Identifying efficient linkage strategies for men (IDEaL): a study protocol for an individually randomised control trial.

INTRODUCTION: Men in sub-Saharan Africa are less likely than women to initiate antiretroviral therapy (ART) and more likely to have longer cycles of disengagement from ART programmes. Treatment interventions that meet the unique needs of men are needed, but they must be scalable. We will test the impact of various interventions on 6-month retention in ART programmes among men living with HIV who are not currently engaged in care (never initiated ART and ART clients with treatment interruption). METHODS AND ANALYSIS: We will conduct a programmatic, individually randomised, non-blinded, controlled trial. 'Non-engaged' men will be randomised 1:1:1 to either a low-intensity, high-intensity or stepped arm. The low-intensity intervention includes one-time male-specific counseling+facility navigation only. The high-intensity intervention offers immediate outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. In the stepped arm, intervention activities build in intensity over time for those who do not re-engage in care with the following steps: (1) one-time male-specific counselling+facility navigation→(2) ongoing male mentorship+facility navigation→(3) outside-facility ART initiation+male-specific counselling+facility navigation for follow-up ART visits. Our primary outcome is 6-month retention in care. Secondary outcomes include cost-effectiveness and rates of adverse events. The primary analysis will be intention to treat with all eligible men in the denominator and all men retained in care at 6 months in the numerator. The proportions achieving the primary outcome will be compared with a risk ratio, corresponding 95% CI and p value computed using binomial regression accounting for clustering at facility level. ETHICS AND DISSEMINATION: The Institutional Review Board of the University of California, Los Angeles and the National Health Sciences Research Council in Malawi have approved the trial protocol. Findings will be disseminated rapidly in national and international forums and in peer-reviewed journals and are expected to provide urgently needed information to other countries and donors. TRIAL REGISTRATION NUMBER: NCT05137210. DATE AND VERSION: 5 May 2023; version 3.

Linkage to HIV Care Following HIV Self-testing Among Men: Systematic Review of Quantitative and Qualitative Studies from Six Countries in Sub-Saharan Africa.

Gender disparities are pervasive throughout the HIV care continuum in sub-Saharan Africa, with men testing, receiving treatment, and achieving viral suppression at lower rates, and experiencing mortality at higher rates, compared with women. HIV self-testing (HIVST) has been shown to be highly acceptable among men in sub-Saharan Africa. However, evidence on linkage to HIV care following a reactive HIVST result is limited. In this systematic review, we aimed to synthesize the quantitative and qualitative literature from sub-Saharan Africa on men's rates of linkage to HIV care after receiving a reactive HIVST result. We systematically searched 14 bibliometric databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram was used to document the screening results. The Mixed Methods Appraisal Tool (MMAT) was used to assess the methodological quality of the included studies. Of 22,446 references screened, 15 articles were eligible for inclusion in this review. Linkage to HIV care following a reactive HIVST result was subject to several barriers: financial constraints due to travelling costs, potential long waiting hours at the clinics, stigma, discrimination, and privacy concerns. Men's rates of seeking confirmatory testing and linking to HIV care following a reactive HIVST result were inconsistent across studies. Combining financial incentives with HIVST was found to increase the likelihood of linking to HIV care following a reactive HIVST result. The variable rates of linkage to HIV care following a reactive HIVST result suggest a need for further research and development into strategies to increase linkage to HIV care.

Future imaging modalities for the assessment of pancreas allografts a scan of the horizon.

Pancreas transplantation (PT) allows improved glycaemic control for patients with complicated type 1 diabetes mellitus and is most commonly performed simultaneously with a renal transplant. Imaging modalities are critical for the assessment of pancreatic graft dysfunction, as clinical assessment and hyperglycaemia lack robust sensitivity for the transplant clinician. Biopsy represents the most conclusive standard of PT graft assessment but is challenging due to its invasive nature and the potential morbidity associated with the procedure. Innovative imaging technologies offer the opportunity to apply these modalities to improve PT outcomes while using non-invasive technologies to provide a diagnostic sensitivity that traditionally only biopsies can provide. Early graft dysfunction has traditionally been investigated with Computed tomography (CT) and ultrasound (US) scans. We explore adjuncts to these modalities including the application of contrast enhanced ultrasound (CEUS) for routine post-operative graft assessment to inform post-operative treatment strategies. There is currently a dearth of imaging modalities to reliably monitor long term graft function, but the use of innovative functional imaging techniques and how they can be applied to PT is discussed. Perfusion CT and glucose stimulated magnetic resonance imaging (MRI) to detect whole organ function are examined. In addition, early phase developments in beta-cell specific imaging methods to quantify beta-cell mass longitudinally are described. The clinical applications of such tools including Mn2+-enhanced MR and GLP-1R targeted PET/CT are reviewed and may demonstrate opportunities to provide the transplant clinician with greater information to support improved patient care.

