Permafrost carbon feedbacks threaten global climate goals.

Rapid Arctic warming has intensified northern wildfires and is thawing carbon-rich permafrost. Carbon emissions from permafrost thaw and Arctic wildfires, which are not fully accounted for in global emissions budgets, will greatly reduce the amount of greenhouse gases that humans can emit to remain below 1.5 °C or 2 °C. The Paris Agreement provides ongoing opportunities to increase ambition to reduce society's greenhouse gas emissions, which will also reduce emissions from thawing permafrost. In December 2020, more than 70 countries announced more ambitious nationally determined contributions as part of their Paris Agreement commitments; however, the carbon budgets that informed these commitments were incomplete, as they do not fully account for Arctic feedbacks. There is an urgent need to incorporate the latest science on carbon emissions from permafrost thaw and northern wildfires into international consideration of how much more aggressively societal emissions must be reduced to address the global climate crisis.

Variations in signal-to-noise characteristics of tissue-equivalent attenuators for mammographic automatic exposure control system performance evaluation.

PURPOSE: This work investigates the impact of tissue-equivalent attenuator choice on measured signal-to-noise ratio (SNR) for automatic exposure control (AEC) performance evaluation in digital mammography. It also investigates how the SNR changes for each material when used to evaluate AEC performance across different mammography systems. METHODS: AEC performance was evaluated for four mammography systems using seven attenuator sets at two thicknesses (4 and 8 cm). All systems were evaluated in 2D imaging mode, and one system was evaluated in digital breast tomosynthesis (DBT) mode. The methodology followed the 2018 ACR digital mammography quality control (DMQC) manual. Each system-attenuator-thickness combination was evaluated using For Processing images in ImageJ with standard ROI size and location. The closest annual physicist testing results were used to explore the impact of varying measured AEC performance on image quality. RESULTS: The measured SNR varied by 44%-54% within each system across all attenuators at 4 cm thickness in 2D mode. The variation appeared to be largely due to changes in measured noise, with variations of 46%-67% within each system across all attenuators at 4 cm thickness in 2D mode. Two systems had failing SNR levels for two of the materials using the minimum SNR criterion specified in the ACR DMQC manual. Similar trends were seen in DBT mode and at 8 cm thickness. Within each material, there was 115%-131% variation at 4 cm and 82%-114% variation at 8 cm in the measured SNR across the four imaging systems. Variation in SNR did not correlate with system operating level based on visual image quality and average glandular dose (AGD). CONCLUSION: Choice of tissue-equivalent attenuator for AEC performance evaluation affects measured SNR values. Depending on the material, the difference may be enough to result in failure following the longitudinal and absolute thresholds specified in the ACR DMQC manual.

Say you'll be there: Associations between observed verbal responses, friendship quality, and perceptions of support in young adult friendships.

Friendships are a primary source of social support during young adulthood; however, little is known about the factors associated with young adults feeling greater support during interactions with friends. We examined how micro-level verbal responses and macro-level judgments of friendship quality were associated with perceptions of support following an interaction between friends. Same-gender friend dyads (N = 132; 66.2% female; 18-24 years, M age = 19.63) took turns speaking about a problem, then participants rated their perceptions of support given and received following the task. We coded each participant's verbal responses while in the listening role. Actor Partner Interdependence Models (APIMs) revealed significant partner effects for negative engagement responses, such that greater negative engagement responses were linked with the partner perceiving poorer support both given and received. Models revealed significant actor effects for supportive responses, such that greater supportive responses predicted the actor perceiving better support both given and received. Additionally, models revealed significant actor effects of friendship quality predicting actors' perceiving better support both given and received. Finally, exploratory models revealed minimal interactions between a few types of verbal responses and positive friendship quality. Taken together, results suggest that (a) negative verbal responding styles may be more meaningfully associated with partners' perceptions of support in the moment than are supportive behaviours, whereas (b) supportive verbal responding styles may be more meaningfully associated with actors' perceptions of support in the moment, and (c) actors' judgments of friendship quality are strongly associated with their overall perceptions of support, and a critical factor to consider in future research.

Proton density water fraction as a reproducible MR-based measurement of breast density.

