of association was similarly observed for alcohol intake in early (15- < 25 years), mid (25- < 40 years) and late adulthood (≥ 40 years), as well as for the intake of specific alcohol beverages over the lifetime., Conclusions: Our results support the hypothesis that a higher alcohol intake modestly increases the risk of overall ovarian cancer, and more specifically, borderline tumours., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To examine the association between rheumatologist access, early treatment, and ongoing care of older-onset rheumatoid arthritis (RA) and healthcare utilization and costs following diagnosis., Methods: We analyzed data from a population-based inception cohort of individuals aged > 65 years with RA in Ontario, Canada, diagnosed between 2002 and 2014 with follow-up to 2019. We assessed 4 performance measures in the first 4 years following diagnosis, including access to rheumatology care, yearly follow-up, timely treatment, and ongoing treatment with a disease-modifying antirheumatic drug. We examined annual healthcare utilization, mean direct healthcare costs, and whether the performance measures were associated with costs in year 5., Results: A total of 13,293 individuals met inclusion criteria. The mean age was 73.7 (SD 5.7) years and 68% were female. Total mean direct healthcare cost per individual increased annually and was CAD $13,929 in year 5. All 4 performance measures were met for 35% of individuals. In multivariable analyses, costs for not meeting access to rheumatology care and timely treatment performance measures were 20% (95% CI 8-32) and 6% (95% CI 1-12) higher, respectively, than where those measures were met. The main driver of cost savings among individuals meeting all 4 performance measures were from lower complex continuing care, home care, and long-term care costs, as well as fewer hospitalizations and emergency visits., Conclusion: Access to rheumatologists for RA diagnosis, timely treatment, and ongoing care are associated with lower total healthcare costs at 5 years. Investments in improving access to care may be associated with long-term health system savings., (Copyright © 2023 by the Journal of Rheumatology.)

Objective: To determine whether there were improvements in rheumatology care for rheumatoid arthritis (RA) between 2002 and 2019 in Ontario, Canada, and to evaluate the impact of rheumatologist regional supply on access., Methods: We conducted a population-based retrospective study of all individuals diagnosed with RA between January 1, 2002 and December 31, 2019. Performance measures evaluated were: (i) percentage of RA patients seen by a rheumatologist within one year of diagnosis; and (ii) percentage of individuals with RA aged 66 years and older (whose prescription drugs are publicly funded) dispensed a disease modifying anti-rheumatic drug (DMARD) within 30 days after initial rheumatologist visit. Logistic regression was used to assess whether performance improved over time and whether the improvements differed by rheumatology supply, dichotomized as < 1 rheumatologist per 75,000 adults versus ≥1 per 75,000., Results: Among 112,494 incident RA patients, 84% saw a rheumatologist within one year: The percentage increased over time (adjusted odds ratio (OR) 2019 vs. 2002 = 1.43, p < 0.0001) and was consistently higher in regions with higher rheumatologist supply (OR = 1.73, 95% CI 1.67-1.80). Among seniors who were seen by a rheumatologist within 1 year of their diagnosis the likelihood of timely DMARD treatment was lower among individuals residing in regions with higher rheumatologist supply (OR = 0.90 95% CI 0.83-0.97). These trends persisted after adjusting for other covariates., Conclusion: While access to rheumatologists and treatment improved over time, shortcomings remain, particularly for DMARD use. Patients residing in regions with higher rheumatology supply were more likely to access care but less likely to receive timely treatment., (© 2022. The Author(s).)