The HPK1 Inhibitor A-745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy.

Hematopoietic progenitor kinase 1 (HPK1) is an MAP4K family member within the Ste20-like serine/threonine branch of the kinome. HPK1 expression is limited to hematopoietic cells and has a predominant role as a negative regulator of T cell function. Because of the central/dominant role in negatively regulating T cell function, HPK1 has long been in the center of interest as a potential pharmacological target for immune therapy. The development of a small molecule HPK1 inhibitor remains challenging because of the need for high specificity relative to other kinases, including additional MAP4K family members, that are required for efficient immune cell activation. Here, we report the identification of the selective and potent HPK1 chemical probe, A-745. In unbiased cellular kinase-binding assays, A-745 demonstrates an excellent cellular selectivity binding profile within pharmacologically relevant concentrations. This HPK1 selectivity translates to an in vitro immune cell activation phenotype reminiscent of Hpk1-deficient and Hpk1-kinase-dead T cells, including augmented proliferation and cytokine production. The results from this work give a path forward for further developmental efforts to generate additional selective and potent small molecule HPK1 inhibitors with the pharmacological properties for immunotherapy.

Reaching for the 'first 95': a cross-country analysis of HIV self-testing in nine countries in sub-Saharan Africa.

OBJECTIVES: HIV self-testing (HIVST) offers a promising approach to increase HIV diagnosis and advance progress towards the UNAIDS 95-95-95 targets. We aimed to understand patterns of HIVST awareness and utilization in nine sub-Saharan African (SSA) countries, with the goal of identifying populations to target in disseminating this technology. DESIGN: A cross-sectional study. METHODS: We pooled individual-level population-based data from nine Demographic and Health Surveys (DHS) in SSA conducted 2015-2019 (Burundi, Cameroon, Guinea, Malawi, Senegal, Sierra Leone, South Africa, Zambia, Zimbabwe). Primary outcomes were HIVST awareness and utilization. We used logistic regression with survey fixed effects to explore the relationship between sociodemographic characteristics and these outcomes. Models were adjusted for sex, age, rural/urban residence, education, wealth, and marital status. We accounted for complex survey design. RESULTS: The study sample included 177 572 people (66.0% women, mean age 29 ±â€Š10 years), of whom 86.6% [95% confidence interval (95% CI) 86.4-86.7] were unaware of HIVST, 11.7% (95% CI 11.6-11.9) were aware of but never used HIVST, and 1.7% (95% CI 1.6-1.8) had used HIVST. In adjusted models, women were less likely to be aware of HIVST [odds ratio (OR) 0.75, 95% CI 0.71-0.79], but more likely to have used HIVST (OR 1.17, 95% CI 1.03-1.32) compared with men. Rural residents, those who were least educated, and poorest were less likely to have heard of or used HIVST. CONCLUSION: HIVST awareness and uptake were low. Rural, less educated, and lower income populations were least likely to have heard of or used HIVST. Efforts to scale-up HIVST in these settings should aim to reach these less advantaged groups.

Joint effect between bisphenol A and alcohol consumption on benign prostatic hyperplasia: A case-control study in Hong Kong Chinese males.

