The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6.

The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/ß-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient.

Mitigating environmental impact by development of ambient-cured EAF slag and fly ash blended geopolymer via mix design optimization.

This article discusses the utilization of industrial by-products, namely, electric arc furnace slag (EAFS) and fly ash to produce cementless geopolymer binder. Taguchi-grey optimization is used for experimental design and for investigating the effects of mix design parameters. Fly ash, in the levels of 0-75% (by mass), partly replaced EAFS in the binary-blended composite system. Experiments were performed on the microstructural development, mechanical properties, and durability of ambient-cured EAFS-fly ash geopolymer paste (EFGP). The optimal mix with 75-25% composition of EAFS and fly ash produced ~ 39 MPa compressive strength accrediting to the co-existence of C-A-S-H and N-A-S-H gels. The initial and final setting times were 127 min and 581 min, respectively, owing to adequate alkali and amorphous contents in the matrix, and the flowability was 108% due to sufficient activator content and the spherical shape of fly ash particles. SEM, XRD, and FTIR results corroborated the mechanical test results.

Strengthening HIV and HIV co-morbidity care in low- and middle-income countries: insights from behavioural economics to improve healthcare worker behaviour.

INTRODUCTION: Despite advances in HIV and HIV co-morbidity service delivery, substantial challenges remain in translating evidence-based interventions into routine practice to bring optimal care and prevention to all populations. While barriers to successful implementation are often multifactorial, healthcare worker behaviour is critical for on-the-ground and in-clinic service delivery. Implementation science offers a systematic approach to understanding service delivery, including approaches to overcoming delivery gaps. Behavioural economics is a field that seeks to understand when and how behaviour deviates from traditional models of decision-making, deviations which are described as biases. Clinical policies and implementation strategies that incorporate an understanding of behavioural economics can add to implementation science approaches and play an important role in bridging the gap between healthcare worker knowledge and service delivery. DISCUSSION: In HIV care in low- and middle-income countries (LMICs), potential behavioural economic strategies that may be utilized alone or in conjunction with more traditional approaches include using choice architecture to exploit status quo bias and reduce the effects of cognitive load, overcoming the impact of anchoring and availability bias through tailored clinical training and clinical mentoring, reducing the effects of present bias by changing the cost-benefit calculus of interventions with few short-term benefits and leveraging social norms through peer comparison. As with any implementation strategy, understanding the local context and catalysts of behaviour is crucial for success. CONCLUSIONS: As the focus of HIV care shifts beyond the goal of initiating patients on antiretroviral therapy to a more general retention in high-quality care to support longevity and quality of life, there is an increasing need for innovation to achieve improved care delivery and management. Clinical policies and implementation strategies that incorporate elements of behavioural economic theory, alongside local testing and adaptation, may increase the delivery of evidence-based interventions and improve health outcomes for people living with HIV in LMIC settings.

The geography of emergency department-based HIV testing in South Africa: Can patients link to care?

BACKGROUND: Emergency Departments (EDs) can serve as clinical sites for identification of new HIV infections and their entry into care. We examined if HIV-positive patients who present to EDs in South Africa are able to successfully link to care. METHODS: We conducted a one-year longitudinal prospective cohort study in four hospitals across the Eastern Cape, South Africa, with participants followed between July 2016 and July 2018. All adult, non-critical patients presenting to the ED were systematically approached, asked about their HIV status, and, if unknown, offered a point-of-care (POC) HIV test. All HIV-positive patients were further consented to participate in a follow-up study to assess subsequent linkage to care and distance from "home" to ED. Linkage to care was defined as self-reported linkage (telephonic) or evidence of repeated CD4/viral load testing in the National Health Laboratory System (NHLS) at either the 6- or 12-months post index ED visit. FINDINGS: A total of 983 HIV-positive patients consented to participate in the study. In the 12 months following their ED visit, 34·1% of patients demonstrated linkage to care (335/983), 23·8% did not link to care (234/983), and 42·1% (414/983) were lost to follow-up. Though not statistically significant, a high percentage of young men (27/50, 54%) and those presenting with a trauma-related complaints (100/205, 48.8%) did not link to care. A considerable proportion of patients (105/454, 23·2%,) resided 50 or more kilometers from their index ED sites, though there was not a significant difference in linkage to care rate between those who lived closer or further from the ED. INTERPRETATION: We have shown that strategies to improve linkage to care from the ED should consider the high rates of poor linkage among young men and those presenting to the ED with trauma. Furthermore, innovative linkage to care solutions will need to account for the unique geographical consideration of this population, given that many ED patients will need to continue care at a site distant from the diagnosis site. FUNDING: This research was supported by the South African Medical Research Council, the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Johns Hopkins Center for Global Health.