PURPOSE: To introduce proton density water fraction (PDWF) as a confounder-corrected (CC) MR-based biomarker of mammographic breast density, a known risk factor for breast cancer. METHODS: Chemical shift encoded (CSE) MR images were acquired using a low flip angle to provide proton density contrast from multiple echo times. Fat and water images, corrected for known biases, were produced by a six-echo CC CSE-MRI algorithm. Fibroglandular tissue (FGT) volume was calculated from whole-breast segmented PDWF maps at 1.5T and 3T. The method was evaluated in (1) a physical fat-water phantom and (2) normal volunteers. Results from two- and three-echo CSE-MRI methods were included for comparison. RESULTS: Six-echo CC-CSE-MRI produced unbiased estimates of the total water volume in the phantom (mean bias 3.3%) and was reproducible across protocol changes (repeatability coefficient [RC] = 14.8 cm3 and 13.97 cm3 at 1.5T and 3.0T, respectively) and field strengths (RC = 51.7 cm3 ) in volunteers, while the two- and three-echo CSE-MRI approaches produced biased results in phantoms (mean bias 30.7% and 10.4%) that was less reproducible across field strengths in volunteers (RC = 82.3 cm3 and 126.3 cm3 ). Significant differences in measured FGT volume were found between the six-echo CC-CSE-MRI and the two- and three-echo CSE-MRI approaches (p = 0.002 and p = 0.001, respectively). CONCLUSION: The use of six-echo CC-CSE-MRI to create unbiased PDWF maps that reproducibly quantify FGT in the breast is demonstrated. Further studies are needed to correlate this quantitative MR biomarker for breast density with mammography and overall risk for breast cancer.

Improved reconstruction stability for chemical shift encoded hyperpolarized 13 C magnetic resonance spectroscopic imaging using k-t spiral acquisitions.

PURPOSE: A multiecho, field of view (FOV)-oversampled k-t spiral acquisition and direct iterative decomposition of water and fat with echo asymmetry and least-squares estimation reconstruction is demonstrated to improve the stability of hyperpolarized 13 C magnetic resonance spectroscopic imaging (MRSI) in the presence of signal ambiguities attributed to low-SNR (signal-to-noise-ratio) species, local uncertainties in metabolite peaks, and echo-to-echo signal inconsistencies. THEORY: k-t spiral acquisitions redistribute readout points to be more densely spaced radially in k-space by acquiring an FOV and matrix that are oversampled by η. These more densely spaced spiral turns constitute effective intraspiral echoes and can supplement conventional interspiral echoes to improve spectral separation and reduce spectral cross-talk to better resolve 13 C-labeled species for spectroscopic imaging. METHODS: Digital simulations and imaging phantom experiments were performed for a range of interspiral echo spacings and η using multiecho, k-t spiral acquisitions. Image spectral cross-talk artifacts were evaluated both qualitatively and quantitatively as the percent error in measured metabolite ratios. In vivo murine experiments evaluated the feasibility of multiecho, k-t spiral [1-13 C]pyruvate MRSI to reduce spectral cross-talk for 3 scenarios of different expected reconstruction stability. RESULTS: Digital simulations and imaging phantom experiments both demonstrated reduced or comparable image spectral cross-talk and percent errors in measured metabolite ratios with increasing η and better choices of echo spacings. In vivo images displayed markedly reduced spectral cross-talk in lactate images acquired with η = 7 versus η = 1. CONCLUSION: The precision of hyperpolarized 13 C metabolic imaging and quantification in the presence of low-SNR species, local uncertainties in metabolite resonances, and echo-to-echo signal inconsistencies can be improved with the use of FOV-oversampled k-t spiral acquisitions.

Peer Information and Substance Use Decision Making in Street-Involved Youth.

In the context of adolescent substance use, peers are a primary source of both influence and information. Substance-related peer information sharing is a relatively understudied phenomenon, particularly in street-involved youth. We recruited 84 youth from a community drop-in center to complete a survey assessing substance use and peer influence on drug use. A subset of youth completed a semi-structured interview assessing factors related to peer information sharing around drug use. Results showed that peer influence was highly relevant to drug use patterns in street-involved youth. Trust in the person supplying information, personal and peer experience, and salience of information played important roles in youths' assessments of drug-related information exchanged with peers. Implications for improving community information dissemination strategies are discussed.

