Envenoming resulting from snake bites is an important public health hazard in many regions of the world, yet public health authorities have given little attention to the problem. Envenoming resulting from snake bites is an important public health hazard in many regions, particularly in tropical and subtropical countries . AlthougIn the tropical developing countries where snake bites occur most commonly, there are few reliable incidence data. One serious attempt to assess global snake bite mortality was the survey undertaken by Swaroop and Grabb in 1954, which was based largely on hospital admissions . SubsequProperly designed population surveys are likely to give a far more accurate picture of snake bite incidence, morbidity, and mortality. In Asia, the highest recorded mortality was 162 snake bite deaths per 100,000 people per year, in the Eastern Terai of Nepal . In AfriEchis sp.  in northern Africa,Bothrops asper andB. atrox (lance-headed pit vipers) in Central and South America, andNaja sp. (cobras) andBungarus sp. (kraits) in Asia [Most severe cases of snake bite envenoming are inflicted by species of the family Elapidae  and the family Viperidae . The species causing the largest numbers of bites and fatalities arein Asia ,9–11  antivenoms is the mainstay and the only specific treatment of snake bite envenoming. Many laboratories produce antivenoms using various methodologies, which yield three different types of products depending on the nature of the active principle. In some cases, antivenoms consist of whole IgG molecules, but the majority of producers manufacture antivenoms composed of F(ab') of IgG ,15. Var of IgG . The lar2. The main problem associated with antivenom efficacy has to do with local tissue damage [Clinical investigations have established that generally antivenoms are highly effective in the neutralisation of toxins responsible for systemic effects such as haemorrhage, coagulopathy, and haemodynamic disturbances. Similarly, a rapid reversal of neurotoxicity caused by postsynaptic neurotoxins in elapid envenomings is well established . In cont damage . This pr damage .Antivenom safety is also of current concern since, although the safety profile of some products is satisfactory, the administration of other antivenoms is associated with a high incidence of early and late adverse reactions ,15. TheBesides antivenom administration, the therapy of snake bite envenoming involves a number of ancillary interventions . Assiste2, and possibly hyaluronidases are mostly responsible for the local tissue damage frequently observed in snake bite envenoming. It is very difficult for IgG and its fragments to neutralise these toxins, so there is an urgent need to develop new therapies to counteract local venom effects. Venom hydrolases are homologous with endogenous mammalian enzymes, such as matrix metalloproteinases, a disintegrin and metalloproteinase (ADAM) enzymes, and inflammatory phospholipases A2. The pharmaceutical industry has developed a large number of inhibitors to these mammalian enzymes because of their relevance in many pathologies. Since many of these drugs have already been tested in clinical trials, there is an excellent opportunity to use some of these inhibitors to prevent local effects of snake bite envenoming. For instance, the peptidomimetic hydroxamate metalloproteinase inhibitor “batimastat” is highly effective in preventing local tissue damage and some systemic effects induced by the venom ofB. asper [2 and hyaluronidase inhibitors have proven successful at reducing the extent of venom-induced tissue damage at the experimental level [2 present in the venoms of different genera and species, since most of them act at the active sites of these enzymes, which are highly conserved.Hydrolases such as metalloproteinases, phospholipases A. asper ,19. Siml level ,21. TheDespite the success of antivenoms in the therapy of snake bite envenoming, a number of research groups are working to improve the quality of antivenoms using different approaches: (1) new immunisation strategies, such as DNA immunisation or the use of purified relevant toxins as antigens instead of the whole venom ; (2) impIn various parts of the world, there is a continuing crisis in the production, deployment, and accessibility of antivenoms. This is particularly serious in Africa since various traditional suppliers have stopped producing antivenoms for this continent, and the privatisation of other producers has also affected supply. It is therefore a matter of great urgency to promote international collaboration—best coordinated by the World Health Organization—involving national and regional health organisations and diverse public–private partnerships in order to accomplish the following goals: (1) to gather accurate epidemiological information on the impact and characteristics of snake bite envenoming in many regions, using properly designed community studies; and (2) to provide effective and safe antivenoms in those regions where they are not currently available. This includes, in the short term, the commitment of various laboratories to produce antivenoms for these regions, such as the efforts being undertaken by various producers to manufacture new antivenoms for use in Africa . InnovatBesides the technological issues of antivenom production and supply, efforts should be devoted in Africa, Asia, Oceania, and Latin America to the preparation of consensus guidelines and protocols for treatment and prevention of snake bites , and to Alternative Language Abstract S1(62 KB DOC).Click here for additional data file.Figure S1(39 KB PPT).Click here for additional data file.


There was a weak, but statistically significant, trend of increasingrisk of all-cancer mortality with increasing weighted cumulativeexposure. A similar deficit in all-cause  and all-cancer  mortality was observed in those exposedto non-volatile organochlorines. No excess risk was observed in cancersof a priori interest, although mortality from Hodgkin disease was elevated . In this study we foundlittle evidence that exposure to organochlorines at the levels experiencedin the pulp and paper industry is associated with an increasedrisk of cancer, apart from a weak but significant association betweenall-cancer mortality and weighted cumulative volatile organochlorineexposure.The objective of this study was to evaluate cancer mortality in pulp andpaper industry workers exposed to chlorinated organic compounds. Weassembled a multinational cohort of workers employed between 1920 and 1996 in 11 countries. Exposure to both volatile and nonvolatile organochlorinecompounds was estimated at the department level using an exposurematrix. We conducted a standardized mortality ratio (SMR) analysisbased on age and calendar-period–specific national mortalityrates and a Poisson regression analysis. The study population consistedof 60,468 workers. Workers exposed to volatile organochlorines experienceda deficit of all-cause  and all-cancer  mortality, withno evidence of increased risks for any cancer of  Pulp and paper production workers have been exposed to a complex mixtureof hazardous substances, including known or suspected carcinogens suchas wood dust, various wood extracts and associated bioaerosols, reducedsulfur compounds, talc, formaldehyde, combustion products, epichlorohydrin, acidmists, auramine and other benzidine-based dyes, and arange of chlorinated organic compounds , 2002. TThe International Agency for Research on Cancer (IARC) therefore coordinatedan international collaborative cohort study to investigate mortalityand cancer incidence in the pulp, paper, paperboard, recycled paper, andpaper product industries. This study has combined cohorts from 13 countries, consistingof 98,665 workers , andincluded the development of a comprehensive database of exposure measurementsfor the retrospective assessment of study participants’ exposure , 2002. Tpara-dioxins (TCDDs) as carcinogenic to humans (group 1) on the basis of bothmechanistic evidence and limited evidence in humans of excess riskof all cancers combined rather than for any specific site cancer; PCBsas probably carcinogenic to humans (group 2A) because of limited evidenceof excess cancers of the liver and biliary tract and of lymphaticand hematopoietic tissues; and PCPs and their sodium salts as possiblycarcinogenic to humans (group 2B) based on findings of excess risk ofsoft tissue sarcoma and NHL ], polychlorinated biphenyls (PCBs), andpolychlorinated dibenzodioxins (PCDDs) or polychlorinateddibenzofurans (PCDFs). IARC has classified the volatile organochlorinestrichloroethylene and perchloroethylene as probably carcinogenic tohumans (group 2A) on the basis of limited evidence in humans of excessrisks of cancer of the liver and biliary tract, non-Hodgkin lymphoma (NHL), andesophageal and cervical cancer, and dichloromethane and trichloromethaneas possibly carcinogenic to humans (group 2B) based onsufficient evidence for carcinogenicity in animals . Of the  and NHL . The aimWorkers employed for at least 1 year in the pulp and paper industry in 13 countriesduring the period 1920–1996 were included in theoverall IARC study, with cohorts from Denmark, Finland, France, Japan, NewZealand, Norway, Poland, Spain, Sweden, Scotland, and the UnitedStates included in this analysis of organochlorine exposure. Brazil andSouth Africa were excluded from this analysis because of inadequaciesin the quality of mortality data. Cohort members were identified fromcompany personnel records, with work histories available for the fullperiod of employment in that