Risk of Tuberculosis Disease in People With Chronic Kidney Disease Without Kidney Failure: A Systematic Review and Meta-analysis.

BACKGROUND: Kidney failure is an established risk factor for tuberculosis (TB), but little is known about TB risk in people with chronic kidney disease (CKD) who have not initiated kidney replacement therapy (CKD without kidney failure). Our primary objective was to estimate the pooled relative risk of TB disease in people with CKD stages 3-5 without kidney failure compared with people without CKD. Our secondary objectives were to estimate the pooled relative risk of TB disease for all stages of CKD without kidney failure (stages 1-5) and by each CKD stage. METHODS: This review was prospectively registered (PROSPERO CRD42022342499). We systematically searched MEDLINE, Embase, and Cochrane databases for studies published between 1970 and 2022. We included original observational research estimating TB risk among people with CKD without kidney failure. Random-effects meta-analysis was performed to obtain the pooled relative risk. RESULTS: Of the 6915 unique articles identified, data from 5 studies were included. The estimated pooled risk of TB was 57% higher in people with CKD stages 3-5 than in people without CKD (adjusted hazard ratio: 1.57; 95% CI: 1.22-2.03; I2 = 88%). When stratified by CKD stage, the pooled rate of TB was highest in stages 4-5 (incidence rate ratio: 3.63; 95% CI: 2.25-5.86; I2 = 89%). CONCLUSIONS: People with CKD without kidney failure have an increased relative risk of TB. Further research and modeling are required to understand the risks, benefits, and CKD cutoffs for screening people for TB with CKD prior to kidney replacement therapy.

Healthcare Utilization After Respiratory Tuberculosis: A Controlled Interrupted Time Series Analysis.

BACKGROUND: Despite data suggesting elevated morbidity and mortality among people who have survived tuberculosis disease, the impact of respiratory tuberculosis on healthcare utilization in the years following diagnosis and treatment remains unclear. METHODS: Using linked health administrative data from British Columbia, Canada, we identified foreign-born individuals treated for respiratory tuberculosis between 1990 and 2019. We matched each person with up to four people without a tuberculosis diagnosis from the same source cohort using propensity score matching. Then, using a controlled interrupted time series analysis, we measured outpatient physician encounters and inpatient hospital admissions in the 5 years following respiratory tuberculosis diagnosis and treatment. RESULTS: We matched 1216 individuals treated for respiratory tuberculosis to 4864 non-tuberculosis controls. Immediately following the tuberculosis diagnostic and treatment period, the monthly rate of outpatient encounters in the tuberculosis group was 34.0% (95% confidence interval [CI]: 30.7%, 37.2%) higher than expected, and this trend was sustained for the duration of the post-tuberculosis period. The excess utilization represented an additional 12.2 (95% CI: 10.6, 14.9) outpatient encounters per person over the post-tuberculosis period, with respiratory morbidity a large contributor to the excess healthcare utilization. Results were similar for hospital admissions, with an additional 0.4 (95% CI: .3, .5) hospital admissions per person over the post-tuberculosis period. CONCLUSIONS: Respiratory tuberculosis appears to have long-term impacts on healthcare utilization beyond treatment. These findings underscore the need for screening, assessment, and treatment of post-tuberculosis sequelae, as it may provide an opportunity to improve health and reduce resource use.

Role of latent tuberculosis infection on elevated risk of cardiovascular disease: a population-based cohort study of immigrants in British Columbia, Canada, 1985-2019.

We investigated cardiovascular disease (CVD) risk associated with latent tuberculosis infection (LTBI) (Aim-1) and LTBI therapy (Aim-2) in British Columbia, a low-tuberculosis-incidence setting. 49,197 participants had valid LTBI test results. Cox proportional hazards model was fitted, adjusting for potential confounders. Compared with the participants who tested LTBI negative, LTBI positive was associated with an 8% higher CVD risk in complete case data (adjusted hazard ratio (HR): 1.08, 95% CI: 0.99-1.18), a statistically significant 11% higher risk when missing confounder values were imputed using multiple imputation (HR: 1.11, 95% CI: 1.02-1.20), and 10% higher risk when additional proxy variables supplementing known unmeasured confounders were incorporated in the highdimensional disease risk score technique to reduce residual confounding (HR: 1.10, 95% CI: 1.01-1.20). Also, compared with participants who tested negative, CVD risk was 27% higher among people who were LTBI positive but incomplete LTBI therapy (HR: 1.27, 95% CI: 1.04-1.55), whereas the risk was similar in people who completed LTBI therapy (HR: 1.04, 95% CI: 0.87-1.24). Findings were consistent in different sensitivity analyses. We concluded that LTBI is associated with an increased CVD risk in low-tuberculosis-incidence settings, with a higher risk associated with incomplete LTBI therapy and attenuated risk when therapy is completed.

