It remains unclear why substantial variations in neurodevelopmental outcomes exist within small-for-gestational-age (SGA) children. We prospectively compared 5-y neurodevelopmental outcomes across SGA etiological subgroups.Children born SGA (N = 1050) from U.S. Early Childhood Longitudinal Study-Birth Cohort (2001–2007) was divided into etiological subgroups by each of 7 well-established prenatal risk factors. We fit linear regression models to compare 5-y reading, math, gross motor and fine motor scores across SGA subgroups, adjusting for socio-demographic confounders.Compared to singleton SGA subgroup, multiple-birth SGA subgroup had lower mean reading  and math  scores. These disadvantages in reading and math existed only among multiple-birth SGA subgroup without ovulation stimulation , but not among those with ovulation stimulation . Compared to singleton SGA subgroup without maternal smoking and inadequate gestational weight gain, singleton SGA subgroup with co-occurrence of maternal smoking and inadequate gestational weight gain (GWG) had lower mean reading  and math  scores. These differences were not mediated by Apgar score.Multiple-birth SGA subgroups (vs. singleton SGA) or singleton SGA subgroup with co-occurrence of smoking and inadequate GWG  have poorer cognitive development up to 5 y. About 10% -16% of children in high-income countries [Body size at birth is well known to be a risk factor for perinatal morbidity and mortality, as well as poor neurodevelopment ,2. A newountries  and 27% ountries  are bornountries .On average, children born SGA are more likely to have worse neurodevelopment than children born appropriate-for-gestational-age (AGA) . HoweverFig 1, we hypothesized that etiological subgroups of SGA have different neurodevelopment measured by cognitive and motor outcomes, through the direct effects of SGA-related prenatal risk factors or mediation by Apgar score (indirect effects).In addition, the extent of neurodevelopmental impairment may vary considerably across SGA etiological subgroups, possibly due to the variation in Apgar score . This vEarly screening and intervention may alter SGA children’s disadvantaged neurodevelopmental paths and thus improve their later outcomes –20. DiviTable 1). Fig 2 shows the sample flow. All reported numbers about sample size are rounded to nearest 50 according to the confidentiality policy of U.S. Department of Education. This secondary data analysis was approved by the Social and Behavioral Sciences Institutional Review Board, State University of New York at Buffalo.We used existing data from the Early Childhood Longitudinal Study-Birth cohort , a U.S. national longitudinal birth cohort with child assessments at birth, 9 months (m), 2 years (y), 4 y (preschool), 5 y (kindergarten 2006), and 6 y (kindergarten 2007) ,22. ThisIn this study, the exposures were SGA etiological subgroups based on each or co-occurrence of maternal pre-pregnancy underweight, short stature, smoking and alcohol use during pregnancy, inadequate GWG, hypertensive conditions, and multiple births. We considered these 7 factors because they are well-established prenatal risk factors for SGA and could explain large proportion of SGA . Also, tth percentile for the same sex and gestational age within a national reference population of U.S. newborns [th-90th percentiles. For the purpose of this analysis, we excluded children with birth weight above 90th percentile .Birth weight in grams, last menstrual period (LMP), and delivery date were extracted from birth certificates of live births in 2001 provided by the State Vital Registration and Statistics Executives . Birth wnewborns . AGA was2. Pre-pregnancy underweight was defined as pre-pregnancy BMI<18.5kg/m2 [Mother reported her height and pre-pregnancy weight in the 9-m postpartum interview. Pre-pregnancy body mass index (BMI) was calculated as weight (kg)/height (m) 8.5kg/m2 . Short s8.5kg/m2 .We extracted information on maternal smoking (# of cigarettes/day) and alcohol use (yes vs. no) during pregnancy from birth certificates. Although these two socially unfavorable behaviors were subject to under-report in birth certificate, it was acceptable to use them for exploratory studies like ECLS-B . If the 2), 11.5 kg for normal weight , 7 kg for overweight , and 5 kg for obese women (BMI ≥30 kg/m2), respectively. For multiple births, inadequate GWG was defined total GWG less than 17 kg for underweight and normal weight, 14 kg for overweight, and 11 kg for obese women, respectively [The information on total GWG was obtained from birth certificates (77.9%) and also from maternal self-reports at 9-m postpartum interview (22.1%) if birth certificate data was unavailable. Inadequate GWG for singletons was defined total GWG less than 12.5 kg for underweight  was extracted from birth certificates.The information on singleton and multiple births  was extracted from birth certificates. Ovulation