Chest Radiograph Screening for Detecting Subclinical Tuberculosis in Asymptomatic Household Contacts, Peru.

The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.

Epidemiological Predictors of Financial Toxicity in Surgical Burn Injuries: A Multicenter, Longitudinal, Cohort Study.

BACKGROUND: Burns constitute a major global health challenge, causing over 11 million injuries and 300,000 deaths annually and surpassing the economic burden of cervical cancer and HIV combined. Despite this, patient-level financial consequences of burn injuries remain poorly quantified, with a significant gap in data from low- and middle-income countries. In this study, we evaluate financial toxicity in burn patients. METHODS: A prospective, multicenter cohort study was conducted across two tertiary care hospitals in India, assessing 123 adult surgical in-patients undergoing operative interventions for burn injuries. Patient sociodemographic, clinical, and financial data were collected through surveys and electronic records during hospitalization and at 1, 3, and 6 months postoperatively. Out-of-pocket costs (OOPCs) for surgical burn treatment were evaluated during hospitalization. Longitudinal changes in income, employment status, and affordability of basic subsistence needs were assessed at the 1-, 3-, and 6-month postoperative time point. Degree of financial toxicity was calculated using a combination of the metrics catastrophic health expenditure and financial hardship. Development of financial toxicity was compared by sociodemographic and clinical characteristics using logistic regression models. RESULTS: Of the cohort, 60% experienced financial toxicity. Median OOPCs was US$555.32 with the majority of OOPCs stemming from direct nonmedical costs (US$318.45). Cost of initial hospitalization exceeded monthly annual income by 80%. Following surgical burn care, income decreased by US$318.18 within 6 months, accompanied by a 53% increase in unemployment rates. At least 40% of the cohort consistently reported inability to afford basic subsistence needs within the 6-month perioperative period. Significant predictors of developing financial toxicity included male gender (odds ratio, 4.17; 95% confidence interval, 1.25-14.29; P = 0.02) and hospital stays exceeding 20 days (odds ratio, 11.17; 95% confidence interval, 2.11-59.22; P ≤ 0.01). CONCLUSIONS: Surgical treatment for burn injuries is associated with substantial financial toxicity. National and local policies must expand their scope beyond direct medical costs to address direct nonmedical and indirect costs. These include burn care insurance, teleconsultation follow-ups, hospital-affiliated subsidized lodging, and resources for occupational support and rehabilitation. These measures are crucial to alleviate the financial burden of burn care, particularly during the perioperative period.

Who Transmits Tuberculosis to Whom: A Cross-Sectional Analysis of a Cohort Study in Lima, Peru.

RATIONALE: The persistent burden of TB disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions towards those at high risk of developing and transmitting tuberculosis is a public health priority. OBJECTIVES: We aimed to identify characteristics of individuals involved in tuberculosis transmission in a community setting, which may guide the prioritization of targeted interventions. METHODS: We collected clinical and socio-demographic data from a cohort of tuberculosis patients in Lima, Peru. We used whole-genome sequencing data to assess the genetic distance between all possible pairs of patients; we considered pairs to be the result of a direct transmission event if they differed by three or fewer SNPs and we assumed that the first diagnosed patient in a pair was the transmitter and the second to be the recipient. We used logistic regression to examine the association between host factors and the likelihood of direct tuberculosis transmission. MAIN RESULTS: Analyzing data from 2,518 tuberculosis index patients, we identified 1,447 direct transmission pairs. Regardless of recipient attributes, individuals less than 34 years old, males, and those with a history of incarceration had a higher likelihood of being transmitters in direct transmission pairs. Direct transmission was more likely when both patients were drinkers or smokers. CONCLUSIONS: This study identifies men, young adults, former prisoners, alcohol consumers, and smokers as priority groups for targeted interventions. Innovative strategies are needed to extend tuberculosis screening to social groups like young adults and prisoners with limited access to routine preventive care. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Forgotten memory storage and retrieval in Drosophila.