A novel bioreactor for combined magnetic resonance spectroscopy and optical imaging of metabolism in 3D cell cultures.

PURPOSE: Fluorescence lifetime imaging microscopy (FLIM) of endogenous fluorescent metabolites permits the measurement of cellular metabolism in cell, tissue and animal models. In parallel, magnetic resonance spectroscopy (MRS) of dynamic nuclear (hyper)polarized (DNP) 13 C-pyruvate enables measurement of metabolism at larger in vivo scales. Presented here are the design and initial application of a bioreactor that connects these 2 metabolic imaging modalities in vitro, using 3D cell cultures. METHODS: The model fitting for FLIM data analysis and the theory behind a model for the diffusion of pyruvate into a collagen gel are detailed. The device is MRI-compatible, including an optical window, a temperature control system and an injection port for the introduction of contrast agents. Three-dimensional printing, computer numerical control machining and laser cutting were used to fabricate custom parts. RESULTS: Performance of the bioreactor is demonstrated for 4 T1 murine breast cancer cells under glucose deprivation. Mean nicotinamide adenine dinucleotide (NADH) fluorescence lifetimes were 10% longer and hyperpolarized 13 C lactate:pyruvate (Lac:Pyr) ratios were 60% lower for glucose-deprived 4 T1 cells compared to 4 T1 cells in normal medium. Looking at the individual components of the NADH fluorescent lifetime, τ1 (free NADH) showed no significant change, while τ2 (bound NADH) showed a significant increase, suggesting that the increase in mean lifetime was due to a change in bound NADH. CONCLUSION: A novel bioreactor that is compatible with, and can exploit the benefits of, both FLIM and 13 C MRS in 3D cell cultures for studies of cell metabolism has been designed and applied.

Medication use and kidney cancer survival: A population-based study.

Several studies demonstrate that use of commonly prescribed medications is associated with improved survival in various malignancies. Methods of classifying medication use in many of these studies, however, do not account for intermittent or cumulative use. Moreover, there are limited data in kidney cancer. Therefore, we performed a population-based cohort study utilizing healthcare databases in Ontario, Canada. We identified patients aged ≥65 with an incident diagnosis of kidney cancer between 1997 and 2013 and examined use of nine putative anti-neoplastic medications using prescription claims. Cox proportional hazard models evaluated the association of medication exposure on cancer-specific and overall survival. We conducted three separate analyses: the effect of cumulative duration of exposure to the study medications on outcomes, the effect of current exposure (in a binary nature) and the effect of exposure at diagnosis. During the 16-year study period, we studied 9,124 patients. Increasing cumulative use of angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors were associated with markedly improved cancer-specific survival; increasing use of NSAIDs was associated with markedly improved overall survival. These results were generally discordant with analyses evaluating the effect of current use and exposure at diagnosis. In conclusion, pharmacoepidemiology studies may be sensitive to the method of analysis; cumulative use analyses may be the most robust as it accounts for intermittent use and supports a dose-outcome relationship. Prospective studies are needed to confirm whether patients diagnosed with kidney cancer should be started on an angiotensin-converting enzyme inhibitor, NSAID or selective serotonin reuptake inhibitor to improve survival.

Predictors of Critical Care and Mortality in Bronchiolitis after Emergency Department Discharge.

OBJECTIVES: To identify the epidemiologic predictors and stratify the risk of critical care unit (CCU) admission or death in bronchiolitis following emergency department discharge. This information has not yet been explored. STUDY DESIGN: A population-based cohort study using Ontario-wide demographic and healthcare databases linked at the individual level. We assessed all infants with bronchiolitis discharged home from all emergency departments in Ontario, Canada, 2003-2014. Targeted information included plausible demographic and clinical predictors of CCU admission/death within 14 days of emergency department discharge. Using multivariable logistic regression analyses, we identified independent predictors of this outcome and stratified the outcome risk by the type of multivariable predictor. RESULTS: Of 34 270 study infants, 102 (0.3%) were admitted to CCU or died after discharge. Predictors of CCU admission/death were: comorbidities (OR 5.33; 95% CI 2.82-10.10), younger age [months] (OR 1.47; 95%CI 1.33-1.61), low income (OR 1.53; 95% CI 1.01-2.34), younger gestational age [weeks] (OR 1.14; 95%CI 1.06-1.22), and emergent presentation (Canadian Triage and Acuity Scale 2) at the index visit (OR 1.55, 95% CI 1.03-2.33). The absolute event risk of CCU admission/death in infants with versus without comorbidities were 1.5% versus 0.26%, respectively (P < .001). The odds of these outcomes in infants with comorbidities plus ≥2 other predictors were 25 times higher than in infants without predictors (OR 25.1, 95% CI 11.4-55.3). CONCLUSIONS: Infants with comorbidities plus other predictors discharged from the emergency department with bronchiolitis are at considerable risk of subsequent CCU admission and death. These risk factors should augment current clinical and social considerations determining patient disposition.

