Preterm birth is associated with abnormalities in growth, body composition, and metabolism during childhood, but adult data are scarce and none exist for their offspring. We therefore aimed to examine body composition and cardiovascular risk factors in adults born preterm and their children.A cohort of 52 adults  and their term-born children  were studied. Auxology and body composition  were measured, and fasting blood samples taken for metabolic and hormonal assessments.2; p=0.021) than men born at term (n=16). Adults born preterm also displayed a less favourable lipid profile, including lower HDL-C concentrations (p=0.007) and greater total cholesterol to HDL-C ratio (p=0.047). Children of parents born preterm tended to have more body fat than the children of parents born at term . Even after adjustment for mean parental BMI, children of parents born preterm had altered fat distribution, with more truncal fat (p=0.048) and greater android to gynoid fat ratio (p=0.009). Adults born preterm had greater abdominal adiposity, displaying more truncal fat (p=0.006) and higher android to gynoid fat ratio (p=0.004). Although women born preterm and at term were of similar weight and BMI, men born preterm (n=8) were on average 20 kg heavier (p=0.010) and of greater BMI (34.2 vs 28.4 kg/mAdults born preterm, particularly men, have markedly increased fat mass and altered fat distribution. A similar increase in abdominal adiposity was observed in the term born offspring of parents born preterm, indicating that adverse outcomes associated with preterm birth may extend to the next generation.  Several studies have described metabolic abnormalities in subjects born preterm (<37 weeks gestation), including reduced insulin sensitivity -3, increLongitudinal studies have evaluated postnatal growth and weight gain in children born preterm, and related these findings to size and measures of adiposity later in adolescence or early adulthood ,14. HoweTransmission of an environmentally acquired phenotype to subsequent generations is well described in animal studies of nutritional deprivation , as wellEthics approval for this study was provided by the Multiregion Ethics Committee . Written informed consent was obtained from parents or guardians, as well as verbal or written consent from each child as was appropriate to their age.1) were the offspring of mothers (F0) from the Auckland Steroid Trial initially recruited between 1969-1974 [The adults for this study (F969-1974 ) to rece969-1974 ,20,21.2). We used these details to recruit all singleton adults who had singleton prepubertal children aged 5–10 years born at term (37–42 weeks gestation)  . Adults All children were assessed at the Maurice & Agnes Paykel Clinical Research Unit . Data on each participant were collected during a single visit to the clinic. Neonatal parameters were recorded, including birth weight and gestational age. Birth weight data were transformed into standard deviation scores (SDS) .TM, GE Medical Systems, Wisconsin, USA). Following an overnight fast, blood samples were taken to measure plasma glucose, insulin, lipids, leptin, and cortisol concentrations. Insulin sensitivity assessments using hyperglycaemic clamps in the adults and intravenous glucose tolerance tests and Bergman’s minimal model in the children have been published previously [Weight and height were recorded, and for the children, weight and height of the parent not involved in the original study were also recorded. Body composition was assessed using whole-body dual-energy X-ray absorptiometry (DXA) scans , 1 (30–60 minutes at least 4 days/week), or 2 (>60 minutes at least 4 days/week). Food diaries were collected for two working days and one weekend day for each participant. Nutritional intake was estimated using standard household measures, and food labels where appropriate. Records were entered into Foodworks software  by a trained investigator, and the calculated mean daily caloric intake used for analysis.Glucose and lipids were measured on a Hitachi 902 autoanalyser  by enzymatic colorimetric assay . Insulin concentrations were measured using an Abbott Imax , by microparticle enzyme immunoassay. Leptin was measured with commercially available enzyme-linked immunosorbent assays . Cortisol was measured by chemiluminescence using a Roche  E170 Modular laboratory analyser, with an inter-assay coefficient of variation of 6%.Potential differences between groups at baseline were tested using one-way ANOVA or non-parametric Kruskal-Wallis, while sex ratio and ethnic composition data were compared with Fisher’s exact tests . All subsequence multivariate analyses were performed in SAS v.9.3 . 0 steroid exposure, age, and gender. For adult data (F1) small-for-gestational-age status was also controlled for in the model, while for the offspring (F2) birth weight SDS was included as a covariate. Other factors were controlled for as required, depending on the outcome response of interest: for lipids, hormones, and outcomes associated with glucose homeostasis – BMI was included; and for anthropometric data – the appropriate parental factor . The interaction effects between group and gender were tested in all models, and outcomes were assessed separately for males and females if there was indication of a differential response between genders.General linear regression models and random effect mixed models were used to assess differences between groups. Important confounding factors were adjusted for in the analyses, including ethnicity, F2, respectively.All statistical tests were two-tailed and maintained at a 5% significance level. Age data are presented as means ± standard deviations. Outcome data are presented as model-adjusted means , with associated 95% confidence intervals. Overweight and obesity for adults were defined as BMI 25–30 and ≥30 kg/m1) survivors previously traced at 30 years of age, 461 were born from singleton pregnancies, 207 had children aged 5–10 years, and 127 were living in the Auckland region  than men born at term (n=16)  . OverallBoth men and women born preterm had more body fat than those born at term p=0.011; . They alConsistent with their greater adiposity, adults born preterm had leptin concentrations that were 21% higher than those born at term p=0.042; . Adults We studied 61 children aged 8.0 ± 1.6 years (range 5.2–10.6 years), of whom 37 had a parent born preterm ; Table 1Children of parents born preterm were of similar height SDS and BMI SDS as the offspring of parents born at term , but chiBaseline cortisol concentrations were 27% higher in children of parents born preterm p=0.048; . HoweverThis study shows that adults born preterm, particularly men, have a marked increase in adiposity  in mid-adult life. Further, the impact of preterm birth on adiposity appears to extend to the following generation, as children of parents born preterm displayed similar alterations in fat distribution, with greater central adiposity.Our study is consistent with previous longitudinal data in young adults indicating greater adult adiposity in those born preterm ,16. ThosThe increase in adiposity in men born preterm was predominantly due to abdominal fat, and it was associated with lower HDL-C concentrations. Further, our recent analysis of insulin sensitivity in this cohort also showed that adults born preterm had higher fasting insulin concentrations and reduced insulin sensitivity . These fin utero [in utero and post-natally). Nonetheless, although the mechanisms underpinning worse outcomes among those born preterm are yet to be determined, our study shows that preterm birth is associated with adverse changes to body composition and metabolic parameters in adulthood. As in other at-risk groups , men born preterm appear more susceptible than women to developing this phenotype as shown by the observed differences in weight and BMI. This sexual dimorphism is consistent with data from maternal undernutrition studies ,28. A stin utero . In our Importantly, we also showed that preterm birth is associated with an adverse phenotype in the next generation. The offspring of parents born preterm tended to have greater fat mass than those of parents born at term, reflecting the effect of parental obesity. Fatter parents tended to have fatter children irrespective of whether the preterm parent studied was male or female. However, even when mean parental BMI was taken into account, alterations in fat distribution were still evident amongst children of parents born preterm, suggesting that parental fat mass did not entirely explain the effect of parental preterm birth on offspring adiposity.Intergenerational effects have been observed in animal models , particuPreterm birth is not uncommon, and more than 10% of babies worldwide are born less than 37 weeks gestation . AlthougThe intergenerational effect of preterm birth is well established, and mothers who were born preterm are also more likely to have preterm deliveries . AlthougIn conclusion, preterm birth is associated with increased fat mass and altered fat distribution in adulthood, particularly among men, as well as evidence of insulin resistance and less favourable lipid profiles. Importantly, similar changes in body composition are also present in mid-childhood in their offspring born at term, showing that the negative consequences of preterm birth may extend to the subsequent generation. The changes in body composition observed in this group suggest ongoing longitudinal studies will be necessary to define the health relevance of preterm birth for future generations.


