Evaluation of Community-Based, Mobile HIV-Care, Peer-Delivered Linkage Case Management in Manzini Region, Eswatini.

The success of antiretroviral therapy (ART) requires continuous engagement in care and optimal levels of adherence to achieve sustained HIV viral suppression. We evaluated HIV-care cascade costs and outcomes of a community-based, mobile HIV-care, peer-delivered linkage case-management program (CommLink) implemented in Manzini region, Eswatini. Abstraction teams visited referral facilities during July 2019-April 2020 to locate, match, and abstract the clinical data of CommLink clients diagnosed between March 2016 and March 2018. An ingredients-based costing approach was used to assess economic costs associated with CommLink. The estimated total CommLink costs were $2 million. Personnel costs were the dominant component, followed by travel, commodities and supplies, and training. Costs per client tested positive were $499. Costs per client initiated on ART within 7, 30, and 90 days of diagnosis were $2114, $1634, and $1480, respectively. Costs per client initiated and retained on ART 6, 12, and 18 months after diagnosis were $2343, $2378, and $2462, respectively. CommLink outcomes and costs can help inform community-based HIV testing, linkage, and retention programs in other settings to strengthen effectiveness and improve efficiency.

Strengthening measurement and performance of HIV prevention programmes.

Indicators for the measurement of programmes for the primary prevention of HIV are less aligned than indicators for HIV treatment, which results in a high burden of data collection, often without a clear vision for its use. As new evidence becomes available, the opportunity arises to critically evaluate the way countries and global bodies monitor HIV prevention programmes by incorporating emerging data on the strength of the evidence linking various factors with HIV acquisition, and by working to streamline indicators across stakeholders to reduce burdens on health-care systems. Programmes are also using new approaches, such as targeting specific sexual networks that might require non-traditional approaches to measurement. Technological advances can support these new directions and provide opportunities to use real-time analytics and new data sources to more effectively understand and adapt HIV prevention programmes to reflect population movement, risks, and an evolving epidemic.

Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis.

Oro-facial fibrosis in systemic sclerosis (Scleroderma;SSc) has a major impact on mouth function, facial appearance, and patient quality of life. Lipotransfer is a method of reconstruction that can be used in the treatment of oro-facial fibrosis. The effect of this treatment not only restores oro-facial volume but has also been found to reverse the effects of oro-facial fibrosis. Adipose derived stem cells (ADSCs) within the engrafted adipose tissue have been shown to be anti-fibrotic in SSc and are proposed as the mechanism of the anti-fibrotic effect of lipotransfer. A cohort of 62 SSc patients with oro-facial fibrosis were assessed before and after stem cell enriched lipotransfer treatment. Clinical evaluation included assessment of mouth function using a validated assessment tool (Mouth Handicap in Systemic Sclerosis Scale-MHISS), validated psychological measurements and pre and post-operative volumetric assessment. In addition, to understand the mechanism by which the anti-fibrotic effect of ADSCs occur, SSc derived fibroblasts and ADSCs from this cohort of patients were co-cultured in direct and indirect culture systems and compared to monoculture controls. Cell viability, DNA content, protein secretion of known fibrotic mediators including growth factor- ß1 (TGF ß-1) and connective tissue growth factor (CTGF) using ELISA analysis and fibrosis gene expression using a fibrosis pathway specific qPCR array were evaluated. Mouth function (MHISS) was significantly improved (6.85±5.07) (p<0.0001) after treatment. All psychological measures were significantly improved: DAS 24 (12.1±9.5) (p<0.0001); HADS-anxiety (2.8±3.2) (p<0.0001), HADS-depression (2.0±3.1) (p<0.0001); BFNE (2.9 ± 4.3) (p<0.0001); VAS (3.56±4.1) (p<0.0001). Multiple treatments further improved mouth function (p<0.05), DAS (p<0.0001) and VAS (p = 0.01) scores. SSc fibroblast viability and proliferation was significantly reduced in co-culture compared to monoculture via a paracrine effect over 14 days (p < 0.0001). Protein secretion of transforming growth factor (TGF-ß1) and connective tissue growth factor (CTGF) was significantly reduced in co-culture compared to monoculture (p < 0.0001). Multiple fibrosis associated genes were down regulated in SSc co-culture compared to monoculture after 14 days including Matrix metalloproteinase-8 (MMMP-8), Platelet derived growth factor-ß (PDGF-ß) and Integrin Subunit Beta 6 (ITG-ß6). Autologous stem cell enriched lipotransfer significantly improved the effects of oro-facial fibrosis in SSc in this open cohort study. Lipotransfer may reduce dermal fibrosis through the suppression of fibroblast proliferation and key regulators of fibrogenesis including TG-ß1 and CTGF. Our findings warrant further investigation in a randomised controlled trial.

