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. METHODS: Data were obtained from a cohort of trial participants with drug-sensitive tuberculosis (DS-TB) whose treatment started between 1 December 2020 and 1 May 2022, and who were using the smart pillbox. Poor engagement with the pillbox was defined as (i) > 20% days with no digital confirmation and (ii) the count of days with no digital confirmation, and calculated over a two evaluation periods (56-days and 168-days). Logistic random effects regression was used to model > 20% days with no digital confirmation and negative binomial random effects regression to model counts of days with no digital confirmation, both accounting for clustering of individuals at the facility-level. RESULTS: Among 1262 participants, 10.8% (133/1262) over 56-days and 15.8% (200/1262) over 168-days had > 20% days with no digital confirmation. The odds of poor engagement was less among participants in the higher stratum of socio-economic position (SEP) over 56-days. Overall, 4,689/67,315 expected doses over 56-days and 18,042/199,133 expected doses over 168-days were not digitally confirmed. Compared to participants in the poorest SEP stratum, participants in the wealthiest stratum had lower rates of days not digitally confirmed over 168-days (adjusted rate ratio [RRa]:0.79; 95% confidence interval [CI]: 0.65, 0.96). In both evaluation periods (56-days and 168-days), HIV-positive status (RRa:1.29; 95%CI: 1.02, 1.63 and RRa:1.28; 95%CI: 1.07, 1.53), single/living independent (RRa:1.31; 95%CI: 1.03, 1.67 and RRa:1.38; 95%CI: 1.16, 1.64) and separated/widowed (RRa:1.40; 95%CI: 1.04, 1.90 and RRa:1.26; 95%CI: 1.00, 1.58) had higher rates of counts of days with no digital confirmation. CONCLUSION: Poorest SEP stratum, HIV-positive status, single/living independent and separated/ widowed were associated with poor engagement with smart pillbox among people with DS-TB in Ethiopia. Differentiated care for these sub-groups may reduce risk of non-adherence to TB treatment.

Social determinants of the changing tuberculosis prevalence in Viet Nam: Analysis of population-level cross-sectional studies.

BACKGROUND: An ecological relationship between economic development and reduction in tuberculosis prevalence has been observed. Between 2007 and 2017, Viet Nam experienced rapid economic development with equitable distribution of resources and a 37% reduction in tuberculosis prevalence. Analysing consecutive prevalence surveys, we examined how the reduction in tuberculosis (and subclinical tuberculosis) prevalence was concentrated between socioeconomic groups. METHODS AND FINDINGS: We combined data from 2 nationally representative Viet Nam tuberculosis prevalence surveys with provincial-level measures of poverty. Data from 94,156 (2007) and 61,763 (2017) individuals were included. Of people with microbiologically confirmed tuberculosis, 21.6% (47/218) in 2007 and 29.0% (36/124) in 2017 had subclinical disease. We constructed an asset index using principal component analysis of consumption data. An illness concentration index was estimated to measure socioeconomic position inequality in tuberculosis prevalence. The illness concentration index changed from -0.10 (95% CI -0.08, -0.16; p = 0.003) in 2007 to 0.07 (95% CI 0.06, 0.18; p = 0.158) in 2017, indicating that tuberculosis was concentrated among the poorest households in 2007, with a shift towards more equal distribution between rich and poor households in 2017. This finding was similar for subclinical tuberculosis. We fitted multilevel models to investigate relationships between change in tuberculosis prevalence, individual risks, household socioeconomic position, and neighbourhood poverty. Controlling for provincial poverty level reduced the difference in prevalence, suggesting that changes in neighbourhood poverty contribute to the explanation of change in tuberculosis prevalence. A limitation of our study is that while tuberculosis prevalence surveys are valuable for understanding socioeconomic differences in tuberculosis prevalence in countries, given that tuberculosis is a relatively rare disease in the population studied, there is limited power to explore socioeconomic drivers. However, combining repeated cross-sectional surveys with provincial deprivation estimates during a period of remarkable economic growth provides valuable insights into the dynamics of the relationship between tuberculosis and economic development in Viet Nam. CONCLUSIONS: We found that with equitable economic growth and a reduction in tuberculosis burden, tuberculosis became less concentrated among the poor in Viet Nam.