company.The exposure assessment procedure used for this study has been describedin detail elsewhere , 2002. BExposure to volatile organochlorine compounds was defined as inhalatoryexposure to chlorinated solvents or other specified compounds  at a level exceeding the nonoccupational backgroundlevel. These substances have been used as cleaning and degreasingagents in most departments, with the highest exposures occurring inmaintenance, repair, and cleaning operations, and medium exposures insulfate pulp and pulp bleaching departments. The high-exposure categorywas defined as workers in those departments in which > 50% wereexposed and in which the mean level of exposure over the work yearwas estimated to exceed 1 ppm for trichloromethane, 2.5 ppm for perchloroethylene, and 5 ppmfor dichloromethane and trichloroethylene [all 1/10thof the threshold limit value of the American Conferenceof Governmental Industrial Hygienists ].Nonvolatile organochlorine exposure was assessed in qualitative terms asever/never exposed, with exposure defined as potential dermal or inhalatoryexposure to PCP or its salts, PCBs, PCDDs, PCDFs, or other non-volatileorganochlorine compounds exceeding the nonoccupational long-termbackground level. PCP has been used to prevent sapstain in softwoodsused for pulp, with consequent worker exposure during pulping operations. Exposureto PCBs is most likely to have occurred during maintenanceand repair of electrical or hydraulic equipment. Both PCP and PCBscontain PCDDs and PCDFs as contaminants of their manufacture, and PCDDsand PCDFs may also be formed as by-products of the bleaching of pulpwith chlorine compounds, resulting in occupational exposure both duringbleaching and downstream for those involved in paper production .International Classification of Diseases, 9th Revision (ICD-9) [Workers were followed up for mortality according to procedures specificto each country. The period of follow-up varied among countries, rangingfrom 12 to 50 years. Details on periods of employment and follow-upare reported in  (ICD-9) . TabulatPoisson regression analysis was used to examine internal dose–responserelations associated with exposure to volatile organochlorinesand to explore the effect of potential confounding factors. Rate ratios (RRs) and 95% CIs derived from the analysis were adjusted forcountry, sex, age, calendar period, and employment status . The reference group for each RR was thefirst level of each variable.The distribution of study participants by exposure status and country isshown in a priori interest, there were reduced SMRs for cancer of the esophagus , liver , and cervix ; forneoplasms of lymphatic or hematopoietic tissues ; and for NHL . Statisticallysignificant excess mortality from pleural neoplasms was observedin the exposed group , mostly due to the even larger excess observed inthe highly exposed subjects  who were maintenance workers also exposed toasbestos. The elevation observed in those never exposed was virtuallyidentical  tothe exposed group, possibly also due to asbestos exposure. Otherstatistically significant findings included excess mortality fromcancer of the penis and other male genital organs  in the exposed group, andcancer of other respiratory organs  in the highly exposed group. The resultsreported here are for the overall cohort including both men and women. Ingeneral, there was little difference in the findings between sexes, althoughthe results among women were based on a relatively smallnumber of deaths.Cause-specific mortality for the workers classified according to exposureto volatile organochlorines is shown in a priori interest was also below expected, including liver cancer , soft tissue sarcoma , lymphaticand hematopoietic tissue neoplasms in general , and NHL in particular . Theonly neoplasms showing elevated risks were penis and other cancerof male genital organs  and Hodgkin disease , and in both sites this wasmore than three times the rate observed in the workers never exposed. Itis of interest to note, however, that the 3-fold excesses in risk ofcancer of the penis and other male genital organs and of Hodgkin diseasein workers not exposed to nonvolatile organochlorines are matchedby deficits (of a similar magnitude) in risk of pleural and other respiratorycancers in those not exposed.Cause-specific mortality for the workers classified according to exposureto nonvolatile organochlorines is shown in p = 0.002) trend of increasing risk of mortality from all cancercombined with increasing weighted cumulative exposure to volatile organochlorines . No othersite of a priori interest showed a statistically significant trend of increasing risk, althoughnonsignificant increases were suggested for liver cancer andfor cancer of the pleura. The risk estimates, and the positive trend, forcancer of the pleura were essentially unchanged after adjustment foreither exposure to or high exposure to asbestos.No consistent pattern of increasing risk with increasing exposure to eithervolatile or nonvolatile organochlorines was apparent for any causeof death after stratification by duration of employment or by yearssince first exposure to both volatile and nonvolatile compounds, or byweighted cumulative exposure to volatile organochlorines (data not shown). ThePoisson regression analyses stratified according to weightedcumulative volatile organochlorine exposure shown in , and adjIn this large multicenter historical cohort study, which examined the risksassociated with exposure to both volatile and nonvolatile organochlorinesin the pulp and paper industry work environment, we found lowerthan expected overall mortality and all-cancer mortality rates. Internalcomparisons based on duration of exposure and time since first exposureshowed no consistent exposure–response trends of riskincreasing with either volatile or nonvolatile organochlorines. A weak, butstatistically significant, trend of increasing risk of all-cancermortality with increasing weighted cumulative exposure to volatile organochlorineswas observed. This finding is similar to the effect seenin other large cohorts with potential exposure to nonvolatile organochlorinescontaminated with TCDD  but has As in most historical cohort studies of industrial workers, we found adeficit in overall mortality and cancer mortality in this study comparedwith rates expected in the national populations. This is common inoccupational cohort mortality studies and has been observed in previousstudies of pulp and paper workers , due to The assessment of exposure was based on a pulp and paper industry exposurematrix developed by an expert team of industrial hygienists familiarwith the pulp and paper industry, although relatively few quantitativedata were available on organochlorine exposure . EstimatAs with most historical cohort studies, there is also a lack of informationon potential lifestyle confounders such as smoking. However, evenfor lung cancer, the relatively small differences in smoking status betweengroups of manual workers are unlikely to account for a relativerisk of > 1.5 in studies involving a comparison with national mortalityrates , and theOverall, we found little evidence of any increased risk of cancer mortalityin pulp and paper workers exposed to organochlorines, apart fromthe weak but statistically significant exposure–response trendfor cumulative exposure to volatile organochlorines. Although there isevidence of such an association for all cancers with exposure to phenoxyherbicides contaminated with TCDD , we are We found little evidence of increased risks for specific cancer sites thathave been previously associated with organochlorine exposure, includingcancer of the esophagus, liver, cervix, and NHL for volatile organochlorines, andcancer of the liver, soft tissue sarcoma, lymphatic, andhematopoietic tissue and NHL for nonvolatile organochlorines. Instead, theonly sites that showed significant excess risks in those exposedto volatile organochlorines were cancer of the pleura, “otherrespiratory,” and “penis and other male genital organs,” andfor all three sites the risk was higher in those withhigh exposure. Interestingly, although the excess risk for cancerof penis and other male genital organs was also elevated in those withexposure to non-volatile organochlorines, the risks for cancer of thepleura and other respiratory cancers were elevated only in those neverexposed to nonvolatile organochlorines and below expected in those withexposure. For pleural cancer, this may be because many of the groupclassified as exposed to nonvolatile organochlorines were bleach plantoperators, whereas the group with volatile organochlorine exposurewere predominantly maintenance workers. So it is possible that these findingscould be due to concomitant exposure to asbestos, because thehighest exposures to these compounds occurred in maintenance, repair, andcleaning operations, and an excess risk of pleural cancer has alreadybeen reported in workers exposed to asbestos in this industry . UnfortuIn summary, there is little evidence that exposure to organochlorines atthe levels experienced in the pulp and paper industry causes an increasedrisk of cancer, apart from a weakly statistically significant associationwith weighted cumulative volatile organochlorine exposure. Therewas little evidence of an increased risk for any specific cancersites, apart from a statistically significant association between nonvolatileorganochlorine exposure and Hodgkin disease and cancer of thepleura. The finding for pleural cancer is consistent with evidence thatmaintenance workers were exposed to asbestos.