BACKGROUND: Whether bisphenol A (BPA) exposure is a contributing factor to benign prostatic hyperplasia (BPH) remains unclear. This study evaluated the association between chronic BPA exposure and BPH risk, and explored whether this association was modified by alcohol drinking. METHODS: This study included a total of 650 BPH cases and 650 controls recruited from the same hospital in Hong Kong during 2011-2016. Chronic BPA exposure level was estimated by a validated cumulative BPA exposure index (CBPAI). We performed unconditional logistic regression model to examine the association of BPH risk with potential sources of BPA exposure via oral intake and CBPAI. We further tested the interactions between CBPAI and alcohol consumption habits on BPH risk. RESULTS: A positive exposure-response relationship was observed between CBPAI and BPH risk. Frequent BPA exposure via oral intake of foods heated in a plastic box/bag (odds ratio [OR] = 3.52, 95% confidence interval [CI]: 1.51-8.22), cooling water in a plastic bottle (OR = 2.65, 95% CI: 1.33-5.27), or using a plastic cup to contain hot water (OR = 4.14, 95% CI: 1.02-16.89), was significantly associated with increased BPH risk. Compared with nonalcohol drinkers, alcohol drinkers was insignificantly associated with BPH risk (OR = 1.10, 95% CI: 0.77-1.57), but it demonstrated a more remarkable positive gradient between CBPAI exposure and BPH risk among alcohol drinkers, indicating an additive interaction between CBPAI and alcohol on BPH risk (synergy index = 4.24, 95% CI: 1.21-14.94). CONCLUSIONS: Chronic oral BPA exposure increased BPH risk with a positive exposure-response relationship among Hong Kong Chinese, and alcohol drinking amplified the effect of BPA on BPH. Hence, minimizations of containing food or water/beverage in plastic containers and drinking alcohol are recommended in the community to mitigate BPH risk. Future larger and designated studies are warranted.

'Too old to test?': A life course approach to HIV-related risk and self-testing among midlife-older adults in Malawi.

BACKGROUND: Despite the aging HIV epidemic, increasing age can be associated with hesitancy to test. Addressing this gap is a critical policy concern and highlights the urgent need to identify the underlying factors, to improve knowledge of HIV-related risks as well as uptake of HIV testing and prevention services, in midlife-older adults. METHODS: We conducted five focus group discussions and 12 in-depth interviews between April 2013 and November 2016 among rural and urban Malawian midlife-older (≥30 years) men and women. Using a life-course theoretical framework we explored how age is enacted socially and its implications on HIV testing and sexual risk behaviours. We also explore the potential for HIV self-testing (HIVST) to be part of a broader strategy for engaging midlife-older adults in HIV testing, prevention and care. Thematic analysis was used to identify recurrent themes and variations. RESULTS: Midlife-older adults (30-74 years of age) associated their age with respectability and identified HIV as "a disease of youth" that would not affect them, with age protecting them against infidelity and sexual risk-taking. HIV testing was felt to be stigmatizing, challenging age norms, threatening social status, and implying "lack of wisdom". These norms drove self-testing preferences at home or other locations deemed age and gender appropriate. Awareness of the potential for long-standing undiagnosed HIV to be carried forward from past relationships was minimal, as was understanding of treatment-as-prevention. These norms led to HIV testing being perceived as a threat to status by older adults, contributing to low levels of recent HIV testing compared to younger adults. CONCLUSIONS: Characteristics associated with age-gender norms and social position encourage self-testing but drive poor HIV-risk perception and unacceptability of conventional HIV testing in midlife-older adults. There is an urgent need to provide targeted messages and services more appropriate to midlife-older adults in sub-Saharan Africa. HIVST which has often been highlighted as a tool for reaching young people, may be a valuable tool for engaging midlife-older age groups who may not otherwise test.

Polyisoprenylated Cysteinyl Amide Inhibitors: A Novel Approach to Controlling Cancers with Hyperactive Growth Signaling.