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. METHODS/DESIGN: We will conduct a pragmatic three-arm cluster-randomised trial with 78 health facilities in two regions in Ethiopia. Facilities are randomised (1:1:1) to either of the two intervention arms or standard of care. Adults aged ≥ 18 years with drug-sensitive (DS) pulmonary TB are enrolled over 12 months and followed-up for 12 months after treatment initiation. Participants in facilities randomised to either of the two intervention arms are offered a DAT linked to the web-based ASCENT adherence platform for daily adherence monitoring and differentiated response to patient adherence for those who have missed doses. Participants at standard of care facilities receive routine care. For those that had bacteriologically confirmed TB at treatment initiation and can produce sputum without induction, sputum culture will be performed approximately 6 months after the end of treatment to measure disease recurrence. The primary endpoint is a composite unfavourable outcome measured over 12 months from TB treatment initiation defined as either poor end of treatment outcome (lost to follow-up, death, or treatment failure) or treatment recurrence measured 6 months after the scheduled end of treatment. This study will also evaluate the effectiveness, feasibility, and cost-effectiveness of DAT systems for DS-TB patients. DISCUSSION: This trial will evaluate the impact and contextual factors of medication label and smart pillbox with a differentiated response to patient care, among adult pulmonary DS-TB participants in Ethiopia. If successful, this evaluation will generate valuable evidence via a shared evaluation framework for optimal use and scale-up. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR202008776694999, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241 , registered on August 11, 2020.

Mosaic structural variation in children with developmental disorders.

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2-1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case-control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e - 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e - 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic-phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.

Symbiodinium biogeography tracks environmental patterns rather than host genetics in a key Caribbean reef-builder, Orbicella annularis.

The physiological performance of a reef-building coral is a combined outcome of both the coral host and its algal endosymbionts, Symbiodinium While Orbicella annularis-a dominant reef-building coral in the Wider Caribbean-is known to be a flexible host in terms of the diversity of Symbiodinium types it can associate with, it is uncertain how this diversity varies across the Caribbean, and whether spatial variability in the symbiont community is related to either O. annularis genotype or environment. Here, we target the Symbiodinium-ITS2 gene to characterize and map dominant Symbiodinium hosted by O. annularis at an unprecedented spatial scale. We reveal northwest-southeast partitioning across the Caribbean, both in terms of the dominant symbiont taxa hosted and in assemblage diversity. Multivariate regression analyses incorporating a suite of environmental and genetic factors reveal that observed spatial patterns are predominantly explained by chronic thermal stress (summer temperatures) and are unrelated to host genotype. Furthermore, we were able to associate the presence of specific Symbiodinium types with local environmental drivers (for example, Symbiodinium C7 with areas experiencing cooler summers, B1j with nutrient loading and B17 with turbidity), associations that have not previously been described.

Incorporating Demand and Supply Constraints into Economic Evaluations in Low-Income and Middle-Income Countries.

Global guidelines for new technologies are based on cost and efficacy data from a limited number of trial locations. Country-level decision makers need to consider whether cost-effectiveness analysis used to inform global guidelines are sufficient for their situation or whether to use models that adjust cost-effectiveness results taking into account setting-specific epidemiological and cost heterogeneity. However, demand and supply constraints will also impact cost-effectiveness by influencing the standard of care and the use and implementation of any new technology. These constraints may also vary substantially by setting. We present two case studies of economic evaluations of the introduction of new diagnostics for malaria and tuberculosis control. These case studies are used to analyse how the scope of economic evaluations of each technology expanded to account for and then address demand and supply constraints over time. We use these case studies to inform a conceptual framework that can be used to explore the characteristics of intervention complexity and the influence of demand and supply constraints. Finally, we describe a number of feasible steps that researchers who wish to apply our framework in cost-effectiveness analyses.

Methodological Issues to Consider When Collecting Data to Estimate Poverty Impact in Economic Evaluations in Low-income and Middle-income Countries.

Out-of-pocket spending is increasingly recognized as an important barrier to accessing health care, particularly in low-income and middle-income countries (LMICs) where a large portion of health expenditure comes from out-of-pocket payments. Emerging universal healthcare policies prioritize reduction of poverty impact such as catastrophic and impoverishing healthcare expenditure. Poverty impact is therefore increasingly evaluated alongside and within economic evaluations to estimate the impact of specific health interventions on poverty. However, data collection for these metrics can be challenging in intervention-based contexts in LMICs because of study design and practical limitations. Using a set of case studies, this letter identifies methodological challenges in collecting patient cost data in LMIC contexts. These components are presented in a framework to encourage researchers to consider the implications of differing approaches in data collection and to report their approach in a standardized and transparent way.