Evidence-Based Practice (EBP) Project has been investigating the implementation of evidence-based mental health practices  in state public mental health systems in the United States since 2001. To date, Project findings have yielded valuable insights into implementation strategy characteristics and effectiveness. This paper reports results of an effort to identify and classify state-level implementation activities and strategies employed across the eight states participating in the Project.The Content analysis and Greenhalgh et al's (2004) definition of innovation were used to identify and classify state-level activities employed during three phases of EBP implementation: Pre-Implementation, Initial Implementation and Sustainability Planning. Activities were coded from site visit reports created from documents and notes from key informant interviews conducted during two periods, Fall 2002 – Spring 2003, and Spring 2004. Frequency counts and rank-order analyses were used to examine patterns of implementation activities and strategies employed across the three phases of implementation.One hundred and six discreet implementation activities and strategies were identified as innovative and were classified into five categories: 1) state infrastructure building and commitment, 2) stakeholder relationship building and communications, 3) financing, 4) continuous quality management, and 5) service delivery practices and training. Implementation activities from different categories were employed at different phases of implementation.Insights into effective strategies for implementing EBPs in mental health and other health sectors require qualitative and quantitative research that seeks to: a) empirically test the effects of tools and methods used to implement EBPs, and b) establish a stronger evidence-base from which to plan, implement and sustain such efforts. This paper offers a classification scheme and list of innovative implementation activities and strategies. The classification scheme offers potential value for future studies that seek to assess the effects of various implementation processes, and helps establish widely accepted standards and criteria that can be used to assess the value of innovative activities and strategies. During the last decade the testing and implementation of evidence-based practices (EBPs) in healthcare systems throughout the United States has increased. While published literature examining implementation of EBPs in health continues to grow -6, relatEvidence-Based Practices (EBP) Project  place over time, between those seeking to put policy [or practice] into effect and those upon whom action depends" . ImplemeHere, activities across all implementation phases, and EBPs, were built on activities set in motion in earlier phases. For example, all states considered consumers key to mental health system reform. This philosophy laid the foundation for regular meetings, and Advisory Groups and technical assistance activities to take place between the state agencies, consumers and other stakeholders. Similarly, the development and implementation of effective financing, and licensing and certification strategies followed successful completion of negotiations  to develop new billing codes, incentives, funding streams, regulations and standards.Project EBPs. Here, state agencies exercised their authority to set policy for the delivery of clinical practice, and voluntarily engaged in an interactive and cooperative relationship, building process with local service and other organizations to meet the full range of needs necessary to solidify EBPs as usual mental health and administrative practice. Therefore, interactions between the macro- or top down actors (state agencies) and the micro- or bottom-up actors  were required to successfully implement and plan for the roll-out of the EBPs.The innovations identified in this study show that "interactions...occur [ed] on various levels, between top and bottom actors" – and that a variety of "interrelationships" ,45 were Project's EBPs. Consequently, "institutions matter [ed]" "  in this EBP Project during its initial implementation. The classification scheme offers potential value for future studies that seek to assess the effects of various implementation processes, and helps establish widely accepted standards and criteria that can be used to assess the value of innovative activities and strategies.Insights into effective strategies for implementing EBPs in mental health and other health sectors require qualitative and quantitative research that seeks to: a) empirically test the effects of tools and methods used to implement EBPs, and b) establish a stronger evidence-base from which to plan, implement, evaluate and sustain such efforts. This paper offers a classification scheme and list of implementation activities and strategies employed by eight states participating in the States employed a diverse range of implementation activities and strategies to address barriers to implementing EBPs ,26,48 wiThe author(s) declares that she has no competing interests.


This Request for Applications (RFA) from the National Institute on Drug Abuse (NIDA) and the National Cancer Institute (NCI) launches the Genes, Environment, and Development Initiative (GEDI). The GEDI will support research using existing research samples to investigate main effects, correlations, and interactions among genetic, environmental, and developmental factors in the etiology of substance abuse and related phenotypes in humans. The term “substance abuse” as used in this RFA refers broadly to several different but related concepts including substance use  and substance abuse and dependence as defined by diagnostic criteria. While it is recognized that these concepts may not be interchangeable, the term “substance abuse” is used for the purposes of fluency. The term “substance” refers primarily to nicotine, alcohol, cannabis, cocaine, stimulants, and opiates, but also includes the entire range of licit and illicit substances of potential addiction. The term “related phenotypes” refers to constructs that have been shown empirically to convey risk for substance abuse, such as behavioral disinhibition. “Developmental research” refers to the study of progressive change that occurs as humans move through the lifecourse.The National Institute on Mental Health (NIMH) has an interest in applications where the research contributes to knowledge about the interplay of genetic, environmental, and developmental factors in the etiology of adverse outcomes; however, no funds will be committed at this time.in utero exposures, parenting, trauma and stress, peer influences and/or neighborhood and societal factors. Many of these correlations have been very strong and frequently replicated, forming the basis for numerous preventive intervention studies with youth at high risk due to individual and familial factors in combination with the social context over the course of development. The role of developmental factors is highlighted not only by the fact that the human brain is an organ that continues to develop until the mid-twenties, but also by the changes in substance abuse patterns associated with significant developmental shifts, including childhood transitions, pubertal transitions (often coinciding with substance use initiation), transitions to greater independence after high school (associated with increased substance use and shifts from use to dependence), and adult role transitions such as marriage, parenting, and full time employment (associated with decreased substance abuse). Although less well understood, developmental timing of substance abuse has been assumed to be important as well, with different outcomes  expected depending on when certain events  occur over the life course. Expression patterns of genes associated with substance abuse change over the course of development, either through epigenetic modifications that are developmental and tissue specific, or through genetic variation that may affect gene expression during certain stages of neurodevelopment. For instance, animal studies have shown that exposure to nicotine during adolescence, compared to adulthood, predicts greater drug-seeking behavior and neurologic change in critical areas of the brain. Similarly, human research has shown that prenatal exposure to nicotine increases the risk of nicotine dependence during adulthood.Prior lines of research have established that genetic, environmental, and developmental factors all contribute to vulnerability to substance abuse and related phenotypes. Both animal and human studies have demonstrated genetic influences on substance abuse, with heritability estimates ranging from 40 to 60%, and promising candidate loci and genes for substance abuse have been identified. Genetic influences have also been shown for many related phenotypes, and some  share genetic factors with substance abuse. As with other complex disorders, it is likely that multiple genes of small effects contribute to vulnerability to substance abuse and related phenotypes, and that environmental conditions moderate genetic influence. A wide variety of environmental variables have been correlated with substance abuse and related phenotypes, including While these lines of research have made important contributions to our understanding of substance abuse, they each have limitations in delineating the etiology of substance abuse and related phenotypes, and they can benefit from integration and interaction with the others. The inferential power of environmental and developmental studies can be significantly enhanced by the inclusion of analyses of gene–environment correlations, that is, genetic influences on environmental exposures. For example, by accounting for family history or genetic susceptibility to substance abuse, studies of prenatal-exposure effects on later behavior can better determine the role of passive gene–environment correlation, which in turn can help distinguish between exposure effects and family history as the source of behavioral outcomes. Similarly, studies of peer influences or parenting behaviors in adolescence will be strengthened by taking into account passive, active, and evocative gene–environment correlations, which can help to clarify the role of the adolescent’s choices and behaviors in eliciting these environmental factors. In addition, molecular genetics studies seeking to identify specific susceptibility genes can be greatly enhanced in their power and accuracy by attending to interactions with environmental and developmental factors that may affect the expression of these genes.in utero and toxic exposures, endophenotypes, and neurocognitive structure and function. In addition, the many randomized intervention trials that have been conducted over the years provide opportunities for strong inferences about the role of social environment in causality by focusing on presumed etiologic social factors and examining covariance of the social environment and adjustment over time. The GEDI seeks to build on this substantial public investment by soliciting applications that integrate environmental and developmental variables with genotypic information to permit comprehensive model building and hypothesis testing for determining genetic, environmental, and developmental contributions to substance abuse and related phenotypes.Over many years, NIDA, other NIH institutes, and other organizations have funded numerous high-quality longitudinal and developmental studies that contain a wealth of data from individuals who are at risk for, or are in the course of development, progression, and desistance of, substance abuse and related phenotypes. A valuable variety of variables associated with these outcomes has been measured on diverse samples across multiple domains and time points, characterizing psychopathology, temperament, familial relations and practices, peer relations and characteristics, school factors, and broader environmental influences, as well as biological variables including Applications qualifying for submission under this FOA must rely exclusively on existing studies of human subjects; new data collection is permitted only for the purpose of obtaining blood from subjects so that DNA and cryopreserved