The Inuit population in Greenland has undergone rapid socioeconomic and nutritional changes simultaneously with an increasing prevalence of obesity. Therefore, the objective was to examine fetal programming as part of the aetiology of obesity among Inuit in Greenland by investigating the association between birth weight and measures of body composition and fat distribution in adulthood.The study was based on cross-sectional data from a total of 1,473 adults aged 18–61 years in two population-based surveys conducted in Greenland between 1999–2001 and 2005–2010. Information on birth weight was collected from birth records. Adiposity was assessed by anthropometry, fat mass index (FMI), fat-free mass index (FFMI), and visceral (VAT) and subcutaneous adipose tissue (SAT) estimated by ultrasound. The associations to birth weight were analyzed using linear regression models and quadratic splines. Analyses were stratified by sex, and adjusted for age, birthplace, ancestry and family history of obesity.Spline analyses showed linear relations between birth weight and adult adiposity. In multiple regression analyses, birth weight was positively associated with BMI, waist circumference, FMI, FFMI and SAT with generally weaker associations among women compared to men. Birth weight was only associated with VAT after additional adjustment for waist circumference and appeared to be specific and inverse for men only.Higher birth weight among Inuit was associated with adiposity in adulthood. More studies are needed to explore a potential inverse association between birth size and VAT. The Inuit population in Greenland has undergone rapid social, nutritional and health transitions during the last decades, coupled with high levels of obesity, type 2 diabetes and ischemic heart disease Globally, changes in lifestyle behaviors as a result of transition and urbanization patterns may play an important role in explaining the observed increase in obesity prevalence and related co-morbidities The role of birth weight in the development of obesity has to our knowledge never been studied in Greenland or in other Arctic populations. The aim of our study was therefore to investigate the relations between birth weight and adult body composition and fat distribution measured by ultrasonography among the adult Inuit population in Greenland.The study was based on cross-sectional data from two population-based surveys conducted in Greenland in 1999–2001 and 2005–2010. Participants were selected as a random sample of adult Inuit in Greenland (aged 18+ years). For both studies, participants were recruited to fill out self-administered questionnaires and personal interviews, and participated in a clinical examination. Written informed consent was obtained from participants before investigation, and the studies were approved by the ethical review committee of Greenland, and have thus been performed in accordance with the 1964 Declaration of Helsinki and its later amendments. The study methods are described in detail elsewhere From a total of 4,221 participants who went through clinical examinations, information on birth weight was available for 1,532 ethnic Greenlanders, primarily those born after 1950. Of those with available birth weight information we excluded individuals born before 1950, as birth weight before this year was not systematically registered (n = 6). Moreover, 50 individuals were excluded due to missing values on one or more of selected covariates. The remaining 1,473 individuals constituted the study population of the present study.Information on birth weight (kg) was gathered from medical records at hospitals. The records included birth records, midwife records and outpatient records of participants, and for the latest years information from the central birth register of Greenland. There was no systematic difference in covariates between individuals with traced and non-traced birth records except for place of birth (town vs. village); slightly more individuals in towns had available information on birth weight compared to individuals in villages. The questionnaires used as survey instruments for personal interviews and self-administered questionnaires were available in both Greenlandic and Danish. A trained research team performed all clinical measurements.2).Weight (kg) and height (cm) were measured with the participants wearing underwear and socks. Waist circumference (cm) was measured midway between the rib cage and the iliac crest on the standing participant. BMI was calculated as weight divided by height squared  was calculated as fat mass divided by height squared and FFMI (kg/m2) was calculated as fat-free mass divided by height squared.Bio impedance and calculation of fat mass were performed on a leg-to-leg Tanita TBF-300MA . Fat mass was calculated as the total weight of fat from the internal algorithm of the device based on height, weight, sex, impedance and age Information on sex and age was retrieved from the central personal register, while birthplace, ancestry, and family history of obesity were collected from the survey questionnaires. Birthplace was categorized as either town or village. Ancestry was based on questions on ethnicity of the four grandparents, and if this information was missing, on the parents' ethnicity. The variable was subsequently recoded as full Inuit  and mixed Inuit (at least one grandparent or parent was not a Greenlander). Family history of obesity was determined based on whether the participant's parents and/or siblings were reported obese or severely overweight. The variable was dichotomized as yes (any parent or sibling was regarded obese/overweight) and no.model 1); multiple regression analyses with adjustment for the chosen potential confounders  (model 2); and regression analyses with further adjustment for adult waist circumference in models including VAT and SAT as outcome measures (model 3). Model 3 was performed to examine the effect of birth weight on VAT and SAT in adulthood conditioned on the effect of adult abdominal body size.Regression models were used to assess the effect estimates of associations between birth weight and adiposity measures. To obtain symmetry of residuals, the adiposity measures were all log-transformed; coefficients were therefore backtransformed and expressed as percentage change per 1 kg change in birth weight. In all models we tested for a sex-birth weight interaction, which resulted in significant interactions in models with waist circumference and FFMI. All analyses were, however, stratified on sex due to biological differences in body composition and fat distribution between genders. The linear regression analyses were performed in three steps; unadjusted regression analyses of the adiposity measures as a function of birth weight  and measures of adult adiposity  (outome variables). The splines were interpolated with three knots placed at 2.5 kg, 3.5 kg and 4.5 kg on the birth weight scale. We calculated predicted values for a person with prespecified values of the covariates . We tested for linearity by comparing the spline model to a model with linear effect of birth weight.Statistical analyses were performed using the statistical software SAS, version 9.3  and R, version 3.0.2 2 was reported among 15% of men and 19% of women. Women had a higher mean fat mass and mean SAT than men, while men on average had a higher fat-free mass and VAT than women.Population characteristics are summarized in (a-f) and (a-f) show the shape of the associations for the continuous relations between birth weight and the different adiposity outcomes for men and women, respectively, estimated by using quadratic splines. The spline analyses in general showed no indication of non-linear associations. Neither did the tests for linearity indicate deviation from linearity except in models with FMI (p = 0.006) and FFMI (p = 0.025) as adiposity outcome among women, where there was an indication of an increase for a birth weight above 4.5 kg.. Birth weight was positively associated with BMI and FMI for both genders after adjustment for potential confounders (model 2). A difference in birth weight of 1 kg corresponded to a 13.1%  higher FMI for men, and a 9.1%  higher FMI for women. Moreover, there was a significant positive association between birth weight and FFMI among men only with a 3.7%  higher FFMI per kg difference in birth weight, significantly different from that in women.The results of the multiple linear regression models are shown in Birth weight was positively related to waist circumference indicating an increased risk of overall abdominal obesity. There was, moreover, a positive association between birth weight and SAT among men with a 15.8%  higher SAT per kg birth weight (model 2), and the same but weaker trend among women. Birth weight was not associated with VAT, however, additional adjustment for waist circumference (model 3) resulted in an inverse association with VAT among men only, with a decrease of 4.1%  per kg difference in birth weight conditioned on waist circumference.We aimed to investigate the relations between birth weight and adult body composition and fat distribution among the Inuit population in Greenland. Our findings showed that birth weight was positively associated with BMI, waist circumference, FMI and FFMI with generally weaker associations among women as compared to men. Birth weight was similarly positively associated with SAT, whereas an association with VAT was only apparent after adjustment for adult waist circumference for men.The demonstrated relation between birth weight and FMI emphasizes that higher birth weight increases the relative fat mass in adulthood. Furthermore, we also found that birth weight was more strongly associated with FMI than with FFMI. This finding contradicts results from other studies reporting positive associations between birth weight and fat-free mass rather than fat mass A challenge mentioned in the literature is that absolute measures of lean and fat mass represent, not only the proportion of compartments, but also body size itself To our knowledge, this is the first study conducted in Greenland or in any other Arctic population, examining birth weight and later development of adult adiposity. An explanation of the observed associations between birth weight and measures of body composition is that the impact of fetal growth on the tendency to deposit fat relative to lean mass is specific for Inuit. An association between the thermal environment during pregnancy and body mass in the offspring has been suggested in the literature, pointing at climatic adaptions which might already start during fetal life When adjusting for waist circumference we found a statistically significant inverse association between birth weight and VAT among men. There was no statistically significant effect among women, but the difference in effects between men and women were not significant either, suggesting that the association was spurious.et al found a similar relation for men and women together after adjustment for overall adiposity et alet alet alThe adjustment for waist circumference in our study was biologically and clinically grounded, as we wanted to elucidate the independent effect of birth weight on VAT and SAT by removing the impact of individual abdominal body size. Other studies have similarly adjusted for an overall adiposity measure, most frequently BMI We have followed the recommendation of Lucas and Cole et al, where birth weight was suggested to have limited influence on SAT. A recent study found that the level of SAT among the Inuit population in general is higher compared to other populations, while VAT does not differ from other populations Our findings of positive associations between birth weight and SAT are in contrast to the findings by Rolfe et alExcept for the association between birth weight and VAT among men conditional on waist circumference, our results did not show an increase in adiposity among individuals with low birth weight. These findings are in agreement with results from a meta-analysis by Schellong Overall, our results indicate that birth weight influences later development of adult adiposity among Inuit in Greenland. Whether our results are due to fetal programming and support the fetal origins hypothesis is hard to determine. Greenland has like many other countries undergone a rapid transition towards a more westernized lifestyle et al examining 1,092 adults in the UK A major strength of this study is that information on birth weight is collected from birth records in contrast to many previous studies that have used self-reported birth weight, which could have introduced recall bias. The large number of participants with fat distribution measured by ultrasound is another strength of this study. The relation between birth size and intra-abdominal fat distribution measured by ultrasound has to our knowledge only previously been studied by Rolfe The use of splines to examine the shape of the associations made it possible to explore and test non-linear relations between birth weight and adult adiposity, and to establish that the log-transformed adiposity measures approximated linear associations with birth weight. The effect of log-transformation, and the results expressed in percentage change see , makes iAs a consequence of lack of information on gestational age we were not able to differentiate between infants born preterm and IUGR infants. Gestational age could therefore confound our findings. However, a number of studies adjusting for gestational age, suggest that gestational age only has limited impact on the association between birth size and later adiposity In conclusion, our data suggest that higher birth weight is associated with a higher degree of adiposity in adulthood. In men, low birth weight is associated with an increased risk for accumulation of VAT after adjustment for waist circumference. However, in the present study we cannot determine whether this result is an effect of birth weight or a result of change in body size between birth and adulthood. Longitudinal studies with repeated measurements of adiposity are needed to distinguish the impact of postnatal growth from that of birth size.