A population-based study of the risk of osteoporosis and fracture with dutasteride and finasteride.

BACKGROUND: Dutasteride is a potent inhibitor of 5-alpha reductase enzymes that reduces concentrations of dihydrotestosterone to a greater extent than finasteride. Whether this has adverse implications for bone health is unknown. We compared the risk of osteoporosis and fractures in older men treated with dutasteride or finasteride. METHODS: We conducted a population-based retrospective cohort study with high-dimensional propensity score matching of Ontario men aged 66 years or older who started treatment with dutasteride or finasteride between January 1, 2006 and December 31, 2012. The primary outcome was a diagnosis of osteoporosis within 2 years of treatment initiation. A secondary outcome was osteoporotic or fragility fractures. RESULTS: We studied 31,615 men treated with dutasteride and an equal number of men treated with finasteride. Dutasteride-treated patients had a lower incidence of osteoporosis than those receiving finasteride [2.2 versus 2.6 per 100 person years; hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.72 to 0.93]. This effect was no longer statistically significant following adjustment for specialty of prescribing physician (HR 0.90; 95% CI 0.78 to 1.02)]. There was no differential risk of fractures with dutasteride (HR 1.04; 95% 0.86 to 1.25). CONCLUSIONS: Despite differential effects on 5-alpha reductase, dutasteride is not associated with an increased risk of osteoporosis or fractures in older men relative to finasteride. These findings suggest that dutasteride does not adversely affect bone health.

The Cardiovascular Safety of Dutasteride.

PURPOSE: Randomized controlled trials suggest an increased risk of heart failure with dutasteride, which inhibits both the type 1 and type 2 isoforms of 5α-reductase. In contrast, no such association has been suggested for finasteride, which selectively inhibits the type 2 isoform. We investigated the risk of cardiovascular events among patients receiving dutasteride relative to finasteride. MATERIALS AND METHODS: We performed a population based cohort study of Ontario men 66 years old or older who commenced treatment with dutasteride or finasteride between October 1, 2005 and March 31, 2015. For each individual treated with dutasteride, we identified 1 treated with finasteride, matching on a propensity score and calendar quarter of treatment initiation to account for temporal changes in prescribing. The primary outcome was hospitalization for heart failure. Secondary analyses were done to examine acute myocardial infarction and stroke. Cox proportional hazards regression was used to adjust for differences between groups. RESULTS: We studied 36,311 men who commenced dutasteride and 36,311 treated with finasteride. In the primary analysis, we found no difference in the risk of heart failure among patients receiving dutasteride relative to those receiving finasteride (adjusted HR 0.98, 95% CI 0.88-1.08). Similarly, we found no difference in the risk of acute myocardial infarction (HR 0.94, 95% CI 0.82-1.08) or stroke (HR 1.03, 95% CI 0.88-1.20). CONCLUSIONS: In this population based cohort study of more than 72,000 older men, dutasteride was not associated with an increased risk of cardiovascular events relative to finasteride.

Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation.

