Maternal Tmprss6 is required for hepcidin suppression and fetal health.

The antenatal role of the hepcidin-regulating protease Tmprss6 has never been elucidated because knockout dams are infertile. Using an in vivo knockdown approach, we confirm Tmprsss6 is critical for hepcidin suppression in pregnancy, and Tmprss6 inhibition drives deleterious fetal outcomes.

Contextual factors influencing implementation of tuberculosis digital adherence technologies: a scoping review guided by the RE-AIM framework.

Introduction: Digital adherence technologies (DATs) may enable person-centred tuberculosis (TB) treatment monitoring; however, implementation challenges may undermine their effectiveness. Using the reach, effectiveness, adoption, implementation and maintenance framework, we conducted a scoping review to identify contextual factors informing 'reach' (DAT engagement by people with TB) and 'adoption' (DAT uptake by healthcare providers or clinics).

Methods: We searched eight databases from 1 January 2000 to 25 April 2023 to identify all TB DAT studies.

Implementation outcomes of tuberculosis digital adherence technologies: a scoping review using the RE-AIM framework.

Introduction: Globally, tuberculosis (TB) remains one of the leading infectious causes of death, with 1.3 million deaths. Digital adherence technologies (DATs) have the potential to provide person-centred care and improve outcomes.

Modelling the epidemiological and economic impact of digital adherence technologies with differentiated care for tuberculosis treatment in Ethiopia.

Background: Digital adherence technologies (DATs) with associated differentiated care are potential tools to improve tuberculosis (TB) treatment outcomes and reduce associated costs for both patients and healthcare providers. However, the balance between epidemiological and economic benefits remains unclear. Here, we used data from the ASCENT trial to estimate the potential long-term epidemiological and economic impact of DAT interventions in Ethiopia.

Cost and cost-effectiveness of digital technologies for support of tuberculosis treatment adherence: a systematic review.

Background: Digital adherence technologies (DATs) may provide a patient-centred approach to supporting tuberculosis (TB) medication adherence and improving treatment outcomes. We synthesised evidence addressing costs and cost-effectiveness of DATs to support TB treatment.

Methods: A systematic review (PROSPERO-CRD42022313531) identified relevant literature from January 2000 to April 2023 in MEDLINE, Embase, CENTRAL, CINAHL, Web of Science along with preprints from medRxiv, Europe PMC and ClinicalTrials.

Treatment adherence and clinical outcomes amongst in people with drug-susceptible tuberculosis using medication monitor and differentiated care approach compared with standard of care in South Africa: a cluster randomized trial.

Background: Poor treatment adherence contributes to lower treatment completion and higher loss to follow-up among people with tuberculosis (PWTB). Medication monitors have shown some evidence of improved adherence.

Methods: We conducted a cluster randomised trial in 18 primary health clinics in South Africa between May 2019-February 2022.

The performance of digital technologies for measuring tuberculosis medication adherence: a systematic review.

Introduction: Digital adherence technologies (DATs), such as phone-based technologies and digital pillboxes, can provide more person-centric approaches to support tuberculosis (TB) treatment. However, there are varying estimates of their performance for measuring medication adherence.

Methods: We conducted a systematic review (PROSPERO-CRD42022313526), which identified relevant published literature and preprints from January 2000 to April 2023 in five databases.

How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial.

Unlabelled: Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation.

Feasibility and acceptability of the smart pillbox and medication label with differentiated care to support person-centered tuberculosis care among ASCENT trial participants - A multicountry study.

Introduction: Digital adherence technologies (DATs) can offer alternative approaches to support tuberculosis treatment medication adherence. Evidence on their feasibility and acceptability in high TB burden settings is limited. We conducted a cross-sectional survey among adults with drug-sensitive tuberculosis (DS-TB), participating in pragmatic cluster-randomized trials for the Adherence Support Coalition to End TB project in Ethiopia (PACTR202008776694999), the Philippines, South Africa and Tanzania (ISRCTN 17706019).

Haemoglobin thresholds to define anaemia from age 6 months to 65 years: estimates from international data sources.

Background: Detection of anaemia is crucial for clinical medicine and public health. Current WHO anaemia definitions are based on statistical thresholds (fifth centiles) set more than 50 years ago. We sought to establish evidence for the statistical haemoglobin thresholds for anaemia that can be applied globally and inform WHO and clinical guidelines.

Quantifying non-adherence to anti-tuberculosis treatment due to early discontinuation: a systematic literature review of timings to loss to follow-up.

Background: The burden of non-adherence to anti-tuberculosis (TB) treatment is poorly understood. One type is early discontinuation, that is, stopping treatment early. Given the implications of early discontinuation for treatment outcomes, we undertook a systematic review to estimate its burden, using the timing of loss to follow-up (LFU) as a proxy measure.

Acceptability of using the medication monitor and experience of a differentiated care approach for TB treatment adherence among people living with TB in South Africa.

Background: The introduction of digital adherence technologies (DATs) such as medication monitors in tuberculosis (TB) programmes supports treatment adherence among people with tuberculosis (PWTB). We evaluated the acceptability of using medication monitors (Wisepill evriMED) prompting a stepwise differentiated care approach (DCA), involving short message service (SMS), phone calls, home visits and motivational counselling, among PWTB in South Africa.

