Kristina Talbert-Slagle

Variation In Health Outcomes: The Role Of Spending On Social Services, Public Health, And Health Care, 2000–09

Although spending rates on health care and social services vary substantially across the states, little is known about the possible association between variation in state-level health outcomes and the allocation of state spending between health care and social services. To estimate that association, we used state-level repeated measures multivariable modeling for the period 2000-09, with region and time fixed effects adjusted for total spending and state demographic and economic characteristics and with one- and two-year lags. We found that states with a higher ratio of social to health spending (calculated as the sum of social service spending and public health spending divided by the sum of Medicare spending and Medicaid spending) had significantly better subsequent health outcomes for the following seven measures: adult obesity; asthma; mentally unhealthy days; days with activity limitations; and mortality rates for lung cancer, acute myocardial infarction, and type 2 diabetes. Our study suggests that broadening the debate beyond what should be spent on health care to include what should be invested in health-not only in health care but also in social services and public health-is warranted.

The Bovine Papillomavirus E5 Protein and the PDGF β Receptor: It Takes Two to Tango

The extremely hydrophobic, 44-amino acid bovine papillomavirus (BPV) E5 protein is the smallest known oncoprotein, which orchestrates cell transformation by causing ligand-independent activation of a cellular receptor tyrosine kinase, the platelet-derived growth factor beta receptor (PDGFbetaR). The E5 protein forms a dimer in transformed cells and is essentially an isolated membrane-spanning segment that binds directly to the transmembrane domain of the PDGFbetaR, inducing receptor dimerization, autophosphorylation, and sustained mitogenic signaling. There are few sequence constraints for activity as long as the overall hydrophobicity of the E5 protein and its ability to dimerize are preserved. Nevertheless, the E5 protein is highly specific for the PDGFbetaR and does not activate other cellular proteins. Genetic screens of thousands of small, artificial hydrophobic proteins with randomized transmembrane domains inserted into an E5 scaffold identified proteins with diverse transmembrane sequences that activate the PDGFbetaR, including some activators as small as 32-amino acids. Analysis of these novel proteins has provided new insight into the requirements for PDGFbetaR activation and specific transmembrane recognition in general. These results suggest that small, transmembrane proteins can be constructed and selected that specifically bind to other cellular or viral transmembrane target proteins. By using this approach, we have isolated a 44-amino acid artificial transmembrane protein that appears to activate the human erythropoietin receptor. Studies of the tiny, hydrophobic BPV E5 protein have not only revealed a novel mechanism of viral oncogenesis, but have also suggested that it may be possible to develop artificial small proteins that specifically modulate much larger target proteins by acting within cellular or viral membranes.

A model for scale up of family health innovations in low-income and middle-income settings: a mixed methods study.