Using Top-down and Bottom-up Costing Approaches in LMICs: The Case for Using Both to Assess the Incremental Costs of New Technologies at Scale.

PURPOSE: Estimating the incremental costs of scaling-up novel technologies in low-income and middle-income countries is a methodologically challenging and substantial empirical undertaking, in the absence of routine cost data collection. We demonstrate a best practice pragmatic approach to estimate the incremental costs of new technologies in low-income and middle-income countries, using the example of costing the scale-up of Xpert Mycobacterium tuberculosis (MTB)/resistance to riframpicin (RIF) in South Africa. MATERIALS AND METHODS: We estimate costs, by applying two distinct approaches of bottom-up and top-down costing, together with an assessment of processes and capacity. RESULTS: The unit costs measured using the different methods of bottom-up and top-down costing, respectively, are $US16.9 and $US33.5 for Xpert MTB/RIF, and $US6.3 and $US8.5 for microscopy. The incremental cost of Xpert MTB/RIF is estimated to be between $US14.7 and $US17.7. While the average cost of Xpert MTB/RIF was higher than previous studies using standard methods, the incremental cost of Xpert MTB/RIF was found to be lower. CONCLUSION: Costs estimates are highly dependent on the method used, so an approach, which clearly identifies resource-use data collected from a bottom-up or top-down perspective, together with capacity measurement, is recommended as a pragmatic approach to capture true incremental cost where routine cost data are scarce.

Dynamic 3D culture: models of chondrogenesis and endochondral ossification.

The formation of cartilage from stem cells during development is a complex process which is regulated by both local growth factors and biomechanical cues, and results in the differentiation of chondrocytes into a range of subtypes in specific regions of the tissue. In fetal development cartilage also acts as a precursor scaffold for many bones, and mineralization of this cartilaginous bone precursor occurs through the process of endochondral ossification. In the endochondral formation of bones during fetal development the interplay between cell signalling, growth factors, and biomechanics regulates the formation of load bearing bone, in addition to the joint capsule containing articular cartilage and synovium, generating complex, functional joints from a single precursor anlagen. These joint tissues are subsequently prone to degeneration in adult life and have poor regenerative capabilities, and so understanding how they are created during development may provide useful insights into therapies for diseases, such as osteoarthritis, and restoring bone and cartilage lost in adulthood. Of particular interest is how these tissues regenerate in the mechanically dynamic environment of a living joint, and so experiments performed using 3D models of cartilage development and endochondral ossification are proving insightful. In this review, we discuss some of the interesting models of cartilage development, such as the chick femur which can be observed in ovo, or isolated at a specific developmental stage and cultured organotypically in vitro. Biomaterial and hydrogel-based strategies which have emerged from regenerative medicine are also covered, allowing researchers to make informed choices on the characteristics of the materials used for both original research and clinical translation. In all of these models, we illustrate the essential importance of mechanical forces and mechanotransduction as a regulator of cell behavior and ultimate structural function in cartilage.

Enhanced chondrogenic potential in GelMA-based 3D cartilage model via Wnt3a surface immobilization.

Cartilage tissue engineering aims to develop functional substitutes for treating cartilage defects and osteoarthritis. Traditional two-dimensional (2D) cell culture systems lack the complexity of native cartilage, leading to the development of 3D regenerative cartilage models. In this study, we developed a 3D model using Gelatin Methacryloyl (GelMA)-based hydrogels seeded with Y201 cells, a bone marrow mesenchymal stem cell line. The model investigated chondrogenic differentiation potential in response to Wnt3a stimulation within the GelMA scaffold and validated using known chondrogenic agonists. Y201 cells demonstrated suitability for the model, with increased proteoglycan content and upregulated chondrogenic marker expression under chondrogenic conditions. Wnt3a enhanced cell proliferation, indicating activation of the Wnt/ß-catenin pathway, which plays a role in cartilage development. GelMA hydrogels provided an optimal scaffold, supporting cell viability and proliferation. The 3D model exhibited consistent responses to chondrogenic agonists, with TGF-ß3 enhancing cartilage-specific extracellular matrix (ECM) production and chondrogenic differentiation. The combination of Wnt3a and TGF-ß3 showed synergistic effects, promoting chondrogenic differentiation and ECM production. This study presents a 3D regenerative cartilage model with potential for investigating cartilage biology, disease mechanisms, and drug screening. The model provides insights into complex cartilage regeneration mechanisms and offers a platform for developing therapeutic approaches for cartilage repair and osteoarthritis treatment.