Using a theory-informed approach to guide the initial development of a post-tuberculosis care package in British Columbia, Canada.

BACKGROUND: The importance of addressing the long-term needs of tuberculosis (TB) survivors is gaining increasing attention. One promising approach to improving post-TB care is implementing a post-TB care package. With a specific focus on the perspectives of healthcare providers in British Columbia, Canada, this study aimed to (1) determine a set of components to be included in a post-TB care package, (2) explore barriers and facilitators influencing their implementation, and (3) propose potential solutions to overcome identified challenges. METHODS: Employing a multi-method approach guided by the Theoretical Domains Framework, we first conducted virtual workshops with TB care providers and utilized a modified Delphi process to establish a preliminary list of care package components. Then, we surveyed healthcare providers using closed-ended, Likert-scale questions to identify implementation barriers and enablers. Lastly, we mapped the identified barriers and enablers to establish behaviour change techniques to identify possible solutions to overcome the challenges identified. RESULTS: Eleven participants attended virtual workshops, and 23 of 51 (45.1%) healthcare providers completed questionnaires. Identified components of the post-TB care package included: 1. Linking people with TB to a primary care provider if they do not have one. 2. Referring people with pulmonary TB for an end-of-treatment chest x-ray and pulmonary function testing. 3. Referring people with TB who smoke to a smoking cessation specialist. 4. Sharing a one-page post-TB information sheet with the patient's primary care provider, including a summary of post-TB health concerns, complications, and recommendations to prioritize age-appropriate screening for cardiovascular disease, lung cancer, and depression. Survey results indicated that domain scores for 'environment, context, and resources' were the lowest, suggesting potential implementation barriers. Care navigation services to help individuals overcome health system barriers while transitioning from TB care, information leaflets, and checklists summarizing key post-TB health concerns for patients and healthcare providers to help facilitate discussions may help overcome the identified barriers. CONCLUSION: Healthcare providers in British Columbia acknowledge that post-TB care is integral to comprehensive health care but are limited by time and resources. Care navigation services, a post-TB checklist, and patient information leaflets may help resolve some of these barriers.

Using Whole-genome Sequencing to Determine the Timing of Secondary Tuberculosis in British Columbia, Canada.

Combined with epidemiological data, whole-genome sequencing (WGS) can help better resolve individual tuberculosis (TB) transmission events to a degree not possible with traditional genotyping. We combine WGS data with patient-level data to calculate the timing of secondary TB among contacts of people diagnosed with active TB in British Columbia, Canada.

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.

A unique urinary metabolomic signature for the detection of pancreatic ductal adenocarcinoma.

Our study aimed to identify a urinary metabolite panel for the detection/diagnosis of pancreatic ductal adenocarcinoma (PDAC). PDAC continues to have poor survival outcomes. One of the major reasons for poor prognosis is the advanced stage of the disease at diagnosis. Hence, identification of a novel and cost-effective biomarker signature for early detection/diagnosis of PDAC could lead to better survival outcomes. Untargeted metabolomics was employed to identify a novel metabolite-based biomarker signature for PDAC diagnosis. Urinary metabolites from 92 PDAC patients (56 discovery cohort and 36 validation cohort) were compared with 56 healthy volunteers using 1 H nuclear magnetic resonance spectroscopy. Multivariate (partial-least squares discriminate analysis) and univariate (Mann-Whitney's U-test) analyses were performed to identify a metabolite panel which can be used to detect PDAC. The selected metabolites were further validated for their diagnostic potential using the area under the receiver operating characteristic (AUROC) curve. Statistical analysis identified a six-metabolite panel (trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone), which demonstrated high potential to diagnose PDAC, with AUROC of 0.933 and 0.864 in the discovery and validation cohort, respectively. Notably, the identified panel also demonstrated very high potential to diagnose early-stage (I and II) PDAC patients with AUROC of 0.897. These results demonstrate that the selected metabolite signature could be used to detect PDAC and will pave the way for the development of a urinary test for detection/diagnosis of PDAC.