Background Many family health innovations that have been shown to be both efficacious and cost-effective fail to scale up for widespread use particularly in low-income and middle-income countries (LMIC). Although individual cases of successful scale-up, in which widespread take up occurs, have been described, we lack an integrated and practical model of scale-up that may be applicable to a wide range of public health innovations in LMIC. Objective To develop an integrated and practical model of scale-up that synthesises experiences of family health programmes in LMICs. Data sources We conducted a mixed methods study that included in-depth interviews with 33 key informants and a systematic review of peer-reviewed and grey literature from 11 electronic databases and 20 global health agency web sites. Study eligibility criteria, participants and interventions We included key informants and studies that reported on the scale up of several family health innovations including Depo-Provera as an example of a product innovation, exclusive breastfeeding as an example of a health behaviour innovation, community health workers (CHWs) as an example of an organisational innovation and social marketing as an example of a business model innovation. Key informants were drawn from non-governmental, government and international organisations using snowball sampling. An article was excluded if the article: did not meet the studys definition of the innovation; did not address dissemination, diffusion, scale up or sustainability of the innovation; did not address low-income or middle-income countries; was superficial in its discussion and/or did not provide empirical evidence about scale-up of the innovation; was not available online in full text; or was not available in English, French, Spanish or Portuguese, resulting in a final sample of 41 peer-reviewed articles and 30 grey literature sources. Study appraisal and synthesis methods We used the constant comparative method of qualitative data analysis to extract recurrent themes from the interviews, and we integrated these themes with findings from the literature review to generate the proposed model of scale-up. For the systematic review, screening was conducted independently by two team members to ensure consistent application of the predetermined exclusion criteria. Data extraction from the final sample of peer-reviewed and grey literature was conducted independently by two team members using a pre-established data extraction form to list the enabling factors and barriers to dissemination, diffusion, scale up and sustainability. Results The resulting model—the AIDED model—includes five non-linear, interrelated components: (1) assess the landscape, (2) innovate to fit user receptivity, (3) develop support, (4) engage user groups and (5) devolve efforts for spreading innovation. Our findings suggest that successful scale-up occurs within a complex adaptive system, characterised by interdependent parts, multiple feedback loops and several potential paths to achieve intended outcomes. Failure to scale up may be attributable to insufficient assessment of user groups in context, lack of fit of the innovation with user receptivity, inability to address resistance from stakeholders and inadequate engagement with user groups. Limitations The inductive approach used to construct the AIDED model did not allow for simultaneous empirical testing of the model. Furthermore, the literature may have publication bias in which negative studies are under-represented, although we did find examples of unsuccessful scale-up. Last, the AIDED model did not address long-term, sustained use of innovations that are successfully scaled up, which would require longer-term follow-up than is common in the literature. Conclusions and implications of key findings Flexible strategies of assessment, innovation, development, engagement and devolution are required to enable effective change in the use of family health innovations in LMIC.

Endothelial Cells Promote Human Immunodeficiency Virus Replication in Nondividing Memory T Cells via Nef-, Vpr-, and T-Cell Receptor-Dependent Activation of NFAT

ABSTRACT Human endothelial cells (ECs) enhance human immunodeficiency virus (HIV) replication within CD4+ memory T cells by 50,000-fold in a Nef-dependent manner. Here, we report that EC-mediated HIV type 1 replication is also dependent on an intact vpr gene. Moreover, we demonstrate that despite a requirement for engaging major histocompatibility complex (MHC) class II molecules and costimulators, EC-stimulated virus-producing cells (p24high T cells) do not proliferate, nor are they arrested in the cell cycle. Rather, they are minimally activated, sometimes expressing CD69 but not CD25, HLA-DR, VLA-1, or effector cytokines. Blocking antibodies to interleukin 2 (IL-2), IL-6, IL-7, or tumor necrosis factor do not inhibit viral replication. Cyclosporine effectively inhibits viral replication, as does disruption of the NFAT binding site in the viral long terminal repeat. Furthermore, in the presence of ECs, suboptimal T-cell receptor (TCR) stimulation with phytohemagglutinin L supports efficient viral replication, and suboptimal stimulation with toxic shock syndrome toxin 1 leads to viral replication selectively in the TCR-stimulated, Vβ2-expressing T cells. Collectively, these data indicate that ECs provide signals that promote Nef- and Vpr-dependent HIV replication in memory T cells that have been minimally activated through their TCRs. Our studies suggest a mechanism for HIV replication in vivo within the reservoir of circulating memory CD4+ T cells that persist despite antiretroviral therapy and further suggest that maintenance of immunological memory by MHC class II-expressing ECs via TCR signaling may contribute to HIV rebound following cessation of antiretroviral therapy.

