Media can influence public and policy-makers’ perceptions of causes of, and solutions to, public health issues through selective presentation and framing. Childhood obesity is a health issue with both individual-level and societal-level drivers and solutions, but public opinion and mass media representations of obesity have typically focused on individual-level framings, at the cost of acknowledgement of a need for regulatory action.To understand the salience and framing of childhood obesity across 19 years of UK national newspaper content.Quantitative content analysis of 757 articles about childhood obesity obtained from six daily and five Sunday newspapers. Articles were coded manually for definitions, drivers and potential solutions. Data were analysed statistically, including analysis of time trends and variations by political alignment of source.The frequency of articles grew from a low of two in 1996 to a peak of 82 in 2008, before declining to 40 in 2010. Individual-level drivers (59.8%) and solutions (36.5%) were mentioned more frequently than societal-level drivers (28.3%) and solutions (28.3%) across the sample, but societal solutions were mentioned more frequently during the final 8 years, coinciding with a marked decline in yearly frequency of articles.Increased focus on societal solutions aligns with public health goals, but coincided with a reduction in the issue’s salience in the media. Those advocating public policy solutions to childhood obesity may benefit from seeking to raise the issue’s media profile while continuing to promote structural conceptualisations of childhood obesity. Methodology includes systematic analysis of a large sample of 19 years of UK national newspaper coverage, facilitating statistical understandings of media frames of childhood obesity, including definitions, drivers and solutions.Features robust manual coding and links to pre-existing dataset to strengthen analysis.Quantitative media content analysis is inherently less sensitive to nuance than qualitative analysis, and our analysis excluded some aspects of media content, such as images, which may influence readers’ interpretations of the text they accompany.Content analysis is a means of documenting what messages are presented by media, but cannot tell us how these messages are received by audiences.Childhood obesity has been described as an international epidemic due to its high prevalence and rapid growth in numerous countries.6 7et alet alet al characterise the German population as ‘ready for obesity prevention’, but in need of education about the definition, prevalence and causes of obesity.12Childhood obesity is a complex problem, with a complex set of drivers and potential solutions ranging from the individual to the environmental.et al demonstrated that people’s perceptions of obesity (as communicated through agreement with metaphor-based descriptions of obesity) predict their support for public policy interventions, illustrating how, for example, framing obesity as being driven by industry manipulation may lead to increased support for a ‘junk-food tax’.19The media represent a key influence on public perceptions of health issues and policies, setting the public agenda by granting differing levels of prominence to different topicset alThe media are frequently accused of contributing to obesity, particularly childhood obesity, through its associations with sedentary behaviour, advertising of unhealthy commodities, promotion of unrealistic body image and other mechanisms.et alBastianIn addition to traditional news media, researchers have analysed representations of childhood obesity in non-news media and new media. For example, Kalin and Fung’sThe aim of this study is to further understandings of media representations of childhood obesity in the UK context, using an approach informed by media framing theory,et al prior studyThe media content analysis methods used were predominantly based on Hilton Due to the nature of this study, patients/public were not involved.A set of six daily newspapers and five Sunday newspapers with high circulation figuresNexis database was searched for the presence of both the term’ obesity’ OR ‘obese’ OR ‘fat’ and the term ‘child’ OR ‘children’ OR ‘kid’ OR kids’ within the headlines of articles published within the selected newspapers. Each chosen publication was archived comprehensively within the Nexis database, with the exceptions of the Daily Telegraph and Sunday Telegraph prior to October 2000 and November 2000, respectively. As such, reporting from those publications during the first 5 years of the sample period was not represented. The initial search returned 1199 articles, which were subsequently subjected to manual application of exclusion criteria, including: less than 50% of article content focussing on childhood obesity ; being a reader’s letter; or being part of television guide section. Following exclusion, the final sample comprised 757 relevant articles.Identifying relevant articles from the chosen publications involved an initial database search, followed by manual filtering of search results. The et al.Article content was coded quantitatively using a coding frame adapted from one initially developed by Hilton Statistical analysis was performed in STATA V.14.2. Statistical procedures included: basic descriptive statistics; Cohen’s kappa test of inter-rater agreement; linear regression of relationships between publication year and mentions of different categories of drivers and solutions; and multiple logistic regression of relationships between political alignment and individual aspects of framing. The multiple logistic regressions were adjusted by publication market because the markets represented were not distributed evenly by political alignment (as is the case in the UK newspaper industry), and previous research has identified significant variation in health news coverage by publication market.21 52 53et al’s previous study on representations of general (not childhood-specific) obesity in the UK media were also analysed which had been collected and described fully elsewhereData from Hilton Independent and Independent on Sunday publishing 61 relevant articles, none of which were on front pages, to the Mirror and Sunday Mirror, which published 198 relevant articles, including two front-page articles. The Daily Telegraph and Sunday Telegraph afforded the issue the greatest prominence, featuring it on their front pages nine times.The changing frequency of relevant articles within the sample between 1996 and 2014 is illustrated in Few articles  characterised obesity as a cosmetic problem. Twice as many articles mentioned childhood obesity in relation to women and/or girls  as men and/or boys , and men and/or boys were more likely to be mentioned in centre-left publications than centre-right publications, after adjusting for market .Mentions of specific drivers of childhood obesity were coded and categorised as either individual , societal  or biological/genetic  drivers . SocietaIn addition to drivers, mentions of potential solutions to childhood obesity were coded into three corresponding categories: individual , societal  and biological  . Table 4Time trends in mentioning each category were analysed. Mentions of individual drivers , individual solutions , societal drivers  and societal solutions  each decreased significantly between 1996 and 2014. Neither biological/genetic drivers  nor biological solutions  varied significantly across the sample period.et al 2012 study of newspaper representations of obesity in the general population.The data collected for this study were compared with data collected in Hilton 10.1136/bmjopen-2018-025646.supp1Supplementary dataSupporting information online By systematically analysing the content of 757 articles, we arrived at several key findings related to UK national newspapers’ representations of childhood obesity. Coverage of the issue grew steadily from two articles in 1996 to a high of 82 articles in 2008, after which article frequency declined to 45 in 2009, before rising to a second peak of 69 in 2014. Childhood obesity was predominantly characterised as driven by individual-level factors, particularly parenting, dietary behaviours and inactivity, though societal drivers such as marketing were also identified. Similarly, there was greater focus on individual-level solutions than societal-level solutions. Societal constructions of the drivers of, and solutions to, obesity, were significantly more frequent within centre-left publications than centre right. Analysis of time trends provided evidence of a small shift towards societal conceptualisations, with mentions of social solutions outnumbering individual solutions throughout the latter half of the sample period. Childhood obesity was frequently defined as a health risk in approximately half of articles, and was associated with females substantially more frequently than males, but more nuanced coding of gender representation in these articles is required.Centre-left publications’ greater focus on societal constructions of the causes of, and solutions to childhood obesity, and on the societal and health service burdens of childhood obesity, are in line with the communal and individual framings associated with left-wing and right-wing political ideologies. Entman describes the core process of building frames as ‘[selecting] some aspects of a perceived reality and [making] them more salient’,Nexis database does not archive articles from the Daily Telegraph and Sunday Telegraph prior to October 2000 and November 2000, respectively. However, the low frequency of reporting on childhood obesity prior to 2000 in the other sources in the sample during those years suggests that the absence of those two sources is unlikely to have had a relevant impact on our analysis. The method allowed quantitative analysis of media frames across a large sample, but not the nuanced analysis of specific aspects of framing that qualitative analysis would permit.This research comprised a systematic analysis of a large sample of nineteen years of UK national newspaper coverage, facilitating statistical understandings of media frames of childhood obesity, including definitions, drivers and solutions. However, the research is subject to some limitations. The The coding frame was extensive, but subject to certain limitations. Coding did not record the types of issues discussed by each articles, which may have been valuable given the variety of different perspectives from which the issue may be viewed. Further, while mentions of males and females in relation to obesity in children were coded, coding did not differentiate between mentions of boys with obesity, girls with obesity, male parents and female parents. Given the frequently gendered nature of societal discourse about obesity, future research may benefit from analysing gendered representations of both children and parents within news coverage of childhood obesity. Additionally, future research may benefit from widening the search scope from childhood obesity to also cover childhood overweight. Our search terms were used to replicate those in a previous studyet alet alet alThis research built on prior research examining media framing of general obesityet al and the present study present some evidence of a shift away from a focus on individual constructions of drivers and solutions across their respective time periods. However, comparison of the two pieces of research suggests that, in comparison to general obesity, media frames of childhood obesity have a greater tendency to attribute responsibility to individuals. The disproportionate individual-level framing of childhood obesity might be explained by the presence of parents as mediators between children and public policy. While children are vulnerable to societal and environmental pressures, and are often publicly viewed as deserving of legislative protection,61Both the original study by Hilton For media content to drive public appetite for policy solutions to childhood obesity, media must both raise perceptions of the issue, through heightened coverage, and frame the issue as one demanding societal level, rather than solely individual level, solutions. Our research demonstrates that, while the salience of childhood obesity in UK national newspapers rose steadily from 1996 to 2008, that level of attention was not maintained subsequent to 2008, although there is reason to suggest that this may change in 2017/2018 with media coverage of the incoming levy on sugar-sweetened beverages in the UK.


