Women with diminished ovarian reserve often respond poorly to controlled ovarian stimulation resulting in retrieval of fewer oocytes and reduced pregnancy rates. It has been proposed that pre-IVF Dehydroepiandrosterone (DHEA) adjuvant therapy may improve ovarian response and pregnancy rates in women with diminished ovarian reserve. This meta-analysis aims to investigate efficacy of DHEA as an adjuvant to improve ovarian response and IVF outcome in women with diminished ovarian reserve. Electronic databases were searched under the following terms: (DHEA) and (diminished ovarian reserve) and/or (poor response). Studies were included if they reported at least one of the following outcomes; clinical pregnancy rate, number of oocytes retrieved, miscarriage rate. We identified 22 publications determining effects of DHEA in clinical trials. Only 3 controlled studies were eligible for meta-analysis. There was no significant difference in the clinical pregnancy rate and miscarriage rates between women pre-treated with DHEA compared to those without DHEA pre-treatment . The number of oocytes retrieved  was significantly lower in the DHEA group. In conclusion, based on the limited available evidence from a total of approximately 200 IVF cycles, there are insufficient data to support a beneficial role of DHEA as an adjuvant to controlled ovarian stimulation in IVF cycle. Well-designed, randomised controlled trials as well as more exact knowledge about DHEA mechanisms of action are needed to support use of DHEA in standard practice for poor-responders. Ovarian ageing, as manifested by reduced ovarian reserve, is responsible for the well-established observation of age related decline in fertility ,2 and ofIt has been proposed that oral administration of Dehydroepiandrosterone (DHEA), an adrenal androgen, may have anti-ageing effects and may improve ovarian response and pregnancy rates in women with reduced ovarian reserve during IVF. Casson et al., in the year 2000, who had interest in the use of DHEA for hormone replacement therapy (HRT) were the first group that reported the benefits of DHEA supplementation for improving the response to ovarian stimulation in a case series . Since tA recent world-wide survey has shown that over a quarter 26%) of IVF clinicians add DHEA as an adjuvant to IVF treatment protocols in women with poor ovarian response % of IVF . While SWe searched EMBASE (1980 to December 2012), MEDLINE (1948 to December 2012), Pubmed and Cochrane Library for all relevant articles under the following Medical Subject Headings (MeSH) terms to generate subsets of studies; i) ‘DHEA’ or Dehydroepiandrosterone’, ii) ‘Poor response’ or ‘low response’, and iii) ‘Diminished ovarian reserve’ or ‘Premature ovarian aging’. Combining these subsets together (subset i with either ii or iii) by ‘AND’ to identify citations appropriate to the question ‘The effect of DHEA supplementation on ovarian stimulation outcomes in diminished ovarian reserve and/or poor responses patients’. The search also tracked on ISI conference abstracts as well as on-going randomised controlled trials registered on ISRCTN database. In addition, all primary papers’ bibliographies were explored to recognize cited publications which had not been identified by electronic-based searches. Only articles written in English were included in the meta-analysis. The searches were conducted by two reviewers independently (AN and KJ).The target population was either poor-responders or those with diminished ovarian reserve, as described above, who were undergoing ovarian stimulation plus IVF/ICSI. DHEA was supplemented before ovarian stimulation in the study group while neither was used in the control. The primary outcome was the clinical pregnancy rate and the secondary outcomes were oocyte yield (numbers of oocytes retrieved), miscarriage rate, live birth rate and aneuploidy rates.All full manuscripts were reviewed for the selection and exclusion of publications with predefined inclusion criteria by two reviewers (AN and KJ) independently. Extraction data for each study, e.g. study design, inclusion/exclusion criteria, population characteristics, definition of diminished ovarian reserve, stimulation protocol, and outcomes, was separately done by two of the authors (AN and KJ) using pre-determined tables and form. Disagreements about either article selection or data extraction were resolved by consensus or arbitration by a third reviewer (BKC). The Newcastle-Ottawa Scale (NOS) scoring system  was used2 statistic to quantify heterogeneity across studies [Relative risks (RR) from individual studies were analysed using random effects models . Heterog studies . StatistThe search yielded 38 publications of which 16 excluded by screening through titles and abstracts, including one paper that is not published in English. Full manuscripts were retrieved for the remaining 22 articles, which included 3 case series -23, 3 ca2< 1%), the study designs were completely different as one was a case control study and the other, a randomised controlled trial.Only two studies, one RCT  and one Similar to primary outcome, only two published controlled studies were eligible for analysis ,25. The Further literature review revealed one particularly retrospective study from Gleicher et al. (2009) which specifically examines miscarriage rates. In this study, they reported that DHEA supplemented pregnancies in women with diminished ovarian reserve had lower miscarriage rates when compared to the national United States IVF database  . Because2) among studies was observed  in the DHEA group. The miscarriage rate was similar between the DHEA and control groups on meta-analysis of the two reported controlled studies. This finding, however, is based on few data as there was only one study [While there are several self-controlled case series on reported significant benefits in terms of ovarian response and pregnancy rates with the use of pre-treatment DHEA adjuvant during IVF, this systematic review of controlled studies failed to demonstrate such a benefit. However, while noting the trend of a positive effect of DHEA on the pregnancy rate in this review, the lack of a significant difference may be because of a small sample size with the overall number of participants that are included in the meta-analysis is only 198. In the study of Barad et al. 2007 included in this review, the authors have also reported spontaneous pregnancy (n=6/16) and pregnancy following IUI (6/9), which occurred during the three to four months waiting time of pre-IVF DHEA adjuvant treatment . When thAt present, there is only a single small randomised controlled trial by Wiser et al. 2010 reported in literature . The smaMost data on the favourable effect of DHEA adjuvant supplementation currently come from the study group led by Barad and Gleicher at the Centre of Human Reproduction, New York. They have published a series of self-controlled studies and retrospective case control analyses in which the benefits of DHEA are summarized as follows; i) increased oocyte yield  ii) highThe data from the self-controlled studies should be interpreted with caution because of potential bias. In one review by Urman and Yakin, the authors retrospectively analysed IVF outcome in the second cycle of 801 patients who have history of poor ovarian response (production of ≤ 4 oocytes) in the first IVF cycle treatment in their centre. It was found that almost 40% of this cohort developed better response yielding more than 4 oocytes in their next cycle . These dThis systematic review did not include any self controlled studies, but included only the studies that had a group of contemporaneous controls. Our results in this review indicate that DHEA decreases the ovarian response as indicated by reduced number of oocytes retrieved at egg collection in the study arm. While this finding is surprising and it is difficult to come up with a scientific explanation, this systematic review is limited by a small number of treatment cycles included in the meta-analysis and by the heterogeneity of the included studies. On the contrary to the above finding, as indicated by trends of improving clinical pregnancy and of reducing miscarriage albeit no statistical significance, DHEA may have a positive effect on improving oocyte and embryo quality. It is already established that poor oocyte quality, which leads to producing poorer quality embryos, represents one of the clinical presentations of ovarian ageing . The finRecent meta-analysis which evaluated the effect of adjuvant androgens (DHEA or Testosterone) or androgen-modulating agents  in previous poor responders has failed to demonstrate any significant difference in the ongoing pregnancy rate, live birth rates, and numbers of oocytes retrieved when compared with the control group, who have had no adjuvant therapy . AnotherIn conclusion, our systematic review of the controlled studies on the effect of pre-treatment DHEA on IVF outcome in women with diminished ovarian reserve suggests that DHEA does not improve the quantitative ovarian response and pregnancy outcome. Based on these data, DHEA adjuvant therapy cannot be recommended in diminished ovarian reserve for improving IVF outcome. However, as the sample size in this analysis was small and the effect of DHEA on pregnancy rates approached close to statistical significance, further large scale multicentre randomised controlled studies are required to clarify the benefits of DHEA adjuvant therapy in routine clinical management of predicted poor responders.The authors declare that they have no competing interests.AN and KJ were responsible for the conception, design, literature identification/selection, data extraction, analysis and interpretation. Critical evaluation and resolving disagreements regarding selection, data extraction and analysis were done by BKC. All four authors  were responsible for writing the manuscript, revision of the article and statistical analyses. All authors read and approved the final manuscript.Amarin Narkwichean, M.D., M.Med.Sci., RTCOG, Currently a PhD student at the Division of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, United Kingdom & Clinical Lecturer, Faculty of Medicine, Srinakharinwirot University, Thailand. Walid Maalouf PhD, Lecturer in Embryology, Division of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, United Kingdom. Bruce Campbell PhD., DSc., Professor, Chair of Reproductive Physiology, Division of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, United Kingdom. Kannamannadiar Jayaprakasan, M.D., PhD., MRCOG., Honorary Associate Professor, Division of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, United Kingdom. Subspecialist in Reproductive Medicine and Fertility Unit Lead, Royal Derby Hospital, Derby.