Artificial Transmembrane Oncoproteins Smaller than the Bovine Papillomavirus E5 Protein Redefine Sequence Requirements for Activation of the Platelet-Derived Growth Factor β Receptor

ABSTRACT The bovine papillomavirus E5 protein (BPV E5) is a 44-amino-acid homodimeric transmembrane protein that binds directly to the transmembrane domain of the platelet-derived growth factor (PDGF) β receptor and induces ligand-independent receptor activation. Three specific features of BPV E5 are considered important for its ability to activate the PDGF β receptor and transform mouse fibroblasts: a pair of C-terminal cysteines, a transmembrane glutamine, and a juxtamembrane aspartic acid. By using a new genetic technique to screen libraries expressing artificial transmembrane proteins for activators of the PDGF β receptor, we isolated much smaller proteins, from 32 to 36 residues, that lack all three of these features yet still dimerize noncovalently, specifically activate the PDGF β receptor via its transmembrane domain, and transform cells efficiently. The primary amino acid sequence of BPV E5 is virtually unrecognizable in some of these proteins, which share as few as seven consecutive amino acids with the viral protein. Thus, small artificial proteins that bear little resemblance to a viral oncoprotein can nevertheless productively interact with the same cellular target. We speculate that similar cellular proteins may exist but have been overlooked due to their small size and hydrophobicity.

Cellular Superspreaders: An Epidemiological Perspective on HIV Infection inside the Body

Worldwide, more than 250 people become infected with HIV every hour [1], yet an individuals chance of becoming infected after a single sexual exposure, the predominant mode of HIV transmission, is often lower than one in 100 [2]. When sexually transmitted HIV-1 infection does occur, it is usually initiated by a single virus, called the founder strain, despite the presence of thousands of genetically diverse viral strains in the transmitting partner [3]. Here we review evidence from molecular biology and virology suggesting that heterogeneity among CD4+ T cells could yield wide variation in the capability of individual cells to become infected and transmit HIV to other cells. Using an epidemiological framework, we suggest that such heterogeneity among CD4+ T cells in the genital mucosa could help explain the low infection-to-exposure ratio and selection of the founder strain after sexual exposure to HIV. During sexual transmission, founder viral strains preferentially infect CD4+ T cells using the CCR5 coreceptor [4], [5]. At the time of initial exposure to HIV, these CD4+ T cells exhibit baseline heterogeneity due to stochasticity in cellular gene expression [6] and dynamic variation in immunological status (activated, resting, etc.) [7]. In addition, because CD4+ T cells are mobile, they are heterogeneously distributed in the genital mucosa, with varying degrees of clustering and contact [8]–[11]. In other contexts, it is well-known that heterogeneity among isogeneic cells inside the body can affect many cellular behaviors and outcomes, including infection dynamics [12], [13]. Epidemiological analyses of disease outbreaks among people indicate that heterogeneity in the ability of individuals in a population to spread disease can have a significant impact on whether a local outbreak becomes an epidemic [14]. Heterogeneity among a population of CD4+ T cells may play a similarly critical role in the establishment and spread of HIV in the genital mucosa after sexual exposure.

A single amino acid substitution converts a transmembrane protein activator of the platelet-derived growth factor β receptor into an inhibitor

Background: Certain artificial small transmembrane proteins can activate the PDGFβ receptor to promote cellular growth transformation. Results: A point mutant of one such protein binds to this receptor and inhibits activation induced by different ligands. Conclusion: Small transmembrane proteins can be engineered to inhibit PDGFβ receptor activity. Significance: This strategy could be generalized for designing novel inhibitors of growth factor receptors, which may have therapeutic implications. Receptors for PDGF play an important role in cell proliferation and migration and have been implicated in certain cancers. The 44-amino acid E5 protein of bovine papillomavirus binds to and activates the PDGFβ receptor (PDGFβR), resulting in oncogenic transformation of cultured fibroblasts. Previously, we isolated an artificial 36-amino acid transmembrane protein, pTM36-4, which transforms cells because of its ability to activate the PDGFβR despite limited sequence similarity to E5. Here, we demonstrated complex formation between the PDGFβR and three pTM36-4 mutants: T21E, T21Q, and T21N. T21Q retained wild type transforming activity and activated the PDGFβR in a ligand-independent manner as a consequence of binding to the transmembrane domain of the PDGFβR, but T21E and T21N were severely defective. In fact, T21N substantially inhibited E5-induced PDGFβR activation and transformation in both mouse and human fibroblasts. T21N did not prevent E5 from binding to the receptor, and genetic evidence suggested that T21N and E5 bind to nonidentical sites in the transmembrane domain of the receptor. T21N also inhibited transformation and PDGFβR activation induced by v-Sis, a viral homologue of PDGF-BB, as well as PDGF-induced mitogenesis and signaling by preventing phosphorylation of the PDGFβR at particular tyrosine residues. These results demonstrated that T21N acts as a novel inhibitor of the PDGFβR and validated a new strategy for designing highly specific short transmembrane protein inhibitors of growth factor receptors and possibly other transmembrane proteins.