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 .).

Latent Tuberculosis Therapy Outcomes in Dialysis Patients: A Retrospective Cohort.

RATIONALE & OBJECTIVES: Maintenance dialysis patients are at an increased risk for active tuberculosis (TB). In 2012, British Columbia, Canada, began systematically screening maintenance dialysis patients for latent TB infection (LTBI) and treating people with evidence of LTBI when appropriate. We examined LTBI treatment outcomes and compared treatment outcomes before and after rollout of the systematic screening program. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: The study comprised 365 people in British Columbia, Canada, initiating at least 90 days of dialysis from January 1, 2001, to May 31, 2017, and starting LTBI therapy: 290 (79.5%) people in the recent cohort and 75 (20.5%) in the historical cohort. People starting LTBI therapy from January 1, 2012, onward were classified as the recent cohort, whereas people starting LTBI therapy before January 1, 2012, were classified as the historical cohort. EXPOSURE: Systematic LTBI screening and therapy. OUTCOMES: Proportion of people who experience grade 3 to 5 adverse events (AEs) or any grade rash and end-of-treatment outcomes. ANALYTICAL APPROACH: Outcomes were reported using descriptive statistics. 2-sample test of proportions using χ2 distribution was used to test for statistical significance between the recent and historical cohorts. RESULTS: 298 (81.6%) people successfully completed LTBI therapy. The proportion of people experiencing a grade 3 to 4 AE or any grade rash was 21.1%. Most AEs were related to gastrointestinal events, general malaise, or pruritus that resulted in regimen changes. 2 (0.5%) people were hospitalized for AEs related to LTBI therapy. No significant difference was found between the recent and historical cohorts in all outcomes of interest. No grade 5 AEs (deaths) were attributed to LTBI therapy. LIMITATIONS: Retrospective data and generalizability outside low-TB-burden settings. CONCLUSIONS: Our findings suggest that a high proportion of people receiving maintenance dialysis can complete LTBI therapy. The rate of grade 3 to 4 AEs was high and associated with frequent medication changes during therapy. LTBI therapy in maintenance dialysis may be safe but requires close monitoring.

Ethical challenges in the treatment of non-refugee migrants with tuberculosis in Canada.

While attention to the ethical issues that migrants face in accessing tuberculosis care has increased in the last few years, most of the attention has focused on challenges that refugees face when emigrating. Less attention has been given to ethical challenges that arise in the context of providing tuberculosis treatment and care to non-refugee migrants in high-income countries (HIC), particularly those that do not face immediate danger or violence. In this paper, we analyze some of the ethical challenges associated with treating migrants with tuberculosis in the Canadian context. In particular, we will discuss (i) inter- and intra-jurisdictional issues that challenge quotidian public health governance structures, and (ii) the ethical imperative for the Canadian government and its provinces to clearly differentiate access to healthcare from a person's immigration status to help overcome power imbalances that may exist between public health workers and their clients. The arguments presented herein could potentially apply to other HIC with some form of universal health coverage.

Evaluation of the implementation process of the mobile health platform 'WelTel' in six sites in East Africa and Canada using the modified consolidated framework for implementation research (mCFIR).

BACKGROUND: Health systems globally are investing in integrating secure messaging platforms for virtual care in clinical practice. Implementation science is essential for adoption, scale-up, spread and maintenance of complex evidence-based solutions in clinics with evolving priorities. In response, the mobile Health (mHealth) Research Group modified the existing consolidated framework for implementation research (CFIR) to evaluate implementation of virtual health tools in clinical settings. WelTel® is an evidence-based digital health platform widely deployed in various geographical and health contexts. The objective is to identify the facilitators and barriers for implementing WelTel and to assess the application of the mCFIR tool in facilitating focus groups in different geographical and health settings. METHODS: Both qualitative and descriptive quantitative approaches were employed. Six mCFIR sessions were held in three countries with 51 key stakeholders. The mCFIR tool consists of 5 Domains and 25 constructs and was distributed through Qualtrics Experience Management (XM). "Performance" and "Importance" scores were valued on a scale of 0 to 10 (Mean ± SD). Descriptive analysis was conducted using R computing software. NVivo 12 Pro software was used to analyze mCFIR responses and to generate themes from the participants' input. RESULTS: We observed a parallel trend in the scores of Importance and Performance. Of the five Domains, Domain 4 (End-user Characteristics) and Domain 3 (Inner Settings) scored highest in Importance (8.9 ± 0.5 and 8.6 ± 0.6, respectively) and Performance (7.6 ± 0.7 and 7.2 ± 1.3, respectively) for all sites. Domain 2 (Outer Setting) scored the lowest in both Importance and Performance for all sites (7.6 ± 0.4 and 5.6 ± 1.8). The thematic analysis produced the following themes: for areas of strengths, the themes brought up were timely diagnosis and response, cost-effectiveness, and user-friendliness. As for areas for improvement, the themes discussed were training, phone accessibility, stakeholder engagement, and literacy. CONCLUSION: The mCFIR tool allowed for a comprehensive understanding of the barriers and facilitators to the implementation, reach, and scale-up of digital health tools. Amongst several important findings, we observed the value of bringing the perspectives of both end users (HCPs and patients) to the table across Domains. TRIAL REGISTRATION: NCT02603536 - November 11, 2015: WelTelOAKTREE: Text Messaging to Support Patients With HIV/AIDS in British Columbia (WelTelOAKTREE). NCT01549457 - March 9, 2012: TB mHealth Study-Use of Cell Phones to Improve Compliance in Patients on LTBI Treatment.