Diabetes is one of the greatest public health challenges to face Australia. It is already Australia’s leading cause of kidney failure, blindness (in those under 60 years) and lower limb amputation, and causes significant cardiovascular disease. Australia’s diabetes amputation rate is one of the worst in the developed world, and appears to have significantly increased in the last decade, whereas some other diabetes complication rates appear to have decreased. This paper aims to compare the national burden of disease for the four major diabetes-related complications and the availability of government funding to combat these complications, in order to determine where diabetes foot disease ranks in Australia. Our review of relevant national literature indicates foot disease ranks second overall in burden of disease and last in evidenced-based government funding to combat these diabetes complications. This suggests public funding to address foot disease in Australia is disproportionately low when compared to funding dedicated to other diabetes complications. There is ample evidence that appropriate government funding of evidence-based care improves all diabetes complication outcomes and reduces overall costs. Numerous diverse Australian peak bodies have now recommended similar diabetes foot evidence-based strategies that have reduced diabetes amputation rates and associated costs in other developed nations. It would seem intuitive that “it’s time” to fund these evidence-based strategies for diabetes foot disease in Australia as well. How. How6]. It has been reported that a person with diabetes (type 1 or type 2) without complications costs Australia around $3,500 to $4,000 per year in healthcare costs, and this escalates to around $7,000 for people with microvascular complications, and $16,700 per year in people with microvascular and macrovascular complications ,36. AcutTable Australian burden of disease and mortality statistics Table  demonstrThe Australian Government and NHMRC have regularly commissioned best-practice guidelines for the management of various diabetes complications -23. EachHealth Insurance Act 1973 (Cth) provides access to services via Medicare benefits which are claimable only for ‘clinically relevant’ services provided by an appropriate health practitioner [National Health Act 1953 (Cth), “provides timely, reliable and affordable access to necessary medicines for Australians” [The cost of most of the NHMRC endorsed diabetes complication guideline recommendations are funded via the Australian Government’s MBS or PBS programs ,39. The titioner . The PBSassessments are publicly funded by the MBS scheme [management of diabetes complications, it appears that all but possibly one of the recommendations outlined for cardiovascular, kidney or eye disease are funded via the MBS; the exception appears to be intravitreal triamcinolone for persistent diabetes macular degeneration management [An examination of the best-practice guideline recommendations endorsed by the NHMRC for both assessment and management of diabetes and its complications reveals that all recommended S scheme -23,38. Inagement -23,38. I(i) total contact cast or other device rendered irremovable;(ii) topical hydrogel and wound dressings;(iii) appropriate footwear;(iv) topical negative pressure therapy; and(v) larval therapy for complex acute foot complication management ,38.Furthermore, it should be noted that the MBS schedule for podiatry consultation is capped at a maximum of five allied health consultations rebatable annually, and therefore, podiatry ‘competes’ with all other allied health consultations . Given tAn examination of all medications recommended for the management of diabetes-related complications suggests that all are publicly funded under the PBS system when prescribed by a medical or nurse endorsed prescriber -23,39,40In addition to PBS and MBS funding, the Federal Government in recent years has invested hundreds of millions of dollars into campaigns, programs, publications, research and/or additional resources  to manage the known complications of diabetes . The disIn reviewing the publicly available information, it is clear that the Australian Government has announced significant investment in the management of kidney, cardiovascular, and eye disease . This inA search for similar Australian Government funding announcements over the last decade failed to identify any significant additional funding announcements specifically addressing foot or lower limb disease . FurtherThis paper identifies that the burden of diabetes-related foot disease faced by the Australian population is the second largest of the four main diabetes complications in terms of burden of disease and numbers of people affected. In contrast, it appears that government funding of national best-practice management recommendations, and any additional government funding programs, ranks the funding of diabetes-related foot disease management as a distant last compared to the other diabetes complications. A summary of these findings can be found in Table Although it would appear that the Australian government has yet to specifically focus on reducing the burden of diabetes-related foot disease, there somewhat promisingly appears to have been an acceleration in the number of recent strategic publications released by national peak consumer, health professional and research bodies targeting the improvement in the prevention, assessment and management of diabetes-related foot disease ,18,23,43The NHMRC endorsed diabetes foot guidelines compiled by national diabetes research, clinical and consumer experts, under the auspices of the Baker IDI Heart & Diabetes Institute and George Institute, suggest that “a co-ordinated, national, multi-faceted, systems approach for implementation (of the guideline) is considered essential” . It reco(i) funding and policy development to support timely access to health professionals and multi-disciplinary foot teams for people with high-risk and acute foot complications; in particular access to podiatrists, nurses and aboriginal health workers;(ii) further training for allied health professionals to assess ulcer risk, wound debridement, appropriate wound dressing and pressure reduction, and;(iii) electronic decision support tools for medical practitioners, allied health professionals and aboriginal health services .Australian Diabetes Foot Network (ADFN), a multi-disciplinary steering committee on diabetes-related foot disease, recently published a six point strategic plan to reduce Australian lower limb amputations in people with diabetes [The Australian Diabetes Society’s diabetes . The pladiabetes . Their s(i) improved access to foot care via MBS for people with foot complications;(ii) subsidies for evidence based treatments including pressure off-loading devices and medical grade footwear;(iii) standardised national model for multi-disciplinary foot teams(iv) national accreditation of multi-disciplinary foot clinics and health professionals;(v) improving holistic diabetes care initiatives to “close the gap” on inequities in diabetes foot outcomes for indigenous Australians, and;(vi) reporting of national incidence and outcomes of diabetes-related foot disease .Interestingly, the previous Australian Diabetes Society (2000)  and natiIn an attempt to provide practical implementable solutions within the constraints of the current MBS and PBS systems, the Australasian Podiatry Council  submitte(i) implementing an annual national diabetes amputation rate report;(ii) increasing access to podiatrists via MBS from a maximum of 5 visits to an average of 12 for those with diabetes-related foot complications and foot ulcers;(iii) subsidising pressure off-loading devices for those with past or present foot ulcers; and(iv) increasing access to MBS services for indigenous Australians with diabetes-related foot complications via indigenous health workers .Subsequently, the peak national consumer body representing people with diabetes, Diabetes Australia, mirrored some of the recommendations of these plans in their recently released Diabetes National Election Agenda report (2012) . The Dia(i) increasing access to MBS allied health visits from 5 – 12 for people with diabetes;(ii) funding National Accredited Diabetes Centres (including multi-disciplinary teams), and;(iii) providing all people with diabetes a comprehensive annual risk assessment .This translates to up to ten national peak health professional, research and consumer bodies recommending similar strategies to reduce diabetes-related foot complications and amputation in this country ,18,23,43(i)  increasing access to podiatry, nursing, indigenous health workers and other allied health services via MBS;(ii)  subsidising evidenced-based treatments such as pressure off-loading devices via government funding;(iii)  implementing standard models of multi-disciplinary foot care teams across the nation;(iv)  reporting and monitoring of annual national diabetes foot disease rates, and;(v)  urging the increased uptake of evidence-based guidelines ,18,23,43These common strategies when implemented in other countries appear to significantly reduce diabetes-related amputation rates and costs -54. ManyOverall, the burden of diabetes-related foot disease in Australia is high and funding evidence-based diabetes-related foot management seems to significantly reduce this burden when implemented in other comparable nations. This simple yet very effective strategy, of funding evidence-based recommendations, also appears to have enjoyed success in other Australian diabetes complications in terms of reducing devastating diabetes complication outcomes in Australia. It would therefore seem intuitive to follow this same strategy and ensure that at a minimum all national best-practice guideline recommendations on the management of diabetes complications are publicly funded to reduce the significant associated morbidity and mortality faced in Australia and improve the limbs and lives of Australians with diabetes.Diabetes has been rated as one of the greatest public health challenges to face Australia. This paper has demonstrated that diabetes-related foot complications, in comparison to other diabetes complications, make up a considerable portion of the diabetes-related burden of disease in Australia. In contrast to other diabetes complications, it appears that a very low number of national best-practice recommendations have been incorporated into publicly funded models of care, and that foot disease lacks any additional public funding. These conspicuous gaps may significantly contribute to the poor outcomes of diabetes-related foot complications facing Australia in comparison to other Australian diabetes complications and international diabetes-related foot disease outcomes. In the spirit of unanimous UN action on diabetes, the promising diabetes-related foot results seen in other nations, and the constant urging of multiple diverse national peak bodies, it seems like “its time” to equally invest in diabetes-related foot disease in Australia.Medical Journal of Australia article cited in this manuscript. PAL, JRR and AS are board members of the Australasian Podiatry Council and were involved in the drafting of the Australasian Podiatry Council Budget Submission cited in this manuscript. PAL was a member of the guidelines advisory committee that oversaw the development of the NHMRC diabetes foot guideline cited in this manuscript. The Australasian Podiatry Council co-funds the Journal of Foot and Ankle Research.PAL and JMG were members of the Australian Diabetes Foot Network and along with SMB co-authored the PAL conceived, designed, searched literature, contributed to discussion, wrote and reviewed/edited the manuscript. JMG searched literature, contributed to discussion, wrote and reviewed/edited the manuscript. JRR, AS, SMB searched literature, contributed to discussion and reviewed/edited the manuscript. All authors read and approved the final manuscript.