lymphocytes can be generated as a renewable resource and stored. Studies with DNA already collected are required to demonstrate that their DNA is a publicly available sharable resource, with a clear process for access to the samples by other qualified investigators. If the DNA samples are stored at a site other than the NIDA repository, plans for electronically depositing clinical data, phenotypic data, and genetic data into the NIDA Repository for access and sharing need to be provided. If the collection of new data is required to evaluate the disorder , plans for collecting these data through another funding mechanism should be included. Data sets drawn from studies that involve an intervention trial are appropriate for this RFA; these proposals should address the approach to handling intervention effects when exploring etiologic questions. If intervention data sets are proposed for use to infer causal influence , then investigators must demonstrate successful randomization procedures and sufficient power to detect and explicate observed short- and long-term environmental intervention effects in the sample. Proposals requesting support to collect new data other than DNA under this RFA research mechanism or to conduct research using animal models will be considered nonresponsive and returned to the applicant.in utero, infancy, early childhood, late childhood, early adolescence, late adolescence, emerging adulthood, and/or adulthood.Established studies/samples eligible for analyses within GEDI applications must include the following characteristics: 1) subjects who are in or through the period of risk for substance abuse and related phenotypes; 2) subjects who have provided the appropriate consent for or can be recontacted for additional consent for GEDI research ; 3) DSMIIIR or DSMIV diagnoses as well as other categorical and/or quantitative measures of substance abuse and related phenotypes with demonstrated heritability; 4) environmental data relevant to substance abuse and related phenotypes; 5) data waves spanning at least two developmental periods, such as a) an explicit rationale for the genotyping approach chosen ; b) a plan to implement the genotyping and milestones for achieving the genotyping in the time frame of the funded period. This proposal should thoroughly discuss and justify the plans for genotyping, assessing genotype quality, and depositing the genotypes into the NIDA Repository; c) all costs for genotyping, taking into account delivery of the DNA, genotyping SNPs, repeating failed samples, assessing genotype quality, deposition of the data, costs of the genotyping facility preferred. Depending on the GEDI Steering Committee recommendations, the genotyping facility may not be the one initially proposed. Budgets for future years may be contingent on the genotyping strategy chosen. Applicants should be aware that future years of allocation of funds for this component may be changed to reflect the scientific approach chosen and the funds needed; d) a detailed analytic plan addressing issues related to the large amount of GEDI data to be generated, such as multiple-testing issues, assessing correlations and complex interactions , impact of population ancestry (stratification), false positives, etc.; e) a rationale for single SNP, multiple SNP  and/or haplotype-based analyses; 16) All phenotypic, environmental, developmental, and genotypic data analyzed through GEDI will be made available in de-identified form to the scientific community through the NIDA Repository. All investigators, whether or not they join the NGC, will be required to provide a timeline for submitting cleaned data to the NIDA Repository, and to participate in the NGC biannual meetings in Rockville, MD; travel and accommodations should be included in the budget; 17) All applicants are encouraged to join the NIDA Genetics Consortium (NGC) and to submit blood samples as well as the required genetic, environmental, and developmental data to the NIDA Repository. Funds for up to 15,000 total samples  for blood processing, DNA extraction, storage, and distribution will be provided for all awards joining the NGC. A budget needs to be presented if > 5,000 samples will be collected. Additionally, a fee structure for distribution of DNA from the NIDA Repository can be found at http://www.nida.nih.gov/about/organization/Genetics/FAQ_NCGS.html and applicants should determine whether additional budgetary allocations are needed for DNA requests exceeding the NIDA Repository allowances. Studies funded under this FOA will not require NIDA Access Committee review; 18) In cases where NGC membership is prohibited  or not chosen, applicants must a) demonstrate that genetic, environmental, and developmental data can be submitted to the NIDA repository; b) demonstrate that DNA samples have been or will be submitted to a publicly available repository that permits data sharing to qualified researchers; c) present the repository’s quality control procedures for processing DNA, cryopreserving or immortalizing blood, and archiving DNA samples; and d) describe the repository’s track record of providing data access by qualified investigators.Applications should present a rationale that carefully balances important substantive, methodologic, and budgetary issues. In particular, applications should fully address each of the following points, where applicable: 1) Sample selection ; 2) Research design ; 3) Statistical power to detect the proposed main effects, correlations, and interactions. In cases where individual data sets lack sufficient power to address study aims, data from multiple sites may be pooled; 4) Where pooling is planned, the application must include procedures for combining data. In all cases where multiple data sets are used, pilot data must be provided within the application to demonstrate reasonable compatibility of data across studies and evidence of feasibility of multisample analyses; 5) In cases where multiple data sets are used, evidence of collaboration among sites must be shown; 6) Generalizability of results ; 7) Phenotype(s) selection ; 8) Number and timing of assessments ; 9) Selection and quality of assessments ; 10) comorbidity ; 11) Timeline to collect and submit clean data  to the NIDA Repository; 12) Consent by subjects to allow qualified investigators to use and analyze data and DNA; 13) In view of the technical complexity of the science called for in this announcement, the GEDI requires transdisciplinary alliances among researchers with appropriate breadth and depth of expertise. Applications should have a substantial commitment of personnel for statistical genetics and bioinformatics, with detailed plans for data collection, storage, communication, integration, analyses, and dissemination; 14) Proposals are required to include detailed plans and timelines for replicating initial GEDI findings within the 5-year award period. Plan(s) for replicating should be fully explained and justified given that there are many approaches for duplicating research findings ; 15) Genotyping and analytic methodologies: Applicants should note that the genotyping platform ultimately chosen will be dependent upon an agreement within the GEDI Steering Committee (described in Section 6.2.A.3) to ensure consistent and standard genotypes and allele names. Although the genotyping approaches  outlined for each funded grant may differ, the GEDI Steering Committee will be expected to provide input on this effort among the cooperative agreements so that a consensus strategy is achieved. Nevertheless, a description and rationale of the platform(s) proposed for genotyping should be included. Applications should address the following: Close interaction among GEDI Investigators will be required to develop appropriate strategies and tools to design and conduct GEDI research. The awardees will convene as a GEDI Steering Committee, which will include representatives from each of the awards and the NIH, will meet twice a year and participate on monthly conference calls to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. Subcommittees and working groups may be established, such as a genotyping or analysis group. A 4–5 member GEDI Advisory Board will also be created by the GEDI Steering Committee. Costs associated with attending meetings and monthly conference calls should be included in the proposed research budget. An additional budgetary item should include costs to support two of the GEDI Advisory Board members who will convene annually.The GEDI has the primary goal of elucidating the contribution of genetic, environmental, and developmental factors to the etiology of substance abuse and related phenotypes. Funded research under the GEDI is expected to lead to improved and tailored preventive and treatment interventions for these common and costly outcomes.GEDI applications must address the interplay of genetic, environmental, and developmental factors related to substance abuse and related phenotypes. Although individual components  may be examined within the application, the ultimate goal of the study must integrate these components.Where possible, investigators are encouraged to explore how relationships differ by sex/gender and race/ethnic group.in utero drug exposure that identify genetic and environmental factors that discriminate individuals who do and do not develop substance abuse and related phenotypes; 17) studies that explore whether effective interventions focusing on social or other environmental elements work by altering gene expression, or whether genetic variability accounts for why interventions work for some participants and not for others; 18) studies that address the interplay of genetic, environmental, and developmental factors within intervention outcome data sets, taking advantage of the unique opportunity within intervention research to infer causal influence by demonstrating changes in mediators that are related to outcomes of interest; 19) studies of the interplay of genetic, environmental, and developmental factors associated with increased risk for behavioral disorders in offspring exposed to smoking in utero; 20) studies of the interplay of genetic, environmental, and developmental factors conferring resilience in individuals at high risk for substance abuse and related outcomes; 21) evaluation of functional polymorphisms that are moderated by environmental and developmental factors; 22) studies analyzing the genetic mechanisms by which environmental factors such as therapeutic compounds, stress, alcohol, and drugs alter the expression of genes, e.g., through changing methylation status; 23) approaches that specifically model combinations of a) single SNPs, multiple SNPs, and/or haplotypes and environmental exposures; b) single SNPs, multiple SNPs, and/or haplotypes and developmental trajectories; c) single SNPs, multiple SNPs, and/or haplotypes and environment and development variables.Examples of appropriate research topics include, but are not limited to, the following: 1) studies of the role of gene–environment–development interactions in the initiation of drug use and progression to addiction, including but not restricted to studies of the impact of environmental factors in individuals with known genotypes for particular alleles; 2) studies of the role of gene-environment correlation that clarify how individuals select and influence their environments over developmental stages, and to help identify true gene–environment–development interactions; 3) studies employing refined and systematic environmental and developmental measures that identify salient factors  associated with risk for substance abuse, stratified by genotypes associated with substance abuse or related disorders; 4) studies to address the salience of initial drug exposure  for subsequent substance abuse risk and course, incorporating the role of genetic risk ; 5) studies that explore the heterogeneity of genetic, environmental, and developmental contributions to substance abuse for different subgroups, including race/ethnic groups, sex/gender groups, cultural groups, etc.; 6) identification of biomarkers, endophenotypes, and subclinical phenotypes that vary or change over development as a function of environmental and genetic risk; 7) studies