The operational taxonomic units (OTUs) (p < 0.05) and the estimators of community richness (Chao) indexes (p < 0.05) showed a significantly lower diversity in LBW than NBW neonates. There were significant variations in the composition of placenta microbiota between the LBW and NBW neonates at the phylum and genus level. Furthermore, it indicated that Lactobacillus percentage was positively associated with birth weight . In conclusion, our present study for the first time detected the relationship between birth weight and placental microbiome profile in full-term neonates. It is novel in showing that the placental microbiome varies in association with low birth weight in full-term neonates.Substantial evidence indicated that low birth weight was an independent risk factor for obesity, impaired glucose regulation, and diabetes later in life. However, investigations into the association between low birth weight and placental microbiome in full-term neonates are limited. Placentas were collected from low birth weight (LBW) and normal birth weight (NBW) full-term neonates  consecutively born at Peking Union Medical College Hospital. The anthropometric measurements were measured and 16S ribosomal DNAamplicon high-throughput sequencing were utilized to define bacteria within placenta tissues. It showed that birth weight, ponderal index, head circumference, and placenta weight were significantly lower in LBW than NBW neonates ( However, the pathogenesis of diabetes has not been clearly understood yet. Traditionally it has been widely acknowledged that genes together with adult lifestyle factors including diet and exercise habits determine the risk of developing some chronic non-communicable diseases such as obesity, insulin resistance, and diabetes mellitus in later life. Recently, attention has been paid to distal risk factors in early life. There is substantial evidence that intrauterine environment plays a critical role in determining our susceptibility to these diseases in adulthood, which is known as “fetal programming hypothesis” . The pio in life . In our  in life ,5.The human microbiome is an enormous community of microorganisms occupying the habitats of the human body. Different microbial communities are found in each of the varied environments of human anatomy. The aggregate microbial gene totally surpasses that of the human genome by orders of magnitude . In 2007The placenta is a vital organ that connects the developing fetus to the uterine wall to allow nutrient uptake and gas exchange (via the mother’s blood supply), fight against internal infection, and produce hormones to support pregnancy . For a lInformed written consent was obtained from all participants, and the study protocol was approved by the Institutional Review Board and Ethics Committee of Peking Union Medical College Hospital (S-002).i.e., sexually transmitted infection, urinary tract infection, skin abscesses, appendicitis, periodontal disease, or bacterial meningitis) were excluded from the study.The risk factors for low birth weight, such as smoking, drug use, poor maternal weight gain, prior low birth weight baby, little education, and low income were also excluded from the study.The study population consisted of 24  full-term neonates  consecutively born at Peking Union Medical College Hospital Birth weight was used to identify cases and controls: low birth weight (LBW) is <3000 g and normal birth weight (NBW) is ≥3000 g and <4000 g. The birth weight of <3000 g but not <2500 g was determined as the cut-off due to the fact that birth weight <2500 g neonates only took a very small proportion in our full-term subjects. The more important reason is that low birth weight (<3000 g) is also an independent risk factor for later impaired glucose tolerance and diabetes in previous studies . All theAll samples were collected by trained pathology personnel according to the method previously described . Briefly3. The body weight of each neonate and placenta weight were determined to the nearest 1 g using an electronic scale. Body length was determined to the nearest 0.1 cm in the supine position with a length board. Head circumference was determined with a plastic tape to the nearest 0.1 cm.Data were collected at delivery according to our previous publication . Three t® DNA Kit . The V3-V4 region of the bacteria 16S ribosomal RNA gene were amplified by PCR using primers 338F 5′-ACTCCTACGGGAGGCAGCA-3′ and 806R 5′-GGACTACHVGGGTWTCTAAT-3′, where barcode is an N-base sequence (N represent a unique 6 to 8-nt barcode) unique to each sample. PCR reactions were performed in 20 μL mixture containing 4 μL of 5 ×FastPfu Buffer, 2 μL of 2.5 mM dNTPs, 0.8 μL of each primer (5 μM), 0.4 μL of FastPfu Polymerase, and 10 ng of template DNA. Because of the concern for bias in low-abundance samples, all specimens were thrice extracted and thrice run to enable triplicate extraction and sequencing. Sequences from all three extractions were combined for analysis, according to the method previously described [Microbial DNA was extracted from placental tissue (about 100–150 mg) using the E.Z.N.A.Amplicons were extracted from 2% agarose gels and purified using the AxyPrep DNA Gel Extraction Kit . Purified amplicons were pooled in equimolar and paired-end sequenced (2 × 300) on an IlluminaMiSeq platform according to the standard protocols. Raw fastq files were demultiplexed, quality-filtered using QIIME (version 1.17) with the following three criteria: (1) The 300 bp reads were truncated at any site receiving an average quality score <20 over a 10 bp sliding window, discarding the truncated reads that were shorter than 50 bp; (2) exact barcode matching, two nucleotide mismatch in primer matching, reads containing ambiguous characters were removed; (3) only sequences that overlap longer than 10 bp were assembled according to their overlap sequence. Reads which could not be assembled were discarded. Operational Units (OTUs) were clustered with 97% similarity cut-off using UPARSE (version 7.1)  and chimt-test. Unweighted UniFrac distance metrics analysis was performed using OTUs for each sample and PCoA plots based on unweighted Unifrac metrics. Metastats was used to compare the relative abundance of each taxon at different taxonomic levels between LBW and NBW neonates [p value < 0.05 were considered to indicate statistical significance. All statistical analysis was calculated with SPSS 21.0 .The data were expressed as the mean ± standard deviation (S.D.). Statistical analyses of anthropometric measurement were performed with Student’s neonates . Correlavs. 3452 ± 96, p < 0.01), ponderal index , head circumference  and placenta weight  were significantly lower in LBW than NBW subjects. The birth weight of normal birth weight subjects in our present study is similar to the birth weight for the babies delivered at Peking Union Medical College Hospital in one previous study [The clinical characteristics and anthropometric measurements were shown in us study . Howevervs. 48.44 ± 7.89, p = 0.026) and Chaoindexes  between NBW and LBW groups, demonstrating the significantly lower richness found in LBW neonates compared to NBW neonates.A total of 403,965 high-quality sequences were produced in this study, with an average of 16,831 sequences per sample . The GooCloser analysis of bacterial differences induced by birth weight were determined by sequencing the 16S rRNA encoding genes present in the placenta. PCA of IlluminaMiSeq amplicon data demonstrated significantly separate clustering of the placenta communities between LBW and NBW groups with principal component (PC1) percent variation explained = 96.89% and PC2 percent variation explained = 0.7%. It indicated that there was a statistically significant clustering by virtue of body weight .Firmicutes. The relative abundance (%) of Firmicutes was decreased in LBW group, while Proteobacteria and Actinobacteria were increased in LBW group, compared with NBW group. At the genus level, the dominant phylum of the two groups was Enterococcus. The relative abundance (%) of Enterococcus was decreased in LBW group, while Lactococcus and Bacillus were increased in LBW group, compared with NBW group. The relative abundance of microbiota sequences revealed that microbial structures of the placenta differed significantly between LBW and NBW groups. The heatmap according to bacterial genus level also demonstrated the same phenomenon . The microbial composition was also significantly different at the genus level, with 13 significantly different genera between LBW and NBW groups (p < 0.05). It is indicated that the relative abundance (%) of Lactobacillus, Clostridium_sensu_stricto_1, Cyanobacteria_unclassified, Ruminococcus, Lawsonia and Cyanobacteria_norank were significantly lower in LBW group at the genus level. Conversely, the relative abundance (%) of Megasphaera, Faecalibacterium, DSSF69_norank, Jeotgalicoccus, Pediococcus, Sneathia, and Sphingobacterium were significantly higher in LBW group, compared with NBW group   of sequences belonging to a specific bacterial genus and birth weight were performed by using Spearman’s correlation analyses. It is indicated that = 0.025) .Substantial studies have shown that low birth weight can significantly increase the predisposition to the development of some metabolic diseases such as obesity and diabetes in adult life. Recently, numerous studies demonstrated that the microbiota could be considered as one major player in the development of obesity and diabetes mellitus ,23. TherOur present study indicated that the placenta of LBW neonates had significantly lower bacterial richness and evenness than NBW neonates. In the gut, one large clinical study also demonstrated that individuals with a low bacterial richness are characterized by more marked overall adiposity, insulin resistance, and dyslipidaemia, which indicated that a low bacterial richness may be associated with abnormal glucose metabolism . SimilarLactobacillus in humans are considered un-harmful. Some strains of Lactobacillus may possess potential therapeutic properties including anti-inflammatory activities, as well as other features of interest. Several studies also showed that probiotic products could regulate blood glucose levels in diabetic human and Lactobacilli are often used as probiotic agents [et al. reported that oral administration of Lactobacillus casei strain Shirota had the potential to prevent obesity-associated metabolic abnormalities by improving insulin resistance in diet-induced obesity mice [Lactobacillus rhamnosus was detected in placenta samples independent of the mode of delivery. It also indicated that DNA from intestinal bacteria was found in most placenta samples and the horizontal transfer of bacterial DNA from mother to fetus may occur via placenta [Lactobacillus may be the potential probiotic to modulate the placenta microbiota. However, more evidence and further investigation will be needed.Furthermore, 16S-based OTU analyses in our study revealed the relative abundance of Lactobacillus was negatively associated with birth weight. Most c agents . Naito eity mice . One stuplacenta . Therefon = 12), it has not been possible to perform a multivariate analysis, whose results are more reliable than those from univariate one. The fourth limitation was that the used definition of low birth weight (<3000 g) is not that universally accepted. This was due to the fact that birth weight <2500 g neonates only took a very small proportion in our full-term subjects. The more important reason is that low birth weight (<3000 g) is also an independent risk factor for later impaired glucose tolerance and diabetes in previous studies. However, our present study is also very meaningful which established an important theoretical foundation of metagenomic studies in placenta of different birth weight neonates. Another potential limitation to our study was the overall low abundance of microbiota in the placenta. However, we were able to overcome the limitations of low-abundance microbiome by multiple biological and technical replicates.To our knowledge, our present study for the first time demonstrated the relationship between birth weight and placental microbiome profile in neonates. Strengths of this study also include that microbial sequences were isolated and identified successfully from placenta tissue which harbors a low-abundance microbiome. More important, the sterile sample collection and robust analysis were rigorously conducted. However, there are some limitations to our study. One primary limitation was the small sample size. Because low birth weight neonates only took a very small proportion in our study subjects which consisted of full-term and spontaneous birth by vaginal delivery neonates in order to minimize the effect of some confounding factors such as gestational age (full-term or preterm) and the mode of delivery . Our ongoing work is aimed to enlarge the sample size for further research. A second limitation was that our study just focused on comparative 16S rDNA analysis but not metagenomic studies which can provide additional insight into the function of complex microbial communities and their role in host health. Therefore, our further research will be focused on the function of microbial communities in placenta and their role in neonates and mothers. A third limitation was that due to the small sample size (In conclusion, our present study is novel in showing that the placental microbiome varies in association with low birth weight in full-term neonates.