The National Collaboratory to Address Elder Mistreatment is a team of experts who have come together to develop, test, and disseminate a care model for addressing elder mistreatment in emergency departments. In this presentation we will demonstrate how a collective impact approach, including a centralized infrastructure, dedicated staff, and structured process allowed the Collaboratory to develop and test the Elder Mistreatment Emergency Department Care Model. The model consists of four core elements: 1) The Elder Mistreatment Emergency Department Assessment Profile, 2) staff training modules, 3) brief screening and response tools adapted from a validated measure, and 4) a roadmap for leveraging community resources to support referral and follow up. We will explore the applicability of this approach for harnessing and integrating multidisciplinary expertise to develop, test, and disseminate innovative solutions to complex health care challenges.


A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa.  We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis.  We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa.  The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape. Prostate cancer (PCa) is the most common noncutaneous cancer in men and one of the leading causes of cancer-related deaths worldwide . It is eScreening using the prostate-specific antigen (PSA) can detect PCa at earlier, asymptomatic stages, when treatments might be more effective , 3. HowePCa is a complex disease influenced by both inherited variants in the germline DNA and somatic mutations acquired during formation of the tumors , 8. WithWith the recent surge of next-generation sequencing and genomic characterization of cancer genomes, discovery of acquired somatic mutations that may drive PCa has come into sharper focus. Large multicenter and multinational projects such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have developed comprehensive catalogues of somatic mutations involved in PCa and other cancers –21. DiscThe objectives of this study were (1) to discover signatures of germline and somatic mutated genes associated with each type and distinguishing the two types of PCa and (2) to map the germline-somatic mutation interaction landscape in indolent and aggressive PCas and discover the molecular networks and signaling pathways enriched with germline and somatic mutations associated with each type of disease. Our working hypothesis was that genomic alterations in genes containing germline or somatic mutations or a combination thereof could lead to measurable changes distinguishing indolent from aggressive disease. We further hypothesized that PCa originates from a complex interplay between germline and somatic mutations mapped to functionally related oncogenes interacting in gene regulatory networks and signaling pathways which in turn drive indolent and aggressive disease. We addressed these hypotheses using an integrative genomics approach that integrates germline mutation information from GWAS with somatic mutation information from next-generation sequencing on indolent and aggressive PCas from TCGA using gene expression data derived from the same patient samples as the intermediate phenotype. Our modeling approach assumed the gene as the unity of association rather than individual mutations and further assumed that interactions and cooperation between germline and somatic mutations are manifested through gene regulatory networks and signaling pathways.versus controls to determine association between SNPs and the probability of developing PCa. Because only 1 or 2 million of approximately 50 million SNPs are assessed, the SNPs associated with PCa through GWAS may not necessarily be the causal genetic risk variants. However, these risk-associated SNPs are segregated from the underlying causal variants, since they are in linkage disequilibrium [We used cohort-level information on germline mutations and genes derived from published reports on GWAS. GWAS compared the frequency of common single-nucleotide polymorphisms  throughout the entire genomes of PCa patients and controls . GWAS geilibrium . Here, wilibrium , 26, 27.ilibrium , 26, 27 ilibrium –32. The ilibrium –13 whichhttps://gdc-portal.nci.nih.gov/legacy-archive/), a data portal using the data transfer tool [We used somatic mutation, gene expression, and clinical data on indolent and aggressive PCas from the TCGA. The data were downloaded from the Genomic Data Commons  filter (>0.5) implemented in R . The resThe project design, sources and types of data, and data analysis workflow are presented in p values [Subsequently, we compared the expression levels of differentially expressed genes between indolent and aggressive disease to identify mutated and nonmutated genes distinguishing the two patient groups. For each analysis, we used the false discovery rate (FDR) procedure to correct for multiple hypothesis testing by computing the adjusted p values .p values. Significantly differentially expressed genes were grouped into different categories: genes significantly associated with indolent disease, aggressive disease, or both diseases and genes distinguishing the two types of PCa. The primary focus of this investigation was on germline and somatic mutated genes. Therefore, for the mutated genes significantly associated with indolent and/or aggressive PCa, we performed additional analysis comparing gene expression levels between the two diseases. To ensure that the results are not confounded, for comparing gene expression levels between the two types of PCa, we used only the sets of mutated genes uniquely associated with indolent PCa and those uniquely associated with aggressive PCa. Mutated genes intersecting or significantly associated with both types of PCa were not included in this analysis.The genes were ranked on adjusted To assess the differences in mutation burden between indolent and aggressive PCas, we quantified the number of somatic mutation events per gene in each type or both types of PCa. We performed this analysis on the sets of genes significantly associated with each type of PCa and genes significantly differentially expressed between indolent and aggressive PCas. A gene was considered highly mutated if it had ≥3 mutation events. From this analysis, we developed comprehensive catalogues of mutated genes and the number of mutation events per gene and used this information to assess the differences in mutation burden between the two types of PCa. To identify genes containing both germline and somatic mutations, we evaluated the 401 genes against all the significantly differentially expressed mutated and nonmutated genes in each type of PCa and between the two types of PCa.p value were calculated to assess the likelihood and reliability of correctly assigning the mutated genes to the correct molecular networks and biological pathways, respectively. A false discovery rate was used to correct for multiple hypothesis testing in pathway analysis. The predicted molecular networks and biological pathways were ranked based on Z-scores and log p values, respectively. Gene ontology (GO) [We performed network and pathways analysis separately for indolent and aggressive PCas using the Ingenuity Pathway Analysis (IPA) software to identify molecular networks and biological pathways enriched with germline and somatic mutations . Using Iogy (GO)  analysisogy (GO)  was perfWe integrated germline mutation information from GWAS reports and somatic mutation information from TCGA to map the landscape of oncogenic interactions and cooperation between genes containing germline and somatic mutations, and to discover the molecular networks and signaling pathways dysregulated by these genetic alterations in indolent and aggressive PCas. Here, we report the findings from this innovative approach.Our first task was to discover and characterize signatures of somatic mutated and nonmutated genes associated with indolent and aggressive PCas and genes distinguishing the two diseases. To address the issue, we compared gene expression levels between indolent and control samples, between aggressive and control samples, and between the two types of PCa.p < 0.05) differentially genes, of which 1,961 (18%) differentially expressed genes had somatic mutations in indolent PCa and 8,818 had no somatic mutations. Comparison of gene expression levels between aggressive and control samples revealed 12,100 significantly (p < 0.05) differentially genes, of which 2,498 (21%) differentially expressed genes in aggressive PCa had somatic mutations and 9,602 had no somatic mutations. A complete list of somatic mutated genes significantly associated with indolent and aggressive PCas is presented in Supplementary Comparison of gene expression levels between indolent and control samples revealed a signature of 10,779 significantly  differentially expressed genes distinguishing indolent from aggressive tumors. This included the 394 genes with somatic mutations in indolent PCa only and the 576 genes with somatic mutations in aggressive PCa only. This confirmed our hypothesis that, for a selected set of genes, there are differences in mutation burden and gene expression between indolent and aggressive PCas. The results showing the most highly mutated (>3 mutation events per gene) genes significantly differentially expressed and differentially mutated between indolent and aggressive PCas are presented in The analysis revealed a signature of 970 significantly  differentially expressed and differentially somatic mutated genes distinguishing indolent from aggressive disease. The results showing the 29-gene signature are presented in One of the objectives of this study was to investigate whether there are differences in expression levels and the number of somatic mutation events among the genes containing both germline and somatic mutations between indolent and aggressive PCas. To address this hypothesis, we created a new data set combining the 23 genes containing both germline and somatic mutations significantly associated with and somatic mutated in indolent PCa only with the 38 genes containing both germline and somatic mutations significantly associated with and somatic mutated in aggressive PCa only . We thenOverall, the analysis of germline and somatic mutation patterns in indolent and aggressive PCas produced evidence that genes containing germline mutations also harbor somatic mutations. Some genes had mutations in indolent PCa only. Others had mutations in aggressive PCa only. We also found evidence of genes mutated in both types of PCa. The somatic mutations in genes containing germline mutations were remarkably heterogeneous, and the somatic mutation profiles were sparse. This could