In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal-containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today.The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model.n = 12–16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles–mumps–rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age-matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate.We administered vaccines to six groups of infant male rhesus macaques (We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors.This comprehensive 5-year case–control study, which closely examined the effects of pediatric vaccines on early primate development, provided no consistent evidence of neurodevelopmental deficits or aberrant behavior in vaccinated animals.http://dx.doi.org/10.1289/ehp.1408257Curtis B, Liberato N, Rulien M, Morrisroe K, Kenney C, Yutuc V, Ferrier C, Marti CN, Mandell D, Burbacher TM, Sackett GP, Hewitson L. 2015. Examination of the safety of pediatric vaccine schedules in a non-human primate model: assessments of neurodevelopment, learning, and social behavior. Environ Health Perspect 123:579–589;  During the 1990s, thimerosal, an ethylmercury (EtHg)–based preservative, was included in several vaccines given to U.S. infants . Many inSince that time, the Advisory Committee on Immunization Practices has markedly expanded pediatric vaccination recommendations . By 2008Much of the research examining the safety of pediatric vaccines is based on rodent data. Specifically, these studies have investigated potential neurobehavioral effects of prenatal and/or postnatal thimerosal exposure . At thimWith these limitations in mind, we developed a non-human primate model to examine the effects of different vaccine schedules on neurobehavioral development. Non-human primates (hereafter referred to as primates) share a great deal of evolutionary history with humans, and as such, are particularly relevant for neurobehavioral and neurocognitive evaluations. Questions addressing more complex cognitive processes and intricate social interactions may therefore be better suited for non-human primate studies . FurtherIn summary, primates provide a relevant animal model for exploring potential neurobehavioral consequences of environmental neurotoxicant exposures, such as thimerosal. In a controlled, blinded primate study, we examined the safety of pediatric vaccines, including TCVs, on a number of neurobehavioral tests: acquisition of neonatal reflexes, development of object permanence, formation of discrimination learning strategies, and assessments of social behavior.Animal assurances. Animal procedures followed the guidelines of the Animal Welfare Act and the Guide for Care and Use of Laboratory Animals  pregnancies were produced by natural mating at the California National Primate Research Center (CNPRC). We selected pregnant dams based on their overall health and confirmation of a male fetus of suitable gestational age by ultrasound. Prior pregnancy records were also reviewed to avoid nulliparous dams or dams with a history of miscarriage. Pregnant dams were transported from the CNPRC to the WaNPRC Infant Primate Research Laboratory (IPRL) by a specialized animal trucking company and monitored 24 hr/day using infrared cameras until delivery.Study design. A total of 79 male infant macaques were studied in six groups (a) control ; b) MMR ; c) TCV ; d) 1990s Pediatric ; e) 1990s Primate ; and f ) 2008 .x groups : a) contp > 0.05). Each infant received standard neonatal care and was raised during infancy in their individual home cage in the same rearing room as the other members of their peer group following standardized protocols . Within each study group, infants were further assigned to a peer group such that their birth dates were within 30 days of each other. The only exception was in one of the four MMR peer groups, for which only three male infants within the appropriate age range were available. Gestational age and birth weight of all infants were within the normal range , with no statistically significant group differences ; diphtheria, tetanus, acellular pertussis (DTaP); Haemophilus influenzae B (Hib); measles, mumps, rubella (MMR); and an oral polio vaccine. The Hep B, DTaP, and Hib vaccines available during that time contained thimerosal, an EtHg-based preservative. The MMR vaccine has always been thimerosal-free. To recreate the TCVs for this study, we purchased single-dose, thimerosal-free vaccines from the manufacturers listed in Supplemental Material, Table S2, and added thimerosal. To calculate the thimerosal content for each vaccine, we first determined the amount of EtHg (micrograms) administered to a male human infant in the 10th percentile for weight at the recommended times of vaccination  to verify that target concentrations were achieved. Matrix effects were evaluated and corrected for using an yttrium internal standard. Furthermore, second-source curve verifiers and spike recoveries were > 95%. Laboratory control samples consisting of three different dilutions of the stock solutions bracketing the expected concentrations of the dosed vaccines were also prepared and analyzed alongside the dosed vaccines on a Nippon MA-2000 mercury analyzer (Nippon Instruments Corporation). Recoveries on the laboratory control samples were again > 95%. The TCVs contained either 1.98 μg EtHg per 0.5 mL dose (Hep B) or 3.96 μg EtHg per 0.5 mL dose (DTaP and Hib). We periodically verified the concentration of EtHg in vaccine aliquots throughout the study using an independent testing laboratory (Quicksilver Scientific).The preparation of TCVs and all quality assurance/quality control were performed at the University of Kentucky Environmental Research and Training Laboratory. Briefly, purchased vaccines were pooled prior to thimerosal addition. Stock thimerosal  solutions were prepared such that a 50-μL dose added to the pooled vaccines would yield the desired EtHg concentrations. Triplicate stock thimerosal solutions and spiked vaccine solutions were digested in 5% nitric acid at 100For the 2008 schedule, additional vaccines were purchased from the manufacturers listed in Supplemental Material, Table S2. These included rotavirus, pneumococcal, inactivated polio virus, varicella, hepatitis A, meningococcal, and influenza vaccines, which were administered according to the schedule listed in Supplemental Material, Table S3. Because the multidose vials of meningococcal and influenza vaccines currently available for pediatric use contain 25 μg EtHg per 0.5 mL dose , we purcVaccine administration. According to study group assignment, all animals received either a vaccine or saline injection, administered IM, subcutaneously, or by oral gavage, depending on the manufacturer’s recommendations . For each IM injection, the needle was inserted at a 90-degree angle and a 0.5 mL dose injected into the left or right biceps femoris of the hamstring. For subcutaneous injections, the skin of the thigh was pinched, the needle inserted at a 45-degree angle, and a 0.5 mL dose administered. When multiple vaccines were to be administered at the same time, different sites within the same area were selected and/or the left and right side alternated.To adjust the timing of vaccination to human age equivalents, we used a truncated schedule of vaccination. The development of the human and macaque infant visual system is very similar, with the postnatal developmental ratio between the two groups being about 4:1 . This 4:Implementation of neurobehavioral assessments. Assessments of infant development were based on protocols developed at the IPRL and have been extensively published  physical-search test consisted of four tasks: plain reach, screen, well, and A-not-B . These animals were moved to the first reversal on discrimination learning without reaching criterion. All of these animals were performing above 70% correct when this was done, but they had not yet met the required 80% correct to reach criterion.In the initial discrimination phase, the color of the rewarded stimulus was randomly chosen for each infant. The initial discrimination was run until the infant reached the criterion of 80% correct on a single day. After attaining criterion, the color of the rewarded stimulus image was reversed to the nonrewarded color and 25 trials/day were run again to the same criterion. This was repeated for a total of four reversals. Six animals were removed from the analysis due to experimenter error  started learning-set testing after this software change, only these animals were included in the analyses . Although the software change did not affect the discrimination/reversal task, the same 54 animals were analyzed for both tasks so that the groups of animals were consistent.Learning set presented the animal with a series of discrimination problems. Each problem had two unique stimulus images, with one randomly selected as the reward image. Each unique problem was presented to the infant for six trials, and then the images were changed to a new problem. Each infant was presented with 6 problems/day and received 240 problems over a minimum of 40 test days. If an infant balked for five trials in a row, that session was terminated. During the study, there was a modification to the software that affected the way the learning set was presented. The spatial distribution of the stimuli changed from three screen locations to nine, potentially increasing the difficulty of this test. Because the majority of animals  and multilevel Cox regression for all reflexes that were highly correlated . Cox proportional hazards regression models were fitted using the R survival package  to determine a significance cutoff . Because duration and frequency were highly correlated, we used only duration as an outcome in the analytic models. Durations of the negative behaviors  were summed for each animal, as were durations of the positive behaviors . Thus, for both social  and nonsocial  behaviors, four behavior outcomes were used in the analysis: passive, explore, negative, and positive. A 30-day average was computed for the duration of each of the four nonsocial and social behaviors for each animal for each 30-day period from 30 days to 360 days of age. Duration values were natural log-transformed to reduce the possibility of disproportionate impact of extreme values. Models were fit following longitudinal model-building strategies in which the unconditional growth model  was established by comparing longitudinal models using the Akaike information criterion. No-change, linear, and quadratic models were fit for each outcome. Time was centered at month 2, the first month of the data. The assessment of unconditional growth