Qualitative data were analyzed under the guidance of structuration model of collaboration, a theoretical model for understanding interprofessional collaboration. From focus group findings we generated 28 possible approaches, and subsequently their acceptability was assessed by a two round Delphi survey amongst BM and TCM policy stakeholders (n = 12). Consensus was reached only on 13 statements. Stakeholders agreed that clinicians from both paradigms should share common goals of providing patient-centered care, promoting the development of protocols for shared care and information exchange, as well as strengthening interprofessional connectivity and leadership for integration. On the other hand, attitudes amongst policy stakeholders were split on the possibility of fostering trust and mutual learning, as well as on enhancing innovation and governmental support. Future policy initiatives should focus on these controversial areas.In Hong Kong, statutory regulation for traditional Chinese medicine (TCM) practitioners has been implemented in the past decade. Increasing use of TCM on top of biomedicine (BM) services by the population has been followed; but corresponding policy development to integrate their practices has not yet been discussed. Using focus group methodology, we explore policy ideas for integration by collating views from frontline BM ( The Declaration regards TCAM policies formulation as a responsibility of governments worldwide, and has reemphasized the importance of including TCAM as part of national health systems amongst member states [Depending on the culture and history of each country, the term “traditional medicine (TM)” covers a wide variety of therapies and practices. In some cultures, the term “complementary and alternative medicine (CAM)” is commonly used to denote a similar meaning to TM. The generic term “traditional, complementary, and alternative medicine” (TCAM) is adopted by the World Health Organization (WHO) to avoid geographical variation . The oriPoint 7) . In the Point 7) . RecogniPoint 7) . In a WHPoint 7) . Subsequr states .Health policy development is tightly intertwined with politics and societal climate. TCAM policy has no exception—evaluation of policy options requires careful consideration on social context where the relationship between TCAM and dominant biomedicine (BM) evolves. Accordingly, historical and policy analysis using case study methodology  is a via TCM policy development is a constitutional mandate of the then newly established Special Administrative Region (SAR) government, and the major policy change was the professionalization of the TCM practitioners (TCMPs) workforce in the 2000s. This included formal statutory regulation on the practice of Chinese herbal medicine (CHM), acupuncture, bone setting, and massages by the Chinese Medicine Council of Hong Kong (CMCHK), as well as the establishment of three full-time TCM undergraduate programs in publicly funded universities . CurrentWhile this usage pattern suggests the populations' tendency to consult both types of practitioners, policy initiatives so far have been limited to regulation rather than service redesigns that response to patients' preference. Rather than adopting mainland China's integrative organizational approach , the HonEnhancement of primary care is at the top of Hong Kong's healthcare reform agenda. Major directions for reform include (i) promoting the family doctor concept; (ii) emphasizing continuity of care, holistic care and preventative care; (iii) encouraging and facilitating collaboration between BM doctors and other healthcare professionals . While tInterprofessional collaboration (IPC) between biomedical doctors (BMDs) and TCAM practitioners has been regarded as a preferred mode of integration, but its implementation would require strong coordination at policy and organization levels . AccordiStructuration Model of Collaboration provided a more comprehensive framework for conceptualizing these determinants. IPC is influenced by two major dimensions: relational and organizational. On the relational dimension, success in IPC depends on shared goals, client-centered orientation on teamwork, trust, and mutual acquaintanceship between partners. On the organizational dimension, the degree of governance success in IPC can be operationalised by four indicators: centrality, leadership, support for innovation, and connectivity. on the other hand, degree of formalization, which clarifies how expectations and responsibilities are shared in IPC, can be reflected in two indicators: formalization tools and information exchange [Based on organizational sociology, the exchange . DetailsStructuration Model of Collaboration, this study aims to generate potential strategies for fostering IPC between BMD and TCMP in Hong Kong, using qualitative methodology and the Delphi technique. Given the strong BM dominance within Hong Kong's healthcare ecology, lessons from Hong Kong may serve as a reference to policy makers in other healthcare systems who are tailoring integration policies to suit their local circumstances.With reference to the This study consisted of two parts. The first part included a series of focus group interviews with frontline BMD and TCMP, with an aim of exploring their views on potential integration strategies. In the second part, results generated from focus group discussion were used as a blueprint for a double-round Delphi study amongst BM and TCM policy stakeholders. The Delphi process aimed to facilitate the development of a consensus-based integrative health policy proposal, and it was conducted after focus group discussion amongst frontline clinicians because: (i) introduction of potentially dominant individuals  in focus groups may lead to unwanted pressure on other participants  and (ii) Structuration Model of Collaboration, as well as recent healthcare reform proposals  the respondents' own rating in round 1, (ii) median agreement rating, (iii) summary of qualitative comments, as well as (iv) whether consensus was achieved at round 1. We reported median instead of mean as it is less affected by outliers . There iFocus group results generated 28 statements for our round 1 Delphi survey . We contStructuration Model of Collaboration showed a very uneven pattern. On the relational dimension, respectively, 2 statements in the goals (no. 2 and no. 3) and client-centered orientation on teamwork (no. 4 and no. 5) indicators achieved consensus, but none of the indicators within the mutual acquaintanceship between partners and Trust domains did so. On the organizational dimension, 2 statements reached consensus in each of the domains of leadership (no. 15 and no. 16), Formalization Tools (no. 24 and no. 25) and information exchange (no. 26 and no. 27). Three statements in the Connectivity domain reached consensus . On the other hand, the experts did not reach consensus on eighteen statements. It is noteworthy that none of the statements from Centrality or Support for Innovation domains reached consensus. From this pattern, it is clear that although policy ideas on mutual acquaintance, trust, centrality and support for innovation were suggested by frontline BMD and TCMP, attitude amongst integration policy stakeholders appeared to be split.The distribution of consensus under the structuration model of collaboration, we have generated a 28 statement policy proposal on integration from focus group interviews of 50 BMD and 50 TCMP. Subsequently, we examined the acceptability of these statements amongst BM and TCM policy stakeholders. Only 13 out of 28 statements reached consensus in the Delphi process. No consensus was reached the areas of mutual acquaintance, trust, centrality, and support for innovation. These areas deserve deeper discussion as they could be important “rate limiting steps” when fostering integration. To promote progress in integration policy, policymakers need to facilitate consultation and discussion on areas which are contentious. Possible policy options for these areas, with reference to international literature on IPC between BMD and TCAMP, will therefore be discussed.Under theoretical guidance from the Existing integration experiences suggested that interprofessional education between BMD and TCAMP is critical for mutual acquaintanceship, and subsequent referral and teamwork –39. NeveAlthough the co-location of BM and TCM clinicians is one of the most effective ways for fostering mutual acquaintance and trust , 48, thiRedistribution of responsibility across professional boundaries is a defining feature of effective integration. The practice of acupuncture by BMD, as well as the rights to order BM diagnostic test by TCMP are examples of cross fertilization between the two paradigms. While these initiatives could foster innovation in their respective fields, the TCM sector may perceive the use of acupuncture by BMD as an explicit absorption of TCM modalities into the BM tool box, and in the longer term this may sideline the role of TCMP . Meanwhiwhom and where TCM research should be done, but the how question should also be considered carefully. While it is acknowledged that clinical evidence could be a potential tool for bridging the two paradigms, a hierarchical view on evidence may have limited applicability in evaluating TCAM. To balance the demand for both internal and external validities, a circular perspective on evidence could provide a rich toolbox of research methods that will contribute to the evidence base of TCAM [Two further critical policy issues deserve deeper debate. Firstly, stakeholders in this study have not reached consensus on the need for a dedicated knowledge translation and dissemination center for supporting integration. Superficially, reasons for disagreement may relate to  of TCAM . The impSecondly, with the future implementation of electronic health system worldwide, leaders of integrative medicine services may consider the addition of a feedback system that provides BMD and TCAMP with timely updates on referral outcomes. BMD may fill their knowledge gaps in TCAM by receiving comments from patients and colleagues via such a system , 56 and In our focus group study, we sampled the views of a broad range of BMD and TCMP who has direct involvement with care provision. However, we cannot eliminate self-selection bias in the recruitment process as those who were more willing to attend discussions are often holding stronger opinion for, or against, integration. While the resultant bias is difficult to quantify, our qualitative approach has enabled an in-depth, diversified understanding on key issues surrounding integration across the two disciplines. This provided a strong foundation to our subsequent Delphi study. In this second part, panel members were selected carefully to represent a wide heterogeneous range of expertise from different settings. While this provided a broad perspective on our final findings, it may also lower the number of consensus reached as experts may find little common ground on the contentious issues of integration policy . We achiWhile the WHO Beijing Declaration is advocating the integration of BM and TCAM, many member states may consider this as a second step subsequent to formal regulation of TCAM practice. With a decade's experience in regulating TCM, Hong Kong represents a unique case for demonstrating how integration, as defined as IPC between BMD and TCAMP, could proceed after regulation. The current consensual policy proposal can be considered as a starting point for fostering IPC between the two paradigms of practice. Findings from this study can be a useful reference for policy makers in other countries. However, given the special circumstance in Hong Kong where TCM development is considered as a constitutional mandate, we have taken an advocacy approach in conducting the present study. We may have overlooked certain barriers to integration, and thus the external validity of our findings should be carefully evaluated via future comparative studies.


