Characterization of Mycobacterium orygis, Mycobacterium bovis, and Mycobacterium caprae Infections in Humans in Western Canada.

Epidemiologic research on zoonotic tuberculosis historically used Mycobacterium bovis as a surrogate measure, however, increased reports of human tuberculosis caused by other animal-associated Mycobacterium tuberculosis complex members like Mycobacterium orygis necessitates their inclusion. We performed a retrospective cohort study including persons infected with any animal-lineage M. tuberculosis complex species in Alberta, Canada, from January 1995 to July 2021, identifying 42 patients (20 M. bovis, 21 M. orygis, one M. caprae). Demographic, epidemiologic and clinical characteristics were compared against persons with culture-confirmed M. tuberculosis infection. The proportion of culture-positive infections caused by M. orygis increased continuously from 2016-2020. Significantly more females at a higher median age were impacted by M. orygis, with all patients originating from South Asia. M. bovis caused significantly more extra-pulmonary disease, and disproportionately impacted young females, particularly those pregnant or post-partum. All infections were acquired abroad. These findings can aid in developing targeted public health interventions.

Time to diagnosis and treatment of pulmonary tuberculosis in indigenous peoples: a systematic review.

BACKGROUND: Time to diagnosis and treatment is a major factor in determining the likelihood of tuberculosis (TB) transmission and is an important area of intervention to reduce the reservoir of TB infection and prevent disease and mortality. Although Indigenous peoples experience an elevated incidence of TB, prior systematic reviews have not focused on this group. We summarize and report findings related to time to diagnosis and treatment of pulmonary TB (PTB) among Indigenous peoples, globally. METHODS: A Systematic review was performed using Ovid and PubMed databases. Articles or abstracts estimating time to diagnosis, or treatment of PTB among Indigenous peoples were included with no restriction on sample size with publication dates restricted up to 2019. Studies that focused on outbreaks, solely extrapulmonary TB alone in non-Indigenous populations were excluded. Literature was assessed using the Hawker checklist. Registration Protocol (PROSPERO): CRD42018102463. RESULTS: Twenty-four studies were selected after initial assessment of 2021 records. These included Indigenous groups from five of six geographical regions outlined by the World Health Organization (all except the European Region). The range of time to treatment (24-240 days), and patient delay (20 days-2.5 years) were highly variable across studies and, in at least 60% of the studies, longer in Indigenous compared to non-Indigenous peoples. Risk factors associated with longer patient delays included poor awareness of TB, type of health provider first seen, and self-treatment. CONCLUSION: Time to diagnosis and treatment estimates for Indigenous peoples are generally within previously reported ranges from other systematic reviews focusing on the general population. However among literature examined in this systematic review that stratified by Indigenous and non-Indigenous peoples, patient delay and time to treatment were longer compared to non-Indigenous populations in over half of the studies. Studies included were sparse and highlight an overall gap in literature important to interrupting transmission and preventing new TB cases among Indigenous peoples. Although, risk factors unique to Indigenous populations were not identified, further investigation is needed as social determinants of health among studies conducted in medium and high incidence countries may be shared across both population groups. Trial registration N/a.

Exploration of inter-jurisdictional TB programming and mobility in a Canadian First Nation community.

BACKGROUND: Colonially imposed jurisdictional boundaries that have little meaning to Indigenous peoples in Canada may confound tuberculosis (TB) prevention and care activities. This study explores how inter-jurisdictional mobility and the current accommodation of mobility through policies and programming sustain a regional TB epidemic in northwestern Saskatchewan, and northeastern Alberta. METHODS: A qualitative instrumental case study was performed using a community based participatory approach. Semi-structured interviews were conducted with First Nations peoples from a high-incidence community in Canada including community-based healthcare workers. These interview data are presented in the context of a multi-level document analysis of TB program guidelines. RESULTS: The location of the community, and related lack of access to employment, services and care, necessitates mobility across jurisdictional boundaries. There are currently no formal federal or provincial guidelines in place to accommodate highly mobile patients and clients within and across provincial TB prevention and care programs. As a result, locally developed community-based protocols, and related ad-hoc strategies ensure continuity of care. CONCLUSION: Indigenous peoples living in remote communities face unique push/pull factors that motivate mobility. When these motivations exist in communities with increased risk of contagion by communicable infectious diseases such as TB, public health risks extend into increasingly large areas with competing jurisdictional authority. Such mobility poses several threats to TB elimination. We have identified a gap in TB services to systematically accommodate mobility, with specific implications for Indigenous peoples and reconciliation. We recommend clearly defined communication paths and inter-jurisdictional coordination to ensure maintenance of care for mobile populations.