Aberrant activation of monomeric G-protein signaling pathways drives some of the most aggressive cancers. Suppressing these hyperactivities has been the focus of efforts to obtain targeted therapies. Polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in various cancers. Its inhibition induces the death of cancer cells that harbor the constitutively active K-Ras proteins. Furthermore, the viability of cancer cells driven by factors upstream of K-Ras, such as overexpressed growth factors and their receptors or the mutationally-activated receptors, is also susceptible to PMPMEase inhibition. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were thus designed to target cancers with hyperactive signaling pathways involving the G-proteins. The PCAIs were, however, poor inhibitors of PMPMEase, with Ki values ranging from 3.7 to 20 µM. On the other hand, they inhibited cell viability, proliferation, colony formation, induced apoptosis in cells with mutant K-Ras and inhibited cell migration and invasion with EC50 values of 1 to 3 µM. HUVEC tube formation was inhibited at submicromolar concentrations through their disruption of actin filament organization. At the molecular level, the PCAIs at 2 to 5 µM depleted monomeric G-proteins such as K-Ras, RhoA, Cdc42 and Rac1. The PCAIs also deplete vinculin and fascin that are involved in actin organization and function while disrupting vinculin punctates in the process. These demonstrate a polyisoprenylation-dependent mechanism that explains the observed PCAIs' inhibition of the proliferative, invasive and angiogenic processes that promote both tumor growth and metastasis.

Tamoxifen induces hypercoagulation and alterations in ERα and ERß dependent on breast cancer sub-phenotype ex vivo.

Tamoxifen shows efficacy in reducing breast cancer-related mortality but clinically, is associated with increased risk for thromboembolic events. We aimed to determine whether breast tumour sub-phenotype could predict propensity for thrombosis. We present two ex vivo Models of Tamoxifen-therapy, Model 1 in which treatment recapitulates accumulation within breast tissue, by treating MCF7 and T47D cells directly prior to exposure to blood constituents; and Model 2 in which we recreate circulating Tamoxifen by treating blood constituents prior to exposure to cancer cells. Blood constituents included whole blood, platelet-rich plasma and platelet-poor plasma. Hypercoagulation was assessed as a function of thrombin activity, expression of CD62P and CD63 activation markers defined as an index of platelet activation, and platelet morphology; while oestrogen receptor expression was assessed using immunocytochemistry with quantitative analysis. We determined, in concert with clinical studies and contrary to selected laboratory investigations, that Tamoxifen induces hypercoagulation, dependent on sub-phenotypes, with the T47D cell line capacity most enhanced. We determined a weak positive correlation between oestrogen receptor expression, and CD62P and CD63; indicating an association between tumour invasion profiles and hypercoagulation, however, other yet unknown factors may play a predictive role in defining hypercoagulation.

Ethical issues in cluster randomized trials conducted in low- and middle-income countries: an analysis of two case studies.

BACKGROUND: Cluster randomized trials are common in health research in low- and middle-income countries raising issues that challenge interpretation of standard ethical guidelines. While the Ottawa Statement on the ethical design and conduct of cluster randomized trials provides guidance for researchers and research ethics committees, it does not explicitly focus on low- and middle-income settings. MAIN BODY: In this paper, we use the lens of the Ottawa Statement to analyze two cluster randomized trials conducted in low- and middle-income settings in order to identify gaps or ethical issues requiring further analysis and guidance. The PolyIran trial was a parallel-arm, cluster trial examining the effectiveness of a polypill for prevention of cardiovascular disease in Golestan province, Iran. The PASTAL trial was an adaptive, multistage, parallel-arm, cluster trial evaluating the effect of incentives for human immunodeficiency virus self-testing and follow-up on male partners of pregnant women in Malawi. Through an in-depth case analysis of these two studies we highlight several issues in need of further exploration. First, standards for verbal consent and waivers of consent require methods for operationalization if they are to be employed consistently. Second, the appropriate choice of a control arm remains contentious. Particularly in the case of implementation interventions, locally available care is required as the comparator to address questions of comparative effectiveness. However, locally available care might be lower than standards set out in national guidelines. Third, while the need for access to effective interventions post-trial is widely recognized, it is often not possible to guarantee this upfront. Clarity on what is required of researchers and sponsors is needed. Fourth, there is a pressing need for ethics education and capacity building regarding cluster randomized trials in these settings. CONCLUSION: We identify four issues in cluster randomized trials conducted in low- and middle-income countries for which further ethical analysis and guidance is required.

Ex vivo interaction between blood components and hormone-dependent breast cancer cells induces alterations associated with epithelial-mesenchymal transition and thrombosis.

