Right Heart Remodeling After Pulmonary Valve Replacement in Patients With Pulmonary Atresia or Critical Stenosis With Intact Ventricular Septum.

Background Patients with pulmonary atresia or critical pulmonary stenosis with intact ventricular septum (PA/IVS) and biventricular circulation may require pulmonary valve replacement (PVR). Right ventricular (RV) remodeling after PVR is well described in tetralogy of Fallot (TOF); we sought to investigate RV changes in PA/IVS using cardiac magnetic resonance imaging. Methods and Results A retrospective cohort of patients with PA/IVS who underwent PVR at Boston Children's Hospital from 1995 to 2021 with cardiac magnetic resonance imaging before and after PVR was matched 1:3 with patients with TOF by age at PVR. Median regression modeling was performed with post-PVR indexed RV end-diastolic volume as the primary outcome. A total of 20 patients with PA/IVS (cases) were matched with 60 patients with TOF (controls), with median age at PVR of 14 years. Pre-PVR indexed RV end-diastolic volume was similar between groups; cases had higher RV ejection fraction (51.4% versus 48.6%; P=0.03). Pre-PVR RV free wall and left ventricular (LV) longitudinal strain were similar, although LV midcavity circumferential strain was decreased in cases (-15.6 versus -17.1; P=0.001). At a median of 2 years after PVR, indexed RV end-diastolic volume was similarly reduced; cases continued to have higher RV ejection fraction (52.3% versus 46.9%; P=0.007) with less reduction in RV mass (Δ4.5 versus 9.6 g/m2; P=0.004). Post-PVR, RV and LV longitudinal strain remained unchanged, and LV circumferential strain was similar, although lower in cases. Conclusions Compared with patients with TOF, patients with PA/IVS demonstrate similar RV remodeling after PVR, with lower reduction in RV mass and comparatively higher RV ejection fraction. Although no differences were detected in peak systolic RV or LV strain values, further investigation of diastolic parameters is needed.

Flexibility: A Hidden But Trainable Morbidity in Pediatric Patients with Congenital Heart Disease.

Flexibility is important for range of motion, muscular performance, and injury prevention with exercise. Promoting exercise is important for patients with congenital and pediatric acquired heart disease (CHD), yet there are a paucity of data addressing flexibility in this population. We hypothesized that flexibility was worse in pediatric patients with CHD than the general population but could be improved with directed training. Patients at Boston Children's Hospital who participated in the pediatric Cardiac Fitness Program between 09/2016 and 11/2022 were retrospectively analyzed. Flexibility was assessed via sit-and-reach (SaR) box. Data from baseline and 60 days into the fitness program intervention were compared to age-matched population norms, and changes over time were assessed. Analyses were also stratified by sex and history of sternotomy. Patients with paired baseline and 60-day data were analyzed (n = 46, age 8-23 years old, 52% male). The mean SaR at baseline for CHD patients was 24.3 cm, significantly lower than the population norm (p = 0.002). The mean for male (n = 24, 21.2 cm) and female (n = 22, 27.2 cm) CHD patients was significantly lower than their respective population norms (p = 0.017 and p = 0.026, respectively). After the fitness intervention, flexibility in CHD patients significantly improved to normal, including patients with a history of sternotomy. Flexibility was significantly lower in CHD patients than the general population, but normalized with training. Further research is warranted to investigate associations of flexibility with other measures of fitness, cardiovascular status, and quality of life, as well as benefits gained with training.

FORCE Risk Stratification Tool for Pediatric Cardiac Rehabilitation and Fitness Programs.