Public health interventions and surveillance and response systems can contribute to disease control. Detection and control of emerging infectious diseases in conflict situations are major challenges due to multiple risk factors known to enhance emergence and transmission of infectious diseases. These include inadequate surveillance and response systems, destroyed infrastructure, collapsed health systems and disruption of disease control programs, and infection control practices even more inadequate than those in resource-poor settings, as well as ongoing insecurity and poor coordination among humanitarian agencies. This article outlines factors that potentiate emergence and transmission of infectious diseases in conflict situations and highlights several priority actions for their containment and control. An emerging infectious disease is one that is either newly recognized in a population or involves a recognized pathogen affecting new or larger populations or geographic areas (Conflict situations are characterized by war or civil strife in a country or area within a country. Affected populations may experience defined periods of violence (weeks to months), ongoing or recurrent insecurity in a protracted conflict (years to decades), or long-term consequences of a previous  war.Conflict may lead to the displacement of large populations into temporary settlements or camps with overcrowding and rudimentary shelters, inadequate safe water and sanitation, and increased exposure to disease vectors during the acute phase of the emergency. In protracted and postconflict situations, populations may have high rates of illness and mortality due to breakdown of health systems, flight of trained staff, failure of existing disease control programs, and destroyed infrastructure. These populations may be more vulnerable to infection and disease because of high levels of undernutrition or malnutrition, low vaccine coverage, or long-term stress. Long-term consequences of civil war can affect entire countries  because of chronic lack of investment in health, education, and public works. These conditions, which are encountered during or after war and conflict, favor emergence of infectious diseases. Examples of emerging infectious diseases in conflict situations, where several overlapping risk factors are often involved, are numerous .Plasmodium falciparum malaria in Tajikistan for first time in 35 years  . The outbreak started in the pediatric ward, where nosocomial transmission likely resulted from use of contaminated multiuse vials and reuse of contaminated needles and syringes. Children discharged into the community were readmitted with suspected Lassa fever into the Lassa ward and comprised most of the pediatric cases in this outbreak .There was a significant recrudescence of sleeping sickness (human African trypanosomiasis) in the 1990s, predominantly in conflict-affected Angola, DRC, and Southern Sudan. In particular, the DRC has had a dramatic resurgence of this disease as a direct consequence of conflict. In 1930, >33,000 new cases were detected; by 1958, after active case finding and treatment, this incidence decreased to ≈1,000 new cases. Control measures were interrupted in the 1990s because of conflict, which resulted in >150,000 new cases from 1989 through 1998, with 26,000 cases in 1998  (19). HoSurveillance systems are often weak in conflict situations, which results in delays in detection and reporting of epidemics. Limited laboratory facilities and lack of expertise in specimen collection may delay confirmation of the causative organism. Outbreak investigation and implementation of control measures may be hampered by fighting, impeded access to populations, destroyed infrastructure, limited coverage of healthcare services, poorly trained health staff, and difficult logistics that prevent delivery of drugs.An outbreak of Marburg hemorrhagic fever in Durba in northeastern DRC from October 1998 through September 2000 was the first large outbreak in rural areas under natural conditions . The area had been affected by civil war since 1997 and was controlled by Congolese rebels and Ugandan soldiers when the outbreak occurred. Although the outbreak was first reported to the national authorities in October 1998 by the chief medical officer for the health zone, an investigation was only launched after the medical officer died of this disease on April 23, 1999 , it took 6 months to respond to a relapsing fever outbreak in 1998, which resulted in >400,000 cases and >2,000 deaths. In 2000, alerts of a relapsing fever outbreak were received within 1 week and responded to by a local team; the outbreak was contained within 2 weeks, resulting in only 154 cases and 8 deaths  from December 2004 through March 2005  in refugee populations compared with 5% (and no multidrug resistance) in nonrefugee populations  to health partners. A rapid response mechanism for investigation alerts and implementation of control measures as outlined in outbreak preparedness plans  are also crucial.Revised International Health Regulations of 2005 provide a global legal framework to guide response to public health events of international concern. Conflict-affected countries represent one of the weakest links in global health security and should be prioritized by the international community in provision of technical and operational support to implement core capacities for detection and response to epidemics.Military forces are increasingly implementing aid programs for conflict-affected populations. These programs have a crucial role and are a valuable resource. However, military aid can affect the neutrality of humanitarian aid. A consistent and transparent policy is needed for military humanitarian interventions, as well as extensive civil-military liaisons and close cooperation with other humanitarian agencies (Given that healthcare in conflict situations is delivered by a wide range of national and international agencies, extensive collaboration between relevant health authorities and implementing partners should be encouraged. During an international response to an outbreak, coordination between partners and national authorities is usually ensured by WHO, which can also mobilize international experts from various institutions belonging to its Global Outbreak Alert and Response Network.Detection, containment, and control of emerging infectious diseases in conflict situations are major challenges because of multiple risk factors that promote disease transmission and hinder control even more than those in many resource-poor settings. Beyond the global public health imperative to prevent the emergence and international spread of infectious diseases, there is also a moral imperative to alleviate the effects of these diseases on already vulnerable conflict-affected populations.


Megacities around the world have significant problems with air pollution , and its constituents: organic and elemental carbon, secondary inorganic aerosols and metals , while SMC children are exposed to high ozone concentrations and PM-associated with lipopolysaccharides. This is important because exposure to specific pollutants may lead to specific detrimental effects  and those in South Mexico City (SMC) are exposed to air pollution, the specific pollutant agents are quite different. NMC children are exposed to high concentrations of fine particulate matter modify the current public school curricula to build executive function skills and cognitive reserves, which require trained supportive teachers and good quality school infrastructure;2)provide access to free school lunch with balanced healthy diets; and3)facilitate access to free good pediatric care, including mental health services.Furthermore, if early childhood air pollution exposures related to SES disadvantage can increase the neurodevelopmental and neurodegenerative risk in the exposed child, then the need for interventions aimed at breaking the cycle of childhood poverty, poor food security, high unemployment, air pollution, and the negative health consequences becomes heightened.We envisioned the protection of children to include cognitive interventions (Diamond and Lee, environmental injustice recognizes that economically disadvantaged groups are adversely affected by environmental hazards more than other groups.” Low SES MC children urgently need a support system involving parents, teachers, the health system, and government initiatives to improve environmental health. Besides addressing short-term brain outcomes, we need to investigate the long effects of neuroinflammation and if we are facing an Alzheimer's/Parkinson's epidemic in 30 years. Comprehensive epidemiologic investigations of air pollutant components exposure in pediatric populations and social health outcomes, including measures of delinquent or criminal activity are also needed (Haynes et al., We need environmental justice for Mexico City exposed children. As Cureton  stated, Unfortunately while we wait for governmental sectors to address these endemic issues, there are no coverings for our children's noses, nor for their lungs, hearts or vulnerable brains. The body of knowledge gleaned from rigorous air pollution studies should be taken seriously by those concerned with health policy and public health. The unfortunate combination of poverty and air pollution are causing serious adverse, and often irreversible, health outcomes in our children.