Social factors affect the risk of very preterm birth and may affect subsequent outcomes in those born preterm. We assessed the influence of neighbourhood socio-economic characteristics on the risk and outcomes of singleton very preterm birth (<32 weeks of gestation) in two European regions with different health systems.Live births (n=1118) from a population-based cohort of very preterm infants in 2003 in Trent (UK) and Ile-de-France (France) regions were geocoded to their neighbourhood census tracts. Odds ratios for very preterm singleton birth by neighbourhood characteristics  were computed using infants enumerated in the census as a control population. The impact of neighbourhood variables was further assessed by pregnancy and delivery characteristics and short term infant outcomes.Risk of very preterm singleton birth was higher in more deprived neighbourhoods in both regions (OR between 2.5 and 1.5 in the most versus least deprived quartiles). No consistent associations were found between neighbourhood deprivation and maternal characteristics or health outcomes for very preterm births, although infants in more deprived neighbourhoods were less likely to be breastfed at discharge.Neighbourhood deprivation had a strong consistent impact on the risk of singleton very preterm birth in two European regions, but did not appear to be associated with maternal characteristics or infant outcomes. Differences in breastfeeding at discharge suggest that socio-economic factors may affect long term outcomes. Preterm birth is related to individual social factors, including maternal education, occupation and ethnicity ,2, as weMechanisms underlying the association between the risk of very preterm birth and social factors are not well understood . AttemptWide variations in very preterm births rates exist in Europe  . ResearcCross-national comparisons of the impact of social factors on the risks and outcomes of very preterm birth have been limited because of the difficulties of defining comparable populations as well as the lack of socioeconomic information in studies on these infants. International variations in procedures for recording births and deaths at early gestational ages  as well We investigated the influence of neighbourhood socio-economic status on the risk of very preterm singleton birth in two French and English regions with different very preterm rates and health systems using data from the population-based MOSAIC study collected with a common protocol and standardized inclusion and validation criteria. A second aim was to study whether the clinical characteristics of pregnancy, very preterm delivery, in-hospital mortality and short term infant health outcomes varied by neighbourhood of residence.Data were available for very preterm infants born between 22+0 to 31+6 weeks from the former Trent health region (UK) and Ile-de-France (France), two regions participating in the population-based MOSAIC study . The oveData were collected on all very preterm births from 01/01/2003 to 31/12/2003 in Trent and from 01/02/2003 to 31/08/2003 in Ile-de-France. Information on maternal and infant’s characteristics were abstracted from medical records using a common protocol. Infants were followed until discharge from hospital (to home or long-term care) or death. Inclusions in the study were cross-checked with birth registers in each maternity unit. After excluding fetal deaths before onset of labour and infants born or resident outside the study regions, 667 infants in Trent (534 singletons) and 809 in Ile-de-France (584 singletons) were available for analysis.th percentile for gestational age), bronchopulmonary dysplasia and neurological morbidity . We also included breast milk feeding at discharge. Definitions have been published previously [Information on characteristics of the very preterm delivery included gestational age, small for gestational age, multiplicity (singleton or twin), indicated delivery (caesarean section before labour) and pregnancy complications: hypertension ; antepartum haemorrhage without hypertension; preterm premature rupture of membranes (PPROM) without hypertension or haemorrhage; and preterm labour without hypertension, haemorrhage or PPROM. Infant outcome measures included in-hospital mortality, mechanical ventilation (>1 day), long hospital stay  and the IRIS-2000 in Ile-de-France (between 1800 to 5000 inhabitants and a median surface of 70.0 Km2).No data were routinely available on maternal socio-economic factors from medical records and so information on the location of mother’s place of residence was collected. Subsequent analysis on the effects of social factors on very preterm birth and health outcomes were carried out in Ile-de-France and the Trent region, as both countries could provide census data on small geographic areas using similar data collection methodology. These data were thus used to characterize neighbourhoods of residence for very preterm infants. Very preterm infants were geocoded to the smallest geographic units for which census data were available based on their mothers’ place of residence: super output areas in Trent  in Trent and from 01/01/1999 to 03/08/1999  in Ile-de-France).Sensitivity analyses were carried out to test that the census accurately reflected the birth cohort’s place of residence, using birth registries for the whole 2003 year in Trent and from one of the districts in 1999 in Ile-de-France.Analyses were restricted to singleton very preterm births as we could not differentiate births by multiplicity in the denominator from the census data. Rates of very preterm singleton births were similar in the two regions (80.9% in Trent and 80.2% in Ile-de-France). Multiples are only 3% of all births and tend to have different characteristics from total births, including older more affluent mothers. Furthermore, the sample was small (133 twins in the Trent region and 225 twins in Ile-de-France) and this sample was inadequate for twin specific analysis which are necessary as maternal complications and outcomes differ for twins.We studied four neighbourhood socio-economic characteristics Table  (unemploWe first compared singleton very preterm infants with census infants by neighbourhood characteristics quartiles within each region. Odds ratios (OR) with 95% confidence intervals were calculated for the risk of very preterm birth; we tested for trends across deprivation quartiles and for interactions between neighbourhood characteristics and region. While we could not exclude multiple births from the census data, these constitute a small fraction of all births and the census population provides a good approximation of the characteristics of the singleton population.Then pregnancy and delivery characteristics and infant outcomes for very preterm singleton births were compared across the four socio-economic neighbourhood characteristics. Adjusted odds ratios (aOR) were calculated, controlling for maternal age, small for gestational age and sex, using logistic regression models. The small number of infants with brain lesions did not make it possible to calculate aOR for this outcome. We tested whether the association between pregnancy and delivery characteristics and infant outcomes varied by each neighbourhood characteristic between the two regions. Interactions were considered significant if p<0.05. Analyses were undertaken to investigate all four neighbourhood deprivation characteristics. Here associations are shown for unemployment rates alone to simplify the presentation of results.Data were analysed using STATA 9 software .Table In both regions, the percentage of very preterm singletons increased with a higher rate of unemployment, a higher proportion of manual workers and non-home owners or a low educational level when compared to infants in the census Table . More thTable After adjustment for maternal age, gestational age, small for gestational age and sex, breastfeeding at discharge was lower in neighbourhoods with the highest unemployment rates (Trent: OR=0.2 (95% CI: 0.1-0.4); Ile-de-France: OR=0.4 (95% CI: 0.2-0.8)). The interaction between hypertension during pregnancy and region was not significant after adjustment. (interaction test p<0.07)  are that we were unable to exclude very preterm infants and multiples from the census population, as gestational age and multiplicity are not available in the census data; but these represent a small proportion of all live births and would thus have a very minor impact on the birth population deprivation quartiles. Infants who died in the first days of life will most likely not be included in the census, although these infants are a very small proportion of total births.Our results were robust despite differences in the definitions used to report census data on socio-economic characteristics in England and France. The magnitudes of the risk of very preterm births for singletons in most deprived versus least deprived neighbourhoods were quite similar for Trent and Ile-de-France, and slightly higher than those reported previously in Europe ,9 using We found no systematic differences between pregnancy and delivery characteristics of very preterm births and neighbourhood of residence in the two regions. This finding corroborates previous studies which found no socio-demographic gradient for spontaneous delivery or PPROM for very preterm births in Australia  and no aVery preterm outcomes varied between the two regions, but they did not vary by neighbourhood socio-economic characteristics within each region, with the exception of breastfeeding. Similar results have been shown recently for survival, respiratory support, length of stay among very preterm infants  and the Despite the absence of an association between neighbourhood socio-economic status and infant mortality and morbidity, the total burden of mortality and respiratory and neurological morbidity will be greater in deprived areas because of their higher rates of preterm birth. In addition, the total burden of these socio-economic differences may be greater in England, where rates of very preterm births are higher, than in France . The neoIn conclusion, trends in the risk of very preterm birth according to area-level socio-economic characteristics were robust in two European regions with different health care systems and rates of very preterm birth leading to a greater health burden in deprived areas despite the absence of socio-economic disparities in mortality and short-term morbidity. Planning for neonatal care provision, social support services for families and follow-up programmes needs to consider the socio-spatial distribution of very preterm children. Extending the methodology used in this paper to other countries with access to area-based census data would make it possible to test whether these trends are similar in other settings.1. Socio-economic disparities are associated with adverse obstetric and birth outcomes and an increased burden of neonatal care2. Neonatal mortality and neonatal care for very preterm infants do not vary across area deprivation levels in the UK3. Very preterm birth rates vary widely between European countries.1. Area deprivation more than doubled the risk of singleton very preterm birth, in two European regions with different health systems and differing rates of very preterm birth.2. There were not consistent associations across the two regions in pregnancy complications and delivery characteristics by neighbourhood deprivation.3. Area deprivation did not affect the outcomes to discharge from hospital for very preterm singletons with the exception of breastfeeding.The authors declare that they have no competing interests.Analysis and interpretation of the data were carried out by MB, LS and JZ. MB wrote the first draft of the paper and all authors participated in revisions and approved the final manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/13/97/prepubAdjusted odds ratio for maternal and infant's outcomes among very preterm singletons by neighbourhood unemployment rate quartiles.Click here for file


