Adapting and Scaling a Digital Health Intervention to Improve Maternal and Child Health Among Ethnic Minority Women in Vietnam Amid the COVID-19 Context: Protocol for the dMOM Project.

BACKGROUND: Due to interconnected structural determinants including low maternal health knowledge, economic marginalization, and remoteness from low-capacity health centers, ethnic minority women in remote areas of Vietnam face severe maternal, newborn, and child health (MNCH) inequities. As ethnic minorities represent 15% of the Vietnamese population, these disparities are significant. mMOM-a pilot mobile health (mHealth) intervention using SMS text messaging to improve MNCH outcomes among ethnic minority women in northern Vietnam-was implemented from 2013-2016 with promising results. Despite mMOM's findings, exacerbated MNCH inequities, and digital health becoming more salient amid COVID-19, mHealth has not yet been scaled to address MNCH among ethnic minority women in Vietnam. OBJECTIVE: We describe the protocol for adapting, expanding, and exponentially scaling the mMOM intervention qualitatively through adding COVID-19-related MNCH guidance and novel technological components (mobile app and artificial intelligence chatbots) and quantitatively through broadening the geographical area to reach exponentially more participants, within the evolving COVID-19 context. METHODS: dMOM will be conducted in 4 phases. (1) Drawing on a review of international literature and government guidelines on MNCH amid COVID-19, mMOM project components will be updated to respond to COVID-19 and expanded to include a mobile app and artificial intelligence chatbots to more deeply engage participants. (2) Using an intersectionality lens and participatory action research approach, a scoping study and rapid ethnographic fieldwork will explore ethnic minority women's unmet MNCH needs; acceptability and accessibility of digital health; technical capacity of commune health centers; gendered power dynamics and cultural, geographical, and social determinants impacting health outcomes; and multilevel impacts of COVID-19. Findings will be applied to further refine the intervention. (3) dMOM will be implemented and incrementally scaled across 71 project communes. (4) dMOM will be evaluated to assess whether SMS text messaging or mobile app delivery engenders better MNCH outcomes among ethnic minority women. The documentation of lessons learned and dMOM models will be shared with Vietnam's Ministry of Health for adoption and further scaling up. RESULTS: The dMOM study was funded by the International Development Research Centre (IDRC) in November 2021, cofacilitated by the Ministry of Health, and is being coimplemented by provincial health departments in 2 mountainous provinces. Phase 1 was initiated in May 2022, and phase 2 is planned to begin in December 2022. The study is expected to be complete in June 2025. CONCLUSIONS: dMOM research outcomes will generate important empirical evidence on the effectiveness of leveraging digital health to address intractable MNCH inequities among ethnic minority women in low-resource settings in Vietnam and provide critical information on the processes of adapting mHealth interventions to respond to COVID-19 and future pandemics. Finally, dMOM activities, models, and findings will inform a national intervention led by the Ministry of Health. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/44720.

Predictors of treatment outcomes among patients with multidrug-resistant tuberculosis in Vietnam: a retrospective cohort study.

BACKGROUND: Improving treatment outcomes for multidrug-resistant tuberculosis (MDR-TB) is a leading priority for global TB control. This retrospective cohort study evaluated the factors associated with treatment success among patients treated for MDR-TB in two provinces in Vietnam. METHODS: Treatment outcomes were evaluated for adult patients treated in Hanoi and Thanh Hoa provinces between 2014 and 2016. The primary outcome was the proportion of patients with treatment success, defined as cure or treatment completion. Logistic regression analysis was used to evaluate the relationship between patient clinical and microbiological characteristics and treatment success. RESULTS: Treatment outcomes were reported in 612 of 662 patients; of these, 401 (65.5)% were successfully treated. The odds of treatment success were lower for male patients (aOR 0.56, 95% CI 0.34-0.90), for people living with HIV (aOR 0.44, 95% CI 0.20-1.00), and for patients treated for extensive antibiotic resistance (pre-XDR-/XDT-TB) (aOR 0.53, 95% CI 0.29-0.97), compared with others. Patients who achieved culture conversion in the first 4 months of treatment had increased odds (aOR 2.93, 95% CI 1.33-6.45) of treatment success. In addition, loss to follow-up was less common among patients covered by social health insurance compared to those who paid for treatment out-of-pocket (aOR 0.55, 95% CI 0.32-0.95). CONCLUSIONS: Among patients with MDR-TB, males, people living with HIV, and those with more extensive antibiotic resistance at diagnosis are at greatest risk of an unsuccessful treatment outcome. Efforts to optimise the management of co-morbidities (such as HIV), ensure rapid bacteriological conversion, and provide financial support for patients promise to improve treatment outcomes.

Biochemical and Structural Characterization of TesA, a Major Thioesterase Required for Outer-Envelope Lipid Biosynthesis in Mycobacterium tuberculosis.