models indicated that a quadratic model  was the best model for all outcomes, except for a linear trend for social positive behavior. After establishing the growth model for each outcome, we added the intervention condition and an interaction between time parameter and the intervention condition to the models to test for differences in experimental conditions and for differences in developmental trajectory of a putative behavior as a function of experimental condition, respectively. An FDR correction was applied to each parameter across the eight models. In the event of either a significant effect for group or a group × time interaction, we estimated simple slope comparisons  between Acquisition of neonatal reflexes. There were no significant differences between groups in days to criterion for the acquisition of neonatal reflexes except for hand top of counter . Survival analysis was significant for both left  and right  hand top of counter .Object concept permanence. Sessions to criterion for the four stages of object permanence testing are shown in Discrimination/reversal learning. During the initial two-choice learning phase, there were no significant differences between groups in the number of trials to criterion , p = 0.013; reversal 3: HR = 2.36 , p = 0.015; and reversal 4: HR = 2.55 , p = 0.013]. The animals in the 1990s Primate group were also significantly more likely to achieve criterion in fewer trials than the control animals except for reversal 3 . During reversal testing, the MMR group took longer to achieve criterion during the second reversal , but performance was not significantly different from the control group on the other three reversal phases, suggesting that this finding was due to random variation.riterion . During An error analysis was conducted to assess differences in perseverative behavior between groups. Perseveration was defined as any day of testing that an animal performed < 34% correct or balked on the session, if the balk day was preceded by a perseverative day. All other test days were classified as nonperseveration. Classifying test days in this way has been shown to be sensitive to prefrontal lesions , as wellLearning set. The key outcome in a successful learning-set analysis is a significant 2-way interaction between Block and Trial that shows better performance on trials 2–6 as the animal progresses through testing. Overall, there was not a significant Block × Trial interaction , nor was there a significant main effect for Group . Percent correct for the Block × Trial interaction for each group revealed a similar pattern to the overall Block × Trial interaction with no evidence for learning-set formation and only modest within-problem learning by trials 5 and 6 in the later blocks . Although there was a significant three-way interaction  = 2.92, p = 0.030] for negative behaviors, indicating that longitudinal change in negative behaviors differed across groups. Follow-up contrasts indicated that at 2 months of age, relative to the controls, animals in the 1990s Primate and 2008 groups exhibited significantly fewer negative behaviors , respectively  = 3.62, p = 0.011] for passive behaviors. However, animals in the control group exhibited no significant differences in passive behaviors from the experimental groups at both 2 months and 12 months. There was a significant Group × Quadratic interaction  for explore behaviors. Follow-up contrasts indicated that at 12 months of age, relative to the controls, the 1990s Pediatric group exhibited significantly fewer explore behaviors   = 3.68, p = 0.021] for negative behaviors. Follow-up contrasts indicated that at 2 months of age, relative to the control group, the 1990s Primate and MMR groups exhibited significantly fewer negative behaviors  and , respectively. We observed no significant differences in negative behaviors in the vaccine groups relative to the control group at 12 months. There was a significant Group × Linear time interaction  for positive behaviors. Follow-up contrasts indicated that, relative to the control group, the 1990s Pediatric group exhibited significantly fewer positive behaviors  at 2 months, and significantly greater positive behaviors at 12 months  .Analyses of nonsocial interaction data revealed a significant Group main effect [In this primate study of vaccine safety, we examined a number of neurobehavioral tests—the acquisition of neonatal reflexes, the development of object permanence, the formation of discrimination learning strategies, and assessments of social behavior—in a primate model of vaccine safety. Using a modified version of the Neonatal Behavioral Assessment Scale, we found that days to criterion for the acquisition of neonatal reflexes was similar for animals irrespective of vaccination status, suggesting that auditory and motor function at this age were normal. The only exception was for the acquisition of the hand top of counter reflex for the 1990s Pediatric group, which took longer than the control group. These data are in contrast to our previous pilot study in which a delay in the acquisition of the root, suck, and snout survival reflexes were reported for primate infants following exposure to the birth dose of the thimerosal-containing Hep B vaccine . This diSeveral rodent studies have examined the effect of thimerosal on auditory and motor function . For exaIn the present study, we also examined OCP, discrimination/reversal, learning set, and social behavior. Attainment of object permanence requires some understanding that objects are permanent in space and time and continue to exist when removed from the visual field , and hasTwo-choice color discrimination tests have been used to evaluate basic learning skills in infant primates for many years . MasterySeveral clinical studies have examined the relationship between infant thimerosal exposure from TCVs and pediatric outcome. For example, in a British cohort study examining child development and behavior, Learning-set formation refers to the learning of visual and other types of discrimination problems progressively more quickly as a function of training on a series of problems . In the p-dioxin)   have als-dioxin) . It is pBased on the observed toxicokinetics in infant primates receiving low-dose IM thimerosal injections , toxicitOur study has several limitations. First, studies of low-dose thimerosal exposure in primates have employed an accelerated schedule of exposure similar to that used in rodent studies . This scSecond, we used only male animals in our study, and many clinical studies have reported gender-specific effects of organomercurials  PDFClick here for additional data file.


Halyomorpha halys, as the model organism because gaps in knowledge exist regarding its developmental physiology, it is expanding its global distribution, and it is of significant economic importance. Model predictions were compared against field observations over 3 years, and the parameter set that enables the largest population growth was applied to eight locations over 10 years, capturing the variation in temperature and photoperiod profiles of significant horticultural crop production that could be affected by H. halys in the US. As a species that overwinters as adults, critical photoperiod significantly impacted H. halys seasonality and population size through its influence on diapause termination and induction, and this may impact other insects with similar life-histories. Photoperiod and temperature interactions influenced life stage synchrony among years, resulting in an order of magnitude difference, for occurrence of key life stages. At all locations, there was a high degree of overlap among life stages and generation. Although all populations produced F2 adults and thus could be characterized as bivoltine, the size and relative contribution of each generation to the total, or overwintering, adult population also varied dramatically. In about half of the years in two locations , F1 adults comprised half or more of the adult population at the end of the year. Yearly degree-day accumulation was a significant covariate influencing variation in population growth, and average maximum adult population size varied by 10-fold among locations. Average final population growth was positive  or marginal , but was negative in one location (Wenatchee WA) due to cooler temperatures coupled with timing of vitellogenesis of F2 adults. Years of the highest population growth in the mid-Atlantic site coincided with years of highest crop damage reports. We discuss these results with respect to assumptions and critical knowledge gaps, the ability to realistically model phenology of species with strongly overlapping life stage and which diapause as adults.We developed an agent-based stochastic model expressing stage-specific phenology and population dynamics for an insect species across geographic regions. We used the invasive pentatomid,  Phenology modeling of insects typically relies on temperature-dependent functions that describe development as the transition among immature life stages and into the adult life stage. Insect development is often expressed in terms of degree-days (DD), which can be modeled to time management applications, can determine the number of generations across locations, and can be integral in invasive species risk assessments  (Hemiptera: Pentatomidae) as an model organism to evaluate a stochastic agent-based model where purely temperature-based models might not be appropriate because it overwinters in adult diapause, has strongly overlapping generations, and sampling methods for defining a field biofix are unclear  female H. halys are pre-vitellogenic , and require an additional period of development prior to sexual maturity. Watanabe . Non-diapausing females continue to reproduce throughout their lifespan, which can last up to a few months post diapause emergence  as influenced by photoperiod and temperature, and compare model outputs with field observations. We use these validation efforts, along with varying specific photoperiod sensitivity for diapause induction and termination, to focus attention to areas in need of further study by demonstrating sensitivity of simple population dynamics models to these parameters defining physiology. We then apply the most effective models to eight locations in the US that are relevant to horticultural crops at risk of damage over a 10 year timeframe, which span the latitudes of recent and potential invasion in the US and current climatic conditions.Our objective is to develop a model to estimate voltinism, stage-specific phenology, and population dynamics of an insect with unclear developmental requirements. We do this