Purpose. To examine the most prevalent risk factors found in patients with permanent obstetric brachial plexus injury (OBPI) to identify better predictors of injury. Methods. A population-based study was performed on 241 OBPI patients who underwent surgical treatment at the Texas Nerve and Paralysis Institute. Results. Shoulder dystocia (97%) was the most prevalent risk factor. We found that 80% of the patients in this study were not macrosomic, and 43% weighed less than 4000 g at birth. The rate of instrument use was 41% , which is 4-fold higher than the 10% predicted for all vaginal deliveries in the United States. Posterior subluxation and glenoid version measurements in children with no finger movement at birth indicated a less severe shoulder deformity in comparison with those with finger movement. Conclusions. The average birth weight in this study was indistinguishable from the average birth weight reported for all brachial plexus injuries. Higher birth weight does not, therefore, affect the prognosis of brachial plexus injury. We found forceps/vacuum delivery to be an independent risk factor for OBPI, regardless of birth weight. Permanently injured patients with finger movement at birth develop more severe bony deformities of the shoulder than patients without finger movement. The incidence of obstetric brachial plexus injury (OBPI) is about 1.51  to 5.8  per 1000In obstetrics, presentation of shoulder dystocia is often emergent because the reported risk factors for its occurrence are not good predictors of it , 14. TheRecently, studies have determined risk factors specifically for permanent brachial plexus injury including birth weight , deliverPatients with permanent obstetric brachial plexus injuries frequently develop bony deformities which are caused by muscle imbalance on the developing bony elements of the infant shoulder developing from the asymmetrical brachial plexus injury, with the upper plexus (C5-6) being injured more commonly than the lower (C8-T1) . These sThis study will explore potential risk factors of permanent brachial plexus injury and determine if these risk factors can predict the development of osseous deformities.During a 19-month period between August 2006 and April 2008, 249 patients from various locations in the United States, Asia, and Europe were surgically treated for the sequelae of permanent obstetric brachial plexus injury at our institute. 241 patients were selected for this study; of the 8 patients excluded, 4 patients were excluded due to insufficient data, and 4 patients sustained their injury during Caesarian section or breech delivery. All the patients in this study were injured severely enough to develop shoulder deformities that required surgical reconstruction. All of the patients in the study have had at least one reconstructive surgery related to the initial nerve injury. All surgeries were performed by the same surgeon (RKN), whose practice has focused on reconstructive surgery in this population for the past 12 years. There were 122 (51%) girls and 119 (49%) boys with an average age of 5.6 years at the time of visit, ranging from 5 months to 27 years.Patients were evaluated with a physical exam which included a modified Mallet functional assessment. Information regarding instrument use during delivery, birth weight, and shoulder dystocia was obtained from the patient's parent or guardian during the initial evaluation. Instrument use was unknown for two patients.Presence of deformity was confirmed with analysis of CT and/or MRI scans obtained prior to surgical treatment. Posterior subluxation  or absence (less deformed) of a pseudoglenoid in CT or MRI images . A pseudA study population of transiently injured patients was not available. Therefore, data including the transiently injured population was gathered from published studies for comparison. National birth statistics were obtained from the Centers for Disease Control and Prevention website for the year 2003 . Macroson = 5) and studies conducted by pediatricians and specialists (n = 5). The two compiled proportions were then compared with Fisher's exact test. Normality of distribution was determined with the Shapiro-Wilk test. P  values < 0.05 were considered significant.Averages are reported as the mean ± one standard deviation and proportions are provided with 95% confidence intervals determined by the modified Wald method. The Mann-Whiney test was used for comparisons of continuous data. Categorical data and proportions were analyzed using Fisher's exact test. The proportion of injuries that remain permanent was pooled from multiple studies into two groups, studies conducted by obstetricians (P = 0.73). Macrosomia was present in 20%  of the patients; 55%  weighed between 3750 and 4499 g at birth; 25%  weighed less than 3750 g at birth  and birth weight was normally distributed (irth see .P = 0.001) and posterior subluxation was not significantly different (P = 0.06), but lower when compared to patients below 4500 g . Posterior subluxation and glenoid version were both worse in children with documented shoulder dystocia, but the difference was not significant because of the small number of patients in the group without documented shoulder dystocia . The rate of instrument use decreased in higher birth weight categories  were used in 41% (35–47%) of the deliveries studied . The avetegories .P = 0.04) in all instrument-assisted deliveries as compared to spontaneous deliveries. The significance was lost when forceps or vacuum extraction used alone was compared separately to spontaneous delivery  but was maintained when both instruments were used for the same delivery (P = 0.03). PHHA and version did not differ between instrument-assisted and spontaneous deliveries . Lack of finger movement at birth was not associated with macrosomia, documented shoulder dystocia, or instrument use  of the patients . Mean biP = 0.046, 0.001, resp. P = 0.055).PHHA and version measurements in children with no finger movement at birth indicated a less severe shoulder deformity in comparison with those with finger movement at birth (P < 0.0001). For these reasons, data gathered from permanent injury in this study were contrasted with findings common to all brachial plexus palsies rather than data specific for transient palsies. Birth weight, shoulder dystocia, instrument use, and finger movement at birth were evaluated as potential risk factors for permanent injury and predictors of future osseous shoulder deformity.Risk factors for sustaining an obstetric brachial plexus injury have been previously identified; however, the most pertinent risk factors, those associated specifically with permanent injury, have only recently been studied –17, 27. The average permanent injury birth weight in this study was 4085 ± 476 g, which is lower than the average birth weight reported in the literature for brachial plexus injuries at 4265 ± 480 g , 4227 g It is not implied that birth weights in permanent injury are similar to the normal population; birth weight among injured patients is higher than average, as demonstrated in Permanent injury is not exclusive to large infants; 80% (74–84%) of the patients in this study were not macrosomic and 43%  weighed less than 4000 g at birth . 52% , which is 4-fold higher than the 10% predicted for all vaginal deliveries in the United States , 43 Tab. InstrumOur data shows that the SHEAR deformity was significantly more severe in instrument-assisted deliveries, especially when both instruments were used. However, posterior subluxation and glenoid retroversion were not significantly different between spontaneous and instrument-assisted deliveries. This result suggests a mechanism of injury or presence of a risk factor that uniquely affects the development of a SHEAR deformity and is associated with the sequential use of instruments. Shoulder dystocia might be the confounding factor in this case. It has been proposed that the sequential use of instruments is associated with severe shoulder dystocia  and bracIt is well established that shoulder dystocia is a significant risk factor for brachial plexus injuries . The shoLack of finger movement indicates a severe initial injury that extends to C8/T1 and affects the entire brachial plexus. All the muscles in the shoulder are weakened and muscle imbalances are greatly reduced in these injuries compared to C5/C6 injuries that retain finger movement. Severe bony deformities caused by muscle imbalances during a time of rapid growth should thus develop more often in children with finger movement at birth. Posterior subluxation and glenoid retroversion were both significantly less severe in patients with no finger movement at birth. Moreover, the proportion of patients who had no finger movement at birth was higher in non-pseudoglenoid shoulders (68%) than in the pseudoglenoid shoulders (51%). Taken together, the results show that lack of finger movement at birth is actually protective against bony deformities of the shoulder, although the patient suffers extensive functional impairment. Permanently injured patients with finger movement at birth develop more severe bony deformities of the shoulder than patients without finger movement at birth due, in part, to asymmetrical muscle action on developing bony structures.n = 241) and a rigorous definition of permanent brachial plexus injury. Risk factors associated with permanent brachial plexus injury should be magnified among patients requiring surgical reconstruction. This study is unique in that it examines the relationship between risk factors at birth and future deformities, as measured by radiographic characteristics. It also determined the value of finger movement at birth, a simple and rapid clinical test, as a predictor of outcome. The birth data in this study is, however, based on retrospective information which was obtained from interviews with patient families. Additionally, a study population of transiently injured patients was not available for comparison.The strengths of this study are a large sample size (


Possible severe bacterial infections (pSBI) continue to be a leading cause of global neonatal mortality annually. With the recent publications of simplified antibiotic regimens for treatment of pSBI where referral is not possible, it is important to know how and where to target these regimens, but data on the incidence and outcomes of pSBI are limited.We used data prospectively collected at 7 rural community-based sites in 6 low and middle income countries participating in the NICHD Global Network’s Maternal and Newborn Health Registry, between January 1, 2010 and December 31, 2013. Participants included pregnant women and their live born neonates followed for 6 weeks after delivery and assessed for maternal and infant outcomes.In a cohort of 248,539 infants born alive between 2010 and 2013, 32,088 (13 %) neonates met symptomatic criteria for pSBI. The incidence of pSBI during the first 6 weeks of life varied 10 fold from 3 % (Zambia) to 36 % (Pakistan), and overall case fatality rates varied 8 fold from 5 % (Kenya) to 42 % (Zambia). Significant variations in incidence of pSBI during the study period, with proportions decreasing in 3 sites , remaining stable in 3 sites  and increasing in 1 site (Pakistan), cannot be explained solely by changing rates of facility deliveries. Case fatality rates did not vary over time.In a prospective population based registry with trained data collectors, there were wide variations in the incidence and case fatality of pSBI in rural communities and in trends over time. Regardless of these variations, the burden of pSBI is still high and strategies to implement timely diagnosis and treatment are still urgently needed to reduce neonatal mortality.NCT01073475).The study was registered at ClinicalTrials.gov ( The annual global burden of mortality in children under age 5 years decreased by 36 % from 9.9 million in 2000 to 6.3 million in 2013, mostly due to reductions in mortality due to pneumonia, diarrhea and measles in children aged 2–59 months , but theThe diagnosis of possible severe bacterial infection/neonatal sepsis is challenging even in well-equipped tertiary care facilities in resource rich settings ,9. In reThe Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Global Network (GN) for Women and Children’s Health Research supports a population based Maternal and Newborn Health (MNH) Registry of pregnant women and their babies living in rural communities in six low and lower middle income countries. The Registry has focused on documentation of pregnancy histories, details of labor and delivery, accurate and timely measurement of birth weight and early and late neonatal morbidity and mortality through day 42 of life, including signs and symptoms similar to those used in the YICSS, and cause of death . We usedThe appropriate Institutional Review Boards and Ethics Research Committees of all participating institutions and the Ministries of Health of the respective countries reviewed and approved participation in the MNH Registry. Prior to initiation of the Registry, approval was also sought from the participating communities through sensitization meetings. Study participants were enrolled in the Registry after they provided written informed consent. No monetary reimbursements were provided to either individual participants or to communities. A Data Monitoring Committee, appointed by the NICHD, oversaw and reviewed the Registry at annual meetings. The MNH Registry study was registered at ClinicalTrials.gov (NCT01073475).The MNH Registry is an ongoing prospective multicenter cohort study of pregnant women and their babies who were residents or resided for at