BACKGROUND: Dabigatran etexilate is a prodrug whose absorption is opposed by intestinal P-glycoprotein and which is converted by carboxylesterase to its active form, dabigatran. Unlike other statins, simvastatin and lovastatin are potent inhibitors of P-glycoprotein and carboxylesterase, and might either increase the risk of hemorrhage with dabigatran etexilate or decrease its effectiveness. METHODS: We conducted 2 population-based, nested case-control studies involving Ontario residents 66 years of age and older who started dabigatran etexilate between May 1, 2012, and Mar. 31, 2014. In the first study, cases were patients with ischemic stroke; in the second, cases were patients with major hemorrhage. Each case was matched with up to 4 controls by age and sex. All cases and controls received a single statin in the 60 days preceding the index date. We determined the association between each outcome and the use of simvastatin or lovastatin, relative to other statins. RESULTS: Among 45 991 patients taking dabigatran etexilate, we identified 397 cases with ischemic stroke and 1117 cases with major hemorrhage. After multivariable adjustment, use of simvastatin or lovastatin was not associated with an increased risk of stroke (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.88 to 2.01). In contrast, use of simvastatin and lovastatin were associated with a higher risk of major hemorrhage (adjusted OR 1.46, 95% CI 1.17 to 1.82). INTERPRETATION: In patients receiving dabigatran etexilate, simvastatin and lovastatin were associated with a higher risk of major hemorrhage relative to other statins. Preferential use of the other statins should be considered in these patients.

Pregabalin and heart failure: A population-based study.

PURPOSE: The anticonvulsant pregabalin is increasingly prescribed for pain, seizures, and psychiatric disorders. Although evidence suggests pregabalin can cause edema and heart failure, its cardiac safety profile in clinical practice is unknown. We sought to examine the risk of heart failure among older patients receiving pregabalin compared to those receiving gabapentin. METHODS: We conducted a population-based cohort study of Ontarians aged 66 and older with a history of seizure who received pregabalin or gabapentin between April 2013 and March 2014. We used propensity scores to match patients commencing pregabalin to those commencing gabapentin. The primary outcome was an emergency department visit or hospitalization for heart failure within 90 days. RESULTS: We studied 9855 patients who initiated pregabalin and an equal number treated with gabapentin. In the primary analysis, we found no difference in the risk of heart failure with pregabalin compared to gabapentin (1.2% versus 1.3%, hazard ratio of 0.77; 95% CI 0.58-1.03). Secondary analyses stratified for baseline history of heart failure yielded similar findings. CONCLUSION: In a large cohort of older patients with a seizure disorder, pregabalin was not associated with an increased risk of heart failure relative to gabapentin.

Concomitant pulmonologist and primary care for chronic obstructive pulmonary disease: a population study.

Background: Pulmonologists provide quality care, however, their number is not adequate to take care of all the chronic obstructive pulmonary disease (COPD) needs of the population and their services come with a cost. Their optimal role should be defined, ideally based on evidence, to ensure that their abilities are applied most efficiently where needed. Objective: To determine if concomitant pulmonologist and primary care physician care after COPD hospital or emergency department discharge was associated with better health outcomes than primary care services alone. Methods: A population cohort study was conducted in Ontario, Canada from 2004 to 2011. All individuals with a COPD hospital or emergency department discharge were included. Patients who visited both a pulmonologist and a primary care physician within 30 days of the index discharge were matched to patients who had visited a primary care physician alone using propensity scores. The composite outcome of death, COPD hospitalization or COPD emergency department visit was compared using proportional hazards regression. Results: In the propensity score matched sample, 39.7% of patients who received concomitant care and 38.9% who received primary care only died or visited the emergency department visit or hospital for COPD within 1 year (adjusted hazard ratio 1.08, 95% confidence interval 1.00-1.17). The former, however, were more likely to receive diagnostic testing and medications. Conclusion: Patients who received concomitant care after COPD emergency department or hospital discharge did not have better outcomes than those who received primary care alone, however, they did receive more testing and medical management.

Onchocerca lupi Nematodes in Dogs Exported from the United States into Canada.

The Onchocerca lupi nematode is an emerging helminth capable of infecting pets and humans. We detected this parasite in 2 dogs that were imported into Canada from the southwestern United States, a region to which this nematode is endemic. We discuss risk for establishment of O. lupi in Canada.

Medication use and survival in diabetic patients with kidney cancer: A population-based cohort study.