Tools for estimating population exposures to environmental carcinogens are required to support evidence-based policies to reduce chronic exposures and associated cancers. Our objective was to develop indicators of population exposure to selected environmental carcinogens that can be easily updated over time, and allow comparisons and prioritization between different carcinogens and exposure pathways.We employed a risk assessment-based approach to produce screening-level estimates of lifetime excess cancer risk for selected substances listed as known carcinogens by the International Agency for Research on Cancer. Estimates of lifetime average daily intake were calculated using population characteristics combined with concentrations (circa 2006) in outdoor air, indoor air, dust, drinking water, and food and beverages from existing monitoring databases or comprehensive literature reviews. Intake estimates were then multiplied by cancer potency factors from Health Canada, the United States Environmental Protection Agency, and the California Office of Environmental Health Hazard Assessment to estimate lifetime excess cancer risks associated with each substance and exposure pathway. Lifetime excess cancer risks in excess of 1 per million people are identified as potential priorities for further attention.Based on data representing average conditions circa 2006, a total of 18 carcinogen-exposure pathways had potential lifetime excess cancer risks greater than 1 per million, based on varying data quality. Carcinogens with moderate to high data quality and lifetime excess cancer risk greater than 1 per million included benzene, 1,3-butadiene and radon in outdoor air; benzene and radon in indoor air; and arsenic and hexavalent chromium in drinking water. Important data gaps were identified for asbestos, hexavalent chromium and diesel exhaust in outdoor and indoor air, while little data were available to assess risk for substances in dust, food and beverages.The ability to track changes in potential population exposures to environmental carcinogens over time, as well as to compare between different substances and exposure pathways, is necessary to support comprehensive, evidence-based prevention policy. We used estimates of lifetime excess cancer risk as indicators that, although based on a number of simplifying assumptions, help to identify important data gaps and prioritize more detailed data collection and exposure assessment needs. The International Agency for Research on Cancer has identified one hundred and nine environmental factors that can increase cancer risk in humans, including a range of chemicals and complex mixtures, exposure circumstances , physical agents , biological agents  and lifestyle factors  ,2. EstimCARcinogen EXposure (CAREX) Canada project as part of its primary prevention efforts. The goal of CAREX Canada is to develop and implement exposure surveillance methods for a range of known or suspected carcinogens. CAREX Canada includes an occupational component that builds off the original CAREX project developed by IARC and the Finnish Institute for Occupational Health pyrene, 1,3-butadiene, or TCDD were identified. No cancer potency factors are reported by Health Canada, the US EPA, or the CA OEHHA for the ingestion of formaldehyde, nickel and cadmium.We did not identify enough publicly available data to provide regional indictors for carcinogens in treated drinking water, in large part due to drinking water quality data being held by many thousands of local municipalities and not in a centralized national database. We also expect significant geographic variation of arsenic levels particularly when drinking water is drawn from private wells, based on geological sources of arsenic. Data that would support the development of regional indicators on drinking water quality in private wells were not publicly available.Estimated LECRs are greater than 1 per million due to ingestion of arsenic, benzene and benzo[a]pyrene in foods and beverages, based on average concentrations and the highest available cancer potency factor. We were able to calculate exposure frequencies for each food, given the number of detections in each sample, and these were used to develop the average daily intake values. In practice, this means that for a given substance and food group  the average daily intake estimate is influenced by the exposure frequencies of each of the included foods.We assigned a data quality rating of very low or low to all relevant substances for which we found data. In general, Canadian data available in peer-reviewed studies, government reports or public online databases are limited in terms of consumption levels, foods tested, substances measured, the geographic representation, and temporal relevance. Typically, data were available only for a few of the 206 included food items. Table We were unable to identify any publicly available data to support the calculation of regional LECRs for exposures via food and beverages. We do not expect significant regional variation in LECRs given the widespread geographical distribution of foods and beverages in general; however, there could be important differences for populations relying on locally grown and harvested foods.Only four of the selected carcinogens are expected to be relevant via ingestion of indoor dust. Estimated LECRs are greater than 1 per million for benzo[a]pyrene and hexavalent chromium respectively, assuming average concentrations, maximum cancer potency factors and an exposure frequency of 1. Data quality is low for benzo[a]pyrene, and very low for hexavalent chromium. Typically, only one or two recent North American studies per substance were identified, limiting data representativeness. No useful data for arsenic or TCDD were identified. We were unable to include recent studies of indoor dust reporting only substance weight per area sampled , because a concentration  is required to calculate LECR.Geographic variation in LECRs for exposure via dust might be influenced by outdoor air concentrations due to industrial and vehicle emissions, as well as by indoor sources for some carcinogens . Data limitations severely hamper any effort to understand regional trends in exposures to benzo[a]pyrene, arsenic, hexavalent chromium, or TCDD via indoor dust.We developed indicators of Canadians’ exposure to known carcinogens in the environment circa 2006, using existing and regularly collected environmental data and a risk-based approach, which are suitable for tracking population trends over time and help to prioritize exposure reduction activities. Known carcinogens with moderate to high levels of data quality and LECRs greater than 1 per million included: benzene and radon in outdoor air; benzene and radon in indoor air; and arsenic and hexavalent chromium in drinking water. The five highest lifetime excess cancer risks in Canada are associated with radon exposure indoors , formaldehyde exposure indoors (LECR 487), radon exposure outdoors (LECR 371), exposure to diesel engine exhaust indoors (LECR 300) and exposure to arsenic and compounds in drinking water (LECR 89). These five substances combined represent 99% of the total LECR estimated for all substances/exposure pathways, although data quality was low for radon in outdoor air and very low for diesel engine exhaust in indoor air. Other important data gaps were identified for asbestos and hexavalent chromium in both indoor and outdoor air, diesel exhaust in outdoor air, and in general for carcinogens dust, and food and beverages.3), and 6 μg/m3 in outdoor air pyrene and that of Loh et al. (2007) for polycyclic aromatic hydrocarbons (PAHs) as a group in air were less than 1 per million.Loh et al. (2007) calculated lifetime excess cancer risks for a number of airborne organic compounds using modeled distributions of concentrations in various microenvironments  to develop estimates of representative total personal exposures . ReporteFew comparable LECR estimates for arsenic, benzo[a]pyrene and benzene in food and beverages were identified. Loh et al. (2007) also calculated LECRs for dioxin and PAHs via ingestion of food specifically . We did We did not find many relevant and comparable studies for drinking water and dust exposure pathways. No current peer-reviewed studies reporting LECR estimates for arsenic in drinking water in North America were identified; however, the current Canadian Drinking Water Guideline for arsenic is 0.3 micrograms per litre (μg/L), which is also stated as being equivalent to a LECR of between 1.9 to 13.9 per million . Our LEC3) dioxin; TEAM: Total exposure assessment measurement; US EPA: United states environmental protection agency; US: United States; μg/m3: Micrograms per cubic meter; μg/L: Micrograms per liter.Bq/mThe authors declare that they have no competing interests.ES developed and led the overall study, conducted data reviews and analysis, and prepared the manuscript. PH participated in data review and analysis, and collaborated in the preparation of the manuscript. KP, RC, and ACL participated in data review and analysis. PAD provided advice during the study development and manuscript preparation. All authors read and approved the final version.


West Nile virus (WNV) is a mosquito-borne flavivirus maintained and amplified among birds and tangentially transmitted to humans and horses which may develop terminal neuroinvasive disease. Outbreaks typically have a three-year pattern of silent introduction, rapid amplification and subsidence, followed by intermittent recrudescence. Our hypothesis that amplification to outbreak levels is contingent upon antecedent seroprevalence within maintenance host populations was tested by tracking WNV transmission in Los Angeles, California from 2003 through 2011.Prevalence of antibodies against WNV was monitored weekly in House Finches and House Sparrows. Tangential or spillover transmission was measured by seroconversions in sentinel chickens and by the number of West Nile neuroinvasive disease (WNND) cases reported to the Los Angeles County Department of Public Health.Elevated seroprevalence in these avian populations was associated with the subsidence of outbreaks and in the antecedent dampening of amplification during succeeding years. Dilution of seroprevalence by recruitment resulted in the progressive loss of herd immunity following the 2004 outbreak, leading to recrudescence during 2008 and 2011. WNV appeared to be a significant cause of death in these avian species, because the survivorship of antibody positive birds significantly exceeded that of antibody negative birds. Cross-correlation analysis showed that seroprevalence was negatively correlated prior to the onset of human cases and then positively correlated, peaking at 4–6 weeks after the onset of tangential transmission. Antecedent seroprevalence during winter (Jan – Mar) was negatively correlated with the number of WNND cases during the succeeding summer (Jul–Sep).Herd immunity levels within after hatching year avian maintenance host populations <10% during the antecedent late winter and spring period were followed on three occasions by outbreaks of WNND cases during the succeeding summer. Because mosquitoes feed almost exclusively on these avian species, amplification was directly related to the availability of receptive non-immune hosts. The epidemiology of mosquitoborne arboviral zoonoses is complex. Frequently extensive maintenance and amplification transmission is required prior to spillover or tangential transmission to humans or domestic animals. The efficiency of amplification depends upon the frequency of blood feeding by competent mosquito vectors upon immunologically naïve and competent hosts during favorable climatic conditions Flaviviridae, genus Flavivirus, WNV) has provided a unique natural experiment to investigate these processes, because transmission intensity seems greatest in urban/periurban environments where cycles are simplified and frequently involve only a few key vector and avian species Carpodacus mexicanus) and the House Sparrow (Passer domesticus) Culex bloodmeal identification studies in California repeatedly have documented that during late winter and spring almost all blood meals are taken from House finches and House sparrows The invasion of North America by West Nile virus (family Culex infection and human incidence 10 plaque forming units (PFU)/mL for 4–5 days Culex quinquefasciatus, the main vector present in the Los Angeles area 10 PFU/mL for 4 