An assessment of federal alcohol policies in Canada and priority recommendations: Results from the 3rd Canadian Alcohol Policy Evaluation Project.

OBJECTIVE: To systematically assess the Canadian federal government's current alcohol policies in relation to public health best practices. METHODS: The 2022 Canadian Alcohol Policy Evaluation (CAPE) Project assessed federal alcohol policies across 10 domains. Policy domains were weighted according to evidence for their relative impact, including effectiveness and scope. A detailed scoring rubric of best practices was developed and externally reviewed by international experts. Policy data were collected between June and December 2022, using official legislation, government websites, and data sources identified from previous iterations of CAPE as sources. Contacts within relevant government departments provided any additional data sources, reviewed the accuracy and completeness of the data, and provided amendments as needed. Data were scored independently by members of the research team. Final policy scores were tabulated and presented as a weighted overall average score and as unweighted domain-specific scores. RESULTS: Compared to public health best practices, the federal government of Canada scored 37% overall. The three most impactful domains-(1) pricing and taxation, (2) marketing and advertising controls, and (3) impaired driving countermeasures-received some of the lowest scores (39%, 10%, and 40%, respectively). Domain-specific scores varied considerably from 0% for minimum legal age policies to 100% for controls on physical availability of alcohol. CONCLUSION: Many evidence-informed alcohol policies have not been adopted, or been adopted only partially, by the Canadian federal government. Urgent adoption of the recommended policies is needed to prevent and reduce the enormous health, social, and economic costs of alcohol use in Canada.

RéSUMé: OBJECTIF: Évaluer de manière systématique les politiques sur l'alcool actuelles du gouvernement fédéral canadien dans le cadre de pratiques de santé publique exemplaires. MéTHODES: Le projet de l'Évaluation des politiques canadiennes sur l'alcool 2022 a évalué les politiques fédérales sur l'alcool dans dix domaines. Ces domaines de politiques ont été pondérés en fonction de preuves sur leurs répercussions relatives, notamment leur efficacité et leur portée. Une échelle d'évaluation descriptive détaillée de pratiques exemplaires a été élaborée et examinée à l'externe. Entre juin et décembre 2022, des données sur les politiques ont été recueillies dans la législation officielle, sur des sites Web du gouvernement et au moyen de sources identifiées comme telles au cours des itérations précédentes du projet de l'Évaluation des politiques canadiennes sur l'alcool. Des personnes-ressources au sein des ministères concernés ont communiqué d'autres sources de données, examiné l'exactitude et le caractère exhaustif de ces données et apporté les modifications nécessaires. Les données ont été évaluées indépendamment par des membres de l'équipe de recherche. Les scores de politiques finaux ont été inscrits dans des tableaux et présentés sous forme d'une moyenne générale pondérée et de scores non pondérés par domaine. RéSULTATS: Comparativement aux pratiques de santé publique exemplaire, le gouvernement fédéral du Canada a obtenu un score général de 37 %. Les trois domaines susceptibles d'avoir les plus grandes répercussions, à savoir 1) la fixation des prix et la taxation, 2) le contrôle du marketing et de la publicité, et 3) les mesures contre la conduite avec facultés affaiblies, se sont vu attribuer parmi les scores les plus bas (39 %, 10 %, et 40 % respectivement). Les scores par domaine variaient considérablement, allant de 0 % pour les politiques sur l'âge minimum légal à 100 % pour le contrôle de la disponibilité physique de l'alcool. CONCLUSION: De nombreuses politiques sur l'alcool reposant sur des preuves n'ont pas été adoptées, ou l'ont été seulement partiellement, par le gouvernement fédéral canadien. Il est urgent d'appliquer les politiques recommandées pour prévenir et réduire les énormes coûts sanitaires, sociaux et économiques de la consommation d'alcool au Canada.

Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease.

BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell-like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis. METHODS: We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis. RESULTS: SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant KrasG12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. CONCLUSIONS: Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease.

Bridge to Weight Loss: A Case Series.