partially be explained by the heterogeneity of the disease.One of the primary objectives of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive PCas, and to discover signaling pathways enriched with germline and somatic mutations. Such information would provide insights into the biological mechanisms through which the germline and somatic genomes cooperate to drive the disease and shape the phenotypes. Our working hypothesis was that indolent and aggressive PCas originate from a complex interplay between genes containing germline and somatic mutations and that these complex arrays of interacting genetic factors affect entire molecular networks and signaling pathways which in turn drive the disease and shape the observed clinical phenotypes as either indolent or aggressive.To address this hypothesis, we performed network and pathway analysis separately for each type of PCa as explained in Materials and Methods. For indolent PCa, we used the 28 genes containing both germline and somatic mutations that were significantly associated with indolent PCa, the 43 genes containing germline mutations only that were highly significantly associated with indolent PCa, and the 216 genes with high somatic mutation events that were significantly associated with indolent PCa. Likewise, for aggressive PCa, we used the 43 genes containing both germline and somatic mutations that were significantly associated with aggressive PCa, the 44 genes containing germline mutations only that were significantly associated with aggressive PCa, and the 343 genes with high somatic mutation events that were significantly associated with aggressive PCa.The scientific premise and rationale for using highly somatic mutated genes with germline mutations only associated with each disease, in addition to genes containing both germline and somatic mutations in network and pathway analysis, were to overcome some of the limitations inherent in GWAS as mentioned earlier in Materials and Methods and elucidated here. GWAS discoveries explain only a small proportion of the phenotypic variation. Crucially, most of the genetic variants from GWAS reported thus far have undefined functions, are not PCa-type specific, and have not been causally associated with PCa. Thus, limiting the analysis to only genes containing both germline and somatic mutations associated with each type of PCa could miss important gene regulatory networks and signaling pathways with somatic mutations driving the two diseases.Z-scores ranging from 2 to 51. The top 6 networks  were merged using IPA's network merge module and are presented in Z-score 51), organismal development (Z-score 43), cellular movement and morphology (Z-score 43), DNA replication, recombination, and repair and cancer (Z-score 38), cancer, connective tissue disorders, and organismal injury and abnormalities (Z-score 36), and cancer, connective tissue disorders, and developmental disorder (Z-score 29) (see Supplementary Z-scores).The results of network analysis for indolent PCa are presented in The remainder of the networks contained genes predicted to be involved in overlapping molecular functions, cellular assembly and organization, cellular function and maintenance, tissue development, cancer, amino acid metabolism, molecular transport, cell cycle, cellular assembly and organization, cellular function and maintenance, cell death and survival, posttranslational modification, and renal and urological disease. A complete list of all the 20 predicted networks and germline-somatic genes mapping to those networks including molecular functions in which the genes are involved is presented in Supplementary CTNNB1, ITGB1, and SMO.Pathway analysis revealed signaling pathways enriched with germline and somatic mutations, many of which have been implicated in PCa including axon guidance; adipogenesis; RAR, GP6, thrombin, WINT, MSP-RON, STAT3, PI3K, and TR/RxR activation; and molecular mechanisms of cancer, NF-KB, prostate cancer, GP6, androgen, and VEGF signaling pathways. The top upstream regulators included Z-scores ranging from 8 to 49. The top 6 networks  were merged and are presented in Z-score 49), hereditary disorder (Z-score 39), cell cycle, embryonic development, and cancer (Z-score 35), organismal development and skeletal and muscular system development and function (Z-score 35), cancer (Z-score 30), and RNA damage and repair, RNA posttranscriptional modification, and cellular development (Z-score 28).The results of network analysis for aggressive PCa are presented in The remainder of the networks contained genes predicted to be involved in overlapping molecular functions, including embryonic development, cancer, organismal injury and abnormalities, cell-to-cell signaling and interaction, organismal development, organismal functions, cell death and survival, connective tissue development and function, carbohydrate metabolism, immunological disease, cell morphology, cell cycle, cellular assembly and organization, cellular function and maintenance, inflammatory disease, cancer, cell cycle and cellular development, and reproductive system development and function. A complete list of all the 25 predicted networks and germline-somatic genes mapping to those networks including molecular functions in which the genes are involved is presented in Supplementary TGFB1 and GLI1. There were some overlaps in pathways between indolent and aggressive disease. There were some overlaps in signaling pathways involved in the two types of PCa.Pathway analysis revealed signaling pathways enriched with germline and somatic mutations, many of which have been implicated in PCa including axon guidance; adipogenesis; MSP-RON, RAR, and GP6 activation; and molecular mechanisms of cancer, NF-KB, prostate cancer, GP6, androgen, and VEGF signaling pathways. The top upstream regulators included Interestingly, for both indolent and aggressive PCas, network and pathway analysis including highly somatic mutated genes revealed interactions and functional relationships between the highly somatic mutated genes and the genes containing germline mutations, confirming our hypothesis that focusing only on genes containing both germline and somatic mutations could miss important gene regulatory networks and signaling pathways. Overall, the investigation revealed that oncogenic interactions and cooperation between genes containing germline and somatic mutations occur through complex gene regulatory networks and signaling pathways.Mapping the landscape of oncogenic interactions in indolent and aggressive PCas: to date, analysis distinguishing indolent from aggressive PCa has focused on using transcriptome data to understand the molecular taxonomy and to discover molecular signatures distinguishing indolent from aggressive disease . Here, wBridging precision medicine with precision prevention: the identification of molecular drivers of PCa such as somatic mutations used in this study is critical for precision oncology . LikewisRisk prediction: prevention is the holy grail of cancer elimination . The resDistinguishing indolent from aggressive tumors in PCa: a critical unmet medical need by clinicians is lack of molecular markers with specificity and sensitivity to accurately distinguish indolent from aggressive tumors. Discoveries from this investigation have demonstrated that integrative analysis provides a framework for a deeper understanding of the genomic differences between indolent and aggressive disease. The discovery of differentially mutated genes which are also differentially expressed distinguishing indolent from aggressive PCa in this study suggests that patient risk stratification may be amenable to mutation-based classification, or a combination of mutation and transcriptome data. This finding has not been previously reported.Discovery of potential therapeutic targets: an important and innovative aspect of this investigation is the discovery of molecular networks and signaling pathways enriched with germline and somatic mutations. These discoveries provide insights into the broader biological context in which interactions and cooperation between germline and somatic mutations are likely to occur. Crucially, they elucidate the potential drug targets dysregulated by germline and somatic alterations, which could be used in the development of novel therapeutics.We report a novel and innovative integrative genomic approach to mapping the landscape of oncogenic interactions and cooperation between germline and somatic mutated genes in indolent and aggressive PCas. Our investigation was driven by the expectation that (1) mapping oncogenic interactions between germline and somatic mutations in indolent and aggressive PCas could lead to understanding of how the germline and somatic genomes cooperate during tumorigenesis and (2) a deeper understanding of genomic differences between indolent and aggressive PCas could improve patient stratification and identification of patients at high risk of developing aggressive PCa to be prioritized for treatment. There are several innovative aspects and clinical relevance of our approach, and the results from this investigation are summarized as follows:Although the study shows great promise in mapping oncogenic interactions and cooperation between germline and somatic mutations, there are several limitations that we outline and acknowledge herein. We are aware of the limitations of GWAS discoveries and sequencing and transcriptome studies. The majority of the germline mutations from GWAS studies used in this investigation map to intronic regions of the genes, and their functions have not been defined. The integration used here relied on GWAS discoveries from diverse clinical phenotypes; thus, they lack specificity to indolent and aggressive disease. Validating the germline mutations in indolent and aggressive PCas would provide additional insights not captured in this investigation.A although we did not investigate the functions of germline and somatic mutations in this study, we have previously shown that germline mutations from GWAS disrupt regulatory sites and regions such as enhancer elements and binding and splice sites , suggestWe report interactions and cooperation between genes containing germline and somatic mutations in indolent and aggressive PCas. The investigation shows that interactions and cooperation between germline and somatic mutations are likely to occur through gene regulatory networks and signaling pathways. The results also revealed differences in somatic mutation events and gene expression between indolent and aggressive PCas. The results highlight the need for integrating germline and somatic mutations for the discovery of molecular markers and potential drug targets in PCa.


