Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy.

BACKGROUND: Recently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress. METHODS: We performed in vitro studies on cardiomyocytes and myocardial tissue samples from patients and performed in vivo investigation with SLIT3 and ROBO1 (roundabout homolog 1) mutant mice undergoing transverse aortic constriction to establish the role of SLIT3-ROBO1 in adverse cardiac remodeling. RESULTS: We first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload. Immunostaining of hearts from WT (wild-type) and reporter mice revealed that SLIT3 is secreted by cardiac stromal cells, namely fibroblasts and vascular mural cells, within the heart. Conditioned media from cardiac fibroblasts and vascular mural cells both stimulated cardiomyocyte hypertrophy in vitro, an effect that was partially inhibited by an anti-SLIT3 antibody. Also, the N-terminal, but not the C-terminal, fragment of SLIT3 and the forced overexpression of SLIT3 stimulated cardiomyocyte hypertrophy and the transcription of hypertrophy-related genes. We next determined that ROBO1 was the most highly expressed roundabout receptor in cardiomyocytes and that ROBO1 mediated SLIT3's hypertrophic effects in vitro. In vivo, Tcf21+ fibroblast and Tbx18+ vascular mural cell-specific knockout of SLIT3 in mice resulted in decreased left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction. Furthermore, α-MHC+ cardiomyocyte-specific deletion of ROBO1 also preserved left ventricular function and abrogated hypertrophy, but not fibrosis, after transverse aortic constriction. CONCLUSIONS: Collectively, these results indicate a novel role for the SLIT3-ROBO1-signaling axis in regulating postnatal cardiomyocyte hypertrophy induced by pressure overload.

Dissemination and implementation of an evidence-based voluntary medical male circumcision program: The Spear & Shield program.

Despite compelling evidence linking voluntary medical male circumcision (VMMC) with 60-70% HIV risk reduction in sub-Saharan Africa, Zambian men have been especially reluctant to undergo VMMC. The Government of Zambia set targets for VMMC uptake and promoted community-level interventions. Spear & Shield (S&S) is an innovative, evidence-based, service program promoting VMMC uptake while ensuring both VMMC supply and demand. This study assessed the large-scale provincial rollout of the program (S&S2) utilizing the RE-AIM model for translating interventions into the community. The S&S2 study was conducted between November 2015 and December 2020, and sequentially rolled out over four Zambian provinces in 96 clinics; 24 observation clinics received VMMC training only. Local clinic healthcare workers were trained to conduct the VMMC procedure and HIV counselors were trained to lead S&S group sessions. Using the RE-AIM model, primary outcomes were: Reach, the number, proportion, and representativeness of S&S attendees; Effectiveness, the impact of S&S2 on VMMC uptake; Adoption, the number, proportion, and representativeness of clinics implementing S&S2; Implementation, fidelity to the S&S intervention manual; and Maintenance, the extent to which S&S2 became an element of standard care within community clinics. Initially, n = 109 clinics were recruited; 96 were sustained and randomized for activation (Adoption). A total of 45,630 clinic patients (n = 23,236 men and n = 22,394 women) volunteered to attend the S&S sessions (Reach). The S&S2 program ran over 2,866 clinic-months (Implementation). Although the study did not target individual-level VMMCs, ~58,301 additional VMMCs were conducted at the clinic level (Effectiveness). Fidelity to the S&S intervention by group leaders ranged from 42%-95%. Sustainability of the program was operationalized as the number of CHCs initially activated that sustained the program. Intervention delivery ended, however, when study funding ceased (Maintenance). The S&S2 program successfully utilized the RE-AIM model to achieve study goals for implementation and dissemination in four Zambian provinces. Innovative VMMC programs such as S&S2 can improve the uptake of VMMC, one of the most effective strategies in the HIV prevention arsenal.

Factors influencing neonatal male circumcision uptake among expecting couples in Zambia: formative findings.