days in Colorado 10 PFU/mL for 2–6 days in California Late summer communal American Crow roosts may be critical for rapid WNV amplification to outbreak levels, spatially delimiting the distribution of Our detailed investigation of WNV epidemiology and ecology in Los Angeles included the systematic monitoring of antibody seroprevalence within House Finch and House Sparrow populations at multiple locations during the 2003–2009 period The ecology of the invasion and persistence of WNV in Los Angeles, descriptions of our principal study areas, sampling methods, and temporal and spatial trends in surveillance data from 2003–2008 were summarized previously Birds were collected by grain-baited drop-down or Australian crow traps Serological test results were used to calculate seroprevalence proportions, as the total number of EIA positive birds/total number of birds bled on each bleed date. To estimate seroconversions, new infections were identified as antibody-positive birds known from recapture data to have been previously negative at the most recent previous bleeding. No time period was specified between blood sampling for conversion to an antibody-positive state.As described previously http://www.cdc.gov/ncidod/dvbid/westnile/clinicians/clindesc.htm). Febrile cases were not included in our study, because of the progressive decline in testing and reporting after 2004 as indicated by decrease in the ratio of febrile to neuroinvasive cases (data not shown). Additional human infections were discovered through blood donor programs and were included if they developed acute symptoms.Human cases of West Nile neuroinvasive disease (WNND) were monitored by the Los Angeles County Department of Health and Human Services, Acute Communicable Disease Control, through passive case detection and reporting. WNND cases were limited to those that matched the Center for Disease Control and Prevention (CDC) definition for WNV-associated neuroinvasive illness and had been laboratory-confirmed, typically by demonstration of immunoglobulin M (IgM) antibody in sera or spinal fluid by EIA . To assess the impact of infection history, banded birds were grouped by species and serological status indicating if they were ever infected, and time retained within our study from banding to last recapture. A linear regression was fitted to the numbers collected per 10 week time step transformed by ln (y+1) as a function of time in weeks, presuming constant population loss due to emigration and death. Survivorship was estimated as the backtransformed slope of the fitted regression function.Time series and correlation analyses of seroprevalence vs. human cases and sentinel chicken seroconversions were used to determine the impact of herd immunity. The herd immunity threshold was defined as the value of seroprevalence that best correlated with the cessation of WNV activity as measured by new WNND cases and sentinel chicken seroconversions. Correlation analyses were performed using SAS version 9.2 Software .The collection, banding, and bleeding of wild birds was done under protocols 11184, 12889 and 15893 approved by the Institutional Animal Care and Use Committee of the University of California, Davis; Master Station Federal Bird Banding permit 22763 issued by the U.S. Geological Survey, California and Resident Scientific Collection permits by the State of California Department of Fish and Game. The husbandry and bleeding of sentinel chickens was done under protocols 11186, 12878 and 15892 approved by the Institutional Animal Care and Use Committee of the University of California, Davis. Use of arboviruses was approved under Biological Use Authorizations #0554 and #0873 issued by the Environmental Health and Safety Committee of the University of California, Davis, and USDA permit #47901. Human data used in this project were granted an exemption from informed consent protocols by the Institutional Review Board at the University of California, Davis .A total of 22,672 sera were collected from 38 species of birds, of which 87% were House Finches and House Sparrows . Other f2 = 76.4, P<0.0001), greater than the proportion of House Sparrow sera positive (0.08). Mourning doves and other birds from rehabilitation centers frequently were positive during 2004 and 2005, but were sampled inconsistently at low numbers and were not tested after 2005. Other species such as feral Nutmeg Manakins and winter resident White-crowned Sparrows were collected frequently, but rarely were positive (0.01). Of the total EIA positives, 1,946 (87%) were confirmed by PRNT, 112 were PRNT negative, and 209 were not retested. WNV was identified as the infecting virus for all EIA positive birds with PRNT titers ≥1∶40; none had been infected previously with SLEV. The displacement of SLEV by WNV throughout California since 2003 was supported by human case, sentinel chicken serology and mosquito pool diagnostics Of the 22,672 sera tested by EIA, 2,267 were positive against flavivirus antigen when tested by EIA, including 1,521 House Finches and 563 House Sparrows . The proportion of House Finch sera positive for WNV (0.12) was slightly, but significantly  House Finches and House Sparrows Secondly, although the mechanisms of WNV overwintering in California have not been fully resolved, several paradigms have been supported by field data, including persistent infection in quiescent female and vertically infected Acquired immunity significantly increased avian survivorship and the mean duration of life within our study areas , and mayAntibody persistence waned over time in naturally infected birds, contrasting laboratory studies In addition to ambient temperature


Food insecurity is associated with poor nutritional and clinical outcomes among people living with HIV/AIDS. Few studies investigate the link between food insecurity, dietary diversity and health-related quality of life among people living with HIV/AIDS.We investigated whether household food access and individual dietary diversity are associated with health-related quality of life among people living with HIV/AIDS in Uganda.We surveyed 902 people living with HIV/AIDS and their households from two clinics in Northern Uganda. Health-related quality of life outcomes were assessed using the Medical Outcomes Study (MOS)-HIV Survey. We performed multivariate regressions to investigate the relationship between health-related quality of life, household food insecurity and individual dietary diversity.p<.001) and physical health status scores that are 1.5 points lower (p<.01). Individuals with high dietary diversity have mean mental health status scores that were 3.6 points higher (p<.001) and physical health status scores that were 2.8 points higher (p<.05).People living with HIV/AIDS from severe food insecurity households have mean mental health status scores that are 1.7 points lower (Food access and diet quality are associated with health-related quality of life and may be considered as part of comprehensive interventions designed to mitigate psychosocial consequences of HIV. Among people living with HIV (PLHIV), health related quality of life (HRQoL) is particularly important in the management of the disease, due to its chronic nature and the disease's myriad mental, emotional and physical manifestations over its course. HRQoL refers to how well a person functions and to his or her perceptions of well-being in the physical, mental, and social domains of life–all distinct areas that are influenced by a person's experiences, beliefs, and expectations Food insecurity is highly prevalent in Uganda and other countries in sub-Saharan Africa, especially among PLHIV Like HRQoL, food security is a multidimensional construct. The four dimensions embodied by the definition of food security within the United Nations framework include (1) physical availability of food, (2) economic and physical access to food, (3) food utilization, and (4) stability of the other three dimensions over time Given the limited existing research investigating the relationship between various dimensions of food security and HRQoL among PLHIV, we assessed whether food access and diet quality are associated with HRQoL among PLHIV in Uganda. We hypothesized that HRQoL outcomes would be negatively correlated with household food insecurity and positively correlated with diet quality.The study protocol was approved by the ethics boards of The AIDS Support Organization (TASO), the Uganda National Council on Science and Technology (UNCST), and the International Food Policy Research Institute (IFPRI). Interviewers read consent forms to participants and participants signed to give informed consent.3, and 4) ART naïve. The WFP poverty assessment tool was administered by TASO personnel and included the following domains: household composition, employment status, income, housing characteristics, basic food sources and consumption, household expenditures, and access to services. The WFP monthly household food basket comprises corn, soy blended flour, vegetable oil, pulses, and maize meal or rice.Data used in this study came from a baseline survey of 902 PLHIV and their households recruited into a study evaluating the impact of a World Food Programme (WFP) supported food assistance program in Uganda. The study was conducted in two districts in Uganda (Soroti and Gulu) among PLHIV registered with TASO between August 2008 and September 2009. TASO has supported over 200,000 individuals directly since its inception in 1987, and is the largest indigenous non-governmental organization in Uganda with 11 service centers providing HIV prevention, care, and treatment services The main outcome in this analysis, HRQoL, was operationalized by the physical health summary (PHS) and the mental health summary (MHS) scores of the Medical Outcomes Study (MOS)-HIV Health Survey The MOS-HIV survey consists of questions which assess 11 dimensions of health-related quality of life, including general health perceptions, physical functioning, role functioning, pain, social functioning, mental health, energy, health distress, cognitive functioning, quality of life, and health transition ; ten of Physical health summary scores (PHS) and mental health summary scores (MHS) were developed using factors derived from factor analyses conducted by Revicki et al. The main independent variables of interest were household food insecurity and individual dietary diversity. Household food insecurity is measured using the Household Food Insecurity Access Scale (HFIAS), which has been validated in several countries We measured individual dietary diversity using the Individual Dietary Diversity Score (IDDS), a proxy measure of the nutritional quality of an individual's diet In multivariate analyses, we controlled for individual, household, and community level factors that may potentially confound the relationship between HRQoL and food insecurity. Individual level variables included age (continuous), sex , education (primary or below v. other), marital status (married/co-habiting for at least two years v. other), relationship to household head (head or spouse v. other) and CD4 count (continuous). Household level variables included household size, per capita monthly household expenditure , and whether the homestead was within an internally displaced camp . Community level variables included travel time to a TASO clinic in minutes, distance to the nearest government hospital in kilometers, and distance to the nearest market in kilometers, as distance to market affects food prices, access to information and resources including food. Finally, we included month and year of the interview, and a district dummy to control for district-level unobservable characteristics.All data were analyzed using Stata Version 11.2 . We performed descriptive analysis and multivariate linear regressions to investigate whether HFIAS and IDDS are associated with HRQoL. We first ran regressions on the two summary HRQoL outcomes, PHS and MHS. Next we ran regressions where the subscale scores were the outcomes.For each outcome , we present three sets of models. First, we present multivariate models with a dichotomous indicator for severe food insecurity ( = 1 if severely food insecure and  = 0 otherwise) as the key explanatory variable. In the second model, the primary explanatory variable is the categorical IDDS variable: low individual dietary diversity ; medium dietary diversity , and high dietary diversity . We ran these two models separately to investigate independent