stimulation is one of the most important reasons for recent rapid increase in rate of multiple births . Thus weTable 2). Neurodevelopmental status assessed around the age for kindergarten has been shown to be strongly related to later school success up to high school [Our key neurodevelopmental outcome measures included reading, math, gross and fine motor scores at 5 y assessed by certified fieldworkers  battery. Specifically, the 5-y reading assessment was based on the child’s performance on certain language-based items (receptive language/ Peabody Picture Vocabulary Test items) and the literacy items . The 5-y math assessment included number sense, properties, operations, measurement, geometry and spatial sense, data analysis, statistics, probability, patterns, algebra, and functions. For reading and math, overall scale scores based on the full set of assessment items were calculated using item response theory (IRT) procedures . IRT metThe gross and fine motor skills were direct assessed using a battery mainly modified from the preschool and/or kindergarten versions of the Early Screening Inventory-Revised (ESI-R) , a reliaNote that child intelligence quotient (IQ) assessment was unavailable in ECLS-B due to the study priority on the learning-related skills  that were more directly related to school readiness, intent to measure cognitive dimensions that were comparable across different assessment waves at different ages , as well as several important constraints including short assessment time (<45 minutes), less controlled home settings, and less professional field examiners with only basic knowledge of child development .We considered 5- minute Apgar score as a perinatal mediator related to poor neurodevelopment of some SGA etiological subgroups. Although 5- minute Apgar score is not designed to predict long term health and development, it can be a valuable indicator for some important fetal complications such as birth asphyxia and cerebral palsy .The confounders in this analysis included family socioeconomic status (SES); maternal age at pregnancy, race/ethnicity, education level, marital status, method of delivery, and diabetes during pregnancy; and the child’s sex. Family SES score was derived from 5 available components including parents’ education, parents’ occupation, and household income .In this study, we divided SGA children into etiological subgroup because it can better control for other prenatal risk factors than regular statistical methods such as multivariable regression modeling and thus offer clear separation of different etiologies of SGA. Although the subgroup approach is subject to lower statistical power due to reduced sample size, it fits our study purposes well.Table 3). All regression models were fitted with generalized estimating equations to control for the correlation between multiple siblings (twins or triplets), by specifying exchangeable covariance matrix among siblings.We fitted multivariable linear regression models to compare neurodevelopmental outcomes between the etiological SGA subgroup with a specific risk factor and the SGA subgroup without the corresponding risk factor , adjusting for confounders .Restricted by sample size, we only considered the co-occurrence of 3 relatively common risk factors  that were associated or marginally associated with neurodevelopmental outcomes in S1 Table).Based on the causal step method for medication analysis , we fittS2 Table). Second, we calculated Pearson correlations across reading, math, gross and fine motor scores at 5 y, which could help to assess their internal reliability , which could help to assess the departure from normal neurodevelopment of healthy children (Table 1).Compared with those in the excluded sample, mothers in the analytic sample were more educated, had higher family SES score, were more likely to have multiple births, and were less likely to smoke during pregnancy and be underweight; children in the analytic sample were less likely to be born preterm (Table 2).Children born SGA had lower mean reading , math , gross  and fine  motor scores than children born AGA (Table 3). Compared with the singleton SGA subgroup, the multiple-birth SGA subgroup had lower mean reading  and math  scores; these cognitive disadvantages were observed only among those without ovulation stimulation  but not among those with ovulation stimulation .Compared to the SGA subgroup with normal GWG, the SGA subgroup with inadequate GWG had lower mean reading , math  and fine motor  scores (Table 4). The singleton SGA subgroup with both, but not single, of maternal smoking and inadequate GWG had lower mean reading  and math  scores. The SGA subgroup with co-occurrence of maternal smoking and multiple births had lower mean math  and fine motor  scores. The SGA subgroup with co-occurrence of maternal inadequate GWG and multiple births (12.9%) had lower mean reading  and math  scores.We