Measuring the uptake of clinic-based HIV treatment and prevention services following HIV testing and referral at private pharmacies in Kenya.

Background: Despite their ubiquity across sub-Saharan Africa, private pharmacies are underutilized for HIV service delivery beyond the sale of HIV self-test kits. To understand what uptake of HIV prevention and treatment services might look like if private pharmacies offered clients free HIV self-testing and referral to clinic-based HIV services, we conducted a pilot study in Kenya.

Methods: At 20 private pharmacies in Kisumu County, Kenya, pharmacy clients (≥ 18 years) purchasing sexual health-related products (e.

Safety and adherence to self-administered intravaginal 5-fluorouracil cream following cervical intraepithelial neoplasia (CIN) 2/3 treatment among HIV-positive women in Kenya: A phase 1 clinical trial.

Objective: To determine the safety, tolerance, and adherence to self-administered intravaginal 5% fluorouracil (5FU) cream as adjuvant therapy following cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) treatment among women living with HIV (WLWH) in Kenya.

Methods: A phase I pilot trial was performed among 12 WLWH in Kenya, aged 18-49 years between March 2023 and February 2024 (ClinicalTrial.gov NCT05362955).

"The peace that I wanted, I got": Qualitative insights from patient experiences of SMART DAPPER interventions for major depression and traumatic stress disorders in Kenya.

SMART DAPPER is an implementation science study responding to mental health treatment gaps for depression and trauma-related disorders in Sub-Saharan Africa (SSA). We report on patient experiences in a study using a Sequential, Multiple Assignment Randomized Trial (SMART) design to test first and second line non-specialist treatment using psychotherapy (Interpersonal Psychotherapy [IPT] or medication (fluoxetine [FLX]), integrated within public sector primary care in western Kenya. An embedded qualitative study conducted in-depth interviews (n = 17) and three (n = 3) focus group discussions with participants (May to October 2021).

Defining a screening tool for post-traumatic stress disorder in East Africa: a penalized regression approach.

Background: Scalable PTSD screening strategies must be brief, accurate and capable of administration by a non-specialized workforce.

Methods: We used PTSD as determined by the structured clinical interview as our gold standard and considered predictors sets of (a) Posttraumatic Stress Checklist-5 (PCL-5), (b) Primary Care PTSD Screen for the DSM-5 (PC-PTSD) and, (c) PCL-5 and PC-PTSD questions to identify the optimal items for PTSD screening for public sector settings in Kenya. A logistic regression model using LASSO was fit by minimizing the average squared error in the validation data.

Enhancing HIV pre-exposure prophylaxis outcomes among Kenyan adolescent girls and young women with a novel pharmacy-based PrEP delivery platform: protocol for a cluster-randomized controlled trial.

Background: In Kenya, 65% of sexually active unmarried women use modern contraceptives, a population at increased risk of HIV acquisition compared to other populations. Anchoring HIV prevention services, including pre-exposure prophylaxis (PrEP), to trusted contraceptive delivery settings offers opportunities to efficiently reach this important population. In Kenya, almost half (40%) of women accessing contraception services do so outside traditional healthcare facilities, such as retail pharmacies.

Safety and adherence to self-administered intravaginal 5-fluorouracil cream following cervical intraepithelial neoplasia (CIN) 2/3 treatment among HIV-positive women in Kenya: A phase 1 clinical trial.

Objective: To determine the safety, tolerance, and adherence to self-administered intravaginal 5% fluorouracil (5FU) cream as adjuvant therapy following cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) treatment among women living with HIV (WLWH) in Kenya.

Methods: A Phase I Pilot trial was performed among 12 WLWH in Kenya, aged 18-49 years between March 2023-February 2024 (ClinicalTrial.gov NCT05362955).

Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH.

Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane.

Feasibility of adjuvant self-administered intravaginal 5-fluorouracil cream following primary treatment of cervical intraepithelial neoplasia grade 2 or 3 among women living with HIV in Kenya: study protocol for a pilot trial.