distinguishing the genetic, environmental, and developmental factors and their interactions in the vulnerability to substance abuse on specific drugs versus factors contributing to general liability; 8) studies that examine the differential effects of salient developmental  and environmental  events interacting with other variables that confer or protect from vulnerability to substance abuse and related phenotypes; 9) studies that explicate the mechanisms by which genes, environment, and development confer risk for substance abuse and related phenotypes ; 10) studies of the interplay of genetic, environmental and developmental factors on differential patterns of risk associated with comorbid psychiatric disorders, including psychotic and internalizing disorders; 11) studies of the interplay of genetic, environmental, and developmental factors on differential patterns of risk associated with the timing and dosages of prescribed medications, including but not limited to psychostimulants; 12) studies of underlying vulnerability factors and endophenotypes that may mediate genetic risk for substance abuse and related phenotypes, including studies of temperament and neurophysiology; 13) studies that explore the impact of population differences in allele frequencies on gene × environment × development interactions for substance abuse and related phenotypes; 14) research using molecular approaches to study the impact of cumulative, acute, and/or chronic environmental exposures or psychosocial stressors in specific developmental periods; 15) research evaluating environment and development data that include the analysis of combined effects of gene variants from a gene family or cellular pathways involved in addiction; 16) studies of http://www.nida.nih.gov/about/organization/Genetics/index.html), and a set of frequently asked questions and staff responses will be posted. Please submit your questions via email to Dr. Weinberg (nw46w@nih.gov) at least one day in advance of the teleconference.NIDA staff will conduct an application information teleconference at a date and time to be determined. This meeting will allow potential applicants to discuss and clarify any issues related to this FOA with NIDA staff. Detailed information about the meeting will be updated and available on the NIDA website . A detailed categorical budget for the “Initial Budget Period” and the “Entire Proposed Period of Support” is to be submitted with the application.This funding opportunity uses the just-in-time budget concepts. It also uses the nonmodular budget format described in the PHS 398 application instructions , or by e-mail:http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling 866-705-5711 or through the website at http://grants/nih.gov/grants/guide/rfa-files/RFA-DA-07-012.The letter of intent receipt date for this RFA is 15 February 2007, with the application receipt date 15 March 2007. The complete version of the RFA is available at nw46w@nih.gov; Glen D. Morgan, Tobacco Control Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, 6130 Executive Boulevard, Room 4034, Bethesda, MD 20892-7337 USA, 301-496-8585, fax: 301-496-86756, e-mail:gmorgan@mail.nih.gov.Contacts: Naimah Weinberg, Division of Epidemiology, Services, and Prevention Research, National Institute on Drug Abuse, 6001 Executive Boulevard, Room 5185, Bethesda, MD 20892-9589 USA, 301-402-1908, fax: 301-443-2636, e-mail:Reference: RFA-DA-07-012.The International Research Scientist Development Award (IRSDA) provides research opportunities, as well as cutting-edge technical training, in leading developing country institutions for U.S. postdoctoral biomedical, epidemiological, clinical, social, and behavioral scientists who are committed to careers in international health research. The award supports the recipient for a 3- to 4-year period of collaboration with a U.S. mentor and an established developing country mentor. This collaboration should be based on a research project of mutual interest in the context of an ongoing research relationship between the U.S. and foreign mentors. It is expected that this experience will prepare scientists to pursue an independently funded global health research career involving ongoing collaboration with developing country scientists.The IRSDA is part of the FIC strategy to support research collaborations in developing countries in order to build research capacity to address global health research priorities. The role of the IRSDA is to: 1) attract new research talent to global health research and enhance research collaboration between the U.S. and foreign sites; 2) advance the career paths of exceptional junior U.S. scientists with mentored training in health issues of developing country populations; 3) extend the impact and scope of existing career research and training support for U.S. scientists committed to international research; and 4) stimulate a more effective translation of the results of research on global health problems into public health practice.With IRSDA support, the investigator will have the opportunity to work closely with an established foreign scientist in the developing world and a U.S. investigator, who are involved in collaborative research. The applicant will conduct research and receive training at both the United States and developing country institutions. It is expected that these awards will serve to forge collaborative relationships between established, developing country researchers and outstanding U.S. junior scientists who are potential leaders of basic, clinical and behavioral/social health research programs in the U.S. Collaborations are expected to lead to advances that will reduce the impact of global health problems and narrow the gap in health disparities between developed and developing countries.All career development proposals must be tailored to meet the individual needs of the candidate. The specific career development and research training activities proposed in the application may be new to the candidate or an extension of the candidate’s prior research, but should focus on global health concerns which include, but are not limited to, infectious diseases, nutrition, chronic/degenerative conditions, trauma/injury and mental health disorders. Basic laboratory, behavioral/social and clinical biomedical research will be supported in clinical, field or laboratory settings.The candidate must devote a minimum of 75% of full professional effort to the goals of this award, including significant time devoted to research in the chosen developing country. Applicants for initial awards must agree to spend a minimum of 50% of the project period of the grant at the foreign research site for at least 3 months per year. Applicants for a competitive 3-year renewal mentored career development award must agree to spend a minimum of 1 year of the total project period at the foreign research site for at least 3 months per year.The candidate and the U.S. and foreign mentors are jointly responsible for the preparation of the plan for career development. The applicant must justify the need for this award and provide a convincing case that the proposed period of support will substantially enhance his or her career as an independent investigator in global health research. The sponsoring institution must be able to demonstrate a commitment to the development of the candidate as a productive, independent investigator. FIC recognizes that there will be significant differences in the applicants, U.S. and foreign institutional environments, U.S. and foreign mentors’ backgrounds, and approaches to international research collaboration among applications. Therefore, applicants should clearly define specific research and training goals related to each mentor and each institution, methods to achieve the goal of an independent research career in global health, and specific measurable objectives to enable assessment of the proposed project.This funding opportunity will use the NIH career development (K01) award mechanism (PA-06-001). Please note that this K01 award has some important differences from the K01 award described in PA-06-001. These include: 1) the original award period is for 3 to 4 years; 2) a competitive renewal mentored career development award is possible for up to 3 years; 3) Both a U.S. and a foreign mentor are required and must share a research collaboration; and 4) requirement of significant time spent in the foreign country.http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the “Initial Budget Period” and the “Entire Proposed Period of Support” is to be submitted with the application.This funding opportunity uses the just-in-time budget concepts. It also uses the nonmodular budget format described in the PHS 398 application instructions  number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling 866-705-5711 or through the web site at http://grants.nih.gov/grants/guide/pa-files/PAR-07-014.html.The letter of intent dates for this PAR are 14 December 2007, and 16 December 2008, with the application receipt dates 16 January 2007, 2008, and 2009. The complete version of this PAR is available at sinab@mail.nih.gov.Contact: Barbara Sina, Division of International Training and Research, Fogarty International Center, National Institutes of Health, 31 Center Drive, Room B2C39, Bethesda, MD 20892-2220, 301-496-1653, fax: 301-402-0779, e-mail:Reference: PAR-07-014.


Terry MB, Gammon MD, Zhang FF, Tawfik H, Teitelbaum SL, Britton JA, Subbaramaiah K, Dannenberg AJ, Neugut AI. 2004. Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291:2433–2440.Aspirin has been used as a nonprescription pain reliever for more than 100 years, with more than 80 million tablets currently consumed in the United States every day. However, it was not until the 1970s that the mechanism of action was discovered; aspirin was found to inhibit the production of proinflammatory prostaglandins. In the past 20 years, regular aspirin use has been shown to protect against heart disease, stroke, and colorectal cancer. Now NIEHS grantee Marilie Gammon of the University of North Carolina School of Public Health and colleagues report that regular aspirin use may also protect against breast cancer.2, inhibition of prostaglandin production will also decrease the production of estrogen. Given the importance of estrogen in the development of breast cancer, Gammon and colleagues undertook an epidemiologic study to determine whether there was any association between regular NSAID use and reduced risk of breast cancer.Research suggests that inhibition of prostaglandin synthesis may prevent cancer. Cyclooxygenase (COX) is involved in the synthesis of prostaglandins. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are known to block the active site of COX and, therefore, inhibit prostaglandin production. Because the final reaction in the synthesis of estrogen depends upon a cytochrome P450 enzyme that is stimulated by prostaglandin EThe team conducted a population-based study of 1,442 women with breast cancer and 1,420 controls. The women were interviewed and asked to report their intake of aspirin, ibuprofen, and acetaminophen. Dose was not considered; instead, the team looked at duration and frequency of use. Regular use was defined as women who took aspirin at least 4 times per week for at least 3 months and initiated use at least 1 year prior to the reference age (age at diagnosis of breast cancer or corresponding age for controls). All exposure information was truncated to 12 months prior to the reference age.Regular aspirin use was inversely associated with hormone-responsive breast tumors, with the strongest results for women who took 7 or more tablets per week. The results of ibuprofen use were generally weaker. There was no association with use of acetaminophen, which does not inhibit prostaglandin synthesis.–Jerry PhelpsThis study adds to the growing body of data that supports the regular use of aspirin as an effective chemopreventive agent for hormone-responsive breast cancer tumors. This effect most likely occurs through the inhibition of prostaglandin and subsequent inhibition of estrogen biosynthesis. However, the reduced risk must be confirmed before clinicians can make definite recommendations to women at risk for breast cancer.