Background: Long-term opioid use is an increasingly important problem related to the ongoing opioid epidemic. The purpose of this study was to identify patient, hospitalization and system-level determinants of long term opioid therapy (LTOT) among patients recently discharged from hospital., Design: To be eligible for this study, patient needed to have filled at least one opioid prescription three-months post-discharge. We retrieved data from the provincial health insurance agency to measure medical service and prescription drug use in the year prior to and after hospitalization. A multivariable Cox Proportional Hazards model was utilized to determine factors associated with time to the first LTOT occurrence, defined as time-varying cumulative opioid duration of ≥ 60 days., Results: Overall, 22.4% of the 1,551 study patients were classified as LTOT, who had a mean age of 66.3 years (SD = 14.3). Having no drug copay status (adjusted hazard ratio (aHR) 1.91, 95% CI: 1.40-2.60), being a LTOT user before the index hospitalization (aHR 6.05, 95% CI: 4.22-8.68) or having history of benzodiazepine use (aHR 1.43, 95% CI: 1.12-1.83) were all associated with an increased likelihood of LTOT. Cardiothoracic surgical patients had a 40% lower LTOT risk (aHR 0.55, 95% CI: 0.31-0.96) as compared to medical patients. Initial opioid dispensation of > 90 milligram morphine equivalents (MME) was also associated with higher likelihood of LTOT (aHR 2.08, 95% CI: 1.17-3.69)., Conclusions and Relevance: Several patient-level characteristics associated with an increased risk of ≥ 60 days of cumulative opioid use. The results could be used to help identify patients who are at high-risk of continuing opioids beyond guideline recommendations and inform policies to curb excessive opioid prescribing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Kurteva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Many clinical and epidemiological applications of survival analysis focus on interval-censored events that can be ascertained only at discrete times of clinic visits. This implies that the values of time-varying covariates are not correctly aligned with the true, unknown event times, inducing a bias in the estimated associations. To address this issue, we adapted the simulation-extrapolation (SIMEX) methodology, based on assessing how the estimates change with the artificially increased time between clinic visits. We propose diagnostics to choose the extrapolating function. In simulations, the SIMEX-corrected estimates reduced considerably the bias to the null and generally yielded a better bias/variance trade-off than conventional estimates. In a real-life pharmacoepidemiological application, the proposed method increased by 27% the excess hazard of the estimated association between a time-varying exposure, representing the 2-year cumulative duration of past use of a hypertensive medication, and the hazard of nonmelanoma skin cancer (interval-censored events). These simulation-based and real-life results suggest that the proposed SIMEX-based correction may help improve the accuracy of estimated associations between time-varying exposures and the hazard of interval-censored events in large cohort studies where the events are recorded only at relatively sparse times of clinic visits/assessments. However, these advantages may be less certain for smaller studies and/or weak associations., (© 2022 Wiley-VCH GmbH.)

Objectives: To describe the agreement of self-reported medication use with claim prescription records and to ascertain factors associated with agreement between the two data sources., Methods: Baseline data on self-reported medication use was extracted from CARTaGENE, a cohort study in Quebec, Canada, and from the provincial health insurance records (dispensation database) of the same individuals. Kappa statistics were used to estimate concordance beyond chance between the two data sources. Logistic regression models were adjusted to estimate the association between agreement and selected individual's characteristics (sex, age, education, region, income, utilization of health care system, and comorbidities)., Results: Agreement between self-reported medication use and administrative data varied considerably across medication classes (kappa 0.54 for respiratory system and 0.91 for systemic hormonal preparations). Overall, agreement improved when a fixed time window of 90 days was used for exposure measurement. Sex, education level, frequency of health care use and the number of reported medications were associated with agreement., Discussion: Overall, there was a reasonable agreement between the two data sources, but important variations were found for the different drug classes. These results could be used by researchers to more accurately assess drug exposures using real-world data, which are increasingly important to regulators.