Characteristics of human adipose derived stem cells in scleroderma in comparison to sex and age matched normal controls: implications for regenerative medicine.

BACKGROUND: Adipose-derived stem cells (ADSCs) are emerging as an alternative stem cell source for cell-based therapies. Recent data suggest that autologous ADSC-enriched micrografting improves the effects of facial involvement in systemic sclerosis (SSc). We have extensively characterised ADSCs from SSc patients and compared their phenotype and function to healthy age- and sex-matched control ADSCs. METHODS: ADSCs were isolated and characterised from a cohort of six SSc patients (ADSC-SSc) and were compared to six healthy age- and sex-matched controls (ADSC-N). Cell surface phenotype lineage commitment was explored by flow cytometric analysis of mesenchymal and hematopoietic markers and by the capacity to differentiate to chondrogenic, osteogenic, and adipogenic lineages. Functional activities of ADSCs were assessed by biochemical and cellular assays for proliferation, metabolism, adhesion, morphology, migration, and invasion. RESULTS: Upon characterization of ADSC-SSc, we found that there was no alteration in the phenotype or surface antigen expression compared to healthy matched control ADSCs. We found that the differentiation capacity of ADSC-SSc was equivalent to that of ADSC-N, and that ADSC-SSc did not display any morphological or adhesive abnormalities. We found that the proliferation rate and metabolic activity of ADSC-SSc was reduced (p < 0.01). We found that the migration and invasion capacity of ADSC-SSc was reduced (p < 0.01) compared to healthy matched control ADSCs. CONCLUSIONS: This study provides important findings that can differentially characterise ADSCs from SSc patients. Results indicate that the surface phenotype and differentiation capacity of ADSCs from SSc patients are identical to healthy matched ADSCs. While the findings indicate that the proliferation and migration capacity of ADSC-SSc is reduced, ADSC-SSc are capable of ex-vivo culture and expansion. These findings encourage further investigation into the understanding by which ADSCs can impact upon tissue fibrosis.

Flavanol concentrations do not predict dipeptidyl peptidase-IV inhibitory activities of four cocoas with different processing histories.

Cocoa and its constituent bioactives (particularly flavanols) have reported anti-diabetic and anti-obesity activities. One potential mechanism of action is inhibition of dipeptidyl peptidase-IV (DPP4), the enzyme that inactivates incretin hormones such as glucagon-like peptide-1 and gastric inhibitory peptide. The objective of this study was to determine the DPP4 inhibitory activities of cocoas with different processing histories, and identify processing factors and bioactive compounds that predict DPP4 inhibition. IC25 values (µg mL-1) were 4.82 for Diprotin A (positive control), 2135 for fermented bean extract, 1585 for unfermented bean extract, 2871 for unfermented liquor extract, and 1076 for fermented liquor extract This suggests mild inhibitory activity. Surprisingly, protein binding activity, total polyphenol, total flavanol, individual flavanol and complex fermentation/roasting product levels were all positively correlated to IC25 concentrations (greater levels correspond to less potent inhibition). For the representative samples studied, fermentation appeared to improve inhibition. This study suggests that cocoa may possess mild DPP4 inhibitory activity, and that processing steps such as fermentation may actually enhance activity. Furthermore, this activity and the variation between samples were not easily explainable by traditional putative bioactives in cocoa. The compounds driving this activity, and the associated mechanism(s) by which this inhibition occurs, remain to be elucidated.

