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Abstract Background Many countries in sub-Saharan Africa are rapidly scaling up “differentiated service delivery” (DSD) models for HIV treatment to improve the quality of care, increase access, reduce costs, and support the continued expansion and sustainability of antiretroviral therapy (ART) programs. Although there is some published evidence about the health outcomes of patients in DSD models, little is known about their impacts on healthcare providers’ job satisfaction, patients’ quality of life, costs to providers or patients, or how DSD models affect resource allocation at the facility level. Methods SENTINEL is a multi-year observational study that will collect detailed data about DSD models for ART delivery and related services from 12 healthcare facilities in Malawi, 24 in South Africa, and 12 in Zambia. The first round of SENTINEL included a patient survey, provider survey, provider time-and-motion observations, and facility resource use inventory. A survey of clients testing for HIV and a supplement to the facility resource use component to describe service delivery integration will be added for the second round. The patient survey will ask up to 10 patients enrolled in each DSD model at each study site about their experiences in HIV care and in DSD models, costs incurred seeking treatment, and preferences for HIV service delivery. The provider survey will ask up to 10 providers per site about the impact of DSD models on their positions and clinics. The time-and-motion component will directly observe the time use of a sample of providers implementing DSD models. Finally, the resource utilization component will collect facility-level data about DSD model availability and enrollment and the human and other resources needed to implement them. SENTINEL is planned to include four or more approximately annual rounds of data collection between 2021 and 2026. Discussion As national DSD programs for HIV treatment mature, it is important to understand how individual healthcare facilities are interpreting and implementing national guidelines and how healthcare workers and clients are adapting to new models of service delivery. SENTINEL will help policy makers and program managers understand the benefits and costs of differentiated service delivery and improve resource allocation going forward.

Retention on antiretroviral therapy (ART) during the early treatment period is one of the most serious challenges facing HIV programs, but the timing and patterns of early disengagement from care remain poorly understood. We describe patterns of engagement in HIV care during the first year after treatment initiation. We analysed retrospective datasets of routinely collected electronic medical register (EMR) data for ≥18-year-old clients who initiated ART at public sector clinics in South Africa after 01/01/2018 and had ≥14 months of potential follow-up. Using scheduled visit dates, we characterized engagement in care as continuous (no treatment interruption), cyclical (at least one visit >28 days late with a return visit observed) or disengaged (visit not attended and no evidence of return). We report 6- and 12-month patterns of retention in care and viral suppression. Among 35,830 participants (65% female, median age 33), in months 0-6, 59% were continuously in care, 14% had engaged cyclically, 11% had transferred to another facility, 1% had died, and 16% had disengaged from care at the initiating facility. Among disengagers in the first 6 months, 58% did not return after their initiation visit. By 12 months after initiation, the overall proportion disengaged was 23%, 45% were classified as continuously engaged in months 7-12, and only 38% of the cohort had maintained continuous engagement at both the 6- and 12-month endpoints. Participants who were cyclically engaged in months 0-6 were nearly twice as likely to disengage in months 7-12 as were continuous engagers in months 0-6 (relative risk 1.76, 95% CI:1.61-1.91) and were more likely to have an unsuppressed viral load by 12 months on ART (RR = 1.28; 95% CI1.13-1.44). The needs of continuous and cyclical engagers and those disengaging at different timepoints may vary and require different interventions or models of care.

Background For patients on HIV treatment in sub-Saharan Africa, the highest risk for loss from care remains the first six months after antiretroviral (ART) initiation, when patients are not yet eligible for differentiated service delivery (DSD) models that offer lower-burden, patient-centred care and thus improve treatment outcomes. To reduce early disengagement from care, the PREFER study will use a sequential mixed-methods approach to describe the characteristics, needs, concerns, and preferences of patients in South Africa and Zambia 0-6 months after ART initiation or re-initiation. Protocol PREFER is an observational, prospective cohort study of adults on ART for ≤6 months at 12 public healthcare facilities in Zambia and 18 in South Africa. Its objective is to describe and understand the needs and preferences of initiating and re-initiating ART clients to inform the design of DSD models for the early HIV treatment period, improve early treatment outcomes, and distinguish the barriers encountered by naïve patients from those facing re-initiators. It has four components: 1) survey of clients 0-6 months after ART initiation (identify characteristics and preferences of clients starting ART); 2) follow up through routinely collected medical records for