The prevalence of breast cancer is steadily increasing with metastasis and thromboembolic complications identified as the most common causes of death. The acquisition of an aggressive phenotype by hormone-dependent breast cancers is mediated by Transforming Growth Factor Beta 1 (TGF-ß1) expression and is associated with epithelial-mesenchymal transition (EMT) and, potentially, increased propensity for thrombosis. We investigated this phenomenon by assessing the effect of platelet-rich plasma (PRP) and whole blood (WB) on parameters of EMT and hypercoagulation in vitro. MCF-7 breast cancer cells were cultured under standard conditions, followed by co-culture with PRP or WB. Cells were processed for real-time PCR (TGF-ß1 and vimentin), electron microscopy or immunocytochemistry (TGF-ß1). Micrographs were qualitatively assessed, and real-time PCR data analyzed with PAST Statistical Software. The addition of blood components heightened TGF-ß1 immunolocalization and significantly increased corresponding gene expression. Both PRP and WB significantly increased vimentin expression and induced a shape change from a typical epithelial phenotype to a spindle-shape morphology, indicative of EMT. Fibrin fiber, network and plaque formation indicated a hypercoagulatory environment. The results thus show that in preparation for hematogenous metastasis, hormone-dependent breast cancer cells assume an aggressive phenotype associated with EMT, simultaneously increasing the propensity for the formation of thrombo-emboli.

A Mechanistic Investigation on the Anticancer Properties of SYA013, a Homopiperazine Analogue of Haloperidol with Activity against Triple Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is one of the most malignant cancers associated with early metastasis, poor clinical prognosis, and high recurrence rate. TNBC is a distinct subtype of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptors (HER2). Development of effective TNBC therapies has been limited partially due to the lack of specific molecular targets and chemotherapy involving different cytotoxic drugs suffers from significant side effects and drug-resistance development. Therefore, there is an unmet need for the development of novel and efficient therapeutic drugs with reduced side effects to treat TNBC. We have previously reported that certain analogues of haloperidol (a typical antipsychotic drug used for treating mental/mood disorders such as schizophrenia and bipolar disorder) suppress the viability of a variety of solid tumor cell lines, and we have identified 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluoro-phenyl)butan-1-one (SYA013) with such antiproliferative properties. Interestingly, unlike haloperidol, SYA013 shows moderate selectivity toward σ2 receptors. In this study, we explored the potential of SYA013 in modulating the important biological events associated with cell survival and progression as well as the mechanistic aspects of apoptosis in a representative TNBC cell line (MDA-MB-231). Our results indicate that SYA013 inhibits the proliferation of MDA-MB-231 cells in a concentration-dependent manner and suppresses cell migration and invasion. Apoptotic studies were also conducted in MDA-MB-468 cells (cells derived from a 51-year old Black female with metastatic adenocarcinoma of the breast.). In addition, we have demonstrated that SYA013 induces MDA-MB-231 cell death through the intrinsic apoptotic pathway and may suppress tumor progression and metastasis. Taken together, our study presents a mechanistic pathway of the anticancer properties of SYA013 against TNBC cell lines and suggests a potential for exploring SYA013 as a lead agent for development against TNBC.

Developing national strategies for reaching men with HIV testing services in Tanzania: results from the male catch-up plan.

BACKGROUND: According to the 2016-2017 Tanzania HIV Impact Survey, 55% of men diagnosed with HIV during the survey self-reported that they were unaware of their HIV status. As a response, the Government of Tanzania launched a Test and Treat campaign in June 2018 with a focus on reaching men and developed the 2018-2020 Male Catch-Up plan. This article reports (1) the enablers and barriers of HIV testing services (HTS) uptake among men (2) and describes the strategies that were proposed as part of the Male Catch-Up Plan to address some of these barriers. METHOD: Qualitative in-depth interviews were conducted with 23 men in Dar es Salaam to explore HTS enablers and barriers. To develop the Male Catch-Up Plan strategies, a desk review of published studies, and analyses of national implementers of HIV/AIDS interventions were conducted. An additional 123 interviews were also carried out with key implementers of HIV/AIDS interventions, healthcare workers, secondary school boys and members of the community in Iringa and Tanga. RESULTS: Enablers of HTS included the desire to check one's health, high HIV risk perception, wanting to protect oneself if tested negative, and being encouraged by their sexual partners. Barriers of HTS were fear of a positive test result, and low HIV risk perception. Proposed strategies from the Male Catch-Up Plan to address these barriers included non-biomedical and biomedical approaches. Non-biomedical strategies are social and cultural approaches to promote an enabling environment to encourage health seeking behavior, safe behavior, and providing peer education programs and social marketing to promote condoms. Biomedical approaches consisted of expanding targeted HIV testing, HIV self-testing, and integrating HIV services with other health services. CONCLUSION: A number of barriers contribute to the low uptake of HTS among men in Tanzania. National strategies have been developed to address these HTS barriers and guide the national Test and Treat campaign focusing on increasing HTS uptake among men.