using H. halys . The initial adults are considered the parent generation (P). The model comprises five major modules: (i) diapause termination of generation P, (ii) fecundity of P and successive generations of adults , (iii) development from egg to adult, (iv) diapause induction of successive (Fx) adults, and (v) survivorship in all generations  prior to oviposition  of  adults F, F2, …Fxs Figure , while ds Figure . Reprodu adults F, F2, …Fxx). The temperature-dependent immature survivorship rates are reported in Table 2 from Nielsen et al. , for overwintering adults (P), and for all the successive generation adults ; and in each specific nymphal and adult reproductive state, and added new births and removed dead individuals to the population. At the end of each simulation, metrics such as daily population size, mean eclosion date for each generation, and degree-day accumulation were collected for further analysis. The model started fresh for a new year  instead of carrying over from the previous year. All scripts  were written and verified in R (v. 3.1.0).The model ran for 100 simulations (replication) per site per year (from Jan. 1st to Dec. 31st) to account for stochasticity associated within all the module/submodules. At the beginning of each simulation (Jan. 1st), 1000 overwintering pre-vitellogenic adults were introduced. The model ran at a discrete daily step to check the potential mortality, fecundity, and developmental transition for each individual. The model also kept track of each individual's life stage or phenological category , and the critical photoperiod for diapause termination prior to the summer solstice is the same as critical photoperiod for diapause induction following the summer solstice. Furthermore, the photoperiod experienced by the Fx adult on the first day of eclosion determines the diapause category for that female. In contrast to the Fx adults, who remain in diapause once they are placed in that category, P adults transition from diapausing to vitellogenic once the critical photoperiod prior to the summer solstice is reached. We chose Allentown, PA  in 2007 to evaluate the influence of photoperiod by comparing the total and adult population size for the F1 and F2 generations under the three photoperiods  from 100 simulations using analysis of variance (ANOVA). For model validation and prediction of voltinism across geographic locations we selected the critical photoperiod that resulted in the highest population size as determined by a one-way ANOVA.The critical photoperiod for diapause termination for H. halys collected twice-weekly were summed across host plants. For validation the population sizes for both observed and predicted populations were scaled relative to the maximum observed population size observed each year and plotted accordingly for comparison. Coefficients of determination (R2) were computed between field observations and model predictions for three life stages  in 3 years (2005–2007).Model predictions for Allentown, PA  were validated using seasonality and density estimates collected with beat sheets from ornamental plants in Allentown, PA, for the years 2005–2007 , Salem, OR , Davis, CA , Riverside, CA , Geneva, NY , Bridgeton, NJ , Asheville, NC , and Homestead, FL . These locations were chosen because of variation in temperature and photoperiod profiles and because they represent locations of significant horticultural crop production that could be affected by H. halys in the US. The daily maximum and minimum temperature data were acquired from National Oceanic and Atmospheric Administration (NOAA), and the photoperiod profiles were computed based latitude and day of year following Forsythe et al. . This time frame also includes 2010, the year in which H. halys populations were very large in the mid-Atlantic region, and years in which temperature extremes occurred. At the end of model simulations for a given location and year, metrics such as mean number of generations, mean and variability of emergence time of various life stages for each generation, and population size , were collected.Subsequent model runs were conducted for the following eight locations representing current and potential areas of e et al. . These mR (ver. 3.1.0), assuming results in different years were independent observations for the same location and using year as a covariate, followed by a Tukey's HSD test to explicitly compare sites.The influence of model predictions on population size was analyzed for maximum adult population, final population size (adults entering overwintering diapause) and total DD accumulation through the entire year. We tested for differences in population sizes among locations with analysis of covariance (ANCOVA) in p < 0.01, Figure 2 adult population where a 13.5 h photoperiod resulted in 22 and 20% larger population size than a 14.0 or 14.5 h photoperiod, respectively. Furthermore, more southern locations  did not have a photoperiod ≥14.0 h and thus a critical photoperiod beyond that was not appropriate for these locations. Among the ranges reported in the literature, 13.5 h of daylength resulted in the largest populations, and thus was the most conservative estimate for considering population growth potential across the entire range of continental US. Therefore, for this study we used a 13.5 h critical photoperiod in the remaining model runs.Photoperiod strongly influenced population dynamics and abundance. Population development in Allentown, PA occurred between April 20–August 23, May 1–August 10, and May 17–July 26, for the critical photoperiods of 13.5, 14, and 14.5 h, respectively. The 1 h difference in critical photoperiod resulted in almost a 2 month shorter time frame during which reproduction and development could occur. Consequently, shorter photoperiod cues resulted in significantly larger total population size and adult population size in both generations and total population entering diapause  for various life stages in 3 years, showing a robust prediction from the model output comparing to the field observations.Model validation was performed using occurrence data collected in Allentown, PA from 2005 to 2007 on ornamental trees and shrubs of various origin  in Davis, CA, and June 9–July 2 (23 d) in Bridgeton, NJ, despite being initiated at a similar time frame and being at similar latitudes Figures 2 eclosion in Davis CA, compared to a 25 d time span for F2 eclosion in Bridgeton NJ  and 6 of 10 years in Salem, OR . A more detailed quantitative description of the range in F1 and F2 adults at the end of the year for each location is provided in Table At all geographic locations, F Figures , 7. The p < 0.01, using ANCOVA) variability of maximum population size and final population size by location  and not significantly different (p = 0.12) based on the Tukey's HSD test . Despite a narrow window for development in the southern locations of Homestead, FL significant population growth is possible. Riverside, CA also has high DD accumulation but was predicted, on average, to not have sustainable population growth. This is likely due to the Tr et al.  suggestsH. halys is typically at low densities early in the spring , and that this absence of diapause in vitellogenic adults resulted in death when temperatures dropped below freezing. In Wenatchee, WA, DD accumulation was the lowest among all sites, resulting in low population densities  influencing All three authors contributed equally to the formulation of the ideas, review of data and the analysis. SF initiated this project. SC conducted the modeling based off of parameters and data derived from AN with input and interpretation by SF. Both AN and SF contributed to evaluation of model outputs and decisions about physiological characteristics. All three authors contributed to drafting and editing the manuscript. This is a truly collaborative effort.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Inhabitants of rural areas can be tempted to migrate to urban areas for the type and range of facilities available. Although urban inhabitants may benefit from greater access to human and social services, living in a big city can also bring disadvantages to some residents due to changes in social and physical environments.We analysed data from 4,208 women aged >15 years old participating in the fourth wave of the Indonesia Family Life Survey. Chronic condition risk factors – systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), and tobacco use – among women in four major cities in Indonesia  were compared against other cities. Fractional polynomial regression models were applied to examine the association between living in the major cities and SBP, DBP, BMI, and tobacco use. The models were also adjusted for age, education, employment status, migration status, ethnic groups, and religion. The patterns of SBP, DBP, and BMI were plotted and contrasted between groups of cities.p<0.005). Living in major cities increased the risk of having higher SBP, DBP, BMI and being a current smoker. Chronic disease risk factors in major cities were evident from younger ages.Chronic condition prevalence was higher for women in major cities than in contrasting cities (Women residing in Indonesia's major cities have a higher risk of developing chronic conditions, starting at younger ages. The findings highlight the challenges inherent in providing long-term healthcare with its associated cost within major Indonesian cities and the importance of chronic disease prevention programmes targeting women at an early age. Urbanisation creates opportunities for people to gain better access to employment and to human and social services. Whereas two decades ago fewer than 40% of the world's population lived in cities, today this figure is greater than 50% . The proUN-Habitat recorded that, globally, more than half the people who moved from rural to urban areas during 2008–2009 were women . Women aStudies show that urban populations have better health on average than non-urban populations , 6. HoweToday, chronic disease has replaced infectious disease as the main specific cause of death among women as a result of their physical and social environments . Many ciIn the last few decades, Indonesia has achieved significant improvement in overall health status. One of the indicators of this improvement is life expectancy. Over the last three decades, life expectancy has increased from 46 years 1971) to 70.5 years (2007) 71 to 70.. This im2 in 2010 , conducted in 2007/2008. The IFLS was first conducted in 1993 and has been repeated three times, in 1997/1998, 2000, and 2007/2008 (IFLS-4) . The samwww.rand.org/labor/FLS/IFLS/ifls4.html). Approval for the IFLS-4 project