Estimated Impact of World Health Organization Latent Tuberculosis Screening Guidelines in a Region With a Low Tuberculosis Incidence: Retrospective Cohort Study.

BACKGROUND: Latent tuberculosis infection (LTBI) screening and treatment is a key component of the World Health Organization (WHO) EndTB Strategy, but the impact of LTBI screening and treatment at a population level is unclear. We aimed to estimate the impact of LTBI screening and treatment in a population of migrants to British Columbia (BC), Canada. METHODS: This retrospective cohort included all individuals (N = 1 080 908) who immigrated to Canada as permanent residents between 1985 and 2012 and were residents in BC at any time up to 2013. Multiple administrative databases were linked to identify people with risk factors who met the WHO strong recommendations for screening: people with tuberculosis (TB) contact, with human immunodeficiency virus, on dialysis, with tumor necrosis factor-alpha inhibitors, who had an organ/haematological transplant, or with silicosis. Additional TB risk factors included immunosuppressive medications, cancer, diabetes, and migration from a country with a high TB burden. We defined active TB as preventable if diagnosed ≥6 months after a risk factor diagnosis. We estimated the number of preventable TB cases, given optimal LTBI screening and treatment, based on these risk factors. RESULTS: There were 16 085 people (1.5%) identified with WHO strong risk factors. Of the 2814 people with active TB, 118 (4.2%) were considered preventable through screening with WHO risk factors. Less than half (49.4%) were considered preventable with expanded screening to include people migrating from countries with high TB burdens, people who had been prescribed immunosuppressive medications, or people with diabetes or cancer. CONCLUSIONS: The application of WHO LTBI strong recommendations for screening would have minimally impacted the TB incidence in this population. Further high-risk groups must be identified to develop an effective LTBI screening and treatment strategy for low-incidence regions.

Cost-effectiveness of Latent Tuberculosis Infection Screening before Immigration to Low-Incidence Countries.

Prospective migrants to countries where the incidence of tuberculosis (TB) is low (low-incidence countries) receive TB screening; however, screening for latent TB infection (LTBI) before immigration is rare. We evaluated the cost-effectiveness of mandated and sponsored preimmigration LTBI screening for migrants to low-incidence countries. We used discrete event simulation to model preimmigration LTBI screening coupled with postarrival follow-up and treatment for those who test positive. Preimmigration interferon-gamma release assay screening and postarrival rifampin treatment was preferred in deterministic analysis. We calculated cost per quality-adjusted life-year gained for migrants from countries with different TB incidences. Our analysis provides evidence of the cost-effectiveness of preimmigration LTBI screening for migrants to low-incidence countries. Coupled with research on sustainability, acceptability, and program implementation, these results can inform policy decisions.

Screening for Latent Tuberculosis Infection in Migrants With CKD: A Cost-effectiveness Analysis.