Inaccessibility of stored memory in ensemble cells through the forgetting process causes animals to be unable to respond to natural recalling cues. While accumulating evidence has demonstrated that reactivating memory-stored cells can switch cells from an inaccessible state to an accessible form and lead to recall of previously learned information, the underlying cellular and molecular mechanisms remain elusive. The current study used Drosophila as a model to demonstrate that the memory of one-trial aversive olfactory conditioning, although inaccessible within a few hours after learning, is stored in KCαß and retrievable after mild retraining. One-trial aversive conditioning triggers protein synthesis to form a long-lasting cellular memory trace, approximately 20 days, via creb in KCαß, and a transient cellular memory trace, approximately one day, via orb in MBON-α3. PPL1-α3 negatively regulates forgotten one-trial conditioning memory retrieval. The current study demonstrated that KCαß, PPL1-α3, and MBON-α3 collaboratively regulate the formation of forgotten one-cycle aversive conditioning memory formation and retrieval.

Utility of Mycobacterium tuberculosis genome sequencing snapshots to assess transmission dynamics over time.

We explored the utility of brief Mycobacterium tuberculosis whole-genome sequencing (WGS) "snapshots" at a sentinel site within Lima, Peru for evaluating local transmission dynamics over time. Within a 17 km2 area, 15/70 (21%) isolates with WGS collected during 2011-2012 and 22/81 (27%) collected during 2020-2021 were clustered (p = 0.414), and additional isolates clustered with those from outside the area. Isolates from the later period were disproportionately related to large historic clusters in Lima from the earlier period. WGS snapshots at a sentinel site may not be useful for monitoring transmission, but monitoring the persistence of large transmission clusters might be.

History of tuberculosis disease is associated with genetic regulatory variation in Peruvians.

A quarter of humanity is estimated to be latently infected with Mycobacterium tuberculosis (Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n=63) or did not progress to TB (controls, n=63). Transcriptomic profiling of monocyte-derived dendritic cells (DCs) and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Five genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was with FAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism. FAH expression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data of Mtb-infected monocyte-derived dendritic cells, we found that Mtb infection results in FAH downregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.

Subjective socioeconomic status: an alternative to objective socioeconomic status.

BACKGROUND: Subjective "ladder" measurements of socio-economic status (SES) are easy-to-administer tools that ask respondents to rate their own SES, allowing them to evaluate their own material resources and determine where it places them relative to their community. Here, we sought to compare the MacArthur Scale of Subjective Social status to the WAMI, an objective measure of SES that includes data on water and sanitation, asset ownership, education, and income. METHODS: Leveraging a study of 595 tuberculosis patients in Lima, Peru, we compared the MacArthur ladder score to the WAMI score using weighted Kappa scores and Spearman's rank correlation coefficient. We identified outliers that fell outside the 95th percentile and assessed the durability of the inconsistencies between scores by re-testing a subset of participants. We then used Akaike information criterion (AIC) to compare the predictability of logistic regression models evaluating the association between the two SES scoring systems and history of asthma. RESULTS: The correlation coefficient between the MacArthur ladder and WAMI scores was 0.37 and the weighted Kappa was 0.26. The correlation coefficients differed by less than 0.04 and the Kappa ranged from 0.26 to 0.34, indicating fair agreement. When we replaced the initial MacArthur ladder scores with retest scores, the number of individuals with disagreements between the two scores decreased from 21 to 10 and the correlation coefficient and weighted Kappa both increased by at least 0.03. Lastly, we found that when we categorized WAMI and MacArthur ladder scores into three groups, both had a linear trend association with history of asthma with effect sizes and AICs that differed by less than 15% and 2 points, respectively. CONCLUSION: Our findings demonstrated fair agreement between the MacArthur ladder and WAMI scores. The agreement between the two SES measurements increased when they were further categorized into 3-5 categories, the form in which SES is often used in epidemiologic studies. The MacArthur score also performed similarly to WAMI in predicting a socio-economically sensitive health outcome. Researchers should consider subjective SES tools as an alternative method for measuring SES, particularly in large health studies where data collection is a burden.

Spatial scale of tuberculosis transmission in Lima, Peru.

