Monkeypox in Montréal: Epidemiology, Phylogenomics, and Public Health Response to a Large North American Outbreak.

BACKGROUND: Monkeypox, a viral zoonotic disease, is causing a global outbreak outside of endemic areas. OBJECTIVE: To characterize the outbreak of monkeypox in Montréal, the first large outbreak in North America. DESIGN: Epidemiologic and laboratory surveillance data and a phylogenomic analysis were used to describe and place the outbreak in a global context. SETTING: Montréal, Canada. PATIENTS: Probable or confirmed cases of monkeypox. MEASUREMENTS: Epidemiologic, clinical, and demographic data were aggregated. Whole-genome sequencing and phylogenetic analysis were performed for a set of outbreak sequences. The public health response and its evolution are described. RESULTS: Up to 18 October 2022, a total of 402 cases of monkeypox were reported mostly among men who have sex with men (MSM), most of which were suspected to be acquired through sexual contact. All monkeypox genomes nested within the B.1 lineage. Montréal Public Health worked closely with the affected communities to control the outbreak, becoming the first jurisdiction to offer 1 dose of the Modified Vaccinia Ankara-Bavarian Nordic vaccine as preexposure prophylaxis (PrEP) to those at risk in early June 2022. Two peaks of cases were seen in early June and July (43 and 44 cases per week, respectively) followed by a decline toward near resolution of the outbreak in October. Reasons for the biphasic peak are not fully elucidated but may represent the tempo of vaccination and/or several factors related to transmission dynamics and case ascertainment. LIMITATIONS: Clinical data are self-reported. Limited divergence among sequences limited genomic epidemiologic conclusions. CONCLUSION: A large outbreak of monkeypox occurred in Montréal, primarily among MSM. Successful control of the outbreak rested on early and sustained engagement with the affected communities and rapid offer of PrEP vaccination to at-risk persons. PRIMARY FUNDING SOURCE: None.

Self-reported impacts of the COVID-19 pandemic among people who use drugs: a rapid assessment study in Montreal, Canada.

BACKGROUND: People who use drugs (PWUD) are at high risk of experiencing indirect harms of measures implemented to curb the spread of COVID-19, given high reliance on services and social networks. This study aimed to document short-term changes in behaviours and health-related indicators among PWUD in Montreal, Canada following declaration of a provincial health emergency in Quebec. METHODS: We administered a structured rapid assessment questionnaire to members of an existing cohort of PWUD and individuals reporting past-year illicit drug use recruited via community services. Telephone and in-person interviews were conducted in May-June and September-December 2020. Participants were asked to report on events and changes since the start of the health emergency (March 13, 2020). Descriptive analyses were performed. RESULTS: A total of 227 participants were included (77% male, median age = 46, 81% Caucasian). 83% and 41% reported past six-month illicit drug use and injection drug use, respectively. 70% of unstably housed participants reported increased difficulty finding shelter since the start of the health emergency. 48% of opioid agonist treatment recipients had discussed strategies to avoid treatment disruptions with providers; 22% had missed at least one dose. Many participants perceived increased difficulty accessing non-addiction health care services. Adverse changes were also noted in indicators pertaining to income, drug markets, drug use frequency, and exposure to violence; however, many participants reported no changes in these areas. Among persons reporting past six-month injection drug use, 79% tried to access needle-syringe programmes during the health emergency; 93% of those obtained services. 45% tried to access supervised injection sites, of whom 71% gained entry. CONCLUSIONS: This snapshot suggests mixed impacts of the COVID-19 pandemic on PWUD in Montreal in the months following declaration of a provincial health emergency. There were signals of increased exposure to high-risk environments as well as deteriorations in access to health services. Pandemic-related measures may have lasting impacts among vulnerable subgroups; continued monitoring is warranted.

Golgi's Role in the Development of Possible New Therapies in Cancer.