was granted by the institutional review boards at RAND and Gadjah Mada University, Yogyakarta, Indonesia. The use of the data set for this study was approved by the Human Research Ethics Committee, University of Newcastle, Australia.The IFLS-4 data are open for public use with prior registration on the study website  and diastolic blood pressure (DBP). BMI was calculated from weight and height measurements conducted at the same time as the blood pressure measurement. Current smoking status was based on participants’ response to questions related to tobacco use.Groups of cities. In this study, cities where the IFLS-4 was conducted were classified into two groups: major cities and contrasting cities. By this classification a major city is 1) the national or provincial capital city; 2) surrounded by satellite cities, representing its status as a centre of business and economic activities; and 3) heterogeneous in population. Following these criteria, we classified Jakarta, Surabaya, Medan, and Bandung as major cities. These are the four largest cities in Indonesia, with each described briefly below.Jakarta is the capital city of Indonesia and is the most populous city in Indonesia. As the capital city of Indonesia, DKI Jakarta has become the centre of national government, the economy, development, and education in the education in the country. Main economic sectors include services and trading, hotels and restaurants, and manufacturing .Surabaya, the capital city of East Java Province, is located on the northern coast of East Java. The inhabitants of Surabaya come from different ethnic groups in the country. They are Malay, Chinese, Arabic, Sundanese, Batak, Dayak, and Balinese, and the majority ethnic groups are native Surabaya and Maduranese . With vaMedan is the third largest city in Indonesia, after Jakarta and Surabaya. Of the four largest cities in the country, Medan is the only city located outside of Java Island. As the capital city of North Sumatra Province, Medan is the centre of provincial government administration, the economy, communication, tourism, and regional trading. Currently there are 86 national companies and 17 international companies operating in industrial locations in the city .Bandung is the capital city of West Java Province. Located not far from Jakarta, Bandung is a centre of education, industry, and tourism. It is where 437 tertiary education institutions, 24 shopping malls, and more than 9,000 stores are located . The citThe other cities in 20 provinces surveyed in the IFLS-4, which did not meet the criteria for major cities, were classified as contrasting cities. Cities included in this group were less populated and included cities that cover suburban or rural areas, cities surrounded by rural areas, or district capital cities. They include newly developed cities, cities with wider suburban areas compared to the major cities, and those with more homogenous backgrounds than the major cities.We included age, educational attainment , five quintiles of household wealth based on household assets, employment status (being in paid work vs not in paid work), in-country migration (migrant vs non-migrant), ethnic background (Javanese vs non-Javanese), and religion (Moslem vs non-Moslem) as predictor variables.t-tests were applied to contrast the mean of SBP, DBP, and BMI. We then applied fractional polynomial (FP) regression models to examine the association between living in major cities and hypertension, obesity, and tobacco use, adjusted with other predictors described above. Next, we plotted SBP, DBP, and BMI against the predicted line across age in both settings to further contrast the pattern of chronic disease risk factors across ages in major and contrasting cities.We compared the prevalence of chronic conditions and current smoking among women in major cities and contrasting cities. Weighted prevalence was calculated using the sampling weight factor constructed by RAND  to allowThe FP model was introduced by Royston and Altman in 1994 , 34. It p, which is chosen from the set {−2, −1, −0.5, 0, 0.5, 1, 2, 3} (p1 as FP1(p1)=α+β1Xp1 and the second-degree FP equation with power p1 and p2 as FP2=α+β1Xp1+β2Xp2. Hence, the general equation of FP is denoted as follows:m=3, and p is chosen from the set {−2, −1, −0.5, 0, 0.5, 1, 2, 3} , although the difference was not large.A total of 4,208 women aged 15 years and above were included in the analysis. Of these women, 1,400 were residing in the major cities, and the other 2,808 were residing in the contrasting cities. The mean age was 36.1 years old (SD=15.1). The mean age in major cities was significantly younger than in contrasting cities , with the prevalence of current smoking almost doubled in the major cities (p<0.05).p<0.001). In general, hypertension, uric acid/gout, and arthritis/rheumatism were the three most prevalent diagnoses among women aged 40 years old in the cities. The prevalence of hypertension, diabetes, lung conditions other than asthma, and uric acid were significantly higher in the major cities than in the contrasting cities (p<0.05).As shown in The association between living in a major city and chronic disease risk factors are shown in As shown in Living in major cities also increased the odds of being a current smoker. Other predictors associated positively with being a current smoker included being a younger woman, being in the lower quintiles of household wealth, and having non-Javanese background.The predicted SBP, DBP and BMI for women in major cities were higher across age groups than those living in contrasting cities . Pre-hypThis study found that the prevalence of chronic conditions among women in major cities was significantly higher than those in contrasting cities (17.5% vs 12%), even though the mean age in the major cities was younger than in contrasting cities (35.1 years old vs 36.6 years old). Among women age 40 years and above living in the cities, the prevalence of chronic disease in major cities was significantly higher than in contrasting cities. Hypertension was indicated as the most prevalent chronic condition, followed by degenerative joint disease, such as gout and arthritis, and lifestyle-related chronic disease, such as diabetes and heart problems. In Indonesia, hypertension is the most frequently diagnosed condition by health centre among the elderly population, and urban life has the potential to increase the risk of having high blood pressure . AnotherAfter adjustment for other predictors, the study found that women who were residing in major cities had a higher probability of high blood pressure (SBP and DBP), higher BMI – which in turn resulted in a higher probability of being overweight – and being a current smoker. Knowing that these three conditions are major risk factors for chronic disease, there is a greater chance that women in major cities have a higher probability of having chronic disease as well. Access to healthy food, rapid shifts in income, and changes in occupation types among the inhabitants of big cities could lead to a shift in lifestyle towards less physical activity and unhealthy dietary habits , 38.In addition, as suggested by Levine , the higWith the higher odds of having hypertension, becoming overweight, and being a current smoker for women in the major cities compared to the contrasting cities, there is an indication of an increasing burden of chronic disease in the major cities over time. Hence, the difference in chronic disease prevalence between major and contrasting cities will be widened further. These findings highlight the importance of chronic disease risk factor screening at an early stage. It is particularly important given that chronic disease has now become the highest burden of disease among urban residents, with particular relevance to urban women.Compared to contrasting cities, the ages of women having pre-hypertension in major cities – SBP between 120 and 130 mmHg or DBP between 80 and 90 mmHg  – were fSocio-economic status, reflected by educational attainment and household wealth, was another factor found to be a significant predictor for high blood pressure, having higher BMI, and being a current smoker. Women in the lower economic group had a higher risk of having hypertension and becoming a smoker. On the contrary, women with higher economic status had a higher risk of being overweight – reflected by higher BMI. It was also shown that well-educated women had a lower risk of being overweight. These findings supported another cross-sectional study among urban dwellers in China, where women with a lower level of education and higher level of income had a higher risk of being obese . With reThis study involves a cross-sectional analysis that provides comparisons between women in different groups of cities, but with limitations in describing the exact patterns of urban living (including the period of living in the cities) and the development of disease. Despite its limitations, the study provides evidence on the emergence of non-communicable disease among women in Indonesia's cities, emphasising the importance of providing a women's health programme that extends beyond reproductive health.This study has shown that even though major cities may offer more access to social and human services compared to other settings, women residing in Indonesia's major cities do not have better chronic condition health outcomes than those who live in the contrasting cities. Better access to healthcare among women in major cities could provide opportunities for better Non-communicable Disease (NCD) control, with a gender-responsive NCD control programme at the primary level. Additionally, in order to expand the NCD control programme among women, integration of the NCD programme with other established primary healthcare programmes, such as family planning and maternal health, is worth considering.With a higher probability for having hypertension and obesity and being a current smoker in the major cities – starting from an early age – we can expect a higher burden of chronic conditions among this population group, into the future. Our findings highlight the challenge of providing long-term healthcare, with its associated financial cost, in the major cities of Indonesia. The ageing population and the importance of a robust chronic disease prevention programme will make this an imperative. Therefore, in an era of decentralised health systems, it will be necessary for local governments to emphasise both healthcare provision and health promotion – targeting women at an early age – to prevent non-sustainable health costs into the future and incorporating ageing health into the current public health agenda.