Objective: Development of new systemic lupus erythematosus (SLE) treatments requires an effective responder index. Toward this end, we have recently developed a new Lupus Multivariable Outcome Score (LuMOS) to optimize discrimination between actively treated patients and those on placebo. We now report on external validation of LuMOS in two independent clinical trials., Methods: Validation was performed with the Illuminate data sets that evaluated tabalumab (TB) in SLE. To accommodate laboratory results assessed on different platforms, we developed a standardized LuMOS 2.0 model that uses z score transformations of biomarker values. For validation, we calculated LuMOS 2.0 scores at week 52 for all participants. Effect size (ES), with 95% confidence intervals (CIs), compared the ability of LuMOS and the SLE Responder Index-5 (SRI-5) to discriminate between outcomes in patients randomized to TB dosage and outcomes in those randomized to a placebo., Results: Mean LuMOS 2.0 scores were significantly higher (P < 0.0001) for the TB groups than the placebo group, including the Illuminate-1 trial, in which the SRI-5 did not identify significant treatment effects. For both TB groups in both trials, LuMOS 2.0-based ES indicated moderately strong treatment effects (>0.4) in contrast to weak SRI-5 effects (<0.25). For monthly TB, LuMOS 2.0-based ES were 0.44 (95% CI: 0.30-0.59) and 0.54 (95% CI: 0.39-0.68) for the Illuminate-1 and Illuminate-2 trials versus corresponding SRI-5-based ES of 0.13 (95% CI: -0.02 to +0.27) and 0.15 (95% CI: 0.01-0.30)., Conclusion: LuMOS 2.0 detected significantly greater treatment effects compared with the SRI-5 in the Illuminate trials. Additional validation of LuMOS 2.0 in trials of non-B cell-directed therapies will be necessary to document its universality as an outcome measure., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Given that pregnant women taking medications are excluded from clinical trials, real-world evidence is essential. We aimed to build a Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO) and compare frequency of prematurity, low-birth-weight (LBW), major malformations, multiplicity, and gestational medication use across four provinces., Methods: CAMCCO is a collaborative research infrastructure that uses real-world data from large provincial health care databases in Canada; developed with standardized methods to similarly construct population-based pregnancy/child cohorts with longitudinal follow-up by linking administrative/hospital/birth databases. CAMCCO also includes a common repository to i) share algorithms and case definitions based on diagnostic and procedural codes for research/training purpose, and ii) download aggregate data relevant to primary care providers, researchers, and decision makers. For this study, data from Quebec (1998-2015), Manitoba (1995-2019), Saskatchewan (1996-2020), and Alberta (2005-2018) are compared (Chi-square tests, p-values), and trends are calculated using Cochran-Armitage trend tests., Results: Almost two-thirds (61%) of women took medications during pregnancy, mostly antibiotics (26%), asthma drugs (8%), and antidepressants (4%). Differences in the prevalence of prematurity (5.9-6.8%), LBW (4.0-5.2%), and multiplicity (1.0-2.5%) were statistically significant between provinces (p<0.001). Frequency of major malformations increased over time in Quebec (7-11%; p<0.001), Saskatchewan (5-11%; p<0.001), and Alberta (from 7-8%; p<0.001), and decreased in Manitoba (5-3%; p<0.001). Cardiovascular and musculoskeletal malformations were the most prevalent., Interpretation: Medications are often used among Canadian pregnancies but adverse pregnancy outcomes vary across provinces. Digitized health data may help researchers and care providers understand the risk-benefit ratios related to gestational medication use, as well as province-specific trends., Competing Interests: The authors have declared that no competing interests exist.

