Background Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications. Methods This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900 mg daily, and an interventional arm of NAC 900 mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong’oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis . Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model. Discussion Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials. Trial registration PACTR202007736854169 Registered 03 July 2020

At least a third of tuberculosis (TB) cases remain undiagnosed, disproportionately so in children and ado-lescents, which is hampering global elimination goals. Prolonged symptom duration presents a high-risk scenario for childhood TB in endemic areas, but the prolonged period of symptoms and its impact on educational attainment are rarely documented. Using a mixed method approach, we aimed to quantify the duration of respiratory symptoms and describe their impact on education among children from a rural area of Tanzania. We used data from a prospectively enrolled cohort of children and adolescents aged 4-17 years in rural Tanzania at the start of active TB treatment. We report on the cohort's baseline characteristics and explore the correlation between duration of symptoms and other vari-ables. In-depth qualitative interviews were designed on the basis of a grounded theory approach to explore the impact of TB on educational attainment among school-aged children. In this cohort, children and adolescents diagnosed with TB experienced symptoms for a median of 85 days (interquartile range: 30,231 days) prior to treatment initiation. In addition, 56 participants (65%) had a TB exposure in the household. Of the 16 families with school-aged children who were inter-viewed, 15 (94%) reported a significant negative impact of TB on the schooling of their children. Children in this cohort experienced a long duration of TB symptoms; the extent of illness impacted absenteeism at school. Screening initiatives for households affected by TB may lead to a shortened duration of symptoms and may minimize the impact on school attendance.

Objective:Latinx people comprise 30% of all new human immunodeficiency virus (HIV) infections in the United States and face many challenges to accessing and engaging with HIV care. To bridge these gaps in care, a Spanish-language mobile health (mHealth) intervention known as ConexionesPositivas (CP) was adapted from an established English-language platform called PositiveLinks (PL) to help improve engagement in care and reduce viral nonsuppression among its users. We aimed to determine how CP can address the challenges that Latinx people with HIV (PWH) in the United States face.Materials and methods:We conducted a post-implementation study of the CP mHealth platform, guided by principles of user-centered design. We enrolled 20 Spanish-speaking CP users in the study, who completed the previously validated System Usability Scale (SUS) and semistructured interviews. Interviews were transcribed and translated for analysis. We performed thematic coding of interview transcripts in Dedoose.Results:The SUS composite score was 75, which is within the range of good usability. Four categories of themes were identified in the interviews: client context, strengths of CP, barriers to use and dislikes, and suggestions to improve CP. Positive impacts included encouraging self-monitoring of medication adherence, mood and stress, connection to professional care, and development of a support system for PWH.Discussion:While CP is an effective and easy-to-use application, participants expressed a desire for improved personalization and interactivity, which will guide further iteration.Conclusion:This study highlights the importance of tailoring mHealth interventions to improve equity of access, especially for populations with limited English proficiency.

Distinct from quantifying the economic sequelae of tuberculosis (TB) in adults, data are scarce regarding lived experiences of youth and their caregivers seeking and sustaining TB treatment in low income communities. Children ages 4–17 diagnosed with TB and their caregivers were recruited from rural and semi-urban northern Tanzania. Using a grounded theory approach, a qualitative interview guide was developed, informed by exploratory research. Twenty-four interviews were conducted in Kiswahili, audio-recorded and analyzed for emerging and consistent themes. Dominant themes found were socioemotional impacts of TB on households, including adverse effects on work productivity, and facilitators and obstacles to TB care, including general financial hardship and transportation challenges. The median percentage of household monthly income spent to attend a TB clinic visit was 34% (minimum: 1%, maximum: 220%). The most common solutions identified by caregivers to mitigate adverse impacts were transportation assistance and nutrition supplementation. To end TB, healthcare systems must acknowledge the total financial burden shouldered by low wealth families seeking pediatric TB care, provide consultations and medications locally, and increase access to TB-specific communal funds to mitigate burdens such as inadequate nutrition. Trial registration: planned sub-study of the registered prospective study, NCT05283967. Trial registration: ClinicalTrials.gov identifier: NCT05283967.