Spatially targeted interventions may be effective alternatives to individual or population-based prevention strategies against tuberculosis (TB). However, their efficacy may depend on the mechanisms that lead to geographically constrained hotspots. Local TB incidence may reflect high levels of local transmission; conversely, they may point to frequent travel of community members to high-risk areas. We used whole-genome sequencing to explore patterns of TB incidence and transmission in Lima, Peru. Between 2009 and 2012, we recruited incident pulmonary TB patients and their household contacts, whom we followed for the occurrence of TB disease. We used whole-genome sequences of 2,712 Mycobacterial tuberculosis isolates from 2,440 patients to estimate pariwise genomic distances and compared these to the spatial distance between patients' residences. Genomic distances increased rapidly as spatial distances increased and remained high beyond 2 km of separation. Next, we divided the study catchment area into 1 × 1 km grid-cell surface units and used household spatial coordinates to locate each TB patient to a specific cell. We estimated cell-specific transmission by calculating the proportion of patients in each cell with a pairwise genomic distance of 10 or fewer single-nucleotide polymorphisms. We found that cell-specific TB incidence and local transmission varied widely but that cell-specific TB incidence did not correlate closely with our estimates of local transmission (Cohen's k = 0.27). These findings indicate that an understanding of the spatial heterogeneity in the relative proportion of TB due to local transmission may help guide the implementation of spatially targeted interventions.

Higher native Peruvian genetic ancestry proportion is associated with tuberculosis progression risk.

We investigated whether ancestry-specific genetic factors affect tuberculosis (TB) progression risk in a cohort of admixed Peruvians. We genotyped 2,105 patients with TB and 1,320 household contacts (HHCs) who were infected with Mycobacterium tuberculosis (M. tb) but did not develop TB and inferred each individual's proportion of native Peruvian genetic ancestry. Our HHC study design and our data on potential confounders allowed us to demonstrate increased risk independent of socioeconomic factors. A 10% increase in individual-level native Peruvian genetic ancestry proportion corresponded to a 25% increased TB progression risk. This corresponds to a 3-fold increased risk for individuals in the highest decile of native Peruvian genetic ancestry versus the lowest decile, making native Peruvian genetic ancestry comparable in effect to clinical factors such as diabetes. Our results suggest that genetic ancestry is a major contributor to TB progression risk and highlight the value of including diverse populations in host genetic studies.

The Contribution of Chest Radiography to the Clinical Management of Children Exposed to Tuberculosis.

Rationale: Although World Health Organization guidelines emphasize contact investigation for tuberculosis (TB)-exposed children, data that support chest radiography as a useful tool are lacking. Objectives: We evaluated the diagnostic and prognostic information of chest radiography in children exposed to TB and measured the efficacy of isoniazid preventive therapy (IPT) in those with relevant radiographic abnormalities. Methods: Between September 2009 and August 2012, we enrolled 4,468 TB-exposed children who were screened by tuberculin skin testing, symptom assessment, and chest radiography. Those negative for TB disease were followed for 1 year for the occurrence of new TB diagnoses. We assessed the protective efficacy of IPT in children with and without abnormal chest radiographs. Measurements and Main Results: Compared with asymptomatic children with normal chest films, asymptomatic children with abnormal radiographs were 25.1-fold more likely to have coprevalent TB (95% confidence interval [CI], 1.02-613.76) and 26.7-fold more likely to be diagnosed with incident TB disease during follow-up (95% CI, 10.44-68.30). Among the 29 symptom-negative and CXR-abnormal child contacts, 20% (3/15) of the isoniazid recipients developed incident TB, compared with 57% (8/14) of those who did not receive IPT (82% IPT efficacy). Conclusions: Our results strongly support the use of chest radiography as a routine screening tool for the evaluation of child TB contacts, which is readily available. Radiographic abnormalities not usually considered suggestive of TB may indicate incipient or subclinical disease, although TB preventive treatment is adequate in most cases.

The Impact of Vitamin A Deficiency on Tuberculosis Progression.

BACKGROUND: Although previous studies have shown that vitamin A deficiency is associated with incident tuberculosis (TB) disease, the direction of the association has not been established. We investigated the impact of vitamin A deficiency on TB disease progression. METHODS: We conducted a longitudinal cohort study nested within a randomized clinical trial among HIV-infected patients in Haiti. We compared serial vitamin A levels in individuals who developed TB disease to controls matched on age, gender, follow-up time, and time to antiretroviral therapy initiation. We also evaluated histopathology, bacterial load, and immune outcomes in TB infection in a guinea pig model of dietary vitamin A deficiency. RESULTS: Among 773 participants, 96 developed incident TB during follow-up, 62.5% (60) of whom had stored serum samples obtained 90-365 days before TB diagnosis. In age- and sex- adjusted and multivariate analyses, respectively, incident TB cases were 3.99 times (95% confidence interval [CI], 2.41 to 6.60) and 3.59 times (95% CI, 2.05 to 6.29) more likely to have been vitamin A deficient than matched controls. Vitamin A-deficient guinea pigs manifested more extensive pulmonary pathology, atypical granuloma morphology, and increased bacterial growth after experimental TB infection. Reintroduction of dietary vitamin A to deficient guinea pigs after established TB disease successfully abrogated severe disease manifestations and altered cellular immune profiles. CONCLUSIONS: Human and animal studies support the role of baseline vitamin A deficiency as a determinant of future TB disease progression.