Risk stratification is required to set an exercise prescription for cardiac rehabilitation, but an optimal scheme for congenital heart disease (CHD) is unknown. We piloted a system based on hemodynamic rather than anatomic factors: function, oxygen level, rhythm, complex/coronary anatomy, and elevated load (FORCE). Feasibility, efficacy, and safety of the FORCE tool were evaluated. Patients < 22 years old participating in the Cardiac Fitness Program at Boston Children's Hospital between 02/2017 and 12/2021 were retrospectively analyzed. Assigned FORCE levels, anatomy, adverse events, fitness and exercise test data were collected. Of 63 attempts at FORCE classification, 62 (98%) were successfully classified while one with restrictive cardiomyopathy was not. Thirty-nine (62%) were FORCE 1, 16 (25%) were FORCE 2, and seven (11%) were FORCE 3. Almost half of FORCE 1 patients had simple or complex CHD and the majority of FORCE 2 patients had single ventricle CHD. FORCE 3 patients were more likely to have serious arrhythmias or cardiomyopathy than those in FORCE 1 or 2 (p < 0.001). Postural orthostatic tachycardia syndrome patients appeared in FORCE 1 only. No adverse events occurred over 958 total sessions. The total number of fitness sessions/participant was similar across FORCE levels. It was feasible to risk stratify patients with CHD using a clinical FORCE tool. The tool was effective in categorizing patients and simple to use. No adverse events occurred with fitness training over nearly 1000 exercise training sessions. Adding diastolic dysfunction to the original model may add utility.

Practical and psychosocial challenges faced by caregivers influence the acceptability of multidrug-resistant tuberculosis preventive therapy for young children.

Drug-resistant (DR) strains of Mycobacterium tuberculosis (M. tb) are increasingly recognised as a threat to global tuberculosis (TB) control efforts. Identifying people with DR-TB exposure/ infection and providing TB preventive therapy (TPT) is a public health priority. TB guidelines advise the evaluation of household contacts of newly diagnosed TB cases, with the provision of TPT to vulnerable populations, including young children (<5 years). Many children become infected with TB through exposure in their household. Levofloxacin is under evaluation as TPT in children exposed to M. tb strains with resistance to rifampicin and isoniazid (multidrug-resistant TB; MDR-TB). Prior to opening a phase 3 prevention trial in children <5 years exposed to MDR-TB, the pharmacokinetics and safety of a novel formulation of levofloxacin given daily was evaluated as part of a lead-in study. We conducted an exploratory qualitative study of 10 caregivers' experiences of administering this formulation. We explored how the acceptability of levofloxacin as TPT is shaped by the broader impacts of MDR-TB on the overall psychological, social, and financial wellbeing of caregivers, many of whom also had experienced MDR-TB. Caregivers reported that the novel levofloxacin formulation was acceptable. However, caregivers described significant psychosocial challenges in the process of incorporating TPT administration to their children into their daily lives, including financial instability, withdrawal of social support and stigma. When caregivers themselves were sick, these challenges became even more acute. Although new child-friendly formulations can ameliorate some of the pragmatic challenges related to TPT preparation and administration, the overall psychosocial burden on caregivers responsible for administering TPT remains a major determinant of effective MDR-TB prevention in children.

Toward a conceptual framework of the acceptability of tuberculosis treatment in children using a theory generative approach.

To describe an early-stage holistic framework towards evaluating factors that impact the overall acceptability of TB treatment along the TB care cascade in children. We developed a conceptual framework utilising a theory generative approach. Domains were developed through review of existing definitions and analysis of existing qualitative data undertaken in acceptability studies of TB treatment in children. Clarity of domain definitions was achieved through iterative refinement among the research team. Three domains, each comprising several dimensions, were identified to holistically evaluate treatment acceptability: (1) usability, which involves the alignment between the requirements of treatment use and caregivers' and children's ability to integrate TB treatment into their everyday routines, (2) receptivity, which describes the end-user's perception and expectations of treatment and its actual use, and (3) integration, which describes the relationship between available health services and caregivers/children's capacity to make use of those services. Our framework addresses the gaps in current research which do not account for the influence of caregivers' and children's contexts on TB treatment uptake and overall acceptability. This approach may support the development of more standard, holistic measures to improve TB treatment delivery and experiences and future research in children.

Women's sexual scripting in the context of universal access to antiretroviral treatment-findings from the HPTN 071 (PopART) trial in South Africa.