Daniel Kramer and colleagues compare strategies for postmarket surveillance of medical devices and discuss ways to improve these systems.Please see later in the article for the Editors' Summary We evaluated strategies for postmarket surveillance of medical devices in the United States, European Union, Japan, and China.Each system shares several common elements, including primary reliance on passive adverse event collection for marketed devices, but vary widely in their allocation of stakeholder responsibilities and mechanisms for evaluating the performance and safety of approved devices.Postmarket surveillance may be improved through greater system transparency, scheduled re-examination of approved devices, and balancing central and local control.Medical devices play an increasingly vital role in health care delivery around the world. These technologies are defined in distinction to drugs as an “instrument, apparatus…machine…implant…or other similar or related article…which is…intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease…and which does not achieve its primary intended purposes through chemical action” After a new medical device is brought to market, the process of postmarket surveillance (PS) provides an ongoing assessment of safety and effectiveness. High-profile international public health crises involving widely used implantable cardioverter-defibrillator leads After a device is approved in the US, companies must maintain quality manufacturing control systems The FDA may require manufacturers to conduct PS studies in two ways. First, “post-approval studies” may be appended to the approval of devices evaluated through the premarket approval (PMA) or Humanitarian Device Exemption (HDE) pathways, which include high-risk devices or those serving patients with rare diseases, (respectively), where premarket testing may be especially limited. Second, so-called “522 studies” (named in reference to the relevant legislation) for select devices (including those medium- or lower-risk devices cleared through the 510(k) pathway based on risk or other criteria) may also be required When PS points to potential device problems, the FDA issues safety communications to inform patients and clinicians. Actual patient harms trigger safety alerts from the FDA, manufacturers, or distributors A recall reflects systemic concerns with a device. A manufacturer may conduct a recall on its own, or in response to an FDA request, and is responsible for developing the strategy for managing the recall process. More serious recalls, such as those issued for metal-on-metal designs for hip prostheses Recently, the FDA proposed adding a unique device identifier (UDI) system to its PS activities. UDIs allow linkage of specific devices to clinical information that can enhance the context of adverse event reports Devices are certified for marketing approval by private, for-profit Notified Bodies (NBs) around the EU based on adherence to European Commission directives that describe standards for device manufacturing, labeling, and expected performance and safety profiles. Competent Authorities (CAs) in each member state oversee NBs and have primary responsibility for PS; there is no equivalent to the FDA or the European Medicines Agency for devices in the EU. Directives also describe the basic standards for manufacturing quality-control systems and responsibilities for adverse event reporting. Non-binding European Commission guidance documents offer greater detail regarding handling adverse events, and communicating safety concerns. They also provide templates for data collection and reports, including “clinical evaluation reports,” which are intended to provide an outline of the technology underlying a specific device and current clinical data supporting its use, ideally in reference to established standards or similar devices Manufacturers must report “any deterioration in the characteristics and performances of a device, as well as any inaccuracies in the instruction leaflet which might lead to or might have led to the death of a patient or to deterioration in his state of health” to CAs where the event occurs. A template outlines the required information to be sent to CAs. CAs must also have processes for collecting reports from manufacturers, relaying to manufacturers event reports submitted to CAs by users, and assessing ongoing risks associated with reported incidents or recalls. Member states notify other states if an assessment of device-related events leads to specific remedial measures.CAs submit adverse event and recall data to the European Databank on Medical Devices (EUDAMED), a central but non-public database run by the European Commission. Some CAs maintain independent publicly available databases of device information. For example, the UK Medicine and Healthcare Products Regulatory Agency (MHRA) keeps adverse event and recall information in a searchable web portal.European Commission directives do not grant authority to NBs or CAs to require post-approval studies. NBs as part of their review of individual devices can provide guidance for PS, though there is no evidence that studies or registry development are commonly  required as conditions of approval. Neither the clinical data forming the basis for approved devices nor the existence, if any, of post-approval studies are systematically publicized because there is no requirement for NBs, manufacturers, or CAs to do so.Manufacturers and regulators have obligations under the directives to manage adverse events and safety problems with marketed devices. Field Safety Corrective Actions (FSCAs) are “actions taken by manufacturers to reduce a risk of death or serious deterioration in the state of health associated with the use of a medical device” already on the market. These actions range from changes in labeling to withdrawal of products. Each CA must disseminate National Competent Authority Reports, which outline major safety issues for medical devices for the CAs of all member states.Though not yet formalized into directives, recent European Commission suggestions for device PS reform include use of UDIs and connecting UDIs to EUDAMED. The provisions also include improved coordination among CAs and greater oversight of NBs, including clarification of NBs' responsibility and authority to conduct unannounced inspections of manufacturing facilities and audits of collected documentation related to adverse events.Device regulation in Japan is led centrally by two government agencies: the Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labor, and Welfare (MHLW). Under Japan's Pharmaceutical Affairs Law, MHLW has the authority to issue approvals for new devices and supervises PS including adverse event reporting and recalls. The PMDA provides the analytic work that informs MHLW's decisions, including inspections and premarket evaluations. PS in Japan includes systems for reporting foreign and domestic adverse events, identification of safety signals emerging from international markets, and postmarket studies PS studies may be required by PMDA for select devices. Approval of particularly risky devices may be paired with requirements to actively monitor domestic use of the device for up to five years, or for a pre-specified number of cases. Certain higher risk devices must “re-file” applications 3–7 years after initial marketing approval Recalls arising from domestic incidents may include problems with documentation or reporting, as well as those related to adverse events. Foreign recalls do not automatically trigger a recall in Japan, but if the sponsor is a global company, marketing a device in Japan that has been recalled elsewhere is generally untenable.The central government's Ministry of Health (MOH) is responsible for drafting basic device oversight regulations and overseeing their implementation through the State Food and Drug Administration (SFDA) Provincial and municipal agencies serve as first-line responders when adverse events are reported and support the CFDA in monitoring and taking action at the regional level Product approvals are renewed quadrennially, using data gathered since the initial registration. Regulations were recently drafted to simplify this re-registration process by only requiring new documentation to establish effectiveness and safety of significant changes made in relevant products. Device vigilance reports consolidating and analyzing adverse events related to these products must also accompany re-registration Device recalls are initiated by manufacturers based on self-investigation and assessment of product defects, ranging from eliminating defects through relabeling or software upgrades, to full market withdrawal China's regional structure grants substantial autonomy to provincial health departments. For example, Shanghai has developed a traceability program for implantable medical devices, adopting a UDI system linking implantable medical devices directly to patients across over 100 hospitals. The database provides detailed records of adverse events and patients involved, allowing the CFDA to hold back potentially dangerous products while still in inventory and limit future injuries These four PS systems share several features , includiFirst, we found substantial variation in public access to PS processes and data. On one end of this spectrum, the US FDA provides access to many high-risk PS decisions through advisory panel meetings and public “conditions of approval” for select devices that include the design and rationale of PS studies. For example, a 1,600-patient post-approval study was mandated for a novel subcutaneous defibrillator system to address specific concerns including shock effectiveness and discrimination of arrhythmias The EU approach to the subcutaneous ICD demonstrates the other end of the transparency spectrum. This device was marketed in 2009 after a 55-patient study demonstrating that the device worked as intended Physicians, device safety researchers, payers, and policymakers should be able to access data supporting approval of new devices, particularly high-risk devices, to understand uncertainties related to safety and effectiveness and the specific goals of PS. Public accountability can also help ensure that post-approval studies are completed in a timely manner and published in peer-reviewed venues or through the regulatory authority itself.Second, the requirement in Japan (and evolving in China) that select devices re-file with the regulatory authority after a fixed time period offers another powerful PS tool. Scheduled reassessment of accumulated clinical experience allows regulators to assess whether safety and effectiveness expectations have been met. Reexamination supports review of labeled indications or safety concerns, and also provides an avenue for evaluating whether, in retrospect, the premarket process for a specific device adequately anticipated safety and effectiveness concerns. This knowledge can provide feedback for that device's premarket review and inform future evaluation of similar devices by influencing study design and sample size calculations affecting safety concerns.before major recalls—perhaps would have helped identify safety problems more quickly, or at least provided more structured PS guidance. To our knowledge, no device in Japan or China has been removed from the market at the time of its re-examination. Yet this may reflect a strength of this approach, as manufacturers faced with a strict deadline with meaningful consequences are strongly motivated to address post-market concerns well in advance of the re-examination. Looking forward, we argue that a scheduled re-examination for devices such as transcatheter aortic valves, left ventricular assist devices, or new hip prostheses would support PS for these new therapies, and may motivate completion of post-approval requirements.An interesting case study of this approach to PS paradoxically comes from the US, where in 2006, the FDA convened an advisory panel to evaluate current knowledge on the safety and effectiveness for the two models of widely used drug-eluting coronary stents Novel, important technology needs to be made accessible to patients, but it is sensible to pair approval of select high-risk devices with comprehensive, public re-assessments of available safety and effectiveness data at a predetermined interval. Such meetings are likely to be most effective when paired with statutorily defined enforcement options, including re-labeling, further study, or withdrawal. These re-examinations hold manufacturers and regulators accountable for their decisions and subjects pre-approval estimates of device performance to scrutiny.Third, the systems we reviewed strikingly different balance between central and regional control. The US system is tightly centralized, so much so that states have limited authority to impose additional requirements for manufacturers Even the most rigorous clinical testing of experimental devices will leave some safety and effectiveness questions unanswered. At the same time, broader dissemination of new technology and longer clinical experience may identify unforeseen concerns. For example, many health policy discussions around improving PS have urged regulators to supplement passive collection of adverse events with ongoing, dynamic assessment of safety and effectiveness during the full life cycle of marketed devices through mechanisms such as UDI systems. However, these strategies will take time to design and implement. As device PS systems move towards more active surveillance, our review reveals important features of current systems around the world that promote coordination among regulators, manufacturers, clinicians, and patients. Broader use of these strategies could preserve patients' access to new technologies while protecting them as well as possible from devices that later turn out to be unsafe or ineffective.