Durable left ventricular assist devices (LVADs) are a well-established therapeutic option for patients with advanced heart failure. These devices are often used to "bridge" patients to an orthotopic heart transplantation (HT). Unfortunately, many patients on LVAD support with a body mass index (BMI) above a certain value are not eligible for HT due a lack of suitable donors and the association between obesity and poor outcomes after HT. This case series describes three individuals on LVAD support who were able to successfully lose enough weight to qualify to be listed for an HT. We highlight a systematic, multidisciplinary approach to implementing guideline-driven weight loss strategies, including some aggressive methods (ie, meal replacements, weight loss medications, and bariatric surgery). In addition to describing the weight loss outcomes, we also discuss barriers and medical challenges during weight loss that are unique to this population.

Cardiac rehabilitation utilization, barriers, and outcomes among patients with heart failure.

Exercise-based cardiac rehabilitation (CR) is effective for improving both primary (i.e., mortality and hospitalizations) and secondary (i.e., functional capacity and quality of life among) clinical outcomes among patients with heart failure (HF). The mechanisms that explain these benefits are complex and are linked to exercise adaptations such as central and peripheral hemodynamics combined with improved overall medical management. Despite the benefits of CR, utilization rates are low among CR eligible patients. Clinician-, patient-, and health system-related barriers have been identified as primary factors contributing to the lack of CR utilization among HF patients. These include patient referrals (clinician-related), psychosocial factors (patient-related), and patient access to CR services (health system-related). The aims of this review are to detail the components of each barrier as well as identify evidence-based strategies to improve CR utilization and adherence among HF. The improvements in primary and secondary outcomes along with the mechanisms that are linked to these changes will also be examined.

Atherosclerosis is a smooth muscle cell-driven tumor-like disease.

Atherosclerosis, the leading cause of cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC "phenotypic switching" plays a central role in atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that atherosclerosis, in terms of SMC behaviors, share extensive commonalities with tumors. SMC-derived cells in the disease show multiple characteristics of tumor cell biology, including genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. SMC-specific expression of oncogenic KrasG12D accelerates SMC phenotypic switching and exacerbates atherosclerosis. Moreover, we present a proof of concept showing that niraparib, an anti-cancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that atherosclerosis is a tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic cardiovascular disease.

A Decision 85 Years in the Making.

On October 6, 2022, President Biden announced that he is taking steps to pardon those convicted of simple marijuana possession at the federal level and reconsider the classification of cannabis as a Schedule I substance. At the same time, Congress is working to pass legislation to streamline research in the cannabis space. These efforts signal that federal marijuana laws that have been in place for the past 85 years have created a multitude of problems, including barriers to research, and the federal government is finally considering decisions to create change.

Evaluating Statin Tolerability in Historically Intolerant Patients After Correcting for Subclinical Hypothyroidism and Vitamin D Insufficiency.

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) is the major cause of morbidity and mortality worldwide. Statins provide primary and secondary ASCVD prevention. Intolerance due to statin-associated myalgias reduces long-term adherence, thus muting potential benefits. AIM: Our analysis sought to determine whether transition from a lipophilic statin to a water-soluble statin, or correction of subclinical hypothyroidism and/or vitamin D insufficiency/deficiency (metabolic abnormalities), improved statin tolerance. METHODS: We performed a retrospective analysis of the data from patients referred to our lipid clinic because of statin intolerance. Patients intolerant to a lipophilic statin were switched to a water-soluble statin. Patients having vitamin D insufficiency/deficiency or subclinical hypothyroidism were re-challenged with a water-soluble statin (or lipophilic statin with minimal systemic exposure) after correction of the metabolic abnormality. RESULTS: 169 patients were statin intolerant. 86% (n = 145) were white and 48% (n = 81) were male. 82 of these patients had one or both metabolic abnormalities. The remaining patients (n = 87) had no metabolic abnormality, however, were unable to tolerate a lipophilic statin. 72% (n = 73) of eligible patients (n = 101), defined as those with a corrected metabolic abnormality or without a metabolic abnormality on a lipophilic statin, were able to tolerate a water-soluble statin or lipophilic statin with minimal systemic exposure. In addition, 75% (n = 127) of this total cohort met their LDL-C goal. CONCLUSIONS: Our findings suggest that either correction of subclinical hypothyroidism and/or vitamin D insufficiency/deficiency or transition from a lipophilic statin to water-soluble statin (or lipophilic statin with minimal systemic exposure) improves statin tolerance.

The Canadian Alcohol Policy Evaluation project: Findings from a review of provincial and territorial alcohol policies.