A number of studies have shown a range of negative psychological symptoms (e.g. depression) after exposure to natural disasters. The aim of this study was to determine risk factors for depression in both children and adults who have survived natural disasters.Four electronic databases  were used to search for observational studies  about depression following natural disasters. The literature search, study selection, and data extraction were conducted independently by two authors. Thirty-one articles were included in the study, of which twenty included adult participants and eleven included child participants. Summary estimates were obtained using random-effects models. Subgroup analysis, sensitivity analysis, and publication bias tests were performed on the data.The prevalence of depression after natural disasters ranged from 5.8% to 54.0% in adults and from 7.5% to 44.8% in children. We found a number of risk factors for depression after exposure to natural disasters. For adults, the significant predictors were being female ;not married;holding religious beliefs; having poor education; prior trauma; experiencing fear, injury, or bereavement during the disaster; or losing employment or property, suffering house damage as a result of the disaster. For children, the significant predictors were prior trauma; being trapped during the disaster; experiencing injury, fear, or bereavement during the disaster; witnessing injury/death during the disaster; or having poor social support.The current analysis provides evidence of risk factors for depression in survivors of natural disasters. Further research is necessary to design interventions to improve the mental health of survivors of natural disasters. Natural disasters have a devastating impact on affected regions and their populations, often causing death and serious personal injury. Survivors of the disaster often experience mental health problems in the aftermath. One of the most common mental health problems for survivors of natural disasters is depression . DepressThe onset of depression following natural disasters has been studied for more than 20 years. Studies have demonstrated that sometimes there is a delay in the onset of depression in both children and adults. Depression can be experienced weeks or months after the natural disaster, and in some cases persists for years ,35. SeveUnderstanding risk factors for experiencing depression after natural disasters can help clinicians provide more tailored treatments to reduce symptoms and aid post-disaster recovery. This study investigates the determinants of depression in survivors of natural disasters using a systematic meta-analysis of observational studies.Methods and reporting were in accordance with MOOSE  guidelines  on risk factors for depression after natural disasters published in English were included in our meta-analysis, irrespective of publication status and article type. Two investigators (B. T. and X. L.) conducted a systematic literature search using the electronic databases PubMed (from 1965 to April 2014), Embase (from 1965 to April 2014), Web of Science (from 1986 to April 2014) and PsychInfo (from 1990 to June 2013). As describing in Additional file In order for studies to be eligible for inclusion in the meta-analysis, they had to fulfil the following criteria: (1) was an epidemiological investigation of risk factors for depression after natural disasters; (2) reported the relative risks (RRs) or odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for risk factors in the development of depression; (3) included risk factors for depression after the natural disasters which we studied; and (4) included a study sample of children, adults, or both. The exclusion criteria were as follows: (1) used depression score as a variable, but did not obtain ORs or RRs; (2) were not published in English; and (3) focused on participant groups known to be susceptible to depression . Studies in which most of the study sample was less than 18 years old were classified as child studies; otherwise, they were classified as adult studies. If more than one article reported data from the same population, then the most recent and complete article was included in our meta-analysis. Study selection and application of inclusion criteria were carried out independently by the two investigators who conducted the literature search (B.T. and X.L.).Data extraction was independently performed by two investigators (B.T. and Y.L.). The following information was extracted from each eligible study: first author’s surname, year of publication, study location, disaster type, study design, study population, diagnosis of depression, sample size, depression prevalence, interval between research and the date of the natural disaster, age and gender of participants, estimated effect size (OR/RR), corresponding 95% CI, and covariates adjusted in the statistical analysis. For studies that reported several multivariable-adjusted effect estimates, we selected the one that adjusted for more potential confounding variables.Quality assessments were conducted independently by two investigators (B.T. and X.L.) using an 11-item instrument recommended by the Agency for Healthcare Research and Quality (AHRQ) for cross-sectional studies  and the The Additional file According to previously published studies ,43,44, r2 test and I2 statistic [We examined risk factors for depression after natural disasters by looking at the adjusted ORs and 95% CIs reported in each study. A random-effects model , which atatistic . The protatistic . SubgrouStata Version 12.0 software  was used for all analyses and all statistical tests were two-sided. A value of p < 0.05 was considered an indication of statistical significance.The prevalence of depression in adults after natural disasters ranged from 5.8% to 54.0%. The risk factors for depression after natural disasters in adults are presented in Table With regard to the trauma characteristics of survivors, people who experienced fear, injury, or bereavement during a natural disaster were more likely to suffer from depression, with pooled ORs of 1.58 , 1.69 , and 1.51  with no heterogeneity or publication bias. All the results were consistent according to the subgroup and sensitivity analyses.Finally, analysis of the post-trauma characteristics of survivors showed that unemployment , loss of property , and house damage  were related to depression. However, heterogeneity was found for unemployment , loss of property , and house damage , suggesting that findings on these variables show inconsistencies.The prevalence of depression in children after natural disasters ranged from 7.5% to 44.8%. The risk factors for depression after natural disasters in children are presented in Table The initial analysis of the trauma characteristics of survivors  revealed that all five factors were associated with risk of depression; the pooled ORs were 1.73  for being trapped, 2.39  for experiencing fear, 2.60  for experiencing injury, 1.68  for witnessing injury/death, and 2.85  for bereavement. However, after excluding low-quality and unadjusted studies, only two factors (bereavement and witnessing an injury or death) were still significantly associated with risk of depression.Finally, with regard to the post-trauma characteristics of survivors, only one study found that social support was a protective factor for onset of depression .To the best of our knowledge, this is the first meta-analysis focusing on risk factors for depression in populations specifically affected by natural disasters. Our synthesis of the relevant published English-language articles provided strong evidence for risk factors of depression following natural disasters. This study analyzed 31 published observational studies . A total of 16 risk factors of depression in the survivors of natural disasters were explored in our study and categorized into three types: basic characteristics, trauma characteristics, and post-trauma characteristics.With regard to basic characteristic, a common risk factor for the development of depression in both children and adults was prior exposure to trauma. This finding is consistent with previous research suggesting that the accumulation of violent traumatic events throughout the life course could increase the risk of depression ,48. FurtWomen were more likely to be depressed following a natural disaster than men were. Previous studies have indicated that women are more sensitive to threats, less likely to use effective coping strategies, and tend to interpret disasters more negatively than men do . In addiIn terms of trauma characteristics, children and adults shared three risk factors: experiencing fear, injury, and bereavement. It is likely that fear per se does not increase risk of depression; this effect is perhaps mediated instead by subjective experience of a natural disaster and personality type . For exaChildren were more likely to develop depression if they were trapped or witnessed injury or death during the disaster. Being trapped is likely to generate a traumatic memory directly associated with the negative event, which is considered an important precursor to depression. It is unsurprising that children who witnessed someone being njured or killed during a disaster may have experienced intense fear during this time; as described above, fear can itself be a predictor of depression.With regard to post-trauma characteristics, lower levels of social support were associated with a higher risk of depression in children. Lack of care and support from others may foster feelings of inferiority and insecurity among children, which act as catalysts for the development of depression . HoweverAdults who were unemployed were more likely to exhibit depressive symptoms after a natural disaster. This suggests that a loss of resources results in people being unable to care for their families to the extent that they could before the disaster ,57. LossThere are several potential limitations to our meta-analysis. First, we included only observational studies, which can be prone to biases in sample selection, recall, and information evaluation, as well as confounding bias. Second, the majority of the studies included in the meta-analysis , were based on risk factors for depression specifically after an earthquake. Thus, it is premature to apply our results to survivors of all types of natural disasters. Finally, many of the variables included in the analysis were only examined in a small proportion of studies, which restricts the