Local Transmission Plays No Important Role in the Occurrence of Multidrug-Resistant Tuberculosis in Immigrants to Canada: An In-depth Epidemiologic Analysis.

BACKGROUND: Multidrug-resistant (MDR) tuberculosis has increased among migrants in Canada. The cause(s) of this increase is unknown. METHODS: We performed a retrospective cohort study in a Canadian province with substantially increased immigration between 1982-2001 and 2002-2019. The proportion of MDR tuberculosis among migrants arriving from high MDR (HMDR) tuberculosis burden countries during these 2 periods was used to estimate the proportion of cases due to immigration versus change in proportion in the country of birth. Epidemiologic, spatiotemporal, and drug resistance pattern data were used to confirm local transmission. RESULTS: Fifty-two of 3514 (1.48%) foreign-born culture-positive tuberculosis patients had MDR tuberculosis: 8 (0.6%) in 1982-2001 and 44 (2.0%) in 2002-2019. Between time periods, the proportion of MDR tuberculosis among migrants with tuberculosis from HMDR tuberculosis countries increased from 1.11% to 3.62%, P = .003; 31.6% attributable to recent immigration and 68.4% to a higher proportion of MDR tuberculosis in cases arrived from HMDR tuberculosis countries. No cases of MDR tuberculosis were attributable to local transmission. CONCLUSIONS: In stark contrast to HMDR tuberculosis countries, local transmission plays no important role in the occurrence of MDR tuberculosis in Canada. Improved tuberculosis programming in HMDR tuberculosis countries is urgently needed.

Safety and Efficacy of Rifampin or Isoniazid Among People With Mycobacterium tuberculosis Infection and Living With Human Immunodeficiency Virus or Other Health Conditions: Post Hoc Analysis of 2 Randomized Trials.

BACKGROUND: The safety and efficacy of rifampin among people living with human immunodeficiency virus (PLHIV) or other health conditions is uncertain. We assessed completion, safety, and efficacy of 4 months of rifampin vs 9 months of isoniazid among PLHIV or other health conditions. METHODS: We conducted post hoc analysis of 2 randomized trials that included 6859 adult participants with Mycobacterium tuberculosis infection. Participants were randomized 1:1 to 10 mg/kg/d rifampin or 5 mg/kg/d isoniazid. We report completion, drug-related adverse events (AE), and active tuberculosis incidence among people living with HIV; with renal failure or receiving immunosuppressants; using drugs or with hepatitis; with diabetes mellitus; consuming >1 alcoholic drink per week or current/former smokers; and with no health condition. RESULTS: Overall, 270 (3.9%) people were living with HIV (135 receiving antiretroviral therapy), 2012 (29.3%) had another health condition, and 4577 (66.8%) had no condition. Rifampin was more often or similarly completed to isoniazid in all populations. AEs were less common with rifampin than isoniazid among PLHIV (risk difference, -2.1%; 95% confidence interval [CI], -5.9 to 1.6). This was consistent for others except people with renal failure or on immunosuppressants (2.1%; 95% CI, -7.2 to 11.3). Tuberculosis incidence was similar among people receiving rifampin or isoniazid. Among participants receiving rifampin living with HIV, incidence was comparable to those with no health condition (rate difference, 4.1 per 1000 person-years; 95% CI, -6.4 to 14.7). CONCLUSIONS: Rifampin appears to be safe and as effective as isoniazid across many populations with health conditions, including HIV. CLINICAL TRIALS REGISTRATION: NCT00170209; NCT00931736.

Safety and Side Effects of Rifampin versus Isoniazid in Children.