Variable pharmacokinetics of rifampin in tuberculosis (TB) treatment can lead to poor outcomes. Urine spectrophotometry is simpler and more accessible than recommended serum-based drug monitoring, but its optimal efficacy in predicting serum rifampin underexposure in adults with TB remains uncertain. Adult TB patients in New Jersey and Virginia receiving rifampin-containing regimens were enrolled. Serum and urine samples were collected over 24 h. Rifampin serum concentrations were measured using validated liquid chromatography-tandem mass spectrometry, and total exposure (area under the concentration-time curve) over 24 h (AUC(0-24)) was determined through noncompartmental analysis. The Sunahara method was used to extract total rifamycins, and rifampin urine excretion was measured by spectrophotometry. An analysis of 58 eligible participants, including 15 (26%) with type 2 diabetes mellitus, demonstrated that urine spectrophotometry accurately identified subtarget rifampin AUC(0-24) at 0-4, 0-8, and 0-24 h. The area under the receiver operator characteristic curve (AUC ROC) values were 0.80 (95% CI 0.67-0.90), 0.84 (95% CI 0.72-0.94), and 0.83 (95% CI 0.72-0.93), respectively. These values were comparable to the AUC ROC of 2 h serum concentrations commonly used for therapeutic monitoring (0.82 [95% CI 0.71-0.92], P = 0.6). Diabetes status did not significantly affect the AUC ROCs for urine in predicting subtarget rifampin serum exposure (P = 0.67-0.92). Spectrophotometric measurement of urine rifampin excretion within the first 4 or 8 h after dosing is a simple and cost-effective test that accurately predicts rifampin underexposure. This test provides critical information for optimizing tuberculosis treatment outcomes by facilitating appropriate dose adjustments.

ObjectivePharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome.DesignProspective diagnostic accuracy study.SettingInpatient wards and outpatient clinics, northern Tanzania.PatientsChildren aged 4–17 years were consecutively recruited on initiation of WHO-approved treatment regimens.InterventionsSamples were collected after directly observed therapy at least 2 weeks after initiation in the intensive phase: serum at pre-dose and 1, 2 and 6 hours post-dose, later analysed by liquid chromatography-tandem mass spectrometry for calculation of rifampin total exposure or area under the concentration time curve (AUC0-24); urine at post-dose intervals of 0–4, 4–8 and 8–24 hours, with rifampin excretion amount measured onsite by spectrophotometry.Main outcome measuresReceiver operating characteristic (ROC) curve for percentage of rifampin dose excreted in urine measured by spectrophotometry to predict serum rifampin AUC0–24target of 31.7 mg*hour/L.Results89 children, 52 (58%) female, with median age of 9.1 years, had both serum and urine collection. Only 59 (66%) reached the serum AUC0–24target, reflected by a range of urine excretion patterns. Area under the ROC curve for percentage of rifampin dose excreted in urine over 24 hours predicting serum AUC0–24target was 69.3% (95% CI 56.7% to 81.8%), p=0.007.ConclusionsUrine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings.

Transfusion of high-titer CIP to non-critically ill patients early after admission with COVID-19 respiratory disease was associated with significantly increased anti-SARS-CoV-2 specific antibodies (compared to baseline) and a non-significant reduction in ICU transfer and death (compared to controls). This prospective phase II trial provides a suggestion that the antiviral effects of CIP from early in the COVID-19 pandemic may delay progression to critical illness and death in specific patient populations.