Almost 32,000 people are living with human immunodeficiency virus (HIV) in Papua New Guinea (PNG). The primary route of transmission in this moderate prevalence setting is through heterosexual sex. Thus a gendered understanding of HIV is required to inform HIV prevention, treatment and care options. The aim of this review is to investigate understandings specifically about women and HIV in PNG and to identify gaps in the literature to inform future HIV research.An integrative review of literature about women, HIV and PNG was conducted using a systematic search of online databases, including book chapters and grey literature. Prior to inclusion, literature was assessed using inclusion and exclusion criteria, and the Critical Appraisal Skills Programme (CASP) appraisal tool. Selected articles, book chapters and reports were coded and a constant comparative method of analysis used to construct a series of themes.The 26 articles, book chapters and reports included in the review were predominantly descriptive, original research (23/26 pieces of literature). Six themes were identified in the literature: economic, social and cultural factors (including mobility); gender issues (including violence against women); knowledge about HIV (including perception of risk of HIV); religious beliefs about HIV; women perceived as responsible for HIV transmission; and prevention of HIV. Literature about women and HIV in PNG is predominantly focussed upon women who sell sex, women as mothers or young women. Women are usually represented as either victims of HIV or responsible for transmitting HIV. Anthropological and social research has described the economic, social and cultural context along with the lived experience of HIV in PNG, but there is limited operations research or implementation research available.The literature reviewed has highlighted the importance of a gendered analysis of HIV prevention, care and treatment in PNG. There is an opportunity for operations, implementation and health systems research about HIV in PNG to shift research from description to action. Almost 32,000 people are living with human immunodeficiency virus (HIV) in Papua New Guinea (PNG) in 2012 . This inPNG is a Pacific Islands country with a population of almost 7 million and over 800 languages ,6. ApproPNG has 90% of all reported HIV infections in the Oceania Region ,9, with Women in PNG occupy a wide variety of roles: from wealthy, urban professional to poor, subsistence farmers. However, the majority of women in PNG live in rural areas and have primary responsibility for food production, with limited access to the cash economy. There are matrilineal societies in PNG (where land is inherited through the mother’s line); however the majority are patrilineal. Educational opportunities for many girls and women are also limited, with approximately 50% of women in PNG considered literate . While tWomen in PNG experience maternal mortality rates of 230/100,000, the highest in the Asia Pacific region . HoweverOver two thirds of women in PNG will experience violence at some time in their life, most often perpetrated by their male partner or family member/s -21. PNG Sixty percent of people living with HIV in PNG are women (NACS 2012), with younger women over-represented in this group . SignifiHIV prevention has been challenged to date by the limited incorporation of social, cultural and economic drivers of HIV . Anti-coThe aim of this integrative review is to investigate understandings about women and HIV in PNG and to identify gaps in the literature to inform future HIV research in PNG.An integrative review was undertaken to examine public health literature about women and HIV in PNG. The key questions guiding the literature review were:(i) What peer-reviewed literature exists about women, HIV and Papua New Guinea?(ii) What is the nature of that literature?(iii) What is the knowledge base upon which future HIV prevention strategies can be planned?(iv) What are the research gaps in the peer-reviewed literature?Pub Med and Scopus using four Medical Subject Headings (MeSH): HIV; women; female; Papua New Guinea conducted on the 7 March 2012. Pub Med comprises 5,632 journals, including all Medline entries for peer-reviewed health and medical journals. Scopus is a large database with almost 19,500 peer-reviewed online journals in areas of science, life sciences, physical sciences, medicine and social sciences. These databases were chosen for their comprehensive focus on health, public health and health and social sciences [An integrative review methodology was employed as it allows for the inclusion of experimental and non-experimental research and for data from the theoretical and empirical literature . This desciences ,39.Google with the same key terms: HIV; women; female; Papua New Guinea, undertaken in March and April 2012. The third phase was a search of HIV literature produced by Papua New Guinea Government departments, the PNG National Research Institute and PNG Institute of Medical Research on their respective websites. The fourth phase was a review of literature sourced from colleagues, researchers and academics in PNG and internationally between March and July 2012, with reference lists from these documents checked for literature that might have been missed.Peer reviewed journal articles constitute one kind of research output and are not always where research activity is reported , as is tThe following inclusion criteria were applied to the identified articles, book chapters and reports:women and HIV in Papua New Guinea(i)   The primary focus of the literature (or a significant section) was about (ii)   Literature was peer reviewed (iii)   Literature published between January 2004 and July 2012(i)   Non-peer reviewed literature was excluded from the review. This included government reports, research institute publications and reviews which were not peer reviewed.(ii)   Literature focused on funding responses to HIV and HIV control  and Pacific wide surveillance were not included in the review.(iii)   A National AIDS Council commissioned literature review of HIV research in PNG was identified but not included in this review as it was not peer-reviewed .(iv)   Literature was not included if it was published before 2004. Although literature published before this year is valuable, the nature of the HIV epidemic in PNG changed with the introduction of ARTs in 2004 . This chThe nature of the literature was classified as: a) original research, b) reviews, c) program descriptions and d) commentary/discussion paper using an adapted research identification schema . OriginaScopus returned 94 references and PubMed 42 references. Once additional reports, book chapters and reports were identified and duplicates removed, a total of 129 references remained  from socially ascribed roles (gender) [women as a gendered category, understood in the diverse sociocultural context of PNG. Wingood and DiClemente [Before continuing to an analysis of this literature, we wish to acknowledge the conceptual challenge of isolating (gender) . From a Clemente  explain Throughout the literature included in this review, women were mostly studied in groups depending upon a role they held in society: women who sell or exchange goods for sex ,30,50-55•Economic, social and cultural factors impacting HIV, including mobility•Gender-based inequality, including violence against women•Knowledge about HIV, including perception of risk of HIV•Religious beliefs about HIV•Women perceived as responsible for HIV transmission•Prevention of HIVThe changing economic, social and cultural context of PNG is reported to influence the risk of HIV for women. Urbanisation and modernisation result in changed economic, social and cultural conditions, including changed sexual practices. Separation from traditional lands and forms of subsistence (such as gardens) means services in exchange for goods or money is required for survival. For women in urban and peri-urban environments in PNG where there are very limited employment opportunities, the selling or exchanging of sex for money or goods is often ‘survival sex’ . Bruce epasinda meri  as a woman who doesn’t belong to anyone or who has given up her social and cultural roles [pasinda meri is often a consequence of a woman’s anger at their treatment within cultural systems of bride price and compensation. Being a pasinda meri results in a freedom to live outside of cultural norms and while an expression of a woman’s agency it often results in stigmatisation, repudiation and physical attacks by both men and women [Cultural factors such as traditional beliefs around sexuality and reproduction, bride price and the inability to discuss sexuality and HIV prevention openly are contributing to increased risk of HIV for women in PNG. Cultural understandings of sexuality and reproduction are discussed at length in a number of the articles reviewed ,56,62-64al roles . Usuallyal roles . Becominnd women ,55,64. Klainups (gang rape) common [lainup[Women in PNG experience gender-based inequality, including less access to economic, education, legal and employment opportunities than men . It was ) common . A studyn [lainup. In PNG,n [lainup,65.sik blong koap  [There is a range of findings about women’s knowledge about HIV represented in the literature, with women who sell sex, young women and mothers the focus of studies that include this topic. The majority of women who sell sex or exchange sex for goods know HIV transmission occurs through sexual intercourse ,58,66,67ection’) . On the ection’) ,53,56,62ection’) ,62,68. Iection’) ,34,63,69ection’) , but rarection’) . As KellSikAIDS, as it is known in Tok Pisin, is linked with immoral behaviour, promiscuous sex and prostitution [SikAIDS is described variously by Christians as a punishment from God, divine retribution, or a call to relinquish sinful sexual practices [The dominance of Christianity influences the way women experience HIV in PNG. Combined with the effects of colonisation, Christianity preserves beliefs about unequal gender roles and expected sexual behaviours of women . One inftitution . SikAIDSractices . Most imractices . This raractices .A dichotomy is present in the literature about women living with HIV in PNG, with women divided into passive victims (the ‘mothers’) and promiscuous vectors (women who sell sex) . Lepani pamuk meri or pasin pamuk (prostitute) or tukina meri  [pasin pamuk or pamuk meri[Women seen as responsible for the spread of HIV in the literature are mostly women who sell sex based in the Highlands and PNG’s capital, Port Moresby ,50,53,61 of PNG) . Women w of PNG) ,53. Ther of PNG) ,55. In W of PNG) ,50,53,62amuk meri.kastom and church requirements [A variety of ideas about HIV prevention are explored in the literature reviewed. These include: encouraging young people to adhere to irements ,34; patrirements ,63; and,irements ,50,53. Sirements .United Nations General Assembly Special Session (UNGASS) 2010 Report was to scale up research on the most-at-risk populations in PNG, which includes women selling sex [Women were typically represented in the literature in this review as victims or vectors, with many of the articles in the review portraying women as victims of their social, cultural and religious context. Social and cultural changes such as urbanisation and increased mobility have increased HIV risk for women ,62. A moling sex ,34.The majority of original research in this review is descriptive research about women and HIV in PNG, with no operations or intervention research. Operations research  is defined as research which aims to “develop solutions to current operational problems of specific health programmes or specific