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BackgroundSystematic screening is a potential tool for reducing the prevalence of tuberculosis (TB) and counteracting COVID-19-related disruptions in care. Repeated community-wide screening can also measure changes in the prevalence of TB over time.MethodsWe conducted serial, cross-sectional TB case finding campaigns in one community in Kampala, Uganda, in 2019 and 2021. Both campaigns sought sputum for TB testing (Xpert MTB/RIF Ultra) from all adolescents and adults. We estimated the prevalence of TB among screening participants in each campaign and compared characteristics of people with TB across campaigns. We simultaneously enrolled and characterised community residents who were diagnosed with TB through routine care and assessed trends in facility-based diagnosis.ResultsWe successfully screened 12 033 community residents (35% of the estimated adult/adolescent population) in 2019 and 11 595 (33%) in 2021. In 2019, 0.94% (95% CI: 0.77% to 1.13%) of participants tested Xpert positive (including trace). This proportion fell to 0.52% (95% CI: 0.40% to 0.67%) in 2021; the prevalence ratio was 0.55 (95% CI: 0.40 to 0.75)). There was no change in the age (median 26 vs 26), sex (56% vs 59% female) or prevalence of chronic cough (49% vs 54%) among those testing positive. By contrast, the rate of routine facility-based diagnosis remained steady in the 8 months before each campaign (210 (95% CI: 155 to 279) vs 240 (95% CI: 181 to 312) per 100 000 per year).ConclusionsFollowing an intensive initial case finding campaign in an urban Ugandan community in 2019, the burden of prevalent TB as measured by systematic screening had decreased by 45% in 2021, despite the intervening COVID-19 pandemic.

In a prospective cohort of children with respiratory symptoms in Kampala, Uganda, C-reactive protein levels were low regardless of tuberculosis status and did not achieve the target accuracy for a triage test for pulmonary tuberculosis.

•Evidence regarding the effect of undernutrition on treatment outcomes is lacking for people with retreatment tuberculosis (TB).•We found a 22.0 % prevalence of undernutrition and a 65.8 % TB treatment success rate.•Undernutrition negatively impacts treatment success and sputum smear conversion.•Nutritional assessment should be an integral component of routine care.•Nutritional counseling and support should be offered to people with comorbid TB and undernutrition.

We assessed attitudes and perceptions and willingness to accept (WTA) varying incentive structures for completing tuberculosis (TB) diagnostic evaluation among patients in Uganda.

Rapid and consistent protein identification across large clinical cohorts is an important goal for clinical proteomics. With the development of data-independent technologies (DIA/SWATH-MS), it is now possible to analyze hundreds of samples with great reproducibility and quantitative accuracy. However, this technology benefits from empirically derived spectral libraries that define the detectable set of peptides and proteins. Here, we apply a simple and accessible tip-based workflow for the generation of spectral libraries to provide a comprehensive overview on the plasma proteome in individuals with and without active tuberculosis (TB). To boost protein coverage, we utilized nonconventional proteases such as GluC and AspN together with the gold standard trypsin, identifying more than 30,000 peptides mapping to 3309 proteins. Application of this library to quantify plasma proteome differences in TB infection recovered more than 400 proteins in 50 min of MS acquisition, including diagnostic Mycobacterium tuberculosis(Mtb) proteins that have previously been detectable primarily by antibody-based assays and intracellular proteins not previously described to be in plasma.

In a prospective cohort of children in Kampala, Uganda, the next generation molecular assay Xpert MTB/RIF Ultra identified the majority of culture-confirmed pulmonary tuberculosis (TB) cases and 11% with culture-negative TB and should be included in the evaluation for childhood TB.

In India, the prevalence of Latent TB infection (LTBI) is estimated to be around 40%. Various formulations of PPD(Purified protein derivative) are available, for diagnosis of LTBI, which may give variable responses. The commercially available PPD in India is by Arkray Healthcare (TST-Arkray). It is unclear if this product may have a similar sensitivity compared to other internationally accepted tuberculins (TST-Tubersol).

T-SPOT.TB(T-SPOT) is an interferon gamma release assay (IGRA) used to detect infection with Mycobacterium tuberculosisbased on the number of spot-forming T cells; however, delays in sample processing have been shown to reduce the number of these spots that are detected following laboratory processing. Adding T-Cell Xtend (XT) into blood samples before processing reportedly extends the amount of time allowed between blood collection and processing up to 32 h.

•The Philippines is among the top countries in the world with a high TB burden.•WGS was utilised to investigate drug resistance in clinical M. tuberculosisisolates.•katGSer315Thr, rpoBSer450Leu and embB Met306Val were found in resistant isolates.•Mutations in the inhApromoter and in pncAand gyrAgenes were also observed.•WGS is a useful tool to study M. tuberculosisresistance in high-burden settings.