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. Studies reporting quantitative data on the performance of DATs for measuring TB medication adherence against a reference standard, with at least 20 participants, were included. Study characteristics and performance outcomes (eg, sensitivity, specificity and predictive values) were extracted. Sensitivity was the proportion correctly classified as adherent by the DAT, among persons deemed adherent by a reference standard. Specificity was the proportion correctly classified as non-adherent by the DAT, among those deemed non-adherent by a reference standard. RESULTS: Of 5692 studies identified by our systematic search, 13 met inclusion criteria. These studies investigated medication sleeves with phone calls (branded as '99DOTS'; N=4), digital pillboxes N=5), ingestible sensors (N=2), artificial intelligence-based video-observed therapy (N=1) and multifunctional mobile applications (N=1). All but one involved persons with TB disease. For medication sleeves with phone calls, compared with urine testing, reported sensitivity and specificity were 70%-94% and 0%-61%, respectively. For digital pillboxes, compared with pill counts, reported sensitivity and specificity were 25%-99% and 69%-100%, respectively. For ingestible sensors, the sensitivity of dose detection was ≥95% compared with direct observation. Participant selection was the most frequent potential source of bias. CONCLUSION: The limited number of studies available suggests suboptimal and variable performance of DATs for dose monitoring, with significant evidence gaps, notably in real-world programmatic settings. Future research should aim to improve understanding of the relationships of specific technologies, settings and user engagement with DAT performance and should measure and report performance in a more standardised manner.

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). Methods: From each country we selected 10 health facilities implementing the DAT intervention (smart pillbox or medication labels, with differentiated care support), ensuring inclusion of urban/rural and public/private facilities. Adults on DS-TB regimen using a DAT were randomly selected from each facility. Feasibility of the DATs was assessed using a standardized tool. Acceptability was measured using a 5-point Likert-scale, using the Capability, Opportunity, Motivation, Behavior (COM-B) model. Mean scores of Likert-scale responses within each COM-B category were estimated, adjusted for facility-level clustering. Data were summarized by country and DAT type. Results: Participants using either the pillbox (n = 210) or labels (n = 169) were surveyed. Among pillbox users, phone ownership (79%), use of pillbox reminders (87%) and taking treatment without the pillbox (22%) varied by country. Among label users, phone ownership (81%), paying extra to use the labels (8%) and taking treatment without using labels (41%) varied by country. Poor network, problems with phone charging and access, not having the pillbox and forgetting to send text were reasons for not using DATs. Overall, people with TB had a favorable impression of both DATs, with mean composite scores between 4·21 to 4·42 across COM-B categories. Some disclosure concerns were reported. Conclusion: From client-perspective, pillboxes and medication labels with differentiated care support were feasible to implement and acceptable in variety of settings. However, implementation challenges related to network, phone access, stigma, additional costs to people with TB to use DATs need to be addressed.

Mesophotic coral bleaching associated with changes in thermocline depth.

As global temperatures continue to rise, shallow coral reef bleaching has become more intense and widespread. Mesophotic coral ecosystems reside in deeper (30-150 m), cooler water and were thought to offer a refuge to shallow-water reefs. Studies now show that mesophotic coral ecosystems instead have limited connectivity with shallow corals but host diverse endemic communities. Given their extensive distribution and high biodiversity, understanding their susceptibility to warming oceans is imperative. In this multidisciplinary study of an atoll in the Chagos Archipelago in the central Indian Ocean, we show evidence of coral bleaching at 90 m, despite the absence of shallow-water bleaching. We also show that the bleaching was associated with sustained thermocline deepening driven by the Indian Ocean Dipole, which might be further enhanced by internal waves whose influence varied at a sub-atoll scale. Our results demonstrate the potential vulnerability of mesophotic coral ecosystems to thermal stress and highlight the need for oceanographic knowledge to predict bleaching susceptibility and heterogeneity.

