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Objective: Current scores for predicting sepsis outcomes are limited by generalizability, complexity, and electronic medical record (EMR) integration. Here, we validate a simple EMR-based score for sepsis outcomes in a large multi-centre cohort., Design: A simple electronic medical record-based predictor of illness severity in sepsis (SEPSIS) score was developed (4 additive lab-based predictors) using a population-based retrospective cohort study., Setting: Internal medicine services across four academic teaching hospitals in Toronto, Canada from April 2010-March 2015 (primary cohort) and 2015-2019 (secondary cohort)., Patients: We identified patients admitted with sepsis based upon receipt of antibiotics and positive cultures., Measurements and Main Results: The primary outcome was in-hospital mortality and secondary outcomes were ICU admission at 72 hours, and hospital length of stay (LOS). We calculated the area under the receiver operating curve (AUROC) for the SEPSIS score, qSOFA, and NEWS2. We then evaluated the SEPSIS score in a secondary cohort (2015-2019) of hospitalized patients receiving antibiotics. Our primary cohort included 1,890 patients with a median age of 72 years (IQR: 56-83). 9% died during hospitalization, 18.6% were admitted to ICU, and mean LOS was 12.7 days (SD: 21.5). In the primary and secondary (2015-2019, 4811 patients) cohorts, the AUROCs of the SEPSIS score for predicting in-hospital mortality were 0.63 and 0.64 respectively, which were similar to NEWS2 (0.62 and 0.67) and qSOFA (0.62 and 0.68). AUROCs for predicting ICU admission at 72 hours, and length of stay > 14 days, were similar between scores, in the primary and secondary cohorts. All scores had comparable calibration for predicting mortality., Conclusions: An EMR-based SEPSIS score shows a similar ability to predict important clinical outcomes compared with other validated scores (qSOFA and NEWS2). Because of the SEPSIS score's simplicity, it may prove a useful tool for clinical and research applications., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cressman 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.)