INTRODUCTION: Effective alcohol control measures can prevent and reduce alcohol-related harms at the population level. This study aims to evaluate implementation of alcohol policies across 11 evidence-based domains in Canada's 13 jurisdictions. METHODS: The Canadian Alcohol Policy Evaluation project assessed all provinces and territories on 11 evidence-based domains weighted for scope and effectiveness. A scoring rubric was developed with policy and practice indicators and peer-reviewed by international experts. The 2017 data were collected from publicly-available regulatory documents, validated by government officials, and independently scored by team members. RESULTS: The average score for alcohol policy implementation across Canadian provinces and territories was 43.8%; Ontario had the highest (63.9%) and Northwest Territories the lowest (38.4%) jurisdictional scores. Only six of 11 policy domains had average scores above 50% with Monitoring and Reporting scoring the highest (62.8%) and Health and Safety Messaging the lowest (25.7%). A 2017 provincial/territorial current best practice score of 86.6% was calculated taking account of the highest scores for any individual policy indicators implemented in at least one jurisdiction across the country. DISCUSSION AND CONCLUSIONS: Most of the evidence-based alcohol policies assessed by the Canadian Alcohol Policy Evaluation project were not implemented across Canadian provinces and territories as of 2017, and many provinces showed declining scores since 2012. However, the majority of policies assessed have been implemented in at least one jurisdiction. Improved alcohol policies to reduce related harm are therefore achievable and could be implemented consistently across Canada.

Is Duration of Symptoms Predictive of Acute Myocardial Infarction?

Patient interviews regarding the duration of symptoms are commonly conducted when evaluating a patient with possible acute myocardial infarction (AMI) and are believed to distinguish between AMI and non-AMI symptoms. In a single center, 569 patients evaluated in the emergency department (ED) for possible AMI from May 2013 to April 2015 were prospectively studied. Patients in the ED were asked by trained research personnel about the duration of their predominant symptom. The final diagnosis of AMI was determined by an independent cardiologist and emergency medicine physician in accordance with the third universal definition of AMI. Disagreements were settled by a third physician (cardiologist) who reviewed the case. There were 44 (8%) AMIs and 484 (85%) patients had chest pain as their predominant symptom. In the 26 type 1 AMIs, the median symptom duration was 3.3 hours, while in the 18 type 2 AMIs it was 1.3 hours. AMI was not present if symptom duration was under 20 minutes and was more likely during the 20-59 minute period. In conclusion, clinical symptoms still play a prominent role in the evaluation of a patient with possible AMI in the ED. Duration of symptoms was not very helpful in distinguishing between patients with AMI and those with non-AMI, except in the time interval of 20-59 minutes.

Gel rupture during dynamic swelling.

Hydrogels have had a profound impact in the fields of tissue engineering, drug delivery, and materials science as a whole. Due to the network architecture of these materials, imbibement with water often results in uniform swelling and isotropic expansion which scales with the degree of cross-linking. However, the development of internal stresses during swelling can have dramatic consequences, leading to surface instabilities as well as rupture or bursting events. To better understand hydrogel behavior, macroscopic mechanical characterization techniques (e.g. tensile testing, rheometry) are often used, however most commonly these techniques are employed on samples that are in two distinct states: (1) unswollen and without any solvent, or (2) in an equilibrium swelling state where the maximum amount of water has been imbibed. Rarely is the dynamic process of swelling studied, especially in samples where rupture or failure events are observed. To address this gap, here we focus on rupture events in poly(ethylene glycol)-based networks that occur in response to swelling with water. Rupture events were visualized using high-speed imaging, and the influence of swelling on material properties was characterized using dynamic mechanical analysis. We find that rupture events follow a three-stage process that includes a waiting period, a slow fracture period, and a final stage in which a rapid increase in the velocity of crack propagation is observed. We describe this fracture behavior based on changes in material properties that occur during swelling, and highlight how this rupture behavior can be controlled by straight-forward modifications to the hydrogel network structure.

Alcohol retail privatisation in Canadian provinces between 2012 and 2017. Is decision making oriented to harm reduction?