generalizability of the findings. Nevertheless, our study helps to highlight areas that would benefit from further investigation.In conclusion, our study demonstrated several risk factors for depression in children and adults following natural disasters. Despite the methodological limitations of the studies that we included in the meta-analysis, these findings are valuable for understanding how to reduce symptoms of depression following a natural disaster. Such research may provide clear intervention directions and result in development of psychosocial support programs for at-risk groups, or assist in the development of prevention programs for depression. General practitioners should be aware of depressive symptoms, and careful consideration should be given to routine screens for depression during the reconstruction process following natural disasters. Further research will also be required to determine suitable interventions for improving the mental health conditions of survivors in areas affected by natural disasters. Above all, post-disaster mental health recovery programs that include early identification, on-going monitoring, preventive and intervention programs, and sustained psychosocial support are needed for the high-risk population of natural disaster survivors.NOS: Newcastle-ottawa scale; AHRQ: Agency for healthcare research and quality; OR: Odds ratio; RR: Relative risk.The authors declare that they have no competing interests.BT, XL and LZ discussed and developed the question for this review. BT and XL carried out the searches. BT and XL assessed the eligibility of the studies for inclusion, extracted data and carried out all analysis. All authors were involved in interpreted and discussed results. BT wrote the first draft of this paper and it was reviewed by XL and LZ All authors agreed on the final draft of this study. LZ is the guarantor.Bihan Tang and Xu Liu are co-first authors of this article.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/14/623/prepubMoose statement - reporting checklist for authors, editors, and reviewers of meta-analyses of observational studies.Click here for fileElectronic databases and search query.Click here for fileSearch results and excluded/Included studies.Click here for fileExcluded studies and reasons for exclusion.Click here for file


Binary definitions of the metabolic syndrome based on the presence of a particular number of individual risk factors are limited, particularly in the pediatric population. To address this limitation, we aimed at constructing composite and continuous metabolic syndrome scores (cmetS) to represent an overall measure of metabolic syndrome (MetS) in a large cohort of metabolically at-risk children, focusing on the use of the usual clinical parameters (waist circumference (WC) and systolic blood pressure (SBP), supplemented with two salivary surrogate variables (glucose and high density lipoprotein cholesterol (HDLC). Two different approaches used to create the scores were evaluated in comparison.Data from 8,112 Kuwaiti children (10.00 ± 0.67 years) were used to construct two cmetS for each subject. The first cmetS (cmetS-Z) was created by summing standardized residuals of each variable regressed on age and gender; and the second cmetS (cmetS-PCA) was defined as the first principal component from gender-specific principal component analysis based on the four variables.p = 0.001 for boys; p = 0.002 for girls), and comparison of cmetS-Z and cmetS-PCA suggested that WC and SBP were main contributory components. Significant alterations in the relationship between cmetS and salivary adipocytokines were demonstrated in overweight and obese children as compared to underweight and normal-weight children.There was a graded relationship between both scores and the number of adverse risk factors. The areas under the curve using cmetS-Z and cmetS-PCA as predictors for severe metabolic syndrome (defined as the presence of ≥3 metabolic risk factors) were 0.935 and 0.912, respectively. cmetS-Z was positively associated with WC, SBP, and glucose, but inversely associated with HDLC. Except for the lack of association with glucose, cmetS-PCA was similar to cmetS-Z in boys, but had minimum loading on HDLC in girls. Analysis using quantile regression showed an inverse association of fitness level with cmetS-PCA (We have derived continuous summary scores for MetS from a large-scale pediatric study using two different approaches, incorporating salivary measures as surrogate for plasma measures. The derived scores were viable expressions of metabolic risk, and can be utilized to study the relationships of MetS with various aspects of the metabolic disease process. Metabolic syndrome (MetS) has been defined as a concurrence of metabolic abnormalities associated with atherosclerotic cardiovascular disease and insulin resistance that are related to the development of type 2 diabetes (T2D). Based on recommendations from the International Diabetes Federation (IDF) and Adult Treatment Panel III (ATPIII) , the corDespite the usefulness of a binary definition of individual risk factor in clinical setting, by which diagnosis of the metabolic syndrome is made in the presence of a certain number of measures exceeding thresholds (e.g. n ≥ 3), growing evidence supports using a continuous approach instead of a dichotomous one –8. AsideVarious strategies have been used to construct a continuous metabolic syndrome scores (cmetS) from its components. The most frequently used methods are the summation of standardized Z scores adjusting for covariates , 11, andThe current analysis is based on a large-scale longitudinal study evaluating factors related to the etiology and development of obesity in over 8,000 Kuwait children aged 8–14 years . In thisImportantly, one aspect worth noting with this cohort is that fasting saliva samples were collected in all subjects and risk factors and many biomarkers were measured, making it possible to evaluate MetS profile using saliva parameters as surrogates of plasma parameters.Based on the unique metabolic risk status of this study population and the increasing utility of cmetS in pediatric research, the focus of our study is to construct and validate cmetS using two different approaches: Z score and PCA. Furthermore, the utility of the scores was evaluated in terms of predicting fitness level, as well as examining the relationship between salivary adipocytokines and metabolic risk.This research study was part of the Kuwait Healthy Life Study (KHLS), which aimed to investigate the obesity-related consequences and the etiology of metabolic syndrome in Kuwait children. The validation study for US subjects was approved by the Forsyth Institutional Review Board in USA, and the study of Kuwaiti subjects (4th or 5th grades) was approved by the Dasman Diabetes Institute Ethical Review Committee in Kuwait. Written consent forms signed by parents/guardians were collected in advance for both US and Kuwait study subjects. Subject assent was obtained on the day of the visit.Saliva samples were collected rather than blood samples in recognition of salivary assay as a source of valuable surrogate information , 19, to KHLS has been previously described . Brieflyth percentile, overweight was ≥85th to <95th percentile, normal healthy weight was ≥5th to <85th percentile and underweight was <5th percentile. Fitness was measured by heart rate elevation (beats/minute) following a standard 3-minute exercise . We chose τ = 0.5 thus it corresponded to median regression. As fitness had an extremely skewed distribution, quantile regression offered a robust alternative to linear regression for modeling this variable.Quantile regression  was used to assess the association of fitness with cmetS, stratified by gender and adjusting for potential confounders including age, BMI, sleep parameters, and regions in which the patient’s school was located. This technique was used to estimate conditional quantiles, requiring no distribution assumption of the dependent variable and was robust to outliers . The linIn the analysis of the random cohort in which 20 salivary biomarkers were assayed, model selection based on stepwise selection was used to develop a parsimonious linear model to predict cmetS . As the distribution of both cmetS scores was approximately normal, they could be reasonably modeled by a linear model. During the selection process, all biomarkers  and variables of subject features were considered. The Schwartz Bayesian Criterion was evaluated for all models by deleting a variable from the current model or adding a variable to this model. To avoid over-fitting, a 10-fold cross validation procedure was adopted to assess the performance, and the best model was determined based on the average predictive performance in the test sets. Subsequently, the selected subsets of significant predictors for each cmetS were examined separately in subgroups, stratified by their WHO body weight categories.p<0.0001 for SBP, p = 0.0002 for DBP), salivary glucose level (p<0.0001), and the proportion identified as obese (p<0.0001). Girls, however, had a significantly lower salivary HDLC level than boys (p<0.0001)In the KHLS study, 3045 boys and 5067 girls  completed clinical measures of BMI, waist circumference, and blood pressure, as well as HDLC and glucose levels in fasting saliva samples collected at baseline . Boys apThe value of cmetS-Z for each child was obtained by summing the standardized residual for individual components of risk factors , after regressing onto age and gender. Meanwhile, PCA was performed using the log-transformed components, stratified by gender. In boys, the first PC (PC1) explained 37.2% of the variance . The loadings of the four components were: WC: 0.70, SBP: 0.70, HDLC: -0.13, glucose: -0.04. In girls, PC1 explained 35.9% of variance , and the loadings of the four components were: WC: 0.70, SBP: 0.71, HDLC: 0.02, glucose: -0.03. Notably, HDLC had a negative loading in boys, consistent with the notion that HDLC is inversely related to metabolic risk. In girls, however, the loading of HDLC was close to zero. Because of this difference in the loading profile, the two groups of participants were not combined for subsequent analysis. To ensure that the score was maximally spread out the four components, cmetS-PCA was constructed using an unrotated PC1.To evaluate the global accuracy of cmetS-Z and cmetS-PCA as predictors for MetS (defined as presence of > = 3 risk factors), ROC curve analysis was performed . The AUCDespite the low