Cranberry extract attenuates hepatic inflammation in high-fat-fed obese mice.

Cranberry (Vaccinium macrocarpon) consumption has been associated with health beneficial effects. Nonalcoholic fatty liver disease (NAFLD) is a comorbidity of obesity. In the present study, we investigated the effect of a polyphenol-rich cranberry extract (CBE) on hepatic inflammation in high fat (HF)-fed obese C57BL/6J mice. Following dietary treatment with 0.8% CBE for 10 weeks, we observed no change in body weight or visceral fat mass in CBE-supplemented mice compared to HF-fed control mice. We did observe a significant decrease in plasma alanine aminotransferase (31%) and histological severity of NAFLD (33% decrease in area of involvement, 29% decrease in lipid droplet size) compared to HF-fed controls. Hepatic protein levels of tumor necrosis factor α and C-C chemokine ligand 2 were reduced by 28% and 19%, respectively, following CBE supplementation. CBE significantly decreased hepatic mRNA levels of toll-like receptor 4 (TLR4, 63%) and nuclear factor κB (NFκB, 24%), as well as a number of genes related to the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3 inflammasome. In conclusion, CBE reduced NAFLD and hepatic inflammation in HF-fed obese C57BL/6J mice. These effects appear to be related to mitigation of TLR4-NFκB related signaling; however, further studies into the underlying mechanisms of these hepatoprotective effects are needed.

Management of patients treated with pertuzumab in the Australian clinical practice setting.

AIM: Treatment with pertuzumab-trastuzumab-taxane combinations has become the international standard of care for patients with HER2-positive metastatic breast cancer. In this paper we discuss the practicalities of treating patients with this combination with a particular focus on treatment in the Australian setting. METHOD: An expert panel was convened to discuss practical aspects for use of pertuzumab in the Australian clinical setting. The findings of this panel are reported in this article. RESULTS: The combination of pertuzumab-trastuzumab-docetaxel has established efficacy in patients with HER2-positive metastatic breast cancer, prolonging progression-free and overall survival compared to trastuzumab-taxane combinations. In Australia, combinations of pertuzumab and trastuzumab with docetaxel or paclitaxel are reimbursed. Management of treatment related side-effects such as diarrhea, febrile neutropenia and neuropathy typically include dose reduction or switching taxane. Specific patients with poorer tolerance of chemotherapy such as the elderly or those from Asian backgrounds may require particular management strategies. CONCLUSIONS: The advent of targeted therapies for women with metastatic HER2-positive breast cancer has markedly improved survival. Combinations of pertuzumab-trastuzumab and a taxane are the standard of care in patients with good performance status. Given prolongation of survival and the importance of quality of life endpoints, the treatment paradigm for patients with metastatic HER2-positive breast cancer is changing rapidly. Careful management of toxicities is required, and dose reduction or switching taxane may be necessary. Further research is required on the efficacy of pertuzumab combinations in patients with brain metastases, and on those who relapse quickly following adjuvant therapy.

Loss of Native Flavanols during Fermentation and Roasting Does Not Necessarily Reduce Digestive Enzyme-Inhibiting Bioactivities of Cocoa.