INTRODUCTION: Policy changes may contribute to increased alcohol-related risks to populations. These include privatisation of alcohol retailing, which influences density of alcohol outlets, location of outlets, hours of sale and prevention of alcohol sales to minors or intoxicated customers. Meta-analyses, reviews and original research indicate enhanced access to alcohol is associated with elevated risk of and actual harm. We assess the 10 Canadian provinces on two alcohol policy domains-type of alcohol control system and physical availability of alcohol-in order to track changes over time, and document shifting changes in alcohol policy. METHODS: Our information was based on government documents and websites, archival statistics and key informant interviews. Policy domains were selected and weighted for their degree of effectiveness and population reach based on systematic reviews and epidemiological evidence. Government representatives were asked to validate all the information for their jurisdiction. RESULTS: The province-specific reports based on the 2012 results showed that 9 of 10 provinces had mixed retail systems-a combination of government-run and privately owned alcohol outlets. Recommendations in each provincial report were to not increase privatisation. However, by 2017 the percentage of off-premise private outlets had increased in four of these nine provinces, with new private outlet systems introduced in several. DISCUSSION AND CONCLUSIONS: Decision-making protocols are oriented to commercial interests and perceived consumer convenience. If public health and safety considerations are not meaningfully included in decision-making protocols on alcohol policy, then it will be challenging to curtail or reduce harms.

Single-Cell Genomics Reveals a Novel Cell State During Smooth Muscle Cell Phenotypic Switching and Potential Therapeutic Targets for Atherosclerosis in Mouse and Human.

BACKGROUND: Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive. METHODS: To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro. RESULTS: We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed "SEM" cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary artery disease risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans RA, an anticancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden, and promoted fibrous cap stability. CONCLUSIONS: Integration of cell-specific fate mapping, single-cell genomics, and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.

Cancer Warning Labels on Alcohol Containers: A Consumer's Right to Know, a Government's Responsibility to Inform, and an Industry's Power to Thwart.

OBJECTIVE: Although the World Health Organization (WHO) declared alcohol a Class 1 carcinogen 30 years ago, few governments have communicated this fact to the public. We illustrate how alcohol industry groups seek to keep their customers in the dark about alcohol-related cancer risks. In Canada, a federally funded scientific study examining the introduction of cancer warning labels on containers was shut down following industry interference. We show that the industry complaints about the study had no legal merit. Of 47 WHO member countries with alcohol warning labels, only South Korea requires cancer warnings on alcohol containers. However, industry complaints, supported by sympathetic governments, helped weaken the warning labels' implementation. Ireland has legislated for cancer warnings but faces continuing legal opposition expressed through regional and global bodies. Cancer societies and the public health community have failed to counter industry pressures to minimize consumer awareness of alcohol's cancer risks. Placing cancer warnings on alcohol containers could make a pivotal difference in motivating both drinkers to consume less and regulators to introduce more effective policies to reduce the serious harms of alcohol consumption.

The increasing role of provincial administrative sanctions in Canadian impaired driving enforcement.

Objective: The object of this study is to document the recent shift in Canadian impaired driving enforcement from federal criminal proceedings to provincial administrative sanctions, examine the deterrent impact of these new administrative measures, and review the numerous legal challenges that they have generated.Methods: This article highlights the expanded role of provincial administrative license suspensions (ALSs) and vehicle impoundments (AVIs) in Canadian impaired driving enforcement, summarizes the evidence of their deterrent impact, and discusses the implications of the related Canadian case law.Results: Provincial administrative sanctions have been used increasingly, both to supplement and replace federal impaired driving charges. Recent experience in British Columbia and Alberta illustrates the potential traffic safety benefits of enacting comprehensive impairment-related roadside administrative measures. In 2010, British Columbia enacted a package of roadside administrative sanctions, which included mandatory ALSs, AVIs, monetary penalties, license-reinstatement fees, and remedial programs. A study conducted two years later reported that alcohol-related fatal crashes had fallen by 52%. Alberta enacted similar provisions, and saw alcohol-related fatalities decrease by 46% within six months of the legislation coming into force. Although effective, these new roadside sanctions generated a flurry of legal challenges. The cases indicate that while the provinces have broad leeway, there are legal limits on their authority to impose onerous administrative sanctions on drivers, particularly if they are based on a single roadside alcohol or drug-screening test.Conclusions: With careful drafting, the provinces can enact cost-effective roadside administrative sanctions that have been shown to significantly reduce impaired driving deaths and injuries. The legality of any administrative sanction will likely depend on its severity, the reliability of the test or evidence upon which it is based, and the extent to which the driver has a meaningful opportunity to challenge the decision.