BACKGROUND: The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid. METHODS: In this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis. RESULTS: Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14). CONCLUSIONS: Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; ClinicalTrials.gov number, NCT00170209 .).

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Health System Costs of Treating Latent Tuberculosis Infection With Four Months of Rifampin Versus Nine Months of Isoniazid in Different Settings.

BACKGROUND: Four months of rifampin treatment for latent tuberculosis infection is safer, has superior treatment completion rates, and is as effective as 9 months of isoniazid. However, daily medication costs are higher for a 4-month rifampin regimen than a 9-month isoniazid regimen. OBJECTIVE: To compare health care use and associated costs of 4 months of rifampin and 9 months of isoniazid. DESIGN: Health system cost comparison using all health care activities recorded during 2 randomized clinical trials. (ClinicalTrials.gov: NCT00931736 and NCT00170209). SETTING: High-income countries (Australia, Canada, Saudi Arabia, and South Korea), middle-income countries (Brazil and Indonesia), and African countries (Benin, Ghana, and Guinea). PARTICIPANTS: Adults and children with clinical or epidemiologic factors associated with increased risk for developing tuberculosis that warranted treatment for latent tuberculosis infection. MEASUREMENTS: Health system costs per participant. RESULTS: A total of 6012 adults and 829 children were included. In both adults and children, greater health system use and higher costs were observed with 9 months of isoniazid than with 4 months of rifampin. In adults, the ratios of costs of 4 months of rifampin versus 9 months of isoniazid were 0.76 (95% CI, 0.70 to 0.82) in high-income countries, 0.90 (CI, 0.85 to 0.96) in middle-income countries, and 0.80 (CI, 0.78 to 0.81) in African countries. Similar findings were observed in the pediatric population. LIMITATION: Costs may have been overestimated because the trial protocol required a minimum number of follow-up visits, although fewer than recommended by many authoritative guidelines. CONCLUSION: A 4-month rifampin regimen was safer and less expensive than 9 months of isoniazid in all settings. This regimen could be adopted by tuberculosis programs in many countries as first-line therapy for latent tuberculosis infection. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Epidemiological and genomic determinants of tuberculosis outbreaks in First Nations communities in Canada.

BACKGROUND: In Canada, tuberculosis disproportionately affects foreign-born and First Nations populations. Within First Nations' peoples, a high proportion of cases occur in association with outbreaks. Tuberculosis transmission in the context of outbreaks is thought to result from the convergence of several factors including characteristics of the cases, contacts, the environment, and the pathogen. METHODS: We examined the epidemiological and genomic determinants of two well-characterized tuberculosis outbreaks attributed to two super-spreaders among First Nations in the province of Alberta. These outbreaks were associated with two distinct DNA fingerprints (restriction fragment-length polymorphisms or RFLPs 0.0142 and 0.0728). We compared outbreak isolates with endemic isolates not spatio-temporarily linked to outbreak cases. We extracted epidemiological variables pertaining to tuberculosis cases and contacts from individual public health records and the provincial tuberculosis registry. We conducted group analyses using parametric and non-parametric statistical tests. We carried out whole-genome sequencing and bioinformatic analysis using validated protocols. RESULTS: We observed differences between outbreak and endemic groups in the mean number of total and child-aged contacts and the number of contacts with new positive and converted tuberculin skin tests in all group comparisons (p < 0.05). Differences were also detected in the proportion of cases with cavitation on a chest radiograph and the mean number of close contacts in selected group comparisons (p < 0.02). A phylogenetic network analysis of whole-genome sequencing data indicated that most outbreak and endemic strains were closely related to the source case for the 0.0142 fingerprint. For the 0.0728 fingerprint, the source case haplotype was circulating among endemic cases prior to the outbreak. Genetic and temporal distances were not correlated for either RFLP 0.0142 (r2 = - 0.05) or RFLP 0.0728 (r2 = 0.09) when all isolates were analyzed. CONCLUSIONS: We found no evidence that endemic strains acquired mutations resulting in their emergence in outbreak form. We conclude that the propagation of these outbreaks was likely driven by the combination of characteristics of the source cases, contacts, and the environment. The role of whole-genome sequencing in understanding mycobacterial evolution and in assisting public health authorities in conducting contact investigations and managing outbreaks is important and expected to grow in the future.