Abstract Background Partner-delivered HIV self-testing kits has previously been highlighted as a safe, acceptable and effective approach to reach men. However, less is known about its real-world implementation in reaching partners of people living with HIV. We evaluated programmatic implementation of partner-delivered self-testing through antenatal care (ANC) attendees and people newly diagnosed with HIV by assessing use, positivity, linkage and cost per kit distributed. Methods Between April 2018 and December 2019, antenatal care (ANC) clinic attendees and people or those newly diagnosed with HIV clients across twelve clinics in three cities in South Africa were given HIVST kits (OraQuick Rapid HIV-1/2 Antibody Test, OraSure Technologies) to distribute to their sexual partners. A follow-up telephonic survey was administered to all prior consenting clients who were successfully reached by telephone to assess primary outcomes. Incremental economic costs of the implementation were estimated from the provider’s perspective. Results Fourteen thousand four hundred seventy-three HIVST kits were distributed – 10,319 (71%) to ANC clients for their male partner and 29% to people newly diagnosed with HIV for their partners. Of the 4,235 ANC clients successfully followed-up, 82.1% (3,475) reportedly offered HIVST kits to their male partner with 98.1% (3,409) accepting and 97.6% (3,328) using the kit. Among ANC partners self-testing, 159 (4.8%) reported reactive HIVST results, of which 127 (79.9%) received further testing; 116 (91.3%) were diagnosed with HIV and 114 (98.3%) initiated antiretroviral therapy (ART). Of the 1,649 people newly diagnosed with HIV successfully followed-up; 1,312 (79.6%) reportedly offered HIVST kits to their partners with 95.8% (1,257) of the partners accepting and 95.9% (1,206) reported that their partners used the kit. Among these index partners, 297 (24.6%) reported reactive HIVST results of which 261 (87.9%) received further testing; 260 (99.6%) were diagnosed with HIV and 258 (99.2%) initiated ART. The average cost per HIVST distributed in the three cities was US$7.90, US$11.98, and US$14.81, respectively. Conclusions Partner-delivered HIVST in real world implementation was able to affordably reach many male partners of ANC attendees and index partners of people newly diagnosed with HIV in South Africa. Given recent COVID-19 related restrictions, partner-delivered HIVST provides an important strategy to maintain essential testing services.

Providing HIV testing at health facilities remains the most common approach to ensuring access to HIV treatment and prevention services for the millions of undiagnosed HIV-infected individuals in sub-Saharan Africa. We sought to explore the costs of providing these services across three southern African countries with high HIV burden.Primary costing studies were undertaken in 54 health facilities providing HIV testing services (HTS) in Malawi, Zambia and Zimbabwe. Routinely collected monitoring and evaluation data for the health facilities were extracted to estimate the costs per individual tested and costs per HIV-positive individual identified. Costs are presented in 2016 US dollars. Sensitivity analysis explored key drivers of costs.Health facilities were testing on average 2290 individuals annually, albeit with wide variations. The mean cost per individual tested was US$5.03.9 in Malawi, US$4.24 in Zambia and US$8.79 in Zimbabwe. The mean cost per HIV-positive individual identified was US$79.58, US$73.63 and US$178.92 in Malawi, Zambia and Zimbabwe respectively. Both cost estimates were sensitive to scale of testing, facility staffing levels and the costs of HIV test kits.Health facility based HIV testing remains an essential service to meet HIV universal access goals. The low costs and potential for economies of scale suggests an opportunity for further scale-up. However low uptake in many settings suggests that demand creation or alternative testing models may be needed to achieve economies of scale and reach populations less willing to attend facility based services.

BackgroundSchistosomiasis is a common cause of pulmonary hypertension (PH) worldwide. Type 2 inflammation contributes to the development of Schistosoma-induced PH. Specifically, interstitial macrophages (IMs) derived from monocytes play a pivotal role by producing thrombospondin-1 (TSP-1), which in turn activates TGF-β, thereby driving the pathology of PH. Resident and recruited IM subpopulations have recently been identified. We hypothesized that in Schistosoma-PH, one IM subpopulation expresses monocyte recruitment factors, whereas recruited monocytes become a separate IM subpopulation that expresses TSP-1.MethodsMice were intraperitoneally sensitized and then intravenously challenged with S. mansoni eggs. Flow cytometry on lungs and blood was performed on wildtype and reporter mice to identify IM subpopulations and protein expression. Single-cell RNA sequencing (scRNAseq) was performed on flow-sorted IMs from unexposed and at day 1, 3 and 7 following Schistosoma exposure to complement flow cytometry based IM characterization and identify gene expression.ResultsFlow cytometry and scRNAseq both identified 3 IM subpopulations, characterized by CCR2, MHCII, and FOLR2 expression. Following Schistosoma exposure, the CCR2+ IM subpopulation expanded, suggestive of circulating monocyte recruitment. Schistosoma exposure caused increased monocyte-recruitment ligand CCL2 expression in the resident FOLR2+ IM subpopulation. In contrast, the vascular pathology-driving protein TSP-1 was greatest in the CCR2+ IM subpopulation.ConclusionSchistosoma-induced PH involves crosstalk between IM subpopulations, with increased expression of monocyte recruitment ligands by resident FOLR2+ IMs, and the recruitment of CCR2+ IMs which express TSP-1 that activates TGF-β and causes PH.