Polyphenol profiles and in vitro digestive enzyme inhibitory activities were compared between cocoa extracts from unfermented beans (UB), fermented beans (FB), unfermented liquor (UL), and fermented liquor (FL). Total polyphenols, total flavanols, and individual flavanols were significantly different between UB/FB and UL/FL. All extracts effectively inhibited α-glucosidase (lowest IC50 = 90.0 µg/mL, UL) and moderately inhibited α-amylase (lowest IC50 = 183 µg/mL, FL) and lipase (lowest IC25 = 65.5 µg/mL, FB). Our data suggest that fermentation does not reduce α-glucosidase inhibition, while roasting may enhance inhibition. For α-amylase, both fermentation and roasting improved inhibition. Finally, for lipase, both fermentation and roasting attenuated inhibition. Conclusive correlations between inhibition and mDP, total polyphenol, and flavanol contents were not found. Our data suggest that enzyme inhibition activities of cocoa are not uniformly reduced by polyphenol/flavanol losses during fermentation and roasting. This paradigm-challenging finding suggests other cocoa constituents, potentially formed during processing, contribute to digestive enzyme inhibition.

ROCK activity and the Gßγ complex mediate chemotactic migration of mouse bone marrow-derived stromal cells.

INTRODUCTION: Bone marrow-derived stromal cells (BMSCs), also known as mesenchymal stem cells, are the focus of intensive efforts worldwide to elucidate their function and biology. Despite the importance of BMSC migration for their potential therapeutic uses, the mechanisms and signalling governing stem cell migration are still not fully elucidated. METHODS: We investigated and detailed the effects of MCP-1 activation on BMSCs by using inhibitors of G protein-coupled receptor alpha beta (GPCR αß), ROCK (Rho-associated, coiled-coil containing protein kinase), and PI3 kinase (PI3K). The effects of MCP-1 stimulation on intracellular signalling cascades were characterised by using immunoblotting and immunofluorescence. The effectors of MCP-1-mediated migration were investigated by using migration assays (both two-dimensional and three-dimensional) in combination with inhibitors. RESULTS: We established the kinetics of the MCP-1-activated signalling cascade and show that this cascade correlates with cell surface re-localisation of chemokine (C motif) receptor 2 (CCR2) (the MCP-1 receptor) to the cell periphery following MCP-1 stimulation. We show that MCP-1-initiated signalling is dependent on the activation of ßγ subunits from the GPCR αßγ complex. In addition, we characterise a novel role for PI3Kγ signalling for the activation of both PAK and ERK following MCP-1 stimulation. We present evidence that the Gßγ complex is responsible for PI3K/Akt, PAK, and ERK signalling induced by MCP-1 in BMSCs. Importantly, we found that, in BMSCs, inhibition of ROCK significantly inhibits MCP-1-induced chemotactic migration, in contrast to previous reports in other systems. CONCLUSIONS: Our results indicate differential chemotactic signalling in mouse BMSCs, which has important implications for the translation of in vivo mouse model findings into human trials. We identified novel components and interactions activated by MCP-1-mediated signalling, which are important for stem cell migration. This work has identified additional potential therapeutic targets that could be manipulated to improve BMSC delivery and homing.

Prevention of sexually transmitted HIV infections through the President's Emergency Plan for AIDS Relief: a history of achievements and lessons learned.

HIV prevention in the President's Emergency Plan for AIDS Relief (PEPFAR) began when both data on HIV prevalence and the toolbox of interventions for prevention of sexual transmission were relatively limited. PEPFAR's early focus was on scaling-up information, education, and communication programs that included messaging on abstinence for youth and faithfulness primarily through nongovernmental organizations, including faith-based organizations. Additional activities included condom promotion, distribution, and social marketing. In epidemics concentrated within key populations, PEPFAR's prevention efforts focused on a minimum package of services including outreach, information, education, and communication programs, STI treatment (where appropriate), and condom promotion and distribution. As more epidemiological data became available and with experience gleaned in these early efforts, the need for tailored and flexible approaches became evident. The next iteration of prevention efforts still emphasized behavioral interventions, but incorporated a sharper focus on key epidemic drivers, especially multiple partners; a data-driven emphasis on high transmission areas and populations, including prevention with people living with HIV; and a more strategic and coordinated approach at the national level. Recently, the paradigm for prevention efforts has shifted yet again. Evidence that biomedical interventions such as male circumcision, treatment for prevention of vertical and horizontal transmission, and treatment itself could lead to declines in incidence has refocused PEPFAR's prevention portfolio. New guidance on sexually transmitted HIV focuses on combination prevention, emphasizing biomedical, behavioral and structural approaches. Landmark speeches by the President and the Secretary of State and new ambitious targets for PEPFAR point toward a new goal: an AIDS-free generation.