Beaconing Signalization Substantially Reduces Blind Pedestrians' Veer on Snow-Covered Pavement.

Veering outside of crosswalks is a common problem experienced by individuals who are blind. One technology found to be effective for reducing this veer when other guidance cues are absent is audible beaconing. However, veering in general and veering from crosswalks in particular have been studied primarily on smooth, flat walking surfaces such as clear pavement. This experiment compared veering on clear pavement with veering on snow-covered pavement, with and without audible beaconing. Eleven blind participants traveling with long canes attempted to walk a straight path for 72 ft (21.9 m), a typical length of a six-lane crosswalk. Beaconing substantially reduced veering at 36 ft (11.0 m) and 72 ft from the starting point and enabled participants to remain within a simulated crosswalk. Walking on snow was not found to affect veering but did increase the number of steps taken. The findings suggest that in snowy and clear conditions alike, audible beaconing is an effective wayfinding tool for intersections equipped with accessible pedestrian signals.

Therapeutic drug monitoring and the conservative management of chronic tuberculous empyema: case report and review of the literature.

BACKGROUND: Chronic tuberculous empyema (CTE) is a rare and unusual, low grade and protracted, infection of the pleural space resulting in marked thickening, even calcification of the visceral and parietal pleura. Historically its management has been extraordinarily challenging. Differential penetration of anti-TB drugs into the pleural space has resulted in acquired drug resistance and surgery to remove the empyema or close a complicating bronchopleural fistula (BPF) has been technically difficult or unacceptably hazardous. On the basis of limited experience, the combination of tube thoracostomy or catheter drainage and high-end dosing of anti-TB drugs has been recommended as an initial approach to these lesions. Herein we report the first well documented case of closure of a BPF and cure of a CTE using this approach. The chances of a favorable outcome are improved, we suggest, by using therapeutic drug monitoring (TDM) to guide high-end drug dosing. CASE PRESENTATION: An 84 year old male immigrant to Canada from Croatia was diagnosed with a CTE after he developed a BPF. The diagnosis was made 62 years after what was, in retrospect, an episode of tuberculous pleurisy. He was treated with computed tomography-guided catheter drainage and TDM-guided high-end dosed anti-TB drugs (serum and pleural fluid drug concentrations) over a 10 month period. Sustained closure of the BPF and mycobacteriologic cure of the CTE was achieved. Drug concentrations in the present case and all other reported cases are summarized and interpreted. CONCLUSION: When serum concentrations of the anti-TB drugs isoniazid, pyrazinamide and ethambutol at the high end of the normal range are achieved, pleural fluid concentrations at the low end of the normal range may be anticipated in CTE. Though highly protein bound drugs such as rifampin and moxifloxacin appear to penetrate CTEs less well, their free concentrations in the pleural space may be proportionately higher on account of lower protein concentrations. Interventional radiology and TDM increase the chances that conservative management of CTE will be successful.

Dispersal of Mycobacterium tuberculosis via the Canadian fur trade.

Patterns of gene flow can have marked effects on the evolution of populations. To better understand the migration dynamics of Mycobacterium tuberculosis, we studied genetic data from European M. tuberculosis lineages currently circulating in Aboriginal and French Canadian communities. A single M. tuberculosis lineage, characterized by the DS6(Quebec) genomic deletion, is at highest frequency among Aboriginal populations in Ontario, Saskatchewan, and Alberta; this bacterial lineage is also dominant among tuberculosis (TB) cases in French Canadians resident in Quebec. Substantial contact between these human populations is limited to a specific historical era (1710-1870), during which individuals from these populations met to barter furs. Statistical analyses of extant M. tuberculosis minisatellite data are consistent with Quebec as a source population for M. tuberculosis gene flow into Aboriginal populations during the fur trade era. Historical and genetic analyses suggest that tiny M. tuberculosis populations persisted for ∼100 y among indigenous populations and subsequently expanded in the late 19th century after environmental changes favoring the pathogen. Our study suggests that spread of TB can occur by two asynchronous processes: (i) dispersal of M. tuberculosis by minimal numbers of human migrants, during which small pathogen populations are sustained by ongoing migration and slow disease dynamics, and (ii) expansion of the M. tuberculosis population facilitated by shifts in host ecology. If generalizable, these migration dynamics can help explain the low DNA sequence diversity observed among isolates of M. tuberculosis and the difficulties in global elimination of tuberculosis, as small, widely dispersed pathogen populations are difficult both to detect and to eradicate.

