Vorinostat Improves Myotonic Dystrophy Type 1 Splicing Abnormalities in DM1 Muscle Cell Lines and Skeletal Muscle from a DM1 Mouse Model.

Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin-long repeat; HSALR) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy.

Understanding the association between neighbourhood socioeconomic status and grocery store alcohol sales following market liberalization in Ontario, Canada.

OBJECTIVES: In 2015, Ontario partially deregulated alcohol sales by allowing grocery stores to sell alcohol. The purpose of this study was to evaluate (1) whether neighbourhood-level socioeconomic status (SES) impacted the likelihood that a grocery store began selling alcohol, and (2) whether increases in alcohol retail availability following deregulation differed between neighbourhoods based on SES. METHODS: This was a repeated cross-sectional analysis of 1062 grocery stores in 17,096 neighbourhoods in urban Ontario. The association between neighbourhood-level SES and whether a grocery store began selling alcohol was modeled using mixed effect logistic regression. The annual change in drive-distance from a neighbourhood to the closest off-premise alcohol outlet between 2015 and 2020 was modeled using mixed effect linear regression. An interaction between time and SES was included to evaluate whether this change differed between neighbourhoods based on SES. RESULTS: Grocery stores in neighbourhoods in the lowest SES quintile were 39% less likely to start selling alcohol than grocery stores in neighbourhoods in the highest SES quintile (odds ratio (OR): 0.61, 95% confidence interval (CI): 0.39-0.94). As grocery store sales expanded, the distance to the closest off-premise alcohol outlet decreased by 51.8 m annually (95% CI: 48.8-54.9, p < 0.01). A significant interaction between year and SES was observed whereby this trend was more pronounced in high- versus low-SES neighbourhoods. CONCLUSION: The expansion of grocery store alcohol sales increased alcohol availability, but this increase was proportionately larger in high- versus low-SES neighbourhoods. This reduced historic disparities in alcohol availability between low- and high-SES neighbourhoods.

RéSUMé: OBJECTIFS: En 2015, l'Ontario a partiellement déréglementé les ventes d'alcool en autorisant les épiceries à en vendre. Notre étude visait à évaluer : 1) si le statut socioéconomique (SSE) du quartier avait un effet sur la probabilité qu'une épicerie commence à vendre de l'alcool et 2) si les augmentations de l'accessibilité de l'alcool au détail après la déréglementation différaient d'un quartier à l'autre selon le SSE. MéTHODE: Il s'agissait d'une analyse transversale répétée de 1 062 épiceries dans 17 096 quartiers urbains de l'Ontario. L'association entre le SSE du quartier et le fait qu'une épicerie commence ou non à vendre de l'alcool a été modélisée par régression logistique à effets mixtes. Le changement annuel de la distance de conduite entre un quartier et le point de vente d'alcool hors site le plus proche entre 2015 et 2020 a été modélisé par régression linéaire à effets mixtes. Une interaction entre le temps et le SSE a été incluse pour évaluer si le changement différait d'un quartier à l'autre selon le SSE. RéSULTATS: Les épiceries des quartiers du quintile SSE le plus défavorisé ont été de 39 points de pourcentage moins susceptibles de commencer à vendre de l'alcool que les épiceries des quartiers du quintile SSE le plus favorisé (rapport de cotes [RC] : 0,61, intervalle de confiance de 95 % [(IC] : 0,39-0,94). Avec l'expansion des ventes des épiceries, la distance jusqu'au point de vente d'alcool hors site le plus proche a diminué de 51,8 mètres par année (IC de 95 % : 48,8-54,9, p < 0,01). Une interaction significative entre l'année et le SSE a été observée : cette tendance était plus prononcée dans les quartiers de SSE élevé que dans les quartiers de faible SSE. CONCLUSION: L'expansion des ventes d'alcool des épiceries a fait augmenter l'accessibilité de l'alcool, mais cette augmentation a été proportionnellement plus grande dans les quartiers de SSE élevé que dans les quartiers de faible SSE. Cela a réduit les disparités historiques d'accessibilité de l'alcool entre les quartiers de SSE élevé et de faible SSE.

Development of the electronic consultation long-term care utilization and savings estimator tool to model the potential impact of electronic consultation for residents living in long-term care.

Ageing populations have resulted in more patients living in long-term care or nursing homes, where they face challenges to accessing prompt specialist care exacerbated in many cases by physical or cognitive decline. Electronic consultation has demonstrated an ability to improve access to specialist care for vulnerable groups and offers a potential solution to this gap in care. To support electronic consultation's uptake among long-term care homes, we created the electronic consultation long-term care utilization and savings estimator, an Excel-based tool that estimates the number of off-site appointments that patients in a long-term care home could avoid through electronic consultation, along with the consequent time and cost savings. In this brief report, we discuss the electronic consultation long-term care utilization and savings estimator's creation and function, and provide a case study using long-term care data to demonstrate its potential impact. We anticipate the electronic consultation long-term care utilization and savings estimator will be a highly impactful tool and intend to test it in real-world conditions following the relaxation of COVID-19 restrictions.

