Study protocol: the Adherence and Intensification of Medications (AIM) study--a cluster randomized controlled effectiveness study.

BACKGROUND: Many patients with diabetes have poor blood pressure (BP) control. Pharmacological therapy is the cornerstone of effective BP treatment, yet there are high rates both of poor medication adherence and failure to intensify medications. Successful medication management requires an effective partnership between providers who initiate and increase doses of effective medications and patients who adhere to the regimen. METHODS: In this cluster-randomized controlled effectiveness study, primary care teams within sites were randomized to a program led by a clinical pharmacist trained in motivational interviewing-based behavioral counseling approaches and authorized to make BP medication changes or to usual care. This study involved the collection of data during a 14-month intervention period in three Department of Veterans Affairs facilities and two Kaiser Permanente Northern California facilities. The clinical pharmacist was supported by clinical information systems that enabled proactive identification of, and outreach to, eligible patients identified on the basis of poor BP control and either medication refill gaps or lack of recent medication intensification. The primary outcome is the relative change in systolic blood pressure (SBP) measurements over time. Secondary outcomes are changes in Hemoglobin A1c, low-density lipoprotein cholesterol (LDL), medication adherence determined from pharmacy refill data, and medication intensification rates. DISCUSSION: Integration of the three intervention elements--proactive identification, adherence counseling and medication intensification--is essential to achieve optimal levels of control for high-risk patients. Testing the effectiveness of this intervention at the team level allows us to study the program as it would typically be implemented within a clinic setting, including how it integrates with other elements of care. TRIAL REGISTRATION: The ClinicalTrials.gov registration number is NCT00495794.

Theory and Practice in Sustainability Science: Influence of Urban Form on the Urban Heat Island and Implications for Urban Systems

As the world population continues to grow past seven billion people and global challenges continue to persist including resource availability, biodiversity loss, climate change and human well-being, a new science is required that can address the integrated nature of these challenges and the multiple scales on which they are manifest. Sustainability science has emerged to fill this role. In the fifteen years since it was first called for in the pages of Science, it has rapidly matured, however its place in the history of science and the way it is practiced today must be continually evaluated. In Part I, two chapters address this theoretical and practical grounding. Part II transitions to the applied practice of sustainability science in addressing the urban heat island (UHI) challenge wherein the climate of urban areas are warmer than their surrounding rural environs. The UHI has become increasingly important within the study of earth sciences given the increased focus on climate change and as the balance of humans now live in urban areas.

In Chapter 2 a novel contribution to the historical context of sustainability is argued. Sustainability as a concept characterizing the relationship between humans and nature emerged in the mid to late 20th century as a response to findings used to also characterize the Anthropocene. Emerging from the human-nature relationships that came before it, evidence is provided that suggests Sustainability was enabled by technology and a reorientation of world-view and is unique in its global boundary, systematic approach and ambition for both well being and the continued availability of resources and Earth system function. Sustainability is further an ambition that has wide appeal, making it one of the first normative concepts of the Anthropocene.

Despite its widespread emergence and adoption, sustainability science continues to suffer from definitional ambiguity within the academe. In Chapter 3, a review of efforts to provide direction and structure to the science reveals a continuum of approaches anchored at either end by differing visions of how the science interfaces with practice (solutions). At one end, basic science of societally defined problems informs decisions about possible solutions and their application. At the other end, applied research directly affects the options available to decision makers. While clear from the literature, survey data further suggests that the dichotomy does not appear to be as apparent in the minds of practitioners.

In Chapter 4, the UHI is first addressed at the synoptic, mesoscale. Urban climate is the most immediate manifestation of the warming global climate for the majority of people on earth. Nearly half of those people live in small to medium sized cities, an understudied scale in urban climate research. Widespread characterization would be useful to decision makers in planning and design. Using a multi-method approach, the mesoscale UHI in the study region is characterized and the secular trend over the last sixty years evaluated. Under isolated ideal conditions the findings indicate a UHI of 5.3 ± 0.97 °C to be present in the study area, the magnitude of which is growing over time.

Although urban heat islands (UHI) are well studied, there remain no panaceas for local scale mitigation and adaptation methods, therefore continued attention to characterization of the phenomenon in urban centers of different scales around the globe is required. In Chapter 5, a local scale analysis of the canopy layer and surface UHI in a medium sized city in North Carolina, USA is conducted using multiple methods including stationary urban sensors, mobile transects and remote sensing. Focusing on the ideal conditions for UHI development during an anticyclonic summer heat event, the study observes a range of UHI intensity depending on the method of observation: 8.7 °C from the stationary urban sensors; 6.9 °C from mobile transects; and, 2.2 °C from remote sensing. Additional attention is paid to the diurnal dynamics of the UHI and its correlation with vegetation indices, dewpoint and albedo. Evapotranspiration is shown to drive dynamics in the study region.