IMPORTANCE: New guidelines recommend that molecular testing replace sputum-smear microscopy to guide discontinuation of respiratory isolation in patients undergoing evaluation for active tuberculosis (TB) in health care settings. OBJECTIVE: To evaluate the implementation and impact of a molecular testing strategy to guide discontinuation of isolation. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study with a pragmatic, before-and-after-implementation design of 621 consecutive patients hospitalized at Zuckerberg San Francisco General Hospital and Trauma Center who were undergoing sputum examination for evaluation for active pulmonary TB from January 2014 to January 2016. INTERVENTIONS: Implementation of a sputum molecular testing algorithm using GeneXpert MTB/RIF (Xpert; Cepheid) to guide discontinuation of isolation. MAIN OUTCOMES AND MEASURES: We measured the proportion of patients with molecular testing ordered and completed; the accuracy of the molecular testing algorithm in reference to mycobacterial culture; the duration of each component of the testing and isolation processes; length of stay; mean days in isolation and in hospital; and mean cost. We extracted data from hospital records and compared measures before and after implementation. RESULTS: Clinicians ordered sputum testing for TB for 621 patients at ZSFG during the 2-year study period. Of 301 patients in the preimplementation period with at least 1 sputum microscopy and culture ordered, clinicians completed the rapid TB testing evaluation process for 233 (77%).Among 320 patients evaluated in the postimplementation period, clinicians ordered molecular testing for 234 (73%) patients and received results for 295 of 302 (98%) tests ordered. Median age was 54 years (interquartile range, 44-63 years), and 161 (26%) were women. The molecular testing algorithm accurately diagnosed all 7 patients with culture-confirmed TB and excluded TB in all 251 patients with Mycobacterium tuberculosis (MTB) culture-negative results. Compared with the preimplementation period, there were significant decreases in median times to final rapid test result (39.1 vs 22.4 hours, P < .001), discontinuation of isolation (2.9 vs 2.5 days, P = .001), and hospital discharge (6.0 vs 4.9 days, P = .003), on average saving $13 347 per isolated TB-negative patient. CONCLUSIONS AND RELEVANCE: A sputum molecular testing algorithm to guide discontinuation of respiratory isolation for patients undergoing evaluation for active TB was safe, feasible, widely and sustainably adopted, and provided substantial clinical and economic benefits. Molecular testing may facilitate more efficient, patient-centered evaluation for possible TB in US hospitals.

Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ.

A key reason for the consistent gaps between evidence and practice across all areas of medicine is that there has been little attempt to identify or target factors critical for successful implementation of an evidence-based intervention. There is either no explicit implementation strategy or the strategy is based on a best guess rather than on a systematic assessment of crucial barriers and enablers. A different approach is needed to close the evidence–practice gap and thereby achieve the triple aim of improved health, improved patient experience and reduced healthcare costs. We present three fundamental principles of implementation science, which is a methodology that offers a systematic and comprehensive approach to improving healthcare practice and a series of ‘how to’ steps to conduct implementation science research. In an accompanying article, a scoping review of the types of implementation science research conducted in emergency medicine is reviewed, and several of the principles related to this review are discussed.

ABSTRACTBlood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S. patients. To be used clinically, transcriptional classifiers need reproducible accuracy in diverse populations that vary in genetic composition, disease spectrum and severity, and comorbidities. In a prospective case-control study, we identified novel transcriptional classifiers for active TB among U.S. patients and systematically compared their accuracy to classifiers from published studies. Blood samples from HIV-uninfected U.S. adults with active TB, pneumonia, or latent TB infection underwent whole-transcriptome microarray. We used support vector machines to classify disease state based on transcriptional patterns. We externally validated our classifiers using data from sub-Saharan African cohorts and evaluated previously published transcriptional classifiers in our population. Our classifier distinguishing active TB from pneumonia had an area under the concentration-time curve (AUC) of 96.5% (95.4% to 97.6%) among U.S. patients, but the AUC was lower (90.6% [89.6% to 91.7%]) in HIV-uninfected Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 90.0% (87.7% to 92.3%) and 82.9% (80.8% to 85.1%) when tested in U.S. patients. Our classifier distinguishing active TB from latent TB had AUC values of 95.9% (95.2% to 96.6%) among U.S. patients and 95.3% (94.7% to 96.0%) among Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 98.0% (97.4% to 98.7%) and 94.8% (92.9% to 96.8%) when tested in U.S. patients. Blood transcriptional classifiers accurately detected active TB among U.S. adults. The accuracy of classifiers for active TB versus that of other diseases decreased when tested in new populations with different disease controls, suggesting additional studies are required to enhance generalizability. Classifiers that distinguish active TB from latent TB are accurate and generalizable across populations and can be explored as screening assays.