Maternal diet during pregnancy was assessed by seven dietary patterns. Multivariable linear regression models described the association of WLZ, WAZ, LAZ, and HCZ with diet patterns controlling for other maternal and child characteristics. In bivariate analyses, WAZ and HCZ were significantly lower for processed and processed-Southern compared to healthy dietary patterns, whereas LAZ was significantly higher for these patterns. In the multivariate models, mothers who consumed a healthy-processed dietary pattern had children with significantly higher HCZ compared to the ones who consumed a healthy dietary pattern . No other dietary pattern was significantly associated with any of the birth outcomes. Instead, the major outcome determinants were: African American race, pre-pregnancy BMI, and gestational weight gain. These findings justify further investigation about socio-environmental and genetic factors related to race and birth outcomes in this population.Despite increased interest in promoting nutrition during pregnancy, the association between maternal dietary patterns and birth outcomes has been equivocal. We examined maternal dietary patterns during pregnancy as a determinant of offspring’s birth weight-for-length (WLZ), weight-for-age (WAZ), length-for-age (LAZ), and head circumference (HCZ) Z-scores in Southern United States ( Pregnancy is a critical period for the offspring’s metabolic development . Inadequa priori and a posteriori approaches [a priori scores of foods and nutrients based on a hypothesis . The seet Score ,21. For et Score ,27,28,29a priori scores [Few studies have examined the association between pregnancy or preconception dietary patterns and birth outcomes; most used principal component analysis or factor analysis ,33,34,35i scores ,36,37,38i scores ,34,35,39i scores ,32,39. TDue to the important differences in eating patterns by geography, culture and other context-specific characteristics of the population, we sought to determine the influence of specific dietary patterns on birth size outcomes in a diverse, largely black African-American and low-income population residing in the South of the US. The objective of this study was to examine the extent to which maternal dietary patterns are associated with offspring size at birth . Dietary patterns were used to describe patterns that emerge from the data and display the unique features of that population which may not be captured by any predefined score. We hypothesized that dietary patterns characterized by energy-dense, nutrient-poor processed foods that are high in saturated and trans fats, sodium, and refined sugars would be associated with lower birth weight, length, and head circumference compared to healthy dietary patterns during pregnancy.This analysis was conducted in a pregnancy cohort of 1151 women who were followed from the second trimester of pregnancy until delivery.The Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study is a longitudinal cohort study set in Shelby County, the southwestern corner of the state of Tennessee. Shelby County is largely African-American with mid-level education, and low income status (<200% poverty level). The CANDLE study aims to investigate the effects of different exposures such as mother’s prenatal habits and characteristics, home environment and childhood experiences, genetics, and exposure to potentially harmful substances on the neurocognitive development of children from birth to age three years. The study was conducted in accordance with the Helsinki Declaration and was approved and reviewed by the Institutional Review Board of the University of Tennessee Health Science Center on 17 June 2014 .Women were eligible to enroll in the CANDLE study if they were between 16–28 weeks pregnant, were a resident of Shelby County, had a low medical risk pregnancy, were between the ages of 16–40 years, spoke and understood English, had a single pregnancy and were willing to give consent. The CANDLE study recruited a total of 1503 pregnant women; 1474 mother-child dyads were available for follow up after excluding post-consent ineligibilities, pre-delivery withdrawals, and fetal demises. Of the 1474 participants, 1151 had diet data at the visit between 16–26 weeks, when their diet was assessed.Outcomes were Z-scores for weight-for-length (WLZ), weight-for-age (WAZ), length-for-age (LAZ), and head circumference (HCZ). Exposure of interest was the maternal dietary patterns that have been previously assessed via factor analysis . IndepenData used for this study were collected during the second trimester and at birth. During the second trimester, participants completed questionnaires asking about demographics, health status, diet, and medical history. At birth, research assistants conducted medical chart abstractions for birth outcomes .Diet Instrument: Diet was assessed at enrollment (16–26 weeks of pregnancy) using the Block 2005 food frequency questionnaire (FFQ) that asks consumption of 111 food and drink items during the previous three months [n = 152).e months ,42,43. Te months . InterviDietary patterns: Seven dietary patterns were identified previously using exploratory factor analysis with principal component extraction and varimax rotation method to determine the frequency of 111 food and beverage groups that made up distinct dietary patterns. Volgyi et al. [i.e., processed meat, fast food items, snacks, sweets, and soft drinks); Southern ; healthy-processed; healthy-Southern; Southern-processed, and mixed. The “mixed” pattern reflects foods from all of the other patterns together. In brief, to create the patterns, Volgyi and colleagues [i et al.  describelleagues  estimatelleagues .The demographic survey: Administered during enrollment asked respondents about formal education, medical insurance, annual household income, age, race and ethnicity.Maternal baseline data form: At the time of enrollment, researchers collected the participant’s self-reported pre-pregnancy length and weight, tobacco use, alcohol use, and total number of pregnancies . Pre-pregnancy body mass index (BMI) was calculated using the self-reported heights and weights.Labor and delivery forms and neonatal summary forms: At the time of labor and delivery, the following information was abstracted from the medical charts: maternal weight and newborn birth weight, length, and head circumference.i.e., mean, standard deviation, frequencies and percent frequencies) were reported for all socio-demographic, behavior, and health characteristics. These variables were cross-tabulated by race, dietary patterns, and birth outcomes, and significant differences were assessed. Pearson correlations were conducted to assess linear relationship between birth outcomes and dietary patterns. Bivariate associations (least square means comparisons) were conducted between outcomes of interest  and maternal socio-demographic  and health characteristics  and sex of the newborn.For full term infants (≥37 weeks), WHO Child Growth Standards were used to calculate Z-scores for each outcome WLZ, WAZ, LAZ and HCZ . Normal p-values reported were not adjusted for multiplicity; therefore, the results must be considered in a hypothesis generating context. All analyses were performed using SAS version 9.3.Multivariable models for each outcome variable were constructed to describe their association with the exposure of interest . These models were adjusted for any maternal socio-demographic or health characteristic that was independently and significantly associated with the outcomes of interest and with the exposure of interest in bivariate models. An alpha level of 0.05 was used for all statistical tests and intrans fats, total grains and potato servings. In contrast, the healthy-Southern dietary pattern had the highest content of fiber, folate, egg-meat equivalents, oils, vegetables  and fruits (including fruit juice). The healthy-processed was characterized by high intake of nuts, seeds, whole grains, and dairy, as well as highly refined foods that are higher in simple sugars and fat. The healthy dietary pattern had the lowest energy, fat, total sugar, sodium, egg-meat equivalents and meats, and highest content of protein, carbohydrate, and soy legumes.2), be less likely to smoke, less likely to have completed higher education, and more likely to have Medicaid/Medicare insurance compared to the European Americans. Dietary patterns were significantly different by racial group, with European Americans and other race more likely to report a healthy dietary pattern. Mean birth weight for age, length for age, and head circumferences were significantly lower for African American offspring. European Americans were less likely to have more than one pregnancy.p < 0.05) with weight-for-age Z-Score (WAZ), and head circumference Z-Score (HCZ), and positively associated with length-for-age Z-score (LAZ).In bivariate analyses, eating processed and processed-Southern dietary patterns compared to healthy dietary pattern were negatively associated . None of the other dietary patterns were significant predictors of any birth size outcome after adjusting for confounders.Variables that were associated with the various outcomes of interest in the bivariate analyses and also with the exposure of interest were included in the final multivariable model using race as a control variable. We also constructed each model for each race sub-group independently, controlling for potential confounders identified in the bivariate analyses. Since results by race groups were similar, we show the multivariable model that includes race as a control variable , which iThis study examined the potential association between maternal dietary patterns during pregnancy and birth outcomes in a diverse population with historical high burden of low birth weight and other adverse birth outcomes ,48,49. TOur findings are somewhat comparable to those from previous publications in which dietary patterns characterized with nutrient-rich foods such as fruits and vegetables, whole grains, and water were associated with larger birth size outcomes,34,35,39A potential explanation for this discrepancy is the antagonistic interaction among nutrients and food sources in the combined dietary patterns consumed by this population. For example, the healthy dietary pattern in the current study includes vegetables, fruits, non-fried fish and chicken, and water, similar to other studies, with the caveat that other studies have also included oils in their healthy pattern ,33,34,50Although each dietary pattern has a variety of foods containing nutrients that have been shown to be antagonistic in their health effects, these dietary patterns were distinct in their nutrient profile and explained a large variance in food intake. Other potential explanations for our findings may have to do with socioeconomic or racial characteristics of the study population. Volgyi and colleagues  showed ti.e., the mixed diet patterns).The results of this study are limited by their reliance on self-reported dietary intake, the inherent limitations of quantifying dietary intake with a food frequency questionnaire, and the inevitable overlap between different dietary patterns. However, we took measures to overcome some of these limitations by excluding from the analyses all potential over and under-reporters of total caloric intake. In addition, the dietary patterns did show distinct factor loadings, suggesting that this population does eat diet patterns that combine “healthy” and “unhealthy” food items in an overlapping manner (In sum, our findings do not provide sufficient evidence that either the healthy or the processed dietary pattern in this population is uniquely associated with positive or negative birth outcomes. The mixed dietary patterns consumed by this study population may provide antagonistic relationships between foods and nutrients that result in null associations with birth outcomes. To further investigate this hypothesis, it would be necessary to discriminate the population by nutrient or micronutrient status, perhaps using biomarkers to potentially disentangle any antagonistic effects in foods or preparations. Our results also imply that there are other socio-environmental and maybe genetic aspects related to race in the Southern US that require careful further investigation in their association with birth outcomes.