Background: Women living with HIV (WLWH), the majority of whom live in low- and middle-income countries (LMICs), are at higher risk of cervical precancer, known as cervical intraepithelial neoplasia (CIN), and are up to six times more likely to get cervical cancer. Current CIN treatment methods, primarily ablation or excision, have high treatment failure rates among WLWH, up to 30% for CIN grade 2 or 3 (CIN2/3) at 24 months following ablation. Without strong follow-up many WLWH with treatment failure are at risk of developing invasive cervical cancer, highlighting the urgent need for improved CIN treatment methods.

Formation of CoA Adducts of Short-Chain Fluorinated Carboxylates Catalyzed by Acyl-CoA Synthetase from sp. Strain NB4-1Y.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) make up a group of anthropogenic chemicals with a myriad of applications. However, some PFAS have been shown to negatively impact human health and the environment, leading to increased regulation, with some countries making efforts to phase out their use. PFAS fate in the environment is driven by physical, chemical, and biological processes, with microbial communities in matrices such as soil and sewage sludge being known to generate a range of low-molecular-weight PFAS metabolites.

SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency.

Natural killer (NK) cells recognize virally infected cells and tumors. NK cell function depends on balanced signaling from activating receptors, recognizing products from tumors or viruses, and inhibitory receptors (such as KIR/Ly49), which recognize major histocompatibility complex class I (MHC-I) molecules. KIR/Ly49 signaling preserves tolerance to self but also conveys reactivity toward MHC-I-low target cells in a process known as NK cell education.

Applying a homogeneous pressure distribution to the upper vertebral endplate: Validation of a new loading system, pilot application to human vertebral bodies, and finite element predictions of DIC measured displacements and strains.

Image-based personalized Finite Element Models (pFEM) could detect alterations in physiological deformation of human vertebral bodies, but their accuracy has been seldom reported. Meaningful validation experiments should allow vertebral endplate deformability and ensure well-controlled boundary conditions. This study aimed to (i) validate a new loading system to apply a homogeneous pressure on the vertebral endplate during vertebral body compression regardless of endplate deformation; (ii) perform a pilot study on human vertebral bodies measuring surface displacements and strains with Digital Image Correlation (DIC); (iii) determine the accuracy of pFEM of the vertebral bodies.

Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses.

Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1).

VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding.

Background: The adoptive transfer of chimeric antigen receptor (CAR)-T cells has emerged as a potent immunotherapy against some hematological malignancies but not yet for epithelial-derived solid tumors. One critical issue is the paucity of broadly expressed solid tumor antigens (TAs), and another is the presence of suppressive mechanisms in the tumor microenvironment (TME) that can impair CAR-T cell homing, extravasation and effector functions. TAs expressed by endothelial cells of the tumor vasculature are of clinical interest for CAR therapy because of their genomic stability and accessibility to circulating T cells, as well as their expression across multiple tumor types.

FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure.

The mechanisms maintaining adult lymphatic vascular specialization throughout life and their role in coordinating inter-organ communication to sustain homeostasis remain elusive. We report that inactivation of the mechanosensitive transcription factor in adult lymphatic endothelium leads to a stepwise intestine-to-lung systemic failure. loss compromised the gut epithelial barrier, promoted dysbiosis and bacterial translocation to peripheral lymph nodes, and increased circulating levels of purine metabolites and angiopoietin-2.

Long-Term Outcomes of Kidney Transplants from Older/Marginal Donors: A Cohort Study.

Introduction: To safely expand the donor pool, we introduced a strategy of biopsy-guided selection and allocation to single or dual transplantation of kidneys from donors >60 years old or with hypertension, diabetes, and/or proteinuria (older/marginal donors). Here, we evaluated the long-term performance of this approach in everyday clinical practice.

Methods: In this single-center cohort study, we compared outcomes of 98 patients who received one or two biopsy-evaluated grafts from older/marginal donors ("recipients") and 198 patients who received nonhistologically assessed single graft from ideal donors ("reference-recipients") from October 2004 to December 2015 at the Bergamo Transplant Center (Italy).

Preimplantation Histological Score Associates with 6-Month GFR in Recipients of Perfused, Older Kidney Grafts: Results from a Pilot Study.

Background: Biopsy-guided selection of older kidneys safely expands the organ pool, and pretransplant perfusion improves the preservation of these fragile organs. Herein, we studied morphofunctional variables associated with graft outcomes in perfused, histologically evaluated older kidneys.