BACKGROUND: HIV treatment-based prevention modalities present new opportunities for women to make decisions around sex, intimacy, and prevention. The Universal test and treat (UTT) strategy, where widespread HIV testing is implemented and all people with HIV can access treatment, has the potential to change how sex is understood and HIV prevention incorporated into sexual relationships. We use the frame of sexual scripting to explore how women attribute meaning to sex relative to UTT in an HIV prevention trial setting. Exploring women's sexual narratives, we explored how HIV prevention feature in the sexual scripts for women who had access to UTT in South Africa (prior to treatment guideline changes) and increased HIV prevention messaging, compared to places without widespread access to HIV testing and immediate access to treatment. METHODS: We employed a two-phased thematic analysis to explore longitudinal qualitative data collected from 71 women (18-35 years old) between 2016 and 2018 as part of an HIV prevention trial in the Western Cape Province, South Africa. Of the participants, 58/71 (82%) were from intervention communities while 13/71 (18%) lived in control communities without access to UTT. Twenty participants self-disclosed that they were living with HIV. RESULTS: We found no narrative differences between women who had access to UTT and those who did not. HIV and HIV prevention, including treatment-based prevention modalities, were largely absent from women's thinking about sex. In their scripts, women idealised romantic sex, positioned sex as 'about relationships', and described risky sex as 'other'. When women were confronted by HIV risk (for example, when a partner disclosed his HIV-positive status) this created a point of disjuncture between this new perception of risk and their accepted relationship scripts. CONCLUSION: These findings suggest that HIV-negative women did not include their partners' use of antiretroviral therapy in their sexual partnership choices. For these women, the preventive benefits of UTT are experienced passively-through community-wide viral suppression-rather than through their own behaviour change explicitly related to the availability of treatment as prevention. We propose that prevention-based modalities should be made available and supported and framed as an intervention to promote relationship well-being.

Implementing 'universal' access to antiretroviral treatment in South Africa: a scoping review on research priorities.

'Universal' access to antiretroviral treatment (ART) has become the global standard for treating people living with HIV and achieving epidemic control; yet, findings from numerous 'test and treat' trials and implementation studies in sub-Saharan Africa suggest that bringing 'universal' access to ART to scale is more complex than anticipated. Using South Africa as a case example, we describe the research priorities and foci in the literature on expanded ART access. To do so, we adapted Arksey and O'Malley's six-stage scoping review framework to describe the peer-reviewed literature and opinion pieces on expanding access to ART in South Africa between 2000 and 2017. Data collection included systematic searches of two databases and hand-searching of a sub-sample of reference lists. We used an adapted socio-ecological thematic framework to categorize data according to where it located the challenges and opportunities of expanded ART eligibility: individual/client, health worker-client relationship, clinic/community context, health systems infrastructure and/or policy context. We included 194 research articles and 23 opinion pieces, of 1512 identified, addressing expanded ART access in South Africa. The peer-reviewed literature focused on the individual and health systems infrastructure; opinion pieces focused on changing roles of individuals, communities and health services implementers. We contextualized our findings through a consultative process with a group of researchers, HIV clinicians and programme managers to consider critical knowledge gaps. Unlike the published literature, the consultative process offered particular insights into the importance of researching and intervening in the relational aspects of HIV service delivery as South Africa's HIV programme expands. An overwhelming focus on individual and health systems infrastructure factors in the published literature on expanded ART access in South Africa may skew understanding of HIV programme shortfalls away from the relational aspects of HIV services delivery and delay progress with finding ways to leverage non-medical modalities for achieving HIV epidemic control.

The act of telling: South African women's narratives of HIV status disclosure to intimate partners in the HPTN 071 (PopART) HIV prevention trial.

BACKGROUND: Public health programming often frames HIV status disclosure as a means to negotiate condom- and abstinence-based prevention or to involve intimate partners in HIV care to garner treatment adherence support. HIV treatment can be used to ensure viral suppression and prevent onward transmission, which provides strong evidence to encourage disclosure. The ideological shift towards HIV treatment as prevention is expected to facilitate disclosure. PURPOSE: There is a lack of research on how the scale-up of universal HIV testing and treatment influences disclosure practices in high burden settings. In this manuscript, we aim to address this gap. METHODS: To this end, we conducted a two-phased narrative performative analysis of the disclosure scripts of 15 women living with HIV in three communities of Western Cape, South Africa where the HPTN 071 (PopART) HIV prevention trial implemented a universal HIV testing and treatment model as part of the intervention. The women were part of a larger cohort nested in the trial. We use Goffman's dramaturgical metaphor, which understands social interactions as 'performances' by 'actors' (people) guided by 'scripts' (anticipated dialogues/interactions), to explore how women living with HIV manage their status disclosure. CONCLUSION: We describe how these women perform HIV status disclosure (or deliberate non-disclosure) to retain, reaffirm or redefine existing social scripts with partners. Their performances reveal priorities other than those imagined by public health programmes driving HIV disclosure (or non-disclosure): establishing trust, resenting betrayal and ensuring self-preservation while simultaneously (re)constructing self-identity. None of the women engaged with the concept of treatment as prevention in their disclosure narratives, either to facilitate disclosure or to 'justify' non-disclosure. HIV prevention, in general, and treatment adherence support were rarely mentioned as a reason for disclosure. To date, there has been a missed opportunity to ease and support disclosure in health programmes by tapping into existing social scripts, impeding potential patient and public health benefits of universal HIV testing and treatment.