The Golgi apparatus is an important organelle found in most eukaryotic cells. It plays a vital role in the processing and sorting of proteins, lipids and other cellular components for delivery to their appropriate destinations within the cell or for secretion outside of the cell. The Golgi complex also plays a role in the regulation of protein trafficking, secretion and post-translational modifications, which are significant in the development and progression of cancer. Abnormalities in this organelle have been observed in various types of cancer, although research into chemotherapies that target the Golgi apparatus is still in its early stages. There are a few promising approaches that are being investigated: (1) Targeting the stimulator of interferon genes protein: The STING pathway senses cytosolic DNA and activates several signaling events. It is regulated by numerous post-translational modifications and relies heavily on vesicular trafficking. Based on some observations which state that a decreased STING expression is present in some cancer cells, agonists for the STING pathway have been developed and are currently being tested in clinical trials, showing encouraging results. (2) Targeting glycosylation: Altered glycosylation, which refers to changes in the carbohydrate molecules that are attached to proteins and lipids in cells, is a common feature of cancer cells, and there are several methods that thwart this process. For example, some inhibitors of glycosylation enzymes have been shown to reduce tumor growth and metastasis in preclinical models of cancer. (3) Targeting Golgi trafficking: The Golgi apparatus is responsible for the sorting and trafficking of proteins within the cell, and disrupting this process may be a potential therapeutic approach for cancer. The unconventional protein secretion is a process that occurs in response to stress and does not require the involvement of the Golgi organelles. P53 is the most frequently altered gene in cancer, dysregulating the normal cellular response to DNA damage. The mutant p53 drives indirectly the upregulation of the Golgi reassembly-stacking protein 55kDa (GRASP55). Through the inhibition of this protein in preclinical models, the reduction of the tumoral growth and metastatic capacity have been obtained successfully. This review supports the hypothesis that the Golgi apparatus may be the target of cytostatic treatment, considering its role in the molecular mechanisms of the neoplastic cells.

Gender-specific associations between psychological distress and injecting risk behaviours among people who inject drugs in Montreal, Canada.

BACKGROUND: Psychological distress is common among people who inject drugs (PWID) and may be associated with HCV-related risk behaviours. Previous studies have documented increased vulnerability to both psychological distress and HCV infection among female relative to male PWID. It is, however, unclear whether behavioural responses to distress differ by gender. This study estimated gender-specific associations between psychological distress and i) binge drug injection, and ii) sharing of injection materials. METHODS: Data were drawn from HEPCO, a longitudinal cohort study involving three-monthly interviews with active PWID in Montreal, Canada. Past-month psychological distress was assessed with the Kessler (K10) scale, categorized for descriptive analyses as minimal (score 10-15), moderate (16-21), high (22-29), or severe (30-50). Binge was defined as injecting large quantities of drugs until participants could no longer continue (past 3 months). Sharing was defined as injection with previously-used needles or equipment (past 3 months). Generalized additive models were fit to estimate smooth, nonlinear associations between K10 scores and risk behaviours, by gender. Models were adjusted for known determinants of drug-related harms and included random intercepts to model within-subject correlation. RESULTS: 805 individuals (82% male) provided 8158 observations (2011-2020). High to severe levels of distress were common and more frequent among women (55% vs 37%). Among men, the odds of binge and sharing monotonically and non-linearly increased with increasing scores of psychological distress. Associations for binge among women were attenuated relative to men but nevertheless increased with distress, albeit in a linear fashion. Sharing was not associated with distress among women. CONCLUSION: Psychological distress was differentially associated with injecting risk behaviours among men and women who inject drugs. Assessment of distress may provide novel prevention opportunities for select PWID. Further investigation into gender differences is warranted to inform development and tailoring of interventions.

IL-17A reprograms intestinal epithelial cells to facilitate HIV-1 replication and outgrowth in CD4+ T cells.

The crosstalk between intestinal epithelial cells (IECs) and Th17-polarized CD4+ T cells is critical for mucosal homeostasis, with HIV-1 causing significant alterations in people living with HIV (PLWH) despite antiretroviral therapy (ART). In a model of IEC and T cell co-cultures, we investigated the effects of IL-17A, the Th17 hallmark cytokine, on IEC ability to promote de novo HIV infection and viral reservoir reactivation. Our results demonstrate that IL-17A acts in synergy with TNF to boost IEC production of CCL20, a Th17-attractant chemokine, and promote HIV trans-infection of CD4+ T cells and viral outgrowth from reservoir cells of ART-treated PLWH. Importantly, the Illumina RNA-sequencing revealed an IL-17A-mediated pro-inflammatory and pro-viral molecular signature, including a decreased expression of type I interferon (IFN-I)-induced HIV restriction factors. These findings point to the deleterious features of IL-17A and raise awareness for caution when designing therapies aimed at restoring the paucity of mucosal Th17 cells in ART-treated PLWH.