Methods: This single-center prospective cohort pilot study evaluated the relationships between preimplantation histologic scores and renal perfusion parameters during hypothermic, pulsatile, machine perfusion (MP) and assessed whether these morphofunctional parameters associated with GFR (iohexol plasma clearance) at 6 months after transplantation in 20 consecutive consenting recipients of a biopsy-guided single or dual kidney transplant from >60-year-old deceased donors.

Interpersonal psychotherapy delivered by nonspecialists for depression and posttraumatic stress disorder among Kenyan HIV-positive women affected by gender-based violence: Randomized controlled trial.

Background: HIV-positive women suffer a high burden of mental disorders due in part to gender-based violence (GBV). Comorbid depression and posttraumatic stress disorder (PTSD) are typical psychiatric consequences of GBV. Despite attention to the HIV-GBV syndemic, few HIV clinics offer formal mental healthcare.

Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression.

Limited clinical benefit has been demonstrated for chimeric antigen receptor (CAR) therapy of solid tumors, but coengineering strategies to generate so-called fourth-generation (4G) CAR-T cells are advancing toward overcoming barriers in the tumor microenvironment (TME) for improved responses. In large part due to technical challenges, there are relatively few preclinical CAR therapy studies in immunocompetent, syngeneic tumor-bearing mice. Here, we describe optimized methods for the efficient retroviral transduction and expansion of murine T lymphocytes of a predominantly central memory T cell (TCM cell) phenotype.

A genetic profile of oxytocin receptor improves moral acceptability of outcome-maximizing harm in male insurance brokers.

In recent years, conflicting findings have been reported in the scientific literature about the influence of dopaminergic, serotonergic and oxytocinergic gene variants on moral behavior. Here, we utilized a moral judgment paradigm to test the potential effects on moral choices of three polymorphisms of the Oxytocin receptor (OXTR): rs53576, rs2268498 and rs1042770. We analyzed the influence of each single polymorphism and of genetic profiles obtained by different combinations of their genotypes in a sample of male insurance brokers (n = 129), as compared to control males (n = 109).

Implementation research for public sector mental health care scale-up (SMART-DAPPER): a sequential multiple, assignment randomized trial (SMART) of non-specialist-delivered psychotherapy and/or medication for major depressive disorder and posttraumatic stress disorder (DAPPER) integrated with outpatient care clinics at a county hospital in Kenya.

Background: Mental disorders are a leading cause of global disability, driven primarily by depression and anxiety. Most of the disease burden is in Low and Middle Income Countries (LMICs), where 75% of adults with mental disorders have no service access. Our research team has worked in western Kenya for nearly ten years.

The ubiquitin-conjugating enzyme UBE2QL1 coordinates lysophagy in response to endolysosomal damage.

The autophagic clearance of damaged lysosomes by lysophagy involves extensive modification of the organelle with ubiquitin, but the underlying ubiquitination machinery is still poorly characterized. Here, we use an siRNA screening approach and identify human UBE2QL1 as a major regulator of lysosomal ubiquitination, lysophagy, and cell survival after lysosomal damage. UBE2QL1 translocates to permeabilized lysosomes where it associates with damage sensors, ubiquitination targets, and lysophagy effectors.

PrEP and the syndemic of substance use, violence, and HIV among female and male sex workers: a qualitative study in Kisumu, Kenya.

Introduction: Female and male sex workers experience heightened vulnerability to HIV and other health harms that are compounded by substance use, physical and sexual violence, and limited access to health services. In Kisumu, Kenya, where sex work is widespread and substance use is a growing public health concern, offering pre-exposure prophylaxis (PrEP) for HIV prevention could help curtail the HIV epidemic. Our study examines "syndemics," or mutually reinforcing epidemics of substance use, violence and HIV, in relation to PrEP acceptability and feasibility among female and male sex workers in Kenya, one of the first African countries to approve PrEP for HIV prevention.

Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells.

The phosphatase Shp-2 was implicated in NK cell development and functions due to its interaction with NK inhibitory receptors, but its exact role in NK cells is still unclear. Here we show, using mice conditionally deficient for Shp-2 in the NK lineage, that NK cell development and responsiveness are largely unaffected. Instead, we find that Shp-2 serves mainly to enforce NK cell responses to activation by IL-15 and IL-2.