TNFα and IFNγ cooperate for efficient pro- to anti-inflammatory transition of macrophages during muscle regeneration.

IFNγ is traditionally known as a proinflammatory cytokine with diverse roles in antimicrobial and antitumor immunity. Yet, findings regarding its sources and functions during the regeneration process following a sterile injury are conflicting. Here, we show that natural killer (NK) cells are the main source of IFNγ in regenerating muscle. Beyond this cell population, IFNγ production is limited to a small population of T cells. We further show that NK cells do not play a major role in muscle regeneration following an acute injury or in dystrophic mice. Surprisingly, the absence of IFNγ per se also has no effect on muscle regeneration following an acute injury. However, the role of IFNγ is partially unmasked when TNFα is also neutralized, suggesting a compensatory mechanism. Using transgenic mice, we showed that conditional inhibition of IFNGR1 signaling in muscle stem cells or fibro-adipogenic progenitors does not play a major role in muscle regeneration. In contrast to common belief, we found that IFNγ is not present in the early inflammatory phase of the regeneration process but rather peaks when macrophages are acquiring an anti-inflammatory phenotype. Further transcriptomic analysis suggests that IFNγ cooperates with TNFα to regulate the transition of macrophages from pro- to anti-inflammatory states. The absence of the cooperative effect of these cytokines on macrophages, however, does not result in significant regeneration impairment likely due to the presence of other compensatory mechanisms. Our findings support the arising view of IFNγ as a pleiotropic inflammatory regulator rather than an inducer of the inflammatory response.

Household food insecurity, sense of community belonging, and access to a regular medical doctor as mediators in the relationship between mood and/or anxiety disorders and self-rated general health in Canada between 2011 and 2016: a serial cross-sectional analysis.

OBJECTIVE: To assess whether (household) food insecurity, access to a regular medical doctor, and sense of community belonging mediate the relationship between mood and/or anxiety disorders and self-rated general health. METHODS: We used six annual cycles of the Canadian Community Health Survey, including Canadian adults aged 18-59 years, between 2011 and 2016. Mediation models, adjusted for key determinants of health, were based on a series of weighted logistic regression models. The Sobel products of coefficients approach was used to estimate the indirect effect, and bootstrapping to estimate uncertainty. RESULTS: The annual (weighted) prevalence of mood and/or anxiety disorders increased from 11.3% (2011) to 13.2% (2016). Across the 6 years, 23.9-27.7% of individuals with mood and/or anxiety disorders reported fair/poor self-rated health as compared with 4.9-6.5% of those without mood and/or anxiety disorders (p<0.001). Similarly, the 7.2-8.9% of the population reporting fair/poor self-rated health were disproportionately represented among individuals reporting food insecurity (21.1-26.2%, p<0.001) and a weak sense of community belonging (10.0-12.2%, p<0.001). A significantly lower prevalence of poor self-rated health was observed among respondents reporting having access to a regular medical doctor in 2012, 2015, and 2016. In 2016, sense of community belonging and food insecurity significantly mediated the effect of mood and/or anxiety disorders on self-rated general health. Access to a regular medical doctor did not mediate this relationship. CONCLUSION: Efficient policies that address food insecurity and sense of community belonging are needed to decrease the mental health burden and improve health satisfaction of Canadians.