The association between phylogenetic lineage and the subclinical phenotype of pulmonary tuberculosis: A retrospective 2-cohort study.

BACKGROUND: Subclinical pulmonary tuberculosis (PTB) is an asymptomatic disease state between established TB infection and symptomatic (clinical) TB disease. It is present in 20-25% of PTB patients in high-income countries. Mycobacterium tuberculosis complex (MTBC) genetic heterogeneity, and differential host immunological responses, have been implicated in its pathogenesis. METHODS: To determine the association between MTBC lineage and PTB disease phenotype, we used two retrospective cohorts of PTB patients in Canada and two independent lineage attribution methods (DNA fingerprinting and genome sequencing). The first cohort, Cohort 1, consisted of consecutively diagnosed PTB patients between 2014 and 2020. The second, Cohort 2, consisted of newly-arrived foreign-born PTB patients who either were or were not referred for post-landing medical surveillance between 2004 and 2017. Univariable and multivariable logistic regression models were sequentially fitted to both cohorts, adjusting for age, sex, disease type, drug resistance and HIV. Evolution of radiographic features was correlated to lineage in Cohort 2. FINDINGS: Cohort 1 and 2 included 874 (209 subclinical) and 111 (44 subclinical) patients, respectively. In both cohorts, subclinical patients were more likely than clinical patients to have relapse/retreatment disease, be smear-negative, have longer times-to-culture positivity and to harbor an ancestral MTBC lineage (Indo-Oceanic or Mycobacterium africanum). Relapse/retreatment disease and ancestral MTBC lineage were independent predictors of subclinical disease (ORs and 95% CIs in Cohort 1, 1.85 [1.07,3.28], p < 0.029 and 2.30 [1.66,3.18], p < 0.001, respectively, and Cohort 2, 5.74 [1.37-24.06], p < 0.017 and 3.21 (1.29,7.97], p < 0.012, respectively). The geographic distribution of Indo-Oceanic strains causing subclinical disease was uneven. Non-progressive lung disease was more common in patients infected with ancestral than modern lineages in Cohort 2, 56.0% vs 25.4%, p < 0.005. INTERPRETATION: MTBC lineage is a strong predictor of PTB disease phenotype. The genetic drivers of this association, and the relative contribution of other explanatory variables, are unknown.

High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial.