Purpose: To quantify and compare citywide disparities in the performance of coronary revascularization procedures in New York residents diagnosed with ischemic heart disease (IHD) by the characteristics of the patients and their neighborhood of residence in 2000–2002 and 2011–2013.Methods: We identify the number of hospitalizations for patients with diagnoses of IHD and/or congestive heart failure (CHF) and the number of revascularization procedures performed on the population 45 years and older, relying on hospital administrative data for New York City, by area of residence, from the Statewide Planning and Research Cooperative System (SPARCS). We conduct multiple logistic regressions to analyze the factors associated with revascularization for hospitalized patients admitted with IHD and CHF over the two time periods.Results: Despite any decline in population health status, both the age-adjusted rates of inpatient hospital discharges for acute myocardial infarction, for IHD and for CHF, decreased as did the rates of revascularization procedures. Racial and ethnic disparities were much smaller in the later period than those documented earlier. However, there were persistent gender, insurance status, and neighborhood-level disparities in the treatment of heart disease.Conclusions: With the declines in rates of heart disease, our findings point to the need for more clinical and population-based research to improve the understanding of why race/ethnicity, gender, insurance status, and neighborhood-level disparities persist in the treatment of heart disease. Along with these efforts, the treatment of heart disease has also contributed to reductions in mortality.4–6 For many patients with CAD, the provision of anti-antigal medications and medications to modify atherosclerosis has improved outcomes.7 For other patients with obstructive CAD, revascularization, in either the form of a coronary artery bypass graft (CABG) or a percutaneous transluminal coronary intervention (PTCI), often using drug eluting stents is an important treatment option.8There has been a striking decline in coronary artery disease (CAD) mortality over the past four decades, but it remains the leading cause of death in the United States.9 An analysis of access to revascularization in Manhattan between 1997 and 2000 found large and significant disparities associated with these factors in the use of revascularization procedures among patients hospitalized with obstructive CAD (captured by including patients with diagnoses of IHD and/or congestive heart failure [CHF]).10Revascularization is widely recognized as an effective treatment for patients with unstable CAD, as well as for those with stable ischemic heart disease (IHD) with progressive or refractory symptoms. Despite increasing reliance on guideline-directed medical therapy, previous research has found that women, racial and ethnic minorities, patients without health insurance, and those who live in low-income neighborhoods may have inadequate access to these procedures.Here, based on analysis for the period 2011–2013, we examine whether disparities in access to revascularization in New York City (NYC) have narrowed. We compare how the use of revascularization procedures has evolved among patients, 45 years and older, hospitalized with IHD or CHF since 2000–2002, the period corresponding with Mayor Michael Bloomberg's tenure in office (2001–2013).12 The city's Department of Health and Mental Hygiene (DOHMH) established the New York City Community Health Survey (NYCCHS) in 2002, the nation's first community-based health and nutrition survey and a host of other efforts to track chronic illness.12 DOHMH uses data on health behaviors and outcomes to target programs and reduce population health and health care disparities. In 2004, DOHMH launched Take Care New York (TCNY) to reduce mortality from causes amenable to public health and health care interventions. TCNY started with 10 priority areas and 16 indicators.13 It has continued beyond the Bloomberg administration and now includes a range of interventions designed to improve population health and reduce health care disparities. The city's smoking ban is noteworthy because heart disease mortality, as well as hospital admissions for acute myocardial infarction (AMI), IHD, and CHF decreased between 2002 and 2013, despite an increase in several well-known risk factors, including obesity, hypertension and high cholesterol , a comprehensive inpatient hospital patient data system established in 1979 by the New York State Department of Health in cooperation with hospitals. To assure an adequate number of hospital discharges and procedures for statistically meaningful comparisons, we calculate two 3-year averages for 2000–2002 and 2011–2013. To calculate age-specific and age-adjusted population rates, we rely on U.S. Census data for 2000 and 2010 and weights derived from the 2000 U.S. Census.15We conducted multiple logistic regressions to analyze the factors associated with revascularization for hospitalized patients admitted with IHD and CHF over two time periods: 2000–2002 and 2011–2013. Both models estimate the probability that patients, ages 45 years and older with these discharge diagnoses, would receive a revascularization procedure (PTCI or CABG). The independent individual variables are age, gender, race/ethnicity, primary payers, and number of diagnoses on record (as a measure of illness severity). The neighborhood-level variables (by zip code) to assess access to these services include median household income quartile, and physician density (Andersen 1995). Drawing on Andersen's terminology, age, gender, race/ethnicity, and income are “predisposing” characteristics; insurance status, physician density, and zip code of residence are “enabling” characteristics.We include the variable, “age squared,” in our models, in addition to continuous age variables, because the probability of revascularization increases between the ages of 45 and 75 and decreases thereafter due to increasing frailty. Because observations on individuals from the same neighborhood may be correlated, we tested for bias due to unobserved neighborhood-level heterogeneity, by estimating the models with a dummy variable for each zip code as a replacement for neighborhood-level variables. The parameter estimates for the individual characteristics were not appreciably different from those generated by the original model.17Over the 2002 and 2013 period, data from the NYCCHS indicate that risk factors associated with heart disease increased . There wincreased by about 2.7% among patients 65 years and older.Overall, for the population cohort aged 45–64 years, the age-adjusted rate of revascularization among patients hospitalized with IHD or CHF decreased by about 23%. Among patients 65 years and older, the rate of revascularization decreased by about 17% . Most ofWe found that, in both time periods, insurance status, race, gender, number of diagnoses, and zip code of residence are all associated with statistically significant odds ratios for revascularization  and 4. RWe also examined race and insurance status. The odds of revascularization were about 75% lower among non-Hispanic blacks and 55% lower among Hispanic than non-Hispanic whites in 2000–2002 . The oddIn 2000–2002, the odds of revascularization, for those without health insurance, were about 59% lower than among their insured counterparts. The odds were 37% lower among Medicaid recipients and 30% lower among Medicare beneficiaries, than among their privately insured counterparts . Likewis18 These guidelines also address the sensitive and controversial issues of self-referral and ad hoc PTCI, while providing detailed recommendations on the indications for revascularization versus optimal medical therapy for stable CAD, PTCI versus CABG for multivessel disease, and PTCI versus CABG for left main disease. Reasonable physicians caring for these patients may differ with respect to their assessments of available evidence and arguments for each management approach.16As with disease prevalence, trends in the overall use of revascularization in NYC mirror national ones. Over the past 50 years, since the performance of the first CABG, treatment of obstructive CAD has changed. Indications for medical therapy versus surgical or percutaneous revascularization remain the subject of extensive discussion and debate. Guidelines from the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) and the European Society of Cardiology/European Association for Cardiothoracic Surgery (ESC/EACTS) have provided standards of care for interventional cardiologists, cardiac surgeons, and the physicians who refer patients for these procedures. Important new issues covered in recent guidelines from the United States and Europe include the need for risk stratification before revascularization and the use of risk scores, with emphasis on the need to develop a multidisciplinary team-based approach.19–21 Although hospital administrative data are inadequate to reach conclusions about adherence to clinical guidelines, we have documented large and persistent disparities in the use of revascularization among patients hospitalized with IHD and CHD. These disparities call for further research.Despite these important shifts in guidelines for revascularization and its role in the treatment of obstructive CAD, there continues to be good reason for concern about the overuse, misuse, and underuse of these treatments. There is evidence that decisions for proceeding with CABG or PTCI, in clinical practice, may not always follow international guidelines and appropriate use criteria.22 or local interventions, but our results offer grounds for cautious optimism.Over the 2011–2013 period, non-Hispanic blacks and Hispanic whites were significantly less likely than non-Hispanic white patients to receive revascularization procedures in NYC. These racial and ethnic disparities were much smaller than those documented over the 2000–2002 period. It is not possible for us to determine whether the narrowing of these disparities is due to national23 The implication of this position is to call for efforts to promote greater awareness among physicians and patients. In 2002, the National Heart, Lung, and Blood Institute (NHLBI), along with several national and community organizations, created The Heart Truth program to raise awareness of heart disease among women. Yet, even with these efforts, differences in the use of revascularization among men and women in NYC did not change by 2013. Because we rely on hospital administrative data, it is not possible to determine whether these differences can be explained by clinical factors, or respect for patients' values and preferences.While our findings are encouraging, the persistence of gender, insurance status, and neighborhood-level disparities in the treatment of heart disease reinforces a looming policy concern on persistent inequalities in access to specialty services. With respect to gender disparities, many have argued that the prevailing conception of heart disease as a “man's disease” may explain gender differences in the treatment of heart disease.Our findings point to the need for more clinical- and population-based research to improve understanding of why race/ethnicity, gender, insurance status, and neighborhood-level disparities persist in the treatment of heart disease even as the rates of heart disease have declined.