RéSUMé: OBJECTIF: Déterminer si l'insécurité alimentaire (du ménage), l'accès à un médecin traitant et le sentiment d'appartenance à la communauté modèrent le lien entre les troubles anxieux et/ou de l'humeur et la santé générale autoévaluée. MéTHODE: Nous avons utilisé six cycles annuels (2011 à 2016) de l'Enquête sur la santé dans les collectivités canadiennes incluant des Canadiens adultes de 18 à 59 ans. Nos modèles de modération, ajustés selon les principaux déterminants de la santé, reposaient sur une série de modèles de régression logistique pondérés. Nous avons utilisé l'approche des produits des coefficients de Sobel pour estimer les effets indirects, et l'autoamorçage pour estimer l'incertitude. RéSULTATS: La prévalence annuelle (pondérée) des troubles anxieux et/ou de l'humeur a augmenté, passant de 11,3 % en 2011 à 13,2 % en 2016. Sur la période de six ans, 23,9 à 27,7 % des personnes ayant des troubles anxieux et/ou de l'humeur ont déclaré avoir une santé moyenne/mauvaise, contre 4,9 à 6,5 % des personnes n'ayant pas de troubles anxieux et/ou de l'humeur (p < 0,001). De même, les 7,2 à 8,9 % de la population ayant déclaré avoir une santé moyenne/mauvaise étaient disproportionnellement représentés chez les personnes disant être en situation d'insécurité alimentaire (21,1-26,2 %, p < 0,001) et avoir un faible sentiment d'appartenance à la communauté (10,0-12,2 %, p < 0,001). Une prévalence significativement plus faible de mauvaise santé autoévaluée a été observée chez les répondants ayant dit avoir accès à un médecin traitant en 2012, 2015 et 2016. En 2016, le sentiment d'appartenance à la communauté et l'insécurité alimentaire modéraient de façon significative l'effet des troubles anxieux et/ou de l'humeur sur la santé générale autoévaluée. L'accès à un médecin traitant ne modérait pas ce lien. CONCLUSION: Des politiques efficaces pour aborder l'insécurité alimentaire et le sentiment d'appartenance à la communauté sont nécessaires pour réduire le fardeau des troubles mentaux et améliorer la satisfaction des Canadiens face à leur santé.

SARS-CoV-2 in mink farms in British Columbia, Canada: A report of two outbreaks in 2020-2021.

Background: Since April 2020, mink have been recognized as a potential reservoir for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a potential source of new variants. The objective of this report is to describe the epidemiological investigation and public health response to two coronavirus disease 2019 (COVID-19) outbreaks that involved both humans and farmed mink. Methods: An outbreak was declared on December 4, 2020, following detection of two COVID-19-positive farmworkers and elevated mink mortality on a mink farm (Farm 1) in British Columbia. The second cluster was detected on Farm 3 following detection of 1) a COVID-19 case among farm staff on April 2, 2021, 2) an indeterminate result from farm staff on May 11, 2021, and 3) subsequent SARS-CoV-2-positive mink in May 2021. Quarantine of infected farms, isolation of workers and their close contacts, and introduction of enhanced infection control practises were implemented to break chains of transmission. Results: Among mink farmworkers, 11 cases were identified at Farm 1 and 6 cases were identified at Farm 3. On both Farm 1 and Farm 3, characteristic COVID-19 symptoms were present in farm employees before signs were observed in the minks. The viral sequences from mink and human samples demonstrated close genetic relation. Phylogenetic analyses identified mink intermediates linking human cases, suggesting anthropo-zoonotic transmission. Conclusion: These were the first COVID-19 outbreaks that included infected mink herds in Canada and identified potential anthropogenic and zoonotic transmission of SARS-CoV-2. We provide insight into the positive impact of regulatory control measures and surveillance to reduce the spillover of SARS-CoV-2 mink variants into the general population.

One Health response to SARS-CoV-2-associated risk from mink farming in British Columbia, Canada, October 2020 to October 2021.

Background: Mink farms are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks and carry an associated risk of novel SARS-CoV-2 variant emergence and non-human reservoir creation. In Denmark, control measures were insufficient to prevent onward transmission of a mink-associated variant, contributing to the nation-wide culling of farmed mink. To date, British Columbia (BC) is the only Canadian province to report mink farm SARS-CoV-2 outbreaks. The objective of this study is to describe BC's One Health response to SARS-CoV-2-associated risk from mink farming, its outcomes, and insights from implementation. Methods: The detection of two mink farm outbreaks in December 2020 catalyzed BC's risk mitigation response for both infected and uninfected farms, including the following: farm inspections and quarantines; Public Health Orders mandating mink mortality surveillance, enhanced personal protective equipment, biosafety measures and worker coronavirus disease 2019 vaccination, at-a-minimum weekly worker viral testing, and wildlife surveillance. Results: A One Health approach enabled a timely, evidence-informed and coordinated response as the situation evolved, including the use of various legislative powers, consistent messaging and combined human and mink phylogenetic analysis. Ongoing mink and worker surveillance detected asymptomatic/subclinical infections and facilitated rapid isolation/quarantine to minimize onward transmission. Voluntary testing and mandatory vaccination for workers were acceptable to industry; enhanced personal protective equipment requirements were challenging. Regular farm inspections helped to assess and improve compliance. Conclusion: British Columbia's One Health response reduced the risk of additional outbreaks, viral evolution and reservoir development; however, a third outbreak was detected in May 2021 despite implemented measures, and long-term sustainability of interventions proved challenging for both industry and governmental agencies involved.

