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The World Health Organization (WHO) recently put forth a Global Strategy on Digital Health 2020–2025 with several countries having already achieved key milestones. We aimed to understand whether and how digital health technologies (DHTs) are absorbed in Africa, tracking Ethiopia as a key node. We conducted a systematic review, searching PubMed-MEDLINE, Embase, ScienceDirect, African Journals Online, Cochrane Central Registry of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform databases from inception to 02 February 2021 for studies of any design that investigated the potential of DHTs in clinical or public health practices in Ethiopia. This review was registered with PROSPERO ( CRD42021240645 ) and it was designed to inform our ongoing DHT-enabled randomized controlled trial (RCT) (ClinicalTrials.gov ID: NCT04216420 ). We found 27,493 potentially relevant citations, among which 52 studies met the inclusion criteria, comprising a total of 596,128 patients, healthy individuals, and healthcare professionals. The studies involved six DHTs: mHealth (29 studies, 574,649 participants); electronic health records (13 studies, 4534 participants); telemedicine (4 studies, 465 participants); cloud-based application (2 studies, 2382 participants); information communication technology (3 studies, 681 participants), and artificial intelligence (1 study, 13,417 participants). The studies targeted six health conditions: maternal and child health (15), infectious diseases (14), non-communicable diseases (3), dermatitis (1), surgery (4), and general health conditions (15). The outcomes of interest were feasibility, usability, willingness or readiness, effectiveness, quality improvement, and knowledge or attitude toward DHTs. Five studies involved RCTs. The analysis showed that although DHTs are a relatively recent phenomenon in Ethiopia, their potential harnessing clinical and public health practices are highly visible. Their adoption and implementation in full capacity require more training, access to better devices such as smartphones, and infrastructure. DHTs hold much promise tackling major clinical and public health backlogs and strengthening the healthcare ecosystem in Ethiopia. More RCTs are needed on emerging DHTs including artificial intelligence, big data, cloud, cybersecurity, telemedicine, and wearable devices to provide robust evidence of their potential use in such settings and to materialize the WHO’s Global Strategy on Digital Health.

Traditionally, single critical concentrations of drugs are utilized for Mycobacterium tuberculosis (Mtb) drug susceptibility testing (DST); however, the level of drug resistance can impact treatment choices and outcomes. Mutations at the katG gene are the major genetic mutations in multidrug resistant (MDR) Mtb and usually associated with high level resistance. We assessed the minimum inhibitory concentrations (MICs) of MDR or rifampin resistant (RR) and isoniazid (INH) resistant Mtb isolates to determine the quantification of drug resistance among key anti-tuberculosis drugs. The study was conducted on stored Mtb isolates collected as part of a national drug resistance survey in Ethiopia. MIC values were determined using Sensititre™ MYCOTB plates. A line probe assay (MTBDRplus) was also performed to identify genetic determinants of resistance for all isolates. MIC testing was performed on 74 Mtb isolates including 46 MDR, 2 RR and 26 INH phenotypically resistant isolates as determined by the Löwenstein Jensen (LJ) method. Four (15%) INH resistant Mtb isolates were detected as borderline rifampin resistance (MIC = 1 μg/ml) using MYCOTB MIC plates and no rifampin resistance mutations were detected by LPA. Among the 48 MDR/RR TB cases, 9 (19%) were rifabutin susceptible (MIC was between ≤0.25 and 0.5μg/ml). Additionally, the MIC for isoniazid was between 2-4 μg/ml (moderate resistance) for 58% of MDR TB isolates and 95.6% (n = 25) of the isolates had mutations at the katG gene. Our findings suggest a role for rifabutin treatment in a subset of RR TB patients, thus potentially preserving an important drug class. The high proportion of moderate level INH resistant among MDR Mtb isolates indicates the potential benefit of high dose isoniazid treatment in a high proportion of katG gene harboring MDR Mtb isolates.

We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution.