Finally, recognizing that a bridge must be established between the physical science community studying the Urban Heat Island (UHI) effect, and the planning community and decision makers implementing urban form and development policies, Chapter 6 evaluates multiple urban form characterization methods. Methods evaluated include local climate zones (LCZ), national land cover database (NCLD) classes and urban cluster analysis (UCA) to determine their utility in describing the distribution of the UHI based on three standard observation types 1) fixed urban temperature sensors, 2) mobile transects and, 3) remote sensing. Bivariate, regression and ANOVA tests are used to conduct the analyses. Findings indicate that the NLCD classes are best correlated to the UHI intensity and distribution in the study area. Further, while the UCA method is not useful directly, the variables included in the method are predictive based on regression analysis so the potential for better model design exists. Land cover variables including albedo, impervious surface fraction and pervious surface fraction are found to dominate the distribution of the UHI in the study area regardless of observation method.

Chapter 7 provides a summary of findings, and offers a brief analysis of their implications for both the scientific discourse generally, and the study area specifically. In general, the work undertaken does not achieve the full ambition of sustainability science, additional work is required to translate findings to practice and more fully evaluate adoption. The implications for planning and development in the local region are addressed in the context of a major light-rail infrastructure project including several systems level considerations like human health and development. Finally, several avenues for future work are outlined. Within the theoretical development of sustainability science, these pathways include more robust evaluations of the theoretical and actual practice. Within the UHI context, these include development of an integrated urban form characterization model, application of study methodology in other geographic areas and at different scales, and use of novel experimental methods including distributed sensor networks and citizen science.

Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.

A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.

Application description and policy model in collaborative environment for sharing of information on epidemiological and clinical research data sets.

BACKGROUND: Sharing of epidemiological and clinical data sets among researchers is poor at best, in detriment of science and community at large. The purpose of this paper is therefore to (1) describe a novel Web application designed to share information on study data sets focusing on epidemiological clinical research in a collaborative environment and (2) create a policy model placing this collaborative environment into the current scientific social context. METHODOLOGY: The Database of Databases application was developed based on feedback from epidemiologists and clinical researchers requiring a Web-based platform that would allow for sharing of information about epidemiological and clinical study data sets in a collaborative environment. This platform should ensure that researchers can modify the information. A Model-based predictions of number of publications and funding resulting from combinations of different policy implementation strategies (for metadata and data sharing) were generated using System Dynamics modeling. PRINCIPAL FINDINGS: The application allows researchers to easily upload information about clinical study data sets, which is searchable and modifiable by other users in a wiki environment. All modifications are filtered by the database principal investigator in order to maintain quality control. The application has been extensively tested and currently contains 130 clinical study data sets from the United States, Australia, China and Singapore. Model results indicated that any policy implementation would be better than the current strategy, that metadata sharing is better than data-sharing, and that combined policies achieve the best results in terms of publications. CONCLUSIONS: Based on our empirical observations and resulting model, the social network environment surrounding the application can assist epidemiologists and clinical researchers contribute and search for metadata in a collaborative environment, thus potentially facilitating collaboration efforts among research communities distributed around the globe.

Knowledge and judgments about events that occurred prior to birth: The measurement of the persistence of information

Data from five laboratories using five different techniques were reanalyzed to measure subjects' knowledge of events that occurred over the past 70 years. Subjects were about 20 years of age, so the measures included events that extended up to 50 years before birth. The functions relating knowledge about the events to age do not decrease precipitously at birth but gradually drop to above-chance levels. Techniques usually used to study retention within the individual can be used to study the persistence of ideas and fashions within an age cohort in a culture.

Latent factor analysis to discover pathway-associated putative segmental aneuploidies in human cancers.

Tumor microenvironmental stresses, such as hypoxia and lactic acidosis, play important roles in tumor progression. Although gene signatures reflecting the influence of these stresses are powerful approaches to link expression with phenotypes, they do not fully reflect the complexity of human cancers. Here, we describe the use of latent factor models to further dissect the stress gene signatures in a breast cancer expression dataset. The genes in these latent factors are coordinately expressed in tumors and depict distinct, interacting components of the biological processes. The genes in several latent factors are highly enriched in chromosomal locations. When these factors are analyzed in independent datasets with gene expression and array CGH data, the expression values of these factors are highly correlated with copy number alterations (CNAs) of the corresponding BAC clones in both the cell lines and tumors. Therefore, variation in the expression of these pathway-associated factors is at least partially caused by variation in gene dosage and CNAs among breast cancers. We have also found the expression of two latent factors without any chromosomal enrichment is highly associated with 12q CNA, likely an instance of "trans"-variations in which CNA leads to the variations in gene expression outside of the CNA region. In addition, we have found that factor 26 (1q CNA) is negatively correlated with HIF-1alpha protein and hypoxia pathways in breast tumors and cell lines. This agrees with, and for the first time links, known good prognosis associated with both a low hypoxia signature and the presence of CNA in this region. Taken together, these results suggest the possibility that tumor segmental aneuploidy makes significant contributions to variation in the lactic acidosis/hypoxia gene signatures in human cancers and demonstrate that latent factor analysis is a powerful means to uncover such a linkage.