Background: Identifying potentially avoidable admissions to Canadian hospitals is an important health system goal. With general internal medicine (GIM) accounting for 40% of hospital admissions, we sought to develop a method to identify potentially avoidable admissions and characterize patient, provider and health system factors., Methods: We conducted an observational study of GIM admissions at our institution from August 2019 to February 2020. We defined potentially avoidable admissions as admissions that could be managed in an appropriate and safe manner in the emergency department or ambulatory setting and asked staff physicians to screen admissions daily and flag candidates as potentially avoidable admissions. For each candidate, we prepared a case review and debriefed with members of the admitting team. We then reviewed each candidate with our research team, assigned an avoidability score (1 [low] to 4 [high]) and identified contributing factors for those with scores of 3 or more., Results: We screened 601 total admissions and staff physicians flagged 117 (19.5%) of these as candidate potential avoidable admissions. Consensus review identified 67 candidates as potentially avoidable admissions (11.1%, 95% confidence interval 8.8%-13.9%); these patients were younger (mean age 65 yr v. 72 yr), had fewer comorbidities (Canadian Institute for Health Information Case Mix Group+ 0.42 v. 1.14), had lower resource-intensity weighting scores (0.72 v. 1.50) and shorter hospital lengths of stay (29 h v. 105 h) ( p < 0.01). Common factors included diagnostic and therapeutic uncertainty, perceived need for short-term monitoring, government directive of a 4-hour limit for admission decision-making and subspecialist request to admit., Interpretation: Our prospective method of screening, flagging and case review showed that 1 in 9 GIM admissions were potentially avoidable. Other institutions could consider adapting this methodology to ascertain their rate of potentially avoidable admissions and to understand contributing factors to inform improvement endeavours., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: Physicians face competing demands of maximizing pathogen coverage while minimizing unnecessary use of broad-spectrum antibiotics when managing sepsis. We sought to identify physicians' perceived likelihood of coverage achieved by their usual empiric antibiotic regimen, along with minimum thresholds of coverage they would be willing to accept when managing these patients., Methods: We conducted a scenario-based survey of internal medicine physicians from across Canada using a 2 × 2 factorial design, varied by infection source (undifferentiated vs genitourinary) and severity (mild vs severe) denoted by the Quick Sequential Organ Failure Assessment (qSOFA) score. For each scenario, participants selected their preferred empiric antibiotic regimen, estimated the likelihood of coverage achieved by that regimen, and considered their minimum threshold of coverage., Results: We had 238 respondents: 87 (36.6%) residents and 151 attending physicians (63.4%). The perceived likelihood of antibiotic coverage and minimum thresholds of coverage (with interquartile range) for each scenario were as follows: (1) severe undifferentiated, 90% (89.5%-95.0%) and 90% (80%-95%), respectively; (2) mild undifferentiated, 89% (80%-95%) and 80% (70%-89.5%); (3) severe genitourinary, 91% (87.3%-95.0%) and 90% (80.0%-90.0%); and (4) mild genitourinary, 90% (81.8%-91.3%) and 80% (71.8%-90%). Illness severity and infectious disease specialty predicted higher thresholds of coverage whereas less clinical experience and lower self-reported prescribing intensity predicted lower thresholds of coverage., Conclusions: Pathogen coverage of 80% and 90% are physician-acceptable thresholds for managing patients with mild and severe sepsis from bacterial infections. These data may inform clinical guidelines and decision-support tools to improve empiric antibiotic prescribing., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Transfusion-associated circulatory overload (TACO) is a leading cause of serious reactions. In regard to TACO, little is known regarding biomarkers as a predictor, their most informative timing, or thresholds of significance or differentiation from other reactions., Study Design and Methods: In this study of inpatients at risk for TACO (age ≥ 50 years) receiving 1 red blood cell unit, cardiac biomarkers, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and high-sensitivity troponin were measured at baseline, 6 to 12 hours (except troponin) posttransfusion, and 18 to 24 hours posttransfusion. Primary outcome was a critical increase in biomarkers (>1.5-fold increase and supranormal) at 18 to 24 hours., Results: Fifty-one patients were analyzed; 29% had cardiovascular disease, 73% had one or more cardiac risk factors, and 50% took cardiac or antihypertensive therapies. Although eight (16%) developed an increase in systolic pressure of at least 30 mmHg and four (8%) reported dyspnea and/or cough, none had TACO. At baseline, BNP level was more than 100 ng/L in 59% and NT-proBNP was more than 300 pg/mL in 83%. A total of 25% had a BNP critical increase, 33% had a NT-proBNP critical increase, and 2% had a troponin critical increase at 18 to 24 hours. Overall, 38% had at least one biomarker critical increase and NT-proBNP/BNP concordance was 84%. An increase in the NT-proBNP (>1.5-fold increase and >300 pg/mL) at 18 to 24 hours was the commonest biomarker change., Conclusions: An increase of the NT-proBNP at 18 to 24 hours may be the preferred surrogate marker for identifying a patient experiencing physiologic difficulty in handling the volume challenge. Larger studies are needed to clarify the risk of TACO for a given pretransfusion biomarker profile and the correlation between TACO and increase in biomarkers after transfusion., (© 2018 AABB.)