Isoniazid (INH) resistant Mycobacterium tuberculosis (Hr-TB) is the most common type of drug resistant TB, and is defined as M tuberculosis complex (MTBC) strains resistant to INH but susceptible to rifampicin (RIF). Resistance to INH precedes RIF resistance in almost all multidrug resistant TB (MDR-TB) cases, across all MTBC lineages and in all settings. Therefore, early detection of Hr-TB is critical to ensure rapid initiation of appropriate treatment, and to prevent progression to MDR-TB. We assessed the performance of the GenoType MTBDRplus VER 2.0 line probe assay (LPA) in detecting isoniazid resistance among MTBC clinical isolates. A retrospective study was conducted among M. tuberculosis complex (MTBC) clinical isolates obtained from the third-round Ethiopian national drug resistance survey (DRS) conducted between August 2017 and December 2019. The sensitivity, specificity, positive predictive value, and negative predictive value of the GenoType MTBDRplus VER 2.0 LPA in detecting INH resistance were assessed and compared to phenotypic drug susceptibility testing (DST) using the Mycobacteria Growth Indicator Tube (MGIT) system. Fisher's exact test was performed to compare the performance of LPA between Hr-TB and MDR-TB isolates. A total of 137 MTBC isolates were included, of those 62 were Hr-TB, 35 were MDR-TB and 40 were INH susceptible. The sensitivity of the GenoType MTBDRplus VER 2.0 for detecting INH resistance was 77.4% (95% CI: 65.5-86.2) among Hr-TB isolates and 94.3% (95% CI: 80.4-99.4) among MDR-TB isolates (P = 0.04). The specificity of the GenoType MTBDRplus VER 2.0 for detecting INH resistance was 100% (95% CI: 89.6-100). The katG 315 mutation was observed in 71% (n = 44) of Hr-TB phenotypes and 94.3% (n = 33) of MDR-TB phenotypes. Mutation at position-15 of the inhA promoter region alone was detected in four (6.5%) Hr-TB isolates, and concomitantly with katG 315 mutation in one (2.9%) MDR-TB isolate. GenoType MTBDRplus VER 2.0 LPA demonstrated improved performance in detecting INH resistance among MDR-TB cases compared to Hr-TB cases. The katG315 mutation is the most common INH resistance conferring gene among Hr-TB and MDR-TB isolates. Additional INH resistance conferring mutations should be evaluated to improve the sensitivity of the GenoType MTBDRplus VER 2.0 for the detection of INH resistance among Hr-TB cases.

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1β-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.

Poor penetration of many anti-tuberculosis (TB) antibiotics into the central nervous system (CNS) is thought to be a major driver of morbidity and mortality in TB meningitis (TBM). While the amount of a particular drug that crosses into the cerebrospinal fluid (CSF) varies from person to person, little is known about the host factors associated with interindividual differences in CSF concentrations of anti-TB drugs. In patients diagnosed with TBM from the country of Georgia (n = 17), we investigate the association between CSF concentrations of anti-TB antibiotics and multiple host factors including serum drug concentrations and CSF concentrations of metabolites and cytokines. We found > 2-fold differences in CSF concentrations of anti-TB antibiotics from person to person for all drugs tested including cycloserine, ethambutol, imipenem, isoniazid, levofloxacin, linezolid, moxifloxacin, pyrazinamide, and rifampin. While serum drug concentrations explained over 30% of the variation in CSF drug concentrations for cycloserine, isoniazid, linezolid, and pyrazinamide (adjusted R 2  ≥ 0.3, p < 0.001 for all), there was no significant association between serum concentrations of imipenem and ethambutol and their respective CSF concentrations. CSF concentrations of carnitines were significantly associated with concentrations of ethambutol and imipenem (q < 0.05), and imipenem was the only antibiotic significantly associated with CSF cytokine concentrations. These results indicate that there is high interindividual variability in CSF drug concentrations in patients treated for TBM, which is only partially explained by differences in serum drug concentrations. With the exception of imipenem, there was no association between CSF drug concentrations and concentrations of cytokines and chemokines.

The physical, paper-based Georgia TB Reference Guide has served as the clinical reference handbook on tuberculosis (TB) diagnostic and treatment guidelines for the state of Georgia in the United States. Supported by the Georgia Department of Public Health, the production of the 112-page palm-sized booklet was previously led by a team of Georgia-based TB experts at Emory University and printed every three-five years with updates to clinical management guidelines and TB consult contact information. However, the costs associated with editorial printing combined with delays in updating a static printed booklet with revised guidance hampered the utility of the tool. Considering the barriers with paper-based production and based on the beneficial use of apps to support the dissemination of clinical management guidance in other settings, the booklet was converted into a mobile application. This paper describes the process of developing a mobile app version of the Georgia TB Reference Guide in an easy-to-update and readily available format. We employed a user-centered design approach to develop the app, including a series of qualitative interviews and quantitative surveys. Participants included a mix of state officials and local TB experts. First, initial foundational interviews were conducted to conceptualize current utilization practices of both the paper and PDF versions of the tool. Second, the findings from the initial interviews were organized thematically and informed the design of the app, which was then beta tested by a round of previously unsampled TB experts as well as a re-sample from the initial interviews. Third, the designs were coded into developmental phases and beta tested among users of the current Georgia TB Reference Guide. Fourth, the app was published and downloaded by a pre-selected group of local users who provided answers to a follow-up survey after using the app for one month. Fifth, user growth, self-reported demographics, and app usage between February and July 2022 were recorded through automatic data metrics built into the app. The paper copy Georgia TB Reference Guide usage themes included commonly referenced content, navigation paths, and desired features and content. The themes were converted into features and designs such as prioritizing commonly reviewed topics and guide customization with bookmarks and notes. Iterations of the designs were driven by feedback from TB experts and included home page featured content, improving content readability, and improving the search feature. The follow-up survey revealed a 90% preference for the app over the paper version of the guide. In the six months following the app's release, the app was downloaded by 281 individuals in the United States. The majority of downloads were in Georgia and the app also expanded organically to 19 other states. The experience of converting the Georgia TB Reference Guide offers specific and effective steps to converting a medical reference guide into a mobile application tool that is readily available, easy to use, and easy to update. The organic dissemination of the app beyond the state of Georgia's borders within the first six months of app launch underscores desire among TB healthcare professionals for high-quality digital reference content outside the state. This experience offers clear outlines for replication in other contexts and demonstrates the utility of similar mobile medical reference tools.