The single most critical intervention to improve maternal and neonatal survival is to ensure that a competent health worker with midwifery skills is present at every birth, and transport is available to a referral facility for obstetric care in case of an emergency. This study aims to describe changes in percentage of skilled birth attendants in Ghana and to identify causes of the observed changes as well as the contribution of different categories of mother’s characteristics to these changes.This study uses two successive nationally representative household surveys: the 2003 and 2008 Ghana Demographic and Health Surveys (GDHS). The two datasets have comparable information on household characteristics and skilled attendants at birth at the time of the survey. The 2003 GDHS database includes information on 6,251 households and 3639 live births in the five years preceding the survey, whereas the 2008 GDHS database had information on11, 778 households and 2909 live births in the five years preceding the survey. A decomposition approach was used to explain the observed change in percentage of skilled birth attendants. Random-effects generalized least square regression was used to explore the effect of changes in population structure in respect of the mother’s characteristics on percentage of skilled birth attendants over the period.Overall, the data showed absolute gain in the proportion of births attended by a health professional from 47.1% in 2003 to 58.7% in 2008, which represents 21.9% of gap closed to reach universal coverage. The increase in skilled birth attendants was found to be caused by changes in general health behaviour. The gain is regardless of the mother’s characteristics. The structural change in the proportion of births in respect of birth order and mother’s education had little effect on the change in percentage of skilled birth attendants.Improvement in general health behaviour can potentially contribute to an accelerated increase in proportion of births attended by skilled personnel in Ghana.The online version of this article (doi:10.1186/s12884-014-0415-x) contains supplementary material, which is available to authorized users. Improvement in maternal and neonatal survival remains a global priority. Globally, the total number of maternal deaths decreased from 543,000 in 1990 to 287,000 in 2010 [The single most critical intervention to improve maternal and neonatal survival is to ensure that a competent health worker with midwifery skills is present at every birth, and transport is available to a referral facility for obstetric care in case of an emergency . IncreasThis study used two successive nationally representative household surveys: the 2003 and 2008 GDHS ,7. The tThe 2003 GDHS database included information on 6,251 households and 3639 live births in the five years preceding the survey, whereas the 2008 GDHS database had information on 11, 778 households and 2909 live births in the five years preceding the survey. The two surveys offered the opportunity for analysing coverage trends in the proportion of births attended by a skilled professional.The exposure of interest for this study include mother’s age at birth, birth order, maternal education ,11, and Examining coverage trends is essential for assessing country progress. Information on trends requires at least two separate and comparable measurements at two points in time. A measure of progress - coverage gap - defined as how much coverage would need to increase from 2003 level to reach universal coverage was estimated to examine coverage trends. The change from 2003 to 2008 was then expressed as a percentage of this gap.To explain the observed change in percentage of skilled birth attendants, the decomposition approach was used. Several regression decomposition approaches exist in the literature. The conventional Blinder-Oaxaca ,15 decomFor these models, Blinder  and OaxaYA − YB is the mean outcome difference, and XA and XB are mean vectors of the estimated coefficient vectors bA and bB for the two groups. In both equations, the first term on the right-hand side displays the difference in the outcome variable between the two groups due to differences in observable characteristics, whereas the second term shows the differential that is due to differences in coefficient estimates.andα)); and 3) variation of the proportion of births attended by skilled professional by exposure variables (β), and the residual effect of other variables not considered as the error term (μ) [The approach used in this paper divides the change in percentage of skilled birth attendants into change in population structure and change in health behaviour and/or public health over the two time periods (or groups) 2003 to 2008 ,17. The term (μ) . This cawhere Δ denotes change,S = percentage of skilled birth attendants,jth category of the exposure variable,wj = the population structure for the jth category of the exposure variable.jth category of the exposure variable,Δwj = change in population structure expressed as a fraction for the jth category of the exposure variable, and,x = the level of an exposure variable, e.g. maternal age was categorized as 1 (<20 years), 2 (20–34 years), and 3 (35–49 years). So x = 1, 2, 3.The parameters in the mathematical model were estimated using an Excel spreadsheet program developed for this analysis and it is attached as an Additional file In a separate analysis, the effect of changes in population structure in respect of the mother’s characteristics (i.e. exposure of interest) on percentage of skilled birth attendants over the period was explored using the random-effects generalized least squares (GLS) regression. Independent panel datasets were constructed for each of the characteristics . The panel was defined as the category of the exposure of interest and the order of observations within panel was considered ordered by the number of surveys (two in this case). For example, the birth order and maternal education datasets each contains eight observations, while the household wealth index dataset contains 10 observations. Each dataset contains the following variables: the panel identifier, time identifier, proportion of births in each category of the characteristics (i.e. population structure), and percentage of skilled birth attendants. The analyses were performed with Stata 12 for Mac  .The random-effects GLS regression model can be specified as follows:vi + ϵit is the residual that we have little interest in; the interest is to estimate β (the effect of change in the structure of the exposure of interest). wit is the population structure of the exposure of interest in the ith panel at survey time, t. vi is the unit-specific residual; it differs between units, but for any particular unit, its value is constant. ϵit is the “usual” residual with the usual properties  [In this model, edastic) .In all analyses, key survey characteristics such as sampling weight, stratification and clustering were accounted for.Ethical approval for the surveys was obtained from the Ghana Health Service. All participants gave a verbal or written consent by either appending their signature or thumb printed the consent form. Parental consent was obtained for children and where the child was capable, an assent was obtained from the child in addition to parental consent. Participants were informed about the aim of the study. Personal identifiers were not taken as part of data collection. The data available for this study cannot be linked to an individual who participated in the study. Approval was granted by Macro International to use the data for this study.The 2008 GDHS recorded 2,909 births compared with 3,639 births in 2003. The more educated a woman was, the more likely she was to have delivered with the assistance of a skilled attendant but this population structure has changed over the period Table . For insThe change in percentage of skilled birth attendants was decomposed by birth order, mother’s education and household wealth index. This decomposition may contribute to the understanding of how the observed changes related to variations in the survey population structure or to changes in public health and/or changes in behaviour. In general, the decomposition results indicated that health behaviour were the principal source of the gain in percentage of skilled birth attendants between 2003 and 2008 regardless of the exposure variable  and mother’s education  on change in percentage of skilled birth attendants (Table This study aims to describe changes in percentage of skilled birth attendants and to identify causes of the observed changes as well as the contribution of different categories of mother’s characteristics to these changes. The results showed that the gain in percentage of skilled birth attendants observed in Ghana between 2003 and 2008 is regardless of the mother’s characteristics, suggesting that the observed changes are due to the general improvement in health behaviour. The findings are consistent with studies, which showed that socio-cultural factors are important predictors of skilled delivery. For example, in a literature review of the determinants of delivery service use, Gabrysch and Campbell 2009 found that perceived benefit and need affect the decision to seek delivery care . The heaSpecific knowledge about the risks of childbirth and the benefits of skilled attendant at delivery can increase preventive care seeking. Similarly, recognition of danger signs and knowledge about availability of key maternal and newborn interventions can increase care seeking for obstetric complications. Most studies like the GDHS on use of delivery care are cross-sectional and it is difficult to establish temporal effect. This then is a limitation of such studies. Studies have shown that women who know danger signs in pregnancy or who are told about complications at antenatal care are more likely to deliver in a health facility ,21. The The results have implications for consideration of culturally acceptable options that increase demand or use of health workers with lesser skill levels. The creative alternatives such as the community-based health planning and services or use of mobile teams of at least one female community health officer that can provide services should be consolidated. Communication for behavioral Impact  strategiImprovement in general health behavior can potentially contribute to an accelerated increase in proportion of births attended by skilled personnel in Ghana. Skilled delivery care would translate into improved maternal and newborn survival.The data used for this study can be accessed through the following links:http://www.measuredhs.com/publications/publication-FR221-DHS-Final-Reports.cfm.http://www.measuredhs.com/publications/publication-FR152-DHS-Final-Reports.cfm.