The participating institutes, centers, and offices of the NIH and the Agency for Healthcare Research and Quality (AHRQ) invite investigators to submit research grant applications on health literacy. The goal of this program announcement (PA) is to increase scientific understanding of the nature of health literacy and its relationship to healthy behaviors, illness prevention and treatment, chronic disease management, health disparities, risk assessment of environmental factors, and health outcomes including mental and oral health. There is a need for increased scientific knowledge of interventions that can strengthen health literacy and improve the positive health impacts of communications between health care/public health professionals  and consumer or patient audiences that vary in health literacy. Such knowledge will help enable health care and public health systems to serve individuals and populations more effectively, and employ strategies that reduce health disparities in the population. Once a general understanding of the various factors influencing current trends has been achieved, a number of secondary goals may be addressed. Applicants may propose secondary goals of modeling the potential impact of new interventions on future national trends and/or determining the impact of targeted cancer control interventions on population outcome .Healthy People 2010 defines “health literacy” as the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. Many factors affect individuals’ ability to comprehend, and in turn use or act on, health information and communication. Proficiency in reading, writing, listening, interpreting, oral communication, and visual analysis is necessary as the modern health system typically relies on a variety of interpersonal, textual, and electronic media to present health information. Individuals and families both must be able to 1) communicate with health professionals; 2) understand the health information in mass communication; 3) understand how to use health-related print, audiovisual, graphic, and electronic materials; 4) understand basic health concepts  and vocabulary ; and 5) connect this health-related knowledge to health decision making and action taking.Access to and understanding of health information and services is a reciprocal process among health professionals, communication professionals, and patients. For instance, these professionals must use science-based strategies and tactics, develop resources and materials, and understand communication interactions between providers and patients.Research on health literacy should assist the NIH in its mission of communicating scientifically based health information to the public and to the health care providers and related professionals who serve the public. The application of scientific knowledge from health literacy research may also strengthen the health information knowledge and communication skills of the public, and further one of the national goals of Healthy People 2010: to improve health literacy by the decade’s end.Health literacy is a complex phenomenon that involves individuals, families, communities, and systems. For instance, consumers, patients, caregivers, and other laypersons may vary with respect to 1) access ; 2) skills ; 3) knowledge ; 4) disabilities ; 5) the features of their health care providers and the public health systems in which these providers practice ; or 6) other important characteristics .Too often, people with the greatest health burdens have limited access to relevant health information. In part, this is due to the complex and cumbersome ways in which health information often is presented; it is also due to individuals’ limited abilities to fully interpret and understand complex health terminology and instructions, and to make personal decisions related to risk-avoidance or -reduction strategies. For instance, to follow health care instructions, patients need to be able to comprehend written and oral prescription instructions, directions for self-care, and plans for follow-up tests and appointments.In addition, health care providers may not communicate effectively with individuals with limited levels of literacy. For instance, achieving informed consent for treatment is difficult when health care personnel cannot explain biological processes or treatment procedures in simplified language, and patients cannot interpret health information. These situations hamper the effectiveness of health professionals’ efforts to prevent, diagnose, and treat medical conditions, and limit many health care consumers’ abilities to make important health care decisions.Low health literacy is a widespread problem, affecting more than 90 million adults in the United States. Low health literacy results in patients’ inadequate engagement in and benefit from health care advances, as well as medical errors. Low health literacy is likely to be a major contributor of adverse health outcomes. Research has linked low or limited health literacy with such adverse outcomes as poorer self-management of chronic diseases, less healthful behaviors, higher rates of hospitalizations, and overall poorer health.This PA invites applications to develop research on health literacy in general areas that include, but are not limited to, the following: 1) modeling and measuring the nature and scope of health literacy; 2) variation in health literacy over the life course or among native and nonnative speakers of English; 3) mediators and moderators of low health literacy; 4) the impact of low health literacy on health outcomes, diseases, behaviors, and treatments, including the contribution of health literacy to informed decision making, adherence to preventative or therapeutic regimens, utilization of health care services, risk avoidance strategies, and other consumer health care–related actions; 5) the identification of effective preventive and other interventions to improve health literacy among populations and to enable the health care and public health systems to communicate effectively across different health literacy levels; and 6) the development of effective methods and new technologies in health literacy research.Applications should be relevant both to the objectives of the PA and to at least one of the participating institutes’ general research interests. Prior to preparing an application, researchers are strongly encouraged both to review the general research interests of the participating institutes and to contact program staff of the relevant institutes to discuss the proposed research.A wide variety of research approaches are encouraged under this PA: basic research that investigates or describes the nature of health literacy and the magnitude of health literacy problems, and applied research addressing issues pertinent to health literacy practices  and research in practice . Applications also may develop theoretical models, refine research constructs, improve methods and measurements, and establish causal relationships . Researchers also may address the effectiveness of interventions, or adapt and test existing programs (including those that are not research-based) to reduce low health literacy and its adverse consequences .The research must involve either 1) health literacy, or one of its many components, as a key outcome; 2) health literacy as a key explanatory variable for some other outcome; 3) methodological or technological improvement to strengthen research on health literacy; or 4) health literacy–focused preventions and interventions. Studies to develop or evaluate the readability or utility of specific materials that are intended for single uses or single audiences are not responsive to this PA unless these investigations are integral to testing a significant research hypothesis related to health literacy. Some potential areas of focus are as follows.1) Assess the prevalence and causes of low health literacy; 2) identify the nature of the mix of abilities and skills required to be functionally “health literate”  and the roles of basic literacy  and mathematics abilities  in health literacy; 3) explore the magnitude and variation, by socioeconomic and/or other group characteristics, in accessing, seeking, evaluating, interpreting, and using health information from a variety of sources; 4) examine the problems and factors involved in the presentation and interpretation of quantitative information  from either the provider or user perspective, or investigate how specific health referents, such as basic genetics and/or environmental risk concepts, are best understood and conveyed; 5) create a conceptual model of “health literacy” or the skill sets that influence the comprehension of relevant health information ; or 6) evaluate the different strategies and channels available, including the role of information technologies, that enable consumers to seek, access, and interpret relevant health information effectively, and how these may differ by cultural and health literacy backgrounds .Applications addressing health literacy as an age-differentiated phenomenon might explore the developmental precursors of low health literacy and the age-related changes in reading and other cognitive skills throughout the life course that may contribute to these difficulties. 1) Identify the reading and oral language comprehension skills crucial for the satisfactory acquisition and understanding of basic health information by children, adolescents, and adults of various ages; 2) determine how intuitive or everyday notions of germs, contagion, environmental exposures, disease, drugs, bodily processes, and other health-related concepts influence health literacy and consequent illness prevention behaviors across the life course, and identify age-appropriate intervention techniques that can be used to mitigate these problems; 3) examine the role of social and cultural factors in the development of health literacy ; 4) explore how the quantity and quality of structured interactions with adult caregivers affects the health literacy of the child from birth to age three; or 5) examine the effect of current age-related differences in media use  on health literacy.1) Describe how patients’ information-seeking abilities and health information interpretation mediates or moderates the effects of provider practices on health literacy; 2) examine bidirectional communication processes between providers and patients/clients in the health care/health promotion system that affect health literacy, including systemic and cultural barriers that help create and sustain health literacy problems, as well as adaptation strategies used by providers and consumers to minimize health literacy problems ; 3) examine how physicians’ or dentists’ nonverbal communication influences patients’ comprehension and implementation of health-related information; 4) examine the influence of social, contextual, and environmental factors  on health literacy outcomes; 5) examine the media  as a socializing agent of health literacy ; or 6) examine the factors that influence the desire for or processing of health literacy information .1) Examine the relationship between health literacy and health disparities; 2) analyze the role of health literacy in the prevention and treatment of chronic diseases; 3) identify the relationship between health literacy variation and the ability to engage in informed decision making for a variety of health issues, such as chronic disease management and participation in clinical trials; 4) evaluate the magnitude of the problems caused by low levels of health literacy or by professionals’ lack of effective communication skills for adapting to the communication needs of consumers with differing levels of literacy; or 5) assess the role of health literacy as a mediator or moderator of health care access across adulthood.1) Explore the role