BACKGROUND: Tuberculosis preventive treatment (TPT) is a key component of tuberculosis elimination. To improve completion and reduce the burden for people and health systems, short, safe, and effective TPT regimens are needed. We aimed to compare safety and treatment completion of various doses and durations of rifampicin in people who were recommended to receive TPT. METHODS: This partially blinded, parallel-arm, non-inferiority, randomised, controlled, phase 2b trial was done at seven university-affiliated clinics in Canada, Indonesia, and Viet Nam. Participants aged 10 years or older were included if they had an indication for TPT according to WHO guidelines for Indonesia and Viet Nam, or Canadian guidelines for Canadian sites, and a positive tuberculin skin test or interferon-γ release assay. Participants were randomly assigned (1:1:1) to receive oral rifampicin at 10 mg/kg once daily for 4 months (standard-dose group), 20 mg/kg daily for 2 months (20 mg/kg group), or 30 mg/kg daily for 2 months (30 mg/kg group). The randomisation sequence was computer generated with blocks of variable size (three, six, and nine) and stratified by country for Indonesia and Viet Nam, and by city within Canada. Participants and investigators were masked to dose in high-dose groups, but unmasked to duration in all groups. The two co-primary outcomes were safety (in the safety population, in which participants received at least one dose of the study drug) and treatment completion (in the modified intention-to-treat [mITT] population, excluding those ineligible after randomisation). Protocol-defined adverse events were defined as grade 3 or worse, or rash or allergy of any grade, judged by an independent and masked panel as possibly or probably related to the study. A margin of 4% was used to assess non-inferiority. This study is registered with ClinicalTrials.gov, NCT03988933 (active). FINDINGS: Between Sept 1, 2019, and Sept 30, 2022, 1692 people were assessed for eligibility, 1376 were randomly assigned, and eight were excluded after randomisation. 1368 participants were included in the mITT population (454 in the standard group, 461 in the 20 mg/kg group, and 453 in the 30 mg/kg group). 589 (43%) participants were male and 779 (57%) were female. 372 (82%) in the standard-dose group, 329 (71%) in the 20 mg/kg group, and 293 (65%) in the 30 mg/kg group completed treatment. No participants in the standard-dose group, one (<1%) of 441 participants in the 20 mg/kg group, and four (1%) of 423 in the 30 mg/kg group developed grade 3 hepatotoxicity. Risk of protocol-defined adverse events was higher in the 30 mg/kg group than in the standard-dose group (adjusted risk difference 4·6% [95% CI 1·8 to 7·4]) or the 20 mg/kg group (5·1% [2·3 to 7·8]). There was no difference in the risk of adverse events between the 20 mg/kg and standard-dose groups (-0·5% [95% CI -2·4 to 1·5]; non-inferiority met). Completion was lower in the 20 mg/kg group (-7·8% [95% CI -13·6 to -2·0]) and the 30 mg/kg group (-15·4% [-21·4 to -9·4]) than in the standard-dose group. INTERPRETATION: In this trial, 2 months of 30 mg/kg daily rifampicin had significantly worse safety and completion than 4 months of 10 mg/kg daily and 2 months of 20 mg/kg daily (the latter, a fully blinded comparison); we do not consider 30 mg/kg to be a good option for TPT. Rifampicin at 20 mg/kg daily for 2 months was as safe as standard treatment, but with lower completion. This difference remains unexplained. FUNDING: Canadian Institutes of Health Research.

Sustainability and impact of an intervention to improve initiation of tuberculosis preventive treatment: results from a follow-up study of the ACT4 randomized trial.

Background: In a cluster randomized trial (clinicaltrials.gov: NCT02810678) a flexible but comprehensive health system intervention significantly increased the number of household contacts (HHC) identified and started on tuberculosis preventive treatment (TPT). A follow-up study was conducted one year later to test the hypotheses that these effects were sustained, and were reproducible with a simplified intervention. Methods: We conducted a follow-up study from May 1, 2018 until April 30, 2019, as part of a multinational cluster randomized trial. Eight sites in 4 countries that had received the intervention in the original trial received no further intervention; eight other sites in the same countries that had not received the intervention (control sites in the original trial) now received a simplified version of the intervention. This consisted of repeated local evaluation of the Cascade of care for TB infection, and stakeholder decision making. The number of HHC identified and starting TPT were repeatedly measured at all 16 sites and expressed as rates per 100 newly diagnosed index TB patients. The sustained effect of the original intervention was estimated by comparing these rates after the intervention in the original trial with the last 6 months of the follow-up study. The reproducibility was estimated by comparing the pre-post intervention changes in rates at sites receiving the original intervention with the pre-post changes in rates at sites receiving the later, simplified intervention. Findings: With regard to the sustained impact of the original intervention, compared to the original post-intervention period, the number of HHC identified and treated per 100 newly diagnosed TB patients was 10 more (95% confidence interval: 84 fewer to 105 more), and 1 fewer (95% CI: 22 fewer to 20 more) respectively up to 14 months after the end of the original intervention. With regard to the reproducibility of the simplified intervention, at sites that had initially served as control sites, the number of HHC identified and treated per 100 TB patients increased by 33 (95% CI: -32, 97), and 16 (-69, 100) from 3 months before, to up to 6 months after receiving a streamlined intervention, although differences were larger, and significant if the post-intervention results were compared to all pre-intervention periods. Interpretation: Up to one year after it ended, a health system intervention resulted in sustained increases in the number of HHC identified and starting TPT. A simplified version of the intervention was associated with non-significant increases in the identification and treatment of HHC. Inferences are limited by potential bias due to other temporal effects, and the small number of study sites. Funding: Funded by the Canadian Institutes of Health Research (Grant number 143350).