Objective: The study objective was to assess adherence to system-level performance measures measuring retention in rheumatology care and disease modifying anti-rheumatic drug (DMARD) treatment in rheumatoid arthritis (RA)., Methods: We used a validated health administrative data case definition to identify individuals with RA in Ontario, Canada, between 2002 and 2014 who had at least 5 years of potential follow-up prior to 2019. During the first 5 years following diagnosis, we assessed whether patients were seen by a rheumatologist yearly and the proportion dispensed a DMARD yearly (in those aged ≥66 for whom medication data were available). Multivariable logistic regression analyses were used to estimate the odds of remaining under rheumatologist care., Results: The cohort included 50,883 patients with RA (26.1% aged 66 years and older). Over half (57.7%) saw a rheumatologist yearly in all 5 years of follow-up. Sharp declines in the percentage of patients with an annual visit were observed in each subsequent year after diagnosis, although a linear trend to improved retention in rheumatology care was seen over the study period (P < 0.0001). For individuals aged 66 years or older (n = 13,293), 82.1% under rheumatologist care during all 5 years after diagnosis were dispensed a DMARD annually compared with 31.0% of those not retained under rheumatology care. Older age, male sex, lower socioeconomic status, higher comorbidity score, and having an older rheumatologist decreased the odds of remaining under rheumatology care., Conclusion: System-level improvement initiatives should focus on maintaining ongoing access to rheumatology specialty care. Further investigation into causes of loss to rheumatology follow-up is needed., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Hydroxychloroquine (HCQ) is a key systemic lupus erythematosus (SLE) drug, making concerns of drug shortages grave. Our objective was to evaluate factors associated with poor outcomes after HCQ taper or discontinuation in SLE., Methods: We studied 5 Canadian SLE cohorts between 1999 and 2019, following patients from the date of HCQ tapering (cohort 1) or discontinuation (cohort 2). A composite outcome was defined as any of the following: a need for therapy augmentation, an increase (of at least 4 points) in the Systemic Lupus Erythematosus Disease Activity Index 2000 score, or hospitalization for SLE. In each cohort, multivariable Cox regression was used to identify demographic and clinical factors associated with time to the earliest of these events. A third cohort continuing to receive HCQ was also studied, to assess whether the same factors influenced the outcome even when the HCQ dose was unchanged., Results: The poor outcome rate, per 100 person-years, was 35.7 (95% confidence interval [95% CI] 31.6-40.3) in the HCQ taper cohort (n = 398), 29.0 (95% CI 25.5-33.0) in the discontinuation cohort (n = 395), and 16.1 (95% CI 13.2-19.6) in the maintenance cohort (n = 395). In patients tapering HCQ, baseline prednisone use was independently associated with greater risk of poor outcomes. In the discontinuation cohort, the risk of poor outcomes was greater for Black patients and those diagnosed with SLE at age ≤25 years. Among those maintaining HCQ, baseline immunosuppressive use and First Nations ethnicity were associated with poor outcomes., Conclusion: We identified demographic and clinical factors associated with poor outcomes after HCQ taper/discontinuation. This information is critical in the current setting of potential shortages, but over the long term, such information could inform personalized therapies., (© 2020 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Wildfires emit many carcinogenic pollutants that contaminate air, water, terrestrial, and indoor environments. However, little is known about the relationship between exposure to wildfires and cancer risk. We aimed to assess the associations between residential exposure to wildfires and the incidence of several cancer outcomes (lung cancer, brain cancer, non-Hodgkin lymphoma, multiple myeloma, and leukaemia) in Canada., Methods: We did a population-based observational cohort study of participants in the 1996 Canadian Census Health and Environment Cohort. The 1996 Canadian Census Health and Environment Cohort is a nationally representative sample of Canadian adults, followed up for cancer incidence and mortality from 1996 to 2015. For this analysis, we excluded participants who lived in major Canadian cities (with a population size greater than 1·5 million people), recent immigrants, and individuals younger than 25 years or 90 years of age or older at baseline. Exposures to wildfires were assigned on the basis of area burned within a 20 km or 50 km radius of residential locations and updated for annual residential mobility. Multivariable Cox proportional hazards models were used to estimate associations between exposure to wildfires and specific cancers associated with carcinogenic compounds released by wildfires, including lung and brain cancer, non-Hodgkin lymphoma, multiple myeloma, and leukaemia, adjusted for many personal and neighbourhood-level covariates., Findings: Our analyses included more than 2 million people followed up for a median of 20 years, for a total of 34 million person-years. Wildfire exposure was associated with slightly increased incidence of lung cancer and brain tumours. For example, cohort members exposed to a wildfire within 50 km of residential locations in the past 10 years had a 4·9% relatively higher incidence (adjusted hazard ratio [HR] 1·049, 95% CI 1·028-1·071) of lung cancer than unexposed populations, and a 10% relatively higher incidence (adjusted HR 1·100, 1·026-1·179) of brain tumours. Similar associations were observed for the 20 km buffer size. Wildfires were not associated with haematological cancers in this study, and concentration-response trends were not readily apparent when area burned was modelled as a continuous variable., Interpretation: Long-term exposure to wildfires might increase the risk of lung cancer and brain tumours. Further work is needed to develop long-term estimates of wildfire exposures that capture the complex mixture of environmental pollutants released during these events., Funding: Canadian Institute for Health Research and Fonds de recherche du Quebec., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance., Methods: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare., Results: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts., Conclusions: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful., Competing Interests: Competing interests: All the following relationships are outside the submitted work. Dr AEC: consulting fees from AstraZeneca, Bristol Myers Squibb, Exagen Diagnostics and GlaxoSmithKline. Dr CG: consulting fees from the Centers for Disease Control (CDC), Morton Grove Pharmaceutical (MGP), Sanofi and UCB. Dr RR-G: consulting fees from GSK, Immuncor and ThermoFisher. Dr DAI: consulting fees from Amgen, Merck Serono, AstraZeneca and Eli Lilly (the honoraria are passed onto a local arthritis charity). Dr AR: consulting fees from Lilly. Dr PRF: participation on advisory boards from AbbVie, AstraZeneca and Lilly. Dr MAK: consulting fees from GSK. Dr MI: consulting fees from AbbVie, UCB, Novartis, Janssen and Lilly., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The accelerated failure time model is an alternative to the Cox proportional hazards model in survival analysis. However, conclusions regarding the associations of prognostic factors with event times are valid only if the underlying modeling assumptions are met. In contrast to several flexible methods for relaxing the proportional hazards and linearity assumptions in the Cox model, formal investigation of the constant-over-time time ratio and linearity assumptions in the accelerated failure time model has been limited. Yet, in practice, prognostic factors may have time-dependent and/or nonlinear effects. Furthermore, parametric accelerated failure time models require correct specification of the baseline hazard function, which is treated as a nuisance parameter in the Cox proportional hazards model, and is rarely known in practice. To address these challenges, we propose a flexible extension of the accelerated failure time model where unpenalized regression B-splines are used to model (i) the baseline hazard function of arbitrary shape, (ii) the time-dependent covariate effects on the hazard, and (iii) nonlinear effects for continuous covariates. Simulations evaluate the accuracy of the time-dependent and/or nonlinear estimates, and of the resulting survival functions, in multivariable settings. The proposed flexible extension of the accelerated failure time model is applied to re-assess the effects of prognostic factors on mortality after septic shock.