Abstract Whether all Schistosoma species cause pulmonary hypertension (PH) is unclear. Experimentally exposing mice to Schistosoma haematobium eggs caused PH, which was less severe than that induced by S. mansoni exposure. These findings align with the relatively uncommon reports of pulmonary arterial hypertension associated with S. haematobium.

Abstract Right ventricular (RV) failure is the primary cause of death in pulmonary hypertension (PH), but the mechanisms of RV failure are not well understood. We hypothesized macrophages in the RV contribute to the RV response in PH. We induced PH in mice with hypoxia (FiO2 10%) and Schistosoma mansoni exposure, and in rats with SU5416‐hypoxia. We quantified cardiac macrophages in mice using flow cytometry. Parabiosis between congenic CD45.1/.2 mice or Cx3cr1‐green fluorescent protein and wild‐type mice was used to quantify circulation‐derived macrophages in experimental PH conditions. We administered clodronate liposomes to Sugen hypoxia (SU‐Hx) exposed rats to deplete macrophages and evaluated the effect on the extracellular matrix (ECM) and capillary network in the RV. In hypoxia exposed mice, the overall number of macrophages did not significantly change but two macrophage subpopulations increased. Parabiosis identified populations of RV macrophages that at steady state is derived from the circulation, with one subpopulation that significantly increased with PH stimuli. Clodronate treatment of SU‐Hx rats resulted in a change in the RV ECM, without altering the RV vasculature, and correlated with improved RV function. Populations of RV macrophages increase and contribute to RV remodeling in PH, including through regulation of the RV ECM.

BackgroundSchistosomiasis, a major cause of pulmonary arterial hypertension (PAH) worldwide, is most clearly described complicating infection by one species, Schistosoma mansoni. Controlled exposure of mice can be used to induce Type 2 inflammation-dependent S. mansoni pulmonary hypertension (PH). We sought to determine if another common species, S. japonicum, can also cause experimental PH.MethodsSchistosome eggs were obtained from infected mice, and administered by intraperitoneal sensitization followed by intravenous challenge to experimental mice, which underwent right heart catheterization and tissue analysis.ResultsS. japonicum sensitized and challenged mice developed PH, which was milder than that following S. mansoni sensitization and challenge. The degree of pulmonary vascular remodeling and Type 2 inflammation in the lungs was similarly proportionate. Cross-sensitization revealed that antigens from either species are sufficient to sensitize for intravenous challenge with either egg, and the degree of PH severity depended on primarily the species used for intravenous challenge. Compared to a relatively uniform distribution of S. mansoni eggs, S. japonicum eggs were observed in clusters in the lungs.ConclusionsS. japonicum can induce experimental PH, which is milder than that resulting from comparable S. mansoni exposure. This difference may result from the distribution of eggs in the lungs, and is independent of which species is used for sensitization. This result is consistent with the clearer association between S. mansoni infection and the development of schistosomiasis-associated PAH in humans.

Patient‐derived samples present an advantage over current cell line models of high‐grade serous ovarian cancer (HGSOC) that are not always reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we set out to characterize a panel of patient‐derived cells and determine their epithelial and mesenchymal characteristics. We analyzed RNA and protein expression levels in patient‐derived xenograft (PDX) models of HGSOC, and functionally characterized these models using flow cytometry, wound healing assays, invasion assays, and spheroid cultures. Besides in vitro work, we also evaluated the growth characteristics of PDX in vivo (orthotopic PDX). We found that all samples had hybrid characteristics, covering a spectrum from an epithelial‐to‐mesenchymal state. Samples with a stronger epithelial phenotype were more active in self‐renewal assays and more tumorigenic in orthotopic xenograft models as compared to samples with a stronger mesenchymal phenotype, which were more migratory and invasive. Additionally, we observed an inverse association between microRNA let‐7 (lethal‐7) expression and stemness, consistent with the loss of let‐7 being an important component of the cancer stem cell phenotype. We observed that lower let‐7 levels were associated with the epithelial state and a lower epithelial mesenchymal transition (EMT) score, more efficient spheroid and tumor formation, and increased sensitivity to platinum‐based chemotherapy. Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: Cells with lower let‐7 levels were more tumorigenic, but less migratory, and with a lower EMT score, than those with higher let‐7 levels. We conclude that let‐7 expression and epithelial/mesenchymal state are valuable predictors of HGSOC proliferation, in vitro self‐renewal, and tumor burden in vivo.

