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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.

Supplemental digital content is available in the text.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 transition towards low-carbon energy sources, such as wind, requires higher levels of public interaction; as such, the ultimate contribution of wind energy relies as much on technological advancements and policies as on societal sentiments. This study evaluates the influence of region, community involvement, and several IEA-recommended practices on social acceptance of wind energy projects among residents (n=350) surveyed from cities in four OECD and three non-OECD countries. The results indicate interurban variations among the generally high levels of acceptance reported, especially among residents of cities in developing countries with lower domestic CO2emissions. The level of community involvement in a hypothetical wind energy project had a positive effect on acceptance, and respondents from cities in countries with the highest installed wind capacity reported the greatest sensitivity towards involvement. Moreover, the results revealed that although the IEA-recommended practices collectively predicted acceptance across all cities, fair distribution of earnings and costs was the only significant individual predictor. These economic considerations, combined with increased community involvement, appear to be paramount to facilitating future development of wind energy. Through its broad geographical coverage, this research provides valuable groundwork for future cross-cultural studies on social acceptance of wind energy.

Suicide is the third most common cause of death among adolescents worldwide, and poisoning is the leading method of attempted suicide. Unlike more violent methods, survival after self-poisoning is common, providing an opportunity for secondary prevention. We determined the risk and time course of completed suicide after adolescent self-poisoning, and explored potential risk factors.

There have been few population-based studies describing the risk of adverse neonatal outcomes among women living with HIV in Canada. Accordingly, we compared the risk of preterm birth (PTB), low birth weight (LBW) and small for gestational age births among Ontario women aged 18 to 49 years living with and without HIV infection.

Trimethoprim–sulfamethoxazole increases the risk of hyperkalemia when used with spironolactone. We examined whether this drug combination is associated with an increased risk of sudden death, a consequence of severe hyperkalemia.

Northern high‐latitude deltas are hotspots of biogeochemical processing, terrestrial‐aquatic connectivity, and, in Alaska's Yukon‐Kuskokwim Delta (YKD), tundra wildfire. Yet, wildfire effects on aquatic biogeochemistry remain understudied in northern delta regions, thus limiting a more comprehensive understanding of high latitude biogeochemical cycles. In this study, we assess wildfire impacts on summertime aquatic biogeochemistry in YKD tundra using a multi‐year (2015–2019) data set of water chemistry measurements (n= 406) from five aquatic environments: peat plateau ponds, fen ponds, fen channels, lakes, and streams. We aimed to (a) characterize variation in hydrochemistry among aquatic environments; (b) determine wildfire effects on hydrochemistry; and (c) assess post‐fire multi‐year patterns in hydrochemistry in lakes (lower terrestrial‐freshwater connectivity) and fen ponds (higher connectivity). Variation in hydrochemistry among environments was more strongly associated with watershed characteristics (e.g., terrestrial‐aquatic connectivity) than wildfire. However, certain hydrochemical constituents showed consistent wildfire effects. Decreases in dissolved organic carbon (DOC) and CO2, and increases in pH, specific conductance, NH4+, and NO3−indicate that, by combusting soil organic matter, wildfire reduces organics available for hydrologic transport and microbial respiration, and mobilizes nitrogen into freshwaters. Multi‐year post‐fire variation in specific conductance, DOC, and CO2in lakes and fen ponds suggest that watershed characteristics underlie ecosystem response and recovery to wildfire in the YKD. Together, these results indicate that increasing tundra wildfire occurrence at northern high latitudes could drive multi‐year shifts toward stronger aquatic inorganic nutrient cycling, and that variation in terrain characteristics is likely to underlie wildfire effects on aquatic ecosystems across broader scales. Warming at northern high latitudes is expected to increase wildfire activity, permafrost thaw, and hydrologic connectivity. Yet, contrasting evidence for wildfire effects on aquatic biogeochemistry hinders a more concrete understanding of potential future changes to northern ecosystems, especially in delta environments, where land‐freshwater linkages are strong. To address this, we made ∼400 measurements of hydrochemistry within the Yukon‐Kuskokwim Delta, Alaska, following high wildfire activity in 2015. Variation in hydrochemistry among five aquatic environments—peat plateau ponds, fen ponds, fen channels, lakes, and streams—was more strongly associated with watershed characteristics (e.g., land‐freshwater linkages) than wildfire. However, wildfire consistently affected some parameters. For instance, dissolved organic carbon and CO2were lower in burned watersheds, likely from combustion of organic matter, whereas, pH, specific conductance, and nitrogen were higher, reflecting solute release from combusted organics. Multi‐year measurements (2015–2019) allowed us to assess post‐fire variation in hydrochemistry among lakes and fen ponds, and indicate that ecosystem response and recovery to wildfire depend on watershed characteristics. Results indicate that increasing tundra wildfire at northern high latitudes could drive multi‐year shifts toward stronger aquatic inorganic nutrient cycling. Across broader spatiotemporal scales, variation in terrain characteristics is likely to underlie wildfire effects on aquatic ecosystems. Variation in hydrochemistry across tundra aquatic environments was more strongly coupled to physiographic factors than to wildfire effectsWildfire generally reduced dissolved organic carbon (DOC) and CO2, and enhanced ion mobility and nitrogen cycling, but effects variedWildfire effects on some hydrochemical constituents persisted beyond 3 years (e.g., DOC, CO2) and were brief for others (conductivity) Variation in hydrochemistry across tundra aquatic environments was more strongly coupled to physiographic factors than to wildfire effects Wildfire generally reduced dissolved organic carbon (DOC) and CO2, and enhanced ion mobility and nitrogen cycling, but effects varied Wildfire effects on some hydrochemical constituents persisted beyond 3 years (e.g., DOC, CO2) and were brief for others (conductivity)