service delivery components of the health systems” , while iLimited literature about the impact or outcomes of strategies implemented by government departments or non-government organisations addressing HIV at a programmatic level is published in the peer-reviewed literature. Health services can be unhelpful or dysfunctional . There atukina meri[In addition to the lack of operations or intervention research, there are still a number of gaps in the descriptive research available. Current prevalence estimates are mostly based on HIV identified in antenatal clinics in PNG. We need to know more about PNG women outside the context of antenatal clinics or selling sex . Unequalkina meri. More rekina meri,76. Do wIn the light of this review about women, it is clear the role of masculinity as perceived and enacted in PNG is important for HIV prevention in PNG. A renewed focus is required “on masculinities and policy and program frameworks that integrate the issues of male sexual privilege and gender violence” . Male prLimited literature in this review focused on the experience of women living with HIV and AIDS or the experience of women caring for a HIV positive person/people. Stigma against people living with HIV was reported . Women bLiterature included in this review provides knowledge about the context of women’s lives in PNG, the gender issues they face, their understanding of HIV and the way women are perceived in relation to HIV. The range of findings about women’s knowledge of HIV reflects the way in which these research findings were generated: from internationally sanctioned knowledge, attitude and practices questions to sociocultural focused, geographically bound ethnographic methods. The current focus on strengthening the capacity of researchers from PNG to undertake HIV research will further enhance the nature and amount of HIV research in PNG .Peer-reviewed literature provides evidence of explicit research methods, results and recommendations which are less able to be influenced by organisational and government agendas . HoweverA limitation of this review is the exclusion of non-peer reviewed literature. There is much valuable information about HIV and prevention options. As identified above, the veracity of this literature is difficult to determine and thus has not been included.Women in PNG have the right to feel safe, have choices about HIV prevention, care and treatment and reach their potential in the context of shifting social, cultural and economic conditions of this moderate prevalence setting. The literature reviewed has highlighted the importance of a gendered analysis of HIV prevention, care and treatment in PNG. Opportunities exist for researchers, in partnership with communities, service providers and policy makers to move from descriptive to action-oriented research in order to reduce HIV in PNG.The authors declare there they have no competing interests.MRM: Conceived of and designed the literature review, acquired and analysed the literature, drafted and edited the manuscript. JM: Provided support for the literature review process, revised the manuscript for important intellectual content and reviewed the final manuscript. RT: Provided literature and advice on sources, revised the manuscript for important intellectual content and reviewed the final manuscript. DM: Provided literature and advice on sources, revised the manuscript for important intellectual content and reviewed the final manuscript. RS: Provided support for the literature review process, revised the manuscript for important intellectual content and reviewed the final manuscript. WJHM: Provided support for the literature review process, revised the manuscript for important intellectual content and reviewed the final manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/13/552/prepub


Emerging infectious diseases (EID) are currently the major threat to public health worldwide and most EID events have involved zoonotic infectious agents. Central Africa in general and Gabon in particular are privileged areas for the emergence of zoonotic EIDs. Indeed, human incursions in Gabonese forests for exploitation purposes lead to intensified contacts between humans and wildlife thus generating an increased risk of emergence of zoonotic diseases. In Gabon, 51 endemic or potential endemic viral infectious diseases have been reported. Among them, 22 are of zoonotic origin and involve 12 families of viruses. The most notorious are dengue, yellow fever, ebola, marburg, Rift Valley fever and chikungunya viruses. Potential EID due to wildlife in Gabon are thereby plentiful and need to be inventoried. The Gabonese Public Health system covers geographically most of the country allowing a good access to sanitary information and efficient monitoring of emerging diseases. However, access to treatment and prevention is better in urban areas where medical structures are more developed and financial means are concentrated even though the population is equally distributed between urban and rural areas. In spite of this, Gabon could be a good field for investigating the emergence or re-emergence of zoonotic EID. Indeed Gabonese health research structures such as CIRMF, advantageously located, offer high quality researchers and facilities that study pathogens and wildlife ecology, aiming toward a better understanding of the contact and transmission mechanisms of new pathogens from wildlife to human, the emergence of zoonotic EID and the breaking of species barriers by pathogens. Despite intensive research and considerable effort from public health agencies to prevent or eradicate infectious diseases, emerging infectious diseases (EID) are currently the major threat to public health worldwide.1 Indeed, many new infectious agents, characterized by a high pathogenic potential, have been recently identified. Furthermore, some well known pathogens have been expanding their territories, causing increasing concerns in the recent decades due to changing epidemiological patterns.2 Most of these EID events have involved zoonotic infectious agents: more than 60% of EID affecting humans have a zoonotic originEmerging and re-emerging zoonoses include recently identified infectious diseases, diseases that have recently evolved from a subclinical state to a clinical syndrome, and previously known diseases that have recently displayed an increase in incidence or that have spread to new regions, hosts or vectors.4 However, a disease may not be recognized as zoonotic at the first outset. The disease can spread undetected for a period of time depending on the incubation period (weeks to years), the epidemiological pattern of a subclinical disease to a clinical picture (the emergence of the symptoms depending on host or pathogen factors) or, if the number of cases, in both human and animal populations, is too small and undetectable during the initial stages of transmission to suspect a link between the two events.Zoonotic EID outbreaks result from a now classically accepted phenomenon of concurrency of fundamentals and territories of emergence. Fundamentals include factors related to the host, the vector (if any), the pathogen, and favorable environmental factors (climate) although territories at risk are the product of human activity and high-risk behavior among the human population. For instance, territories  with an inefficient disease detection system or a failure to control vectors and other carriers of diseases as well as man-made environmental changes  will force an increase in contact between the human population and wildlife.Tropical forests form the ecosystem harboring the highest species richness of all terrestrial ecosystems and shelter almost 50% of the total global biodiversity.Latest reviews on EID show that nearly 75% of zoonotic EID have a wildlife origin.As anthropogenic activities have been identified as the cause of a significant majority of outbreaks,In Gabon, rainforests cover ∼80% of the territory.At least 51 endemic or potential endemic viral infectious diseases have been reported in GabonZaïre ebola virus (ZEBOV): in Gabon, ZEBOV outbreaks occurred in 1994, 1996, 1997 and 2001;29 primary human cases were generally contaminated by direct contact with dead wild animals, such as great apes (chimpanzee and gorilla), which are highly susceptible to the disease, and therefore human outbreaks were often preceded by an animal epizootic (great apes). Since the first recorded outbreak in 1976, 20 human epidemics have occurred in Central AfricaAedes albopictus, the mosquito known as the main vector of the most recent epidemics of CHIKV.albopictus as the main vector of epidemics and an adapted virus strain presenting an original mutation suspected to be responsible for an increase of pathogenicity.Chikungunya virus (CHIKV): CHIKV has recently dispersed to new regions of the world including Gabon where two outbreaks in 2006 and 2007 mainly hit the capital, Libreville.Aedes aegypti mosquito, which is strongly affected by ecological and human drivers, but also influenced by climate .Dengue virus (DENV): a DENV outbreak occurred in Gabon simultaneously with the CHIKV outbreak in 2007,Yellow Fever Virus (YFV): Gabon is officially designated as an infected country. A YFV outbreak occurred in 1994 in Ogooue-Ivindo Province, North East of Gabon with 44 cases reported.					During the past two decades, several outbreaks of these zoonotic viral diseases have been reported in Gabon. All of them had a major impact on the public health:Foamy virus: simian foamy virus (SFV), a retrovirus in the Spumaretrovirinae subfamily, is widely prevalent in wild-caught and captive-born non human primates.Human monkeypox: Human monkeypox, caused by the MPXV, a member of the genus Orthopoxvirus, is clinically almost identical to ordinary smallpox.Rift valley fever virus (RVFV): Rift Valley fever is an African disease that affects both livestock and humans. RVF outbreaks are associated with persistent heavy rainfall, sustained flooding and appearance of large numbers of mosquitoes, the main vector. Localized heavy rainfall is seldom sufficient to create conditions for an outbreak;					Based on serological evidence, several pathogens identified among wild or domestic animals, are suspected to infect the human populations of Gabon and therefore represent a potential threat to public health. Among them are the follows:?C by 2100.Climatic variations and extreme weather events have a profound impact on infectious diseases:Concerning other zoonotic infectious diseases like ebola, marburg or RVF, too little information is available concerning their ecology to be able to assess the impact of climate changes on the potential emergence or re-emergence of these diseases. However some preliminary reports show a strong association between wet environment  and the recent reemergence of ebola fever in Gabon and RDC.Gabon has one of the highest expenditure on health per capita in Africa. In 2006, Gabon's total health care expenses were comparable to eastern European countries and most southern American countries:The Gabonese Public Health System comprises five different health sectors: (1) the civilian public sector under the public Health and Hygiene Ministry, (2) the public military sector under the Ministry of Defense, (3) the National Health Social Security Funding and private insurances, (4) the private health sector and (5) the traditional health sector.This public Health system geographically covers most of the country allowing a good access to sanitary information and efficient monitoring of emerging diseases. However, access to treatment and prevention is much better in urban areas where medical structures are more developed, more organized with higher level of technicality and materialTo fight against diseases, Gabon has developed 17 national health control programs. These programs monitor diseases such as HIV and sexually transmitted diseases, malaria, tuberculosis and also include a wide vaccination program, which covers 100% of the Gabonese territory. Despite the existence of 10 epidemiological stations distributed around the country in both rural and urban areas  that actThe CENAREST  that evaluates and carries out research in Gabon, contributes to the application and promotion of research results and supports research training.The CIRMF , a Gabonese world-renowned scientific research center, inaugurated in 1979, the CIRMF had for an initial focus to study the reasons for infertility in Central African populations. By the mid 1980s, CIRMF broadened its research to focus also on tropical diseases including HIV, trypanosomiasis and malaria. More recently CIRMF concentrated also on EIDs including the deadly ebola and marburg viruses, CHIKV and DENV.International NGOs  are also involved in research on emerging diseases in Gabon. For example, the WCS (Wildlife Conservation Society) with its ‘One World, One Health’ Program and the Zoological Society of London and its ‘Mikongo Conservation Centre’ are working on great ape diseases, wildlife monitoring and the bush meat trade.					