"It Stays Between Us": Managing Comorbidities and Public/Private Dichotomies in HPTN071 (POPART) Trial Communities.

In contexts of scarcity, managing comorbidities is a complex process, shaped by divergent understandings of causes, prognoses, and social meanings of illness. Drawing on research with one young South African woman living with HIV and epilepsy, and 13 other people with comorbidities, we describe how concepts of "public" and "private" shape the management of co-morbid conditions. Despite narratives of HIV "normalization," participants labored to keep their HIV status private, while sharing other illness experiences more publicly. We challenge simple dichotomies between public and private spheres and emphasize the need for more fluid understandings of how people negotiate social space.

Universal HIV testing and treatment and HIV stigma reduction: a comparative thematic analysis of qualitative data from the HPTN 071 (PopART) trial in South Africa and Zambia.

Despite continued development of effective HIV treatment, expanded access to care and advances in prevention modalities, HIV-related stigma persists. We examine how, in the context of a universal HIV-testing and treatment trial in South Africa and Zambia, increased availability of HIV services influenced conceptualisations of HIV. Using qualitative data, we explore people's stigma-related experiences of living in 'intervention' and 'control' study communities. We conducted exploratory data analysis from a qualitative cohort of 150 households in 13 study communities, collected between 2016 and 2018. We found that increased availability of HIV-testing services influenced conceptualisations of HIV as normative (non-exceptional) and the visibility of people living with HIV (PLHIV) in household and community spaces impacted opportunities for stigma. There was a shift in community narratives towards individual responsibility to take up (assumingly) widely available service - for PLHIV to take care of their own health and to prevent onward transmission. Based on empirical data, we show that, despite a growing acceptance of HIV-related testing services, anticipated stigma persists through the mechanism of shifting responsibilisation. To mitigate the responsibilisation of PLHIV, heath implementers need to adapt anti-stigma messaging and especially focus on anticipated stigma.

Stigma and HIV service access among transfeminine and gender diverse women in South Africa - a narrative analysis of longitudinal qualitative data from the HPTN 071 (PopART) trial.

BACKGROUND: Transgender women have a disproportionately high HIV prevalence compared to cisgender women and men who have sex with men, which puts them at risk of HIV-related stigma (Baral SD et al., Lancet Infect Dis, 13;3, 2013). People whose gender identities are in tension with dominant social norms (including transgender women) often also experience gender identity-related stigma. There has been increasing attention to transgender people in HIV research and interventions. However, very little research has been done in sub-Saharan African countries. METHODS: We conducted a qualitative cohort study which included eight transfeminine and/or gender diverse women (four living with HIV) in Western Cape, South Africa, for a follow-up period of 12-18 months. Using a narrative analysis approach, we set out to understand how transfeminine and gender diverse participants in the cohort anticipated, experienced and internalised HIV stigma and gender identity stigma, and how these stigmas affected HIV service access. RESULT: We found that participants reported anticipated, experienced, and internalised stigma relating both to their gender identity and to living with HIV. Participants reported inconsistent uptake of antiretroviral therapy (ART) services (including ART initiation and adherence) that they linked to stigma. We also found that gender diverse women and transfeminine women are challenged with other stigmatising social identities, like being a sex worker, drug user and/or a man (or assigned male sex at birth) who have sex with men (MSM). We use the terms 'transfeminine' and 'gender diverse' as terms that are inclusive of gender variant people who were all assigned male sex at birth and identify as women in some or all aspects of their lives. The persons in our study also showed gender identifications that were fluid and sometimes varied in different contexts and situations, therefore gender identity and sexual identity were often conflated for these individuals. Participants managed high levels of reported stigma by drawing on social support networks like families, friends and peers. CONCLUSION: Our study provides exploratory work on how stigma may affect HIV services uptake amongst gender diverse women and transfeminine women in South Africa. We recommend future studies to further explore the unique HIV risks of gender diverse individuals. TRIAL REGISTRATION: DOH-27-0513-4253 .