of kindergarten through twelfth-grade (K–12) education systems in increasing levels of health literacy and improving health communication skills ; 2) assess the role of K–12 education  on health literacy; or 3) determine the specific content and components of undergraduate, graduate, and in-service training experiences needed to adequately prepare provider groups to communicate with low-literacy patient populations ; examine policies that support the development, implementation, and effectiveness of such training experiences; and evaluate the roles of information technology in training to improve health literacy.1) Evaluate the effectiveness of health literacy interventions directed at the general public, different audience segments, patients, providers, or the health care or public health systems ; 2) examine the development and dissemination of effective information sources and materials for audiences with different levels of health literacy ; 3) design and evaluate health literacy diagnostic and/or communication tools to help health care professionals identify and communicate more effectively with consumers with different levels of health literacy ; 4) identify innovative strategies, practices, and policies currently in use that can be disseminated immediately to promote health literacy across the various participants in the health care systems; 5) conduct cost-effectiveness analyses of various health literacy interventions; or 6) further multilevel health literacy intervention approaches .1) Assess the efficacy of current methods of health literacy assessment and develop, as needed, audience-appropriate methodologies to understand the prevalence of low health literacy in different populations, the interaction of low health literacy with other demographic and social factors, and the contribution of low health literacy to health care costs and health outcomes; 2) identify effective approaches of combining qualitative and quantitative methods to further knowledge of health literacy; 3) identify a core set of constructs, variables, and quantitative measures for conducting health literacy research; 4) develop and pilot-test new tools and technologies to identify health literacy barriers ; or 5) in the context of understanding and promoting health literacy, develop technologies related to data reduction, data mining, and knowledge extraction; develop tools for meta-databases and integrative services to enhance the utility of existing databases; or develop new methods or technologies for timely, appropriate communication of pertinent health information and knowledge .Projects may employ any one or combination of study designs, research approaches, and data collection techniques. Secondary analyses of existing data sets as well as meta-analytic studies are also suitable for this PA. Multilevel, multidisciplinary, and interdisciplinary research is also encouraged, especially studies that incorporate individual, family, community, and societal mediators of health literacy in childhood and adulthood, or state-of-the-art health communication theory and knowledge. Researchers are encouraged to address ongoing investigations of prevention, healthy living, chronic disease management, patient-based health care, cultural competence, and health disparities to inform the research on health literacy. Research questions can focus on consumers, patients, clients, or other population groups; the strategies and tactics used by providers of medical and health information/communication to enable them to effectively reach literacy-challenged populations; or the influences of health literacy upon interactions between consumers, patients, clients, providers, and organizations or systems.Health Literacy: A Prescription to End Confusion reviews the current body of knowledge about health literacy, and identifies actions for the promotion of health literacy in society. Applicants are encouraged to consult this report as a general reference.The Institute of Medicine’s 2004 report http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm.This PA will use the NIH R01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This PA uses just-in-time concepts. It also uses the modular budgeting format . Applications must have a Dun and Bradstreet Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for federal grants or cooperative agreements. The DUNS number can be obtained by calling 1-866-705-5711 or through the website at Applications submitted in response to this PA will be accepted at the following receipt dates: 13 October 2004, 13 October 2005, and 13 October 2006.http://grants1.nih.gov/grants/guide/pa-files/PAR-04-116.html. Reference: PA No. PAR-04-116Contact: For the complete listing of contacts, please consult the full PA, available online at


In this article we describe the development of an information system for environmental childhood cancer surveillance. The Wisconsin Cancer Registry annually receives more than 25,000 incident case reports. Approximately 269 cases per year involve children. Over time, there has been considerable community interest in understanding the role the environment plays as a cause of these cancer cases. Wisconsin’s Public Health Information Network (WI-PHIN) is a robust web portal integrating both Health Alert Network and National Electronic Disease Surveillance System components. WI-PHIN is the information technology platform for all public health surveillance programs. Functions include the secure, automated exchange of cancer case data between public health–based and hospital-based cancer registrars; web-based supplemental data entry for environmental exposure confirmation and hypothesis testing; automated data analysis, visualization, and exposure–outcome record linkage; directories of public health and clinical personnel for role-based access control of sensitive surveillance information; public health information dissemination and alerting; and information technology security and critical infrastructure protection. For hypothesis generation, cancer case data are sent electronically to WI-PHIN and populate the integrated data repository. Environmental data are linked and the exposure–disease relationships are explored using statistical tools for ecologic exposure risk assessment. For hypothesis testing, case–control interviews collect exposure histories, including parental employment and residential histories. This information technology approach can thus serve as the basis for building a comprehensive system to assess environmental cancer etiology. Even though the environment is known to play an important role in human health, no comprehensive, integrated, state or national system exists to track the countless hazards, exposures, and ensuing health effects that could be due to environmental factors . For exaIn response to this challenge, the EPHTN program was established to develop a comprehensive environmental public health surveillance system. The program involvesthe ongoing collection, integration, analysis, interpretation, and dissemination of data on environmental hazards; exposures to those hazards; and related health effects. The goal of tracking is to provide information that can be used to plan, apply, and evaluate actions to prevent and control environmentally related diseases. Public health depends heavily upon information science. Increasingly, modern public health practice requires advanced, networked, computer-assisted technology to process a wide variety of information assets that monitor disease, analyze and detect risks, provide decision support, alert and communicate with those who need to know, continuously educate and train, support and manage public health response, and measure effectiveness. This recognition has brought about the specification and development of the Public Health Information Network (PHIN) by the Centers for Disease Control and Prevention (CDC) and its public health partners .It has been estimated that environmental pollutants are responsible for a substantial attributable fraction of certain childhood diseases and their associated health care costs . The attIndeed, studies of childhood cancer have discovered a number of biologically plausible environmental associations , includiIn Wisconsin an estimated 25,800 new cases of cancer are expected to have occurred in 2003 . ApproxiThe maturation of networked information systems holds the promise of automating much of public health practice . By autoA number of stakeholder committees were established to guide Wisconsin’s PHIN (WI-PHIN) development and establish functional system requirements. Members included public health staff from the Wisconsin Department of Health and Family Services, the University of Wisconsin [university information technology staff (UW-DoIT)], WiscNet (networking provider), University of Wisconsin Medical School, and Wisconsin State Laboratory of Hygiene); other state agencies; local public health services; hospitals, the health insurance industry; and the Wisconsin business community.The “Wisconsin Idea,” used to develop the state’s PHIN, involves rapid, state-of-the-art technology transfer from the university to government, businesses, and all citizens of the state and nation . The WI-Wisconsin has combined its financial support from several categorical funding sources to develop a secure, web-based WI-PHIN portal to respond to bioterrorism and all other public health threats. Funding resources have included bioterrorism public health preparedness funding, National Electronic Disease Surveillance System (NEDSS)–NEDSS Base System (NBS) deployment, Wisconsin Maternal and Child Health Program, audiometric newborn screening, environmental public health tracking, among others.Nationally, the PHIN has nine architectural functional specifications to guide development. Available data systems were inventoried and included systems describing hazards, exposures, health outcomes, and populations at risk. Sources of data included statewide health and environmental monitoring information and nationally available environmental and demographic data sets. Each system was qualitatively evaluated for its ability to be linked with other systems and for its coverage . These systems would be contained in an integrated data repository (IDR) and linked through common attributes such as time and geographic location. System specifications required the support of two surveillance tracks—hypothesis generation and hypothesis testing—to provide a more complete view of environmental disease risk. Under the first track (hypothesis generation), cancer case data are sent electronically to WI-PHIN to populate the IDR, and basic surveillance/descriptive analyses are performed. Environmental data are then linked, and exposure–disease relationships are modeled using statistical and geographic information system (GIS) tools for ecologic exposure risk assessment. In the second track (hypothesis testing), case follow-back interviews are conducted using secure web-based data entry forms to obtain person-level exposure histories, including parental employment and residential histories, on cases and controls.Childhood cancer data were obtained from the Wisconsin Cancer Registry for 1990 through 2000 (the most recent available year) . Cases wKnown exposure–disease relationships were ascertained by performing searches of the National Library of Medicine’s To begin work on hypothesis generation, initial ecologic risk assessments were performed by correlating county air pollution exposure estimates  with couSubstantial progress has been made on the secure WI-PHIN portal since its start in 1999. Since its inception, > $7 million has been expended by combining public health information technology funding sources. The WI-PHIN has the capability to perform automated data exchange, use electronic clinical data for event