Male circumcision is a protective HIV prevention strategy. However, uncircumcised Zambian men are reluctant to undergo voluntary medical male circumcision (VMMC). Tailored interventions are necessary to stimulate the uptake of early infant male circumcision (EIMC) and VMMC in Zambia. This feasibility study presents the formative process of utilising the PRECEDE framework in the development of a family-centred EIMC/VMMC intervention, Like Father Like Son, and its application in an existing VMMC intervention, Spear & Shield. We found that fear of the pain associated with EIMC procedures, foreskin disposal, beliefs in children's autonomy and rights, and men's dominance in health decision-making were factors affecting EIMC uptake. Perceived benefits for infants included improved hygiene, protection from HIV infection, and faster recovery. Reinforcing factors included female partners and fathers' MC status. The availability and access to EIMC services and information, skill and experience of health workers, and engagement and belief in traditional circumcision practices were factors enabling EIMC uptake. These individual, interpersonal, and structural factors positively and negatively influencing EIMC uptake in the Zambian clinic context were integrated into the intervention for expecting parents. Feedback from community advisory boards suggested the process was effective in developing a culturally tailored and acceptable EIMC/VMMC promotion intervention.

Increasing early infant male circumcision uptake in Zambia: Like father like son.

Voluntary Medical Male Circumcision (VMMC) is an effective strategy for HIV prevention in areas with high prevalence of, and risk for, HIV. More than 361,000 male neonates are born each year in Zambia, many of whom could be eligible for Early-Infant Medical Circumcision (EIMC). Building on successful implementation strategies utilized in our Spear & Shield program, this pilot study, "Like Father, Like Son" (LFLS), evaluated the feasibility and acceptability of offering combined EIMC and VMMC services and couple-level behavioral interventions. A total of N = 702 pregnant women and their male partners (n = 351 couples) were recruited and enrolled. Couples were assessed twice pre-birth, 2 weeks post birth, and 6 months post birth. Expectant mothers were an average of 15.05 weeks pregnant (SD = 8.83). Thirty-nine pregnancies did not result in a live birth (11%), 14 couples withdrew from the study or were lost to follow-up prior to delivery (4%), and 148 babies were born female (42%), leaving 150 couples with a male infant in the analytic sample (43%). The LFLS study achieved significantly higher EIMC rates (35%) in comparison with previously observed EIMC study rates in Zambia (11%), and significantly higher than hypothetical comparison rates up to 30%. Relative to baseline rates, odds of VMMC among couples' older sons increased by 31% at post-intervention and by 90% at two-weeks following birth. Overall, this pilot study found the LFLS intervention to be feasible, acceptable, and effective in doubling the rate of EIMC in comparison with a previous longitudinal study in Zambia. Future research should consider a family-centric approach to promotion of male circumcision for infants and adolescents. LFLS may be effective in promoting father-son "bonding" by MC status; a bond that may be a bridge to increase both EIMC and VMMC uptake in newborns and couples' older sons and is a novel leverage point for promotion of this HIV prevention strategy.

The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease.

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.

Proteolytic regulation of a galectin-3/Lrp1 axis controls osteoclast-mediated bone resorption.

Bone-resorbing osteoclasts mobilize proteolytic enzymes belonging to the matrix metalloproteinase (MMP) family to directly degrade type I collagen, the dominant extracellular matrix component of skeletal tissues. While searching for additional MMP substrates critical to bone resorption, Mmp9/Mmp14 double-knockout (DKO) osteoclasts-as well as MMP-inhibited human osteoclasts-unexpectedly display major changes in transcriptional programs in tandem with compromised RhoA activation, sealing zone formation and bone resorption. Further study revealed that osteoclast function is dependent on the ability of Mmp9 and Mmp14 to cooperatively proteolyze the ß-galactoside-binding lectin, galectin-3, on the cell surface. Mass spectrometry identified the galectin-3 receptor as low-density lipoprotein-related protein-1 (Lrp1), whose targeting in DKO osteoclasts fully rescues RhoA activation, sealing zone formation and bone resorption. Together, these findings identify a previously unrecognized galectin-3/Lrp1 axis whose proteolytic regulation controls both the transcriptional programs and the intracellular signaling cascades critical to mouse as well as human osteoclast function.