SUMMARYIdentification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-?) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosisexposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosisinfection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

ABSTRACTAccess to sputum smear microscopy in high-tuberculosis (TB)-burden regions is limited by a scarcity of microscopes and experienced technicians. We evaluated the accuracy of CellScope, a novel digital fluorescence microscope that may expand access to microscopy. The study utilized smear microscopy slides prepared from sputum specimens submitted by consecutive adults with =2 weeks of cough who were admitted to Mulago Hospital (Kampala, Uganda). Conventional light-emitting diode (LED) fluorescence microscopy (FM) and mycobacterial culture were performed by experienced technicians. Two U.S.-based postgraduate researchers without prior microscopy experience restained, imaged, and interpreted the slides using CellScope. We assessed whether sensitivity and specificity of CellScope-based LED FM was noninferior to conventional LED FM by using a preselected margin of inferiority of 15%. Of 525 patients included, 72% were HIV seropositive and 39% had culture-confirmed TB. The proportions of positive results were similar with CellScope and conventional LED FM (34% versus 32%, respectively; P= 0.32), and agreement was substantial. CellScope accuracy was within the noninferiority margin for both sensitivity (63% versus 70%; difference, -7%; 95% confidence interval [CI], -13% to -1%) and specificity (85% versus 92%; difference, -7%; 95% CI, -12% to -3%). A subanalysis of 43 slides evaluated by each CellScope reader found substantial interreader reliability (custom-weighted kappa, 0.65) and variable intrareader reliability (custom-weighted kappa, 0.11 versus 0.48). CellScope offers promise for expanding microscopy services. Future studies should evaluate the device when operated by health workers in low-resource settings, the feasibility of image transmission and analysis by experienced microscopists, and the accuracy of automated image analysis algorithms.

To provide a narrative synthesis of evidence on interferon-gamma release assays (IGRAs) for the diagnosis of latent tuberculosis infection (LTBI) in individuals with immune-mediated inflammatory disorders (IMIDs).

ABSTRACTLaboratory methods to improve smear microscopy are an urgent priority for global tuberculosis control. The novel universal sample processing (USP) method has been reported to improve conventional diagnostic testing for tuberculosis while also providing inhibitor-free specimens for molecular assays. However, no studies evaluating the method in the field have been conducted. In this study, we compared the performance of the USP method to that of the standard N-acetyl-l-cysteine-NaOH (NALC) method for conventional diagnosis of tuberculosis in 252 adults admitted to Mulago Hospital in Kampala, Uganda, with a clinical suspicion of pneumonia. A single early-morning sputum specimen collected from each patient was divided into two aliquots, each of which was assigned a random identification number. One randomly numbered specimen was processed by the USP method and the other by the NALC method. Mycobacterial cultures were more frequently negative in USP compared to NALC specimen aliquots (58% versus 43%; P< 0.001). There was no difference in the proportion of contaminated mycobacterial cultures (12% versus 11%; P= 0.87). The sensitivity and specificity of smear microscopy for the USP method were 52% and 86%, respectively, and were not significantly different from those for the NALC method (56% and 86%, respectively) using mycobacterial culture results as a reference standard. These results suggest that the USP method did not provide any significant advantage over the standard NALC method for conventional diagnosis of tuberculosis in our setting and illustrate the importance of well-designed, field-level evaluations of novel diagnostic techniques.

Published criteria for the diagnosis of Mycobacterium kansasiilung disease require the presence of clinical symptoms, positive microbiologic results, and radiographic abnormalities. In patients with HIV infection, the radiographic findings of M kansasiilung disease are not well described.

Though great progress has been realized over the last decade in extending HIV prevention, care and treatment in some of the least resourced settings of the world, a substantial gap remains between what we know works and what we are actually achieving in HIV programs. To address this, leaders have called for the adoption of an implementation science framework to improve the efficiency and effectiveness of HIV programs. Implementation science (IS) is a multidisciplinary scientific field that seeks generalizable knowledge about the magnitude of, determinants of and strategies to close the gap between evidence and routine practice for health in real-world settings. We propose an IS approach that is iterative in nature and composed of four major components: 1) Identifying Bottlenecks and Gaps, 2) Developing and Implementing Strategies, 3) Measuring Effectiveness and Efficiency, and 4) Utilizing Results. With this framework, IS initiatives draw from a variety of disciplines including qualitative and quantitative methodologies in order to develop new approaches responsive to the complexities of real world program delivery. In order to remain useful for the changing programmatic landscape, IS research should factor in relevant timeframes and engage the multi-sectoral community of stakeholders, including community members, health care teams, program managers, researchers and policy makers, to facilitate the development of programs, practices and polices that lead to a more effective and efficient global AIDS response. The approach presented here is a synthesis of approaches and is a useful model to address IS-related questions for HIV prevention, care and treatment programs. This approach, however, is not a panacea, and we will continue to learn new ways of thinking as we move forward to close the implementation gap.