We describe a rare case of intramammary lymphadenopathy due to Kikuchi-Fujimoto disease. A 15-year old female presented to the Breast Clinic with complaints of a tender, palpable right breast lump. An ultrasound of the area of concern demonstrated an enlarged 2.9 cm intramammary lymph node with preservation of the fatty hilum. An ultrasound guided core biopsy of the lymph node confirmed the diagnosis of Kikuchi-Fujimoto disease.

Thrombospondin-1 (TSP-1) activates latent TGF-β in the extracellular matrix. Here the authors show that inappropriate activation of latent TGF-β in murine, bovine and human lung by monocyte-produced TSP-1 causes pulmonary hypertension, and that interference with the activation process prevents disease development.

Background Inflammation underlies many forms of pulmonary hypertension (PH), including that resulting from Schistosoma infection, a major cause of PH worldwide. Schistosomiasis‐associated PH is proximately triggered by embolization of parasite eggs into the lungs, resulting in localized type 2 inflammation. However, the role of CD4+ T cells in this disease is not well defined. Methods and Results We used a mouse model of schistosomiasis‐associated PH, induced by intraperitoneal egg sensitization followed by intravenous egg challenge, with outcomes including right ventricle systolic pressure measured by cardiac catheterization, and cell density and phenotype assessed by flow cytometry. We identified that embolization of Schistosoma eggs into lungs of egg‐sensitized mice increased the perivascular density of T‐helper 2 (Th2) CD4+ T cells by recruitment of cells from the circulation and triggered type 2 inflammation. Parabiosis confirmed that egg embolization is required for localized type 2 immunity. We found Th2 CD4+ T cells were necessary for Schistosoma‐induced PH, given that deletion of CD4+ T cells or inhibiting their Th2 function protected against type 2 inflammation and PH following Schistosoma exposure. We also observed that adoptive transfer of Schistosoma‐sensitized CD4+ Th2 cells was sufficient to drive type 2 inflammation and PH. Conclusions Th2 CD4+ T cells are a necessary and sufficient component for the type 2 inflammation‐induced PH following Schistosoma exposure.

OBJECTIVES/GOALS: A workflow management tool is essential in order to help support consistent processes with transparency in next steps of the study process. Prior to this tool, staff has relied upon extensive training and coaching on the study process. While resources and guidelines exist, it requires additional time for staff to identify these resources and allows for confusion and rework. Implementation of a systematic workflow management tool was identified as a critical need in order to support streamlined processes, improve transparency and support business continuity, and to accelerate the study process. METHODS/STUDY POPULATION: This effort was undertaken as part of the Protocol Lifecycle Management effort to implement a comprehensive clinical trial management system for clinical research studies. Mayo Clinic has designed a workflow management tool within the Velos eResearch system. The workflow manager is dynamic and will present specific activities based on the study design and responses to data entered on the ad hoc forms. A Workflow Build group contributed to the design of the workflow in order to reflect appropriate, current operational processes. The workflow was vetted and validated with research teams. In addition to designing activities, planned dates and target timelines were established for relevant workflows to help promote transparency in the study start-up timelines and allow study staff to identify overdue activities. Study status controls were designed in the workflow to protect study staff from inadvertently changing the status until appropriate activities are complete. RESULTS/ANTICIPATED RESULTS: A dynamic workflow has been designed and implemented in the Velos eResearch system to support Mayo Clinic research sites. This system will be implemented February 24, 2020 to all consenting studies. DISCUSSION/SIGNIFICANCE OF IMPACT: The implementation of this workflow management tool is critical to help support research operations in a large, academic medical center. Benefits to implementation are expected to include improved transparency in the study status and next steps, reductions in rework due to confusion in next steps, better understanding from new staff in the appropriate study process, and improved timelines for study start-up. As we prepare for the implementation of the Velos eResearch system at Mayo Clinic, the workflow management tool has been identified in training sessions as a positive benefit.