Exciton superfluid is a macroscopic quantum phenomenon in which large quantities of excitons undergo the Bose-Einstein condensation. Recently, exciton superfluid has been widely studied in various bilayer systems. However, experimental measurements only provide indirect evidence for the existence of exciton superfluid. In this article, by viewing the exciton in a bilayer system as an electric dipole, we derive the London-type and Ginzburg-Landau-type equations for the electric dipole superconductors. By using these equations, we discover the Meissner-type effect and the electric dipole current Josephson effect. These effects can provide direct evidence for the formation of the exciton superfluid state in bilayer systems and pave new ways to drive an electric dipole current. Since the idea of excitonic condensation was proposed about fifty years ago124678910111213141011121617Before any further discussion, we need first to point out the specificity of excitons in bilayer systems. Because the electrons and holes are separated in space and bound with each other by the Coulomb interaction, the exciton in a bilayer system can be seen as a charge neutral electric dipole  describes the i-direction current with the electric dipole pointing to the j-direction. In analogy with the spin current (or the magnetic dipole current)32n in the classical system or ψ in the quantum system. In this work, we focus on the situation where the direction of the electric dipole p0 is fixed in the z-direction (as is the case in a bilayer exciton system), thus we only need a vector Jp = np0v to describe the electric dipole current with p0. To combine Jp = np0v and Jp with respect to time iswhich accelerates the dipole. Here, E accelerates the super electric currentE = −∂B/∂t, we have C being independent of the time t. In the present case, Jp = 0 deep inside the dipole superconductor, the variation of the magnetic field along the z direction, C. First, we consider a limiting case when the external magnetic field Bext is zero. Then if Jp is zero, the magnetic field Bind induced by Jp is also zero, the total magnetic field B = Bext + Bind = 0 and the constant C is zero. Obviously, in this case, the free energy of the system is the lowest and it is lower than the case with a non-zero constant C. Thus we take C to be zero due to the requirement of thermodynamic stability. Second, when the external magnetic field Bext changes from zero to a finite value, the constant C remains zero because that it is a conserved quantity. Thus, we get the London-type equation for Jp,where gradient of a magnetic field B will induce a super electric dipole current. As is shown in Bz/∂z < 0, the super dipole current flows in the counterclockwise direction  B = μ0(jf + ∇ × M + ∂D/∂t)jf stands for the free electric current and D is the effective electric field. In the equilibrium case, ∂D/∂t = 0 and with no free electric current present, only the super dipole current exists, so we obtain the magnetic field equation in the electric dipole superconductor:Equations gradient of an external magnetic field, which will be studied below. We can see the effect of equation β → ∞. In this case, the total magnetic field gradient ∂zBz has to vanish everywhere inside an electric dipole superconductor in order to satisfy the equation gradient ∂zBz is completely screened out.The London-type equation ψ(r) to describe it. Then its free energy can be written as Fs = ∫Vfsdr, where fs is the free energy density. In analogy with the superconductor, fs can be expressed as:Since the electric dipole condensate is a macroscopical quantum state, we can use a quasi-wave function (or the order parameter) fn is the density of free energy in normal state and the momentum operator α(T)|ψ(r)|2 and β(T)|ψ(r)|4/2 are the lower order terms in the series expansion of the free energy fs, which have similar meanings as those in the normal superconductor22p + p0 × B)ψ(r)|2/2m* can be viewed as the kinetic energy of the electric dipole superconductor (see Methods). Substitute B = ∇ × A and minimize the free energy with respect to ψ* and the magnetic vector potential A respectively, we get (see Methods)where whereJp is exactly the super dipole current density. It should be noted that equation ψ(r) can be written as |ψ(r)|eiθ(r), where |ψ(r)|2 is proportional to the density of dipoles n and θ represents the phase. For simplicity, we assume the amplitude |ψ| is the same everywhere in the dipole superconductor, whereas the phase θ(r) are allowed to change in order to account for the super dipole current. Substitute ψ = |ψ(r)|eiθ(r) into equation Equations rout located in a non-uniform external magnetic field Bext created by a cylindrical hollow conductor with an inner (outer) radius Rin (Rout) and a height h :In the following, we use the London-type equations to analyse the Meissner-type effect. We begin by considering a two-dimensional circular electric dipole superconductor with a radius shown in . The disent see , which cBind. Since the counterflow current in bilayer and the rotational symmetry about the z axis, the induced magnetic field Bind in middle plane m only has the nonzero r-component gradientm which can easily be calculated from the Biot-Savart law  superconductor. Also notice in d of the dipole superconductor is very small now. If for the thick dipole superconductor or for very small m*, gradient of the total magnetic field vanishes inside of the dipole superconductor. A/m) in the Hall specimenA/m, so it should be detectable using the same method.In the calculation, we take cylindrical hollow conductor sizes as here see . The twoThe most remarkable phenomenon of the Bose-Einstein condensate macroscopic quantum system is superfluid, e.g. the zero resistance phenomenon of the (monopole) superconductor19zE can excite a super dipole current. This excited super dipole current will maintain for a very long time if the dipole resistance is zero. Now, consider an annular dipole superconductor specimen. This annular specimen is placed below the cylindrical hollow conductor  superconductor are similar, i.e., the super electric dipole current is jp = j0 sin γ0, where γ0 = γ1 − γ2. j0 is the Josephson critical super dipole current, and γ1, γ2 are phases of the dipole superconductors.The Josephson effect is another highlight of the superconductorzEx. From the first Ginzburg-Landau-type equation x-direction) passes through the Josephson junction. Its expression is γ = γ0 − ω0t with jp = j0 sin(γ − ω0t). It shows that the dipole current is an alternating current, although the electric field spatial variation is time-independent. We can compare this with the (monopole) superconductor. For the superconductor, a time-independent electric field (or bias) can drive an AC Josephson current. Now a spatial variation of an electric field drives an AC dipole Josephson current.Now we study the AC dipole current Josephson effect and consider an electric field variation ∂V2 and V2 to the right sides between the bilayer, it establishes an electric field in −x (x) direction in the bottom (top) layer  = v ⋅ (p0 × B)34m* is the effect mass of the electric dipole. The canonical momentum is An electric dipole moving with velocity p0 × B is analogous to the term eA/c for an electron in a magnetic field. So the kinetic energy term of the electric dipole superconductor can be written as: The term ψ*. For the second and third terms of Eq. First of all, we minimize the free energy shown in For the fourth term, we getIt should be noted thatCombining Eqs. andJPn = 0, which means that there is no electric dipole current entering or leaving the electric dipole superconductor. Similar discussions on boundary condition of the [monopole] superconductor can be found in the original paper written by Ginzburg and LandauEq. A. For the fourth term of Eq. Next, we minimize the free energy with respect to the vector potential A, we getIf we variate the last term of Combining Eqs. It should be noted that in the derivation the surface integral vanishes due to the requirement of free energy minimization22How to cite this article: Jiang, Q.-D. et al. Theory for electric dipole superconductivity with an application for bilayer excitons. Sci. Rep.5, 11925; doi: 10.1038/srep11925 (2015).