associations of HFIAS and IDDS with HRQoL. The third set of models includes both HFIAS and IDDS categorical variables to assess whether the association between HFIAS and HRQoL attenuates when controlling for IDDS. We tested for multicollinearity of independent variables in all models and found no evidence of multicollinearity; therefore we included all proposed controls. Individual, household and community level characteristics elaborated above were controlled for and robust standard errors were calculated in all models.Interviews were conducted with 902 individuals, and the sample size for analysis was 899. The mean Household Food Insecurity Access Scale (HFIAS) score was 3.6 (SD = 0.6) and individual dietary diversity score (IDDS) was 6.4 , and the mean MHS score was 46.86 (SD = 7.24). Subscale scores ranged from an average of 32.29  to 82.67 .3. Education levels were low, with more than a third of the sample not having completed primary level education. Most of the study participants (89%) were either the household head or the spouse of the household head. Nine percent of the sample resided in an IDP camp, and average household size was six persons. Average per capita monthly expenditures was 49,133 Ugandan Shillings (25 USD based on exchange rate as of February 2009). Average distance to the nearest government hospital was four kilometers and to the market was 1.6 kilometers. Average travel time to a TASO clinic was 86 minutes.The average age of study participants was 39 years, and 72 percent of the sample was female . Averagep<.001; p<.01; Results from our multivariate analysis indicated that the HFIAS and IDDS measures were correlated with MHS and PHS scores in the hypothesized directions . PLHIVs p<.001; p<.05; Individual dietary diversity was positively correlated with both MHS and PHS. Individuals with high dietary diversity had MHS scores that were 3.6 to 3.9 points higher than individuals with low dietary diversity , CD4 count , distance to a government hospital , travel time to TASO clinic , and district of residence  and to a lesser extent, relationship status, residing in an IDP camp, education, expenditures, and household size .Using a sample of 899 PLHIV in Uganda, we estimated the association between household food insecurity, individual dietary diversity, and HRQoL, controlling for disease severity and other individual, household, and community level characteristics. Our findings on the relationship between HRQoL and diet quality are novel and we highlight key results from our study below.First, household food insecurity and poor individual dietary diversity, measured using validated scales, were correlated with lower mental and physical health summary scores; there is no evidence that the relationship between household food security and HRQoL was attenuated by including individual dietary diversity scores in the analyses. Second, compared to household food security, the association between individual dietary diversity and HRQoL measures were consistently larger. To our knowledge, our study is the first to demonstrate the association between dietary diversity and HRQoL among PLHIV. Furthermore, our study adds to the limited literature on food and nutrition security and quality of life among PLHIV in resource-poor settings. These findings suggest a possible role for interventions designed to improve food access and diet quality as part of a comprehensive package of interventions designed to mitigate the psycho-social consequences of HIV and AIDS.Food and nutrition insecurity may affect HRQoL through different pathways, including chronic stress and nutritional status Heightened stress may lead to physiologic changes that influence health outcomes The second hypothesized pathway is undernutrition. The value of a diverse diet to meet the requirements for essential nutrients has long been recognized. Undernutrition weakens the immune system and may lead to increased rate of progression through compromised immunity i.e., income and education), both food security and diet quality predicted HRQoL among PLHIV in our sample. The link between HRQoL and food insecurity may not be exclusive to PLHIV In a study in the United States, Semba et al. found that improvements in hemoglobin concentrations were significantly associated with increased HRQoL among individuals living with AIDS A general limitation of our study is the cross-sectional nature of our data; we cannot draw any conclusions about causality in the relationships studied. A limitation of self-reported HRQoL measures is that some aspects of HRQoL may be affected by factors in a respondent's life which are not related to treatment for HIV/AIDS or food security but nevertheless affect a respondent's mood and possibly their answers. By restricting eligibility for this study to individuals who qualified for World Food Programme rations and accessing TASO HIV care and treatment services, our findings pertaining to PLHIV may not be generalizable to a wider HIV positive population. In addition, we do not have biomarkers for nutrient deficiencies in our data. Finally, our study design cannot account for unobserved confounders, and this limitation may bias our estimate of the associations between HRQoL and food insecurity measures.Implications for future research arise from this study. First, research should focus on understanding the different physiological, psychological, and behavioral pathways through which food security and dietary quality influence HRQoL among PLHIV and other populations with chronic diseases. Second, longitudinal data and rigorous impact evaluations are needed that examine changes in different HRQoL domains and mental and physical health summary scores, with different intervention modalities; little is known about what food and nutrition interventions specifically influence improvements in HRQoL. This focus on implementation science is best positioned to inform programming and policy decisions and to ensure that outcomes of mental health are included in HIV care and treatment program objectives, alongside more traditional HIV-related outcomes, particularly in developing country settings.In summary, our findings demonstrate a link between food security, diet quality, and HRQoL that could influence food and nutrition security programming within the context of HIV/AIDS. Conventional food and nutrition security interventions targeted to PLHIV have the stated goals of ensuring nutritional recovery and treatment success through nutrition and/or food support; and mitigating the effects of AIDS on individuals and households through safety nets


ABO blood groups have been suggested to contribute to the development of certain tumors; however, the associations between ABO blood groups and the incidence and metastases of cutaneous malignant melanomas have not been fully evaluated in Chinese populations. Thus, we investigated these associations with a case-controlled study in northeast of China.A total of 482 patients with cutaneous malignant melanoma and 3,068 healthy- controls were enrolled for the study between 2001 and 2012 at The Tumor Hospital of Harbin Medical University. A multivariate logistic model was used to evaluate adjusted odds ratios (ORs) and 95% confidence intervals (CI) for the incidence and metastases of cutaneous malignant melanoma.Blood type A individuals had higher tumor incidence and metastasis compared to those with blood type O , after adjusting for age, gender, smoking status and alcohol consumption.Blood type A was associated with higher incidence and metastasis of cutaneous malignant melanoma but future studies are needed to examine the mechanisms linking cutaneous malignant melanoma to ABO blood types. Derived from abnormal melanocytes, malignant melanoma is the most dangerous primary malignant skin tumor, responsible for more than 75% of skin cancer deaths ABO blood groups were established by Landsteiner in 1900. According to the presence of A, B, or O blood group antigens erythrocyte surfaces, individual blood types of A, B, AB, or O exist. Also, ABO blood group antigens are expressed in various human issues. Recently, increasing attention has been directed at a possible association between ABO blood groups and the risk of certain malignancies, such as hepatocellular carcinoma This is a retrospective study and written consent was given by the patients for their information to be stored in the hospital database and used for research. Approval was obtained from the Ethics Committee of The Tumor Hospital, Harbin Medical University, Harbin, People’s Republic of China.A total of 482 patients with cutaneous malignant melanoma were enrolled for the study between 2001 and 2012 at The Tumor Hospital of Harbin Medical University, Harbin, People’s Republic of China. We excluded participants with other tumors. The inclusion criteria for cases were as follows: definitive histopathological confirmation of cutaneous malignant melanoma; definitive anatomic site of cutaneous malignant melanoma; data regarding blood type; sex, age, alcohol consumption and smoking status as obtained through medical records, and a residence within northeast China of more than ten years. In addition, 3,068 healthy-controls, admitted to the hospital for a checkup, were randomly selected during the same period at the same hospital. The inclusion criteria for controls were the same as those for cases, except for the cancer diagnosis.Detailed information for all patients was collected from individual medical records. Melanoma stages were determined according to the American Joint Committee on Cancer staging system. Smokers and non-smokers were segregated based on whether the person had smoked more than 100 cigarettes during his lifetime The SPSS 14.0 statistical software program was used for statistical analysis. Age, gender, smoking status and alcohol consumption between the cases and healthy-controls, as well as metastatic and non-metastatic cases were assessed with Pearson’s chi-square test. We also used Pearson’s chi-square test to compare proportions regarding anatomic site of tumors among cases with various blood groups. To evaluate associations between ABO blood groups and the incidence for cutaneous malignant melanoma, as well as ABO blood types and metastases in cutaneous malignant melanoma patients, crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) for each variable were calculated by using unconditional logistic regression. P<0.05 was considered statistically significant.The characteristics of cases and healthy-controls are shown in The association between ABO blood types and the incidence of cutaneous malignant melanoma was estimated using unconditional logistic regression analysis . Blood tAnatomic site of cutaneous malignant melanoma in the present study grouped by blood type are shown in Metastatic and non-metastatic patient characteristics are shown in Previous studies suggest a relationship between ABO blood types and the risk of various cancers. For instance, it is widely accepted that there is a relationship between blood group A and gastric cancer To date, only two studies At present, how ABO blood types trigger carcinogenesis is unclear. However, an explanation may be that the alleles for the ABO gene located on chromosome 9q34 encode three glycosyltransferases to form the antigenic structures of the ABO blood groups. Blood group antigens are present on key receptors, which differ according to the cancer type, and control cell proliferation, resistance to apoptosis and adhesion, such as receptors for integrins, cadherins, epidermal growth factor and CD44 To date, ours is the first study to investigate the relationship between ABO blood types and metastasis in patients with cutaneous malignant melanoma, although some studies have been undertaken analysis of such a relationship in tumors We found that blood group A contributed to metastases of cutaneous malignant melanoma. So, ABO blood group may play different roles in tumor development. ABO blood group antigens are also expressed on cancer cells and can be modified by hypermethylation of the ABO gene promoter, a feature of malignant tumors. Such changes in the ABO blood antigens on cancer cells may be related to tumor invasiveness or metastatic potential.In conclusion, we found that blood type A was associated with a higher incidence and metastasis of cutaneous malignant melanoma but future studies are needed to examine the mechanisms linking the cutaneous malignant melanoma risk to ABO blood types.