prevalence of MetS in this study population (1.15%), there was a much larger group with at least 2 risk factors present (12.86%). Such children may be susceptible to developing MetS later in life. Therefore, we also tested an alternative outcome among children using a less stringent criterion for MetS (i.e. ≥2 risk factors present). As shown in To examine the metabolic risk in obese children as compared with healthy-weight children, average cmetS-Z and cmetS-PCA were compared across WHO body weight categories. Both obese and overweight children had significantly higher scores than did normal-weight children , indicating a significant risk even existed in overweight children. Correspondingly, the distribution of these two scores exhibited a gradual shift towards higher values across the four body weight categories p = 0.001). In girls, for every 1 SD increase in cmetS-PCA there was an average increase of 2.01 beats/min in heart rate (p = 0.002). Thus, cmetS-PCA demonstrated a strong association with fitness level in children, but not cmets-Z, although it exhibited a marginal significant association with fitness level in girls (p = 0.07).The association of both cmetS scores with fitness was assessed using quantile regression. The analysis was stratified by gender, adjusting for age, BMI, sleep parameters, and region . In bothp = 0.01). In contrast, in the overweight/obese sub-group most biomarkers became significant predictors for cmetS, with insulin being the strongest predictor for both cmetS-Z (p<0.0001) and cmetS-PCA (p<0.0001), followed by adiponectin , CRP , and fitness status . Leptin, although was selected as a significant predictor for cmetS-PCA from the entire cohort, did not manifest as such in the overweight/obese sub-group.In a previously reported randomly selected cohort of 744 children , variousIn this population of 8,112 children who are at risk of metabolic disease, we used two approaches to construct continuous metabolic syndrome scores (cmetS) in order to summarize the inter-correlated risk factors for MetS. The first approach was based on the sum of sample-specific Z scores (cmetS-Z), and the second was based on the first principal component from principal components analysis (cmetS-PCA). We assessed their respective global accuracy in predicting MetS and compared each to that of individual metabolic risk components. We also evaluated the predictive utility of these scores by their ability to predict cardiovascular health as measured by fitness level, and investigated their relationships with salivary adipocytokines in subgroups within different body weight categoriesSince it is not clear whether the definition of metabolic risk of adulthood can be extended to childhood where MetS is at its emergent stage, there has been little consensus on the criteria for defining MetS in children and adolescents, both in terms of the choice of risk factors and their respective threshold values . In thisa priori, which included waist circumference (WC), systolic blood pressure (SBP), saliva HDLC, and saliva glucose. As triglycerides and HDLC have a strong inverse correlation [In our study, variables of risk factors used to derive cmetS were selected relation , 30 we crelation .The two cmetS constructed in our study increased progressively with increasing number of risk factors . As showp = 0.001 for boys, 0.002 for girls), independent from BMI which was always a strong predictor of fitness (p = 0.07). The fact that cmetS-PCA demonstrated a stronger association with fitness than cmetS-Z suggested that central adiposity and hypertension were the two main components correlated with cardiovascular fitness in these children. Therefore, for the outcome of fitness level, cmetS-PCA appeared to be a superior predictor to cmetS-Z.Previous studies suggested that physical fitness, especially cardiorespiratory or aerobic fitness, is correlated with metabolic risk , 33. Thu fitness . In the Dysregulation of adipocytokines from adypocytes has been a subject of extensive study, which is believed to be a key mechanism in obesity-related sequelae . Among tDue to the low prevalence of MetS in children, it is a challenge to conduct association studies using the binary variable (defined as presence of > = 3 risk factors). Therefore, the continuous score of cMets has its advantage as a more sensitive measure. In modeling fitness using the binary variable, we were unable to detect a significant effect of MetS  in eitheBased on our analysis in the entire population, salivary measures appeared to be reasonable surrogates of plasma measures for evaluating metabolic risk in children. Moreover, our finding with the random cohort concurred with other findings on the relationship of blood adipocytokines and inflammatory markers with Mets in obese children , validatOne of the strengths of this study is the unusually large sample size, combined with homogeneity of the study subjects. As cmetS thus constructed is sample specific, which provides a relative measure of risk with each individual’s risk being compared to the study population, a large and relatively homogenous sample is advantageous. The two summary measures developed within this population enabled us to compare these two strategies comprehensively, and to our knowledge, no previous investigation has done so in children. Our data showed that these two differently constructed scores both constitute viable measures of metabolic risk in our study population. The performance of these two scores, however, was not always comparable. For instance, cmetS-PCA was a much more robust predictor for fitness level than cmetS-Z. Hence the choice of which cmetS score to use will depend on the objective of the study. Evidently, as compared to cmetS-Z, cmetS-PCA that weighs the inter-correlated components based on their variance structure would be more dynamically reflective of the data. In evaluation of longitudinal data of pediatric populations, the weighting of the components in cmetS-PCA will change at each time point a new score is constructed, reflecting the changing pattern of risk factors as body grows and matures.One limitation of this study lies in the lack of plasma measures of HDLC and glucose in the Kuwaiti children. Due to the reticence of Kuwaiti parents, blood samples from the children were not collected. Hence, we were unable to examine the correlation between plasma and salivary measures of these two parameters in this study population. Instead, a validation study to measure this correlation was carried out in a small separate group of children instead . FurtherWe have constructed two continuous summary scores for metabolic syndrome from a large, metabolically at-risk pediatric population, using summation of standardized Z scores and principal component analysis, with salivary measures incorporated as surrogate for plasma measures. With cmetS as an indicator of metabolic risk, our findings demonstrated that fitness level in these children are inversely associated with MetS profile, and the relationships between Mets status and salivary adipocytokines/inflammatory markers are drastically dysregulated in overweight and obese children. Either score may be useful in investigating associations between metabolic risk and various aspects of disease process, and either could potentially be utilized to track the metabolic profile from childhood into young adulthood.S1 Appendix(DOCX)Click here for additional data file.S1 Dataset(XLS)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Trypanosoma cruzi. An estimated eight million people infected with T. cruzi currently reside in the endemic regions of Latin America. However, as the disease has now been imported into many non-endemic countries outside of Latin America, it has become a global health issue. We reviewed the transmission patterns and current status of disease spread pertaining to American trypanosomiasis at the global level, as well as recent advances in research. Based on an analysis of the gaps in American trypanosomiasis control, we put forward future research priorities that must be implemented to stop the global spread of the disease.American trypanosomiasis, commonly known as Chagas disease, is caused by the flagellate protozoan parasite The online version of this article (doi:10.1186/s40249-015-0092-7) contains supplementary material, which is available to authorized users. Please see Additional file Trypanosoma cruzi. It has been a neglected tropical disease and an important health problem in Latin America for many decades. With no vaccine yet available, only two proven drugs, namely benznidazole and nifurtimox, can be used for efficient treatment of acute cases. However 95 % of untreated patients advance into the chronic stage of the disease; at least 30 % then develop chagasic cardiomyopathy and up to 10 % can develop digestive, neurological, or mixed alterations. These all can lead to high morbidity and mortality rates among adults in endemic countries; the current number of annual deaths is at least 10,000 [American trypanosomiasis, commonly known as Chagas disease, is caused by the hemoflagellate protozoan parasite t 10,000 . The WorT. cruzi in Latin America [The disease is estimated to affect around eight million people in the Western Hemisphere, who are mainly distributed in Latin America. At least 120 million people are at risk of contracting the disease , 5 , sponsored by the European Community and the Latin America Triatominae Network, was launched in 2002. This programme has three main objectives, namely to (i) evaluate the risks of Chagas disease in these regions and propose monitoring and prevention of disease transmission, (ii) identify the research requirements for the monitoring and prevention of Chagas disease and, (iii) promote or establish an international cooperation system for the disease . To fulf created .T. dimidiata and R. ecuadoriensis may be feasible candidates for elimination in Ecuador and northern Peru, T. barberi may be a candidate for eradication in Mexico, and T. pallidipennis may require a more long-term control approach in Central America [T. cruzi” as an alternative to the “interruption of the vector transmission of T. cruzi” in endemic countries was proposed by the Southern Cone Initiative to Control/Eliminate Chagas Disease (INCOSUR) [Although there have been many achievements related to Chagas disease in endemic countries, controlling the disease still poses many challenges due to its zoonotic nature, which involves different domestic and wild reservoirs. Some of the