Methods: We conducted 62 in-depth interviews with participants in local languages across three provinces (January-October 2020), purposively selected by treatment month, adherence history and gender.

Risk factors for poor engagement with a smart pillbox adherence intervention among persons on tuberculosis treatment in Ethiopia.

Background: Non-adherence to tuberculosis treatment increases the risk of poor treatment outcomes. Digital adherence technologies (DATs), including the smart pillbox (EvriMED), aim to improve treatment adherence and are being widely evaluated. As part of the Adherence Support Coalition to End TB (ASCENT) project we analysed data from a cluster-randomised trial of DATs and differentiated care in Ethiopia to examine individual-factors for poor engagement with the smart pillbox.

Does diabetes mellitus comorbidity increase the risk of drug-induced liver injury during tuberculosis treatment?

Background: The growing burden of diabetes worldwide is a threat to tuberculosis (TB) control. Drug-induced liver injury (DILI) due to TB drugs is a significant concern and there is currently limited evidence on the effect of diabetes on TB DILI. This study sought to investigate the effect of diabetes as a risk factor for DILI and to further study any potential co-factors.

Evaluating the equity impact and cost-effectiveness of digital adherence technologies with differentiated care to support tuberculosis treatment adherence in Ethiopia: protocol and analysis plan for the health economics component of a cluster randomised trial.

Background: Tuberculosis remains a leading infectious cause of death in resource-limited settings. Effective treatment is the cornerstone of tuberculosis control, reducing mortality, recurrence and transmission. Supporting treatment adherence through facility-based observations of medication taking can be costly to providers and patients.

Trial-of-antibiotics to assist tuberculosis diagnosis in symptomatic adults in Malawi (ACT-TB study): a randomised controlled trial.

Background: Clinical practice and diagnostic algorithms often assume that tuberculosis can be ruled out in mycobacteriology-negative individuals whose symptoms improve with a trial-of-antibiotics. We aimed to investigate diagnostic performance, clinical benefit, and antimicrobial resistance using a randomised controlled trial.

Methods: In this three-arm, individually randomised, open-label, controlled trial, we enrolled Malawian adults (aged ≥18 years) attending primary care who reported being unwell for at least 14 days (including cough) with no immediate indication for hospitalisation at Limbe and Ndirande Health Centres in Blantyre.

Costs of implementing universal test and treat in three correctional facilities in South Africa and Zambia.

Introduction: Universal test and treat (UTT) is a population-based strategy that aims to ensure widespread HIV testing and rapid antiretroviral therapy (ART) for all who have tested positive regardless of CD4 count to decrease HIV incidence and improve health outcomes. Little is known about the specific resources required to implement UTT in correctional facilities for incarcerated people. The primary aim of this study was to describe the resources used to implement UTT and to provide detailed costing to inform UTT scale-up in similar settings.

Cluster randomised trials with a binary outcome and a small number of clusters: comparison of individual and cluster level analysis method.

Background: Cluster randomised trials (CRTs) are often designed with a small number of clusters, but it is not clear which analysis methods are optimal when the outcome is binary. This simulation study aimed to determine (i) whether cluster-level analysis (CL), generalised linear mixed models (GLMM), and generalised estimating equations with sandwich variance (GEE) approaches maintain acceptable type-one error including the impact of non-normality of cluster effects and low prevalence, and if so (ii) which methods have the greatest power. We simulated CRTs with 8-30 clusters, altering the cluster-size, outcome prevalence, intracluster correlation coefficient, and cluster effect distribution.

Forgiveness Is the Attribute of the Strong: Nonadherence and Regimen Shortening in Drug-sensitive Tuberculosis.

"Forgiveness" charts the ability of a drug or regimen to withstand nonadherence without negative clinical consequences. We aimed to determine the influence of regimen length, regimen drugs, and dosing, and when during treatment nonadherence occurs on the forgiveness of antituberculosis regimens. Using data from three randomized controlled trials comparing experimental 4-month regimens for drug-sensitive tuberculosis with the standard 6-month regimen, we used generalized linear models to examine how the risk of a negative composite outcome changed as dose-taking decreased.

Risk Factors for Hospitalization or Death Among Adults With Advanced HIV at Enrollment for Care in South Africa: A Secondary Analysis of the TB Fast Track Trial.

Background: Individuals with advanced HIV experience high mortality, especially before and during the first months of antiretroviral therapy (ART). We aimed to identify factors, measurable in routine, primary health clinic-based services, associated with the greatest risk of poor outcome.

Methods: We included all individuals enrolled in the standard-of-care arm of a cluster-randomized trial (TB Fast Track); adults attending participating health clinics with CD4 ≤150 cells/µL and no recent ART were eligible.

Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion.

Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this "resister" (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after M.

Evaluation of implementation and effectiveness of digital adherence technology with differentiated care to support tuberculosis treatment adherence and improve treatment outcomes in Ethiopia: a study protocol for a cluster randomised trial.

Background: Digital adherence technologies (DATs) are recommended to support patient-centred, differentiated care to improve tuberculosis (TB) treatment outcomes, but evidence that such technologies improve adherence is limited. We aim to implement and evaluate the effectiveness of smart pillboxes and medication labels linked to an adherence data platform, to create a differentiated care response to patient adherence and improve TB care among adult pulmonary TB participants. Our study is part of the Adherence Support Coalition to End TB (ASCENT) project in Ethiopia.