Electrical energy is a type of energy that is commonly used in daily life. Ventricular premature beats, ventricular tachycardia, ventricular fibrillation, atrial tachycardia, atrial fibrillation, bundle branch blocks, and AV block are arrhythmic complications that are encountered in case of electric shocks. Myocardial infarction is one of the rarely seen complications of electric shocks yet it has fatal outcomes. Coronary arteries were detected to be normal in most of the patients who had myocardial infarction following an electric shock. So, etiology of myocardial infarction is thought to be unrelated to coronary atherosclerosis in these cases. Coronary artery vasospasm is thought to be the primary etiological cause. In our case report, we presented a patient who developed ST elevation MI with atrial fibrillation after an electric shock. Electrical energy is the commonly used energy type in daily life. However, electric shocks can lead to a wide range of clinical conditions from skin burns to fatal arrhythmic complications. Cardiac effects of electric shock include accelerated hypertension, arrhythmia, acute myocardial infarction (MI), and cardiac rupture –3. VentrIn our case report, we presented a patient who developed ST elevation MI with atrial fibrillation after an electric shock.A 50-year-old male patient admitted to the emergency because of an electric shock which occurred 15 minutes before . The patient indicated that as soon as he touched the wall plug to switch on light, he was shocked from his right hand and found himself lying on the floor of his home. He stated that he had lost his consciousness with the shock and after recovery he had found out he had a tightening chest pain radiating to his left arm. His pain had continued increasingly. Arterial blood pressure ratio was measured as 140/80 mmHg on examination of the patient. Pulse was arrhythmic and tachycardic. No lesion was observed regarding the electric shock entry and exit points. Sinus tachycardia, increase in the amplitude of the T-wave at inferior derivations, and ventricular premature beats were monitored in the performed ECG .After establishing a vascular access, routine blood tests were performed and the patient was monitored by connecting to a defibrillator. Nearly after ten minutes, atrial fibrillation developed with a sharpened chest pain. In the performed ECG, ST segment elevation in inferior derivations and ST segment depression in V1–V3 derivations were observed . In ordeElectric shock can cause adverse outcomes on human body. Various clinical conditions from simple burn lesions to fatal arrhythmias could be observed in case of electric shocks. In a recently conducted study, electric shock was found to be only 2.2% of the injuries admitted to emergency service; however, it was reported to be 42.9% of the fatal injuries . It is iCoronary arteries were detected to be normal in most of the patients who had MI following an electric shock. So, etiology of myocardial infarction is thought to be unrelated to coronary atherosclerosis in these cases. Coronary arterial vasospasm , direct In our case, association of electric shock induced ST elevation at inferior derivations and AF was observed. The AF developed during monitorization can be due to either direct arrhythmic effect of the electric shock or ischemic myocardium. AF disappeared soon after normalization of ST segment. This makes us consider the ischemic etiology on foreground.Since the primary cause is vasospasm, fibrinolytic therapy should not be considered as the first option for electric shock induced ST elevation MI treatment. Electric shock induced multiple traumas and/or hematomas may also cause contraindication for fibrinolytic treatment. According to all of these, in such cases first treatment option should be percutaneous coronary angioplasty , 16.Electric shock injuries can result in serious situations such as arrhythmia and myocardial infarction. Arterial vasospasm should be considered as one of the etiologies of ST-elevated MI developed after an electric shock.


Recent surveillance data suggest that mean birth weight has begun to decline in several developed countries. The aim of this study is to examine the changes in birth weight among singleton live births from 2002 to 2012 in Guangzhou, one of the most rapidly developed cities in China.We used data from the Guangzhou Perinatal Health Care and Delivery Surveillance System for 34108 and 54575 singleton live births with 28–41 weeks of gestation, who were born to local mothers, in 2002 and 2012, respectively. The trends in birth weight, small (SGA) and large (LGA) for gestational age and gestational length were explored in the overall population and gestational age subgroups.The mean birth weight decreased from 3162 g in 2002 to 3137 g in 2012 . The adjusted change in mean birth weight appeared to be slight (−6 g from 2002 to 2012) after controlling for maternal age, gestational age, educational level, parity, newborn's gender and delivery mode. The percentages of SGA and LGA in 2012 were 0.6% and 1.5% lower than those in 2002, respectively. The mean gestational age dropped from 39.2 weeks in 2002 to 38.9 weeks in 2012. In the stratified analysis, we observed the changes in birth weight differed among gestational age groups. The mean birth weight decreased among very preterm births (28–31 weeks), while remained relatively stable among other gestational age subcategories.Among local population in Guangzhou from 2002 to 2012, birth weight appeared to slightly decrease. The percentage of SGA and LGA also simultaneously dropped, indicating that newborns might gain a healthier weight for gestational age. Birth weight is an important predictor of both short and long-term child health outcomes. Low or high birth weight is associated with higher risks for neonatal morbidity and mortality In recent years, a few studies examined secular trends of birth weight in China. Data from Perinatal Health Care Surveillance System in southeast China showed the mean birth weight for all term infants increased from 3296 g in 1994 to 3378 g in 2000, then leveled off to 3369 g in 2005 Guangzhou is one of the most developed regions in China. During the last few decades, there has been a dramatic change in the economic conditions and the number of births per year in Guangzhou. Demographic, social and economic conditions are known as determinants of health in general, including birth weight In Guangzhou Annual Maternal and Child Health Report, we found that the mean birth weight tended to decrease linearly from 2002 to 2012 The electronic Guangzhou Perinatal Health Care and Delivery Surveillance System (GPHCDSS) database was implemented in 2000, and covers over 97% of deliveries in Guangzhou The analyses limited to singleton live births among local population delivered between 28 and 41 completed weeks of gestation in 2002 and 2012. The following data were extracted from the electronic GPHCDSS records: maternal age and educational level, parity, delivery mode, date of birth, newborn gender, gestational age and birth weight. A total of 88822 records of singleton live births (28–41 completed weeks of gestation) born in 2002 and 2012 were retrieved and 139 were excluded due to misclassification of gestational age or invalid birth weight. Final analyses included 88683 singleton births (34108 births in 2002 and 54575 births in 2012). Of the total, 47420 were delivered vaginally.Newborns were categorized according to gestational age in completed weeks as: very preterm birth (28–31 weeks), moderate or late preterm birth (32–36 weeks) The institutional review board of Guangzhou Women and Children's Medical Center approved the study.pf, the primary component which describes the actual weight distribution, and sf, the secondary component, which consisted of implausible values. That can be briefly expressed in a formula as: x, y) belongs to the pf distribution depends on the weight estimation: p/fw =  qf. The birth weight values that have a lower probability of belonging to primary distribution than 0.5 were considered implausible To avoid misclassification of gestational age and invalid birth weight that might bring bias in gestational age-specific birth weight distributions At each of the weeks of gestational age 35 to 41, where birth weight distributions were symmetric unimodal with long tails, robust regression was used to do M estimation to identify invalid birth weights We performed multiple linear regression analysis to examine the birth weight changes after adjustment for maternal age, gestational age, educational level, parity, newborn's gender and delivery mode. To examine the impact of maternal and newborn's characteristics changes over time on birth weight for gestational age, we standardized the proportions of SGA and LGA in 2012 to the population in 2002 by maternal age, educational level, parity, delivery mode and gestational age distributions (direct standardization).Statistical analyses were performed using SAS statistical software version 9.2 .Over the 10-year period, the number of births per year increased by 60.0% in Guangzhou. There were no significant tendencies for a systematic change in birth weight within different completed weeks of gestation. In the overall singleton live births, the proportion of very low birth weight remained fairly stable at 0.2%, while low birth weight increased from 4.2% in 2002 to 4.9% in 2012. Macrosomia decreased from 3.2% to 2.3%. The percentage of SGA and LGA simultaneously dropped, respectively, by 0.6% and 1.5% . Table 3The present study analyzing a large sample size based on the local population in Guangzhou, China has shown that birth weight had a slight decrease and the shifts in birth weights between 2002 and 2012 were inconsistent among gestational age groups. The crude birth weight decreased among singleton preterm births, while remained relatively stable among early term (37–38 weeks) and full term (39–40 weeks) births and increased among late term (41 weeks) births. Results of adjusted regression analyses showed that the decreasing birth weight change was limited to very preterm birth (28–31 weeks), while birth weight among other gestational age subcategories remained relatively stable.This finding of changes in birth weight is not consistent with that found in previous studies investigating birth weight trends. Most of previous studies included only births that occurred before 2005 and the analyses were restricted to full term births. On analysis of term singleton births in the United States from 1990 to 2005 observed decreases in birth weight  and the mean birth weight declined within each completed week of gestational age Weight for gestational age is a better outcome measure accounting fetal growth The changes in gestational age and birth weight for gestational age might be affected more strongly among preterm than term births due to changes over time in the assessment of gestational age The principal limitation of our study was lack of more precise information to answer more specific questions that were addressed in other studies from general population We analyzed the changes in birth weight between 2002 and 2012 in singleton live births in a large population in Guangzhou. There was a slight decrease in mean birth weight. The percentage of SGA and LGA also simultaneously dropped, indicating that newborns might gain a healthier weight for gestational age.S1 FigFrequency distributions of birth weight for 28-33 weeks of gestation before (upper) and after (lower) excluding the implausible data in 2002. The upper one shows the frequency distributions of birth weight before excluding. The lower one shows the frequency distributions of birth weight after excluding.(TIF)Click here for additional data file.S2 FigFrequency distributions of birth weight for 28-33 weeks of gestation before (upper) and after (lower) excluding the implausible data in 2012. The upper one shows the frequency distributions of birth weight before excluding. The lower one shows the frequency distributions of birth weight after excluding.(TIF)Click here for additional data file.