RATIONALE & OBJECTIVE: In countries with a low tuberculosis (TB) incidence, TB disproportionately affects populations born abroad. TB persists in these populations through reactivation of latent TB infection (LTBI) acquired before immigration. Those with chronic kidney disease (CKD) are at increased risk for reactivation and may benefit from LTBI screening and treatment. STUDY DESIGN: Health administrative data from British Columbia, Canada, were used to inform a cost-effectiveness analysis evaluating LTBI screening in those diagnosed with stage 4 or 5 CKD not requiring dialysis (late-stage CKD) and those who began dialysis therapy. SETTING & POPULATION: Permanent residents establishing residency in British Columbia, Canada, between 1985 and 2012 who had late-stage CKD diagnosed or began dialysis therapy. INTERVENTIONS: Screening with the tuberculin skin test or interferon-gamma release assay (IGRA) compared to no LTBI screening at the time of late-stage CKD diagnosis and time of dialysis therapy initiation. Treatment for those who tested positive was isoniazid for 9 months. OUTCOMES: Costs (2016 Can $), TB cases, and quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio for QALYs gained was calculated. MODEL, PERSPECTIVE, & TIMEFRAME: Discrete event simulation model using a health care system perspective, 1.5% discount rate, and 5-year time horizon. RESULTS: Screening with IGRA was superior to the tuberculin skin test in all situations. Screening with IGRA was less expensive and resulted in better outcomes compared to no screening in those initiating dialysis therapy from countries with an elevated TB incidence. In individuals with late-stage CKD, screening with IGRA was only cost-effective in those 60 years or older (cost per QALY gained, <$48,000) from countries with an elevated TB incidence. LIMITATIONS: This study has limitations in generalizability to different epidemiologic settings and in modeling complicated clinical decisions. CONCLUSIONS: LTBI screening should be considered in non-Canadian-born residents initiating dialysis therapy and those with late stage CKD who are older.

Genotyping and Whole-Genome Sequencing to Identify Tuberculosis Transmission to Pediatric Patients in British Columbia, Canada, 2005-2014.

Background: Tuberculosis (TB) in children is often an indicator of recent transmission. Genotyping and whole-genome sequencing (WGS) can enhance pediatric TB investigations by confirming or refuting transmission events. Methods: Mycobacterium tuberculosis isolates from all pediatric patients <18 years with culture-confirmed TB in British Columbia (BC) from 2005 to 2014 (n = 49) were genotyped by Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat (MIRU-VNTR) and compared with adult isolates. Genotypically clustered cases underwent WGS. Clinical, demographic, and contact data were reviewed for each case. Results: Twenty-three children were Canadian-born, 7 to Canadian-born parents (CBP) and 16 to foreign-born parents (FBP). Of the 26 foreign-born children, all were born in Asia (81%) or Africa (19%). Using molecular and epidemiological data, we determined that 15 children had acquired their infection within BC, and household transmission explained all 7 Canadian-born (FBP) children that acquired TB locally. In contrast, 6 of 7 Canadian-born (CBP) children were exposed via a non-household community source. Eight Canadian-born (FBP) children acquired their infections through travel to their parents' place of birth. All but 1 of the foreign-born children acquired their infection outside of BC. Conclusions: Genotyping and genomic data reveal that drivers of pediatric transmission vary according to a child's age, birthplace, and their parents' place of birth.

Molecular Epidemiology of Tuberculosis in British Columbia, Canada: A 10-Year Retrospective Study.

Background: Understanding regional molecular epidemiology allows for the development of more efficient tuberculosis prevention strategies in low-incidence settings. Methods: We analyzed 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) genotyping for 2290 Mycobacterium tuberculosis clinical isolates collected in the province of British Columbia (BC), Canada, in 2005-2014. Laboratory data for each isolate were linked to case-level clinical and demographic data. These data were used to describe the molecular epidemiology of tuberculosis across the province. Results: We detected >1500 distinct genotypes across the 4 major M. tuberculosis lineages, reflecting BC's diverse population. Disease site and clustering rates varied across lineages, and MIRU-VNTR was used to group the 2290 isolates into 189 clusters (2-70 isolates per cluster), with an overall clustering rate of 42.4% and an estimated local transmission rate of 34.1%. Risk factors for clustering varied between Canadian-born and foreign-born individuals; the former had increased odds (odds ratio, 7.8; 95% confidence interval [CI], 6.2-9.6) of belonging to a genotypic cluster, although nearly one-quarter of clusters included both Canadian- and foreign-born persons. Large clusters (≥10 cases) occurred more frequently within the M. tuberculosis Euro-American lineage, and individual-level risk factors associated with belonging to a large cluster included being Canadian born (adjusted odds ratio, 3.3; 95% CI, 2.3-4.8), residing in a rural area (2.3; 1.2-4.5), and illicit drug use (2.0; 1.2-3.4). Conclusions: Although tuberculosis in BC largely arises through reactivation of latent tuberculosis in foreign-born persons, locally transmitted infections occur in discrete populations with distinct disease and risk factor profiles, representing groups for targeted interventions.