Public randomization ceremonies have been proposed as a strategy to strengthen stakeholder engagement and address concerns and misconceptions associated with trial randomization. However, there are few published examples that describe how to conduct a public randomization ceremony with meaningful stakeholder engagement or how such ceremonies impact stakeholder perceptions about randomization and the randomization process. Cluster randomization for the GeneXpert Performance Evaluation for Linkage to Tuberculosis Care (XPEL-TB) trial was conducted at a public randomization ceremony attended by 70 stakeholders in Kampala, Uganda. Presentations given by the Acting Assistant Commissioner from the Uganda National Tuberculosis and Leprosy Programme and trial investigators emphasized how the trial aimed to further national TB goals, as well as how stakeholders contributed to the intervention design. The purpose and process of randomization were described using simple text and visuals. Randomization was an interactive activity that required participation of stakeholders from each trial site. A survey administered to stakeholders at the end of the ceremony suggested high comprehension of randomization (98%), trust in the randomization process (96%), and satisfaction with randomization outcomes (96%). Public randomization ceremonies should be considered more routinely to engage stakeholders in and address potential concerns about the fairness and impartiality of the randomization process for community-based trials.

Policies implemented to slow transmission of COVID-19 are expected to have disrupted delivery of routine health services, including tuberculosis (TB) care.

Globally, several diabetes prevention interventions have been shown to be cost-effective, yet they have had limited adaptation, implementation, and evaluation in the Caribbean and among Caribbean-descent individuals, where the burden of type 2 diabetes is high. We report on the protocol for the Lifestyle Intervention with Metformin Escalation (LIME) study – an evidence-based diabetes prevention intervention to reduce the incidence of diabetes among Caribbean-descent individuals with prediabetes.

Variation in healthcare delivery is increasingly recognized as an important metric of healthcare quality. Directly observed therapy (DOT) has been the standard of care for tuberculosis (TB) treatment supervision for decades based on World Health Organization (WHO) guidelines. However, variation in implementation of DOT and associated TB treatment supervision practices remains poorly defined.

The objective of this prospective cross-sectional study, conducted at a national referral hospital in Kampala, Uganda, was to determine diagnostic performance of serum C-reactive protein (CRP) as a triage test for tuberculosis (TB) among HIV-seronegative inpatients. We calculated the sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values to determine the diagnostic performance of a CRP enzyme-linked immunosorbent assay (ELISA) (Eurolyser) in comparison to that of a reference standard of Mycobacterium tuberculosisculture on two sputum samples.

•Gaps in cascade of care remain with referral-based xpert testing in Uganda.•Systematic approach identified key reasons for gaps at multiple levels.•Theory-informed strategy to streamline TB diagnosis reduced the gaps.•Co-interventions are needed for effective implementation of novel diagnostics.

Pathogen cell-free DNA (pcfDNA) in blood and urine is an attractive biomarker; however, the impact of preanalytical factors is not well understood. Blood and urine samples from healthy donors spiked with cfDNA from Mycobacterium tuberculosis, Salmonella enterica, Aspergillus fumigatus, and Epstein-Barr virus (EBV) and samples from tuberculosis patients were used to evaluate the impact of blood collection tube, urine preservative, processing delay, processing method, freezing and thawing, and sample volume on pcfDNA.

Pre-treatment loss to follow-up is common for patients diagnosed with tuberculosis (TB) in high-burden countries. Delivering test results by Short-Messaging-Service (SMS) is increasingly being considered as a solution, but there is limited information about its feasibility as a public health tool in low resourced settings.

Many high-burden countries are scaling-up Xpert MTB/RIF using a hub-and-spoke model. We evaluated the quality of care for patients undergoing TB evaluation at microscopy centers (spokes) linked to Xpert testing sites (hubs) in Uganda.

Pneumocystis jirovecii pneumonia (PCP) typically presents as an interstitial and alveolar process with ground glass opacities on chest computed tomography (CT). The absence of ground glass opacities on chest CT is thought to have a high negative predictive value for PCP in individuals with AIDS. Here, we report a case of PCP in a man with AIDS who presented to our hospital with subacute shortness of breath and a nonproductive cough. While his chest CT revealed diffuse nodular rather than ground glass opacities, bronchoscopy with bronchoalveolar lavage and transbronchial biopsies confirmed the diagnosis of PCP and did not identify additional pathogens. PCP was not the expected diagnosis based on chest CT, but it otherwise fit well with the patient’s clinical and laboratory presentation. In the era of combination antiretroviral therapy, routine prophylaxis for PCP, and increased use of computed tomography, it may be that PCP will increasingly present with nonclassical chest radiographic patterns. Clinicians should be aware of this presentation when selecting diagnostic and management strategies.