Prediction Tool to Identify Children at Highest Risk of Tuberculosis Disease Progression Among Those Exposed at Home.

BACKGROUND: There is a dearth of research to understand which children, among those who are exposed at home to tuberculosis (TB), are at the highest risk of TB disease, to tailor care. We sought to identify predictors of TB progression in children. METHODS: We conducted a prospective cohort study of children living with adults with pulmonary TB in Lima, Peru (2009-2012). We applied classification and regression tree analysis to examine potential predictors of incident TB disease during 12 months in 3 age groups (0-4, 5-9, and 10-14 years). We calculated the relative risk (RR) for top predictors in each age group. RESULTS: Among 4545 children 0-14 years old, 156 (3.4%) were diagnosed with TB within 1 year of household exposure to TB (3.4%, 2.3%, and 4.7% in children 0-4, 5-9, and 10-14 years old, respectively). The most important predictor of TB was having a positive tuberculin skin test (TST) result, with RRs of 6.6 (95% CI, 4.0-10.7), 6.6 (95% CI, 3.2-13.6), and 5.2 (95% CI, 3.0-9.0) in the age groups 0-4, 5-9, and 10-14 years, respectively. In young children with a positive TST, not using isoniazid preventive treatment further increased risk of disease (RR, 12.2 [95% CI, 3.8-39.2]). CONCLUSIONS: We present a tool that identifies child household contacts at high risk of TB disease progression based on data collected during contact tracing. In addition to the use of TB preventive therapy for all children exposed at home to TB, those children at highest risk of progressing to TB disease may benefit from more frequent follow-up.

Characterization of Drug-Resistant Lipid-Dependent Differentially Detectable Mycobacterium tuberculosis.

An estimated 15-20% of patients who are treated for pulmonary tuberculosis (TB) are culture-negative at the time of diagnosis. Recent work has focused on the existence of differentially detectable Mycobacterium tuberculosis (Mtb) bacilli that do not grow under routine solid culture conditions without the addition of supplementary stimuli. We identified a cohort of TB patients in Lima, Peru, in whom acid-fast bacilli could be detected by sputum smear microscopy, but from whom Mtb could not be grown in standard solid culture media. When we attempted to re-grow Mtb from the frozen sputum samples of these patients, we found that 10 out of 15 could be grown in a glycerol-poor/lipid-rich medium. These fell into the following two groups: a subset that could be regrown in glycerol after "lipid-resuscitation", and a group that displayed a heritable glycerol-sensitive phenotype that were unable to grow in the presence of this carbon source. Notably, all of the glycerol-sensitive strains were found to be multidrug resistant. Although whole-genome sequencing of the lipid-resuscitated strains identified 20 unique mutations compared to closely related strains, no single genetic lesion could be associated with this phenotype. In summary, we found that lipid-based media effectively fostered the growth of Mtb from a series of sputum smear-positive samples that were not culturable in glycerol-based Lowenstein-Jensen or 7H9 media, which is consistent with Mtb's known preference for non-glycolytic sources during infection. Analysis of the recovered strains demonstrated that both genetic and non-genetic mechanisms contribute to the observed differential capturability, and suggested that this phenotype may be associated with drug resistance.

Are neighbourhoods of tuberculosis cases a high-risk population for active intervention? A protocol for tuberculosis active case finding.