Background. Whether community-associated methicillin-resistant Staphylococcus aureus (MRSA) genotypes (e.g., USA300) are a major cause of bloodstream infections (BSIs) and health care—associated infections has been poorly defined. Methods. Consecutive MRSA isolates recovered from patients with BSIs were prospectively collected at an urban public hospital. Molecular typing studies were performed. Prevalence and risk factors for the MRSA USA300 genotype were assessed. Results. One hundred thirty-two cases of MRSA BSI were documented over 7.5 months in 2004 (incidence, 6.79 per 1000 admissions); 116 isolates were available for genotyping. Characteristics of the 116 evaluable cases included: a mean age 47 years; 62% were male, 82% were African American, and 22% were HIV seropositive. The crude in-hospital mortality rate was 22%. In 107 cases (92%), there was contact with a health care facility within the year prior to infection, and a nosocomial infection (defined as positive blood culture results obtained >48 h after admission) occurred in 49 cases (42%). PFGE demonstrated that 39 (34%) of the 116 isolates were the MRSA USA300 genotype; 34 (29%) were USA100; 42 (36%) were USA500; and 1 (1%) was USA800. MRSA USA300 accounted for 28% of health care—associated BSIs and 20% of nosocomial MRSA BSIs. In multivariate analysis, isolation of the USA300 genotype was associated with injectiondrug use (OR, 3.67; 95% CI, 1.10–12.28) and skin and soft tissue infection (OR, 4.26; 95% CI, 1.08–16.84). Patients who resided in long-term care facilities (OR, 0.09; 95% CI, 0.01–0.82) and those who were treated with antimicrobials in the prior year were less likely to have MRSA USA300 genotype recovered (OR, 0.10; 95% CI, 0.02–0.49). Conclusions. MRSA USA300 genotype, the predominant cause of community-associated MRSA infections in our area (Atlanta, GA), has now emerged as a significant cause of health care—associated and nosocomial BSI. MRSA USA300 as a nosocomial pathogen presents new challenges to infection control programs.

Meticillin-resistant Staphylococcus aureus (MRSA), usually known as a nosocomial pathogen, has emerged as the predominant cause of skin and soft-tissue infections in many communities. Concurrent with the emergence of community-acquired MRSA (CA-MRSA), there have been increasing numbers of reports of community-acquired necrotising pneumonia in young patients and others without the classic health-care-associated risk factors. Community-onset necrotising pneumonia due to CA-MRSA is now recognised as an emerging clinical entity with distinctive clinical features and substantial morbidity and mortality. A viral prodrome (eg, influenza or influenza-like illness) followed by acute onset of shortness of breath, sepsis, and haemoptysis is the most frequent clinical presentation. The best treatment of this partly toxin-mediated disease has not been clearly defined. Whereas cases of CA-MRSA pneumonia have now been reported from almost every continent, the overall burden of disease of this emerging syndrome remains incompletely described. We report two related cases of community-onset pneumonia due to the MRSA USA300 genotype and review the literature regarding the emergence of CA-MRSA pneumonia.

Little is known regarding the relationship between common comorbidities in persons with tuberculosis (TB) (including human immunodeficiency virus [HIV], diabetes, and hepatitis C virus [HCV]) and post-TB mortality. We conducted a retrospective cohort study among persons who initiated treatment for rifampicin-resistant or multi/extensively drug-resistant (RR or M/XDR) TB reported to the country of Georgia’s TB surveillance during 2009–2017. Exposures included HIV serologic status, diabetes, and HCV status. Our outcome was all-cause post-TB mortality determined by cross-validating vital status with Georgia’s death registry through November 2019. We estimated adjusted hazard rate ratios (aHR) and 95% confidence intervals (CI) of post-TB mortality among participants with and without comorbidities using cause-specific hazard regressions. Among 1032 eligible participants, 34 (3.3%) died during treatment and 87 (8.7%) died post-TB treatment. The median time to post-TB death was 21 months (interquartile range 7–39) after TB treatment. After adjusting for confounders, the hazard rates of post-TB mortality were higher among participants with HIV co-infection (aHR = 3.74, 95%CI 1.77–7.91) compared to those without HIV co-infection. In our cohort, post-TB mortality occurred most commonly in the first 3 years post-TB treatment. Linkage to care for common TB comorbidities post-treatment may reduce post-TB mortality rates.