REAPing the benefits: development and use of a structured evaluation framework to codify learning resources for Global Health professionals.

BACKGROUND: The learning opportunities for global health professionals have expanded rapidly in recent years. The diverse array of learners and wide range in course quality underscore the need for an improved course vetting process to better match learners with appropriate learning opportunities. METHODS: We developed a framework to assess overall course quality by determining performance across four defined domains Relevance, Engagement, Access, and Pedagogy (REAP). We applied this framework across a learning catalogue developed for participants enrolled in the Sustaining Technical and Analytic Resources (STAR) project, a global health leadership training program. RESULTS: The STAR learning activities database included a total of 382 courses, workshops, and web-based resources which fulfilled 531 competencies across three levels: core, content, and skill. RELEVANCE: The majority of activities were at an understanding or practicing level across all competency domains (486/531, 91.5%). Engagement: Many activities lacked any peer engagement (202/531, 38.0%) and had limited to no faculty engagement (260/531, 49.0%). Access: The plurality of courses across competencies were offered on demand (227/531, 42.7%) and were highly flexible in pace (240/531, 45.2%). Pedagogy: Of the activities that included an assessment, most matched activity learning objectives (217/531, 40.9%). CONCLUSIONS: Through applying REAP to the STAR project learning catalogue, we found many online activities lacked meaningful engagement with faculty and peers. Further development of structured online activities providing learners with flexibility in access, a range of levels of advancement for content, and opportunities to engage and apply learning are needed for the field of global health.

Training Global Health Leaders: A Critical Review of Competency Gaps.

Background: Global health leadership training seeks to strengthen the existing global health workforce to build leaders that have the necessary knowledge, attitudes, and skills to deliver a vision for public health and healthcare delivery. In order to develop impactful training curricula, there is a greater need to understand the areas of focus required to strengthen the global health workforce. Objectives: This paper seeks to present a critical analysis of the competency gaps among participants of a single global health training program. Methods: This is a cross-sectional observational study conducted during the implementation of the Sustaining Technical and Analytical Resources (STAR) project from May 1, 2018 to May 31, 2020. We utilized descriptive statistics to analyze the baseline competency assessment of STAR participants using a customized framework that was developed for the program. Findings: Among the 74 individuals enrolled in the study, we identified that there were significant differences in milestone achievement across participant types for all eight competencies (p < 0.001). Overall, US-based fellows reported higher perceived competency levels than low- and middle-income (LMIC)-based fellows in all categories except Capacity Strengthening (4, 23.5% leading vs. 12, 63.5% leading). LMIC fellows reported lower achieved milestones in Gender Equity (only 6, 31.5% at practicing) and Development Practice (only 6, 31.5% at practicing). Conclusions: Our study identified critical needs in the domains of public health ethics, health equity, and social justice and gender equity. Further emphasis on these domains in global health curricula and other professional development is critical to strengthen the knowledge and skills of individuals who are well-placed to advance the development of an equitable global health workforce.

Systems Analysis to Increase HIV Testing Delivery and HIV Diagnosis in Primary Care Clinics in South Africa.

BACKGROUND: Provider-initiated testing and counseling remains highly underused in many South African health facilities. We implemented a systems analysis to investigate whether simple adjustments to HIV testing services (HTS) delivery can increase HTS provision. SETTING: Ten primary care facilities in the Ekurhuleni District in South Africa. METHODS: Following a baseline HTS assessment that showed limited offering of HTS by clinicians, clinic staff had the option to adopt several change approaches to increase HTS delivery using existing human resources. Approaches included adjusting HTS timing, strengthening HTS promotion, counsellor management, and implementing reward systems. Evaluation was conducted identically to the baseline study using patient exit interviews to quantify HTS engagement and value stream mapping to map patient flow through the clinic. RESULTS: We conducted 2163 exit interviews and followed 352 patients for value stream mapping. After change implementation, a significantly higher proportion of patients reported being offered HTS (742/2163, 34.3% vs. 231/2206, 10.5% during the baseline period; χ2P < 0.001) and having undertaken testing (527/2163, 24.4% vs. 197/2206, 8.9% during the baseline period; χ2P < 0.001) with only a 3-percentage point decrease in HIV-positive yield (14.0% vs. 17.1% during the baseline period). The median time to HTS offer decreased from 77 minutes to 3 minutes after clinic arrival during the intervention (χ2P = 0.001). CONCLUSIONS: A systems approach can be an effective and appropriate implementation strategy to augment HTS delivery and increase HIV diagnoses. This low-cost approach may be extended to optimize other aspects of clinic service delivery.