Introduction: The main harm reduction interventions for people who inject drugs (PWID) are supervised injection facilities, needle and syringe programmes and opioid agonist treatment. Current evidence supporting their implementation and operation underestimates their usefulness by excluding skin, soft tissue and vascular infections (SSTVIs) and anoxic/toxicity-related brain injury from cost-effectiveness analyses (CEA). Our goal is to conduct a comprehensive CEA of harm reduction interventions in a setting with a large, dispersed, heterogeneous population of PWID, and include prevention of SSTVIs and anoxic/toxicity-related brain injury as measures of benefit in addition to HIV, hepatitis C and overdose morbidity and mortalities averted., Methods and Analysis: This protocol describes how we will develop an open, retrospective cohort of adult PWID living in Québec between 1 January 2009 and 31 December 2020 using administrative health record data. By complementing this data with non-linkable paramedic dispatch records, regional monthly needle and syringe dispensation counts and repeated cross-sectional biobehavioural surveys, we will estimate the hazards of occurrence and the impact of Montréal's harm reduction interventions on the incidence of drug-use-related injuries, infections and deaths. We will synthesise results from our empirical analyses with published evidence to simulate infections and injuries in a hypothetical population of PWID in Montréal under different intervention scenarios including current levels of use and scale-up, and assess the cost-effectiveness of each intervention from the public healthcare payer's perspective., Ethics and Dissemination: This study was approved by McGill University's Institutional Review Board (Study Number: A08-E53-19B). We will work with community partners to disseminate results to the public and scientific community via scientific conferences, a publicly accessible report, op-ed articles and open access peer-reviewed journals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Influenza immunization protects seniors against influenza and its potentially serious complications. It is uncertain whether standard-dose (SD) quadrivalent vaccine offers better protection over other formulations in the elderly. In this study, we compared the effectiveness of SD-trivalent, high-dose (HD) trivalent, SD-quadrivalent, and adjuvanted trivalent vaccines in seniors (≥65 years) in a real-world setting. We selected over 200,000 individuals in each of 6 influenza seasons from 2012 to 2018 using MarketScan® databases. The two outcomes were hospitalization or emergency room (ER) visit due to (1) influenza or (2) pneumonia. Here, SD-quadrivalent was associated with higher risk of influenza-related hospitalization/ER visit (adjusted hazard ratio (aHR) 1.14 and 95% confidence interval (95% CI) 1.05-1.24) and of pneumonia-related hospitalization/ER visit (aHR 1.04 and 95% CI 1.01-1.07) vs. HD-trivalent. SD-trivalent followed similar trends compared to HD-trivalent (aHR 1.16 and 95% CI 1.06-1.27 for hospitalized/ER visit influenza; aHR 1.07 and 95% CI 1.05-1.10 for hospitalized/ER visit pneumonia). We could not demonstrate risk differences between SD vaccine formulations and between adjuvanted trivalent and one of the other three vaccines. Risk estimates slightly varied across seasons. These findings suggest that SD vaccine formulations vs. HD-trivalent were associated with higher risk of hospitalization/ER visit for influenza and pneumonia in seniors., (© 2021. The Author(s).)

Importance: Radiocontrast has long been thought of as nephrotoxic; however, a number of recent observational studies found no evidence of an association between intravenous contrast and kidney injury. Because these studies are at high risk of confounding and selection bias, alternative study designs are required to enable more robust evaluation of this association., Objective: To determine whether intravenous radiocontrast exposure is associated with clinically significant long-term kidney impairment, using a study design that permits stronger causal interpretation than existing observational research., Design, Setting, and Participants: This cohort study included all emergency department patients aged 18 years or older undergoing D-dimer testing between 2013 and 2018 in the Canadian province of Alberta. A fuzzy regression discontinuity design was used, exploiting the fact that individuals just either side of the eligibility cutoff for computed tomographic pulmonary angiogram (CTPA)-typically 500 ng/mL-have markedly different probabilities of contrast exposure, but should otherwise be similar with respect to potential confounders., Exposures: Intravenous contrast in the form of a CTPA., Main Outcomes and Measures: Estimated glomerular filtration rate (eGFR) up to 6 months following the index emergency department visit., Results: During the study period 156 028 individuals received a D-dimer test. The mean age was 53 years, 68 206 (44%) were men and 87 822 (56%) were women, and the mean baseline eGFR level was 86 mL/min/1.73 m2. Patients just above and below the CTPA eligibility cutoff were similar in terms of measured confounders. There was no evidence for an association of contrast with eGFR up to 6 months later, with a mean change in eGFR of -0.4 mL/min/1.73 m2 (95% CI, -4.9 to 4.0) associated with CTPA exposure. There was similarly no evidence for an association with need for kidney replacement therapy (risk difference [RD], 0.07%; 95% CI, -0.47% to 0.61%), mortality (RD, 0.3%; 95% CI, -2.9% to 3.2%), and acute kidney injury (RD, 4.3%; 95% CI, -2.7% to 12.9%), though the latter analysis was limited by missing data. Subgroup analyses were potentially consistent with harm among patients with diabetes (mean eGFR change -6.4 mL/min/1.73 m2; 95% CI, -15.4 to 0.2), but not among those with other reported risk factors for contrast-induced nephropathy; these analyses, however, were relatively underpowered., Conclusions and Relevance: Using a cohort study design and analysis that permits stronger causal interpretation than existing observational research, we found no evidence for a harmful effect on kidney function of intravenous contrast administered for CTPA in an emergency setting.