In addition to public health Ministry activities, there are the following in Gabon:The OCEAC  is an organization of coordination and cooperation to fight major endemic diseases in Central Africa. Created in 1963, in Yaounde, by the determination of the health ministers of Cameroon, Congo, Gabon, CAR and Chad, it was originally known as the OCCGEAC until 1965. The Equatorial Guinea joined later the OCEAC. Its goals are to (1) coordinate public health policies and actions in Central African region, (2) participate in the training of the medical staff of member countries of the organization, (3) coordinate applied research projects undertaken by national institutions, (4) implement missions of expertise in the different areas of health sciences, (5) contribute to the public health promotion in the member countries and (6) support the actions undertaken in response to health emergencies. Today OCEAC is in charge of regional health programs and projects like the Sub Regional Program against HIV/AIDS, the Harmonization Program for Pharmaceutical Policy, the Regional Program to fight human African trypanosomiasis and research projects on malaria.The CEMAC  is an economic community of the African Union for promotion of regional economic co-operation in Central Africa. Member countries include Gabon, Republic of Congo, Equatorial Guinea, CAR, Cameroon and Chad. It ‘aims to achieve collective autonomy, raise the standard of living of its populations and maintain economic stability through harmonious cooperation’. It was established in 1983 and its ultimate goal is to establish a Central African Common Market. However CEMAC may have a role in the public health systems in Central Africa: in 2009, CEMAC signed a memorandum of understanding with Germany, which donated a 23 million euro grant for the prevention of HIV in Central Africa.The CIESPAC  is a sub-regional public health training institution, originally located in Brazzaville. It was created to provide Central African countries with qualified health service staff and managers. It offers several courses, the most recent of which is recognized with a professional diploma in public health and targets mainly potential health district managers.The CAMES  exists to (1) promote and encourage the understanding and the solidarity between member States, (2) establish a permanent cultural and scientific cooperation between member states, (3) collect and diffuse all academic and research documents, (4) prepare agreement drafts between states concerned by Higher Education and Research and contribute to their implementation and finally (5) develop and promote dialogues to coordinate the higher education system and research so as to standardize programs and recruitment levels. This means that Gabonese university lecturers and researchers  are assessed by CAMES before obtaining a promotion.					In Central Africa there are few regional organizations involved in public health:http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/vhf.htm). Moreover, in November 2007, a meeting to discuss the integrated control of neglected zoonotic diseases in Africa was held in Nairobi, Kenya. It was organized by the WHO and jointly supported by the European Commission, the ILRI , the Danish Centre for Health Research and Development (formerly the Danish Bilharziasis Laboratory), the FAO (United Nations Food and Agriculture Organization), the OIE  and the African Union.Gabon is part of the Global Outbreak Alert and Response Network (GOARN), which contributes towards global health security by,Infectious diseases, including zoonoses, remain the major and increasing health threat in most developing countries.et al. advocated for the re-allocation of resources to EID hotspots in lower latitudes, such as tropical Africa because of the critical need for health monitoring and identification of new potentially zoonotic pathogens in African wildlife populations, and this to be used as a forecast measure for EIDs.However, global effort in EID surveillance and investigation is inadequately allocated. Indeed, the majority of scientific resources focus on places from where the next important emerging pathogen is least likely to originate.Like other African countries, Gabonese resources for public health and health monitoring are unequally allocated; 60% are spent at a central level. Public health services and clinical practitioners need more resources to be able to actively educate the public about the risks of repeated contacts with wildlife or other sources potentially harmful for health.


Following the 1990 Global Burden of Disease (GBD) study, Disability-Adjusted Life Years (DALYs) have been used widely to quantify the population health burden of diseases and to prioritise and evaluate the impact of specific public health interventions. In the context of the recent release of the 2010 GBD study, we explore the novel use of DALYS to determine health-based targets (HBTs). As with the more traditional use of DALYs, the main advantage of using DALYs as HBTs is the ability to account for differential disease severity, identify the most appropriate public health interventions, and measure the positive and negative outcomes of these interventions. Australia is currently considering adopting DALYs for setting HBTs for drinking water quality, as recommended by the WHO. Adoption of DALY HBTs could be relevant in other areas, including air quality, food safety, health care-associated infections, and surgical complications. In the context of the recent release of the 2010 GBD study,2 we explore the novel use of DALYS to determine health-based targets (HBTs).Following the 1990 Global Burden of Disease (GBD) study,3 DALYs are the sum of years of life lost (YLL) due to premature death and years lost due to disability (YLD) for incident cases of the particular health condition in a population (DALY=YLL+YLD). Calculation of YLL requires information on the number of people who died from the disease and their life expectancy at age of death. YLD incorporates the number of incident cases, symptom duration, and symptom severity . Differing health outcomes for a single health condition  can be incorporated into the DALY model.DALYs measure the population impact of specific health conditions, accounting for both premature death and morbidity. One DALY equates to 1 lost year of ‘healthy' life. The DALY metric quantifies the gap between a population's current health status and an ideal where everyone lives to advanced age, free from disease and disability.4,5The DALY metric has been used for quantification and comparison of the burden of diseases in a population; comparison of disease burdens between countries, regions, and population groups; comparison of the impact of risk factors  on disease burden; and prioritisation and evaluation of public health interventions.6 Acute gastroenteritis has four possible courses – mild, moderate, or severe disease, and death. In addition, gastroenteritis caused by certain pathogens  can be followed by sequelae such as Guillain-Barré syndrome, reactive arthritis, and irritable bowel syndrome.7 The contribution of these sequelae to the disease-specific DALY/case can exceed that of the acute gastroenteritis.8 By considering the frequency and duration of different possible disease outcomes and the relevant disability weights, the average DALY/case can be calculated for each reference pathogen. Different pathogens have different average DALY/case impacts because of their unique morbidity and mortality characteristics.When DALYs are used to set HBTs, it is necessary to nominate a tolerable population DALY burden, or acceptable risk; calculate the average burden of a single case of disease (the DALY/case); and determine the tolerable number of disease cases see . As with6,9 They promote the use of DALYs to determine HBTs, stating that provision of safe drinking water should involve: (i) setting HBTs; (ii) ensuring adequate and properly managed systems; and (iii) providing independent surveillance. The tolerable disease burden set in the GDWQ is 10−6 DALYs per person-year, meaning that each reference pathogen in drinking water should not cause the loss of more than 365 healthy days in a population of one million people in a year.6 Reference pathogens are chosen to represent viruses, bacteria, and protozoa, based on criteria that include: being sufficiently well characterised in terms of dose-response, infectivity, and disease outcomes; occurrence in source waters and sensitivity to removal or inactivation by treatment processes; and having a high public health impact.6,10 To determine the level of water treatment required to meet this HBT, DALY/case values for each reference pathogen and the tolerable number of water-related disease cases caused by that pathogen must first be defined. Quantitative microbial risk assessment (QMRA) is then applied to determine the likelihood of infection or illness following exposure to the reference pathogen in drinking water. Finally, pathogen surveillance data for source waters is combined with QMRA and DALY/case data to quantify the amount of source water treatment required to achieve adequate pathogen reduction to meet the HBT.The WHO Guidelines for Drinking Water Quality (GDWQ) define safe drinking water as ‘not representing any significant risk to health over a lifetime of consumption'.9 no country has adopted this approach in national drinking water or other health-related guidelines, other than the Australian Guidelines for Water Recycling (AGWR).11 The current Australian Drinking Water Guidelines provide quantitative (non-DALY) health-based guideline values for chemical and radiological water contaminants, but lack quantitative targets for microbial water quality.12 In Australia, therefore, quantitative microbial HBTs are currently defined if highly treated sewage effluent, stormwater, or greywater is used to supplement drinking water supplies (covered in the AGWR), but not for drinking water drawn from conventional water sources.Although the WHO GDWQ first published in 2004 the recommendation for use of DALYs in setting HBTs for drinking water quality,annual infection risk approach, with an accepted risk of one infection per 10 000 person-years. This target relates only to infection, not to the occurrence, severity, or outcome of symptomatic