With the high number of patients infected by tuberculosis and the sharp increase of drug-resistant tuberculosis cases, developing new drugs to fight this disease has become increasingly urgent. In this context, analogs of the naturally occurring enolphosphates Cyclipostins and Cyclophostin (CyC analogs) offer new therapeutic opportunities. The CyC analogs display potent activity both in vitro and in infected macrophages against several pathogenic mycobacteria including Mycobacterium tuberculosis and Mycobacterium abscessus. Interestingly, these CyC inhibitors target several enzymes with active-site serine or cysteine residues that play key roles in mycobacterial lipid and cell wall metabolism. Among them, TesA, a putative thioesterase involved in the synthesis of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), has been identified. These two lipids (PDIM and PGL) are non-covalently bound to the outer cell wall in several human pathogenic mycobacteria and are important virulence factors. Herein, we used biochemical and structural approaches to validate TesA as an effective pharmacological target of the CyC analogs. We confirmed both thioesterase and esterase activities of TesA, and showed that the most active inhibitor CyC17 binds covalently to the catalytic Ser104 residue leading to a total loss of enzyme activity. These data were supported by the X-ray structure, obtained at a 2.6-Å resolution, of a complex in which CyC17 is bound to TesA. Our study provides evidence that CyC17 inhibits the activity of TesA, thus paving the way to a new strategy for impairing the PDIM and PGL biosynthesis, potentially decreasing the virulence of associated mycobacterial species.

Oxadiazolone derivatives, new promising multi-target inhibitors against M. tuberculosis.

A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc26230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M. tb growth only with moderated MIC50, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. Of interest, all OX derivatives exhibited very low toxicity towards host macrophages. Among the six potential OXs identified, HPOX, a selective inhibitor of extracellular M. tb growth, was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP, in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for in vitro growth of M. tb and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that OX derivatives may represent a novel class of multi-target inhibitors leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes.

Cyclipostins and cyclophostin analogs inhibit the antigen 85C from Mycobacterium tuberculosis both in vitro and in vivo.

An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of cyclipostins and cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds. These targets included members of the antigen 85 (Ag85) complex (i.e. Ag85A, Ag85B, and Ag85C), responsible for biosynthesis of trehalose dimycolate and mycolylation of arabinogalactan. Herein, we used biochemical and structural approaches to validate the Ag85 complex as a pharmacological target of the CyC analogs. We found that CyC7ß, CyC8ß, and CyC17 bind covalently to the catalytic Ser124 residue in Ag85C; inhibit mycolyltransferase activity (i.e. the transfer of a fatty acid molecule onto trehalose); and reduce triacylglycerol synthase activity, a property previously attributed to Ag85A. Supporting these results, an X-ray structure of Ag85C in complex with CyC8ß disclosed that this inhibitor occupies Ag85C's substrate-binding pocket. Importantly, metabolic labeling of M. tuberculosis cultures revealed that the CyC compounds impair both trehalose dimycolate synthesis and mycolylation of arabinogalactan. Overall, our study provides compelling evidence that CyC analogs can inhibit the activity of the Ag85 complex in vitro and in mycobacteria, opening the door to a new strategy for inhibiting Ag85. The high-resolution crystal structure obtained will further guide the rational optimization of new CyC scaffolds with greater specificity and potency against M. tuberculosis.

Cyclophostin and Cyclipostins analogues, new promising molecules to treat mycobacterial-related diseases.

The progression of mycobacterial diseases requires the development of new therapeutics. This study evaluated the efficacy and selectivity of a panel of Cyclophostin and Cyclipostins analogues (CyCs) against various bacteria and mycobacteria. The activity 26 CyCs was first assayed by the agar plate method. Compounds exhibiting 50-100% growth inhibition were then selected to determine their minimum inhibitory concentrations (MICs) by the resazurin microtiter assay (REMA). The best drug candidate was further tested against clinical mycobacterial isolates and bacteria responsible for nosocomial infections, including 6 Gram-negative bacteria, 5 Gram-positive bacteria, 29 rapid-growing mycobacteria belonging to the Mycobacterium chelonae-abscessus clade and 3 slow-growing mycobacteria (Mycobacterium marinum, Mycobacterium bovis BCG and Mycobacterium tuberculosis). Among the 26 CyCs tested, 10 were active and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate (CyC17) was further tested against 26 clinical strains and showed high selectivity for mycobacteria, with MICs (<2-40 µg/mL) comparable with those of most classical antimicrobials used to treat M. abscessus infections. Together, these results support the fact that such CyCs represent a new family of potent and selective inhibitors against mycobacteria. This is of particular interest for future chemotherapeutic developments against mycobacterial-associated infections, especially against M. abscessus, the most drug-resistant mycobacterial species.

Cyclipostins and Cyclophostin analogs as promising compounds in the fight against tuberculosis.

A new class of Cyclophostin and Cyclipostins (CyC) analogs have been investigated against Mycobacterium tuberculosis H37Rv (M. tb) grown either in broth medium or inside macrophages. Our compounds displayed a diversity of action by acting either on extracellular M. tb bacterial growth only, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth with very low toxicity towards host macrophages. Among the eight potential CyCs identified, CyC 17 exhibited the best extracellular antitubercular activity (MIC50 = 500 nM). This compound was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 23 potential candidates, most of them being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA and HsaD, have previously been reported as essential for in vitro growth of M. tb and/or survival and persistence in macrophages. Overall, our findings support the assumption that CyC 17 may thus represent a novel class of multi-target inhibitor leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes participating in important physiological processes.