least 4 weeks in rural communities (clusters) in Argentina, Guatemala, 2 states in India, Kenya, Pakistan and Zambia . DetailsFor this secondary data analysis, we included infants born alive between January 1, 2010 and December 31, 2013 to the pregnant women enrolled in the seven sites participating in the MNH Registry. We excluded infants with missing birth weights, as well as those with birth weight measured more than 7 days after delivery or with unknown timing of measurement. We excluded babies with missing birth weights as these were rare in the MNH registry (<1 %) due to a focus on collection of birth weight data. The data collection forms changed at the end of 2013 with symptoms used to define pSBI no longer collected. Infants for whom the 42 day assessment was conducted using the revised forms were excluded from analysis. During the study period, women were enrolled in a total of 118 communities (clusters) in the seven sites: Argentina, 6 clusters; Guatemala, 18; Kenya, 16; Zambia, 10; Belgaum, India, 24; Nagpur, India, 20; Pakistan, 24. In Argentina, Kenya, Zambia, and Nagpur all clusters participated throughout the 4 year study period. However, in Guatemala, Belgaum, India and Pakistan, only 9 of 18 clusters, 16 of 24 and 20 of 24 clusters respectively participated throughout the 4 year study period.Estimates of pSBI during the first 6 weeks of life were derived retrospectively for all live born infants using symptoms reported on the data collection forms based on the WHO YICSS criteria  to the eThe specific signs and symptoms of pSBI are challenging, even in resource intense studies ,4,10 becNeonatal/early infant case fatality after diagnosis of pSBI was defined as the number of deaths due to any reported cause among infants with pSBI occurring up to 6 weeks after birth divided by the number of infants with pSBI. The cause of death was determined by the registry administrator who conducted a basic death audit, per the MNH manual of operations, by interviewing the birth attendant, and/or family members and the mother, whenever possible.Covariates examined included maternal age, maternal education, location of delivery, mode of delivery, infant birth weight, infant sex, and early initiation of breast feeding within an hour of delivery. A hospital was defined as a residential establishment equipped with inpatient facilities for 24-h medical and nursing care and staffed with at least one physician providing essential obstetrical/neonatal care . A clinic/health center was defined as a facility that provided (ambulatory) medical services to a specific group in a population and that did not have caesarean section capability. Births that occurred at home, whether at the mother’s home, a birth attendant’s home, or a relative’s home, were grouped together for analysis. Other delivery locations were infrequent. Birth weight was recorded using locally available scales, calibrated per local facility protocols.Maternal, delivery, and neonatal characteristics were compared descriptively across the study sites and over the years studied at each site. The cumulative incidence of pSBI in the first 6 weeks of life was defined as the proportion of infants who developed pSBI during the 42 day follow-up period divided by the number of infants studied, with 95 % confidence intervals estimated using the normal approximation to the binomial distribution. Crude estimates of pSBI incidence and case fatality rates are reported in text and figures. Percentages of infants with each symptom of pSBI were also compared descriptively between the sites.Statistical testing was conducted using logistic regression models to compare incidence of pSBI across study sites, and to examine trends in the proportion with pSBI by birth year and trends in the proportion with pSBI who died at each study site, while adjusting for covariates. Adjusted analyses were utilized to compare incidence and assess trends after accounting for differences across site and over time in the distribution of maternal, delivery, and neonatal characteristics potentially impacting risk of pSBI. All models included effects for study site, maternal age , maternal education , cesarean section delivery , facility birth , infant sex , infant birth weight , and initiation of breastfeeding within 1 h of delivery . A test of the null hypothesis that the incidence of pSBI was the same at all sites against the alternative that the incidence of pSBI differed across the sites was conducted using a main effects model with statistical significance determined by the Score chi-square test for study site. Site-specific tests of the null hypothesis that pSBI incidence remained stable during the study period against the alternative that incidence changed, and similar tests of trend in case fatality rates, were conducted using data from all sites in models that included the main effects above plus birth year and all 2 way interactions between study site and each covariate. Birth year was treated as a continuous variable in order to assess linear trend. Contrasts involving the site by birth year interaction were used to assess whether or not changes over time were significant at each site with statistical significance determined by Wald chi-square tests. Analyses examining trends in pSBI incidence by birth year and trends in the case fatality rate were repeated excluding clusters in Guatemala, Belgaum, and Pakistan that did not participate all four years. In a secondary analysis, interactions between site, birth year and facility birth were added to the primary pSBI trends model in order to test whether trends were the same or differed by location of delivery at each site. Generalized estimating equations were used in all models to produce robust standard errors that accounted for clustering of women and infants in geographic areas (“clusters”) at each study site with an independent working correlation structure specified. Just under 2 % of the data were excluded from models due to missing values of covariates. Variables were assumed to be missing at random. Analyses were implemented using SAS version 9.3 .The GN MNH Registry included 266,340 live births between 2010 and 2013. After exclusions, a total of 248,539 live born infants with birth weight measured within 7 days after delivery were included in the analysis  and most frequent in Argentina (36 %). Nearly all women in the Argentina site (99 %) delivered in hospital. Over 90 % of births in the Indian sites occurred in a facility, compared to 63 % in Zambia, 53 % in Pakistan and less than half of the births in Guatemala and Kenya. A clean razor was used to cut the baby’s cord and new gloves were used by the birth attendant in almost all deliveries, except in Guatemala, where use of a clean razor was reported for 68 % of deliveries (99 % by 2013) and in Pakistan where use of new gloves was reported for 78 % of births.Only 1–2 % of infants at each site were from a multiple birth, and slightly over half were male. Mean birth weight ranged from 2,677 g in Nagpur to 3,303 g in Argentina. In Guatemala 75 % of infants were breastfed within 1 h of delivery, 83 % in Kenya, 85–86 % in the Indian sites, and 90 % or more in Argentina and Zambia, while in Pakistan only 24 % were breastfed within an hour of birth.In general, maternal educational level increased during the period 2010–2013 at all sites. The proportion of facility births remained at 99 % in Argentina throughout the period. At the other sites the proportion of facility births increased: from 39 % in 2010 to 58 % in 2013 in Guatemala, 38 to 52 % in Kenya, 55 to 71 % in Zambia, 92 to 96 % in Belgaum, 90 to 99 % in Nagpur, and 49 to 62 % in Pakistan. The percent of cesarean section deliveries increased at all sites except Zambia where only 1 % of infants were delivered by cesarean section, from 27 to 40 % of infants in Argentina, 16 to 26 % in Guatemala, 1 to 2 % in Kenya, 10 to 19 % in Belgaum, 18 to 23 % in Nagpur, and 7 to 12 % in Pakistan. The percent of infants who were breastfed within 1 h of delivery remained about 90 % in Argentina and 83 % in Kenya throughout the 4 year period, increased from 85 % in 2010 to 93 % in 2013 in Zambia, and decreased from 80 to 67 % in Guatemala, from 90 to 77 % in Belgaum, 92 to 84 % in Nagpur, and from 31 to 15 % in Pakistan.p < 0.001, from a low of 3.2 % (95 % CI 3.0–3.4 %) in Zambia to 6.4 % (95 % CI 6.2–6.5 %) in Belgaum, 6.4 % (95 % CI 6.1–6.6 %) in Nagpur, 10.6 % (95 % CI 9.9–11.3 %) in Argentina, 13.8 % (95 % CI 13.4–14.2 %) in Guatemala, 16.5 % (95 % CI 16.1–16.9 %) in Kenya, and a high of 35.7 % (95 % CI 35.2–36.2 %) in Pakistan . The percent of infants with pSBI varied widely by study site, p = 0.03 accounting for clustering and maternal and neonatal covariates). In Kenya incidence of pSBI decreased from 19.1 % (95 % CI 18.2–19.9 %) in 2010 to 10.7 % (95 % CI 10.1–11.4 %) in 2013 (adjusted p < 0.001), with decreases occurring among infants born at home as well as in a facility . In Nagpur, India, the proportion with pSBI decreased for infants born in a facility  but not for those born at home . In Guatemala there was a small non-significant decrease in the proportion of infants with pSBI . However, after exclusion of clusters not participating all 4 years the change in Guatemala became statistically significant  and these changes did not differ significantly for home or facility births . In contrast, in Pakistan the proportion of neonates/young infants with pSBI increased from 26.7 % (95 % CI 25.9–27.5 %) in 2010 to 55.0 % (95 % CI 53.9–56.1 %) in 2013, adjusted p < 0.001 .Incidence of pSBI in the first 6 weeks changed significantly over time at some sites Fig. . The proAcross the sites, 60–72 % of neonates/young infants with pSBI met criteria for pSBI based on a single sign or symptom, while the remaining babies met criteria based on multiple symptoms . Breathing problems and/or high fever were the most frequently reported symptoms at each study site, followed by feeding problems Fig. . In PakiOf the 32,088 neonates with pSBI during the first 6 weeks, 27,410 85 %) survived to 6 weeks of age, 4,564 (14 %) died, and 6–week status was missing for 114 (<1 %). In contrast, only 0.5 % of infants without pSBI died by 6 weeks. Case fatality rates in neonates with pSBI varied across sites  neonates met symptomatic criteria for pSBI. The incidence of pSBI in the first 6 weeks of life, trends in incidence, and in case fatality rates in the first 6 weeks for infants with pSBI varied widely across sites with a 10–fold variation in incidence of pSBI from 3 % (Zambia) to 36 % (Pakistan) and an 8 fold variation in case fatality from 5 % (Kenya) to 42 % (Zambia). Our incidence estimates are in range or somewhat higher than the upper range recently estimated by Seale et al. . OverallBetween 2010 and 2013 there were significant increases in facility deliveries and survival of neonates born preterm in our study sites as well as in the countries our sites represent. Against this background, we found decreases in the incidence of pSBI in the first 6 weeks of life during the period in Argentina, Kenya, and Nagpur, India after accounting for clustering and maternal and neonatal factors. Argentina was the one site where nearly all infants were born in hospital throughout the study period, and the decrease in Kenya occurred among infants born at home as well as in a facility suggesting that changes at these sites cannot be attributed simply to facility birth. In contrast, in Nagpur, India, the decrease in pSBI rate occurred among facility births alone with no significant change in pSBI incidence among infants born at home. While facility births increased from 49 to 62 % of all births in Pakistan, pSBI incidence increased during the period for infants born in a facility as well as for those born at home, after accounting for birth weight and other factors. Reporting or diagnostic changes may have contributed to the increase in Pakistan.Our prospective study has several important strengths. First, we attempted to define pSBI based on the presence of any one of seven signs found to be predictive of severe illness in young infants . HoweverThe high burden of pSBI in neonates and young infants, regardless of definitions and changes in location of birth, is an important reminder that investment in ways to reduce delays in early recognition /diagnosis and treatment of pSBI continues to be needed and is consistent with the research priorities outlined in the Every Newborn Action Plan . PrioritIn a prospective population based registry with trained data collectors, there were wide variations in the reported incidence and case fatality of pSBI in rural communities and in trends over time. Regardless of these variations, the burden of pSBI is still high and strategies to implement timely diagnosis and treatment are still urgently needed to reduce neonatal mortality.