disease. Similar to the DALY/case approach, the annual infection risk approach identifies reference waterborne gastrointestinal pathogens, uses QMRA to determine the likelihood of infection following exposure, and applies surveillance data concentrations to quantify the required pathogen reduction.An alternative HBT used in water safety guidelines by the US Environmental Protection Agency, Health Canada, the Netherlands, and New Zealand is the Staphylococcus aureus, and Clostridium perfringens; whereas the greatest population disease burden (DALYs) were attributed to Toxoplasma gondii, Campylobacter, rotavirus, norovirus, and Salmonella.8 Differences were due to differential disease severity, age at death for fatal cases, and disease burden from sequelae related to these pathogens, resulted in Campylobacter causing a higher average disease burden per case (41 DALYs per 1000 cases) than rotavirus (4·9) or norovirus (2·4). Differences in impact-ranking of pathogens are even more pronounced if number of infections (rather than number of symptomatic cases) is compared with DALYs. The prevalence of asymptomatic norovirus infection has been reported at 12 per cent among healthy individuals in England.13 Therefore, if norovirus were used as a reference pathogen to set HBTs using either an annual infection or DALY/case approach, more water treatment resources would be consumed to reduce the norovirus load to meet the annual infection target (because of high numbers of asymptomatic and relatively mild cases) compared with the DALY/case approach (relatively low DALY/case for norovirus). When used to set water-related HBTs, the DALY/case approach might reduce requirements for unnecessary and costly water treatments.6 An additional advantage of the DALY/case approach is that it can compare potential public health impacts posed by disparate health risks , along with health impacts and economic costs of proposed interventions.6,14 Furthermore, the application of DALYs as HBTs is not limited to water guidelines; other potential areas include air quality, food safety, health care-associated infections, and surgical complications. Use of DALY HBTs for non-microbial health conditions, such as those associated with exposure to radiation or chemicals, is currently limited due to knowledge gaps.6When used for setting microbial HBTs, the DALY/case approach takes into consideration the potential public health impact of each pathogen, whereas the annual infection approach treats all pathogens as equally significant. In a study examining the disease burden attributable to foodborne pathogens in the Netherlands in 2009, the highest number of disease cases were attributed to norovirus, rotavirus, 15 Second, HBTs are often somewhat arbitrary and require a degree of value-judgement, which may be country- or situation-specific .16 Similarly, disability weights used in different studies vary and revised disability weights from the 2010 GBD study were recently released.2,17 Inherent uncertainties in DALY estimates are due to limited data on number, duration, and potential for sequelae following disease cases of each severity.8 In addition, there are uncertainties in QMRA models and insufficient data regarding pathogen concentrations in source waters (necessary elements for implementation of DALY HBTs).6,10 Use of HBTs requires selection of reference conditions and extrapolation of DALY/case estimates to other related conditions: for water guidelines, water treatment requirements for an entire class of pathogens  are based on DALY/case calculations for a single reference pathogen within each class, relying on the premise that water treatment options that control the reference pathogens are expected to control other important pathogens within each pathogen class.10 Uncertainties regarding use of DALY HBTs also apply to other HBT approaches such as the annual infection approach, including the judgement-based nature of determining tolerable risk, QMRA uncertainty, and the use of reference pathogens to represent an entire pathogen class.There are limitations to using DALYs in setting HBTs. First, this was not the intended use of the DALY metric, as it was developed to quantify the population burden of disease and injury.18 as has been recommended by the WHO.6 Adoption of DALY HBTs could also be relevant in other areas.In conclusion, while DALYs were developed and have been widely used to compare diseases within and between populations and to prioritise and evaluate public health interventions, this metric can also be used to set meaningful HBTs. As with the more traditional use of DALYs, the main advantage of using DALYs as HBTs is the ability to account for differential disease severity and to prioritise and measure public health interventions more meaningfully. Australia is currently considering adopting DALYs for setting HBTs for drinking water quality,


The causes of autism spectrum disorders (ASD) remain largely unknown and widely debated; however, evidence increasingly points to the importance of environmental exposures. A growing number of studies use geographic variability in ASD prevalence or exposure patterns to investigate the association between environmental factors and ASD. However, differences in the geographic distribution of established risk and predictive factors for ASD, such as maternal education or age, can interfere with investigations of ASD etiology. We evaluated geographic variability in the prevalence of ASD in central North Carolina and the impact of spatial confounding by known risk and predictive factors.Children meeting a standardized case definition for ASD at 8 years of age were identified through records-based surveillance for 8 counties biennially from 2002 to 2008 (n=532). Vital records were used to identify the underlying cohort , and to obtain birth addresses. We used generalized additive models (GAMs) to estimate the prevalence of ASD across the region by smoothing latitude and longitude. GAMs, unlike methods used in previous spatial analyses of ASD, allow for extensive adjustment of individual-level risk factors  when evaluating spatial variability of disease prevalence.P=0.003). However, geographic gradients of ASD prevalence were attenuated after adjusting for spatial confounders .Unadjusted maps revealed geographic variation in surveillance-recognized ASD. Children born in certain regions of the study area were up to 1.27 times as likely to be recognized as having ASD compared to children born in the study area as a whole  range across the study area 0.57-1.27; global In these data, spatial variation of ASD in central NC can be explained largely by factors impacting diagnosis, such as maternal education, emphasizing the importance of adjusting for differences in the geographic distribution of known individual-level predictors in spatial analyses of ASD. These results underscore the critical importance of accounting for such factors in studies of environmental exposures that vary across regions. Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by impaired social interaction and communication, and restrictive and repetitive behavior. EstimatOne problem with evaluating the geographically non-random prevalence of ASD for etiologic purposes lies in difficulties disentangling the geographic distribution of other factors associated with diagnosis,11. For Two previous studies investigated geographic variability of ASD as a means of identifying environmental exposures related to ASD prevalence,16. BothIn order to determine the potential for environmentally distributed exposure to be associated with ASD in central North Carolina (such as contaminants in air or water), we first explored whether spatial differences in ASD prevalence existed and then whether differences remained after accounting for spatially distributed covariates associated with ASD risk and diagnosis. We used a method of spatial epidemiology that applies generalized additive models (GAMs) to assess the spatial variation of disease in a region while simultaneously adjusting for other geographically distributed individual-level factors,18 such The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active, population-based surveillance program that monitors the prevalence of developmental disabilities among children aged 8 years, an age by which most children with ASD have been evaluated, in seleTo represent the underlying population, we randomly selected a 15% sample of birth records for children born in the same study counties and years as children included in ADDM . FigureTo fully explore the impact of spatial confounding on the geographic distribution of developmental disability, we considered 4 different disability groups: all children with an ASD, 2 subgroups within all ASD classified by the co-occurrence of ID (ASD+ID and ASD-ID), and the independent group of all children with ID without regard to ASD status. Examining these independent and cross-classified groups provided a more nuanced disentanglement of factors which may act differently to promote ASD, versus ID, recognition, as follows. Diagnosis of ASD requires comprehensive evaluation of a constellation of behaviors that can be more involved than a singular evaluation assessment of Intelligence Quotient (IQ) to determine ID. Yet, ASD often occurs with ID, frequently presenting more severe disability that is recognized at an earlier age. In addition, Durkin et al. (2010) reported a differential socioeconomic (SES) gradient in ASD prevalence by the presence or absence of ID; SES acts as a stronger risk factor for ASD-ID compared to ASD+ID. BecauseTM criteria for Autistic Disorder, Asperger Disorder, or Pervasive Developmental Disorder Not-Otherwise-Specified[Children met the standardized case definition for ASD if clinician reviewers determined their developmental evaluation records indicated behaviors consistent with ASD, based on the Diagnostic and Statistical Manual IVpecified. Childrepecified, Differepecified, Stanforpecified, Wechslepecified, and thepecified, or, in pecified. Our anaSurveillance data were linked to birth records to obtain the residential address and covariate information at the time of birth of children with ASD and ID. Birth data were chosen to reflect the most etiologically relevant time period for brain development.We combined several methods to geocode (i.e. assign latitude and longitude coordinates) the residential birth addresses of study children to improve geocoding accuracy and reduce positional errors. First, We estimated the log odds of ASD and ID using GAMs, an extension of linear regression models that can analyze binary outcome data and accommodate both parametric and non-parametric model components. For nonWe used a locally weighted regression smoother (loess) which adapts to changes in the data density that are likely to occur in analyses of residential locations due to variability in population density. To predict prevalence the loess smoother utilizes information from nearby data points (weighting information based on its distance from the prediction point). The region or neighborhood from which data are drawn to predict prevalence is based on the percentage of data points in the neighborhood and is referred to as the span size. Choice of span size is a trade-off between bias and variability. A larger span size (more data included) results in a flatter surface with low variability but increased bias, while a small span size results in high variability and comparatively low bias. We determined the optimal amount of smoothing , by minimizing Akaike’s Information Criterion (AIC),18. A laWe created a grid covering the study area that extended across all latitude and longitude coordinates