Voluntary medical male circumcision: an HIV prevention priority for PEPFAR.

As the science demonstrating strong evidence for voluntary medical male circumcision (VMMC) for HIV prevention has evolved, the President's Emergency Plan for AIDS Relief (PEPFAR) has collaborated with international agencies, donors, and partner country governments supporting VMMC programming. Mathematical models forecast that quickly reaching a large number of uncircumcised men with VMMC in strategically chosen populations may dramatically reduce community-level HIV incidence and save billions of dollars in HIV care and treatment costs. Because VMMC is a 1-time procedure that confers life-long partial protection against HIV, programs for adult men are vital short-term investments with long-term benefits. VMMC also provides a unique opportunity to reach boys and men with HIV testing and counseling services and referrals for other HIV services, including treatment. After formal recommendations by WHO in 2007, priority countries have pursued expansion of VMMC. More than 1 million males have received VMMC thus far, with the most notable successes coming from Kenya's Nyanza Province. However, a myriad of necessary cultural, political, and ethical considerations have moderated the pace of overall success. Because many millions more uncircumcised men would benefit from VMMC services now, US President Barack Obama committed PEPFAR to provide 4.7 million males with VMMC by 2014. Innovative circumcision methods-such as medical devices that remove the foreskin without injected anesthesia and/or sutures-are being rigorously evaluated. Incorporation of safe innovations into surgical VMMC programs may provide the opportunity to reach more men more quickly with services and dramatically reduce HIV incidence for all.

Voluntary medical male circumcision: a framework analysis of policy and program implementation in eastern and southern Africa.

BACKGROUND: Following confirmation of the effectiveness of voluntary medical male circumcision (VMMC) for HIV prevention, the World Health Organization and the Joint United Nations Programme on HIV/AIDS issued recommendations in 2007. Less than 5 y later, priority countries are at different stages of program scale-up. This paper analyzes the progress towards the scale-up of VMMC programs. It analyzes the adoption of VMMC as an additional HIV prevention strategy and explores the factors may have expedited or hindered the adoption of policies and initial program implementation in priority countries to date. METHODS AND FINDINGS: VMMCs performed in priority countries between 2008 and 2010 were recorded and used to classify countries into five adopter categories according to the Diffusion of Innovations framework. The main predictors of VMMC program adoption were determined and factors influencing subsequent scale-up explored. By the end of 2010, over 550,000 VMMCs had been performed, representing approximately 3% of the target coverage level in priority countries. The "early adopter" countries developed national VMMC policies and initiated VMMC program implementation soon after the release of the WHO recommendations. However, based on modeling using the Decision Makers' Program Planning Tool (DMPPT), only Kenya appears to be on track towards achievement of the DMPPT-estimated 80% coverage goal by 2015, having already achieved 61.5% of the DMPPT target. None of the other countries appear to be on track to achieve their targets. Potential predicators of early adoption of male circumcision programs include having a VMMC focal person, establishing a national policy, having an operational strategy, and the establishment of a pilot program. CONCLUSIONS: Early adoption of VMMC policies did not necessarily result in rapid program scale-up. A key lesson is the importance of not only being ready to adopt a new intervention but also ensuring that factors critical to supporting and accelerating scale-up are incorporated into the program. The most successful program had country ownership and sustained leadership to translate research into a national policy and program. Please see later in the article for the Editors' Summary.

Proximal esophageal amyloidoma presenting with life-threatening dysphagia.