Toxoplasma gondii infection is considered a major risk factor for miscarriage, prematurity and low birth weight in animals. However, studies focusing on this topic in humans are scarce. The objective of this study is to determine whether anti-Toxoplasma gondii maternal serum profiles correlate prematurity and low birth weight in humans. The study examined 213 pregnant women seen at the High-Risk Pregnancy Hospital de Base, São José do Rio Preto, São Paulo, Brazil. All serological profiles  were determined by ELISA commercial kits. Maternal age, gestational age and weight of the newborn at birth were collected and recorded in the Statement of Live Birth. Prematurity was defined as gestational age <37 weeks and low birth weight ≤ 2499 grams. The t-test was used to compare values (p < 0.05). The mean maternal age was 27.6±6.6 years. Overall, 56.3% (120/213) of the women studied were IgM-/IgG+, 36.2% (77/213) were IgM-/IgG- and 7.5% (16/213) were IgM+/IgG+. The average age of the women with serological profile IgM+/IgG+ (22.3±3.9 years) was different from women with the profile IgM-/IgG+  and IgM-/IgG- . There was no statistically significant difference between the different serological profiles in relation to prematurity (p = 0.6742) and low birth weight (p = 0.7186). The results showed that prematurity and low birth weight did not correlate with anti-Toxoplasma gondii maternal serum profiles.Gestational  Toxoplasma gondii is an obligate intracellular parasite that causes toxoplasmosis, one of the most widespread zoonotic diseases in the world. In all countries there is a high number of humans and animals infected with T. gondii. In some regions, about 30–60% of the population is positive for toxoplasmosis in serological tests [al tests –4.T. gondii life cycle alternates between intermediate hosts , where the asexual stage occurs, and definitive hosts (felines), harboring the sexual stage. The infection in the intermediate host occurs by eating raw or undercooked meat containing cysts, and water or food contaminated with oocysts secreted in the feces of infected cats [The ted cats .In the acute phase, rapid replication of tachyzoites predominates and in approximately 60–90 days the infection becomes chronic. As the immune response is effective in controlling the infection, tachyzoites differentiate into bradyzoites, which divide more slowly and form cysts in various cells, particularly in the brain, heart and muscles. About 80% of chronically infected individuals are asymptomatic although in some cases eye injuries occur ,5–11.When the primary infection occurs during pregnancy, the parasites can infect the fetus through the placenta, causing birth defects and ocular complications. The consequences of maternal and fetal infection depend on the degree of exposure of the fetus to parasites, the virulence of the strain and the gestational period in which there was infection, and the classic signs of congenital toxoplasmosis are: hydrocephalus; chorioretinitis; cranial calcifications and mental retardation ,12–23.T. gondii infection in humans has been directed to risk groups such as patients with immunodeficiency, transplant patients, patients with eye injuries and even normal individuals. In addition to these, pregnant women and newborns are targeted for medical attention given the risks of congenital transmission and the sequelae [Contemporary research on sequelae ,24–30.T. gondii infection was investigated in different Brazilian states in recent decades and the results revealed great variability in its contents, including previous studies by our group [T. gondii infection in risk groups has grown considerably in recent years, as well as the interest in studies to establish some relation to the conditions presented by newborns, such as prematurity and disease severity [The prevalence of ur group ,31–34. Iur group . The intseverity ,18,35–42T. gondii, and may cause neurologic damage the baby, being a disease of epidemiological significance to pregnant women and women of childbearing age and recently included in the list of by the CDC of neglected diseases [Toxoplasmosis thus constitutes a serious public health problem, especially in pregnant women who were not infected by diseases ,44.The aim of this study was to correlate prematurity and low birth weight with the serological profile of pregnant women for toxoplasmosis.This study was approved by the Ethics Committee in Research of the Faculty of Medicine of São José do Rio Preto–FAMERP (protocol 168/2007). The need for a written consent of patients was waivered as all the data were retrospectively collected from the patients' hospital records and was anonymized.Data records were consulted for 310 pregnant women who met at the Clinic of High Risk Pregnancy and Fetal Medicine from the Hospital de Base de São José do Rio Preto, Brazil from 2005 to 2007. Complete data were found for 213 women regarding serological screening for toxoplasmosis during the prenatal period; weight data, gestational age and maternal age were collected from their Statement of Live Birth.Preterm birth was defined as gestational age less than 37 weeks and low birth weight as less than or equal to 2499 grams according to the criteria of the World Health Organization .I = IgM positive/ IgG positive; II = IgM negative/IgG positive; III = IgM negative/IgG negative. The profile IgM positive/IgG negative was not found in the analyzed cases. All maternal serum profiles were identified at the first medical consultation.All serological profiles were determined by ELISA commercial kits  and all manufacturer’s instructions were strictly followed. Three serological profiles were constructed: t-test was used to compare the data according to the serological profiles. The alpha value less than or equal to 5% was considered significant.The The average age of the selected pregnant women was 27.6±6.6 years. The results are shown in Tables The average birth weight of newborns analyzed was 1,916 ± 617.1 grams. The mean gestational age was 33.7 ± 3.7 weeks. The objective of this study was to correlate prematurity and low birth weight with the maternal serum profiles in 213 pregnant women for toxoplasmosis the northwestern region of São Paulo State who gave birth a single baby for both sexes, whose data prematurity and low birth were obtained from the official Statement of Live Birth. The decision to use this document as a data source is due to the fact that they constitute an official record established by Brazilian legislation. ,42,46.T. gondii infection is high in the northwest of São Paulo State and it has been shown that most pregnant women have the anti-T. gondii IgG class. Even so, a large percentage of individuals do not present specific antibodies for this parasite and this may result from having contact with the infective form. The simultaneous presence of anti-T. gondii IgM and IgG classes is transient in most cases and therefore the percentage of pregnant women with this profile is smaller than the other mentioned above [The frequencies of the identified serological profiles in patients in our study are consistent with findings in the literature ,48. The ed above ,47,49,50Toxoplasma IgG antibodies (profile II) have an average age of pregnant women as the negative for both classes of antibodies (profile III). However, the mean age of the women with these serological profiles was higher than that of positive pregnant women for both antibody classes (profile I).The results showed that the pregnant women’s positive containing only anti-There are reports that the average age of pregnant women at increased risk of congenital infection (IgM+/IgG- and IgM+/IgG+) is lower than those with other serological profiles (IgM-/IgG- and IgM-/IgG+). Pessanha et al.  reportedT. gondii compared to those not exposed to the parasite. These observations are supported by the data observed in this study. In fact, chronic infection maintenance and the risk of reinfection contribute to the production of IgG class antibodies and with a higher avidity index [T. gondii IgG class antibodies in the population [Dias et al. , Rodriguty index ,14,54–56pulation ,47,57–60The average age of pregnant women with serological profile III did not differ from that observed in women with pattern II and this can be a result that the series were selected in a reference center caring for high-risk pregnant women.This study also explored the relationships between serum maternal profile with low-birth and prematurity since these variables were previously reported –42,59–64T. gondii. Although Pessanha did not correlate serological profiles of pregnant women with birth weight, their data underlie, at least in part, the results reported in this study.Comparison of birth weight with different serological profiles did not show statistically significant differences. Pessanha et al.  observedT. gondii NE II are associated with prematurity and/or severity of congenital toxoplasmosis but did not establish correlations of these conditions to the serological profiles of the analyzed pregnant women. [Prematurity observed in the analyzed sample showed no correlations with the maternal serum profiles found. McLeod et al. found that serotypes of t women. T. gondii antibodies and it present some limitations. Persistent IgM antibodies can be detected for several months after the primary infection and therefore IgM+/IgG+ serum profile does not correlate acute infection necessarily [T. gondii.n conclusion, our data show that maternal age is related to the serological profile, but prematurity and low birth weight did not correlate with anti-T. gondii maternal serum profiles.This study present some limitations and therefore their data must be considered as preliminary. First, only ELISA test was performed to detect IgM and IgG anti-essarily ,56,66,67essarily ,39,68–70


Separate birthweight percentiles curves for male and female twins were constructed. In summary, our study firstly presents percentile curves of birthweight by gestational age for Chinese twin neonates. Further research is required for the validation and implementation of twin birthweight curves into clinical practice.Localized birthweight references for gestational ages serve as an essential tool in accurate evaluation of atypical birth outcomes. Such references for twin births are currently not available in China. The aim of this study was to construct up-to-data sex specific birth weight references by gestational ages for twin births in China. We conducted a population-based analysis on the data of 22,507 eligible living twin infants with births dated between 8/01/2006 and 8/31/2015 from all 95 hospitals within the Wuhan area. Gestational ages in complete weeks were determined using a combination of last-menstrual-period based (LMP) estimation and ultrasound examination. Smoothed percentile curves were created by the Lambda Mu Sigma (LMS) method. Reference of the 3 Several population-based studies have documented a strong temporal increase in the frequency and rate of multiple births13489The average birthweight of twins is significantly lower than singletons beginning around week 30 to 32310So far, birth weight standards for twins have been published and updated in several countries including Argentina, Australia, Canada, Japan, Norway and Taiwan11161718The mean gestational age and birthweight were calculated according to sex, sex combination within the twin pair, method of delivery, birth order, parity, presence of preterm birth, and low birthweight as represented in th percentile of birthweight by gestational age