Objective: To evaluate secular trends in 10-year risk of incident cerebrovascular accidents (CVA), in incident RA relative to the general population., Methods: We conducted a retrospective study of a population-based incident cohort with RA onset from 1997 to 2004 in British Columbia, Canada, with matched general population controls (2:1), using administrative health data. RA and general population cohorts were divided according to year of RA onset, defined according to the first RA visit of the case definition. Incident CVA was defined as the first CVA occurring within 10 years from the first RA visit. Secular trend was assessed using delayed-entry Cox models with a two-way interaction term between the year of RA onset and indicator of RA vs general population. Linear, quadratic and spline functions of year of RA onset were compared with assess non-linear effects. The model with the lowest Akaike Information Criterion was selected., Results: Overall, 23 545 RA and 47 090 general population experienced 658 and 1220 incident CVAs, respectively. A spline Cox model with a knot at year of onset 1999 was selected. A significant decline in risk of CVA was observed in individuals with RA onset after 1999 [0.90 (0.86, 0.95); P = 0.0001]. The change in CVA risk over time differed significantly in RA with onset from 1999 onwards compared with the general population (P-value of interaction term = 0.03), but not before 1999 (P = 0.06)., Conclusion: Our findings suggest that people with RA onset from 1999 onwards, had a significantly greater decline in 10-year risk of CVA compared with the general population., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Although better pain management has guided policies for opioid use over the past few decades, evidence is limited regarding how patterns of use are associated with the risk of potentially avoidable opioid-related adverse events., Objective: To estimate the risk of harms associated with opioid dose and duration of use, and to ascertain whether the risk is modified by treatment indication and age., Design, Setting, and Participants: This ad hoc cohort study followed up patients who were enrolled in a cluster randomized trial of medication reconciliation between October 1, 2014, and November 30, 2016, 12 months after they were discharged from the McGill University Health Centre in Montreal, Quebec, Canada. To be eligible for this study, patients needed to have filled at least 1 opioid prescription 3 months after discharge. Patients with a history of using methadone or buprenorphine were excluded. Data analyses were performed between February 1, 2019, and February 28, 2020., Exposures: Time-varying measures of opioid use included current use, daily morphine milligram equivalent (MME) dose, cumulative and continuous use duration, and type of ingredients in prescription opioids used. Hospitalization records, dispensed prescriptions records, and postdischarge interviews were used to evaluate adherence to the opioid prescriptions after discharge., Main Outcomes and Measures: Opioid-related emergency department visits, hospital readmissions, or all-cause death. Outcomes were ascertained using provincial medical services claims and hospitalization databases., Results: Of 3486 participants in the cluster randomized trial (mean [SD] age of 69.6 [14.9] years; 2010 men [57.7%]), 1511 patients were included in this ad hoc cohort study. Among those with at least 1 opioid dispensation, 241 patients (15.9%) experienced an opioid-related emergency department visit, hospital readmission, or death. Results from marginal structural Cox proportional hazards regression models showed more than a 2-fold increase in the risk of opioid-related adverse events associated with a cumulative use duration of more than 90 days (adjusted hazard ratio, 2.56; 95% CI, 1.25-5.27) compared with 1 to 30 days. A 3-fold risk increase was found with a mean daily dose higher than 90 MME (adjusted hazard ratio, 3.51; 95% CI, 1.58-7.82) compared with 90 MME or lower., Conclusions and Relevance: This study found an association between risk of adverse health care events and higher opioid doses and longer treatment duration. This finding can inform policies for limiting opioid duration and dose to attenuate the risk of avoidable morbidity.