Functional data analysis (FDA) is increasingly being used to better analyze, model and predict time series data. Key aspects of FDA include the choice of smoothing technique, data reduction, adjustment for clustering, functional linear modeling and forecasting methods.A systematic review using 11 electronic databases was conducted to identify FDA application studies published in the peer-review literature during 1995–2010. Papers reporting methodological considerations only were excluded, as were non-English articles.In total, 84 FDA application articles were identified; 75.0% of the reviewed articles have been published since 2005. Application of FDA has appeared in a large number of publications across various fields of sciences; the majority is related to biomedicine applications (21.4%). Overall, 72 studies (85.7%) provided information about the type of smoothing techniques used, with B-spline smoothing (29.8%) being the most popular. Functional principal component analysis (FPCA) for extracting information from functional data was reported in 51 (60.7%) studies. One-quarter (25.0%) of the published studies used functional linear models to describe relationships between explanatory and outcome variables and only 8.3% used FDA for forecasting time series data.a priori age and time effects assumptions.Despite its clear benefits for analyzing time series data, full appreciation of the key features and value of FDA have been limited to date, though the applications show its relevance to many public health and biomedical problems. Wider application of FDA to all studies involving correlated measurements should allow better modeling of, and predictions from, such data in the future especially as FDA makes no  Recent increased interest in the application of statistical modeling to medicine, biomedicine, public health, biology, biomechanics and environmental science has largely been driven by the need for good data to inform government policy and planning processes for health service delivery and disease prevention. Importantly, such models will only be useful in the long term if they are accurate, based on good quality data, and generated through application of robust appropriate statistical methods. Functional data analysis (FDA) is one such approach towards modeling time series data that has started to receive attention in the literature, particularly in terms of its public health and biomedical applications.Commonly, time series data are treated as multivariate data because they are given as a finite discrete time series. This usual multivariate approach completely ignores important information about the smooth functional behavior of the generating process that underpins the data . It alsoRamsay and Dalzell  present 1) smoothing and interpolation procedures can yield functional representations of a finite set of observations;2) it is more natural to think through modeling problems in a functional form; and3) the objectives of an analysis can be functional in nature, as would be the case if finite data were used to estimate an entire function, its derivatives, or the values of other functionals.Müller has recently described important characteristics of FDA . The FDAThere are a number of good illustrations of applications of FDA; for example, Ramsay and Silverman ,10 usingFunctional Data Analysis, Ramsay and Silverman [Applied Functional Data Analysis, the same authors [Statistica Sinica published a special issue that included two relevant review articles that dealt exclusively with the close connection between longitudinal data and functional data [http://www.psych.mcgill.ca/misc/fda/>.In contrast to most other methods commonly used to model trends in time series data, a key strength of the FDA approach is that it makes no parametric assumptions about age or time effects. The FDA methods for modeling and forecasting data across a range of health and demographic issues also have significant advantages for better understanding trends, risk factor relationships, and the effectiveness of preventive measures ,25. In tilverman  give an  authors  provide nal data ,27. In hnal data  describeBecause the application of FDA is still relatively novel, especially to public health and biomedical data, this paper reviews applications of the approach to date with the aim of encouraging researchers to adopt FDA in future studies. This paper begins with a systematic review of the focus and application features of published peer-reviewed FDA studies. In doing so, it provides a summary of the extent to which FDA has been applied in different fields, including an overview of the nature of the time series variables/data used. For each of the identified studies, this paper also describes the features of FDA that were used, including the:(1) representation of data via principal components analysis, which plays a key role in defining smoothness and continuity conditions of the resulting data;(2) classification of data, which produces different functional groups (or clusters) for gaining more sophisticated knowledge of different pathways and/or functions for large scale data;(3) functional linear models used for testing the effects on outcomes in functional form; and(4) forecasting via stochastic methods, to measure the forecast uncertainty through the estimation of a prediction interval.functional data analysis to identify relevant articles, and considered only English language articles published in peer-reviewed journals. In addition to the electronic database search, the search strategy included secondary searching of the reference lists of identified articles.This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement . We condStudies were eligible for inclusion if they were original research articles in peer-reviewed journals reporting an application of FDA. We excluded studies of statistical methodology development without application, and abstracts, letters, and conference papers.The first author, with the assistance of two research assistants, sourced and screened all identified articles. This included viewing titles and reading abstracts. We obtained full text versions of potentially eligible articles, assessed them against the exclusion/inclusion criteria, and removed obvious exclusions.In the first review phase, 334 articles were identified. Figure In the second phase, we conducted a complete detailed review of the remaining 174 retrieved articles to ensure they fully met the inclusion and exclusion criteria. A further 102 articles were excluded at this stage, leaving 72 peer reviewed articles for the third phase. Studies excluded at this stage were mainly those that justified FDA theory rather than presenting examples of its application ,33-35. AWe retained a final set of 84 articles for detailed review. The lead author reviewed each paper in terms of key FDA criteria, as outlined below, and assessed its field of application and the specific FDA methods applied. Figure Table • smoothing technique;• use of functional principal component analysis (FPCA);• type of clustering adjustment;• functional linear modeling (FLM) approach adopted to relate explanatory and outcome variables; and• type of forecasting (if any).The earliest identified application of FDA was in 1995 and 75% of the reviewed articles were published since 2005. This reflects increasing recognition of the important features of functional data and awareness of the development of new statistical approaches and software for handling them.While diverse fields were covered in the published studies, almost 21% of the studies related specifically to biomedical science (18 identified papers), followed by biomechanics applications (11 papers). Other fields of application were medicine (10), linguistics (6), biology (4), ecology (4), psychology (4), meteorology (4), environmental studies (4), demography (3), finance (3), neurology (2), economics (2), engineering (2), agriculture (1), physiology (1), information technology (1), education (1), chemistry (1), geophysics (1), and behavioral science (1). In relation to specific health issues, the most common topics were analyses of kinematics gait data (9 papers), magnetic resonance imaging (6 papers), and yeast cell cycle temporal gene expression profiles (6 papers).Table Smoothing is the first step in any FDA, and its purpose is to convert raw discrete data points into a smoothly varying function. This emphasizes patterns in the data by minimizing short-term deviations due to observational errors, such as measurement errors or inherent system noise. When reporting FDA studies, it is important to state the smoothing approach used because observational errors always exist in longitudinal data.Table Overall, B-spline smoothing was the most popular smoothing technique used (25 papers), presumably because of its simplicity and flexibility for tackling a wide range of nonparametric and semiparametric modeling situations. A common approach towards B-spline smoothing is to construct a large number of knots (as the smoothing parameter) to reduce the effective degrees of freedom and increase smoothness in the overall function estimate ,115. Othx cycles [Ramsay and Silverman  emphasizx cycles ,116, trex cycles , cash flx cycles  and fetax cycles ,19 are ex cycles ,51,84, ax cycles ,118. Mosx cycles  used conThe FPCA is one of the most popular multivariate analysis techniques for extracting information from functional data ,120. ThiThe use of FPCA was reported in 51 (60.7%) of the reviewed studies . The number of published applications involving functional data has been steadily growing. In functional linear models, the functions could be the outcome or the predictors or both.Of the reviewed studies in Table The recent introduction of stochastic methods for forecasting functional data has significant advantages over the standard approaches for better understanding trends, risk factor relationships, and the effectiveness of preventive measures. A major advantage of these methods is that they can measure forecast uncertainty through the estimation of prediction intervals for future data. For this reason, the FDA forecasting approach has started to receive attention in both demographic and medical applications ,25,28,60Overall, only seven of the reviewed studies (8.3%) reported any FDA-derived forecasting. A state space model was the most common approach for forecasting functional data in these studies (5 papers). In the forecasting process, the authors estimated the coefficients from a time series, with one value representing each time point, and a state space model was used to model and forecast these time series coefficients ,28,130.Modern data analysis has greatly benefited from the development of FDA methods and their application to time series data. Although used by statisticians for many years, FDA provides a relatively novel approach to modeling and prediction that is highly suitable for public health and biomedical applications. This paper has summarized papers describing FDA applications with a main emphasis on five popular features: smoothing, FPCA, clustering, FLM, and forecasting.Overall, the published FDA application studies demonstrate the value of this approach for exploring complex multivariate functional relationships and its major strength of being able to model the functional form of time series data. Different approaches allow for FDA representations as smooth functions, and the published studies used a range of smoothing techniques for the estimation of discretely observed data. The FDA approach of initially smoothing the data and then using the smoothed observations for modeling and forecasting is a major methodological improvement over methods that simply fit linear/non-linear trends to observed data. These FDA approaches are very suitable for widespread public health and biomedical applications. Although some authors believe that FDA can be considered as a