Selective loss of phosphoserine aminotransferase 1 (PSAT1) suppresses migration, invasion, and experimental metastasis in triple negative breast cancer.

Breast cancer is the second leading cause of cancer-related deaths among women and 90% of these mortalities can be attributed to progression to metastatic disease. In particular, triple negative breast cancer (TNBC) is extremely aggressive and frequently metastasizes to multiple organs. As TNBCs are categorized by their lack of hormone receptors, these tumors are very heterogeneous and are immune to most targeted therapies. Metabolic changes are observed in the majority of TNBC and a large proportion upregulate enzymes within the serine synthesis pathway, including phosphoserine aminotransferase 1 (PSAT1). In this report, we investigate the role of PSAT1 in migration and invasion potential in a subset of TNBC cell types. We found that the expression of PSAT1 increases with TNBC clinical grade. We also demonstrate that suppression of PSAT1 or phosphoglycerate dehydrogenase (PHGDH) does not negatively impact cell proliferation in TNBC cells that are not dependent on de novo serine synthesis. However, we observed that suppression of PSAT1 specifically alters the F-actin cytoskeletal arrangement and morphology in these TNBC cell lines. In addition, suppression of PSAT1 inhibits motility and migration in these TNBC cell lines, which is not recapitulated upon loss of PHGDH. PSAT1 silencing also reduced the number of lung tumor nodules in a model of experimental metastasis; yet did not decrease anchorage-independent growth. Together, these results suggest that PSAT1 functions to drive migratory potential in promoting metastasis in select TNBC cells independent of its role in serine synthesis.

Households, fluidity, and HIV service delivery in Zambia and South Africa - an exploratory analysis of longitudinal qualitative data from the HPTN 071 (PopART) trial.

INTRODUCTION: Population distributions, family and household compositions, and people's sense of belonging and social stability in southern Africa have been shaped by tumultuous, continuing large-scale historical disruptions. As a result, many people experience high levels of geographic and social fluidity, which intersect with individual and population-level migration patterns. We describe the complexities of household fluidity and HIV service access in South Africa and Zambia to explore implications for health systems and service delivery in contexts of high household fluidity. METHODS: HPTN 071 (PopART) is a three-arm cluster randomized controlled trial implemented in 21 peri-urban study communities in Zambia and South Africa between 2013 and 2018. A qualitative cohort nested in the trial included 148 purposively sampled households. Data collection was informed by ethnographic and participatory research principles. The analysis process was reflexive and findings are descriptive narrative summaries of emergent ideas. RESULTS: Households in southern Africa are extremely fluid, with people having a tenuous sense of security in their social networks. This fluidity intersects with high individual and population mobility. To characterize fluidity, we describe thematic patterns of household membership and residence. We also identify reasons people give for moving around and shifting social ties, including economic survival, fostering interpersonal relationships, participating in cultural, traditional, religious, or familial gatherings, being institutionalized, and maintaining patterns of substance use. High fluidity disrupted HIV service access for some participants. Despite these challenges, many participants were able to regularly access HIV testing services and participants living with HIV were especially resourceful in maintaining continuity of antiretroviral therapy (ART). We identify three key features of health service interactions that facilitated care continuity: disclosure to family members, understanding attitudes among health services staff including flexibility to accommodate clients' transient pressures, and participants' agency in ART-related decisions. CONCLUSIONS: Choices made to manage one's experiential sense of household fluidity are intentional responses to livelihood and social support constraints. To enhance retention in care for people living with HIV, policy makers and service providers should focus on creating responsive, flexible health service delivery systems designed to accommodate many shifts in client circumstances.

Community narratives about women and HIV risk in 21 high-burden communities in Zambia and South Africa.