Curative treatment for low-grade arteriovenous malformations.

BACKGROUND: Spetzler-Martin (SM) grade I-II (low-grade) arteriovenous malformations (AVMs) are often considered safe for microsurgery or radiosurgery. The adjunctive use of preoperative embolization to reduce surgical risk in these AVMs remains controversial. OBJECTIVE: To assess the safety of combined treatment of grade I-II AVMs with preoperative embolization followed by surgical resection or radiosurgery, and determine the long-term functional outcomes. METHODS: With institutional review board approval, a retrospective analysis was carried out on patients with ruptured and unruptured SM I-II AVMs between 2002 and 2017. Details of the endovascular procedures, including number of arteries supplying the AVM, number of branches embolized, embolic agent(s) used, and complications were studied. Baseline clinical and imaging characteristics were compared. Functional status using the modified Rankin Scale (mRS) before and after endovascular and microsurgical treatments was compared. RESULTS: 258 SM I-II AVMs (36% SM I, 64% SM II) were identified in patients with a mean age of 38 ± 17 years. 48% presented with hemorrhage, 21% with seizure, 16% with headache, 10% with no symptoms, and 5% with clinical deficits. 90 patients (68%) in the unruptured group and 74 patients (59%) in the ruptured group underwent presurgical embolization (p = 0.0013). The mean number of arteries supplying the AVM was 1.44 and 1.41 in the unruptured and ruptured groups, respectively (p = 0.75). The mean number of arteries embolized was 2.51 in the unruptured group and 1.82 in the ruptured group (p = 0.003). n-Butyl cyanoacrylate and Onyx were the two most commonly used embolic agents. Four complications were seen in four patients (4/164 patients embolized): two peri-/postprocedural hemorrhage, one dissection, and one infarct. All patients undergoing surgery had a complete cure on postoperative angiography. Patients were followed up for a mean of 55 months. Good long-term outcomes (mRS score ≤ 2) were seen in 92.5% of patients with unruptured AVMs and 88.0% of those with ruptured AVMs. Permanent neurological morbidity occurred in 1.2%. CONCLUSIONS: Curative treatment of SM I-II AVMs can be performed using endovascular embolization with microsurgical resection or radiosurgery in selected cases, with very low morbidity and high cure rates. Compared with other published series, these outcomes suggest that preoperative embolization is a safe and effective adjunct to definitive surgical treatment. Long-term follow-up showed that patients with low-grade AVMs undergoing surgical resection or radiosurgery have good functional outcomes.

Machine Learning-Based Integration of High-Resolution Wildfire Smoke Simulations and Observations for Regional Health Impact Assessment.

Large wildfires are an increasing threat to the western U.S. In the 2017 fire season, extensive wildfires occurred across the Pacific Northwest (PNW). To evaluate public health impacts of wildfire smoke, we integrated numerical simulations and observations for regional fire events during August-September of 2017. A one-way coupled Weather Research and Forecasting and Community Multiscale Air Quality modeling system was used to simulate fire smoke transport and dispersion. To reduce modeling bias in fine particulate matter (PM2.5) and to optimize smoke exposure estimates, we integrated modeling results with the high-resolution Multi-Angle Implementation of Atmospheric Correction satellite aerosol optical depth and the U.S. Environmental Protection Agency AirNow ground-level monitoring PM2.5 concentrations. Three machine learning-based data fusion algorithms were applied: An ordinary multi-linear regression method, a generalized boosting method, and a random forest (RF) method. 10-Fold cross-validation found improved surface PM2.5 estimation after data integration and bias correction, especially with the RF method. Lastly, to assess transient health effects of fire smoke, we applied the optimized high-resolution PM2.5 exposure estimate in a short-term exposure-response function. Total estimated regional mortality attributable to PM2.5 exposure during the smoke episode was 183 (95% confidence interval: 0, 432), with 85% of the PM2.5 pollution and 95% of the consequent multiple-cause mortality contributed by fire emissions. This application demonstrates both the profound health impacts of fire smoke over the PNW and the need for a high-performance fire smoke forecasting and reanalysis system to reduce public health risks of smoke hazards in fire-prone regions.