between singletons and twins. For all gestational ages twins births had significantly lower birthweight than singletons (P < 0.001). This difference increased with increasing gestational age from 32 weeks. The minimum average divergence of birthweight was 58 grams at 32 weeks, while the maximum divergence of birth weight was 900 grams at 42 weeks.rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles for male (A) and female (B) live born twins are shown in rd, 10th, 25th, 50th, 75th, 90th, and 97th birthweight percentiles by gestational age for female and male twins were presented in Smoothed reference curves for birthweight by gestational age of the 3th and 50th percentile curves of Wuhan twins were similar to the Australian curves until at the 36th week of gestational age in both sex, and the 90th birthweight percentile of Wuhan twins shows slightly heavier than that of Australian twins from 26 to 36 weeks. However, the Wuhan curves are significant below Australian curves after 37 weeks of gestational age. Meanwhile, the 10th, 50th, and 90th percentiles birthweight of the Japan curve were significantly lower than that of Wuhan’s from 26–40 weeks of gestational age in both sexes.We also compared the reference curves of birthweight for Wuhan twins with that of JapanThis paper presented sex-specific twin birthweight references between 26 and 42 weeks of gestation, based on a cross-sectional study of city-wide population in Wuhan, China, during 2006–2015. This study is the first to provide gestational-age-specific weight references for twins in the center China area. Although this study concerned primarily with the Wuhan population, these references should be considered meaningful for a majority of twin infants in the center China provinces , due to the homogeneity of their ethnic (predominantly Han), economic, geographical, and other features that had potential impact on birthweight distribution. Since more than 99.0% of all living twin births in Wuhan during that period were included in this analysis, we believe our data can represent the entire Wuhan population. Thus, these gestational-age-specific birthweight percentile charts are helpful as references for neonatal health care professionals and researchers to identify the high risk neonates who require more intensive observation and special care. However, it is important to note that percentile charts do not represent fetal growth standards in utero but weight at birthSeveral population-based studies globally have documented a strong increase in the frequency and rate of multiple birth2et al.et al.21When compared with their singleton counterparts, the mean birthweight for twins falls below that of singletons at every gestational age. However, this difference is small up to 35 weeks (an average divergence of <130 g). From 35 weeks of gestation, the mean birthweight for twins falls increasingly below that of singletons. Our result is comparable to other studies that also reported similar findings. A population-based study of twins from England showed that the divergence may occur as early as 24 weeks of gestation; a time at which singletons were 100 gram heavier than twins on averageIt is well known that there are racial and ethnic differences in birthweight. A comparison of twin birthweight data from Australia, United States, The Netherlands, Japan, and South Korea showed the total phenotypic variances of birthweight were about 45% larger in Caucasians than in East Asians. The largest phenotypic variances were mainly attributable to a greater shared environmental  variance of birthweight in Caucasians (ranging from 62% to 67% of variance) than Asians (48% to 53%)th, 50th, and 90th birthweight percentile curves of twins made by our data to those of Asian twins (i.e. Japanese) and Caucasian twins . When compared with Australian reference of percentile curves, we found the Chinese reference value were slightly higher in preterm twins but significantly lower in term twins. However, when compared with Japanese reference, all the 10th, 50th and 90th percentile reference values of Chinese twin were completely higher than that of Japanese twins in both sexes. The data that used to produce the percentiles of birthweight in other studies were not update to the same time period as in our study. This difference in time period when the measurements were taken may be a main contribution to the differences observed between our study and studies from other regions. For example, the socioeconomic status in difference periods is one of the major contributors to the variation of newborns’ birthweight over timeSo far, reference birthweight was also developed from population-based data in other countries such as Norway, Australia, Belgium, Israel, and Taiwan etc11172633In this study, we set strict exclusion criteria and excluded extreme outliers. The abnormal birthweight of malformed fetuses or stillbirths may indicate an early death with a birthweight not corresponded to the gestational age. For some births, reported gestational age and birthweight combinations were implausible, especially very high birthweight recorded for some preterm infants. Those exclusion criteria enable a fair comparison with other current birthweight standards, most of which are based on livebirths, and provide birthweight references for the risk assessment of neonatal and infant mortality and morbidity.There are some limitations in the present study. Firstly, the data in WBRIS were obtained from different centers which probably added an inter-center variance. Furthermore, Birth records in this study were collected within a long period. The environment of pregnant women including socioeconomic status, diet and nutrition had a remarkable improvement in Wuhan from 2006 to 2015. During the last decade, the rate of twining pregnancy had increased from 1.8% to 3.9%, while the average maternal age at childbirth was raised from 27.3 (4.7) year old to 30.1 (5.7) year old. These changes indicated that twin births due to assisted conception are becoming more popular. Besides these changes, the rate of preterm birth had also increased from 38.7% to 62.0%. On the other hand, the prevalence of neonatal death (from 1.5% to 0.4%) and stillbirth (from 3.5% to 2.2%) decreased significantly during this time period (data not shown), which indicates increasing preterm and low birthweight twins survival. Consequently, these changes may have skewed cutoff values toward lower weights in the percentile charts. Unfortunately, we did not collect data with regard to environmental conditions of pregnant women including socioeconomic status, diet, or nutrition. Thus, we could not directly analyze the association between environmental changes and birthweight distributions. Secondly, like other population-based studies, our data is cross-sectional nature based on birth registration rather than longitudinal measurement of the same fetus over the course of gestation. Thus, preterm infants may be somewhat smaller that fetuses of the same gestational ages who remain in uteroIn summary, our study was the first to present percentile curves of birthweight by gestational age for Chinese twin neonates using a ten-year population-based dataset. Twin specific birthweight curves are important for obstetricians to predict the birth weights of twins. Pediatricians can use these curves to situate the birthweight of the individual twins by gender in relation to other twins. However, further research is required for the validation and implementation of twin birthweight curves into clinical practice. Only when this condition is satisfied, twins at risk of perinatal morbidity and mortality can be identified.2. During 2006–2015, the population growth rate was 7.25‰, and birth rate in Wuhan was about 12.22‰.Wuhan is the capital and largest city of Hubei province in the center of mainland China . The city has around 10.33 million permanent residents by the end of 2014 and covers 8494 kmBirth record data were obtained from the Wuhan Birth Registry Information System (WBRIS) affiliated to Bureau of Health and Family Planning Commission which was established in 2003. Since then, birth certificates of all live births have been directly reported to this database by obstetricians or well-trained midwives, as well as guardians. The WBRIS included all registered births from 95 hospitals within the Wuhan area, which covered almost 100% of all hospital-registered births. Considering the steadiness, we used data of new births from 2006 to 2015 in this study. During this period of time, records for 836,229 newborns, including 11,726 complete pairs of twins , were presented in WBRIS.Each record in the database of WBRIS contained information on parent’s residential address, birth outcome , parity (Primary or Multiple), plurality , modes of delivery , as well as infant’s sex, gestational age in complete weeks, birth weight, body length, chest circumference, and head circumference. Specifically, gestational age in complete weeks was determined primarily through last-menstrual-period (LMP) estimation, and estimates from the last ultrasound scan before delivery . These two methods were cross-referenced when available. Stillbirths have been recorded in the WBRIS since 16 weeks of gestation. The birthweight of each neonate is measured twice to the nearest of 0.1 gram within 24-hour after the childbirth.The inclusion criteria for this study are twin births, a birthweight greater that 400 grams, and a gestational age at least 26 weeks. Only liveborn twin individuals were included in the preparation of birthweight percentiles. We excluded non-live twin births (stillbirth and those that died within seven days after delivery) (2.93%) and births with congenital anomalies (0.7%). Lastly, we excluded extreme birthweight outliers (0.3%)  away from the mean of twin births born at the same gestational age in weeks). After all exclusion criteria, 22,507 births of twin individual remained in the data set, including 11,861 (52.7%) male and 10, 646 (47.3%) female twins. See the  below.The methods were carried out in “accordance” with the approved guidelines and regulation. Ethical approval to conduct the research was obtained from the Research Ethics Committee of Wuhan Medical & Healthcare Center for Women and Children, Wuhan, China (NO. 2015-62). And informed consent was obtained from all subjects.All data were analyzed by using SAS, version 9.2 . The percentile values for birthweight were analyzed using gestational age by sex. Differences were considered to be significant at the 0.05.t-test for two groups and ANOVA for three groups or more. We estimated and presented in percentiles the distribution of birthweight for each 1-week increment of gestational age from 26 to 42 weeks .The significance of differences in mean values of gestational age and birthweight was statistically analyzed using Students’ th, 10th, 25th, 50th, 75th, 90th, 97th percentiles by using the Cole’s Lambda Mu Sigma (LMS) methodZ = [(X/M)L − 1]/LS, where X indicates the measured value of birth weight; and the centile = M*(1 + L*S*Zα)1/L, where Zαis the z-score that corresponds to a given percentile . The Z-score is a measure of the distance in SDs of a sample from the mean. To create smoothed percentile charts for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles, LMS Chart Maker light version 2.54  was used.Furthermore, we plotted the curves along the 3How to cite this article: Zhang, B. et al. Birthweight percentiles for twin birth neonates by gestational age in China. Sci. Rep.6, 31290; doi: 10.1038/srep31290 (2016).