BACKGROUND: Indonesia has the second largest tuberculosis (TB) burden globally. Attempts to scale-up TB control efforts have focused on TB households. However, in most high burden settings, considerable Mycobacterium tuberculosis (Mtb) transmission occurs outside TB households. A better understanding of transmission dynamics in an urban setting in Indonesia will be crucial for the TB Control Program in scaling up efforts towards elimination of TB in a more targeted way. Therefore, the study aims to measure TB prevalence and incidence in household contacts and neighbourhoods in the vicinity of known TB cases and to assess their genomic and epidemiological relatedness. METHODS AND ANALYSIS: Individuals (~1000) living in the same household as a case diagnosed with pulmonary TB (n = 250) or in a neighbouring household (~4500 individuals) will be screened for TB symptoms and by chest x-ray. Two sputum samples will be collected for microbiological analysis from anyone with a productive cough. Any person found to have TB will be treated by the National TB Control Program. All those with no evidence of TB disease will have a repeat screen at 12 months. Whole-genome sequencing (WGS) and social network analysis (SNA) will be conducted on Index cases and contacts diagnosed with TB.

Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease.

Multimodal T cell profiling can enable more precise characterization of elusive cell states underlying disease. Here, we integrated single-cell RNA and surface protein data from 500,089 memory T cells to define 31 cell states from 259 individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady state >4 years after infection and disease resolution, we found that, after accounting for significant effects of age, sex, season and genetic ancestry on T cell composition, a polyfunctional type 17 helper T (TH17) cell-like effector state was reduced in abundance and function in individuals who previously progressed from Mycobacterium tuberculosis (M.tb) infection to active TB disease. These cells are capable of responding to M.tb peptides. Deconvoluting this state-uniquely identifiable with multimodal analysis-from public data demonstrated that its depletion may precede and persist beyond active disease. Our study demonstrates the power of integrative multimodal single-cell profiling to define cell states relevant to disease and other traits.

Smoking Cessation in Tuberculosis Patients and the Risk of Tuberculosis Infection in Child Household Contacts.

BACKGROUND: While previous studies have shown that cigarette smoking increases the infectiousness of tuberculosis patients, the impact of smoking cessation on tuberculosis transmissibility has not been evaluated. METHODS: Between 2009 and 2012, we enrolled 4500 tuberculosis patients and followed 14 044 household contacts in Lima, Peru. Tuberculosis patients were classified into 4 categories: never smoked, quit in the distant past (stopped smoking >2 months prior to time of diagnosis), recently quit (stopped smoking ≤2 months prior to time of diagnosis), and active smokers. We used a modified Poisson generalized estimating equation to assess the risk of tuberculosis infection of child contacts at enrollment and by 6 months of follow-up. RESULTS: In total, 1371 (76.8%) child contacts were exposed to patients who had never smoked, 211 (11.8%) were exposed to distant quitters, 155 (8.7%) were exposed to recent quitters, and 49 (2.7%) were exposed to active smokers. Compared with child contacts of index patients who had never smoked, child contacts of recent quitters had a similar risk of tuberculosis infection at enrollment (adjusted risk ratio, 95% confidence intervals [0.81, 0.50-1.32]) and by six months of follow-up (0.76, 0.51-1.13); and by 6 months of follow-up (aRR, 0.76; 95% CI, .51-1.13); child contacts of recent quitters had a significantly reduced risk of tuberculosis infection compared with contacts of active smokers (enrollment 0.45, 0.24-0.87; 6-month follow-up 0.48, 0.29-0.79). CONCLUSIONS: Our results show that the adverse effects of smoking on the transmissibility of tuberculosis are significantly reduced shortly after quitting smoking, reinforcing the importance of smoking cessation interventions in tuberculosis control.

Dysglycemia is associated with Mycobacterium tuberculosis lineages in tuberculosis patients of North Lima-Peru.

This study was performed to investigate the role of dysglycemia on the genetic diversity of Mycobacterium tuberculosis (MTB) among pulmonary tuberculosis (TB) patients to build scientific evidence about the possible mechanisms of TB transmission. MTB isolates obtained of patients affected by pulmonary tuberculosis from health care facilities of North Lima-Peru, were analyzed using whole genome sequencing and 24-locus mycobacterial interspersed repetitive-unit -variable-number tandem repeats (MIRU-VNTR). Subsequently, clinical and epidemiological characteristics were associated with clustering, lineages and comorbid conditions. The analysis carried out 112 pulmonary TB patients from various health centers in North Lima, 17 (15%) had diabetes mellitus (DM) and 33 (29%) had pre-diabetes (PDM). Latin American-Mediterranean, Haarlem and Beijing were the most frequent MTB lineages found in those patients. Previous TB (adjusted odds ratio [aOR] = 3.65; 95%CI: 1.32-17.81), age (aOR = 1.12; 95%CI: 1.03-1.45) and Beijing lineage (aOR = 3.53; 95%CI: 1.08-13.2) were associated with TB-DM comorbidity. Alcoholism (aOR = 2.92; 95%CI: 1.10-8.28), age (aOR = 1.05; 95%CI: 1.03-1.12) and Haarlem lineage (aOR = 2.54; 95%CI: 1.04-6.51) were associated with TB-PDM comorbidity. Beijing and Haarlem lineages were independently associated with TB-DM and TB-PDM comorbidities, respectively. Although these findings may be surprising, we must be cautious to suggest that dysglycemia could be associated with a highly clustering and predisposition of MTB lineages related to a serious impact on the severity of TB disease, which requires further research.