further stratified SGA by the co-occurrence of smoking during pregnancy, inadequate GWG, and multiple births, as they were associated or marginally associated with neurodevelopmental outcomes in single factor analysis shown above. Compared with the reference SGA subgroup without smoking, inadequate GWG, or multiple births, the multiple-birth SGA subgroup without smoking and inadequate GWG had lower mean reading  and math  score at 5 y (S4 Table).In addition, among singleton SGA children, the co-occurrence of inadequate GWG and moderate smoking during pregnancy (vs. absence of these 2 risk factors) was associated with lower mean reading score , while the co-occurrence of inadequate GWG and heavy smoking during pregnancy was associated with lower mean math score  (S1 Table). Therefore, Apgar score did not mediate the associations between SGA etiological subgroups and neurodevelopmental outcomes.There was no significant difference in Apgar score across SGA subgroups by co-occurrence of maternal smoking, inadequate GWG, and multiple births  the SGA subgroup with co-occurrence of maternal smoking and inadequate GWG was particularly disadvantaged in reading and math skills at 5 y; 2) the multiple-birth SGA subgroup without ovulation stimulation was at an increased risk of developmental delay in reading at 5 y; 3) these cognitive disadvantages could not be explained by low Apgar score at birth. Our novel findings supported the importance of considering prenatal factors in the understanding of heterogeneity in neurodevelopmental outcomes among SGA children. It is necessary to screen SGA children based on their potential etiology and identify SGA subgroups at the greatest neurodevelopmental risk for referrals to early intervention.Consistent with the literature , we obseOne of our most important findings was that the singleton SGA subgroup with co-occurrence of maternal smoking during pregnancy and inadequate GWG had worse reading and math outcomes up to 5 y. This cognitive disadvantage seemed not be explained by low Apgar score. Prenatal exposure to tobacco metabolites may alter and damage fetal brain development reflected by small head circumference, lower cortical grey matter and total parenchymal volumes in the offspring , and thuS5 Table). Positive parenting may well offset the potential disadvantages related to multiple births. Finally, we could not rule out the possibility that mother of multiple-birth SGA subgroup with ovulation stimulation might have involved genetic screening or selection of healthier embryos, which could be associated with the better neurodevelopmental outcomes.Our second novel finding was that the multiple-birth SGA subgroup without ovulation stimulation was at an increased risk of developmental delay in reading. This finding is consistent with the literature on neurodevelopmental disadvantages related to multiple births . It is hWe noticed that SGA children with co-occurrence of maternal smoking, inadequate GWG, and multiple births did not have statistically significantly worse neurodevelopmental outcomes than those without any of these 3 risk factors. This finding was different from our hypothesis (this subgroup being the worst). Particular caution is needed to interpret this finding, given the very small sample size of this SGA subgroup (2.6% within SGA). It might be related to survival bias of live babies, i.e., SGA newborns who survive in harsh intrauterine environment tend to be healthier than other babies who otherwise die before birth such as miscarriage.We found SGA children as a whole group had poorer gross and fine motor development than AGA children, which was consistent with findings of some previous studies  but not First, the attrition rate at 5-y visit was considerably high (~33%) in the ECLS-B sample. Our analytic sample was somewhat different from the excluded sample especially in maternal education, which could introduce selection bias. Second, the low prevalence of alcohol use limited statistical power to compare neurodevelopment across SGA subgroups by these factors. Also, we could not examine SGA subgroup due to some genetic factors such as maternal low birth weight as this information was unavailable in ECLS-B. Third, the relatively low reliability and validity of some non-medical measures on birth certificates needed to be taken in account when interpreting our findings . For exaIn summary, we found that multiple-birth SGA subgroup or singleton SGA subgroup with co-occurrence of smoking and inadequate GWG were particularly disadvantaged in cognitive development up to 5 y. From a clinical perspective, the effect size of these disadvantages appeared moderate (Cohen’s d<0.4) at individual level, however, a downward shift in mean neurodevelopmental level might result in many children with neurodevelopmental disabilities at population level . If our S1 Table(DOCX)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.