Here, we demonstrate resonant electric field enhancement structures, which concentrate the incident electric field in sub-diffraction size volumes and show an electric field enhancement as high as ~14,000 at 50 GHz. These values have been confirmed through a combination of near-field imaging experiments and electromagnetic simulations.Today's pulsed THz sources enable us to excite, probe, and coherently control the vibrational or rotational dynamics of organic and inorganic materials on ultrafast time scales. Driven by standard laser sources THz electric field strengths of up to several MVm Over the past 20 years, continuous progress in Terahertz (THz) technologies has facilitated numerous breakthroughs in scientific and industrial research129EQ through the relation τ is the temporal pulse duration and A the beam area. The available pulse energy is naturally limited by the THz system at hand and the pulses are often already single-cycle, so that the electric field strength cannot be increased by adjusting the parameters Q and Δτ. The beam area can be minimized through tight focusing, however, the diffraction limit imposes a lower boundary on A.Despite all progress, the generation of THz pulses with high peak electric fields is still rather limited, mostly due to technological constraints such as available laser power and low conversion efficiencies514151617Diffraction limited focusing can be overcome, for example, by using suitable metallic structures which act as antennas efficiently collecting the incident radiation and concentrating it in a small sub-wavelength sized volume. In the process, part of the incident radiation is typically converted to charge density oscillations, which in turn generate an enhanced and localized electric field distribution on a length scale well beyond the diffraction limit202122242521|E|2 and |E|4 enhancement factors are 2·10−1; such electric field strength are usually only achieved with amplified femtosecond laser systems.Here, we report on a novel antenna design, i.e. a split ring resonator featuring a nanometer sized gap, which extends into the inner part of the split ring resonator. Such structures, as outlined below, show promise for extremely high THz electric field enhancement at their resonance frequencies. These frequencies can be easily tuned throughout the entire THz spectrum by changing the structure's dimensions. Since there exists no detection modality with sufficient spatial resolution to map out the in-gap electric field we have to resort to indirect methods. Based on near-field measurements of the oscillating charge distribution on the split ring resonator we calibrate detailed finite element simulations to derive the THz electric field enhancement and THz electric field amplitude in the gap. Throughout the manuscript the electric field enhancement as well as the in-gap electric field are averaged over the gap volume and may be lower or higher at specific points within the gap. At the lowest order resonance of the specific design we find that the THz electric field enhancement reaches 14,300 at 50 GHz for a 100 nm wide gap and is the highest reported to date in this frequency regime. The corresponding maximum L = 200 μm, w =  10 μm, s =  20 μm, and h =  60 nm  triad – where E is the electric and H the magnetic field and k the wave vector – of the incident THz pulse is indicated in z(t)E averaged over 9 pixels around the top right corner of the split ring resonator. Note that the incident THz pulse has a negligible longitudinal electric field component and the measured electric field is solely due to the THz-induced charge oscillations. zE at successive times jt = 9.2 ps, 10 ps, 10.8 ps, and 11.8 ps as marked by the vertical red lines in Exemplarily, we discuss the results for the split ring resonator with a 500 nm wide gap. The incident single-cycle THz pulses cover a spectral range from 10 GHz to about 1.5 THz with the peak at approximately 0.32 THz. They propagate along the zE we calculate the spectral electric field distribution zE by Fourier transforming the time dependent electric field at every position . The intensity graph in z|E at the third resonance, i.e. at 3ν = 180 GHz. The signal at the first resonance is close to the noise floor and not considered here.From the calibrated temporal electric field distribution zE| shows excellent agreement. The simulations are performed in frequency-domain and in three spatial dimensions using a commercial software package (COMSOL Multiphysics)x(t)E with no split ring resonator on the substrate. The simulations not only yield the out-of-plane electric field distribution but any other relevant quantity, most importantly the electric field distribution and the electric field enhancement in the gap where the measurements, due to the limited spatial resolution, cannot reveal any information. That is, we experimentally verify that the simulations accurately reproduce the spatially resolved out-of-plane electric field at the third resonance (3ν = 180 GHz), and thus the charge distribution on the split ring resonator which is responsible for the capacitive charging of the gap, and then extract the in-gap electric field and field enhancement from the simulations.Comparing the measured  to the sν3. For a 100 nm wide gap the maximum electric field enhancement is as high as 14300 at the fundamental resonance and 3400 at the third order resonance. As mentioned above the electric field enhancement at the individual resonances differ because of the different character of the charge distribution on the split ring structure. At the lowest order resonance the charge is known to accumulate predominantly around the gap. Conversely, at the third order resonance, the charges accumulate at the two corners opposite to the gap1v = 56 GHz) is shown in 3ν = 175 GHz (broad line width) and a long lived at 3ν = 50 GHz (narrow line width), and reaches peak values on the order of 80 kVm−1. The results suggest that even a conventional tabletop THz source, as it is used in many THz time domain spectrometers, combined with such a split ring resonator can result in electric field amplitudes as high as several hundreds of kVm−1. A more powerful THz source will yield electric fields sufficiently high for many nonlinear THz effects, for example in semiconductors.We would like to point out that the dimensions of the split ring resonators used here have been chosen to allow for sophisticated near-field THz imaging and not for achieving the highest possible electric field strengths. For such purpose one would aim for a better overlap between the incident THz spectrum and the electric field enhancement curve. Although available fabrication techniques permit narrower gap widths , and thus even higher electric field enhancements, these are not necessarily advantageous as they result in a smaller and more difficult to access interaction volume. Therefore, a compromise should be found between electric field enhancement and interaction volume.Hz the corresponding maximum |E|2 and |E|4 enhancement factors are 2·10Through a combination of THz near-field imaging measurements and sophisticated electromagnetic simulations we have demonstrated giant electric field enhancement in split ring resonators featuring a nano-gap. Electric field enhancement values as high as ~14,000 and ~3,400 were observed for a 100 nm wide gap with the resonance frequencies at 50 GHz and 175 GHz. At 50 GF.E. and S.B. performed the experiments; S.B. fabricated the sample; J.F. and F.E. performed the simulations; S.B., H.S. and T.F. wrote the manuscript; all authors discussed the results and contributed to the manuscript.Supplementary informationTime dependent electric field distribution


To examine the association of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anthropometry in the offspring of mothers with gestational diabetes mellitus (GDM).We performed a retrospective cohort study in 1263 GDM mother-child pairs. General linear models and Logistic regression models were used to assess the single and joint associations of maternal pre-pregnancy BMI  and GWG  with anthropometry and overweight status in the offspring from birth to 1-5 years old.Maternal pre-pregnancy BMI and GWG were positively associated with birth weight for gestational age Z score and birth weight for length for gestational age Z score at birth, and weight for age Z score, length/height for age Z score, and weight for length/height Z score at of 1-5 years old offspring. Maternal pre-pregnancy overweight, obesity, and excessive GWG were associated with increased risks of large for gestational age  and macrosomia  at birth and childhood overweight at 1-5 years old .Offspring born to GDM mothers with pre-pregnancy overweight/obesity or excessive GWG were associated with increased risks of large for gestational age and macrosomia at birth, and childhood overweight at 1-5 years old, compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG. Obesity has progressed in a few decades from a public health footnote in developed countries to a top-priority international issue, affecting all socioeconomic classes and age groups including children younger than 5 years old , 2. The Maternal pre-pregnancy overweight and obesity have also increased nowadays , 8. MoreTianjin is the fourth largest city in Northern China. All pregnant women who live in six urban districts have participated in the universal screening for GDM since 1999  by usingTianjin Gestational Diabetes Mellitus Prevention Program from August 2009 to July 2011. Finally, 1263 GDM women and their children had completed the baseline survey for the TGDMPP from August 2009 to July 2011 (participation rate 27%) . In. In2), oth percentile. Macrosomia was defined as birth weight ≥4000 grams. At baseline (1–5 years of offspring age), z scores for weight for age, height for age, weight for length and BMI for age, and childhood overweight were calculated based on the standards for the WHO growth reference [th percentiles for age and gender using the WHO BMI growth reference (≥1.035 Z score) [Z scores for birth weight for gestational age and birth weight for length for gestational age were calculated using our own study population means and standard deviations  in 2009–2011 . A largeeference . ChildreZ score) .The general characteristics of both GDM mothers and offspring according to different categories of maternal pre-pregnancy BMI and GWG were compared using one-way ANOVA and chi-square test. General Linear Models were used to compare the differences in Z scores for birth weight for gestational age and birth weight for length for gestational age, Z scores for weight for age, height for age, weight for height and BMI for age at baseline survey, and changes in Z scores for weight for age and weight for