How has access to legal cannabis changed over time? An analysis of the cannabis retail market in Canada 2 years following the legalisation of recreational cannabis.

INTRODUCTION: This study describes the legal recreational cannabis market across Canada over the 2 years following legalisation. We compared changes in access to the legal cannabis retail market for all provinces and territories (jurisdictions) in Canada and explored differences between jurisdictions. METHODS: We collected data for all legal cannabis stores in Canada over five time periods following legalisation in October 2018. We examined the following measures by jurisdiction and retail model (public vs. private operation): absolute and per capita store numbers, hours of operation and store access across neighbourhoods. RESULTS: Two years following legalisation, there were a total of 1183 legal cannabis stores open across Canada (3.7 stores per 100 000 individuals aged 15+). There was wide variation between jurisdictions in access to retail stores, with the lowest stores per capita in Quebec and Ontario (0.6 and 1.6 per 100 000), and the highest in Alberta and Yukon (14.3 per 100 000 in both). Jurisdictions with private retail models had more stores (4.8 vs. 1.0 per 100 000), held greater median weekly hours (80 vs. 69) and experienced greater store growth over time compared to public models. After adjusting for confounders, there were 1.96 times (95% confidence intervals: 1.84, 2.09) more cannabis stores within 1000 m of the lowest- compared to the highest-income quintile neighbourhoods. DISCUSSION AND CONCLUSIONS: While access to the recreational cannabis retail market has increased following legalisation, there is substantial variation in access between jurisdictions and evidence of concentration in lower-income neighbourhoods. These differences may contribute to disparities in cannabis use and harms.

Do Patients Retain their Family Physicians after Long-Term Care Entry? A Retrospective Cohort Study.

OBJECTIVE: Older adults value and benefit from the long-standing relationship they have with their family physicians. This dynamic has not been researched in a long-term care (LTC, ie, nursing home) setting. We sought to determine the proportion of LTC residents who retain their community family physician within the first 180 days of LTC, and the resident, physician, and LTC home factors that may influence retention. DESIGN: Population-based retrospective cohort study. SETTING AND PARTICIPANTS: Individuals from Ontario, Canada, aged 60 years or older who were newly admitted to a LTC home between April 1, 2014 and March 31, 2017. METHODS: Residents were indexed upon LTC admission, and their data was linked across ICES databases. Residents were matched to their rostered family physician, and physician retention was defined as having at least 1 visit by their matched physician within 0 to 90 days and 90 to 180 days of LTC admission. RESULTS: Out of 50,089 LTC residents, 12.1% retained their family physicians post-LTC admission. Resident factors associated with reduced odds of retention included physical impairment [odds ratio OR (95% confidence interval, CI) = 0.59 (0.42‒0.83)], cognitive impairment [0.39 (0.33‒0.47)], and a dementia diagnosis [0.80 (0.74‒0.86)]. Physician factors associated with lower retention included a greater distance from the LTC home to the family physician's clinic [30+ kilometers 0.41 (0.35‒0.48)], having a physician who is female [0.90 (0.83‒0.98)], an international medical graduate [0.89 (0.81‒0.97)] or someone who practices in a capitation-based Family Health Organization [0.86 (0.78‒0.95)]. Factors associated with greater odds of retention were residing in a rural LTC home [2.23 (1.78‒2.79)], having a rural family physician [1.70 (1.52‒1.90)], or a family physician who has billed LTC fee codes in the past year [2.64 (2.45‒2.85)]. CONCLUSIONS AND IMPLICATIONS: Few LTC residents retained their family physician post-LTC admission, underscoring this healthcare transition as a breakdown point in relational continuity. Factors that influenced retention included resident health, LTC home geography, and family physician demographics and practice patterns.

1D Self-Assembly and Ice Recrystallization Inhibition Activity of Antifreeze Glycopeptide-Functionalized Perylene Bisimides.

Antifreeze glycoproteins (AFGPs) are polymeric natural products that have drawn considerable interest in diverse research fields owing to their potent ice recrystallization inhibition (IRI) activity. Self-assembled materials have emerged as a promising class of biomimetic ice growth inhibitor, yet the development of AFGP-based supramolecular materials that emulate the aggregative behavior of AFGPs have not yet been reported. This work reports the first example of the 1D self-assembly and IRI activity of AFGP-functionalized perylene bisimides (AFGP-PBIs). Glycopeptide-functionalized PBIs underwent 1D self-assembly in water and showed modest IRI activity, which could be tuned through substitution of the PBI core. This work presents essential proof-of-principle for the development of novel IRIs as potential supramolecular cryoprotectants and glycoprotein mimics.