Amyloidoses are abnormal deposits of insoluble proteins in tissues that can lead to tissue dysfunction. Although elderly patients often have amyloid deposition in the gastrointestinal tract, they are usually asymptomatic. When symptoms are present, they are most often functional in nature; rarely are they caused by a localized amyloid deposition (amyloidoma). We report the case of an elderly man who presented with severe dysphagia secondary to an upper esophageal amyloidoma. Unfortunately, the patient died of his disease before management could be instituted.

Assessment of the routine, occupation-based gonorrhea and syphilis screening program in Moscow, Russia: an analysis of sexually transmitted infection prevalence and cost-effectiveness.

OBJECTIVES: In the Russian Federation, large sectors of the population regularly undergo mandatory occupational screening for sexually transmitted infections (STIs). Objectives of our study were to determine the prevalence of syphilis and gonorrhea in the screened occupational groups in Moscow and to conduct a cost-effectiveness evaluation of the occupational screening program. STUDY DESIGN: Serum samples from 4 main occupational groups (food handlers and other food industry workers, market salespersons, education and health care providers, and hotel and other public utility workers) were tested for syphilis and gonorrhea. We conducted a cost-effectiveness analysis (in 2003 rubles) of the screening program using decision analysis models. RESULTS: In the total sample of 1000 study participants, overall prevalence for syphilis was 1.2% with the highest rate in market salespersons (4.4%) and for gonorrhea 0.3%. The incremental cost per case of STI treated was 8409 rubles ($252) for syphilis screening (compared with no screening) with higher incremental costs associated with expanding the program to include gonorrhea screening. The relatively low STI prevalence in the screened groups and the poor performance of the diagnostic tests used were important factors in the estimated cost-effectiveness of occupation-based screening. CONCLUSIONS: Modifications to occupation-based screening, including an increased focus on higher risk population and the adoption of more current diagnostic technologies, could help to use prevention resources more effectively.

On-site rapid antenatal syphilis screening with an immunochromatographic strip improves case detection and treatment in rural South African clinics.

OBJECTIVES: Congenital syphilis is a significant cause of adverse pregnancy outcomes. In South Africa, rural clinics perform antenatal screening offsite, but unreliable transport and poor client follow up impede effective treatment. We compared 3 syphilis screening strategies at rural clinics: on-site rapid plasma reagin (RPR), on-site treponemal immunochromatographic strip (ICS) test, and the standard practice offsite RPR with Treponema pallidum hemagglutination assay (RPR/TPHA). METHODS: Eight rural clinics performed the on-site RPR and ICS tests and provided immediate treatment. Results were compared with RPR/TPHA at a reference laboratory. Chart reviews at 8 standard practice clinics established diagnosis and treatment rates for offsite RPR/TPHA. FINDINGS: Seventy-nine (6.3%) of 1,250 women screened on-site had active syphilis according to the reference laboratory. The on-site ICS resulted in the highest percentage of pregnant women correctly diagnosed and treated for syphilis (89.4% ICS, 63.9% on-site RPR, 60.8% offsite RPR/TPHA). The on-site RPR had low sensitivity (71.4% for high-titer syphilis). The offsite approach suffered from poor client return rates. One percent of women screened with the ICS may have received penicillin unnecessarily. There were no adverse treatment outcomes. CONCLUSIONS: The on-site ICS test can reduce syphilis-related adverse outcomes of pregnancy through accurate diagnosis and immediate treatment of pregnant women with syphilis.

Role of screening for infectious mononucleosis in patients admitted with isolated, unilateral peritonsillar abscess.

Two hundred and four cases of in-patient admission with isolated, unilateral peritonsillar abscess over the three-year period 1999-2001 were reviewed retrospectively. One hundred and fifty-one patients had been screened for infectious mononucleosis (IM) using the heterophile antibody screening test. Of these 142 (94 per cent) tested negative and nine (six per cent) positive. There were no IM-typical clinical or haematological signs in any of the IM positive patients to facilitate the prediction of the diagnosis. Due to the comparatively high prevalence of positives, the low cost of screening, the lack of predictive signs and the diversity of potential complications of IM, routine screening in all patients presenting with peritonsillar abscess is recommended.