A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling.

Osteoclasts are bone-resorbing polykaryons responsible for skeletal remodeling during health and disease. Coincident with their differentiation from myeloid precursors, osteoclasts undergo extensive transcriptional and metabolic reprogramming in order to acquire the cellular machinery necessary to demineralize bone and digest its interwoven extracellular matrix. While attempting to identify new regulatory molecules critical to bone resorption, we discovered that murine and human osteoclast differentiation is accompanied by the expression of Zeb1, a zinc-finger transcriptional repressor whose role in normal development is most frequently linked to the control of epithelial-mesenchymal programs. However, following targeting, we find that Zeb1 serves as an unexpected regulator of osteoclast energy metabolism. In vivo, Zeb1-null osteoclasts assume a hyperactivated state, markedly decreasing bone density due to excessive resorptive activity. Mechanistically, Zeb1 acts in a rheostat-like fashion to modulate murine and human osteoclast activity by transcriptionally repressing an ATP-buffering enzyme, mitochondrial creatine kinase 1 (MtCK1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration. Together, these studies identify a novel Zeb1/MtCK1 axis that exerts metabolic control over bone resorption in vitro and in vivo.

Zambian Parents' Perspectives on Early-Infant Versus Early-Adolescent Male Circumcision.

Despite increasing interest in Early-Infant and Early-Adolescent Medical Circumcision (EIMC and EAMC, respectively) in Zambia, parental willingness to have their sons undergo the procedure has not been explored. This study describes Zambian parents' perspectives on EIMC and EAMC. A total of N = 600 men and women (n = 300 couples) were recruited. Most parents, 89% and 83%, planned to have their newborn or adolescent sons circumcised, respectively, and 70% and 57% had plans for EIMC and EAMC, respectively. Most (91% for infants and 86% for adolescents) reported they were considering the pros and cons of circumcision. Parents' age (OR 1.05), having children living in one's home (OR 3.58), and lower education (OR 0.63) were associated with sons' circumcision. The minimal risks associated with circumcision and the lifetime benefits conferred underscore its contribution to public health in high HIV prevalence areas.

RESUMEN: A pesar del creciente interés en la Circuncisión Médica Temprana de Niños y Adolescentes (EIMC y EAMC, respectivamente, por su siglas en ingles) en Zambia, no se ha explorado la voluntad de los padres, de dar consentimiento, para que sus hijos se sometan al procedimiento. Este studio, describe las perspectivas de los padres de Zambia sobre EIMC y EAMC. Se reclutaron un total de N = 600 hombres y mujeres (n = 300 parejas) que esperaban tener un hijo. La mayoría de los padres, 89% y 83%, planeaban circuncidar a sus hijos recién nacidos o adolescentes, respectivamente, y 70% y 57% tenían planes para EIMC y EAMC, respectivamente. La mayoría (91% para bebés y 86% para adolescentes) informaron que estaban considerando las ventajas y desventajas de la circuncisión. La edad de los padres (OR 1,05), tener hijos viviendo en el hogar (OR 3,58) y menor educación (OR 0,63) se asociaron con la circuncisión de los hijos. Los riesgos mínimos asociados con la circuncisión y los beneficios conferidos de por vida subrayan su contribución a la salud pública en áreas de alta prevalencia del VIH.

Discoidin domain receptor 2 regulates aberrant mesenchymal lineage cell fate and matrix organization.