L. interrogans serovar Copenhageni FioCruz L1-130 (Leptospira) through exposure of a dermis wound and through oral and nasal mucosa, in comparison to uninfected mice and to mice infected via standard intraperitoneal inoculation. In striking contrast to oral mucosa inoculation, transdermal and nasal mucosa infections led to weight loss, renal colonization and inflammation, as previously observed for conjunctival and intraperitoneal infections. However, the timing at which Leptospira gained access to blood, as well as Leptospira’ colonization of the kidney and shedding in urine, differed from intraperitoneal infection. Furthermore, a comparative analysis of transcription of pro-inflammatory mediators in kidney and total immunoglobulin isotyping in serum from infected mice, showed increased innate immune response markers  and lower Th1 associated IFN-γ in kidney, as well as lower Th1 associated IgG2a in mice infected through the nasal mucosa as compared to intraperitoneal infection. We conclude that the route of infection affects the timing at which Leptospira gains access to blood for dissemination, as well as the dynamics of colonization and inflammation of the kidney.The goal of this study was to characterize how natural routes of infection affect the kinetics of pathogenic Leptospira dissemination to blood and kidney. C3H/HeJ mice were sublethally infected with  Leptospira that affects humans and animals. Hosts contract Leptospira after exposure to contaminated water through cuts and bruises on skin and mucous membranes. We hypothesized that the route of infection may affect the kinetics of Leptospira dissemination to tissues and leptospirosis progression. In this study, we evaluated the clinical outcomes, and kidney colonization and inflammation after exposure of mice to pathogenic Leptospira using three natural routes of infection. In contrast to transdermal and nasal mucosa, infection through oral mucosa did not cause weight loss and did not result in renal colonization or inflammation. We also found that different natural routes of infection affect the timing at which Leptospira gain access to blood for dissemination, as well as bacterial burden and levels of pro-inflammatory markers in kidney. Precise timing of bacterial dissemination in blood and urine are important differences to consider for assessment of clinical signs of leptospirosis and for development of diagnostic assays for direct detection of Leptospira in human and veterinary biological samples. These studies also provide disease model tools in which to test the efficacy of vaccine candidates using natural routes of infection.Leptospirosis is a neglected disease caused by pathogenic  Leptospira spp. is a neglected emerging zoonotic disease prevalent in industrialized urban, suburban, and rural regions, and is endemic to areas with tropical and temperate climate. Pathogenic Leptospira spp. infect a wide range of vertebrate animals as reservoir hosts, most of which are asymptomatic carriers. Rodents, specifically rats and mice, are carrier hosts that contaminate water and soil with their urine. Humans are considered incidental hosts that acquire infection after exposure to contaminated sources through abraded skin and mucous membranes or consumption of contaminated food , , . T. TLeptosptospira , [2] comtiva, CJ .Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 (henceforth Leptospira), culture passage 2 after hamster infection, originally isolated from a patient in Brazil. Leptospira was cultured as previously described ). Leptospira in urine exponentially, which could be driving an innate immune response pre full colonization. In previous studies we observed a good correlation between RNA transcription and protein expression of the chosen mediators in kidneys . Th. ThLeptoLeptospira in human and veterinary biological samples. These studies also provide disease model tools in which to test the efficacy of vaccine candidates using natural routes of infection.Precise timing of bacterial dissemination in blood and urine are important differences to consider for assessment of clinical signs of leptospirosis and for development of diagnostic assays for direct detection of S1 FigL. interrogans serovar Copenhageni strain Fiocruz L1-130; the inset shows a magnified image of an aggregate of Leptospira; B, histogram depicting the difference in glomeruli size between infected and control groups and C, viability of Leptospira cultured from kidney tissue. P values by unpaired t test with Welch’s correction; *** p<0.001. Data represents one of three experiments.A, PAS-D staining showing mononuclear cell infiltration and reduced size of glomeruli in infected tissue and silver stain (Warthin-Starry) images showing (TIF)Click here for additional data file.


Gerontology and geriatrics are conceptualized as quintessential interdisciplinary fields. To understand aging and provide quality care to older adults, you need an interdisciplinary perspective and an interprofessional team. However, academic and clinical settings—with their vertical structures—require bridging strategies to connect the disciplinary dots. Implicit in this approach is the need for creating networks to support interdisciplinary education in both classroom and experiential settings. Taking on these challenges requires emphasizing the importance of key competencies for both gerontology and interprofessional practice with older adults, including foundational, interactional, and contextual dimensions. These competencies recognize the unique perspectives, contributions, and roles of different disciplines, and create the connections critical for promoting and sustaining interprofessional education. Strategies for developing and maintaining interprofessional networks include: (1) identifying forces driving and restraining change, (2) matching strategies for promoting networks to readiness for system change, and (3) enlisting external forces to make and maintain changes.


We describe the development of an intervention strategy for the indicated prevention of depression in older adults living in Goa, India. Of particular novelty, the intervention is deliverable by lay health counselors and is grounded in problem solving therapy for primary care and brief behavioral treatment for insomnia. We have named the intervention “DIL” (the Hindi word for “heart” and an acronym for “depression in late life.”) Additional DIL strategies include psychoeducation in self-management of co-occurring medical disorders such as diabetes mellitus, together with assistance in navigation to needed social and economic resources. We present the results of a preliminary open-trial case series involving 21 participants with subsyndromal symptoms of depression, demonstrating feasibility, acceptability, and benefit to participants. We then present the design of a larger confirmatory trial into which 181 participants have been enrolled. “DIL” is a novel and large depression prevention trial conducted with lay health counselors in a low-resource country. Its results are likely to have implications for depression prevention in older adults in other low- and middle-income countries and to inform contemporary models of the staging of depressive illness in later life. The training of lay health counselors to deliver simple behavioral interventions such as problem solving therapy and brief behavioral treatment for insomnia, combined with education in the self-management of common co-occurring medical disorders and navigational assistance to social services, may prove to be a pragmatic and scalable approach to reducing incidence of clinical depression among at-risk older adults in low-resource settings. Preventing depression may also repay down-stream benefits of prolonged health span and independence by promoting cognitive health in the later years of life.Prevention of depressive and anxiety disorders is of great public health significance in low- and middle-income countries (LMIC), and represents one of the grand challenges in global mental health . Late-life depression and anxiety disorders, which frequently co-exist, are of particular concern in LMIC due to rapid demographic transition and aging in countries such as India; increased prevalence of social conditions that are recognized as risk factors ; and the weak response of health systems to address the needs  of the elderly. Because of the lack of mental health specialists, there is a need to focus on preventive interventions that can be delivered by nonspecialists and lay health counselors (LHCs) in nonhealth care or primary care settings . The ongMeta-analyses of more than 30 randomized trials in high-income countries show that the incidence of new and recurrent episodes of major depression and commonly co-occurring anxiety disorders can be reduced by 20%–25% over 1–2 years compared to usual care . The MANWe have followed the Medical Research Council Guidelines in formative research for the development of complex interventions, to create and standardize a preventive intervention for use by LHCs in primary care clinics in Goa, India. We have named our model “DIL” . Using an uncontrolled case series enrolling 21 participants, we conducted an initial test of the feasibility and acceptability of the DIL model. As now developed, DIL comprises psychoeducational interventions delivered by LHCs and previously shown to have preventive efficacy: (a) education about symptoms of depression and anxiety; (b) scheduling of activities, including pleasurable activities, to manage symptoms of depression; and (c) provision of social case work to help older adults navigate to needed resources. Based upon a review of the global depression prevention literature, these psychoeducational strategies are grounded within two approaches that appear to work by strengthening protective factors: problem solving therapy for primary care  and brieFollowing the completion of formative research, we are now performing a randomized clinical trial of indicated prevention enrolling 181 older primary care participants with subsyndromal symptoms of depression and anxiety. This has allowed us to gather data on the feasibility of identifying, enrolling, randomizing, and retaining participants; implementing the experimental intervention (“DIL”) and control arm of enhanced usual care under the real-world conditions of public, primary care clinics in Goa; and assessing the fidelity of the DIL implementation.The work described here has been supported by an NIMH intervention development grant (R34 MH 96997) to the University of Pittsburgh and carried out in partnership with Sangath, an NGO in Goa that has conducted scalable mental health research across the life cycle for over 20 years. Additional partners are the London School of Hygiene and Tropical Medicine, the Goa Medical College, the Free University of Amsterdam, and Harvard Medical School. We have registered “DIL” at clinicaltrials.gov.Why is prevention of major depression in later life important, especially in LMIC? The public health case for depression prevention in older adults rests upon the following factors:(1) The number of older adults in LMICs, including India, will grow substantially in the next few decades.Prevalence and course of major depression: Episodes of major depression in older adults are prevalent and disabling .(2a) (2b) The disorder often runs a relapsing and chronic course, and social factors related to economic and social disadvantages (low education and violence) are major determinants.(2c) Major depression often co-occurs with other chronic conditions like diabetes and hypertension, amplifying the disability associated with these conditions, undermining treatment adherence and worsening family caregiver burden.(2d) Depression is associated with excess mortality after myocardial infarction, stroke, and cancer and is the major risk factor stroke in old age.Available treatments: Current treatments are only partially satisfactory in reducing symptom burden, sustaining remission, and averting years lived with disability.(3) Problems for treatment of depression inLMIC: The treatment gap for people with mental disorders has been extensively documented, especially in LMICs where up to 90% of affected persons do not receive treatment.