Excess burden of age-associated comorbidities among people living with HIV in British Columbia, Canada: a population-based cohort study.

OBJECTIVES: As people living with HIV (PLWH) live longer, morbidity and mortality from non-AIDS comorbidities have emerged as major concerns. Our objective was to compare prevalence trends and age at diagnosis of nine chronic age-associated comorbidities between individuals living with and without HIV. DESIGN AND SETTING: This population-based cohort study used longitudinal cohort data from all diagnosed antiretroviral-treated PLWH and 1:4 age-sex-matched HIV-negative individuals in British Columbia, Canada. PARTICIPANTS: The study included 8031 antiretroviral-treated PLWH and 32 124 HIV-negative controls (median age 40 years, 82% men). Eligible participants were ≥19 years old and followed for ≥1 year during 2000 to 2012. PRIMARY AND SECONDARY OUTCOME MEASURES: The presence of non-AIDS-defining cancers, diabetes, osteoarthritis, hypertension, Alzheimer's and/or non-HIV-related dementia, cardiovascular, kidney, liver and lung diseases were identified from provincial administrative databases. Beta regression assessed annual age-sex-standardised prevalence trends and Kruskal-Wallis tests compared the age at diagnosis of comorbidities stratified by rate of healthcare encounters. RESULTS: Across study period, the prevalence of all chronic age-associated comorbidities, except hypertension, were higher among PLWH compared with their community-based HIV-negative counterparts; as much as 10 times higher for liver diseases (25.3% vs 2.1%, p value<0.0001). On stratification by healthcare encounter rates, PLWH experienced most chronic age-associated significantly earlier than HIV-negative controls, as early as 21 years earlier for Alzheimer's and/or dementia. CONCLUSIONS: PLWH experienced higher prevalence and earlier age at diagnosis of non-AIDS comorbidities than their HIV-negative controls. These results stress the need for optimised screening for comorbidities at earlier ages among PLWH, and a comprehensive HIV care model that integrates prevention and treatment of chronic age-associated conditions. Additionally, the robust methodology developed in this study, which addresses concerns on the use of administrative health data to measure prevalence and incidence, is reproducible to other settings.

Phenotypic diversity and genotypic flexibility of Burkholderia cenocepacia during long-term chronic infection of cystic fibrosis lungs.

Chronic bacterial infections of the lung are the leading cause of morbidity and mortality in cystic fibrosis patients. Tracking bacterial evolution during chronic infections can provide insights into how host selection pressures-including immune responses and therapeutic interventions-shape bacterial genomes. We carried out genomic and phenotypic analyses of 215 serially collected Burkholderia cenocepacia isolates from 16 cystic fibrosis patients, spanning a period of 2-20 yr and a broad range of epidemic lineages. Systematic phenotypic tests identified longitudinal bacterial series that manifested progressive changes in liquid media growth, motility, biofilm formation, and acute insect virulence, but not in mucoidy. The results suggest that distinct lineages follow distinct evolutionary trajectories during lung infection. Pan-genome analysis identified 10,110 homologous gene clusters present only in a subset of strains, including genes restricted to different molecular types. Our phylogenetic analysis based on 2148 orthologous gene clusters from all isolates is consistent with patient-specific clades. This suggests that initial colonization of patients was likely by individual strains, followed by subsequent diversification. Evidence of clonal lineages shared by some patients was observed, suggesting inter-patient transmission. We observed recurrent gene losses in multiple independent longitudinal series, including complete loss of Chromosome III and deletions on other chromosomes. Recurrently observed loss-of-function mutations were associated with decreases in motility and biofilm formation. Together, our study provides the first comprehensive genome-phenome analyses of B. cenocepacia infection in cystic fibrosis lungs and serves as a valuable resource for understanding the genomic and phenotypic underpinnings of bacterial evolution.