Background: Latinx people in the United States are disproportionately diagnosed with HIV and are more likely to experience worse HIV-related health outcomes. Although m-health has demonstrated success in improving HIV care, a gap remains in the development of m-health platforms tailored to Latinx populations. Methods: We conducted formative study to guide the adaptation of an evidence-based m-health intervention, PositiveLinks (PL), for Spanish-speaking Latinx people living with HIV (PLWH). Spanish-speaking Latinx PLWH in the nonurban Southern United States completed semistructured interviews and viewed a demo version of the m-health intervention. Qualitative analysis was performed using a grounded theory approach. Emerging themes were identified in four topic areas: (1) prior experiences with technology, (2) desired m-health features, (3) experiences with prototype app, and (4) iteration of prototype. Results: All PLWH who participated (n?=?22) were born outside the continental United States. Participants included 10 men, 10 women, and 2 transgender participants. Mean age was 41.1 years (standard deviation 11.6 years). Participants expressed concerns about privacy, a need for reliable information, and interest in practical m-health features such as appointment and medication reminders. After trialing the Spanish-language PL prototype, participants reported that peer support and positive reinforcement were strong motivators to use the app. The ability to individualize the app to meet one's own needs was also considered important. Conclusion: This formative study provides baseline attitudes about m-health among Latinx PLWH as well as desired m-health features. m-Health interventions are acceptable to Spanish-speaking PLWH and involving the target population in a user-centered formative process led to improvements in app accessibility and usability.

Latinx people living with HIV (PLWH) experience disparities in health outcomes and face unique barriers to care related to language, intersectional stigma, and immigration status. We aimed to explore the lived experience of Spanish-speaking Latinx PLWH in the non-urban South to better understand how to improve care for this minority language population. We conducted semi-structured interviews with 22 participants (10 men, 10 women, 2 transgender women) who were recruited from a Ryan White HIV/AIDS program (RWHAP) and a community-based organization. Almost all participants were foreign born. Emerging themes included language barriers, cultural differences, inadequate interpreter services, HIV-related and intersectional stigma, isolation, and relationships as a source of support. These barriers may contribute to disparities in outcomes for Latinx PLWH. New interventions are needed to overcome barriers, foster community, and ensure culturally tailored models of care. Potential clinic-level interventions include the development of specialized training for RWHAP interpreters and inclusion of interpreters in care teams.

BACKGROUND:Molecular diagnostics have revolutionized the diagnosis of multidrug resistant tuberculosis (MDR-TB). Yet in Tanzania we found delay in diagnosis with more than 70% of MDR-TB patients having a history of several previous treatment courses for TB signaling prior opportunities for diagnosis. We aimed to explore patients' viewpoints and experiences with personal and socio-behavioral obstacles from MDR-TB diagnosis to treatment in an attempt to understand these prior findings. METHODS:The study was conducted in December 2016 with MDR-TB patients admitted at Kibong'oto Infectious Diseases Hospital. A qualitative approach deploying focus group discussions (FGDs) was used to gather information. Groups were sex aggregated to allow free interaction and to gauge gender specific issues in the social and behavioral contexts. The FGDs explored pathways and factors in the service delivery that may have contributed in the delay in accessing MDR-TB diagnostics and/or treatment. Collected data were coded, categorized and thematically interpreted. RESULTS:Forty MDR-TB patients participated in six FGDs. Challenges and barriers contributing to the delay in accessing MDR-TB diagnosis to treatment were as follows: 1) Participants had a different understanding of MDR-TB that led to seeking services outside the conventional health system; 2) Socio-economic adversity made health-seeking behavior difficult and often unproductive; 3) In the health system, challenges included inadequacy of MDR-TB diagnostic centers, lack of knowledge on behalf of health care providers to consider MDR-TB and order appropriate diagnostics; 4) The specimen referral system for early diagnosis of MDR-TB was inefficient. Non-adherence of TB patients to first-line anti-TB drugs prior to MDR-TB diagnosis, given the multitude of barriers discussed, was coupled with both intentional and unintentional non-adherence of health care providers to international standards of TB care. CONCLUSION:Patient-centered strategies bridging communities and the health system are urgently required for optimum MDR-TB control in Tanzania.