Transmission of Mycobacterium tuberculosis Beijing Strains, Alberta, Canada, 1991-2007.

Beijing strains are speculated to have a selective advantage over other Mycobacterium tuberculosis strains because of increased transmissibility and virulence. In Alberta, a province of Canada that receives a large number of immigrants, we conducted a population-based study to determine whether Beijing strains were associated with increased transmission leading to disease compared with non-Beijing strains. Beijing strains accounted for 258 (19%) of 1,379 pulmonary tuberculosis cases in 1991-2007; overall, 21% of Beijing cases and 37% of non-Beijing cases were associated with transmission clusters. Beijing index cases had significantly fewer secondary cases within 2 years than did non-Beijing cases, but this difference disappeared after adjustment for demographic characteristics, infectiousness, and M. tuberculosis lineage. In a province that has effective tuberculosis control, transmission of Beijing strains posed no more of a public health threat than did non-Beijing strains.

Severe combined immunodeficiency (SCID) in Canadian children: a national surveillance study.

PURPOSE: Severe Combined Immune Deficiency (SCID) is universally fatal unless treated with hematopoietic stem cell transplantation (HSCT). Following the identification of disseminated Bacille Calmette-Guérin (BCG) infections in Canadian First Nations, Métis and Inuit (FNMI) children with unrecognized primary immune deficiencies, a national surveillance study was initiated in order to determine the incidence, diagnosis, treatment and outcome of children with SCID in Canada. METHODS: Canadian pediatricians were asked to complete a monthly reporting form if they had seen a suspected SCID case, from 2004 to 2010, through the Canadian Paediatric Surveillance Program (CPSP). If the case met CPSP SCID criteria, more detailed data, including demographics and clinical information about investigations, treatment and outcome was collected. RESULTS: A total of 40 cases of SCID were confirmed for an estimated incidence of SCID in non-FNMI Canadian children of 1.4 per 100,000 live births (95 % CI 1 to 1.9/100,000). The proportion of SCID cases that were FNMI (17.5 %) was almost three times higher than was expected on the basis of proportion of the pediatric population estimated to be FNMI (6.3 %) resulting in an estimated incidence of 4.4 per 100,000 live births (95 % CI 2.1 to 9.2/100,000) in FNMI Canadian children. The mean age at diagnosis for all SCID cases was 4.2 months (range 1­583 days). There were 12 deaths (30 %; 95 % CI 18­46 %); seven died of confirmed or suspected infections before they could receive an HSCT. CONCLUSIONS: The frequency of SCID cases in FNMI children is higher than in the general Canadian pediatric population. The high mortality rate, due primarily to infection, suggests that early diagnosis by newborn screening followed by HSCT could significantly benefit children with SCID.

Scientific and Regulatory Policy Committee (SRPC) paper: validation of digital pathology systems in the regulated nonclinical environment.

Digital Pathology Systems (DPS) are dynamic, image-based computer systems that enable the acquisition, management, and interpretation of pathology information generated from digitized glass slides. This article provides a roadmap for (1) qualification of a whole slide scanner (WSS) during a validation project, (2) validation of software required to generate the whole slide image (WSI), and (3) an introduction to visual digital image evaluation and image analysis. It describes a validation approach that can be utilized when validating a DPS. It is not the intent of this article to provide guidance on when validation of DPS is required. Rather, the article focuses on technical aspects of validation of the WSS system (WSS, IT infrastructure, and associated software) portion of a DPS and covers the processes of setting up the WSS for scanning a glass slide through saving a WSI on a server. Validation of a computerized system, such as a DPS, for use in a regulated nonclinical environment is governed by Code of Federal Regulations (CFR) Title 21 part 11: Electronic Records; Electronic Signature and predicate rules associated with Good Laboratory Practices documents including 21 CFR part 58. Similar regulation and predicate rules apply in the European Union and Japan.