Keeping It Political and Powerful: Defining the Structural Determinants of Health.

Policy Points The structural determinants of health are 1) the written and unwritten rules that create, maintain, or eliminate durable and hierarchical patterns of advantage among socially constructed groups in the conditions that affect health, and 2) the manifestation of power relations in that people and groups with more power based on current social structures work-implicitly and explicitly-to maintain their advantage by reinforcing or modifying these rules. This theoretically grounded definition of structural determinants can support a shared analysis of the root causes of health inequities and an embrace of public health's role in shifting power relations and engaging politically, especially in its policy work. Shifting the balance of power relations between socially constructed groups differentiates interventions in the structural determinants of health from those in the social determinants of health.

Theory in Action: Public Health and Community Power Building for Health Equity.

CONTEXT: Within the field of public health, there is growing awareness of how complex social conditions shape health outcomes and the role that power plays in driving health inequities. Despite public health frameworks lifting up the need to tackle power imbalances to advance equity, there is little guidance on how to accomplish this as an integral part of health promotion. OBJECTIVE: This article addresses the need for public health professionals to better understand power and identifies opportunities for shifting power to achieve more equitable outcomes. First, it defines power and community power building. Next, it reviews a pragmatic theoretical framework that organizes power into 3 faces: (1) exercising influence in formal decision-making processes; (2) organizing the decision-making environment; and (3) shaping worldviews about social issues. Finally, it connects each face of power to community power-building practices using concrete examples. IMPLEMENTATION: This article highlights real-world case examples to demonstrate how theory translates to action by describing how public health practitioners in government, academic, and nonprofit settings incorporate the 3 faces of power into their work. The case examples illustrate how public health organizations and practitioners can partner with those most impacted by inequities to help shape decision making, agenda setting, and worldviews to influence policy and practice toward more equitable outcomes. DISCUSSION: The public health field can learn from and build on these innovative examples to establish new practices, scale up promising approaches, and evaluate what works to shift power for the greater good.

Advancing efforts to achieve health equity: equity metrics for health impact assessment practice.

Equity is a core value of Health Impact Assessment (HIA). Many compelling moral, economic, and health arguments exist for prioritizing and incorporating equity considerations in HIA practice. Decision-makers, stakeholders, and HIA practitioners see the value of HIAs in uncovering the impacts of policy and planning decisions on various population subgroups, developing and prioritizing specific actions that promote or protect health equity, and using the process to empower marginalized communities. There have been several HIA frameworks developed to guide the inclusion of equity considerations. However, the field lacks clear indicators for measuring whether an HIA advanced equity. This article describes the development of a set of equity metrics that aim to guide and evaluate progress toward equity in HIA practice. These metrics also intend to further push the field to deepen its practice and commitment to equity in each phase of an HIA. Over the course of a year, the Society of Practitioners of Health Impact Assessment (SOPHIA) Equity Working Group took part in a consensus process to develop these process and outcome metrics. The metrics were piloted, reviewed, and refined based on feedback from reviewers. The Equity Metrics are comprised of 23 measures of equity organized into four outcomes: (1) the HIA process and products focused on equity; (2) the HIA process built the capacity and ability of communities facing health inequities to engage in future HIAs and in decision-making more generally; (3) the HIA resulted in a shift in power benefiting communities facing inequities; and (4) the HIA contributed to changes that reduced health inequities and inequities in the social and environmental determinants of health. The metrics are comprised of a measurement scale, examples of high scoring activities, potential data sources, and example interview questions to gather data and guide evaluators on scoring each metric.

A simulation-approximation approach to sample size planning for high-dimensional classification studies.

Classification studies with high-dimensional measurements and relatively small sample sizes are increasingly common. Prospective analysis of the role of sample sizes in the performance of such studies is important for study design and interpretation of results, but the complexity of typical pattern discovery methods makes this problem challenging. The approach developed here combines Monte Carlo methods and new approximations for linear discriminant analysis, assuming multivariate normal distributions. Monte Carlo methods are used to sample the distribution of which features are selected for a classifier and the mean and variance of features given that they are selected. Given selected features, the linear discriminant problem involves different distributions of training data and generalization data, for which 2 approximations are compared: one based on Taylor series approximation of the generalization error and the other on approximating the discriminant scores as normally distributed. Combining the Monte Carlo and approximation approaches to different aspects of the problem allows efficient estimation of expected generalization error without full simulations of the entire sampling and analysis process. To evaluate the method and investigate realistic study design questions, full simulations are used to ask how validation error rate depends on the strength and number of informative features, the number of noninformative features, the sample size, and the number of features allowed into the pattern. Both approximation methods perform well for most cases but only the normal discriminant score approximation performs well for cases of very many weakly informative or uninformative dimensions. The simulated cases show that many realistic study designs will typically estimate substantially suboptimal patterns and may have low probability of statistically significant validation results.

The anticancer activity of the transcription inhibitor terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid) formulated for systemic administration.

Terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid, formerly known as EM-1421 and M4N) is a semi-synthetic small molecule with antitumor activity occurring via selective targeting of Sp1-regulated proteins, including survivin and cdc2 that control cell cycle and apoptosis. Terameprocol is in clinical development as a site-specific transcription inhibitor in solid refractory tumors. The present studies were designed to investigate the in-vitro and in-vivo anticancer activity of terameprocol in a novel hydroxypropyl beta-cyclodextrin and polyethylene glycol solvent formulation (designated CPE) designed for safe parenteral administration. Terameprocol powder was dissolved in CPE (20% hydroxypropyl beta-cyclodextrin and 50% polyethylene glycol 300 or 30% hydroxypropyl beta-cyclodextrin and 25% polyethylene glycol 300) or dimethyl sulfoxide and used for in-vitro cell proliferation assays, and in human carcinoma xenograft studies using female athymic nude mice injected with SW-780 human bladder cells. Terameprocol (50 and 100 mg/kg), paclitaxel (5 mg/kg), terameprocol and paclitaxel or vehicle was administered intraperitoneally daily for 21 days. Stock solutions of the CPE formulation were stable for up to 12 months. Terameprocol CPE formulation showed concentration-dependent inhibition of HeLa and C33A cell proliferation, and was less toxic than terameprocol dimethyl sulfoxide formulation. The terameprocol CPE formulation showed no overt toxicities in tumor-bearing mice. Terameprocol alone reduced the rate of tumor growth, and a combination of terameprocol/paclitaxel reduced both the rate and extent of tumor growth. These preclinical results confirm the tumoricidal activity of terameprocol formulated in a solvent suitable for parenteral administration and suggest that terameprocol has improved efficacy when coadministered with paclitaxel.

Tetra-O-methyl nordihydroguaiaretic acid inhibits growth and induces death of leukemia cells independent of Cdc2 and survivin.

Tetra-O-methyl nordihydroguaiaretic acid (M4N) was shown to induce G2 arrest and suppress human xenograft tumor growth by inhibiting Cdc2 and survivin. We examined the effect of M4N on leukemia and found that M4N inhibited growth and induced cell death in leukemic cell lines and blasts from AML patients. However, no significant changes in Cdc2 and survivin levels and G2 arrest were observed. Cell death and growth inhibition were dependent neither on XIAP, Bcl-2, and Bcl-X(L) levels nor on caspase-8. M4N did not promote cell differentiation in HL-60 cells. Interestingly, significant inhibition of AKT phosphorylation was observed in M4N treated OCI-AML3 cells. Collectively, our data showed that M4N inhibited cell growth and induced cell death in both leukemic cell lines and AML patient sample via a mechanism not mediated by Cdc2 and survivin inhibition and suggested that the extrinsic and the mitochondrial apoptotic pathways are not essential.

An automated, sheathless capillary electrophoresis-mass spectrometry platform for discovery of biomarkers in human serum.

A capillary electrophoresis-mass spectrometry (CE-MS) method has been developed to perform routine, automated analysis of low-molecular-weight peptides in human serum. The method incorporates transient isotachophoresis for in-line preconcentration and a sheathless electrospray interface. To evaluate the performance of the method and demonstrate the utility of the approach, an experiment was designed in which peptides were added to sera from individuals at each of two different concentrations, artificially creating two groups of samples. The CE-MS data from the serum samples were divided into separate training and test sets. A pattern-recognition/feature-selection algorithm based on support vector machines was used to select the mass-to-charge (m/z) values from the training set data that distinguished the two groups of samples from each other. The added peptides were identified correctly as the distinguishing features, and pattern recognition based on these peptides was used to assign each sample in the independent test set to its respective group. A twofold difference in peptide concentration could be detected with statistical significance (p-value < 0.0001). The accuracy of the assignment was 95%, demonstrating the utility of this technique for the discovery of patterns of biomarkers in serum.

Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression.

We previously reported that Sp1-dependent Cdc2 gene expression is inhibited by tetra-O-methyl nordihydroguaiaretic acid (M(4)N) and that M(4)N is likely responsible for causing growth arrest in M(4)N-treated transformed C3 cells. Here, we show that after M(4)N treatment and cell-cycle arrest, expression of the Sp1-dependent survivin gene, a member of the inhibitor of apoptosis family, is also suppressed, and the mitochondrial apoptotic pathway is activated. To confirm that inhibition of Cdc2 and survivin gene expression is necessary for M(4)N-induced growth arrest and apoptosis, we tested the effect of adding Cdc2 and survivin back to M(4)N-treated cells. Cell division was transiently restored in the presence of M(4)N after transfection of an exogenous Cdc2 gene copy under the control of the Sp1-independent cytomegalovirus promoter. Caspase-3 activation was also reduced by 50% and 75% in transiently and stably survivin-transfected C3 cells, respectively. The results suggest that M(4)N induces growth arrest and apoptosis by suppressing Cdc2 and survivin expression, which constitutes the cellular basis of its antitumoric action.

Developmental control of blood cell migration by the Drosophila VEGF pathway.

We show that a vascular endothelial growth factor (VEGF) pathway controls embryonic migrations of blood cells (hemocytes) in Drosophila. The VEGF receptor homolog is expressed in hemocytes, and three VEGF homologs are expressed along hemocyte migration routes. A receptor mutation arrests progression of blood cell movement. Mutations in Vegf17E or Vegf27Cb have no effect, but simultaneous inactivation of all three Vegf genes phenocopied the receptor mutant, and ectopic expression of Vegf27Cb redirected migration. Genetic experiments indicate that the VEGF pathway functions independently of pathways governing hemocyte homing on apoptotic cells. The results suggest that the Drosophila VEGF pathway guides developmental migrations of blood cells, and we speculate that the ancestral function of VEGF pathways was to guide blood cell movement.