detection, and use the web for secure data entry for case follow-up. An online survey capability was created that can support web-based manual entry for case reporting. Storage capacity for laboratory results is established, as is case management capability. Specific case management rules continue to be refined with the integration of PAM business requirements. SAS  has been integrated into the portal for automating statistical analyses and visualization, and GIS services  continue to be developed. A directory of personnel has been established containing more than 2,400 registered WI-PHIN users from more than 900 agencies . The directory contains user contact information  along with other attributes . Users can create personal groups from the directory and synchronize entries to their personal digital assistants (PDAs).A considerable alerting and information dissemination capability has been developed. A commercial call-tree service  has been integrated into the portal. Scenarios are being developed that contact appropriate responders to specific public health emergencies. In addition, the web portal has public and private topic areas and threaded discussion forums that are associated with public health programs such as environmental tracking. Users may bookmark topic areas and receive E-mail updates (digests) when new content is added to their subscribed content areas. All users can easily add content to the portal  and add events to the calendar. Calendar entries can be synchronized to a PDA. Distance training and streaming media services are available within the portal. These features have been used to create on-line courses to train public health staff throughout the state on public health topics  and on portal features and use techniques.Advanced security controls are a part of the portal design. Users must register with the State of Wisconsin Web Access Management System and obtain a login ID and password to access the system. Users then reach the web site with an encrypted secure socket layer (SSL) connection. RBAC determines end-user access to surveillance programs such as the NBS (infectious disease reporting), SPHERE , WE-TRAC , and the EPHTN childhood cancer pilot.Hardware is also protected. Servers have redundant firewalls, virus scanning, continuous external port scanning and probing, and intrusion detection appliances. The system is continually backed up, and continuity of operations is assured through site mirroring planning and procedural implementation. Administrative security policies cover appropriate conduct and use documents, access auditing and logging, and on-line training.R = 0.31, p < 0.01). Indeed, benzene appears repeatedly in the literature as a potential cause of leukemia.A preliminary hypothesis-generating assessment was made with some of the currently available data. These data consisted of the Wisconsin Cancer Registry , NationaThe PHIN information technology functions provide a clear implementation plan to automate public health practice. Automation will be a tremendous benefit to the public health system, improving efficiency, coordination, assurance, response, and evaluation. However, substantial resources are necessary to accomplish this. An EPHTN program meeting the PHIN requirements is only possible by combining multiple funding sources that support public health information technology. Wisconsin has done this and has made substantial progress in its development of WI-PHIN and EPHTN, but much work remains. Continued federal funding and support from other sources will be necessary if the many ambitious PHIN goals are to be achieved.Wisconsin’s EPHTN childhood cancer pilot PAM has established a PHIN-compatible framework to track the environmental causes of disease. Two mechanisms are specified—hypothesis generating and hypothesis testing. Hypothesis generation occurs through the linking of environmental exposure databases (by time and place) with health outcome and population data. Ecologic risks can be generated that suggest avenues for further investigation. When a subset of the available data was used, a population-level rank correlation was found between estimated human inhalation benzene exposures and childhood leukemia risk, corroborating previous findings. However, the “ecologic fallacy” is the chief limitation of this approach: There can be underlying heterogeneity of exposure levels and covariates within the group or area assigned its population-level fixed value . HypotheBut both of these approaches are limited in that neither obtains biologic or environmental markers of actual exposures or individual susceptibility. In addition, pre-existing exposure monitoring data may be further limited because much of the available information is collected for regulatory purposes. These environmental monitoring systems have not been designed to substantially support environmental health tracking systems. Reliable and valid laboratory measures of environmental exposures, cancer risk, and individual susceptibility  are needed, and they would considerably increase our understanding of the environment’s contribution to childhood cancer . AlthougThrough the Wisconsin Idea, the WI-PHIN program has developed innovative information technology solutions that can serve as an implementation model for others. Best practices and lessons learned are emerging as the WI-PHIN develops its pilot program for environmental childhood cancer tracking. This experience will be shared with other states seeking to better understand the relationship between childhood cancer and the environment using advanced information technology. This approach can then serve as the foundation building toward a comprehensive system to assess environmental cancer etiology while extending the method to tracking other environmental exposure and disease relationships.


Citrus, the largest fruit crop of international economic value, has recently been imperiled due to the introduction of the bacterial disease Citrus canker. No significant improvements have been made to combat this disease by plant breeding and nuclear transgenic approaches. Chloroplast genetic engineering has a number of advantages over nuclear transformation; it not only increases transgene expression but also facilitates transgene containment, which is one of the major impediments for development of transgenic trees. We have sequenced the Citrus chloroplast genome to facilitate genetic improvement of this crop and to assess phylogenetic relationships among major lineages of angiosperms.The production of Citrus sinensis is 160,129 bp in length, and contains 133 genes . Genome organization is very similar to the inferred ancestral angiosperm chloroplast genome. However, in Citrus the infA gene is absent. The inverted repeat region has expanded to duplicate rps19 and the first 84 amino acids of rpl22. The rpl22 gene in the IRb region has a nonsense mutation resulting in 9 stop codons. This was confirmed by PCR amplification and sequencing using primers that flank the IR/LSC boundaries. Repeat analysis identified 29 direct and inverted repeats 30 bp or longer with a sequence identity ≥ 90%. Comparison of protein-coding sequences with expressed sequence tags revealed six putative RNA edits, five of which resulted in non-synonymous modifications in petL, psbH, ycf2 and ndhA. Phylogenetic analyses using maximum parsimony (MP) and maximum likelihood (ML) methods of a dataset composed of 61 protein-coding genes for 30 taxa provide strong support for the monophyly of several major clades of angiosperms, including monocots, eudicots, rosids and asterids. The MP and ML trees are incongruent in three areas: the position of Amborella and Nymphaeales, relationship of the magnoliid genus Calycanthus, and the monophyly of the eurosid I clade. Both MP and ML trees provide strong support for the monophyly of eurosids II and for the placement of Citrus  sister to a clade including the Malvales/Brassicales.The complete chloroplast genome sequence of rps19 and part of rpl22 and presence of two truncated copies of rpl22 is unusual among sequenced chloroplast genomes. Availability of a complete Citrus chloroplast genome sequence provides valuable information on intergenic spacer regions and endogenous regulatory sequences for chloroplast genetic engineering. Phylogenetic analyses resolve relationships among several major clades of angiosperms and provide strong support for the monophyly of the eurosid II clade and the position of the Sapindales sister to the Brassicales/Malvales.This is the first complete chloroplast genome sequence for a member of the Rutaceae and Sapindales. Expansion of the inverted repeat region to include  Chloroplasts are dynamic organelles of prokaryotic origin within the plant cell that house the photosynthetic apparatus. In addition to photosynthesis, other important metabolic activities take place within chloroplasts including the production of starch, certain amino acids and lipids, some of the colorful pigments in flowers, vitamins and several key aspects of sulfur and nitrogen metabolism. Chloroplasts possess their own genome and a full complement of transcriptional and translation machinery to express their genetic information. In particular, chloroplast gene expression machinery is a distinctive assembly of prokaryotic, eukaryotic, and phage-like components–likely the result of acquisition of a great number of regulatory proteins during evolution. The presence of nucleic acids within chloroplasts was established in 1963 . StudiesChloroplast bioengineering offers a number of advantages over nuclear transformation including high levels of transgene expression and gene containment . In addiCitrus is the largest fruit crop of international economic value because of its many uses including its value as a nutritive food source and for its valuable essential oils utilized by the food, pharmaceutical, and cosmetic industries. The valuable Citrus industry in Florida (USA) has recently been put in peril because of the accidental introduction of the exotic disease Citrus canker. This bacterial disease, which can infect all cultivars of Citrus, is the result of infection by Xanthomonas pv citri . Further, searches against a custom database of the previously published chloroplast genomic sequences using BLASTX were used to identify additional putative protein-coding genes. Both tRNAs and rRNAs were identified by searches against the same database using BLASTN.The Citrus chloroplast genome, REPuter [To determine the repeat structure of the  REPuter  was usedCitrus sinensis ESTs that contained chromatograms [Positional determination of potential RNA edits was accomplished using 1505 cp sequences from GenBank without chromatographic traces in addition to in-house atograms . Only rePhylogenetic analysis was performed by using PAUP* version 4.10 b10 . PhylogecpDNA, chloroplast DNA; IR, inverted repeat; SSC, small single copy; LSC, large single copy; bp, base pair; MP, maximum parsimony; ML, maximum likelihood; EST, expressed sequence tags; cDNA, complementary DNA; PCR, Polymerase Chain Reaction.MGB compared DNA and EST sequences for RNA editing, DNA sequencing and initial genome assembly and writing sections of the manuscript including those regarding RNA editing; NDS performed the repeat analyses, drew the circular map and assisted in writing the first and subsequent drafts of this manuscript; SBL isolated chloroplasts, performed RCA amplification of cpDNA, genome annotation, analysis and submission of data to the GenBank; RKJ assisted with extracting and aligning DNA sequences, performed phylogenetic analyses, and wrote the phylogenetic portions of this manuscript; HD conceived and designed this study, interpreted data, wrote several sections and revised several versions of this manuscript. All authors have read and approved the final manuscript.