Birthweight remains one of the strongest predictors of perinatal mortality and disability. Birthweight percentiles form a reference that allows the detection of neonates at higher risk of neonatal and postneonatal morbidity. The aim of the study is to present updated national birthweight percentiles by gestational age for male and female twins born in Australia.Population data were extracted from the Australian National Perinatal Data Collection for twins born in Australia between 2001 and 2010. A total of 43,833 women gave birth to 87,666 twins in Australia which were included in the study analysis. Implausible birthweights were excluded using Tukey’s methodology based on the interquartile range. Univariate analysis was used to examine the birthweight percentiles for liveborn twins born between 20 and 42 weeks gestation.Birthweight percentiles by gestational age were calculated for 85,925 live births . Of these infants, 53.6 % were born preterm (birth before 37 completed weeks of gestation) while 50.2 % were low birthweight (<2500 g) and 8.7 % were very low birthweight (<1500 g). The mean birthweight decreased from 2462 g in 2001 to 2440 g in 2010 for male twins, compared with 2485 g in 1991–94. For female twins, the mean birthweight decreased from 2375 g in 2001 to 2338 g in 2010, compared with 2382 g in 1991–94.The birthweight percentiles provide clinicians and researchers with up-to-date population norms of birthweight percentiles for twins in Australia. Birthweight remains one of the strongest predictors of perinatal mortality and disability , 2. BirtThe aim of the study is to present updated national birthweight percentiles for all male and female liveborn twins born in Australia over the 10-year period between 2001 and 2010.Population-based data on twins born in Australia between January 2001 and December 2010 were obtained from Australian Institute of Health and Welfare National Perinatal Data Collection (NPDC). The NPDC is a national collation of jurisdictional population-based cross sectional data collections of pregnancy, childbirth and perinatal outcomes. Information is included in the NPDC on both live births and stillbirths of at least 400 g birthweight or at least 20 weeks gestation.Records with missing birthweight, infant sex or gestational age values were excluded from calculating the birthweight-by-gestation percentiles. In addition, records with implausible birthweight were identified using Tukey’s methodology  based onLevel of remoteness was based on the geographical location of the usual residence of the mother, and was classified into five groups: major cities of Australia, inner regional Australia, outer regional Australia, remote Australia and very remote Australia.Univariate analysis was used to examine the birthweight distributions and to determine the interquartile range for each gestational age for twins born in Australia. After removing outliers exact percentiles of birthweight in grams were calculated for each gestational week between 20 and 42 weeks. Results for the 5th and 95th percentile are presented only for gestational ages with a minimum of 100 records and the 10th and 90th percentile are plotted only for gestational ages with a minimum of 50 records, to be consistent with previously published Australian birthweight percentiles [Ethics approval for this study was granted by the Human Research Ethics Advisory Panel of the University of New South Wale, Australia (Reference number: 2013-7-07) and Australian Institute of Health and Welfare Ethics Committee (Reference number: EO 2013/2/17). As secondary data analysis of de-identified data set, additional consent from participants was not required. Approval for use of data was provided by all states and territories.Between 2001 and 2010, a total of 43,833 women gave birth to 87,666 twins in Australia. Table Among the 85,925 live births , 53.6 % were born preterm (birth before 37 completed weeks of gestation) while 50.2 % were low birthweight (<2500 g) and 8.7 % were very low birthweight (<1500 g) (Table p = 0.49). For female twins, the mean birthweight significantly decreased from 2375 g in 2001 to 2338 g in 2010 (p < 0.001)  and female .Figure We developed the contemporary population-based birthweight percentile charts to provide an up-to-date reference for twins born in Australia.Growth in twin pregnancies slows progressively from around 32 weeks until term . When coTwin pregnancies have an increased risk of adverse outcome compared to single pregnancies. The increase in perinatal mortality and morbidity is primarily related to preterm delivery, complications of monochorionicity, and fetal growth restriction. Accurate population data is required to accurately diagnose growth restriction in twin pregnancies.Secular trends for a decrease in the overall mean birthweight for liveborn twins were observed for both male and females in Australia in the study period. In contrast the mean birthweight for liveborn singletons in Australia from a similar time period has been relatively stable . The obsPopulation-based birthweight percentile charts for twins are scarce –17. WhenThere is inherent appeal in the customisation of growth charts that incorporate maternal weight, height, ethnicity as well as plurality. The intent is to identify fetuses that are small as a consequence of growth restriction rather than constitutionally small for clinical decision-making. Several large observational studies have suggested that customised charts improve the identification of infants with intrauterine growth restriction compared with population based charts, although contrasting opinions exist –22. BirtThe provision of these updated birthweight percentile charts allows clinicians and researchers to re-evaluate the success of pregnancy management by determining the rate of detection of growth restriction. As previously described, growth restriction is the major cause of late fetal death in twin pregnancies and its accurate diagnosis a focal point of good obstetric care.in utero until term [One limitation of this study is that birthweight percentile charts do not measure intrauterine growth but rather size at birth. The birthweight of babies born prematurely is likely to be influenced by the pathological process leading to preterm birth and therefore likely to differ from those remaining til term , 26. It til term . Howevertil term . To datetil term , 28. In This study presents the up-to-date national population-based birthweight percentile charts for male and female live born twins in Australia. These new charts provide a valuable reference for clinicians and researchers correctly identifying high-risk twins in Australia.


MACS) showed no benefit in the reduction of major neonatal mortality/morbidity or neurodevelopment at 2 and 5 years of age. Using the data from the randomized controlled trial and its follow-up, the aim of this study was to evaluate the association between gestational ages at birth in children exposed to single versus multiple courses of antenatal corticosteroid (ACS) therapy in utero and outcomes at 5 years of age.The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study  compared to 38/249 (15.3%) in the single ACS therapy; OR = 1.69 ; p = 0.037.Gestational age at birth was strongly associated with the primary outcome, Preterm birth (<37 weeks gestation) remained the primary factor contributing to an adverse outcome regardless of the number of courses of ACS therapy. Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment by 5 years of age. To optimize outcomes for infants/children, efforts in reducing the incidence of preterm birth should remain the primary focus in perinatal research.NCT00187382)This study has been registered at (identifier The online version of this article (doi:10.1186/1471-2393-14-272) contains supplementary material, which is available to authorized users. MACS) is an international, multicenter, double-masked, randomized controlled trial that compared multiple courses of antenatal corticosteroids (ACS) given every 14 days to a single course in women at increased risk for preterm birth; p = 0.004. There was no interaction between ACS group and gestational age at birth with respect to neurocognitive/neurobehavioral disability or death.Gestational age at birth was strongly associated with primary outcome as defined for 5 years of age, In this secondary analysis, we were able to demonstrate that preterm birth remained the primary driver contributing to an adverse neurodevelopmental outcome regardless of the number of courses of ACS. The earlier an infant was born, the higher the chances of experiencing an adverse outcome. In this study, half of the children who were born <30 weeks gestation were presenting with at least one of the components of the composite outcome. These figures are consistent with many studies that show that the more preterm infant continues to be at high-risk for adverse outcomes and that these numbers have not changed dramatically over the past decades–10. ChilMACS found no improvement in preterm birth outcomes and demonstrated a significant decrease in birth weight, length and head circumference following administration of multiple ACS, generating concern that there may be potential for harm[As with most interventions there are benefits but also potential risks that must be balanced. for harm. With thfor harm. PreviouMACS, 32% of the women gave birth at term[MACS cohort, less than 1% of the infants born at term had any components of the primary neonatal outcomes and less than 5% of the adverse neurodevelopmental outcomes at 18–24 months[In  at term. InfantsThe term infant may be seen as one means of observing specific effects of ACS as they, in general, are less at risk for many of the growth and neurologic impairments often seen in children born preterm, 13. MorAnimal studies have demonstrated the deleterious effects of multiple courses of ACS on critical nerves within the central nervous system such as the optic and auditory nerve–14. DunlThere are limitations to this secondary analysis, as the groups based on gestational age at birth were defined after randomization thus making it plausible that there may have been pre-existing differences to account for the findings. Notwithstanding, the strengths of the study are that the data came from a large randomized controlled trial and that greater than 80% of the cohort has been followed. The neonatal outcomes of the children who were followed and those who were not followed were comparable reassuring us that there was a balance in the gestational groups and that the numbers were not inappropriately inflated in one group more so than another. Thus the results do present some concern about potential long-term consequences of multiple ACS therapy which clinicians need to consider especially if the benefits of multiple ACS are not substantial.In this secondary analysis, preterm birth was found to be the primary factor contributing to an adverse neurodevelopmental outcome regardless of the number of courses of ACS. Children born ≥ 37 weeks and exposed to multiple ACS therapy may have an increased risk of neurodevelopmental/neurosensory impairment. To optimize outcomes for infants/children, efforts in reducing the incidence of preterm birth should remain a primary focus in perinatal research as the morbidities associated with preterm birth continue to play an important role in the presence of long-term outcomes. Future research should focus on ensuring that ACS therapy be given at the most beneficial time for the fetus to optimize its outcome in the event of a preterm birth. Continued research is needed to answer questions on the long-term effects of exposure to ACS therapy, single and multiple, on later neurobehavioral function, disabilities, mental disorders, and any susceptibility to metabolic and cardiovascular disease.Additional file 1: Table S1: Initial perinatal/neonatal outcomes for all infants, those followed, and those not followed to 5 years of age. (DOCX 33 KB)