Background: Naloxone is life-saving when administered after opioid overdose. In March 2016, the Canadian government made the antidote available without prescription, but anecdotal reports suggest members of the public have difficulty in procuring it. We examined the availability of naloxone in community pharmacies across Canada., Methods: We identified community pharmacies in Canada ( n = 10 296) and randomly selected 506, stratified using proportionate allocation by population size. We excluded pharmacies in Alberta and Manitoba because these provinces released data indicating which pharmacies made naloxone available to the public during the data collection phase of the study. We contacted pharmacies by telephone during working hours and used a standardized survey to enquire about the availability of naloxone, the associated cost and the need for a prescription. When a pharmacy did not have naloxone available, we ascertained if it could be procured within 7 days., Results: We contacted 429 community pharmacies. Of these, 103 (24.0%) had naloxone available. Availability was highest in British Columbia (33 of 65; 50.8%), followed by the Maritimes (12 of 35; 34.3%), Ontario (52 of 193; 26.9%) and central and northern Canada (5 of 21; 23.8%). In Quebec, 1 of 115 (0.9%) pharmacies had naloxone available. Of pharmacies without naloxone, fewer than 1 in 5 anticipated being able to provide it within 1 week (63 of 326; 19.3%)., Interpretation: Most community pharmacies in Canada did not have naloxone on hand and in those without naloxone available, fewer than 1 in 5 anticipated being able to provide it within 1 week. Our findings emphasize the need for increased availability of naloxone in pharmacies across Canada., Competing Interests: Competing interests: Dr. Gomes reports receiving grants from the Ontario Ministry of Health and Long-Term Care for research unrelated to the present work., (Copyright 2017, Joule Inc. or its licensors.)

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.

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., (© 2015 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Cocaine abuse during pregnancy is a significant public health problem but is infrequently discussed between physicians and patients. The impact of in utero cocaine exposure on pregnancy and the baby has received significant media attention in preceding decades because of fears of teratogenicity, long-term health consequences, and poor cognitive and neurodevelopmental outcomes. We sought to review the medical literature examining these phenomena. We identified risks to the pregnancy and baby in women abusing cocaine during pregnancy. These include preterm birth, placenta-associated syndromes (e.g., placental abruption, preeclampsia, and placental infarction), and impaired fetal growth. Long-term neurodevelopmental and cognitive deficits include (but are not limited to) poorer language development, learning and perceptual reasoning, behavioural problems, and adverse effects on memory and executive function. However, these results should be interpreted cautiously because cocaine abuse may be accompanied by many other maternal and sociodemographic risk factors, so it is difficult to ascertain the effect of cocaine alone. Therefore, it is critical to counsel patients about potential risk, and perhaps more importantly, to treat addiction and to better understand, and advocate for improvements to, these patients' high-risk environment.

Preventing and treating malaria in pregnancy is a global health priority. However little is known regarding the impact of malaria infection on the maternal and fetal disposition of pharmaceuticals and other xenobiotics. Our objective was to characterize expression of key determinants of drug-disposition in maternal and fetal tissues in a validated murine model of experimental placental malaria. Balb/c mice were infected with Plasmodium berghei at mid gestation [gestational day (GD) 13] and maternal, placental, and fetal tissues were collected at GD19. Expression of key ABC drug transporters and Cyp3a11 was examined by quantitative polymerase chain reaction. Western blotting was used to examine the protein expression of multidrug resistance protein 1 (MDR1, ABCB1). Compared with controls, placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the malaria-infected group (P < 0.05), as was placental MDR1 protein (P < 0.05). Significantly decreased hepatic expression of Abcc2, Abcg2, and Abcb11 and significantly increased expression of Abcb1b, Abcc1, and Abcc3 were seen in malaria-infected dams (P < 0.05) in comparison with uninfected controls. The expression of Abcb1a and Abcg2 was significantly decreased in fetal liver of infected dams, whereas levels of Abcb1b were increased (P < 0.05). Maternal and fetal hepatic expression of Cyp3a11 was significantly downregulated in the malaria group (P < 0.05). Together, malaria-induced alterations in the expression of transporters and drug-metabolizing enzymes in maternal and fetal tissues may alter the disposition of endogenous and therapeutic substrates, potentially impacting maternal and fetal outcomes.

Molecular medicine is moving beyond genomics to encompass the new scientific field of epigenetics. First described as a conceptual model of how genes might interact with their surroundings to produce a phenotype, epigenomic research currently investigates mechanisms of nongenetic modification contributing to gene regulation and examines the impact of these changes on human health and behavior.