height from birth to baseline (1–5 years of offspring age) according to different categories of maternal pre-pregnancy BMI and GWG. Logistic regression was used to estimate the odd ratios (ORs) and 95% confidence intervals (95% CIs) of large for gestational age and macrosomia at birth, and childhood overweight at baseline survey with maternal pre-pregnancy BMI and GWG categories. We set up two models: Model 1, adjusted for variables with significant differences according to maternal pre-pregnancy BMI and gestational weight gain categories, including maternal age, family history of diabetes, education, income, gestational diabetes treatment during pregnancy, gestational weeks of birth, and infant feeding; Model 2, adjusted for variables in Model 1 and also for variables at birth, including birth weight for gestational age Z-score or birth weight for length for gestational age Z score. All statistical analyses were performed with SAS for Windows, version 9.3 .Maternal and offspring’s general characteristics were presented in Maternal pre-pregnancy BMI and GWG were positively associated with birth weight for gestational age Z score  and birtMaternal pre-pregnancy BMI and GWG were positively associated with weight for age Z score, length/height for age Z score , and weiWhen maternal pre-pregnancy BMI and GWG were examined as continuous variables, ORs (95% CIs) of large for gestational age, macrosomia and childhood overweight were 1.14 (1.09–1.19), 1.17 (1.12–1.22) and 1.07 (1.03–1.19) with pre-pregnancy BMI, and 1.09 (1.07–1.12), 1.09 (1.06–1.12) and 1.03 (1.01–1.06) with GWG, respectively.The subgroup analyses of associations of large for gestational age, macrosomia and childhood overweight risks with pre-pregnancy obesity and excessive GWG were presented in 2) and non-excessive GWG, pre-pregnancy overweight (BMI ≥24 kg/m2) and non-excessive GWG, pre-pregnancy normal weight and excessive GWG, as well as pre-pregnancy overweight and excessive GWG  compared with those born to mothers with pre-pregnancy normal weight and adequate GWG, after adjusted for birth size.Our study also assessed the joint association of maternal pre-pregnancy BMI and GWG with the risks of offspring overweight at birth and 1–5 years old at baseline survey. We found that offspring born to GDM mothers with pre-pregnancy overweight/obesity and excessive GWG presented the highest risk of macrosomia and large for gestational age at birth and overweight at 1–5 years old compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG. Another important observation was that the associations of maternal excessive GWG with macrosomia and large for gestational overweight of their offspring at birth were similar to that of maternal pre-pregnancy overweight/obesity, but the effects of maternal excessive GWG on their offspring’s overweight status at 1–5 years old were smaller than that of maternal pre-pregnancy overweight/obesity. This finding was confirmed in the subgroup analyses that the association of childhood overweight with maternal pre-pregnancy obesity tended to be larger among older children, while the association of childhood overweight with maternal excessive GWG tended to be smaller among older children. Previous studies suggested that among the general population, maternal pre-pregnancy overweight was a risk factor for both early onset overweight (persisted throughout childhood) and late onset overweight (after age 8) of their offspring, while maternal excessive GWG was only associated with the early onset overweight of their offspring . AlthougIn the present study, GDM women with pre-pregnancy obesity had a lower mean value of GWG. Since it has been suggested that pre-pregnancy obese women may benefit from low GWG , the IOMThere are several mechanisms that maternal pre-pregnancy overweight/obesity and excessive GWG might confer the risk of overweight/obesity of their offspring, including the child’s inheritance of genes susceptible to overweight/obesity , the intOur study has several strengths, including use of GWG category instead of net weight gain, a large number of GDM mother-child pairs, and adjustment for multiple prenatal and perinatal factors in analyses. However, there were several limitations. First, the study was a retrospective cohort which might produce recall bias. Second, the participation rate was only 27%. Although there were no differences in age, 2-h glucose, fasting glucose, and the prevalence of IGT and diabetes at 26–30 weeks’ gestation (based on OGTT) between those returned and those not returned, whether there was a difference between the postpartum outcomes cannot be verified. Third, even though our analyses adjusted for an extensive set of confounding factors, residual confounding due to the measurement error in the assessment of confounding factors, unmeasured factors such as genetic and environmental factors of GDM mothers and their children, cannot be excluded.In summary, we found that offspring born to GDM mothers with pre-pregnancy overweight/obesity or excessive GWG had increased risks of large for gestational age and macrosomia at birth, and childhood overweight at 1–5 years old, compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Isolated hydatid cyst of kidney is very rare. Hydatid cyst of a duplex renal system is even more rare. We report a 13-year old girl with duplex system of right kidney with isolated hydatid cyst in upper moiety. Right nephrectomy was done to cure the condition. Kidney involvement in echinococcosis is extremely rare. Primary involvement of the kidney without the involvement of the liver and lungs is even rarer.[1] Though, a duplex collecting system is one of the most common congenital renal tract abnormality, it is seen in only 0.7% of the normal adult population and in 2-4% of patients investigated for urinary tract symptoms. There are only a few case reports of hydatid cyst in an anomalous kidney and most were in Horseshoe kidneys. We present a case of primary renal hydatid cyst in upper moiety of right duplex kidney.A 13-year old female presented with continuous dull pain localized to the right flank region for three months. She had no urinary complaints. General examination was unremarkable. Abdominal examination revealed a 10 cms x 10 cms lump in the right lumbar region which was bimanually palpable. Her routine blood and urine investigations were normal with no eosinophilia, and had normal renal function tests. X-ray chest was normal. Ultrasonography whole abdomen suggested a heterogeneous cyst of size 13 cms x 10 cms with multiple daughter cysts and septation in the right lobe of liver with non-visualisation of right kidney. Contrast Enhanced Computed Tomography (CECT) showed a large multiloculated cyst of size 11.5cms x 10.5cms x 15.5cms with internal septations arising from the upper pole of right kidney, with typical cysts within cyst appearance and thinned out peripheral parenchyma. Liver was pushed upwards and medially, which otherwise was normal . ELISA test for echinococcus antibodies was positive. A course of albendazole was given for one month and subsequently patient was planned for surgery.On exploration, there was a large hydatid cyst in the upper moiety of right incomplete duplex kidney, compressing the lower moiety into thin rim of parenchyma with two separate ureters that were united caudally. Heminephrectomy was not feasible, so a simple nephrectomy was done. Cut specimen of the right kidney had two moieties with two ureters. The upper moiety was turned into a bag of cysts while lower moiety had compressed thinned out renal parenchyma with no evidence of any cystic disease . The histopathological examination of the cyst was consistent with the diagnosis of hydatid disease of kidney. Albendazole was continued for eight weeks after surgery. USG abdomen after 6 months suggested no recurrence.It is postulated that the renal hydatid cyst form when the echinococcous larvae are lodged into the kidneys through retroperitoneal lymphatics while passing through portal system to the liver or through systemic circulation after passing liver and lungs.[6] The hydatid cyst of the kidney is considered closed if all three layers of the cyst i.e. pericyst, ectocyst and endocyst are intact.[1] When the cyst is no longer protected by the third layer, i.e pericyst or by the lining of the collecting system, it is considered to be an exposed cyst. If all the three layers of the cyst have been ruptured, resulting in free communication with the calyces and pelvis, it is called an open or communicating cyst.[7] Cystic rupture into the collecting system, causing hydatiduria is pathognomonic of renal hydatidosis, though it is usually microscopic and is seen in only 10-20% of renal hydatidosis.Renal hydatid cysts are usually asymptomatic or may present with chronic dull pain or lower backache due to enlarging cyst.[6] Rarely they may present with colicky pain due to hydatiduria and chronic renal failure when bilateral kidneys are involved.[6] A thin rim of calcification delineating a cyst is suggestive of an echinococcal cyst. Ultrasonography helps in the diagnosis of hydatid cysts when the daughter cysts and hydatid sand are demonstrated. On changing the patient's posture under real time, there is shifting of hydatid sand, which may give rise to the "falling snowflake pattern".[7] The mainstay of diagnosis is by advanced radiological techniques like CT scan and magnetic resonance imaging (MRI). CECT has an accuracy of 98% to demonstrate the daughter cysts. The CT scan usually demonstrates an expansile, hypo-attenuating tumor with a well-defined wall and daughter cysts within the parent cyst. MRI usually reveals a solitary, high-signal-intensity mass consisting of multiple thin-walled lesions and outlined by a thick, hypointense rim. The high signal intensity is due to the characteristic high fluid content of the mass. The small peripheral cysts are usually hypointense relative to the central component. The MRI shows the cysts adequately, but MRI offers no real advantage over CT scan.Surgery is the treatment of choice in cases of renal hydatidcyst.[6] Kidney sparing hydatid cyst removal (cystectomy with pericystectomy), is possible in most (75%) cases. Nephrectomy is considered only if the kidney is destroyed by the cyst. Both open and laparoscopic techniques have been described. There is risk of cyst rupture and dissemination during laparoscopy.[6] During kidney-sparing surgery scolicidal solutions such as hypertonic saline should be used. Pre- and postoperative course of albendazole is recommended to sterilize the cyst, decrease the chance of anaphylaxis and decrease the tension in the cyst wall thus reducing the risk of spillage during surgery and recurrence.Source of Support: NilConflict of Interest: None declared