of all addresses. We excluded grid points in regions of the study area where no children in our sample were born. The resulting grid comprised approximately 4,300 points. We predicted the log odds for each of the 4 developmental outcome groups (e.g. ASD) at each point on the grid and calculated an odds ratio using the entire study area as the referent group; the odds at each point was divided by the odds from a reduced model which omitted the latitude and longitude smooth term. We did To provide information in the interpretation of spatial patterns that could be driven by sparse data, we preformed a 2-step statistical screening procedure, as follows. First, we tested the null hypothesis that developmental disability does not depend on geographic location, generally . Residential locations of individuals were permuted 999 times while preserving their case status and covariates [as described in. In eachStatistical analyses were performed in the R Package 2.12.02  using the gam library and a local scoring algorithm GAM estimation procedure and publically available statistical code,33. All We adjusted models for several previously established ASD predictive factors including year of birth; plurality; maternal age, race/ethnicity, and level of education; and report of tobacco use during pregnancy  similarities rather than geographically-linked factors. To assess the robustness of our results to including a small number of sibling groups, we conducted secondary analyses including only one randomly selected child per family. Families were defined as children for whom the mother had the same first and maiden name and date of birth (obtained from birth certificates). Because information for fathers was missing and incomplete on many birth records, we did not attempt to identify paternal siblings.Selected characteristics for the birth cohort and children with ASD or ID are displayed in TableP=0.003; TableP=0.052; TableWe found geographic variability in ASD prevalence across the study area in unadjusted analyses, as indicated by the global statistical test , a similar range of prevalence ratios, and were visually very similar to the fully adjusted maps. When we examined the patterns of maternal educational attainment and age across the study area, both were similar to the unadjusted ASD pattern. For example, mothers living in the areas where the unadjusted ASD prevalence was highest were approximately 1.75 times as likely to have completed college than women in the study area as a whole ; but these same mothers were less likely than mothers with some postsecondary education to have a child with ASD + ID .Among the 532 children with ASD, 214 (40.22%) also had an ID. The spatial patterns of both subgroups (ASD+ID and ASD-ID) were similar to each other and to the map of the combined group ; the locations of increased prevalence and the intensity of the increases were similar across all maps (TableP < 0.001). Geographic gradients in prevalence ratios were somewhat attenuated in the adjusted analyses, however, patterns of residual variability in the prevalence of ID remained after accounting for known predictors . Additionally, although adjusting for spatial confounding resulted in a larger span size, the optimal span size of the adjusted analyses remained small (0.30), indicating spatial variability; however the adjusted analyses did not reach global statistical significance at the alpha = 0.025 level.When ID was analyzed as a separate disability, unadjusted analyses revealed significant spatial variability in prevalence across the study area; several areas of increased and decreased ID prevalence were observed .Although we observed spatial variability in ASD prevalence in unadjusted analyses, the pattern of ASD appeared to be largely explained by factors influencing diagnosis -- maternal age and education -- which differed across the study area. The larger optimal span size and global p-value in the adjusted analyses, as well as decreased variability in prevalence ratios across the study area, all indicated less geographic variability after adjustment for known risk and predictive factors for ASD. Our results corroborate previous reports,16 demonOur results highlight the importance of adjusting for the geographic distribution of known individual-level predictors in spatial analyses. Here, adjustment for socioeconomic factors associated with diagnosis greatly attenuated geographic variability in ASD prevalence. This has implications for studies of ASD etiology that assign environmental exposures based on geography, such as air pollutants and agricultural pesticides, for which we caution the causal interpretation of geographic patterns that are not controlled for individual-level factors. Using GAMs allowed us to carefully account for known risk and diagnostic factors, a major strength of these analyses. In addiNC-ADDM Network provided a large population based sample with information on co-occurring conditions, allowing us to consider differences in spatial confounding by the severity and type of disability. Patterns for separate disability groups, ASD+ID and ASD-ID, were visually similar to those for all ASD; however, ASD-ID appeared to be more impacted by spatial confounding as indicated by a greater attenuation in prevalence ratios and a increase of the optimal span size in the adjusted analysis. The associations between ASD (+/−ID) and maternal education and age that we observed in these analyses are consistent with previously reported associations in non-spatial analyses,4 which Although the global significance test did not indicate variability, our results suggest that ID prevalence varied geographically across the study area; even after adjusting for known spatial confounders the optimal span size remained small and results were visually suggestive of geographic differences in ID prevalence. There are several possible explanations for the observed variability in ID, including residual confounding by unmeasured variables and differences in the distribution of environmental factors across the study area.Linking data from the NC-ADDM Network and vital records also strengthened our analyses. Vital records provided individual-level data on a number of covariates, allowing us to account for spatial confounding by these factors, and also provided residential location at the time of birth, which may be more relevant to ASD etiology than the address at diagnosis. Although the majority of children with ASD at age 8 in ADDM were also born in the study area, local changes in address were common . If the spatial patterns we observed are due to difference in diagnosis, spatial variability may be more apparent using a later address corresponding to the time of diagnosis.A final strength of our study was our ability to evaluate the influence of potential sibling clusters in analyses. While it is often suggested that including siblings in analyses will induce clustering, we did not observe this pattern in our data. One possible explanation is that the number of siblings in our analyses was relatively small , due in part to the biennial study design and the selection of only part of the source population (15%).There are also several important limitations of our methods. We chose the optimal tradeoff between bias and variance of the smooth  by minimizing the AIC. Selecting the optimal span size for a dataset, however, may obscure important small scale variability in maps; it is possible that our analyses were conducted on a scale too large to identify small scale environmental exposures relevant in the etiology of ASD. Examining different span sizes may reveal important features of the data. Similarly, we assessed spatial confounding by visually comparing maps of prevalence before and after adjustment holding the span size and included observations constant and by investigating changes in the optimal span size before and after adjustment; howeverOur results demonstrate the importance of adjusting for predictive and diagnostic factors that may spatially confound the search for novel environmentally-distributed risk factors for ASD. These adjustment methods can help the search for causes of developmental disabilities proceed more efficiently by aiding the interpretation of geographic patterns. Cumulatively, our results suggest that known predictive factors for ASD account for a large portion of the observed geographic variability in prevalence in central North Carolina. Although we did not identify spatial variability in ASD in NC after controlling for known predictive and risk factors, follow up of these results in other regions is may provide clues for ASD etiology.AF: Additional file; APR: Adjusted prevalence ratio; ADDM Network: Autism and developmental disabilities monitoring network; AIC: Akaike’s information criterion; ASD: Autism spectrum disorders; ASD+ID: Autism spectrum disorders with intellectual disability; ASD-ID: Autism spectrum disorders without intellectual disability; ID: Intellectual disability; GAM: Generalized additive model; GIS: Geographic information systems; PR: Prevalence ratio; SES: Socioeconomic status.All authors declare that they have are no actual or potential competing interests.KH assisted in conceiving the study, conducted analyses, and drafted the manuscript. AK assisted conceiving the study and the analysis plan, and assisted in manuscript editing. VV collaborated on statistical issues, and assisted in the analysis plan and manuscript editing. JD, the principle investigator of the North Carolina Autism and Developmental Disabilities Monitoring Network, assisted in the analysis plan and manuscript editing. All authors read and approved the final manuscript.Figure S1. Mother's educational attainment at the time of birth n=11,034. Map reflects the optimal span size of the ASD analyses ; the optimal span size of the education analysis was 0.05 . Larger prevalence ratios indicate a higher prevalence of mothers with college or more education at the child’s birth. Areas of significantly increased and decreased risk are indicated by black contour bands. Figure S2. Adjusted maps for (A) ASD prevalence , (B) ASD-ID , and (C) ASD+ID . Maps are not significantly different than flat . Adjustment factors were year of birth; plurality; maternal age, race, and level of education; and report of tobacco use during pregnancy.Click here for file


The tumor microenvironment is acidic due to glycolytic cancer cell metabolism, hypoxia, and deficient blood perfusion. It is proposed that acidosis in the tumor microenvironment is an important stress factor and selection force for cancer cell somatic evolution. Acidic pH has pleiotropic effects on the proliferation, migration, invasion, metastasis, and therapeutic response of cancer cells and the function of immune cells, vascular cells, and other stromal cells. However, the molecular mechanisms by which cancer cells and stromal cells sense and respond to acidic pH in the tumor microenvironment are poorly understood. In this article the role of a family of pH-sensing G protein-coupled receptors (GPCRs) in tumor biology is reviewed. Recent studies show that the pH-sensing GPCRs, including GPR4, GPR65 (TDAG8), GPR68 (OGR1), and GPR132 (G2A), regulate cancer cell metastasis and proliferation, immune cell function, inflammation, and blood vessel formation. Activation of the proton-sensing GPCRs by acidosis transduces multiple downstream G protein signaling pathways. Since GPCRs are major drug targets, small molecule modulators of the pH-sensing GPCRs are being actively developed and evaluated. Research on the pH-sensing GPCRs will continue to provide important insights into the molecular interaction between tumor and its acidic microenvironment and may identify new targets for cancer therapy and chemoprevention. In the athymic nude mouse tumor model or TRAMP prostate cancer mouse model, systemic basic buffer therapy was used to increase the pH of the body and tumor microenvironment with the overall goal of reducing tumor development and metastasis (Ibrahim Hashim et al., Acidosis in the tumor microenvironment has also been exploited to specifically deliver cancer therapeutics and imaging agents to the tumor sites (Vavere et al., Since GPCRs are important pharmaceutical targets (Jacoby et al., All authors contributed to data collection and manuscript writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