reasons why controlling the transmission of the disease is so difficult are: native vectors reinfesting human habitats, modifications in population dynamics, and the development of resistance to insecticides. The other possible distracting element is that, in some areas, another species of triatomine bugs has adapted or substituted the principal vectors. For example,  America . More reINCOSUR) –37. ThusINCOSUR) , 37, 38.T. cruzi infection is the main measure implemented in all of the endemic Latin American countries, though the coverage has not yet reached 100 %  clinic diagnosis, case management, and treating patients, including infected newborns through congenital transmission; and (iii) sharing information about Chagas disease, and training health personnel to facilitate diagnosis and medical care [First, more joint efforts should be made at the global level to stop the disease spreading. Since 2007, the WHO has conducted a series of meetings, including “Control and prevention of Chagas disease in Europe (2009)” and “Informal Consultation on Chagas Disease in the Western Pacific (2011),” and issued the World Health Assembling resolution of “WHA63.20 Chagas disease: control and elimination (2010)". The general aim is to control Chagas disease in non-endemic countries and contribute to global efforts to interrupting disease transmission by (i) preventing cal care .T. cruzi infection, which has been carried out since 1999. Since then, mandatory screening of blood donors at risk for T. cruzi infection has been implemented in Spain (2005), Italy (2005), France (2009), and Switzerland (2013) [T. cruzi has not been mandated and remains voluntary [T. cruzi infection are excluded from giving blood [Second, a system for serological screening of blood or tissue donors needs to be established. The United Kingdom (UK) was the first country to implement the systematic screening of at-risk blood donations for d 2013) . In the oluntary . In Swedng blood . In othe013 . In ng blood . In the ng blood . In otheng blood .Third, a surveillance system for Chagas disease supported by prompt detection tests is urgently needed. The surveillance system for Chagas disease has been established at both the national and regional levels in European countries with the coordination of the WHO. However, biological diagnosis is not standardized in terms of the choice of tests and algorithms, and no practical gold standard diagnostics are available. It is recommended that commercial tests become available in non-endemic regions. Frequently, the use of only one test may be sufficient for screening blood donors, but the WHO recommends using two different serological tests for disease diagnosis. The main issue is to screen and treat chronically infected non-pregnant women of childbearing age in order to prevent vertical transmission.In general, all of non-endemic countries need to work together to increase networking at the global level, which focuses on strengthening global epidemiological surveillance and the sharing of information; prevent transmission by blood transfusions, organ transplantation, and congenital transmission; and promote diagnostic tools for the management of diagnosed cases.Given that more than 100 species of domestic and wild mammals serve as reservoirs for the transmission of Chagas disease, and a number of species of Triatominae serve as potential vectors in nature, this has made the control Chagas disease transmission very difficult. Despite the remarkable progress made by the aforementioned control initiatives, key challenges still need to be addressed.T. infestans, as contributing to the ongoing active transmission of Chagas disease in the Bolivian Chaco region in spite of progress in vector control. In such a scenario, vector monitoring is still a priority.Further efforts are required to maintain and consolidate the achievements made in Chagas disease control, particularly in endemic areas where prevalence is at a low level, and in non-endemic areas where Chagas disease is a new public health issue. Research priorities must be diversified to simultaneously support the development of multiple, alternative control strategies that adapt to these new epidemiological scenarios. In endemic countries, although experience from campaigns against Triatominae throughout the Latin Americas should have led to the main species of domestic populations being interrupted, transmission data from some areas pertaining to peridomestic and wild vectors, rather than domestic ones, is still not available. It is in these areas where disease emergence has been reported and may include local oral outbreaks of food-borne Chagas disease. There have also been reports on the emergence of some resistance foci to pyrethroid insecticides of the main domestic vector, e.g. The development of innovative strategies to explore the biological and behavioral traits of triatomine bugs and paying more attention to new triatomine species is a way to sustain the control programme. This is an important approach for the control of Chagas disease transmission. At the global level, there is a continual need to support established community-based surveillance networks and develop new community networks in disease emerging regions. In order to sustain control efforts, information sharing is of great importance. There needs to be a better integration of knowledge and disciplines into disease prevention and control programmes that goes beyond the involvement of the academic sector, private industry, ministries of government, and local communities. The development of a national database for epidemiological surveillance of Chagas disease using geographical information system (GIS) techniques has also been proposed . The UNIT. cruzi, whereas diagnosis of chronic American trypanosomiasis relies on serological methods. Serological methods include indirect hemagglutination, indirect immunofluorescence antibody, and enzyme-linked immunosorbent assay (ELISA). Up until now, 11 commercialized T. cruzi infection rapid diagnostic tests have been evaluated, with the SERODIA®-Chagas test, the ImmunoComb® II Chagas Ab Kit, and the SD Bioline Chagas Ab Rapid test showing higher performance rates than the other tests [T. cruzi-infected individuals. Another scholar has evaluated five serological methods and two molecular methods by rapid diagnostic tests for Chagas disease and proposed that the commercial Bioelisa Chagas® test showed the highest sensitivity and specificity; the amplification of T. cruzi DNA in blood samples showed low values of sensitivity, but high values of specificity [T. cruzi antigens is being conducted [T. cruzi epimastigotes has also shown to be effective in the diagnosis of Chagas disease, and it has been reported that this technique can be used as a confirmatory test [T. cruzi from urine and was useful for the early diagnosis of congenital Chagas disease [The diagnosis of Chagas disease is an important component of national control programmes. Cure rates with early treatment with benznidazole or nifurtimox in infants is close to 100 % and 60–80 % in children under 15 years old, but declines to nearly 0 % in the late chronic phase of the disease –53. It ier tests . Moleculcificity . Rapid dcificity . Therefoonducted . Secondlonducted . Thirdlyory test . A proof disease . MeanwhiT. cruzi parasite will not develop major clinical manifestations, and only a third of these infections will develop into the chronic phase [T. cruzi, namely posaconazole and ravuconazole, have been entered into controlled proof-of-concept studies [Current treatment options for Chagas disease are limited to only two drugs: benznidazole (Rochagan/LAFEPE and Abarax/ELEA) and nifurtimox (LAMPIT/Bayer). Often, these two drugs are effective in treating acute cases, but show limited efficacy in chronically infected patients. Most people infected with the ic phase . Even inic phase . Treatmeic phase –62. Receic phase , 64. In  studies . Unfortu studies . The new studies .T. cruzi genotypes and coinfection with HIV/AIDS has been raised. For example, different pathologies of Chagas disease are caused by six discrete typing units of T. cruzi (TcI- TcVI) [T. cruzi congenital infection in Chile has been reported, and TcII and TcV lineages of T. cruzi were the most frequent in mixed infections [T. cruzi/HIV coinfection, and this will be extended to form a Latin American network in the future [With the interruption of Chagas disease and rapid urbanization, smaller numbers of new cases and acute cases are being reported. Most cases of Chagas disease are now in the chronic stage and frequently turn into a life-long infection. Therefore, awareness on the number of coinfections between mixed infections of different I- TcVI) . Variabifections . Coinfecfections –72. Out fections . Polypare future . Scientie future , 74.T. cruzi in the continent. However, more recently, Chagas disease has become a global health issue as it has started spreading to non-endemic countries. With globalization and climate change, much more attention has been paid to the spreading of American trypanosomiasis at the global level. More initiatives, such as serological screening of blood donors and surveillance systems to respond to imported cases of Chagas disease, have been established in European and other non-endemic countries.It has been demonstrated that the transmission of American trypanosomiasis, commonly known as Chagas disease, can be effectively interrupted by controlling the main vectors in endemic areas, which has been implemented in many Latin American countries. Other initiatives to control disease transmission have also been implemented, with great success, to protect the approximately eight million people infected with To prevent the introduction of the disease into non-endemic countries, three main actions are needed: (i) making more joint efforts at the global level to stop the disease spreading, (ii) establishing a system for the serological screening of blood or tissue donors, and (iii) forming a surveillance system for Chagas disease supported by prompt detection tests. In order to stop the current global spreading of the disease, research priorities should focus on the development of (i) innovative strategies to sustain control successes, (ii) new and sensitive diagnostic tools, (iii) new drugs and chemotherapy schemes, and (iv) determinants for measuring coinfection and comorbidities, as well as polyparasitism. These activities will all support Chagas disease control and elimination programmes.