State variation in HIV/AIDS health outcomes: the effect of spending on social services and public health.

Objective:Despite considerable advances in the prevention and treatment of HIV/AIDS, the burden of new infections of HIV and AIDS varies substantially across the country. Previous studies have demonstrated associations between increased healthcare spending and better HIV/AIDS outcomes; however, less is known about the association between spending on social services and public health spending and HIV/AIDS outcomes. We sought to examine the association between state-level spending on social services and public health and HIV/AIDS case rates and AIDS deaths across the United States. Design:We conducted a retrospective, longitudinal study of the 50 U.S. states over 2000–2009 using a dataset of HIV/AIDS case rates and AIDS deaths per 100 000 people matched with a unique dataset of state-level spending on social services and public health per person in poverty. Methods:We estimated multivariable regression models for each HIV/AIDS outcome as a function of the social service and public health spending 1 and 5 years earlier in the state, adjusted for the log of state GDP per capita, regional and time fixed effects, Medicaid spending as % of GDP, and socio-demographic, economic, and health resource factors. Results:States with higher spending on social services and public health per person in poverty had significantly lower HIV and AIDS case rates and fewer AIDS deaths, both 1 and 5 years post expenditure (P ⩽ 0.05). Conclusion:Our findings suggest that spending on social services and public health may provide a leverage point for state policymakers to reduce HIV/AIDS case rates and AIDS deaths in their state.

Innovation spread: lessons from HIV

Efficient spreading of evidence-based innovations among complex health systems remains an elusive goal despite extensive study in the social sciences. Biology provides a model of successful spread in viruses, which have evolved to spread with maximum efficiency using minimal resources. Here we explore the molecular mechanisms of human immunodeficiency virus (HIV) spread and identify five steps that are also common to a recent example of spread in complex health systems: reduction in door-to-balloon times for patients with ST-segment elevation myocardial infarction (STEMI). We then describe a new model we have developed, called AIDED, which is based on mixed-methods research but informed by the conceptual framework of HIV spread among cells. The AIDED model contains five components: Assess, Innovate, Develop, Engage and Devolve, and can describe any one of the following: the spread of HIV among cells, the spread of practices to reduce door-to-balloon time for patients with STEMI and the spread of certain family health innovations in low- and middle-income countries. We suggest that by looking to the biological sciences for a model of spread that has been honed by evolution, we may have identified fundamental steps that are necessary and sufficient for efficient, low-cost spread of health innovations among complex health systems.

Community factors related to healthy eating & active living in counties with lower than expected adult obesity rates

BackgroundAdult obesity rates in the United States have reached epidemic proportions, yet vary considerably across states and counties. We sought to explore community-level factors that may be associated with reduced adult obesity rates at the county level.MethodsWe identified six U.S. counties that were positive deviants for adult obesity and conducted semi-structured interviews with community leaders and government officials involved in efforts to promote healthier lifestyles. Using site visits and in-depth qualitative interviews, we identified several recurrent themes and strategies.ResultsParticipants: 1) developed a nuanced understanding of their communities; 2) recognized the complex nature of obesity, and 3) implemented a county-wide strategic approach for promoting healthy living. This county-wide approachwas used to a) break down silos and build partnerships, b) access community resources and connections, and c) transfer ownership to community members.ConclusionsWe found that county leaders focused on establishing a county-wide structure to connect and support community-led initiatives to promote healthy living, reduce obesity, and foster sustainability. Findings from this study can help inform county-level efforts to improve healthy living and combat the multi-faceted challenges of adult obesity across the U.S.