Extracellular matrix (ECM) interactions regulate both the cell transcriptome and proteome, thereby determining cell fate. Traumatic heterotopic ossification (HO) is a disorder characterized by aberrant mesenchymal lineage (MLin) cell differentiation, forming bone within soft tissues of the musculoskeletal system following traumatic injury. Recent work has shown that HO is influenced by ECM-MLin cell receptor signaling, but how ECM binding affects cellular outcomes remains unclear. Using time course transcriptomic and proteomic analyses, we identified discoidin domain receptor 2 (DDR2), a cell surface receptor for fibrillar collagen, as a key MLin cell regulator in HO formation. Inhibition of DDR2 signaling, through either constitutive or conditional Ddr2 deletion or pharmaceutical inhibition, reduced HO formation in mice. Mechanistically, DDR2 perturbation alters focal adhesion orientation and subsequent matrix organization, modulating Focal Adhesion Kinase (FAK) and Yes1 Associated Transcriptional Regulator and WW Domain Containing Transcription Regulator 1 (YAP/TAZ)-mediated MLin cell signaling. Hence, ECM-DDR2 interactions are critical in driving HO and could serve as a previously unknown therapeutic target for treating this disease process.

A small cluster randomised clinical trial to improve health outcomes among Argentine patients disengaged from HIV care.

Background: Patients disengaged from HIV care, e.g., missed medication pick-ups, not attending physician visits, account for ≥70% of new HIV infections. Re-engaging and sustaining engagement is essential to controlling the HIV pandemic. This study tested a physician-delivered evidence-based intervention, Motivational Interviewing (MI), to improve health outcomes, adherence to antiretroviral therapy (ART), HIV virologic suppression, CD4+ count, retention in HIV care, and self-efficacy among patients disengaged from care in Argentina. Methods: Regional clinics (n = 6) were randomised to condition, MI Intervention or Enhanced Standard of Care (ESOC), and recruited N = 360 patients disengaged from HIV care. ART adherence, HIV RNA viral load, CD4+ count retention, and self-efficacy were assessed at baseline, 6, 12, 18, and 24-months. Indirect effects from condition to main outcomes were examined using patient-provider relationship as a mediator. The study was a cluster-randomised clinical trial entitled Conexiones y Opciones Positivas en la Argentina 2 (COPA2) and was registered at clinicaltrials.gov, NCT02846350. Findings: Participants were an average age of 39·15 (SD = 10·96), 51% were women; intervention participants were older (p = ·019), and more ESOC participants were women (60% vs. 42%, p = 0·001). Using mixed models, the intervention had no effect on ART adherence over time by condition on HIV RNA viral load, CD4+ count retention, or self-efficacy. However, analysing mediated paths, there was an indirect effect of condition on ART adherence (B = 0·188, p = 0·009), HIV viral load (B = -0·095, P = 0·027), and self-efficacy (B = 0·063, P = 0·001), suggesting the intervention was associated with improved patient-provider relationships, which was in turn associated with increased ART adherence, lower HIV viral load, and higher self-efficacy. Interpretation: These findings suggest that physician-delivered MI may enhance the patient-provider relationship, self-efficacy, and ART adherence, and reduced HIV viral load in patients disengaged from HIV care. However, these findings are preliminary due to the small number of clusters randomised, and replication is warranted. Funding: National Institutes of Health.

Divergent regulation of basement membrane trafficking by human macrophages and cancer cells.

Macrophages and cancer cells populations are posited to navigate basement membrane barriers by either mobilizing proteolytic enzymes or deploying mechanical forces. Nevertheless, the relative roles, or identity, of the proteinase -dependent or -independent mechanisms used by macrophages versus cancer cells to transmigrate basement membrane barriers harboring physiologically-relevant covalent crosslinks remains ill-defined. Herein, both macrophages and cancer cells are shown to mobilize membrane-anchored matrix metalloproteinases to proteolytically remodel native basement membranes isolated from murine tissues while infiltrating the underlying interstitial matrix ex vivo. In the absence of proteolytic activity, however, only macrophages deploy actomyosin-generated forces to transmigrate basement membrane pores, thereby providing the cells with proteinase-independent access to the interstitial matrix while simultaneously exerting global effects on the macrophage transcriptome. By contrast, cancer cell invasive activity is reliant on metalloproteinase activity and neither mechanical force nor changes in nuclear rigidity rescue basement membrane transmigration. These studies identify membrane-anchored matrix metalloproteinases as key proteolytic effectors of basement membrane remodeling by macrophages and cancer cells while also defining the divergent invasive strategies used by normal and neoplastic cells to traverse native tissue barriers.