Genital epithelial cells (ECs) are the first line of defense that sexually transmitted viruses encounter. The mechanism of viral pathogenesis in these cells is not well understood. Here, we show that a primary cell culture model from human reproductive tract tissues can be used as a novel ex vivo model in examining the interaction of herpes simplex virus, type 2 (HSV-2), with female genital mucosa. Confluent, polarized primary cultures of human endometrial and cervical ECs were established and shown to be free from any significant contamination of any other cell type. Both endometrial and cervical ECs were found to be highly susceptible to HSV-2 infection. The kinetic of infection was similar to in vivo infection, with the earliest viral shedding seen at 18 h postinfection. Primary EC monolayers could be infected both apically and basolaterally, but preferential viral shedding was seen on the apical side of cells. Following treatment of the monolayers with poly (I:C), an innate immune activator that acts via TLR3, viral shedding was reduced significantly, comparable to levels seen when an antiviral formulation, acyclovir, was used. Treatment of epithelial and stromal co-cultures with estradiol increased HSV-2 infection in endometrial ECs, but viral shedding decreased following treatment with progesterone. To the best of our knowledge, this is the first study that examines the interaction of primary human female genital ECs with HSV-2, using an ex vivo culture model. The results provide valuable information regarding the susceptibility of women's genital ECs to HSV-2 and the ability of innate immunity and hormones to modify this susceptibility.

The relative significance of mechanical penetration versus the action of substrate-degrading enzymes during solid tissue invasion has not been established for any fungal disease. Pythium insidiosumis an oomycete fungus (or stramenopile) that causes a rare, but potentially lethal infection in humans and other mammalian hosts. Experiments with miniature strain gauges showed that single hyphal apices of this pathogen exert forces of up to 6.9 μN, corresponding to maximum pressures of 0.3 μN μm−2or MPa. Samples of cutaneous and subcutaneous tissue from fresh human cadavers displayed a mean strength (resistance to needle puncture) of 24 μN μm−2, and a mean pressure of 30 μN μm−2was necessary to penetrate skin strips from slaughtered horses. These experiments demonstrate that P. insidiosumdoes not exert sufficient pressure to penetrate undamaged skin by mechanics alone, but must effect a decisive reduction in tissue strength by proteinase secretion.