Background: Angiotensin-converting enzyme 2 (ACE2) has been identified as the entry receptor for coronaviruses into human cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Since hypertension (HT) is a leading comorbidity in non-survivors of COVID-19, we tested for association between ACE2 gene and HT in interaction with specific pre-existing conditions known to be associated with COVID-19 severity., Methods: Genetic analysis of ACE2 gene was conducted in French-Canadian (FC) and British populations., Results: In FC individuals, the T allele of the single nucleotide polymorphism rs2074192 of ACE2 gene was a risk factor for HT in adult obese males [odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.06-1.83)] and even more so in obese males who smoked (OR = 1.67, CI: 1.24-2.55), but not in lean males, non-smoker males or females. The T allele was significantly associated with severity of HT and with earlier penetrance of HT in obese smoking males. Significant interaction between the T allele and obesity was present in both sexes. The association of ACE2 (rs233575) genotype with blood pressure was also seen in adolescents but the interaction with obesity was present only in females. Several variants in ACE2 gene were found to be associated with HT in obese, smoking males in British individuals of the UK Biobank. In addition, we observed more severe outcomes to COVID-19 in association with ACE2 risk alleles in obese, smoking males., Conclusions: This is the first report that ACE2 variants are associated with earlier penetrance and more severe HT and with more severe outcomes of COVID-19 in obese smoking males., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Objective: To evaluate secular trend in ten-year risk of incident acute myocardial infarction (AMI) in incident rheumatoid arthritis (RA) relative to the general population., Methods: We conducted a retrospective study of population-based incident RA cohorts with RA incidence from 1997 to 2004 in British Columbia, Canada, with matched general population comparators, using administrative health data. RA and their matched cohorts were divided according to the year of RA incidence, defined according to the first RA visit of the case definition. Incident AMI was defined as the first event occurring within 10 years from RA incidence. Secular trend was assessed using delayed-entry Cox models with an interaction term between the year of RA onset and indicator of RA vs. general population. Linear, quadratic and spline functions of year of RA onset were compared to assess possibility of nonlinear trends. The model with the lowest AIC was selected to interpret the results. Sensitivity analyses were conducted to account for potential effect of unmeasured (e.g. smoking) or partially measured (e.g. obesity) confounders in administrative data, on the interaction term., Results: Overall, 23,237 RA and 46,474 general population controls experienced 1,133 and 1,606 incident AMIs, respectively. A linear Cox model was selected as the model best fitting the AMI events. Overall, RA patients were found to have a 21% higher risk of AMI than the matched general population controls [1.21 (1.10, 1.32); p < 0.001]. A significant linear decline in risk of AMI was observed in RA patients [0.94 (95% CI 0.91, 0.97) p = <0.0001], and in the general population [0.93 (0.91, 0.95); p = <0.0001]. The change in AMI risk over time did not differ in RA compared to the general population [p-value of interaction term=0.49]. Our results remained similar after adjusting for the potential effect of confounders on the interaction term, and no difference in the change in risk of AMI over time was observed between RA and the general population., Conclusion: Our findings suggest a decline in 10-year risk of AMI in RA, and in the general population. The decline in the risk of AMI over time did not differ between RA and the general population, such that the excess risk of AMI in RA relative to the general population, has remained the same., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: We describe an innovative research protocol to: (a) examine patient-level longitudinal associations between nurse staffing practices and the risk of adverse events in acute care hospitals and; (b) determine possible thresholds for safe nurse staffing., Design: A dynamic cohort of adult medical, surgical and intensive care unit patients admitted to 16 hospitals in Quebec (Canada) between January 2015-December 2019., Methods: Patients in the cohort will be followed from admission until 30-day postdischarge to assess exposure to selected nurse staffing practices in relation to the subsequent occurrence of adverse events. Five staffing practices will be measured for each shift of an hospitalization episode, using electronic payroll data, with the following time-varying indicators: (a) nursing worked hours per patient; (b) skill mix; (c) overtime use; (d) education mix and; and (e) experience. Four high-impact adverse events, presumably associated with nurse staffing practices, will be measured from electronic health record data retrieved at the participating sites: (a) failure-to-rescue; (b) in-hospital falls; (c) hospital-acquired pneumonia and; and (d) venous thromboembolism. To examine the associations between the selected nurse staffing exposures and the risk of each adverse event, separate multivariable Cox proportional hazards frailty regression models will be fitted, while adjusting for patient, nursing unit and hospital characteristics, and for clustering. To assess for possible staffing thresholds, flexible non-linear spline functions will be fitted. Funding for the study began in October 2019 and research ethics/institutional approval was granted in February 2020., Discussion: To our knowledge, this study is the first multisite patient-level longitudinal investigation of the associations between common nurse staffing practices and the risk of adverse events. It is hoped that our results will assist hospital managers in making the most effective use of the scarce nursing resources and in identifying staffing practices that minimize the occurrence of adverse events., (© 2020 John Wiley & Sons Ltd.)

The accelerated failure time (AFT) model has been suggested as an alternative to the Cox proportional hazards model. However, a parametric AFT model requires the specification of an appropriate distribution for the event time, which is often difficult to identify in real-life studies and may limit applications. A semiparametric AFT model was developed by Komárek et al based on smoothed error distribution that does not require such specification. In this article, we develop a spline-based AFT model that also does not require specification of the parametric family of event time distribution. The baseline hazard function is modeled by regression B-splines, allowing for the estimation of a variety of smooth and flexible shapes. In comprehensive simulations, we validate the performance of our approach and compare with the results from parametric AFT models and the approach of Komárek. Both the proposed spline-based AFT model and the approach of Komárek provided unbiased estimates of covariate effects and survival curves for a variety of scenarios in which the event time followed different distributions, including both simple and complex cases. Spline-based estimates of the baseline hazard showed also a satisfactory numerical stability. As expected, the baseline hazard and survival probabilities estimated by the misspecified parametric AFT models deviated from the truth. We illustrated the application of the proposed model in a study of colon cancer., (© 2020 John Wiley & Sons Ltd.)

This paper provides guidance for researchers with some mathematical background on the conduct of time-to-event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time-dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative., (© 2020 John Wiley & Sons Ltd.)

