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Tuberculosis, a deadly infectious lung disease caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of bacterial disease-related deaths worldwide. Mtb reprograms and disables key antibacterial response pathways, many of which are regulated by epigenetic mechanisms that control the accessibility of chromatin to the transcriptional machinery. Recent reports suggest that host phosphatases, such as PPM1A, contribute to regulating chromatin accessibility during bacterial infections. However, changes in genome-wide chromatin accessibility during Mtb infection and whether PPM1A plays a role in this process remains unknown. Herein, we use combinatorial chromatin accessibility (ATAC-seq) and transcriptomic (RNA-seq) profiling of wild-type, PPM1A knockout and PPM1A overexpressing macrophages to demonstrate that Mtb infection induces global chromatin remodelling consistent with changes in gene expression. The strongest concordant changes to chromatin accessibility and gene expression triggered by Mtb infection were enriched for genes involved in type I interferon (IFN) signalling pathways. A panel of 15 genes with the strongest concordant changes in chromatin accessibility and gene expression were validated to be significantly upregulated in Mtb-infected human monocyte-derived macrophages. PPM1A expression affects chromatin accessibility profiles during Mtb infection that are reflected in the total number, chromosome location, and directionality of change. Transcription factor binding motif analysis revealed enrichment for transcription factors involved in the type I IFN pathway during Mtb infection, including members of the IRF, MEF2, and AP-1 families. Our study shows that altered type I IFN responses in Mtb-infected macrophages occur due to genome-wide changes in chromatin accessibility, and that PPM1A could influence a subset of these signatures. [ABSTRACT FROM AUTHOR]

Background: Seasonal respiratory viral infections are associated with exacerbations and morbidity among patients with COPD. The real‐world clinical outcomes associated with seasonal viral infections are less well established among hospitalized patients. Research Question: To estimate the association between seasonal respiratory viral infections, 30‐day mortality, and intensive care unit (ICU) admission among hospitalized COPD patients. Study Design and Methods: We conducted an analysis of a national prospective multicenter cohort of COPD patients hospitalized with acute respiratory illness during winter seasons (2011–2015) in Canada. Nasopharyngeal swabs were performed on all patients at the onset of hospital admission for diagnosis of viral infection. Primary outcomes were 30‐day mortality and ICU admissions. Secondary outcomes included invasive/non‐invasive ventilation use. Results: Among 3931 hospitalized patients with COPD, 28.5% (1122/3931) were diagnosed with seasonal respiratory viral infection. Viral infection was associated with increased admission to ICU (OR 1.5, 95% CI 1.2–1.9) and need for mechanical ventilation (OR 1.9, 95% CI 1.4–2.5), but was not associated with mortality (OR 1.1, 95% CI 0.8–1.4). Patients with respiratory syncytial virus (RSV) were equally likely to require ICU admission (OR 1.09, 95% CI 0.67–1.78), and more likely to need non‐invasive ventilation (OR 3.1; 95% CI 1.8–5.1) compared to patients with influenza. Interpretation: Our results suggest COPD patients requiring hospitalization for respiratory symptoms should routinely receive viral testing at admission, especially for RSV and influenza, to inform prognosis, clinical management, and infection control practices during winter seasons. Patients with COPD will be an important target population for newly developed RSV therapeutics. Clinical Trial Registration: ClinicalTrials.gov ID: NCT01517191. [ABSTRACT FROM AUTHOR]

Background In the last decade, tuberculosis (TB) incidence among Inuit in the Canadian Arctic has been rising. Our aim was to better understand the transmission dynamics of TB in this remote region of Canada using whole-genome sequencing. Methods Isolates from patients who had culture-positive pulmonary TB in Iqaluit, Nunavut, between 2009 and 2015 underwent whole-genome sequencing (WGS). The number of transmission events between cases within clusters was calculated using a threshold of a ≤3 single nucleotide polymorphism (SNP) difference between isolates and then combined with detailed epidemiological data using a reproducible novel algorithm. Social network analysis of epidemiological data was used to support the WGS data analysis. Results During the study period, 140 Mycobacterium tuberculosis isolates from 135 cases were sequenced. Four clusters were identified, all from Euro-American lineage. One cluster represented 62% of all cases that were sequenced over the entire study period. In this cluster, 2 large chains of transmission were associated with 3 superspreading events in a homeless shelter. One of the superspreading events was linked to a nonsanctioned gambling house that resulted in further transmission. Shelter to nonshelter transmission was also confirmed. An algorithm developed for the determination of transmission events demonstrated very good reproducibility (κ score.98, 95% confidence interval,.97–1.0). Conclusions Our study suggests that socioeconomic factors, namely residing in a homeless shelter and spending time in a gambling house, combined with the superspreading event effect may have been significant factors explaining the rise in cases in this predominantly Inuit Arctic community. [ABSTRACT FROM AUTHOR]

Abstract Background Tuberculosis (TB) in migrants is an ongoing challenge in several low TB incidence countries since a large proportion of TB in these countries occurs in migrants from high incidence countries. To meet these challenges, several countries utilize TB screening programs. The programs attempt to identify and treat those with active and/or infectious stages of the disease. In addition, screening is used to identify and manage those with latent or inactive disease after arrival. Between nations, considerable variation exists in the methods used in migration-associated TB screening. The present study aimed to compare the TB immigration medical examination requirements in selected countries of high immigration and low TB incidence rates. Methods Descriptive study of immigration TB screening programs Results 16 out of 18 eligible countries responded to the written standardized survey and phone interview. Comparisons in specific areas of TB immigration screening programs included authorities responsible for TB screening, the primary objectives of the TB screening program, the yield of detection of active TB disease, screening details and aspects of follow up for inactive pulmonary TB. No two countries had the same approach to TB screening among migrants. Important differences, common practices, common problems, evidence or lack of evidence for program specifics were noted. Conclusions In spite of common goals, there is great diversity in the processes and practices designed to mitigate the impact of migration-associated TB among nations that screen migrants for the disease. The long-term goal in decreasing migration-related introduction of TB from high to low incidence countries remains diminishing the prevalence of the disease in those high incidence locations. In the meantime, existing or planned migration screening programs for TB can be made more efficient and evidenced based. Cooperation among countries doing research in the areas outlined in this study should facilitate the development of improved screening programs.

Background: Tuberculosis (TB) remains a significant public health problem in Canadian Inuit communities. In 2016, Canadian Inuit had an incidence rate 35 times the Canadian average. Tobacco use is an important risk factor for TB, and over 60% of Inuit adults smoke. We aimed to estimate changes in TB-related outcomes and costs from reducing tobacco use in Inuit communities.Methods: Using a transmission model to estimate the initial prevalence of latent TB infection (LTBI), followed by decision analysis modelling, we conducted a cost-effectiveness analysis that compared the current standard of care for management of TB and LTBI without additional tobacco reduction intervention (Status Quo) with (1) increased tobacco taxation, (2) pharmacotherapy and counselling for smoking cessation, (3) pharmacotherapy, counselling plus mass media campaign, and (4) the combination of all these. Projected outcomes included the following: TB cases, TB-related deaths, quality-adjusted life years (QALYs), and health system costs, all over 20 years.Results: The combined strategy was projected to reduce active TB cases by 6.1% (95% uncertainty range 4.9-7.0%) and TB deaths by 10.4% (9.5-11.4%) over 20 years, relative to the status quo. Increased taxation was the only cost-saving strategy.Conclusions: Currently available strategies to reduce commercial tobacco use will likely have a modest impact on TB-related outcomes in the medium term, but some may be cost saving. [ABSTRACT FROM AUTHOR]