SNAI1 is upregulated during muscle regeneration and represses FGF21 and ATF3 expression by directly binding their promoters.

During skeletal myogenesis, the zinc-finger transcription factors SNAI1 and SNAI2, are expressed in proliferating myoblasts and regulate the transition to terminally differentiated myotubes while repressing pro-differentiation genes. Here, we demonstrate that SNAI1 is upregulated in vivo during the early phase of muscle regeneration induced by bupivacaine injury. Using shRNA-mediated gene silencing in C2C12 myoblasts and whole-transcriptome microarray analysis, we identified a collection of genes belonging to the endoplasmic reticulum (ER) stress pathway whose expression, induced by myogenic differentiation, was upregulated in absence of SNAI1. Among these, key ER stress genes, such as Atf3, Ddit3/Chop, Hspa5/Bip, and Fgf21, a myokine involved in muscle differentiation, were strongly upregulated. Furthermore, by promoter mutant analysis and Chromatin immune precipitation assay, we demonstrated that SNAI1 represses Fgf21 and Atf3 in proliferating myoblasts by directly binding to multiple E boxes in their respective promoter regions. Together, these data describe a new regulatory mechanism of myogenic differentiation involving the direct repressive action of SNAI1 on ER stress and Fgf21 expression, ultimately contributing to maintaining the proliferative and undifferentiated state of myoblasts.

Dissemination of the Spear & Shield Project using a Training of Trainers Model: A reflection on challenges and successes.

Several large-scale clinical trials have conclusively demonstrated that voluntary medical male circumcision (VMMC) could provide a 50%-70% reduction in HIV acquisition, but willingness to undergo VMMC has been lowest in Zambia compared to other countries in eastern and southern Africa. This manuscript describes training for "task-shifting" among local healthcare workers at Community Health Centers (CHCs) applying state of the art strategies (e.g., Training of Trainers, i.e., ToT, and Training of Facilitators, ToF) to provide novel clinical services. Staff at 96 CHCs from four Provinces in Zambia were sequentially trained to provide the Spear & Shield intervention. A total of 45,630 men (n = 23,236) and women (n = 22,394) volunteered to participate in the S&S intervention service program when offered in the CHCs. Group session (total = 5313 sessions; 2,736 men's and 2,582 women's sessions) were conducted over 4.5 years. Remarkably, both men and women's groups achieved 97% retention. Of these, 256 sessions recorded from 128 group leaders were assessed and scored for intervention fidelity; fidelity was 80%-90% among the majority of clinics. S&S program sustainment exceeded expectations among 85% of clinics (82/96) in all provinces across the duration of the study. Of note, attendance in the S&S program was encouraged by CHC staff, but no financial incentives were provided to those attending S&S. This study examined the effectiveness of the ToT/ToF model in dissemination of the S&S program, which proved to be feasible even in resource-limited settings. Benefits and challenges are discussed.

Understanding barriers and facilitators to voluntary medical male circumcision and Spear and Shield uptake in Zambian community health centers.

Voluntary medical male circumcision (VMMC) has been an effective method for reducing the risk of HIV transmission by 50%-70% in Eastern and Southern Africa. The Spear and Shield (S&S) program is a community health center (CHC)-based biobehavioral VMMC HIV prevention intervention that increased VMMC uptake in male CHC attendees in Lusaka, Zambia. Qualitative data organized using the Consolidated Framework for Implementation Research (CFIR) has been used to characterize factors that may impact S&S/VMMC implementation. This manuscript uses the CFIR to examine S&S implementation across 96 CHCs in four Zambian provinces using a mixed-methods approach to (a) quantify successful S&S implementation; (b) understand how CFIR domains might provide insight into the degree of implemental success; (c) identify major themes among least and most successful CHCs; and (d) help guide future prevention efforts and policy related to VMMC promotion in the Zambian CHC context. In contrast with CFIR quantitative analyses, 12 major qualitative themes associated with the least and most successful CHCs provided unique insight into S&S and VMMC implementation and guidance for future implementation studies. Themes included lack of resources (staff, space, transportation) for the former and strong staff relationships and active community engagement for the latter. The CFIR framework appears extremely useful for the identification of qualitative themes related to intervention implementation, and reduction of qualitative data for quantitative analyses may sacrifice more nuanced information. Consideration of CFIR themes may be useful to inform HIV prevention strategies in Zambia and similar contexts.