Question: In my practice several patients have struggled with cocaine abuse during their pregnancies. One woman, now postpartum, wants to breastfeed her infant. Despite being abstinent for the final few months of her pregnancy, I am concerned about the potential adverse effects on her child if she happens to relapse. What is the current evidence about the risks of cocaine exposure during breastfeeding?, Answer: Given the substantial benefits of breastfeeding for infant health and development, there is no reason for mothers who previously abused cocaine to avoid breastfeeding. It is important for the health care team to counsel patients both on the serious potential risks of cocaine exposure for babies and on the benefits of breastfeeding, to allow for an informed choice. Additionally, attempts should be made to estimate maternal commitment to breastfeeding and discontinuation of cocaine use, and to offer addiction counseling to mitigate the potential risks of infant cocaine exposure. It is paramount to minimize the risk to the infant, which would certainly include mothers ceasing use of cocaine while breastfeeding. For mothers who elect to breastfeed and use cocaine intermittently, breastfeeding should be delayed sufficiently after cocaine use to allow for drug elimination (approximately 24 hours).

Question: Despite being highly motivated to quit, many of my patients struggle with smoking cessation during pregnancy. Can you comment on the current treatment options and discuss their safety and efficacy during pregnancy?, Answer: Given the considerable and well-documented adverse effects of antenatal smoking on mother and fetus, pharmacotherapy for smoking cessation should be considered. Available medications include nicotine replacement therapy, sustained-release bupropion, and varenicline. Nicotine replacement therapy and bupropion do not appear to increase the risk of major malformations; however, there is currently limited evidence on the use of varenicline during pregnancy. Given that these agents are only marginally successful in smoking cessation, their use should always be accompanied by behavioural counseling and education to maximize quit rates.

Inflammation plays a critical role in host defense, maintaining cellular and tissue integrity following chemical, physical and biological insults. Inflammation presents in a variety of acute and chronic disease states and can contribute to disease resolution or progression depending upon the type, magnitude and duration of response. Importantly, it has been shown to modulate pharmacokinetic processes leading to variability in therapeutic drug response. Membrane-associated drug transporters are important determinants of drug disposition and pharmacokinetics and we, among others, have identified inflammation-mediated changes in their expression and regulation. Here, we discuss the current state of knowledge on drug transporter expression during acute and chronic inflammatory conditions and postulate how the altered expression of these transporters may modify the pharmacokinetics and pharmacodynamics of clinically important therapeutics. As understanding determinants of interpatient variability in therapeutic drug response is essential to the practice of medicine, this area of research warrants future clinical focus.

Drug efflux transporters in the placenta can significantly influence the materno-fetal transfer of a diverse array of drugs and other xenobiotics. To determine if clinically important drug efflux transporter expression is altered in pregnancies complicated by gestational diabetes mellitus (GDM-I) or type 1 diabetes mellitus (T1DM-I), we compared the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2) and the breast cancer resistance protein (BCRP) via western blotting and quantitative real-time polymerase chain reaction in samples obtained from insulin-managed diabetic pregnancies to healthy term-matched controls. At the level of mRNA, we found significantly increased expression of MDR1 in the GDM-I group compared to both the T1DM-I (p<0.01) and control groups (p<0.05). Significant changes in the placental protein expression of MDR1, MRP2, and BCRP were not detected (p>0.05). Interestingly, there was a significant, positive correlation observed between plasma hemoglobin A1c levels (a retrospective marker of glycemic control) and both BCRP protein expression (r = 0.45, p<0.05) and BCRP mRNA expression (r = 0.58, p<0.01) in the insulin-managed DM groups. Collectively, the data suggest that the expression of placental efflux transporters is not altered in pregnancies complicated by diabetes when hyperglycemia is managed; however, given the relationship between BCRP expression and plasma hemoglobin A1c levels it is plausible that their expression could change in poorly managed diabetes.