However, biomedical research has not been the primary focus in these countries even though such activities are likely to produce economic and health benefits for all. Here, we propose several recommendations and guidelines to facilitate participation of developing countries in genetic variation data documentation, ensuring an accurate and comprehensive worldwide data collection. We also summarize a few well-coordinated genetic data collection initiatives that would serve as paradigms for similar projects. Hum Mutat 31:1–8, 2010. © 2010 Wiley-Liss, Inc.Developing countries have significantly contributed to the elucidation of the genetic basis of both common and rare disorders, providing an invaluable resource of cases due to large family sizes, consanguinity, and potential founder effects. Moreover, the recognized depth of genomic variation in indigenous African populations, reflecting the ancient origins of humanity on the African continent, and the effect of selection pressures on the genome, will be valuable in understanding the range of both pathological and nonpathological variations. The involvement of these populations in accurately documenting the extant genetic heterogeneity is more than essential. Developing nations are regarded as key contributors to the Human Variome Project (HVP;  The recent elucidation of the genome sequence of several individuals, such as Causacians , a large number of which reside in developing countries. Despite the fact that data content is rather homogeneous, facilitated by the existence of an off-the-shelf database management system , because access to specific cases is password-protected [Zlotogora et al., The depth of the ethnic and geographic origin data should be determined in advance, particularly in the case of small villages where carriers of rare variants could be identified even if personal information were not provided. In this case, data donors should be well informed and provided with an explanation as to why their data documentation is useful and how their privacy is secured. These individuals should consent to the inclusion of their genetic information in the database and reserve the right to withdraw their data from the database whenever they desire. This is particularly important for persons unable to consent because of disability or young age. Standardized consent forms need to be translated to different local languages and/or dialects.Finally, these databases would also benefit from some independent/external ethical review, perhaps from an international group (HGVS or HVP) who could advise them accordingly.By definition, a nation-wide genomic project is a national multicentre initiative to determine the underlying genetic heterogeneity of a population with the goal to ascertain the genetic variation leading to common or rare inherited diseases. Such initiatives consist of three parts: (1) documenting the genetic heterogeneity that has already been reported in the published literature, (2) generating new genetic data by screening a large proportion of the population using high throughput genotyping approaches, and (3) accumulating data causing inherited disease from hospitals, laboratories, and other healthcare facilities. In every case, except perhaps (3), a large national genetic database/portal is being developed to accommodate the sheer amount of data gathered. To date, there are few nation-wide genomic projects in various developing countries that are currently in progress. These projects (summarized in http://www.geenivaramu.ee/index.php?lang = eng) is a research venture of the University of Tartu initiated in 2001 [Metspalu, The Estonian Genome Project  is a consortium activity established in 2003 to document the inherent genetic variability of the Indian subpopulations as a first step toward identifying genetic biomarkers to understand susceptibility for any genetic disease and population migration, pharmacogenomic markers to understand variable drug response. The Indian Genome Variation (IGV) consortium aims to provide data on validated SNPs and repeats, both novel and reported, along with gene duplications, in over 1,000 genes , in 15,000 individuals drawn from Indian subpopulations [Indian Genome Variation Consortium, The Indian Genome Variation database , integrated within a research laboratory, which is focused on delivering state-of-the-art diagnostic service for the Kuwaiti population. These services, which focus on autozygosity mapping in families with consanguineous marriages, provide the research laboratory with a unique opportunity to identify novel genes in autosomal recessive disorders. Moreover, various unique cases suffering from cancer are currently being analyzed using the Affymetrix Array 6.0 microarray technology to identify copy number changes and homozygosity stretches. The data generated from these studies are deposited in CAGS database (see above), and LOVD, whereas the Kuwaiti NEMDB has been recently established databases to encourage data storage for genetic diseases in different subpopulations in Kuwait.Kuwait established within the Faculty of Medicine, Department of Pathology a Molecular Genetics Diagnostic Service Division (http://ngrl.org.uk/Manchester/dmudb.html) provides a route for sharing mutation data within and between diagnostic laboratories in the United Kingdom to support genetic testing services for patients. Currently DMuDB has over 4,884 records for 33 genes, namely Breast Cancer , Lowe Syndrome (OCRL), Sotos Syndrome (NSD1), HNPCC , cystic fibrosis (CFTR), X-linked retinitis pigmentosa (XLRP), neurofibromatosis, Types I and II , Alstrom Syndrome (ALMS1), CADASIL (NOTCH3), familial adenomatous polyposis (FAP), and muscular dystrophy (DMD), containing over 10,985 individual variants.The United Kingdom has developed a central database to collect all UK genome variation data, and their effects, from participating diagnostic laboratories. The diagnostic mutation database  is an international multidisciplinary, scientific organization with a mission “... to improve the quality of care of patients and their families with any condition resulting in hereditary gastrointestinal tumours.” The InSiGHT consortium maintains a LOVD-based database for genetic variations for the EPCAM, MLH1, MLH3, MSH2, MSH6, MUTYH, PMS1, and PMS2 genes leading to gastrointestinal tumors and encourages the establishment of national repositories for patients suffering from gastrointestinal tumors, particularly in developing countries.The International Society for Gastrointestinal Hereditary Tumours  is a European Commission-funded project that comprises a network of all major European research institutions active in the field of molecular and clinical research of thalassemia and related hemoglobinopathies [Lederer et al., http://globin/bx.psu.edu/hbvar) [Patrinos et al., The International Thalassemia Network  is a European Consortium, funded by the European Commission, aiming to expand the human expertise in clinical genetics in Mediterranean Partner Countries (MPC) through the transfer of knowledge and technology between the two rims of the Mediterranean that share a common burden of genetic diseases. Among the actions foreseen by MEDGENET is the building of Medical Genetics databases for the various partner countries. Several NEMDBs are built from scratch, such as the Tunisian and Egyptian NEMDBs or expanded from the existing NEMDBs, such as the Israeli [Zlotogora et al., The MEDGENET project (http://www.pgeni.org) that aims to determine the frequencies of the commonest pharmacogenomic markers in various populations, particularly from developing countries worldwide.The Pharmacogenomics for Every Nation Initiative  or the Biomaterial Banking Medical Research Initative (BBMRI) in Malta, which of course lie at the borderline of the nation-wide genomic projects described above.Finally, there are a few nation-wide DNA biobanks, such as the National Laboratory for the Genetics of Israeli Populations, representing a national repository for human cell lines and DNA from the unique and large ethnic variation of the Israeli populations  represents such initiative that have already received funding from the EC and aims to unify human and model organism genetic variation databases toward increasingly holistic views into genotype-to-phenotype data, and to link this system into other biomedical knowledge sources via genome browser functionality. Linking population and ethnic-specific information into LSDBs and diagnostic databases, creating NEMDBs and developing genomic databases, similar to the Indian Genome Variation database are key activities for the main GEN2PHEN work packages. Obviously, other strategically minded funding agencies , charities, and foundations would also launch similar calls. Recently the Australian Node of the HVP has been funded to pilot software for data flow from hospitals/clinics via country specific databases to LSDBs and NCBI/EBI/UCSC browsers (unpublished). Involving universal organizations such as the WHO and UNESCO in the fund-raising project will clearly have a strong impact.Funding for collecting genetic variation data has traditionally been difficult due to the extreme fragmentation of the field [Patrinos and Brookes, On the other hand, the development of comprehensive analyses of human genetic variation often reaches a barrier in the form of the reward system for clinicians and academic researchers. First of all, database entries could be made a mandatory quality control standard for clinical laboratories and clinicians. Notably, according to a new initiative of the Israeli government, genetic laboratories are mandated to report the details of the tests they are performing in the Israeli NEMDB in order to obtain accreditation from the Israeli Ministry of Health [van Baal et al., http://www.sage-hindawi.com/journals/hgp), which is affiliated with FINDbase (http://www.findbase.org) [van Baal et al., Human Genetics has been accepting mutation data and this is linked to HGMD (http://www.hgmd.org).For researchers, a publication or Web-based system establishing microattribution and community annotation of mutations and cited data will enable measurable contributions to the scientific knowledge base [Anonymous, Journals, tenure, and promotion committees, and funding agencies would be encouraged to cite these contributions to and citations of LSDB and international national databases [Patrinos and Brookes, As stated above, documenting population/ethnic-specific data in developing countries are among the primary objectives of the HVP that appreciates the genomic sovereignty/equality for all countries to be involved and acknowledges the value of “human capital” within all populations. Real and tangible benefits of the HVP to improve health will be generated for participating populations. Hence, the voluntary participation of the greatest number of countries would ensure a more general applicability, and it is hoped that many countries will eventually decide to participate.