Breast cancer cell-induced platelet activation is compounded by tamoxifen and anastrozole in vitro.

Platelet-tumour cell interaction is implicated in the initiation of breast cancer-associated thrombosis, with hormone-therapy (Tamoxifen/Anastrozole), increasing this risk. However, recent in vitro research indicates that Tamoxifen inhibits platelet activation, while the effects of Anastrozole on platelet activation are not well characterised. This study investigated platelet activation caused by Tamoxifen or Anastrozole-treated breast cancer cells in vitro. MCF7 and T47D cells were pre-treated with Tamoxifen or Anastrozole to mimic the effects of the drugs in vivo, and co-cultured with whole blood. Platelet activation was determined using flow cytometry. Platelet (CD41a+CD62P+) was determined using an interval gating strategy. Platelet morphology was visualised using scanning electron microscopy. Our results support clinical findings, showing that hormone-therapy is associated with platelet activation. Tamoxifen-treated MCF7 cells increased P-selectin expression, with ultrastructural analysis showing fully spread platelets. Conversely, Tamoxifen-treated T47D cells decreased P-selectin expression with platelets showing signs of early aggregation. Anastrozole pre-treatment decreased P-selectin expression, with treated MCF7 cells inducing platelet membrane folds and lamellipodia extension, and treated T47D cells inducing platelet aggregation and fibrin network formation indicating hypercoagulation. The findings support clinical studies. Hormone-therapy augments tumour cell-induced platelet activation, which may be linked to cell phenotype. This may have clinical implications for treatment strategies.

Polyisoprenylated Cysteinyl Amide Inhibitors Deplete K-Ras and Induce Caspase-dependent Apoptosis in Lung Cancer Cells.

BACKGROUND: Non-small cell lung cancers (NSCLC) harboring mutation-induced dysregulation of Ras signaling present some of the most difficult-to-manage cases, since directly targeting the constitutively active mutant Ras proteins has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need. OBJECTIVE: In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes. METHODS: The effect of the PCAIs on intracellular K-Ras levels, cell viability, apoptosis, spheroid and colony formation were determined. RESULTS: Treatment of the lung cancer cells with the PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA- 040 and NSL-BA-055 resulted in concentration-dependent cell death in both K-Ras mutant (A549, NCI-H460, and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H1975, NCIH1563) NSCLC cells. The PCAIs at 1.0 -10 µM induced the degeneration of 3D spheroid cultures, inhibited clonogenic cell growth and induced marked apoptosis via the extrinsic pathway. The most potent of the PCAIs, NSL-BA-055, at 5 µM induced a seven-fold increase in the activity of caspase- 3/7 and a 75% selective depletion of K-Ras protein levels relative to GAPDH in A549 cells that correlated with PCAIs-induced apoptosis. NSL-BA-040 and NSL-BA-055 also induced the phosphorylation of MAP kinase (ERK 1/2). CONCLUSION: Taken together, PCAIs may be potentially useful as targeted therapies that suppress NSCLC progression through disruption of Ras-mediated growth signaling.

Exploring social harms during distribution of HIV self-testing kits using mixed-methods approaches in Malawi.