The effect of text messaging on latent tuberculosis treatment adherence: a randomised controlled trial.

There is limited high-quality evidence available to inform the use of text messaging to improve latent tuberculosis infection (LTBI) treatment adherence.We performed a parallel, randomised controlled trial at two sites to assess the effect of a two-way short message service on LTBI adherence. We enrolled adults initiating LTBI therapy from June 2012 to September 2015 in British Columbia, Canada. Participants were randomised in a 1:1 ratio to standard LTBI treatment (control) or standard LTBI treatment plus two-way weekly text messaging (intervention). The primary outcome was treatment completion, defined as taking ≥80% prescribed doses within 12 months (isoniazid) or 6 months (rifampin) of enrolment. The trial was unblinded except for the data analyst.A total of 358 participants were assigned to the intervention (n=170) and control (n=188) arms. In intention-to-treat analysis, the proportion of participants completing LTBI therapy in the intervention and control arms was 79.4% and 81.9%, respectively (RR 0.97, 95% CI 0.88-1.07; p=0.550). Results were similar for pre-specified secondary end-points, including time-to-completion of LTBI therapy, completion of >90% of prescribed LTBI doses and health-related quality of life.Weekly two-way text messaging did not improve LTBI completion rates compared to standard LTBI care; however, completion rates were high in both treatment arms.

Universal Genotyping for Tuberculosis Prevention Programs: a 5-Year Comparison with On-Request Genotyping.

Prospective universal genotyping of tuberculosis (TB) isolates is used by many laboratories to detect clusters of cases and inform contact investigations. Prior to universal genotyping, most TB prevention programs genotyped isolates on request only, relying on requests from public health professionals whose knowledge of a patient's clinical, demographic, and epidemiological characteristics suggested potential transmission. To justify the switch from on-request to universal genotyping-particularly in the public health domain, with its limited resources and competing priorities-it is important to demonstrate the additional benefit provided by a universal genotyping program. We compared the clustering patterns revealed by retrospective 24-locus mycobacterial interspersed repetitive unit-variable-number tandem repeat genotyping of all culture-positive isolates over a 5-year period to the patterns previously established by our genotyping-on-request program in the low-incidence setting of British Columbia, Canada. We found that 23.8% of isolates were requested during the study period, and while requested isolates had increased odds of belonging to a genotype cluster (adjusted odds ratio, 2.3; 95% confidence interval, 1.5 to 3.3), only 54.6% clustered with the requested comparator strain. Universal genotyping revealed 94 clusters ranging in size from 2 to 53 isolates (mean = 5) and involving 432 individuals. On-request genotyping missed 54 (57.4%) of these clusters and 130 (30.1%) clustered individuals. Our results underscore that TB patient networks are complex, with unrecognized linkages between patients, and a prospective province-wide universal genotyping program provides an informative, bias-free tool to explore transmission to a degree not possible with on-request genotyping.

Stomatal behaviour and stem xylem traits are coordinated for woody plant species under exceptional drought conditions.

Isohydry (maintenance of plant water potential at the cost of carbon gain) and anisohydry (gas exchange maintenance at the cost of declining plant water status) make up two ends of a stomatal drought response strategy continuum. However, few studies have merged measures of stomatal regulation with xylem hydraulic safety strategies based on in situ field measurements. The goal of this study was to characterize the stomatal and xylem hydraulic safety strategies of woody species in the biodiverse Mediterranean-type ecosystem region of California. Measurements were conducted in situ when California was experiencing the most severe drought conditions in the past 1,200 years. We found coordination among stomatal, hydraulic, and standard leaf functional traits. For example, stem xylem vulnerability to cavitation (P50 ) was correlated with the water potential at stomatal closure (Pclose ); more resistant species had a more negative water potential at stomatal closure. The degree of isohydry-anisohydry, defined at Pclose -P50 , was correlated with the hydraulic safety margin across species; more isohydric species had a larger hydraulic safety margin. In addition, we report for the first time Pclose values below -10 MPa. Measuring these traits in a biodiverse region under exceptional drought conditions contributes to our understanding of plant drought responses.