A public health intervention package for increasing tuberculosis notifications from private practitioners in Bandung, Indonesia (INSTEP2): A cluster-randomised controlled trial protocol.

Background. A significant proportion of tuberculosis (TB) patients globally make their initial visit for medical care to either an informal provider or a private practitioner, and many are not formally notified. Involvement of private practitioners (PPs) in a public-private mix for TB (TB-PPM) provides an opportunity for improving TB control. However, context-specific interventions beyond public-private agreements and mandatory notification are needed. In this study we will evaluate whether a tailored intervention package can increase TB notifications from PPs in Indonesia. Methods. This is a cluster-randomized trial of a multi-component public health intervention. 36 community health centre (CHC) areas will be selected as study locations and randomly allocated to intervention and control arms (1:1). PPs in the intervention areas will be identified using a mapping exercise and recruited into the study if they are eligible and consent. They will receive a tailored intervention package including in-person education about TB management along with bimonthly electronic refreshers, context-specific selection of referral pathways, and access to a TB-reporting app developed in collaboration with the National TB programme. The primary hypothesis is that the intervention package will increase the TB notification rate. The primary outcome will be measured by collecting notification data from the CHCs in intervention and control arms at the end of a 1-year observation period and comparing with the 1-year pre-intervention. The primary analysis will be intention-to-treat at the cluster level, using a generalised mixed model with repeated measures of TB notifications for 1 year pre- and 1 year post-intervention. Discussion. The results from this study will provide evidence on whether a tailored intervention package is effective in increasing the number of TB notifications, and whether the PPs refer presumptive TB cases correctly. The study results will guide policy in the development of TB-PPM in Indonesia and similar settings.

Training Nonradiologist Clinicians in Diagnostic Breast Ultrasound in Rural Rwanda: Impact on Knowledge and Skills.

OBJECTIVE: To assess the effectiveness of diagnostic breast ultrasound training provided for general practitioners and nurses in Rwanda via intensive in-person and subsequent online supervision and mentorship. METHODS: Four breast radiologists from Brigham and Women's Hospital trained two general practitioner physicians and five nurses in Rwanda over 9 total weeks of in-person training and 20 months of remote mentorship using electronic image review with emailed feedback. Independently recorded assessments were compared to calculate the sensitivity and specificity of trainee assessments, with radiologist assessments as the gold standard. We compared performance in the first versus second half of the training. RESULTS: Trainees' performance on written knowledge assessments improved after training (57.7% versus 98.1% correct, P = .03). Mean sensitivity of trainee-performed ultrasound for identifying a solid breast mass was 90.6% (SD 4.2%) in the first half of the training (period 1) and 94.0% (SD 6.7%) in period 2 (P = .32). Mean specificity was 94.7% (SD 5.4%) in period 1 and 100.0% (SD 0) in period 2 (P = .10). Mean sensitivity for identifying a medium- or high-suspicion solid mass increased from 79.2% (SD 11.0%) in period 1 to 96.3% (SD 6.4%) in period 2 (P = .03). Specificity was 84.4% (SD 15.0%) in period 1 and 96.7% (SD 5.8%) in period 2 (P = .31). DISCUSSION: Nonradiologist clinicians (doctors and nurses) in a rural sub-Saharan African hospital built strong skills in diagnostic breast ultrasound over 23 months of combined in-person training and remote mentorship. The sensitivity of trainees' assessments in identifying masses concerning for malignancy improved after sustained mentorship. Assessment of impact on patient care and outcomes is ongoing.