INTRODUCTION: HIV self-testing (HIVST) provides couples and individuals with a discreet, convenient and empowering testing option. As with all HIV testing, potential harms must be anticipated and mitigated to optimize individual and public health benefits. Here, we describe social harms (SHs) reported during HIVST implementation in Malawi, and propose a framework for grading and responding to harms, according to their severity. METHODS: We report findings from six HIVST implementation studies in Malawi (2011 to 2017) that included substudies investigating SH reports. Qualitative methods included focus group discussions, in-depth interviews and critical incident interviews. Earlier studies used intensive quantitative methods (post-test questionnaires for intimate partner violence, household surveys, investigation of all deaths in HIVST communities). Later studies used post-marketing reporting with/without community engagement. Pharmacovigilance methodology (whereby potentially life-threatening/changing events are defined as "serious") was used to grade SH severity, assuming more complete passive reporting for serious events. RESULTS: During distribution of 175,683 HIVST kits, predominantly under passive SH reporting, 25 serious SHs were reported from 19 (0.011%) self-testers, including 15 partners in eight couples with newly identified HIV discordancy, and one perinatally infected adolescent. There were no deaths or suicides. Marriage break-up was the most commonly reported serious SH (sixteen individuals; eight couples), particularly among serodiscordant couples. Among new concordant HIV-positive couples, blame and frustration was common but rarely (one episode) led to serious SHs. Among concordant HIV-negative couples, increased trust and stronger relationships were reported. Coercion to test or disclose was generally considered "well-intentioned" within established couples. Women felt empowered and were assertive when offering HIVST test kits to their partners. Some women who persuaded their partner to test, however, did report SHs, including verbal or physical abuse and economic hardship. CONCLUSIONS: After more than six years of large-scale HIVST implementation and in-depth investigation of SHs in Malawi, we identified approximately one serious reported SH per 10,000 HIVST kits distributed, predominantly break-up of married serodiscordant couples. Both "active" and "passive" reporting systems identified serious SH events, although with more complete capture by "active" systems. As HIVST is scaled-up, efforts to support and further optimize community-led SH monitoring should be prioritized alongside HIVST distribution.

Systematic review to assess the possibility of return of cerebral and cardiac activity after normothermic regional perfusion for donors after circulatory death.

BACKGROUND: Normothermic regional perfusion (NRP) is a novel technique that aids organ recovery from donors after circulatory death (DCDs). However, ethical concerns exist regarding the potential return of spontaneous cerebral and cardiac activity (ROSCCA). This study aimed to determine the likelihood of ROSCCA in NRP-DCDs of abdominal organs. METHODS: Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory out-of-hospital cardiac arrest (OOHCA) was identified as a comparator for NRP-DCDs and as a validation cohort. A systematic search identified all articles relating to NRP-DCDs and ECPR-OOHCA. Rates of ROSCCA and survival outcomes (ECPR-OOHCA only) were recorded and analysed according to the duration of no perfusion. RESULTS: In NRP-DCDs, 12 of 410 articles identified by database searching were eligible for inclusion. There were no instances of ROSCCA recorded among 493 donors. In ECPR-OOHCA, eight of 947 screened articles were eligible for inclusion (254 patients). Where the absence of perfusion exceeded 5 min in ECPR-OOHCA, there were no survivors with a favourable neurological outcome. CONCLUSION: ROSCCA is unlikely following commencement of NRP and has not occurred to date. Strict observance of the 5-min interval following asystole provides satisfactory assurance that ROSCCA will not occur following NRP.

A pilot trial of the peer-based distribution of HIV self-test kits among fishermen in Bulisa, Uganda.

BACKGROUND: HIV self-testing (HIVST) addresses barriers to HIV diagnosis among men, but current approaches to distributing HIVST kits only reach a subset of the men requiring testing. METHODS: We conducted a pilot trial of the secondary distribution of HIVST kits through peer networks in fishing communities of Buliisa district (Uganda). We recruited distributors ("seeds") among male patients of a health facility, and among community members. Seeds were trained in HIVST and asked to distribute up to five kits to their peers ("recruits"). Recruits were referred to the study using a coupon, and asked to return the HIVST kit (used or unused). The accuracy of HIVST was measured against a confirmatory test conducted by a health worker. We conducted audio computer assisted self-interviews to measure the occurrence of adverse events, and evaluate the potential yield of peer-delivered HIVST. We also assessed how seeds and recruits rated their experience with peer-distributed HIVST. RESULTS: Nineteen seeds offered an HIVST kit to 116 men, and 95 (81.9%) accepted the offer. No recruit reported coercion, but two seeds experienced hostility from recruits or their family members. The sensitivity of peer-distributed HIVST, as interpreted by recruits, was 100%, and its specificity was 92.8%. Among recruits, 29 had never tested (25.8%), and 42 (44.2%) had tested more than a year ago. Three men living with HIV learned their status through peer-distributed HIVST (yield = 1 new diagnosis per 6.3 seeds). Most recruits (85/88) and seeds (19/19) reported that they would recommend HIVST to their friends and family. All seeds stated that they would accept acting as peer distributors again. CONCLUSIONS: This novel peer-based distribution model of HIVST is safe, and has high uptake. It could help reduce the gender gap in HIV testing in under-served fishing communities in Uganda and elsewhere.