Survival rates in kidney cancer have improved little over time, and diabetes may be an independent risk factor for poor survival in kidney cancer. We sought to determine whether medications with putative anti-neoplastic properties (statins, metformin and non-steroidal anti-inflammatory drugs (NSAIDs)) are associated with survival in diabetics with kidney cancer. We conducted a population-based cohort study utilizing linked healthcare databases in Ontario, Canada. Patients were aged 66 or older with newly diagnosed diabetes and a subsequent diagnosis of incident kidney cancer. Receipt of metformin, statins or NSAIDs was defined using prescription claims. The primary outcome was all-cause mortality and the secondary outcome was cancer-specific mortality. We used multivariable Cox proportional hazard regression, with medication use modeled with time-varying and cumulative exposure analyses to account for intermittent use. During the 14-year study period, we studied 613 patients. Current statin use was associated with a markedly reduced risk of death from any cause (adjusted hazard ratio 0.74; 95% CI 0.59-0.91) and death due to kidney cancer (adjusted hazard ratio 0.71; 95% CI 0.51-0.97). However, survival was not associated with current use of metformin or NSAIDs, or cumulative exposure to any of the medications studied. Among diabetic patients with kidney cancer, survival outcomes are associated with active statin use, rather than total cumulative use. These findings support the use of randomized trials to confirm whether diabetics with kidney cancer should be started on a statin at the time of cancer diagnosis to improve survival outcomes.

Socioeconomic status and risk of hemorrhage during warfarin therapy for atrial fibrillation: A population-based study.

BACKGROUND: Among patients taking warfarin, lower socioeconomic status is associated with poorer control of anticoagulation. However, the extent to which socioeconomic status influences the risk of hemorrhage is unknown. We examined the extent to which socioeconomic status influences the risk of hemorrhage in older individuals newly commencing warfarin therapy for atrial fibrillation. METHODS: We conducted a population-based cohort study of individuals 66 years or older with atrial fibrillation who commenced warfarin therapy between April 1, 1997, and November 30th 2011, in Ontario, Canada. We used neighborhood-level income quintiles as a measure of socioeconomic status. The primary outcome was an emergency department visit or hospitalization for hemorrhage, and the secondary outcome was fatal hemorrhage. RESULTS: We studied 166,742 older patients with atrial fibrillation who commenced warfarin therapy. Of these, 16,371 (9.8%) were hospitalized for hemorrhage during a median follow-up of 369 (interquartile range 102-865) days. After multivariable adjustment using Cox proportional hazards regression, we found that those in the lowest-income quintile faced an increased risk of hospitalization for hemorrhage relative to those in the highest quintile (adjusted hazard ratio 1.18, 95% CI 1.12-1.23). Similarly, the risk of fatal hemorrhage (n = 1,802) was increased in the lowest-income relative to the highest-income quintile (adjusted hazard ratio 1.28, 95% CI 1.11-1.48). CONCLUSIONS: Among older individuals receiving warfarin therapy for atrial fibrillation, lower socioeconomic status is a risk factor for hemorrhage and hemorrhage-related mortality. This factor should be carefully considered when initiating and monitoring warfarin therapy.

Prescription Stimulant Use and Hospitalization for Psychosis or Mania: A Population-Based Study.

Small studies suggest that prescription stimulants can precipitate psychosis and mania. We conducted a population-based case-crossover study to examine whether hospitalization for psychosis or mania was associated with initiation of stimulant therapy. Between October 1, 1999 and March 31, 2013, we studied 12,856 young people who received a stimulant prescription and were subsequently hospitalized for psychosis or mania. Of these, 183 commenced treatment during 1 of 2 prespecified 60-day intervals (defined as the "risk interval" and "control interval," respectively) prior to admission. We found that stimulant initiation was associated with an increased risk of hospitalization for psychosis or mania in the subsequent 60 days (odds ratio, 1.86; 95% confidence interval, 1.39-2.56). The risk was marginally higher in patients treated with antipsychotic drugs (odds ratio, 2.06; 95% confidence interval, 1.38-3.28), but remained in patients with no such history (odds ratio, 1.66; 95% confidence interval, 1.09-2.66). One third of subjects received another stimulant prescription after hospital discharge. Of these, 45% were readmitted with psychosis or mania shortly thereafter. We conclude that initiation of prescription stimulants is associated with an increased risk of hospitalization for psychosis or mania. Resumption of therapy is common, which may reflect a lack of awareness of the potential causative role of these drugs.

A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors.

AIMS: Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. METHODS: We conducted a nested case-control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor. RESULTS: Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings. CONCLUSIONS: Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.