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

Background: Heart failure (HF) is the leading cause of death in adult patients with congenital heart disease (ACHD). No risk prediction model exists for HF hospitalization (HFH) for ACHD patients. We aimed to develop a clinically relevant one-year risk prediction system to identify ACHD patients at high risk for HFH., Methods: Data source was the Quebec CHD Database. A retrospective cohort including all ACHD patients aged 18-64 (1995-2010) was constructed for assessing the cumulative risk of HFH adjusting for competing risk of death. To identify one-year predictors of incident HFH, multivariable logistic regressions were employed to a nested case-control sample of all ACHD patients aged 18-64 in 2009. The final model was used to create a risk score system based on adjusted odds ratios., Results: The cohort included 29,991 ACHD patients followed for 648,457 person-years. The cumulative HFH risk by age 65 was 12.58%. The case-control sample comprised 26,420 subjects, of whom 189 had HFHs. Significant one-year predictors were age ≥ 50, male sex, CHD lesion severity, recent 12-month HFH history, pulmonary arterial hypertension, chronic kidney disease, coronary artery disease, systemic arterial hypertension, and diabetes mellitus. The created risk score ranged from 0 to 19. The corresponding HFH risk rose rapidly beyond a score of 8. The risk scoring system demonstrated excellent prediction performance., Conclusions: One eighth of ACHD population experienced HFH before age 65. Age, sex, CHD lesion severity, recent 12-month HFH history, and comorbidities constructed a risk prediction model that successfully identified patients at high risk for HFH., Competing Interests: Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: To compare the effects of group-based and individual physiotherapy for stress or mixed urinary incontinence (UI) on pelvic floor morphometry, pelvic floor muscle (PFM) function, and related self-efficacy, immediately after treatment and at 1 year., Methods: This is a planned secondary analysis of the group rehabilitation or individual physiotherapy study, an assessor-blinded, randomized, noninferiority trial. Eligible participants included 362 community-dwelling older women with symptoms of stress/mixed UI. After learning how to contract PFMs, participants completed 12 weeks of PFM training, either individually (one-on-one) or as part of a group (eight women). Pelvic floor transperineal ultrasound volumes (morphometry), PFM intravaginal dynamometric data (function), and self-efficacy in performing PFM exercises were acquired at baseline, posttreatment, and at 1 year., Results: Groups were comparable at all time points. Immediately posttreatment, both groups demonstrated significant changes in pelvic floor morphometry during coughs, and in PFM function during contractions and coughs. Participants also reported improved self-efficacy in performing PFM exercises. Results were sustained at 1 year. When participants coughed, pelvic floor structures were better supported (reflected by less caudal movement of the puborectalis sling and a smaller opening of the levator hiatus) in a pattern consistent with the "knack" strategy. Furthermore, both interventions resulted in stronger, faster, more coordinated, and more endurant PFMs., Conclusion: In older women with stress or mixed UI, both individual and group-based PFM training resulted in comparable improvements in overall PFM function, pelvic floor morphometry during coughs, and related self-efficacy in performing PFM exercises, which were sustained at 1 year., (© 2020 Wiley Periodicals LLC.)

Numerous studies have demonstrated that sex (a biological variable) and gender (a psychosocial construct) impact health and have discussed the mechanisms that may explain these relationships. Funding agencies have called for all health researchers to incorporate sex and gender into their studies; however, the way forward has been unclear to many, particularly due to the varied definition of gender. We argue that just as there is no standardized definition of gender, there can be no standardized measurement thereof. However, numerous measurable gender-related variables may influence individual or population-level health through various pathways. The initial question should guide the selection of specific gender-related variables based on their relevance to the study, to prospectively incorporate gender into research. We outline various methods to provide clarification on how to incorporate gender into the design of prospective clinical and epidemiological studies as well as methods for statistical analysis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In health research, statistical methods are frequently used to address a wide variety of research questions. For almost every analytical challenge, different methods are available. But how do we choose between different methods and how do we judge whether the chosen method is appropriate for our specific study? Like in any science, in statistics, experiments can be run to find out which methods should be used under which circumstances. The main objective of this paper is to demonstrate that simulation studies, that is, experiments investigating synthetic data with known properties, are an invaluable tool for addressing these questions. We aim to provide a first introduction to simulation studies for data analysts or, more generally, for researchers involved at different levels in the analyses of health data, who (1) may rely on simulation studies published in statistical literature to choose their statistical methods and who, thus, need to understand the criteria of assessing the validity and relevance of simulation results and their interpretation; and/or (2) need to understand the basic principles of designing statistical simulations in order to efficiently collaborate with more experienced colleagues or start learning to conduct their own simulations. We illustrate the implementation of a simulation study and the interpretation of its results through a simple example inspired by recent literature, which is completely reproducible using the R-script available from online supplemental file 1., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)