Information tracking changes of birthweight is scarce in China. To examine trends of low birthweight (birthweight < 2500 g) and macrosomia (birthweight ≥ 4000 g) and potential risk factors in Beijing, hospital records from two major obstetrics and gynecology hospitals in urban districts in Beijing were analyzed.Hospital records from 1996 to 2010 were retrieved. Information of prenatal examination and birth outcomes was entered into a structured database. Live births were used for trend analysis. Information of live births in 2010 was used to identify potential risk factors.A total of 63 661 live births were delivered during 1996–2010 in the study hospitals. The average birthweight increased from 3271 g in 1996 to 3 359 g in 2000 and slightly declined to 3 331 in 2010. The percentage of low birthweight fluctuated around 4.0%. No significant increase or decrease was observed. Preterm birth was the main cause of low birthweight, accounting for more than 73% of low birthweight. The average percentage of macrosomia was 7.6%. The percentages of macrosomia increased from 6.6% in 1996 to 9.5% in 2000 and declined to 7.0% in 2010. Excessive gestational weight gain and gestational diabetes were significantly associated with macrosomia.Continuously monitoring abnormal birthweight is needed and intervention should focus on appropriate gestational weight gain and reduction of preterm birth and gestational diabetes. Birthweight is an important indicator of the nutritional and developmental status of a newborn infant. Body mass index (BMI) before pregnancy, gestational weight gain, gestational diabetes mellitus (GDM), mother’s age and gender were reported to be associated with macrosomia (birthweight ≥ 4000) , while iFew studies examined secular trends of abnormal birthweight in recent years in China. One study reported an 11-year trend of macrosomia in southeast China with the prevalence increasing from 6.0% to 7.8% from 1994 to 2005 . The ChiThe purpose of this study is to examine trends of low birthweight and macrosomia and related factors in Beijing. China has undergone a dramatic economic and nutritional transition in the past several decades . Along wTwo hospitals in Beijing were selected based on the availability and completeness of hospital records: Beijing Obstetrics and Gynecology Hospital (BOGH) and Haidian Maternal and Child Health Care Hospital. Both hospitals focus on services in obstetrics and gynecology and have a large volume of birth delivery services. Their hospital records are more complete and reliable than other general hospitals. A total of 63 661 live birth records were retrieved in 1996, 1997, 1998, 1999, 2000, 2005, and 2010 from the two selected hospitals. Years of information were chosen based on how useful and complete the hospital records were. Eight records were discarded when using the gender variable because of missing information. Pre-pregnancy weight and height was not collected in the records before 2000. Records after 2000 collected weight and height based on self-reported information when mothers had their first prenatal care visit (within 14 weeks). Information of 11 006 live births from BOGH in 2010 was used to examine factors related to birthweight, because records from BOGH in 2010 had complete maternal information for the analysis of related factors. Information on 9674 first-born singletons was used in the final analysis.The study was approved by the research ethics committee of the Capital Institute of Pediatrics.2 in meter). According to BMI cutoffs for overweight and obesity in Chinese [According to the World Health Organization , a low b Chinese , maternaThe adequacy of gestational weight gain during pregnancy was classified into inadequate, adequate and excessive using the new recommendations from the Institute of Medicine (IOM) . These rPregnancy-induced hypertension (PIH) in this study was defined as hypertension (systolic blood pressure ≥ 140 mHg and/or diastolic blood pressure ≥ 90 mHg) that developed after 20 weeks with or without proteinuria. According to the recommendation from the Chinese Medical Association Obstetrics Group , GDM waschi square analysis for trends. Data in 2010 were analyzed to identify risk factors for abnormal birthweight. Multivariable logistic regression models were used to examine the association between maternal characteristics and abnormal birthweight and potential risks. Stepwise logistic regression was used for modeling to select independent variables among mother’s age, pre-pregnancy BMI, adequacy of gestational weight gain, amniotic fluid volume, gestation, gestational diabetes, PIH, newborns’ gender, mother’s education and nationalities. These variables were considered based on literature review for their relevance to abnormal birth weight and availability in the sample. Independent variables were selected by forward selection using maximum likelihood estimates and a significance level of 0.05. In logistic regression analysis only first-born singletons’ data was used since most children were first-born singletons under the one-child policy during the study period. Consistency and plausibility checks were conducted after data entry to minimize errors. Data analyses were performed with SPSS18.0 . The statistical significance was inferred at a 2-tailed P < 0.05.All information was entered in to EpiData3.1. One-way ANOVA was conducted to compare the means of birthweight among groups. Linear regression was performed to examine linear trends in birthweight over time using birthweight as the dependent variable. Percentages of low birthweight and macrosomia were compared using P < 0.001; after 2000, P < 0.001). Among a total of 63661 live births delivered during 1996–2010, 33402 (52.5%) were boys and the ratio of boys to girls was 110:100. No significant change in the ratio of gender was observed in the past 15 years. There was a steady increase in preterm birth from 1999 to 2010. The average birthweight is 3329 g (95% CI:2250-4250 g). Birthweight of male infants was about 4% higher than that of female infants.Maternal and birth outcome information is shown in Table The maternal age for giving birth increased significantly. The mean age of giving birth was 26.5 years in 1996 and increased to 29.9 years in 2010. The proportion of women older than 30 years increased significantly. Especially, the proportion of women 35 years or older in 2010 (11.5%) was fivefold of that in 1996 (2.1%). No significant change in maternal weight status was observed, though this information was only available after 2000. The gestational weight gain stayed at a relatively high level from 2000 onwards compared to IOM recommendations. The average weight gain in normal weight, overweight and obese women amounted to 1.1, 3.5 and 4.0 kg respectively, which corresponds to the upper level of IOM recommendations.P > 0.05), though an increase in very low birthweight percentage (birthweight < 1500 g) was observed (data shown in Table P = 0.017). Further analysis shows the portion of preterm low birthweight increased markedly over time. Among low birthweight infants, 73% were preterm in 2010. The figure also shows that the percentage of low birthweight infants born full term declined from 2.0% in 1996 to 1.2% in 2010.There is no clear trend of change in low birthweight percentages during this period of time Figure  (P > 0.0The percentage of macrosomia increased by the year of 2000 and slightly declined in 2005 and 2010 (Table When computing adjusted odds ratios for non-normal birthweight, stepwise logitstic regression using forward selection was performed to build the final models Table . The resSince a considerable number of women had excessive gestational weight gain, which is one of the risk factor for abnormal birthweight, the percentage of meeting or not meeting the IOM recommendations was tabulated according to their BMI categories Table . No moreThis study is the latest one that has examined the abnormal birthweight trends and related factors in the region. There has been no significant change in average birthweight in the past 15 years. It increased until 2000, and decreased since then. A woman’s age at the time of having a first birth increased significantly. The proportion of low birth weight varied between 3.3% and 4.9%, with no clear change patterns. The proportion of macrosomia increased from 6.6% in 1996 to 9.5% in 2000, then decreased to 7.0% in 2010.We believe our results represent the change of birthweight in the Beijing urban area for the past 15 years. Women who chose the two selected hospitals were regular residents of Beijing. They were presumably not different in demographics from others. Births in our study hospitals in 2005 and 2010 accounted for 17.2% and 14.0% of all births in Beijing, respectively. Hospital births accounted for 99.2% of all births in cities in 2010 . TherefoThe percentage of low birthweight in the study was higher than that in other major cities. Data show the percentage of low birthweight was 4.6% at the national level, 3.9% in cities and 4.8% in rural areas in 2005 . The perIt appears that there has been no significant reduction in percentages of low birthweight and preterm births in the past 15 years. The increase in preterm live births was observed in recent years. This could be due to the advanced perinatal care which has increased the survival rate of high-risk births including extremely preterm births and births with extremely low birthweigth. A national survey showed infants with birthweight less than 1500 g accounted for 3.8% of low birthweight in 1998 in major cities , while tPregnancy-induced hypertension was also found to be positively associated to low birthweight in this study. This finding is consistent with several other studies ,30. In aThe prevalence of macrosomia was relatively high varying from 6.6% to 9.5%, and the secular trend was similar to a recent report of macrosomia in southeastern cities in China , experieOf note, gestational weight gain exceeding the recommended amount is a concern because it is strongly related to macrosomia in the study. More than half of the women in the study gained more weight than recommended during pregnancy, while inadequate weight gain was of less concern. Further analysis shows that heavier women were more likely to exceed the recommended weight gain during pregnancy. These findings may reflect the traditional perception of weight gain during pregnancy—‘the bigger and heavier, the better’. This traditional notion came from the time when food was scarce and malnutrition was prevalent both among children and pregnant women in China. With the economic growth and great improvement in nutrition and living conditions during the past several decades, food has become more readily available than ever before. Dietary structure in the Chinese population has changed towards high calories, high fat and low fiber . Over-nuThis study was able to update the percentages of abnormal birthweight by utilizing 15-year obstetric records from two large obstetrics and gynecology hospitals in Beijing. However, some limitations need to be mentioned. Though the obstetric records provided relatively complete information about birth outcomes and maternal characteristics, we were not able to assess individual lifestyle factors such as diet, smoking and drinking that are reported to be related to birth outcomes. Due to limited resources, we were not able to assess data annually during 2000–2010, rather we included data of every five years to represent the change during this period of time. In addition, the results in the study only represent metropolitan and urban areas. Rural areas may have different patterns in the change of abnormal birthweight. Further study should be conducted to assess the percentages of low birthweight and macrosomia in non-urban regions in order to make appropriate recommendations and interventions. The number of available hospital records increased dramatically after 2000 because of improved completeness of records, an increase of the population, particularly of migrant workers , and theWhile the prevalence of low birthweight was maintained at a relatively low level, the prevalence of macrosomia was high over the past 15 years, which might have contributed to the current sharp rise in overweight and obesity among children and adolescents. As many studies show, birthweight is associated with health outcomes. Therefore, low birthweight and macrosomia should be closely monitored in order to plan prompt and effective intervention. Continuing efforts should be taken to address preterm birth, gestational weight gain as well as PIH and gestational diabetes, all of which may contribute to abnormal birthweight.The authors declare that they have no competing interests.XS, FC and WW contributed to the data analysis and manuscript writing. HT, JZ, YT, MW, XZ, HQ, XL, CT and JM contributed to the data collection, analysis and interpretation of the results. JM conceived, designed and directed this study, made critical revisions of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/14/105/prepub