smoothed version of multivariate data analysis, recent work has shown the advantage of direct application of smoothing techniques to reduce some of the inherent randomness in the observed data ,25,113.The theoretical and practical developments that have occurred over recent years mean that researchers can now successfully apply FPCA to many practical problems, with main attention given to the reduction of data dimensions to a finite level and identification of the most significant components of the data. High dimensional data significantly slow down conventional statistical algorithms and in some cases it is not feasible to use them in practice. This means that standard classification methods can suffer from difficulties when handling such data. Some studies need to compress their data to facilitate exploration of the most important features . In such instances, dimension reduction should be applied to keep only the relevant information and for removing correlations. This will both speed up and improve the accuracy of subsequent analyses and modeling. The FPCA has proven to be a key technique for dimension reduction, reported in most of studies reviewed here. It can also be used to investigate the variability of data with respect to individual curve shapes .a priori knowledge of data.One of the major application areas highlighted in this review is an apparent increasing interest in clustering and classification techniques, especially for time-course gene expression data. The clustering is useful for detecting patterns and clusters in high dimensional functional data. Functional clustering is used to search for natural groupings of data with similar characteristics. Unlike conventional clustering that requires measuring multivariate data at the same time points to calculate Euclidean ‘distances’ between observations, functional clustering can derive a broader class of distance measures even if the original measurements are not time-aligned among sampling units, as is common in public health applications. The reason for the popularity of functional clustering is that it can classify time series data into different classes without requiring A very interesting application of FDA involves the construction of linear models that describe the relation between an outcome variable and explanatory variables with functional nature. The FLMs have recently gained popularity and the related literature has been steadily growing with several studies using covariates to explain functional variables. Overall, FRM and FANOVA methods were the most prominent in the reviewed literature. Reasons for not using FLM techniques are unclear but might include a lack of knowledge about the value of building functional models for public health and biomedical data. However, the use of FLM is not always necessary and depends on the specific research questions.Public health researchers now recognize the importance of understanding trends in high dimensional time series data. Policy makers, for example, need information about predicted trends to inform their decision-making about public health and economic investments to reduce the burden into the future . It is cIn summary, this paper describes FDA and its important features as applied to time series data from various fields. Functional data analysis provides a relatively novel modeling and prediction approach, with the potential for many significant applications across a range of public health and biomedical applications. Importantly, not all FDA features always need to be used in a single study and the selection of specific analysis features will depend on the underlying behavior of the data, the nature of study and the specific research questions being posed. Consideration should be given to wider application of FDA and its important modeling features so that more accurate estimates for public health and biomedical applications can be generated.FDA: Functional data analysis; FPCA: Functional principal component analysis; FLM: Functional linear modeling; LDA: Linear discriminant analysis; KNN: K-nearest neighbours; SVM: Support vector machine; MBC: Model based clustering; QDA: Quadratic discriminant analysis; EDO: Estimated differential operators; FRM: Functional linear regression model; FANOVA: Functional ANOVA; FFT: Functional F-test; FLRM: Functional logistic regression model; FMANOVA: Functional multivariate analysis of variance.The authors have no conflicts of interest that are directly relevant to the content of this review.As first author, SU conceived and designed the study reported in this paper. He took the lead role in drafting the manuscript and reviewed all relevant articles and analysed their content. The second author, CF, provided expertise in the conduct of systematic reviews and also contributed to the writing and editing of the paper. She reviewed the article and revised it critically for important intellectual content. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/13/43/prepub


Clozapine effectiveness in the treatment of refractory schizophrenia has been sustained by published evidence in the last two decades, despite the introduction of safer options.Current clinical practice guidelines have strongly recommended the use of clozapine in treatment-resistant schizophrenia, but prescribing trends do not appear to have followed such recommendations. Clozapine is still underutilized especially in patients at risk of suicide. It seems that physicians are hesitant in prescribing clozapine due to concerns about serious adverse effects. Recent reports have highlighted the need to inform health professionals about the benefits of treating patients with clozapine and have voiced concerns about the underutilization of clozapine especially in patients at risk of suicide.Guidelines and prescribing patterns reported in various countries worldwide are discussed. Suggestions on how to optimize clozapine utilization have been published but more efforts are needed to properly inform and support prescribers’ practices. Clozapine efficacy as an “atypical” antipsychotic agent has been recognized since the early 1960s [It was not until fourteen years after its withdrawal that the results of the pivotal US Clozaril Study were published and the important role of clozapine in clinical practice was discovered . Clozapi3 and ANC ≥2000/mm3) throughout treatment [The recognized risk for agranulocytosis, assessed at a prevalence of 1-2%, has been managed since then by mandatory monitoring systems administered by the manufacturers of the clozapine products (now generized in most countries) to assure that patients undergo routine blood testing before each dispensation. Current product monographs mandate that patients start therapy gradually and that normal WBC and absolute neutrophil counts (ANC) are maintained at safe levels . These agents, developed to obtain efficacious medications similar to clozapine without the hematological toxicity, generated hope for improved compliance and Quality of Life (QoL) in patients affected by schizophrenia. Early studies of SGAs demonstrated superiority over the FGAs, including a lower incidence of EPS, superior efficacy for positive, negative and mood symptoms, improved tolerability, as well as cognitive enhancing effects -8. DespiThe main objectives of this article are to provide information on clozapine place in therapy and to discuss clozapine’s prescribing trends since the publication of the most recent schizophrenia clinical practice guidelines in North America and Europe.Clinical practice guidelines, meta-analyses, and reports on clozapine prescribing trends have been identified from searches in PubMed, Psychinfo, EMBASE and Cochrane databases. The search was focused on publications in the last 10-year period (2004 and 2014). Articles selection was limited to those written in the English language. Individual clinical trials and older landmark studies have been cited where appropriate. Keywords used in the literature search included: clozapine, prescribing, schizophrenia, antipsychotic(s), utilization, guidelines.Clozapine effectiveness was initially demonstrated against chlorpromazine, the prototype of the FGAs . EvidencThe landmark study CUtLASS 2 found that in patients failing to respond to two or more antipsychotics, clozapine produced significant improvement in symptoms over 1 year . The phaMore recent evidence has confirmed clozapine superiority to other SGAs and olanzapine ,38.Effects of clozapine treatment on patient mortality has been assessed and reviewed over the years in various populations. The evidence supports a clear advantage of clozapine therapy in terms of reduced mortality over other antipsychotic agents including FGAs, risperidone and quetiapine -42.The evidence produced in the last 20 years, and summarized by published clinical practice guidelines and algorithms, has confirmed clozapine to be the gold standard for treatment-resistant schizophrenia. Please refer to Table Treatment-resistant schizophrenia has been established to affect 20-30% of all patients diagnosed with schizophrenia ,31. NeveAdherence to treatment guidelines in the UK was also very poor in terms of clozapine initiation as in more than 34% of patients’ polypharmacy and high dose treatments were used before commencing clozapine .Recent Canadian statistics, based on physician drug recommendations from 2005 to 2009, show a 48% increase in clozapine recommendations over a 5-year period ; howeverDespite the long and still ongoing debate about the comparative safety and effectiveness of FGAs and SGAs ,6, durinWhile clinical practice guidelines have strongly endorsed clozapine as the gold standard of therapy, its use has been lower that recommended. Reasons for physicians’ reluctance to prescribe clozapine have been evaluated and the relatively high incidence of agranulocytosis has certainly had great influence; however, the careful monitoring of WBC counts and ANC has almost completely abolished the risk of fatal agranulocytosis; frequency of blood tests has recently been simplified and once WBC counts and ANCs have been maintained within normal levels for one year, blood tests are now only required once every 4 weeks ,47. It iConcerns over other adverse effects, which include weight gain, hyperglycemia, seizures, tachycardia, myocarditis and neuromalignant syndrome , can aff• Published clinical evidence has supported clozapine as the gold standard in the treatment of refractory schizophrenia as it is reflected in the recommendations of many clinical practice guidelines.• Clinical practice guidelines, however, do not appear to have been followed by prescribers and clozapine remains an underutilized medication in patients with treatment-resistant schizophrenia.• Efforts are needed to encourage and optimize clozapine utilization.AA: Antipsychotic agent; ANC: Absolute neutrophil count; APA: American Psychiatric Association; BAP: British Association for Psychopharmacology; BPRS: Brief Psychiatric Rating Scale; CADTH: Canadian Agency for Drugs and Technologies in Health; CPA: Canadian Psychiatry Association; CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness; CUtLASS: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study; EPS: Extrapyramidal Symptoms; FDA: Food and Drug Administration; FGAs: First Generation Antipsychotics; NICE: National Institute of Health and Clinical Excellence; PAP: Psychopharmacology Algorithm Project; PORT: Patient Outcomes Research Team; QoL: Quality of Life; SANS: Scale for the Assessment of Negative Symptoms; SGAs: Second Generation Antipsychotics; TD: Tardive dyskinesia; TMAP: Texas Medication Algorithm Project; WBC: White blood cells.The authors declare that they have no competing interests.SW conducted the bibliographic research and drafted the article. SAS designed and supervised the project, and wrote the final draft. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/14/102/prepub