(4a) (4b) The scarcity of mental health specialists in most countries and the inequity of the distribution of these specialists is a major barrier to closing the treatment gap. The existence of the treatment gap and the attendant workforce issues underscore the need for developing effective models of prevention that can be implemented by health workers with shorter training and fewer qualifications, to optimize the efficient use of the available human resources for health. Finally, mental health practices targeting the prevention, early detection, and treatment of depression across the lifespan (particularly later in life) could contribute to the reduction in the incidence and prevalence of dementing disorders .If one conceptualizes a staging model of depressive illness, analogous to the stages of cancer, then prevention, or early intervention, in persons with subsyndromal symptoms (the essence of what the Institute of Medicine has termed “indicated” prevention) may represent an opportunity to delay, mitigate, or altogether prevent the development of a later stage of illness, namely, the syndromal expression of major depression and its attendant risk for relapse, recurrence, and other down-stream consequences, including dementia and suicide. Just as in oncology early intervention targets more treatable stages of illness with better prognosis, so also with respect to depression, early intervention may prevent the emergence of more treatment-resistant illness with worse prognosis. In LMIC, where mental illness treatment resources are scarce, the argument for prevention is all the more compelling for this reason. A staging model of depression, as posited here, represents a useful hybrid of traditional categorical or binomial approaches to diagnosis and of dimensional models representing a continuum of severity. A staging model offers the possibility of different platforms for interventions, prevention- and treatment-oriented, depending upon the stage of illness.Both randomized prevention trials and epidemiological modeling suggest that prevention of major depression in later life may be most efficiently accomplished by targeting elderly persons who experience risk factors, particularly functional limitations as a result of illnesses such as stroke or macular degeneration, have a small social network, and/or have subsyndromal symptoms . EfficieImpact is reflected by the proportion of cases that would be prevented if the adverse effects of targeted risk factors were completely blocked (attributable fraction). Effort is reflected in the number of persons who would need to receive a depression prevention intervention to avoid one new case of late-life depression (number needed to treat [NNT]). Investigators have estimated that preventive interventions would have the highest impact and lowest effort in the presence of subsyndromal depressive symptoms (NNT = 3–4 in “indicated” prevention versus 7–9 in “selective” prevention with at-risk but asymptomatic persons) . That isA study conducted in Amsterdam by van’t-Veer Tazelaar and colleagues  evaluaten = 58) were more likely over the course of 12 months to suffer a major or minor depressive episode than patients receiving low-dose escitalopram  or receiving a course of problem solving therapy (n = 58). This study reported an NNT of 8.A study exemplifying selective prevention  enrolledWe conducted a meta-analysis of incidence rate reduction in major depression, pooling data from 32 studies enrolling mixed-aged samples . Thirty-Brief learning-based approaches, already shown to have efficacy in the treatment of depressive disorders, offer a promising strategy to develop and test innovative interventions to reduce risk and positively alter trajectory of depressive illness (by intervening at an earlier stage of illness). While antidepressant medications are the most widely used modality for treating prevalent cases of major depression, their use in subsyndromal depression may be ill-advised due to a lack of evidence for efficacy in mild depression, as well as adverse effects in older adults such as hyponatremia, risk for falls, bone de-mineralization, and cataracts . PsycholDIL is generating the first evidence of a potentially scalable intervention for prevention of common mental disorders in a low- and middle-income country in the midst of rapid demographic transition . The empDIL has followed the Medical Research Guidelines for developing and evaluating complex interventions . These gWe enrolled 21 participants into DIL’s formative pilot study, aged 60 or older with subsyndromal symptoms of depression and anxiety as indicated by a score of 4 or greater on the General Health Questionnaire (GHQ) , but witBecause of the low levels of literacy among DIL participants, we found it essential to use flip charts illustrations, as shown in Quantitative results were available from 19 of the 21 participants initially enrolled, demonstrating a high level of retention (SD]: 1.5). The postintervention GHQ score was 3.3 (SD: 2.0); paired t = 4.7, df = 18, p < .05.etention . BaselinQualitative analyses of in-depth interviews with participants showed that participants preferred the use of “tension” rather than “depression.” Many endorsed worries regarding an uncertain future related to relationships with their grown children and to deteriorating health . Because of the broad spectrum of risk for depression and anxiety disorders, interventions need to allow for some degree of tailoring to meet the specific needs of the individual. Thus, DIL enacts a structured but tailored approach that are responsive to individual needs and preferences.The design of the ongoing randomized trial testing indicated depression prevention is depicted in Our primary outcomes are both symptomatic burden (as reflected in GHQ scores) and the cumulative incidence of episodes of major depression and anxiety disorders over 12 months in the two arms of the study: “DIL” and enhanced usual care. We are tracking both depression and anxiety episodes because of their frequent co-occurrence as common mental health disorders in primary care. We are also tracking functional status via the WHODAS-II. Repeated assessments are conducted at baseline, upon completion of the DIL intervention, and at 6 and 12 months.For ethical reasons related to the protection of human subjects, results of repeated assessments of mood and anxiety symptoms among DIL participants randomly assigned to enhance care as usual are made known to participants and their physicians on an ongoing basis. While enhancing care as usual in this fashion may make it more challenging to demonstrate meaningful differences between the intervention (DIL) and control arms , we believe that it is ethically mandatory to share such information. Thus, by monitoring all participants, regardless of randomized intervention assignment, we are able to identify early on those with need for clinical care for emerging depression, suicidal ideation, anxiety disorders, or dementia. We document the content of enhanced care as usual, that is, the extent to which participants receive either psychosocial or pharmacologic interventions for depression or anxiety.Data analyses encompass both descriptive and inferential modeling. We are examining data descriptively using cross-tabulations, histograms, and tests for normality. Imputation strategies based in random regression models handle missing data. Time to onset of major depression or anxiety disorders as an outcome are modeled via survival analysis.n = 181), with fewer than 20% of eligible subjects refusing randomization. Retention is also high, better than 85%. Randomization (via permuted block) has also been shown to be adequate by producing equal numbers of participants assigned to each condition, and having similar sociodemographic and clinical characteristics  identification of bio- and psychosocial risk markers, (b) expansion of outcomes to include measures of physical and neurological health status, and (c) enhancement of external validity and generalizability using large cluster-randomized trials to capture greater diversity in populations of interest. Markers of biological and psychosocial risk may provide important clues as to which persons, in particular, may benefit from the use of prevention strategies, thereby enabling more rational and efficient use of scare mental health resources in LMICs. Biomarkers could also have relevance to the development of staging models of depressive illness, thereby providing clues as to which type of intervention platform could be helpful to a given patient. In other words, such markers may also serve as moderators of intervention response, and they may tell us something about how interventions work to reduce the risk for common mental disorders. Because depression and anxiety do not occur in “pure” culture but rather co-occur with, and exacerbate, medical polymorbidity, mental illness depression research should also examine measures of medical and neurologic burden over time. It may be that by preventing depression, general measures of medical health will improve also and show lesser rates of incident disability. As such, depression prevention may be a key strategy to preserving the functional independence of older adults for as long as possible.Innovation in Aging online.Supplementary data are available at igx030_suppl_Supplementary_FiguresClick here for additional data file.This work was supported by US National Institute of Mental Health , the Brain and Behavior Research Foundation, and the UPMC Endowment in Geriatric Psychiatry.None reported.


Survivors of war throughout the world experience illnesses and injuries that are crucial to understand, given the ongoing treatment and adaptation they demand. In developing countries like Vietnam, where population aging and chronic disease burdens are rapidly rising, aging populations have seen a disproportionate share of armed conflict and related casualties. This paper describes the Vietnam Health and Aging Study (VHAS), a unique resource for investigating mechanisms of association between diverse exposures to armed conflict during the Vietnam War and multiple dimensions of older adult health among survivors of that war.The VHAS utilizes a longitudinal design, the first wave of data collection conducted in 2018 among 2447 older adults. A second wave of follow-up data collection, scheduled to take place in 2021, will examine life course, social relational and health and mortality transitions. The VHAS was conducted in four northern Vietnamese districts purposively selected to represent a spectrum of war exposure as indicated by intensity of bombings. Additionally, VHAS uses random sampling within gender and military service subdomains to permit unique gender-specific analyses of military service, trauma exposure and health.The VHAS’ face-to-face interviews include modules detailing war and military service experiences; warzone stressors; and multiple dimensions of health such as chronic disease, functional limitation, disability, health behaviors, cognition and psychological health. Biomarker data collected for the full VHAS sample includes anthropometric and functional tests such as grip strength and blood pressure, hair samples for cortisol assay, and capillary blood samples to assay C-reactive protein, cholesterol, HbA1c, and other markers of interest for cardiovascular and other disease risks and for testing the impact of early life stressors on later life health. Blood samples will also permit epigenetic analysis of biological aging.Future VHAS investigations will examine dynamic linkages between war exposure, mortality and morbidity, while taking into account the selective nature of each of these processes. Longitudinal analyses will examine late-life health transitions and war-related resiliency. Survivors of war live throughout the world and their numbers are increasing. Their illnesses and injuries are arguably as challenging to societies as war deaths and as crucial to understand, given the ongoing treatment and adaptation they demand –9. It isLate 20th and early twenty-first century wars, as well as related post-war recovery and readjustment challenges, have concentrated in low-middle income countries where war-damaged institutions and infrastructure layer upon fragile economies, unstable political systems, and weakly developed healthcare systems . Yet, poThe Gerontologist on Veterans Aging [Due to protracted military conflicts with the French and Americans over much of the twentieth century, Vietnam is a critical context for furthering knowledge of war’s lasting public health impacts. The Vietnam War (known among Vietnamese study participants as the “American War”) exacted a severe toll upon Vietnamese society , 20, yetns Aging –26), knons Aging –31. Resens Aging –38. In dns Aging , 40.The Vietnam Health and Aging Study (VHAS) is a collaborative research study allowing for investigation of the mechanisms of association between diverse exposures to armed conflict during the Vietnam War and multiple dimensions of health among older adults. The VHAS will provide a unique, publicly available data resource for methodologically rigorous exploration of the implications of armed conflict for older adult health and aging processes. The rich combination of health and war exposure measurements are unprecedented and allow analysis of the dynamic linkages between war exposure, mortality, and morbidity, while taking into account the selective nature of each of these processes. The VHAS also equips investigators to understand how family relationships, stressful experiences in the life course, and current material, social and stressor conditions serve as mediating factors between wartime experiences, aging processes and late life health outcomes.Funded by a grant from the National Institutes of Health/National Institute on Aging (R01 AG052537), the VHAS is conducted by an interdisciplinary team of social scientists and health scientists from the University of Utah, USA; Mount Saint Vincent University, Canada; the National University of Singapore; University of Washington, Seattle, USA; Hanoi Medical University, Vietnam; and the Institute for Family and Gender Studies, Vietnam.The VHAS utilizes a longitudinal design in order to examine dynamics in the life course, health transitions of older adults, and the developmental processes of resiliency and scarring linked to early life war exposures. Aspects of sampling and the interview components are geared toward documenting the wide-ranging severity and forms of war exposure that characterize this cohort of older Vietnamese adults. The first wave of VHAS data collection was conducted between May and August 2018, among 2447 men and women born in 1959 or earlier . A second wave of follow-up data collection, scheduled to take place in 2021, will revisit original respondents in order to ascertain mortality and, among survivors, changes in health behaviors and health conditions, socioeconomic conditions, living arrangements, intergenerational and social relationships. Both waves of data collection include face-to-face, home-based interviews, conducted by staff members of Hanoi Medical University and the Institute for Family and Gender Studies, and biomarker measurement conducted by staff members of Hanoi Medical University in local commune health centers. Senior personnel from all six participating academic institutions trained and supervised the interviewer and biomarker data collection teams.The VHAS relied upon a multistage probability design to arrive at the study sample. We began by purposively selecting four districts in northern Vietnam, which represent a spectrum of exposures to war as indicated by the intensity of bombings during the 1960s and 1970s . SpecifiThanh Niên Xung Phong). The latter, a military corps established in 1950 and widely reactivated by Democratic Republic of Vietnam during 1965–1975, recruited more youthful, teenage volunteers, including many young women, into military support roles such as defusing bombs, maintaining roads, and provisioning arms and food to the troops [To create our sampling frame of eligible respondents within each PSU  the VHAS team collaborated with local officials to access current, regularly updated household registration databases. In particular, VHAS staff sought the assistance of population volunteers (cộng tác viên dân sộ) to derive the sampling frame. Population volunteers are members of the community tasked with liaising with local governments regarding population-related matters within their village/ward, such as population enumeration and routine reporting of births and deaths. The population volunteers utilized local record-keeping systems to generate a list of all households with at least one member age 60 or older. From these households we delineated the following information among potential respondents: (a) address, (b) name, (c) age, (d) sex, and (e) veteran status. If local officials lacked information about the individual characteristics (b)-(e), they contacted households via phone or home visit to confirm the information. A full listing of characteristics a) - e) was created for all persons 60 and older in each commune/ward, thus comprising our sampling frame. If more than one person in the household was age 60 or older, both members were included in the listing. “Veteran status” for the purpose of our study includes participation in both formal military roles or as voluntary participants in militia/paramilitary units such as the Youth Shock Brigades  as they varied across men and women who were differently exposed to the “treatment” effect of military service during the Vietnam War . For exaIn addition to conventional statistical power calculations, we also consulted Peduzzi et al’s ‘rule of thumb’ for a minimum number of ‘events per variable,’  to arrivAs noted below, due to minor difficulties in identifying eligible individuals for inclusion in the sampling frame and a few refusals during in-progress interviews, the final VHAS sample size is 2447. With the application of sampling weights, VHAS data are representative of the older adult population ages 60 and older residing in the twelve communes/wards from which the sample was drawn.In order to recruit participants to the study, local population volunteers contacted potential respondents via telephone and in person, described the study, and invited their participation. Population volunteers made up to three attempts to contact the randomly selected eligible participants to invite their participation and schedule an interview. When a person within the sampling list could not be contacted or refused to be interviewed, a replacement was sought from within the same subdomain in that commune’s/ward’s sampling frame list.Upon agreeing to participate, the VHAS staff scheduled a two-hour appointment with each prospective respondent, specifying that the private interview could be conducted in the participant’s household or at another preferred location, as well as an appointment for an approximately 35 min health exam, which included a series of anthropometric measures, hair and capillary blood collection. The biomarker collection appointment was scheduled to take place within the commune health center (CHC) one or 2 days after the interview. The VHAS staff also provided those who agreed to participate with an appointment reminder and a copy of the study consent form so that they could become more familiar with the study procedures and their rights as human subjects in advance of the team’s reviewing the consent form and obtaining their informed consent at the start of the interview.As part of the recruitment and study invitation, each prospective respondent was informed that they would be paid an incentive payment of 90,000 Vietnamese Dong, approximately $US 4.50, for their participation in the study. In addition, VHAS staff cooperated with local health clinic staff to provide a general health examination and consultation alongside the biomarker collection exam.The project team offered to assist with prospective respondents’ transportation to the CHC if the individual was unable to travel on their own or with family assistance. In the case that a respondent was unable to travel to the CHC, even with assistance, the VHAS staff arranged for a clinic staff member to make an in-home visit to collect the biomarker measures, excluding the collection of blood, per Ministry of Health policy. Additionally, for persons who missed their scheduled biomarker collection appointment, the VHAS staff followed up and offered an in-home visit for collection.Numbers and rates of nonresponse were calculated for the total VHAS sample, for each of the 12 PSUs (communes and wards), and within-PSU, for each of our four study subdomains. Nonresponse was due to refusal to participate, lack of availability to participate, or inability of project staff to locate the enumerated individual. The overall response rate for the VHAS Wave I data collection is 84.7%, ranging from 81.0 to 93.2% across PSUs. In terms of the study subdomains, those in the female veteran domain had the highest response rate (91.2%), while the female nonveteran domain had the lowest response rate (81.7%). The male veteran and nonveteran domain response rates were intermediate: 86.2 and 85.8%, respectively. The refusal rate, i.e., the percentage of those selected for study participation who refused to participate, was 9.7% overall (ranging across communes from 2.5 to 16.7%).For individuals selected from the frame, but who did not participate due to refusal or other reasons, a replacement was randomly selected from within the same gender and veteran status subdomain for that ward/commune. There are 458 of such cases. Apart from refusing to participate in the survey, another main reason for case replacement is temporary migration  during the time the survey was taking place.The VHAS Wave I data collection was conducted over 4 months during 2018. The dates for data collection were as follows: Bo Trach district and Dong Hoi city, Quang Binh Province: May 7 to June 1; Ba Vi district, Ha Noi city, June 5–16 and July 2–17; Yen Khanh district, Ninh Binh Province: July 25–August 21.Interviews were conducted privately in the homes of participants. The interview began by introducing the research project and obtaining informed consent of individuals to participate in the study. After informed consent was obtained, face-to-face interviews were conducted using the Computer Assisted Personal Interviewing (CAPI) system, COMMCARE. Each interviewer utilized a tablet PC to enter data as they conducted the interview. The use of CAPI enhanced the detection and correction of on-the-spot data entry errors. When the interviewer entered an answer with a logic error or abnormal value, the system showed a prompt to caution the interviewer. Interviewers uploaded the data to the data server after each day’s data collection. The average duration of each in-home interview was approximately 2.5 h. Given this duration, interviewers were advised to attend to the comfort, attention and fatigue of the participants. They offered a break when it appeared necessary, or approximately half way through the interview.If a sampled respondent was too frail to answer the entirety of the interview questions, we identified a proxy respondent to either fully complete or assist in the completion of the interview. Proxy respondents tend to be the spouse or adult child of the respondent, knowledgeable about his/her life history and familiar with his/her current health and living conditions.The need for a proxy respondent for the full interview was determined at the study invitation stage, or by the interviewer at the beginning of the interview. Where necessary, such as in cases of ambiguous cognitive functioning, interviewers sought the guidance and approval of field supervisors to make the determination. Once this was determined, the CAPI system automatically switched to the substitution mode before entering the first section. Compared to the normal mode, the proxy respondent was asked only a subset of questions. Proxy respondents answered only factual questions, not subjective questions such as self-rated health, feelings of depression, or marital satisfaction. At the end of each section as well as at the end of the entire interview, interviewers made an assessment about the extent to which proxy respondents assisted in the interview. Possible responses included (1) sampled respondent answered all questions him/herself; (2) sampled respondent received some assistance from others who happened to be present; (3) sampled respondent was somewhat incapable of answering the questions and thus received assistance; (4) proxy respondent answered all of the questions.As shown in Table A household roster, including demographic characteristics of the respondent and all household members;In-depth description of military service ;War era experiences and stressors associated with warzone activity, including stressors experienced by combatants and noncombatants, in battle and in civilian life;Self-reports of myriad dimensions of health, including chronic disease, functional limitation, disability, health behaviors, cognitive and psychological health;Rosters of all siblings and children, those living and deceased;Co-resident