ObjectiveTo develop and validate a set of practical prediction tools that reliably estimate the outcome of subarachnoid haemorrhage from ruptured intracranial aneurysms (SAH).DesignCohort study with logistic regression analysis to combine predictors and treatment modality.SettingSubarachnoid Haemorrhage International Trialists’ (SAHIT) data repository, including randomised clinical trials, prospective observational studies, and hospital registries.ParticipantsResearchers collaborated to pool datasets of prospective observational studies, hospital registries, and randomised clinical trials of SAH from multiple geographical regions to develop and validate clinical prediction models.Main outcome measurePredicted risk of mortality or functional outcome at three months according to score on the Glasgow outcome scale.ResultsClinical prediction models were developed with individual patient data from 10 936 patients and validated with data from 3355 patients after development of the model. In the validation cohort, a core model including patient age, premorbid hypertension, and neurological grade on admission to predict risk of functional outcome had good discrimination, with an area under the receiver operator characteristics curve (AUC) of 0.80 (95% confidence interval 0.78 to 0.82). When the core model was extended to a “neuroimaging model,” with inclusion of clot volume, aneurysm size, and location, the AUC improved to 0.81 (0.79 to 0.84). A full model that extended the neuroimaging model by including treatment modality had AUC of 0.81 (0.79 to 0.83). Discrimination was lower for a similar set of models to predict risk of mortality (AUC for full model 0.76, 0.69 to 0.82). All models showed satisfactory calibration in the validation cohort.ConclusionThe prediction models reliably estimate the outcome of patients who were managed in various settings for ruptured intracranial aneurysms that caused subarachnoid haemorrhage. The predictor items are readily derived at hospital admission. The web based SAHIT prognostic calculator (http://sahitscore.com) and the related app could be adjunctive tools to support management of patients.

Objective To determine the association between vasectomy and prostate cancer, adjusting for measures of health seeking behaviour.Design Population based matched cohort study.Setting Multiple validated healthcare databases in Ontario, Canada, 1994-2012.Participants 326 607 men aged 20 to 65 who had undergone vasectomy were identified through physician billing codes and matched 1:1 on age (within two years), year of cohort entry, comorbidity score, and geographical region to men who did not undergo a vasectomy.Main outcomes measures The primary outcome was incident prostate cancer. Secondary outcomes were prostate cancer related grade, stage, and mortality.Results 3462 incident cases of prostate cancer were identified after a median follow-up of 10.9 years: 1843 (53.2%) in the vasectomy group and 1619 (46.8%) in the non-vasectomy group. In unadjusted analysis, vasectomy was associated with a slightly increased risk of incident prostate cancer (hazard ratio 1.13, 95% confidence interval 1.05 to 1.20). After adjustment for measures of health seeking behaviour, however, no association remained (adjusted hazard ratio 1.02, 95% confidence interval 0.95 to 1.09). Moreover, no association was found between vasectomy and high grade prostate cancer (adjusted odds ratio 1.05, 95% confidence interval 0.67 to 1.66), advanced stage prostate cancer (adjusted odds ratio 1.04, 0.81 to 1.34), or mortality (adjusted hazard ratio 1.06, 0.60 to 1.85).Conclusion The findings do not support an independent association between vasectomy and prostate cancer.

ObjectiveTo determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death.DesignPopulation based nested case-control study.SettingOntario, Canada, from 1 April 1994 to 1 January 2012.ParticipantsOntario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes.Main outcome measureOdds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index.ResultsOf 39 879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin.ConclusionsIn older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.

Objective: To describe the effects of montelukast, a leukotriene receptor antagonist commonly used in the treatment of allergic rhinitis and asthma, on the symptoms of interstitial cystitis (IC).Case Summary: A 64-year-old male had a history of IC with previous trials of solifenacin, dutasteride, and tamsulosin and little improvement in IC symptom reduction. When montelukast 10 mg was initiated for allergic rhinitis symptoms, a substantial improvement in urinary urgency and pain during therapy was noted. This improvement subsequently disappeared when montelukast was stopped.Discussion: IC, a rare occurrence in the male population, is related to an inflammatory process and has also been associated with inappropriate leukotriene release, which is the target of montelukast therapy. In general, treatment for IC Includes systemic medical therapy, local bladder treatment, surgical and neurosurgical procedures, and intravesical drug installation. Currently, montelukast is Food and Drug Administration approved for use in the treatment and prevention of mild-to-moderate asthma and exercise-induced asthma, as well as treatment of seasonal and perennial allergic rhinitis. While montelukast treatment did not cure the patient's IC, it improved his quality of life through substantial symptomatic relief, including less pain and urgency.Conclusions: Montelukast may be an effective treatment option in the management of interstitial cystitis. Further research is needed to substantiate this novel use.