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. Digital adherence technologies (DATs) may facilitate treatment monitoring and differentiated care. The ASCENT-Ethiopia study is a three-arm cluster randomised trial assessing two DATs with differentiated care for supporting tuberculosis treatment adherence in Ethiopia. This study is part of the ASCENT consortium, assessing DATs in South Africa, the Philippines, Ukraine, Tanzania and Ethiopia. The aim of this study is to determine the costs, cost-effectiveness and equity impact of implementing DATs in Ethiopia. METHODS AND DESIGN: A total of 78 health facilities have been randomised (1:1:1) into one of two intervention arms or a standard-of-care arm. Approximately 50 participants from each health facility will be enrolled on the trial. Participants in facilities randomised to the intervention arms are offered a DAT linked to the ASCENT adherence platform for daily adherence monitoring and differentiated response for those who have missed doses. Participants at standard-of-care facilities receive routine care. Treatment outcomes and resource utilisation will be measured for each participant. The primary effectiveness outcome is a composite index of unfavourable end-of-treatment outcomes (lost to follow-up, death or treatment failure) or treatment recurrence within 6 months of end-of-treatment. For the cost-effectiveness analysis, end-of-treatment outcomes will be used to estimate disability-adjusted life years (DALYs) averted. Provider and patient cost data will be collected from a subsample of 5 health facilities per study arm, 10 participants per facility (n = 150). We will conduct a societal cost-effectiveness analysis using Bayesian hierarchical models that account for the individual-level correlation between costs and outcomes as well as intra-cluster correlation. An equity impact analysis will be conducted to summarise equity efficiency trade-offs. DISCUSSION: Trial enrolment is ongoing. This paper follows the published trial protocol and describes the protocol and analysis plan for the health economics work package of the ASCENT-Ethiopia trial. This analysis will generate economic evidence to inform the implementation of DATs in Ethiopia and globally. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR) PACTR202008776694999. Registered on 11 August 2020,  https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241 .

Connectivity of Caribbean coral populations: complementary insights from empirical and modelled gene flow.

Understanding patterns of connectivity among populations of marine organisms is essential for the development of realistic, spatially explicit models of population dynamics. Two approaches, empirical genetic patterns and oceanographic dispersal modelling, have been used to estimate levels of evolutionary connectivity among marine populations but rarely have their potentially complementary insights been combined. Here, a spatially realistic Lagrangian model of larval dispersal and a theoretical genetic model are integrated with the most extensive study of gene flow in a Caribbean marine organism. The 871 genets collected from 26 sites spread over the wider Caribbean subsampled 45.8% of the 1900 potential unique genets in the model. At a coarse scale, significant consensus between modelled estimates of genetic structure and empirical genetic data for populations of the reef-building coral Montastraea annularis is observed. However, modelled and empirical data differ in their estimates of connectivity among northern Mesoamerican reefs indicating that processes other than dispersal may dominate here. Further, the geographic location and porosity of the previously described east-west barrier to gene flow in the Caribbean is refined. A multi-prong approach, integrating genetic data and spatially realistic models of larval dispersal and genetic projection, provides complementary insights into the processes underpinning population connectivity in marine invertebrates on evolutionary timescales.

Economic evaluation of task-shifting approaches to the dispensing of anti-retroviral therapy.

BACKGROUND: A scarcity of human resources for health has been identified as one of the primary constraints to the scale-up of the provision of Anti-Retroviral Treatment (ART). In South Africa there is a particularly severe lack of pharmacists. The study aims to compare two task-shifting approaches to the dispensing of ART: Indirectly Supervised Pharmacist's Assistants (ISPA) and Nurse-based pharmaceutical care models against the standard of care which involves a pharmacist dispensing ART. METHODS: A cross-sectional mixed methods study design was used. Patient exit interviews, time and motion studies, expert interviews and staff costs were used to conduct a costing from the societal perspective. Six facilities were sampled in the Western Cape province of South Africa, and 230 patient interviews conducted. RESULTS: The ISPA model was found to be the least costly task-shifting pharmaceutical model. However, patients preferred receiving medication from the nurse. This related to a fear of stigma and being identified by virtue of receiving ART at the pharmacy. CONCLUSIONS: While these models are not mutually exclusive, and a variety of pharmaceutical care models will be necessary for scale up, it is useful to consider the impact of implementing these models on the provider, patient access to treatment and difficulties in implementation.