Matrix remodeling controls a nuclear lamin A/C-emerin network that directs Wnt-regulated stem cell fate.

Skeletal stem cells (SSCs) reside within a three-dimensional extracellular matrix (ECM) compartment and differentiate into multiple cell lineages, thereby controlling tissue maintenance and regeneration. Within this environment, SSCs can proteolytically remodel the surrounding ECM in response to growth factors that direct lineage commitment via undefined mechanisms. Here, we report that Mmp14-dependent ECM remodeling coordinates canonical Wnt signaling and guides stem cell fate by triggering an integrin-activated reorganization of the SCC cytoskeleton that controls nuclear lamin A/C levels via the linker of nucleoskeleton and cytoskeleton (LINC) complexes. In turn, SSC lamin A/C levels dictate the localization of emerin, an inner nuclear membrane protein whose ability to regulate ß-catenin activity modulates Wnt signaling while directing lineage commitment in vitro and in vivo. These findings define a previously undescribed axis wherein SSCs use Mmp14-dependent ECM remodeling to control cytoskeletal and nucleoskeletal organization, thereby governing Wnt-dependent stem cell fate decisions.

Predicting cardiovascular risk using a novel risk score in young and middle-age adults with HIV: associations with biomarkers and carotid atherosclerotic plaque.

BACKGROUND: Traditional risk factors associated with cardiovascular disease (CVD) include older age, smoking, poor diet, lack of exercise, obesity, high blood pressure, high cholesterol, and family history. Young-to-middle age adults (YMAA) are less often identified as being at risk of CVD, but traditional risk scores primarily target older adults and do not accurately estimate risk among YMAA. METHODS: This study examined biomarkers associated with CVD risk in YMAA in the context of HIV and cocaine use; risk was assessed by two methods: (1) a relative cardiovascular (CV) risk score that includes several factors and (2) carotid atherosclerotic plaque. Associations between CVD risk (CV risk score and carotid atherosclerotic plaque) and proinflammatory cytokines, markers of immune activation, HIV status, and cocaine use were examined. Participants (N = 506) included people with and without HIV and people who use or do not use cocaine. RESULTS: Participants' mean age was 36 (SD = 9.53); half (51%) were men. Cocaine use and C-reactive protein were associated with greater relative CV risk scores, but no associations between biomarkers and CV risk emerged. Age and CV risk scores were associated with carotid atherosclerotic plaque, but biomarkers were not. HIV was not associated with CV risk scores or carotid atherosclerotic plaque. CONCLUSIONS: Among YMAA, CV risk scores may help providers identify lifestyle changes needed among those at risk for CVD before more advanced risk (e.g., atherosclerotic plaque) is identified. Implications are discussed.

Examining Factors Associated with Gender Identity Among Individuals Disengaged from HIV Care in Argentina.

BACKGROUND: Transgender women (TGW) consistently show lower adherence to antiretroviral treatment (ART), than cisgender people (CP) living with HIV. This study examined sociodemographic and psychosocial factors associated with gender identity among individuals disengaged from HIV care in Argentina. METHODS: Data for this study was obtained at baseline from the Conexiones y Opciones Positivas en la Argentina 2 (COPA2) study. Forty-one TGW and 360 CP (177 male, 183 female) disengaged from HIV care completed questionnaires assessing sociodemographic information, severity of depressive symptoms, substance and alcohol use, patient-provider relationship quality, self-efficacy, ART adherence motivation, self-reported adherence, and treatment-related factors. Analyses included chi-square tests exploring the association between categorical variables and gender identity, and ANCOVAs comparing groups controlling for age. RESULTS: Being a TGW was associated with having only public health insurance; substance use, particularly cocaine; substance-related problems; and hazardous drinking. TGW showed more negative consequences related to substance use, more hazardous alcohol use, lower patient-provider relationship quality, and lower self-reported adherence, than CP. CONCLUSIONS: Harm reduction should be a key component in HIV care for TGW to address substance use. Health care teams should receive formal training in patient-provider communication skills and trans-specific competencies to enhance TGW's adherence and retention. Public policies to address structural factors that negatively affect TGW's adherence to ART are also needed.