Public health researchers repeatedly represent women as a group vulnerable to ill health. This has been particularly true in the field of HIV research, where women are disproportionately affected by HIV in terms of disease burden and the social effects of the epidemic. Although women have been the focus of many prevention and treatment programs, structural barriers to implementation of these targeted programs persist. In this article we explore how high HIV-burden communities in South Africa and Zambia engage with the concepts of "woman" and "HIV risk". The data are drawn from participatory storytelling activities completed with 604 participants across 78 group discussions between December 2012 and May 2013. During discussions we found that participants made use of the core archetypal caricatures of "goodness," "badness," and "vulnerability" when describing women's HIV risk. Community members shifted between these categories in their characterizations of women, as they acknowledged the multiple roles women play, internalized different stories about women, and sometimes shifted register in the same stories. Findings suggest that health implementers, in consultation with community members, should consider the multiple positions women occupy and how this impacts the wider community's understandings of women and "risk". This approach of taking on board community understandings of the complexity of HIV risk can inform the design and implementation of HIV prevention and care programs by rendering programs more focused and in-line with community needs.

Expression of the lncRNA Maternally Expressed Gene 3 (MEG3) Contributes to the Control of Lung Cancer Cell Proliferation by the Rb Pathway.

Maternally expressed gene 3 (MEG3, mouse homolog Gtl2) encodes a long noncoding RNA (lncRNA) that is expressed in many normal tissues, but is suppressed in various cancer cell lines and tumors, suggesting it plays a functional role as a tumor suppressor. Hypermethylation has been shown to contribute to this loss of expression. We now demonstrate that MEG3 expression is regulated by the retinoblastoma protein (Rb) pathway and correlates with a change in cell proliferation. Microarray analysis of mouse embryonic fibroblasts (MEFs) isolated from mice with genetic deletion of all three Rb family members (TKO) revealed a significant silencing of Gtl2/MEG3 expression compared to WT MEFs, and re-expression of Gtl2/MEG3 caused decrease in cell proliferation and increased apoptosis. MEG3 levels also were suppressed in A549 lung cancer cells compared with normal human bronchial epithelial (NHBE) cells, and, similar to the TKO cells, re-constitution of MEG3 led to a decrease in cell proliferation and elevated apoptosis. Activation of pRb by treatment of A549 and SK-MES-1 cells with palbociclib, a CDK4/6 inhibitor, increased the expression of MEG3 in a dose-dependent manner, while knockdown of pRb/p107 attenuated this effect. In addition, expression of phosphorylation-deficient mutant of pRb increased MEG3 levels in both lung cancer cell types. Treatment of these cells with palbociclib also decreased the expression of pRb-regulated DNA methyltransferase 1 (DNMT1), while conversely, knockdown of DNMT1 resulted in increased expression of MEG3. As gene methylation has been suggested for MEG3 regulation, we found that palbociclib resulted in decreased methylation of the MEG3 locus similar to that observed with 5-aza-deoxycytidine. Anti-sense oligonucleotide silencing of drug-induced MEG3 expression in A549 and SK-MES-1 cells partially rescued the palbociclib-mediated decrease in cell proliferation, while analysis of the TCGA database revealed decreased MEG3 expression in human lung tumors harboring a disrupted RB pathway. Together, these data suggest that disruption of the pRb-DNMT1 pathway leads to a decrease in MEG3 expression, thereby contributing to the pro-proliferative state of certain cancer cells.

Inhibition of 6-phosphofructo-2-kinase (PFKFB3) suppresses glucose metabolism and the growth of HER2+ breast cancer.