Two-Dimensional and Three-Dimensional Cartilage Model Platforms for Drug Evaluation and High-Throughput Screening Assays.

Osteoarthritis (OA) is a severely painful and debilitating disease of the joint, which brings about degradation of the articular cartilage and currently has few therapeutic solutions. Two-dimensional (2D) high-throughput screening (HTS) assays have been widely used to identify candidate drugs with therapeutic potential for the treatment of OA. A number of small molecules which improve the chondrogenic differentiation of progenitor cells for tissue engineering applications have also been discovered in this way. However, due to the failure of these models to accurately represent the native joint environment, the efficacy of these drugs has been limited in vivo. Screening systems utilizing three-dimensional (3D) models, which more closely reflect the tissue and its complex cell and molecular interactions, have also been described. However, the vast majority of these systems fail to recapitulate the complex, zonal structure of articular cartilage and its unique cell population. This review summarizes current 2D HTS techniques and addresses the question of how to use existing 3D models of tissue-engineered cartilage to create 3D drug screening platforms with improved outcomes. Impact statement Currently, the use of two-dimensional (2D) screening platforms in drug discovery is common practice. However, these systems often fail to predict efficacy in vivo, as they do not accurately represent the complexity of the native three-dimensional (3D) environment. This article describes existing 2D and 3D high-throughput systems used to identify small molecules for osteoarthritis treatment or in vitro chondrogenic differentiation, and suggests ways to improve the efficacy of these systems based on the most recent research.

Hydrostatic pressure promotes chondrogenic differentiation and microvesicle release from human embryonic and bone marrow stem cells.

Mechanical stimulation plays in an important role in regulating stem cell differentiation and their release of extracellular vesicles (EVs). In this study, effects of low magnitude hydrostatic pressure (HP) on the chondrogenic differentiation and microvesicle release from human embryonic stem cells (hESCs) and human bone marrow stem cells (hBMSCs) are examined. hESCs were differentiated into chondroprogenitors and then embedded in fibrin gels and subjected to HP (270 kPa, 1 Hz, 5 days per week). hBMSC pellets were differentiated in chondrogenic media and subjected to the same regime. HP significantly enhanced ACAN expression in hESCs. It also led to a significant increase in DNA content, sGAG content and total sGAG/DNA level in hBMSCs. Furthermore, HP significantly increased microvesicle protein content released from both cell types. These results highlight the benefit of HP bioreactor in promoting chondrogenesis and EV production for cartilage tissue engineering.

Coverage and effectiveness of conditional cash transfer for people with drug resistant tuberculosis in Zimbabwe: A mixed methods study.

The End TB strategy recommends social protection to mitigate socio-economic impacts of tuberculosis. Zimbabwe started implementing a conditional cash transfer (CCT) programme for people on drug resistant tuberculosis (DR-TB) treatment in 2013. We aimed to determine the proportion of people receiving CCT and effectiveness of CCT in improving treatment outcomes, explore their experiences with registering for CCT and understand the impact of CCT from the perspective of beneficiaries. Data from 2014-2021 were extracted from TB registers and CCT payment records within the National TB Programme. Sixteen in-depth interviews were conducted with people who were completing treatment or had completed treatment within two months. Poisson regression, adjusted for province, year of treatment, age and sex was used to investigate associations between receiving CCT and successful treatment outcomes among people who were in DR-TB care for ≥3 months after treatment initiation. Qualitative data were analyzed using thematic analysis. A total of 481 people were included in the quantitative study. Of these, 53% (254/481) received CCT at some point during treatment. People who exited DR-TB care within three months were 73% less likely to receive CCT than those who did not (prevalence ratio (PR) = 0.27 [95%CI: 0.18-0.41]). Among those who were alive and in care three months after treatment initiation, CCT recipients were 32% more likely to have successful outcomes than those who did not (adjusted PR = 1.32, [95%CI: 1.00-1.75]). Qualitative results revealed lack of knowledge about availability of CCT among people with DR-TB and missed opportunities by healthcare providers to provide information about availability of CCT. Delays and inconsistencies in disbursements of CCT were frequent themes. CCT were associated with successful treatment outcomes. Improvements in coverage, timeliness and predictability of disbursements are recommended.