Suppression of focal adhesion formation may account for the suppression of cell migration, invasion and growth of non-small cell lung cancer cells following treatment with polyisoprenylated cysteinyl amide inhibitors.

Migratory cells form extracellular matrix attachments called focal-adhesions. Focal adhesion assembly and disassembly are regulated by the Rho family of small GTPases. We previously reported that polyisoprenylated cysteinyl amide inhibitors (PCAIs) suppress Rho protein levels, disrupting F-actin cytoskeleton remodeling in the formation of lamellipodia and filopodia. In this study, we investigated whether these observations effect focal adhesion formation, which involves cell surface receptors known as integrins and several signaling/adaptor proteins such as vinculin, α-actinin, Rock kinases and phospho-Myosin Light Chain-2 (p-MLC-2), that foster the linkage of the actin cytoskeleton to the extracellular matrix. We observed that treatment of H1299 cells with 5 µM PCAIs for 24 h markedly diminished the level of full-length integrin α4 by at least 24% relative to controls. PCAIs at 5 µM, diminished the levels of vinculin by at least 50%. Immunofluorescent analysis showed at least a 76% decrease in the number of vinculin-focal adhesion punctates. In addition, PCAIs diminished Rock1 levels by 25% and its substrate, p-MLC-2 by 75%. PCAIs did not significantly alter the levels of integrin ß5, α-actinin, and Rock2, suggesting that the effects of the PCAIs are target specific. Our data indicate that the PCAIs alter the levels of the Rho proteins and their effectors to abrogate their functions in cytoskeleton remodeling thereby suppressing focal adhesion formation. This in turn results in a PCAIs-induced decrease in cell invasion, thus making the PCAIs propitious agents for the inhibition of cancer growth and metastasis.

Assessment of ovarian follicular dynamics and folliculogenesis associated endocrine profiles following gonadotropin stimulation in the bonnet monkey.

We evaluated ovarian follicular dynamics in bonnet monkeys by employing trans-abdominal ultrasonography. Following the administration of human follicle stimulating hormone (hFSH) and/or human menopausal gonadotropin (hMG), multiple follicular development was assessed and their numbers, size and growth profiles were monitored. The ultrasonograms showed that the follicular antrum appeared distinctly anechoic with well-defined hyperechoic borders. Depending on the type, quantity (12.5-25IU), and duration (6-9days) of hormones administered, the number of developing follicles was 2-12 per ovary with their lowest diameter being 2mm. With continued hormone administration, their numbers and diameters increased; which were more pronounced in animals administered with hFSH than with hMG, with follicles of 6-8mm. Interestingly, human chorionic gonadotropin (hCG) injection (2000-3000IU), when follicles acquiring >6-8mm sizes, induced the maximum expansion of antral follicles with sizes reaching up to 14mm. On days 3-5 post-hCG, the ultrasonograms showed loosely demarcated multiple hypoechoic structures and well-demarcated hyperechoic structures with anechoic/hypoechoic cores corresponding to unruptured luteinized follicles and corpora lutea, respectively. On day 4 post-hCG, there was a substantial reduction in the number of antral follicles. In stimulated animals, follicular growth, ovulation, and formation of luteal structures were accompanied by corresponding physiological changes in the serum estradiol and progesterone profiles. These findings, for the first time, showed that ultrasonographic imaging approach is useful for precise monitoring of temporal changes in follicular developmental dynamics and to time the hCG induced ovulation in the bonnet monkey.