Psychological and physical intimate partner violence and sexual risk behavior among South African couples: a dyadic analysis.

This study aimed to examine intimate partner violence (IPV) as it relates to both partners' perceptions of IPV and sexual behaviors, considering how their IPV might be interdependent within the relationship dynamics. The sample consisted of 713 female-male dyads in which women were pregnant and living with HIV in rural South Africa. Using an actor-partner interdependence model (APIM), we examined the interdependent influence of psychological and physical IPV on men by their female partners and psychological and physical IPV on women by their male partners on sexual risk behavior. The APIM model found there were no actor (b = -0.06, SE = 0.05, p = .221) or partner (b = -1.2, SE = 0.06, p = .056) effects contributing to protected sex by female IPV victimization. In contrast, significant actor (b = -0.28, SE = 0.06, p < .001) and partner (b = -0.29, SE = 0.06, p < .001) effects for protection were related to male IPV victimization. The model also found that the covariate of female HIV disclosure was associated with both male (b = 0.5, SE = 0.12, p < .001) and female protected sexual intercourse (b = 0.58, SE = 0.1, p < .001). Female HIV disclosure was related to an increased likelihood of protected sex by both male and female partners. As male partners reported more IPV victimization, the likelihood of protected sex between male and female partners decreased.Trial registration: ClinicalTrials.gov identifier: NCT02085356.

Blood Pressure, Depression, and Suicidal Ideation Among Pregnant Women with HIV.

Although prior research has examined associations between blood pressure (BP), depression, and suicidal ideation, few studies have examined this in high-risk populations such as pregnant women with HIV (WHIV). The current study examined the association of BP with depression and suicidal ideation among pregnant WHIV (n = 217) in rural South Africa. BP data (measured ≤ 1 month before the study visit) was extracted from medical records. Depressive symptomatology and suicidal ideation were assessed using the Edinburgh Postnatal Depression Scale. Diastolic BP was positively associated with both suicidal ideation and depressive symptomatology, even after controlling for demographic variables, gestational age, and intimate partner violence. These findings suggest that WHIV with elevated BP may be at greater risk for antenatal depression and suicidal ideation. Future research should utilize longitudinal designs to examine potential mechanisms and the directionality of the relationship, as well as other contributing factors.

RESUMEN: Aunque investigaciones anteriores han examinado las asociaciones entre la presión arterial (PA), depresión e ideación suicida, pocos estudios han examinado esto en poblaciones de alto riesgo, como las mujeres embarazadas con VIH. El estudio actual examinó la asociación de la PA con la depresión y la ideación suicida entre mujeres embarazadas con VIH (n = 217) en zonas rurales de Sudáfrica. Los datos de PA (medidos ≤ 1 mes antes de la visita del estudio) se extrajeron de los registros médicos. La sintomatología depresiva y la ideación suicida se evaluaron mediante la Escala de depresión posnatal de Edimburgo. La PA diastólica se asoció positivamente tanto con la ideación suicida como con la sintomatología depresiva, incluso después de controlar variables demográficas, edad gestacional y violencia de la pareja íntima. Estos hallazgos sugieren que mujeres embarazadas con VIH con PA elevada puede tener un mayor riesgo de depresión prenatal e ideación suicida. Las investigaciones futuras deberían aprovechar diseños longitudinales para examinar los posibles mecanismos y la direccionalidad de la relación, así como otros factores contribuyentes.

Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance.

Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.