Prevalence and predictors of giving birth in health facilities in Bugesera District, Rwanda.

BACKGROUND: The proportion of births attended by skilled health personnel is one of two indicators used to measure progress towards Millennium Development Goal 5, which aims for a 75% reduction in global maternal mortality ratios by 2015. Rwanda has one of the highest maternal mortality ratios in the world, estimated between 249-584 maternal deaths per 100,000 live births. The objectives of this study were to quantify secular trends in health facility delivery and to identify factors that affect the uptake of intrapartum healthcare services among women living in rural villages in Bugesera District, Eastern Province, Rwanda. METHODS: Using census data and probability proportional to size cluster sampling methodology, 30 villages were selected for community-based, cross-sectional surveys of women aged 18-50 who had given birth in the previous three years. Complete obstetric histories and detailed demographic data were elicited from respondents using iPad technology. Geospatial coordinates were used to calculate the path distances between each village and its designated health center and district hospital. Bivariate and multivariate logistic regressions were used to identify factors associated with delivery in health facilities. RESULTS: Analysis of 3106 lifetime deliveries from 859 respondents shows a sharp increase in the percentage of health facility deliveries in recent years. Delivering a penultimate baby at a health facility (OR = 4.681 [3.204 - 6.839]), possessing health insurance (OR = 3.812 [1.795 - 8.097]), managing household finances (OR = 1.897 [1.046 - 3.439]), attending more antenatal care visits (OR = 1.567 [1.163 - 2.112]), delivering more recently (OR = 1.438 [1.120 - 1.847] annually), and living closer to a health center (OR = 0.909 [0.846 - 0.976] per km) were independently associated with facility delivery. CONCLUSIONS: The strongest correlates of facility-based delivery in Bugesera District include previous delivery at a health facility, possession of health insurance, greater financial autonomy, more recent interactions with the health system, and proximity to a health center. Recent structural interventions in Rwanda, including the rapid scale-up of community-financed health insurance, likely contributed to the dramatic improvement in the health facility delivery rate observed in our study.

CPAG: software for leveraging pleiotropy in GWAS to reveal similarity between human traits links plasma fatty acids and intestinal inflammation.

Meta-analyses of genome-wide association studies (GWAS) have demonstrated that the same genetic variants can be associated with multiple diseases and other complex traits. We present software called CPAG (Cross-Phenotype Analysis of GWAS) to look for similarities between 700 traits, build trees with informative clusters, and highlight underlying pathways. Clusters are consistent with pre-defined groups and literature-based validation but also reveal novel connections. We report similarity between plasma palmitoleic acid and Crohn's disease and find that specific fatty acids exacerbate enterocolitis in zebrafish. CPAG will become increasingly powerful as more genetic variants are uncovered, leading to a deeper understanding of complex traits. CPAG is freely available at www.sourceforge.net/projects/CPAG/.

Genome-wide association study of perioperative myocardial infarction after coronary artery bypass surgery.

OBJECTIVES: Identification of patient subpopulations susceptible to develop myocardial infarction (MI) or, conversely, those displaying either intrinsic cardioprotective phenotypes or highly responsive to protective interventions remain high-priority knowledge gaps. We sought to identify novel common genetic variants associated with perioperative MI in patients undergoing coronary artery bypass grafting using genome-wide association methodology. SETTING: 107 secondary and tertiary cardiac surgery centres across the USA. PARTICIPANTS: We conducted a stage I genome-wide association study (GWAS) in 1433 ethnically diverse patients of both genders (112 cases/1321 controls) from the Genetics of Myocardial Adverse Outcomes and Graft Failure (GeneMAGIC) study, and a stage II analysis in an expanded population of 2055 patients (225 cases/1830 controls) combined from the GeneMAGIC and Duke Perioperative Genetics and Safety Outcomes (PEGASUS) studies. Patients undergoing primary non-emergent coronary bypass grafting were included. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome variable was perioperative MI, defined as creatine kinase MB isoenzyme (CK-MB) values ≥10× upper limit of normal during the first postoperative day, and not attributable to preoperative MI. Secondary outcomes included postoperative CK-MB as a quantitative trait, or a dichotomised phenotype based on extreme quartiles of the CK-MB distribution. RESULTS: Following quality control and adjustment for clinical covariates, we identified 521 single nucleotide polymorphisms in the stage I GWAS analysis. Among these, 8 common variants in 3 genes or intergenic regions met p<10(-5) in stage II. A secondary analysis using CK-MB as a quantitative trait (minimum p=1.26×10(-3) for rs609418), or a dichotomised phenotype based on extreme CK-MB values (minimum p=7.72×10(-6) for rs4834703) supported these findings. Pathway analysis revealed that genes harbouring top-scoring variants cluster in pathways of biological relevance to extracellular matrix remodelling, endoplasmic reticulum-to-Golgi transport and inflammation. CONCLUSIONS: Using a two-stage GWAS and pathway analysis, we identified and prioritised several potential susceptibility loci for perioperative MI.