and non-co-resident children characteristics, including intergenerational support and relations;Individual and household socioeconomic details such as wealth and education, sources of income, health insurance and other benefits, and employment history;Migration history, focused upon mobility during the war era;Family background information, childhood health conditions;Religion and practice of religion;Stressful life events and stress appraisal;Social engagement and social support relationships.The VHAS survey covers subject areas that allow for testing hypotheses derived from the project’s conceptual framework as well as areas that touch on matters of common interest in the study of aging populations. Specifically, survey modules include the following:Biomarker data collection is central to the VHAS assessment of health conditions and aging processes. The study investigators seek to understand how early life stressors experienced during wartime influence health and aging over the life course. Accordingly, the VHAS biomarker collection and assay plan focuses upon measuring the physiological pathways linking traumatic stress, chronic stress, health outcomes and physiological aging. The biomarker data includes blood samples that are to be used to assay markers of interest for cardiovascular and other disease risks pertinent to an aging population and for testing the impact of early life stressors on later life health and physiological aging. Biomarkers of interest include, but are not limited to, C-reactive protein, total and HDL cholesterol, and glycated hemoglobin (HbA1c). Other biomarker data collected include blood pressure, hair samples for the testing of cortisol, anthropometric tests and functional tests such as grip strength.Overall, participation in the biomarker collection component of the study was high, with a participation rate similar to or better than rates observed in comparable studies such as the China Health and Retirement Longitudinal Study and Health and Aging in Africa Longitudinal Study. 2342 participants  agreed to participate in the biomarker data collection, and at least one valid body measure or function test data point was collected from 2325 participants. 2288 participants (93.5% of the sample) provided blood samples for point-of-care test(s), and a sample of capillary blood was retained from 2210 participants (90.4%) for subsequent laboratory-based analyses.All VHAS participants were asked to visit a CHC near their homes for biomarker data collection. Twelve CHCs hosted biomarker data collection. Trained VHAS staff conducted biomarker data collection in two phases: hair sample collection, body measures and functional tests were conducted in one room or clinic area, and blood sample collection and testing were carried out in a separate space. Where possible, biomarker data collection areas were private, but in some cases the collection procedures were visible from common areas of the clinic. At each study location, two study staff were responsible for collecting hair samples, body measures and functional measures. Blood collection and testing required three study staff. A biomarker supervisor was responsible for overseeing both parts of the biomarker procedure, and for assisting the participants in checking in and moving through the steps of the biomarker data collection process.For study participants deemed by VHAS interview staff or local CHC staff to be too frail to visit the CHC setting, VHAS staff conducted in-home measurement of a subset of biomarkers. VHAS biomarker staff exercised their best judgement to collect only those physical measures that were not too taxing upon the participant. In accordance with Vietnam’s Ministry of Health policies, hair collection and blood sample collection were only conducted in the clinic setting; no biological samples were collected in the home-based visits.We list the biomarker variables collected in the VHAS in Table For the majority of participants, the biomarker testing procedures took approximately 35 min to complete, with approximately 15 additional minutes of wait time.Anthropometric measurements included standing height, weight, body fat percent, mid upper arm circumference, calf circumference, hip circumference and waist circumference. Procedures for anthropometry followed methods described in the National Health and Nutrition Examination Survey Anthropometry Procedures Manual . Height Peak expiratory flow was measured using a Clement Clarke Airzone peak flow meter, with three measures taken per participant. Grip strength was measured using Charder MG4800 Digital Handgrip Dynamometers, with two measures taken per hand; participants were asked to report their dominant hand. Blood pressure was measured, two times, using Omron BP786N automated blood pressure monitors; systolic and diastolic blood pressure were recorded as well as pulse.A section of hair was collected for cortisol analysis. A hair sample approximately the diameter of a pencil was tied with string, and cut as close as possible to the scalp from the posterior vertex of the occipital lobe. Samples were wrapped in foil and stored noting the scalp end of the sample. Cortisol will be tested using a one-centimeter segment of hair closest to the scalp.A phlebotomist on the biomarker team collected blood from a finger puncture with a sterile lancet. Blood was collected into BD Microtainer collection tubes with K2-EDTA anticoagulant. A minimum of 0.4 mL and up to 0.6 mL of whole blood was collected into microtainer tubes from each participant. Within 15 min of collection, blood was centrifuged, the plasma fraction and buffy coat layer were separated, and each retained in cryovials. All samples were frozen within one hour of collection, and most were frozen within 15 min of collection. Samples were stored in a -20C freezer at the CHC for up to 1 week. At the end of data collection in each CHC, specimens were transported on ice to a central facility and frozen at -80C. At the end of data collection in all provinces, all samples were transferred on ice to Hanoi Medical University for long-term storage at -80C. The plasma fraction will be used for testing biomarkers indicative of immune function, metabolism, and cardiovascular disease risk. The buffy coat fraction containing peripheral blood mononuclear cells may be used for genetic analyses (pending funding), including DNA methylation and telomere length. For 80 participants , the obtained sample either lacked adequate volume or for other reasons was not adequate for laboratory assays.A QBC STAR Centrifugal Hematology System was used to perform complete blood count. The QBC STAR uses 65 to 75 uL of whole blood collected in a capillary tube containing reagents to differentially stain white blood cells. The instrument separates blood by cell type within the capillary tube by centrifugation then uses optical scanning to quantify the cell fractions. The QBC STAR system has on-board automatic quality control procedures that were performed each day at the start of testing. HbA1c was measured using a Diazyme SMART assay system. The test is a direct enzymatic assay of HbA1c requiring 20uL of whole blood. A single finger puncture was used for both capillary blood sample collection and for blood used in the point-of-care instruments; in some cases, a second finger puncture was required to produce enough blood to complete the full protocol. Blood collection was adequate to carry out at least one point-of-care test in every case but one.Capillary blood collection, while less invasive, yields a limited volume of sample. However, collection from a finger puncture was typically successful in producing adequate volume for point-of-care tests and for later testing in a laboratory using multiplex assay methods that allow multiple measures simultaneously in a single test. The most significant biomarker challenge was controlling the temperature and humidity in the room where point-of-care testing was conducted. A portable dehumidifier and a portable air conditioner were positioned near the testing instruments, and temperature and humidity were tracked throughout the day.Performance of the Diazyme SMART HbA1c instrument was of particular concern given previous reports of difficulty with HbA1c measurement in hot and humid climates , 49. QuaDoes war exposure exert enduring effects on older adults’ health? What forms of exposure are most influential? Are combat and severe war traumas associated with distinct mortality and morbidity patterns in later stages of the life course?How do socioeconomic conditions, stress experiences and responses, and social relational factors mediate and moderate relationships linking war exposure and old-age health?Does war exposure influence late-life health transitions? Does the onset of disease vary by forms and degrees of wartime exposure? Is war-related resiliency implicated in health transitions?To date, data on exposure to war and extreme stress is almost entirely lacking in studies of health and aging in the developing world. The Vietnam Health and Aging Study has created a longitudinal data resource for analyses of war exposure and its long-term impacts on health and wellbeing. The Wave I VHAS data were collected in 2018 through in-person interviews and biomarker data collection among 2447 adults age 60 and older. VHAS study participants are survivors of the Vietnam War, which was waged for over a decade during their adolescence and young adulthood. Analyses of the VHAS cohort’s war-time and subsequent life experiences, current health conditions and health trajectories between Waves I (2018) and II (2021) will allow scholars to address the following broad sets of questions based on both social survey measures and biomarkers:Alongside these broad lines of inquiry, a broader aim of the project investigators is to open a new field of inquiry on the global demographic and health consequences of armed conflict.The VHAS has both strengths and limitations. As an omnibus survey of health and aging, the VHAS provides a holistic picture of participants’ material, social, familial and health conditions. A notable strength of the VHAS is the one-of-a-kind, in-depth information that it provides on wartime experiences, as well as rich, detailed information on physical, mental, and functional health status. Yet taking into consideration budget constraints and respondent burden, there are domains for which we would have liked to collect information that is more detailed. Particularly salient issues that we wish we knew more about, such as experiences with economic stress, cognitive decline, and chronic and daily life stressors, will be considered for inclusion in the VHAS Wave II data collection.As is the case with any population-based study initiated among older adults, samples are necessarily impacted by selective survivorship. This is particularly true in a setting such as Vietnam that has experienced much war-induced premature mortality. The VHAS provides exhaustive information on participants’ sibships. This information can be leveraged to discern differential survivorship across and within families and thereby to ascertain the social dimensions of selective survivorship.Data collection for the VHAS was influenced by periods of very high heat and humidity. The VHAS study team undertook many efforts, such as implementing early morning scheduling and portable cooling systems, in attempts to maintain suitable climatic conditions for conducting interviews in the homes of elderly individuals and blood collection in CHCs that lacked air conditioning. VHAS interviewers were attentive to and addressed older adults’ levels of comfort during the interview. However the lengthy interview (approximately 2.5 h on average), coupled with the high heat, resulted in fatigue for certain participants, especially the oldest among them. Undoubtedly, the VHAS survey and biomarker data bear the influences of these challenging climatic conditions and interpretation of the study results should take these conditions into account.Finally, our extensive measures of past events during the wartime are reliant upon respondent recall of events that took place many decades prior. While memories may fade and recall may be biased, it is commonplace to rely upon aging study participants’ assessments of the past to characterize early life conditions. Several major studies of health and aging have unambiguously shown that survey questions about early life conditions can be successfully linked to later-life outcomes –54. Many