PURPOSE: Human epidermal growth factor receptor-2 (HER2) has been implicated in the progression of multiple tumor types, including breast cancer, and many downstream effectors of HER2 signaling are primary regulators of cellular metabolism, including Ras and Akt. A key downstream metabolic target of Ras and Akt is the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 isozyme (PFKFB3), whose product, fructose-2,6-bisphosphate (F26BP), is a potent allosteric activator of a rate-limiting enzyme in glycolysis, 6-phosphofructo-1-kinase (PFK-1). We postulate that PFKFB3 may be regulated by HER2 and contribute to HER2-driven tumorigenicity. METHODS: Immunohistochemistry and Kaplan-Meier analysis of HER2+ patient samples investigated the relevance of PFKFB3 in HER2+ breast cancer. In vitro genetic and pharmacological inhibition of PFKFB3 was utilized to determine effects on HER2+ breast cancer cells, while HER2 antagonist treatment assessed the mechanistic regulation on PFKFB3 expression and glucose metabolism. Administration of a PFKFB3 inhibitor in a HER2-driven transgenic breast cancer model evaluated this potential therapeutic approach in vivo. RESULTS: PFKFB3 is elevated in human HER2+ breast cancer and high PFKFB3 transcript correlated with poorer progression-free (PFS) and distant metastatic-free (DFMS) survival. Constitutive HER2 expression led to elevated PFKFB3 expression and increased glucose metabolism, while inhibition of PFKFB3 suppressed glucose uptake, F26BP, glycolysis, and selectively decreased the growth of HER2-expressing breast cancer cells. In addition, treatment with lapatinib, an FDA-approved HER2 inhibitor, decreased PFKFB3 expression and glucose metabolism in HER2+ cells. In vivo administration of a PFKFB3 antagonist significantly suppressed the growth of HER2-driven breast tumors and decreased 18F-2-deoxy-glucose uptake. CONCLUSIONS: Taken together, these data support the potential clinical utility of PFKFB3 inhibitors as chemotherapeutic agents against HER2+ breast cancer.

"The difference that makes a difference": highlighting the role of variable contexts within an HIV Prevention Community Randomised Trial (HPTN 071/PopART) in 21 study communities in Zambia and South Africa.

This paper explores contextual heterogeneity within a community randomised trial HPTN 071 (Population Effects of Antiretroviral Treatment to Reduce HIV Transmission) carried out in 21 study communities (12 Zambian, 9 South African). The trial evaluates the impact of a combination HIV prevention package (including household-based HIV counselling and testing and anti-retroviral treatment (ART) eligibility regardless of CD4-count) on HIV incidence. The selection, matching and randomisation of study communities relied on key epidemiological and demographic variables and community and stakeholder support. In 2013, following the selection of study communities, a "Broad Brush Survey" (BBS) approach was used to rapidly gather qualitative data on each study community, prior to the implementation of the trial intervention. First-year process indicator intervention data (2014-2015) were collected during the household-based intervention by community lay workers. Using an open/closed typology of urban communities (indicating more or less heterogeneity), this qualitative inquiry presents key features of 12 Zambian communities using a list of four meta-indicators (physical features, social organisation, networks and community narratives). These indicators are then compared with four intervention process indicators in a smaller set of four study communities. The process indicators selected for this analysis indicate response to the intervention (uptake) amongst adults. The BBS qualitative data are used to interpret patterns of similarity and variability in the process indicators across four communities. We found that meta-indicators of local context helped to interpret patterns of similarity and variability emerging across and within the four communities. Features especially significant for influencing heterogeneity in process indicators include proportion of middle-class residents, proximity to neighbouring communities and town centre, the scale of the informal economy, livelihood-linked mobility, presence of HIV stakeholders over time and commitment to community action. Future interdisciplinary analysis is needed to explore if these patterns of difference continue to hold up over the full intervention period and all intervention communities.

Interrogating concepts of care in the HIV care continuum: ethnographic insights from the implementation of a "Universal Test and Treat" approach in South Africa.

South Africa currently sustains the largest antiretroviral treatment (ART) programme in the world. The number of people on ART is set to grow even more in the coming years as incidence remains stable, people on ART stay healthy, and guidelines for initiation become increasingly inclusive. The South African public health sector has increasingly relied on community- and home-based lay and professional "carers" to carry out the everyday tasks of rolling out the ART programme. Drawing on ethnographic research in one locality in the Western Cape, the paper explores the care practices of two such groups of carers implementing a 'Universal Test and Treat' (UTT) approach. The UTT approach being evlauated in this place is based on one model of the HIV treatment cascade, or care continuum, which focuses on the steps necessary to identify and link HIV-positive individuals to care and retain them in lifelong HIV treatment. In this context, community-based care workers are responsible for carrying out several discrete steps in the HIV care continuum, including testing people for HIV, linking HIV-positive individuals to care, and supporting adherence. In order to retain clients within the continuum, however, carers also perform other forms of labour that stretch their care work beyond more bounded notions of a stepwise progression of care. These broader forms of care, which can be material, emotional, social or physical in nature, appear alongside the more structured technical and biomedical tasks formally expected of carers. We argue that understanding the dynamics of these more distributed and relational forms of care is essential for the effective implementation of the care continuum, and of the UTT approach, in diverse contexts.