Schistosomiasis is a leading cause of pulmonary hypertension (PH) worldwide. Recent studies reveal that the type-2 immune cytokines IL-4 and IL-13, as well as consequent activation of TGF-β, are key factors in the pathogenesis of Schistosoma -PH. Paclitaxel has been reported to act as an adjuvant for Th2 inflammation while downregulating TGF-β activation. Moreover, paclitaxel blocks PH in monocrotaline and SU5416-hypoxia models. We hypothesized that paclitaxel would augment Th2 inflammation while blocking TGF-β activation and PH after schistosomiasis exposure. Wild-type mice (C57BL6/J; 6/group) were intraperitoneally (IP) sensitized and then intravenously (IV) challenged with Schistosoma mansoni eggs. One day after IV egg challenge, the mice were treated with a single IP dose of 25 mg/kg paclitaxel or vehicle. Right ventricular (RV) catheterization was performed and granuloma volumes and vascular remodeling were quantified. Lung cytokines were quantified by ELISA and reverse transcription polymerase chain reaction, and the quantity of active TGF-β was determined using a cell reporter line. We also investigated hypoxia-induced PH. Paclitaxel treatment significantly protected mice from Schistosoma -PH, with decreased RV systolic pressure ( P = 0.005) and pulmonary vascular media thickness. Inflammation was significantly suppressed, contrary to our hypothesis, with decreased IL-4 and IL-13 levels, smaller granulomas, and less active TGF-β following paclitaxel treatment. There was no change in IFN-γ or FoxO1 or FoxO3 expression. Paclitaxel did not suppress chronic hypoxia-induced PH, which is also TGF-β-driven but independent of type-2 immunity. Paclitaxel protects against Schistosoma -induced PH in mice, although by blocking proximate Th2 inflammation rather than suppressing distal TGF-β activation.

El concepto de entorno personal se refiere a los sistemas que facilitan a los aprendices a tomar control de manera autónoma de sus aprendizajes. Esto incluye apoyos para determinar sus propias metas, comprensión de contenidos y de los procesos implicados en el proceso de aprendizaje. Usualmente el mayor impulso se ofrece en torno a las nuevas tecnologías, ya que se supone que el alumno es capaz de interactuar de manera efectiva con los lenguajes y entornos tecnológicos, pues más jóvenes las generaciones, más conocimiento tienen del uso y manejo de la información en medios digitales. Partir de este supuesto, y suponer que el alumno es capaz por sí mismo de encontrar su propio camino, lleva a mucha frustración, especialmente cuando se considera como factor clave las diferencias culturales. El presente trabajo busca reconocer que existen diferencias culturales en el manejo de herramientas que se consideran usuales como las redes sociales para desarrollar propuestas académicas que permitan apoyar el aprendizaje de los estudiantes y se encuentra que existen factores que pueden potencialmente beneficiar o entorpecer el desarrollo académico de los estudiantes si estas no son consideradas en los programas educativos. Reconocer dichas diferencias es clave para trabajar en programas de apoyo a los estudiantes, pues una vez que éstos reconocen sus potencialidades y son capaces de generar las estrategias adecuadas a los requerimientos de las nuevas tecnologías, serán más eficientes en su aprendizaje.

Bacterial infection of lung airways underlies some of the main complications of COPD, significantly impacting disease progression and outcome. Colonization by bacteria may further synergize, amplify, or trigger pathways of tissue damage started by cigarette smoke, contributing to the characteristic airway inflammation and alveolar destruction of COPD. We sought to elucidate the presence and types of lung bacterial populations in different stages of COPD, aimed at revealing important insights into the pathobiology of the disease. Sequencing of the bacterial small subunit ribosomal RNA gene in 55 well-characterized clinical lung samples, revealed the presence of Novosphingobium spp. (>2% abundance) in lungs of patients with GOLD 3-GOLD 4 COPD, cystic fibrosis and a subset of control individuals. Novosphingobium-specific quantitative PCR was concordant with the sequence data and high levels of Novosphingobium spp. were quantifiable in advanced COPD, but not from other disease stages. Using a mouse model of subacute lung injury due to inhalation of cigarette smoke, bronchoalveolar lavage neutrophil and macrophage counts were significantly higher in mice challenged intratracheally with N. panipatense compared to control mice (p

This article examines the courtroom as a workplace using Brown and Levinson's politeness model. It is argued that while the model is a valuable tool for analyzing courtroom discourse, the courtroom, as well as institutional and organizational contexts in general, possesses characteristics that demand a more complex contextual analysis. The article first looks at some of the distinct characteristics of language use in a courtroom setting, and then analyzes excerpts drawn from a courtroom transcript. Institutional factors that affect the model's performance in this workplace are delineated. The article concludes that these institutional factors are not unique to the courtroom; they are relevant to understanding language use in many types of workplace, including corporate, public, and organizational contexts.