SummaryCells inversely adjust the plasma membrane levels of integrins and cadherins during cell migration and cell-cell adhesion but the regulatory mechanisms that coordinate these trafficking events remain unknown. Here, we demonstrate that the small GTPase Rab35 maintains cadherins at the cell surface to promote cell-cell adhesion. Simultaneously, Rab35 supresses the activity of the GTPase Arf6 to downregulate an Arf6-dependent recycling pathway for b1-integrin and EGF receptors, resulting in inhibition of cell migration and attenuation of signaling downstream of these receptors. Importantly, the phenotypes of decreased cell adhesion and increased cell migration observed following Rab35 knock down are consistent with the epithelial-mesenchymal transition, a feature of invasive cancer cells, and we show that Rab35 expression is suppressed in a subset of cancers characterized by Arf6 hyperactivity. Our data thus identify a key molecular mechanism that efficiently coordinates the inverse intracellular sorting and cell surface levels of cadherin and integrin receptors for cell migration and differentiation.
Background The COVID-19 pandemic has exacerbated the opioid crisis. Opioid-related deaths have increased and access to treatment services, including opioid agonist treatment (OAT), has been disrupted. The Ontario COVID-19 OAT Treatment Guidance document was developed to facilitate access to OAT and continuity of care during the pandemic, while supporting physical distancing measures. In particular, the Guidance expanded access to unsupervised OAT dosing. It is important to evaluate the changes in unsupervised OAT dosing after the release of the Ontario COVID-19 OAT Guidance based on patients’ and prescribers’ reports. Method Online questionnaires were developed collaboratively with people with lived and living expertise, prescribers, clinical experts, and researchers. Patients ( N =402) and prescribers ( N =100) reported their experiences with changes in unsupervised dosing during the first six months of the pandemic. Results Many patients (57%) reported receiving additional unsupervised OAT doses (i.e., take away doses). Patients who received additional unsupervised doses were not significantly more likely to report adverse health outcomes compared to patients who did not receive additional unsupervised doses. Patients with additional unsupervised doses and prescribers agreed that changes in OAT care were positive (e.g., reported an improved patient-prescriber relationship and more openness between patient and prescriber). Prescribers and some patients reported the need for continued flexibility in unsupervised doses after the pandemic restrictions lift. Conclusions Results support the need to re-evaluate historical approaches to OAT care delivery, particularly unsupervised doses. It is crucial to implement policies, regulations, and supports to reduce barriers to OAT care during the pandemic and once the pandemic response restrictions are eased. Flexibility in OAT care delivery, particularly unsupervised dosing, will be key to providing patient-centred care for persons with opioid use disorder.
Objective Cannabis legalization in many jurisdictions worldwide has raised concerns that such legislation might increase the burden of transient and persistent psychotic illnesses in society. Our study aimed to address this issue. Methods Drawing upon emergency department (ED) presentations aggregated across Alberta and Ontario, Canada records (April 1, 2015–December 31, 2019), we employed Seasonal Autoregressive Integrated Moving Average (SARIMA) models to assess associations between Canada's cannabis legalization (via the Cannabis Act implemented on October 17, 2018) and weekly ED presentation counts of the following ICD-10-CA-defined target series of cannabis-induced psychosis (F12.5; n = 5832) and schizophrenia and related conditions (“schizophrenia”; F20-F29; n = 211,661), as well as two comparison series of amphetamine-induced psychosis (F15.5; n = 10,829) and alcohol-induced psychosis (F10.5; n = 1,884). Results ED presentations for cannabis-induced psychosis doubled between April 2015 and December 2019. However, across all four SARIMA models, there was no evidence of significant step-function effects associated with cannabis legalization on post-legalization weekly ED counts of: (1) cannabis-induced psychosis [0.34 (95% CI −4.1; 4.8; P = 0.88)]; (2) schizophrenia [24.34 (95% CI −18.3; 67.0; P = 0.26)]; (3) alcohol-induced psychosis [0.61 (95% CI −0.6; 1.8; P = 0.31); or (4) amphetamine-induced psychosis [1.93 (95% CI −2.8; 6.7; P = 0.43)]. Conclusion Implementation of Canada's cannabis legalization framework was not associated with evidence of significant changes in cannabis-induced psychosis or schizophrenia ED presentations. Given the potentially idiosyncratic rollout of Canada's cannabis legalization, further research will be required to establish whether study results generalize to other settings.
Introduction Given the recent and impending changes to the legal status of nonmedical cannabis use in Canada, understanding the effects of cannabis use on the health care system is important for evaluating the impact of policy change. The aim of this study was to examine pre-legalization trends in hospitalizations for mental and behavioural disorders due to the use of cannabis, according to demographics factors and clinical conditions. Methods We assessed the total number of inpatient hospitalizations for psychiatric conditions with a primary diagnosis of a mental or behavioural disorder due to cannabis use (ICD-10-CA code F12) from the Hospital Mental Health Database for ten years spanning 2006 to 2015, inclusive. We included hospitalizations from all provinces and territories except Quebec. Rates (per 100 000 persons) and relative proportions of hospitalizations by clinical condition, age group, sex and year are reported. Results Between 2006 and 2015, the rate of cannabis-related hospitalizations in Canada doubled. Of special note, however, is that hospitalizations during this time period for those with the clinical condition code "mental and behavioural disorders due to use of cannabinoids, psychotic disorder" (F12.5) tripled, accounting for almost half (48%) of all cannabis-related hospitalizations in 2015. Conclusion Further research is required to investigate the reasons for the increase in hospitalizations for cannabis-related psychotic disorder. The introduction of high-potency cannabinoid products and synthetic cannabinoids into the illicit market are considered as possible factors.
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