Usually animals reproduce into old age, but a few species such as humans and killer whales can live decades after their last reproduction. The grandmother hypothesis proposes that such life-history evolved through older females switching to invest in their existing (grand)offspring, thereby increasing their inclusive fitness and selection for post-reproductive lifespan. However, positive grandmother effects are also found in non-menopausal taxa, but evidence of their associated fitness effects is rare and only a few tests of the hypothesis in such species exist. Here we investigate the grandmother effects in Asian elephants. Using a multigenerational demographic dataset on semi-captive elephants in Myanmar, we found that grandcalves from young mothers (<20 years) had 8 times lower mortality risk if the grandmother resided with her grandcalf compared to grandmothers residing elsewhere. Resident grandmothers also decreased their daughters’ inter-birth intervals by one year. In contrast to the hypothesis predictions, the grandmother’s own reproductive status did not modify such grandmother benefits. That elephant grandmothers increased their inclusive fitness by enhancing their daughter’s reproductive rate and success irrespective of their own reproductive status suggests that fitness-enhancing grandmaternal effects are widespread, and challenge the view that grandmother effects alone select for menopause coupled with long post-reproductive lifespan. Orcinus orca) and short-finned pilot whales  have an exceptional life-history, with a notable proportion of all females in a given population post-reproductive and one quarter to half of the long lifespan spent as post-reproductive1256Humans, killer whales (Chlorocebus aethiops sabaeus)Macaca fuscata)1918182122Panthera leo)19However, a recent review of the current evidence for the grandmother hypothesis highlighted the need to scrutinize its predictions more widely in species that do not exhibit verified menopause and long post-reproductive lifespans, to provide a comparison and to further our understanding of the evolution and selection pressures on post-reproductive lifespan and long life in general101112131516Elephas maximus) females which survive to old age can have relatively long lives after last reproduction, at the population level, 17 years after age 47  and at the individual level 11 years for those females living beyond 40 yearsLoxodonta africana) females live 16 years on average after age 49273029323334Elephants provide a particularly promising opportunity to test the hypothesis by investigating several of its key predictions. Well-known for their close relationships between females within multi-generational herds led by matriarchs263Here we test the key predictions of the grandmother hypothesis by taking advantage of multigenerational longitudinal data recorded for Asian elephants working in timber extraction locations in Myanmar. The dataset provides a good opportunity for the following reasons: the population is semi-captive but with free interaction outside working hours, social groups roam in the forest unsupervised during free time, mortality rates are close to wild elephants12 = 4.85, Adjusted p = 0.019). If the mother was younger than average (20 years) when the calf was born and the grandmother resided in another location, the calf had an 8 times greater risk of dying than if the grandmother was present in the same logging location (Hazard ratio (95% CLs): 8.40 ; pairwise comparison: χ12 = 4.33, p = 0.037; 12 = 0.57, p = 0.45; Overall, 23% of calves died before reaching 5 years. Only 6 of the 161 calves lost a mother before age 5 years and all of the calves in the sample had a living grandmother at the time of their birth. After controlling for all fixed and random terms, we found that having a grandmother residing in the same location as the grandcalf significantly decreased calf mortality, but the strength of this effect varied depending on the age of the calf’s mother . This beneficial effect of grandmothers was similar irrespective of maternal age, so the birth rate of all females was improved by grandmother presence. Inter-birth intervals were also generally significantly decreased if the previous calf died before reaching age 2 .Grandmother’s presence in the same location had beneficial effects also on shortening the daughter’s inter-birth intervals. If the grandmother was alive and in the same location with the daughter’s two subsequent calves, the birth interval of these calves was 0.95 years (21%) shorter than if the grandmother resided in a different location (reproducing gm): 1.70 ). However, the more offspring the grandmother had given birth to before the grandcalf was born, the lower the mortality of the grandcalf . Calf mortality was also affected by the maternal age  did not have an effect on the grandcalf mortality  until the calves reach their first birthday64From the large multi-generational dataset available, we extracted a subset of live-born calves, for which the grandmother was known to be alive at the time of their birth in captivity. For these calves we collected information on the specific working locations where the calves were born as well as where their mother and grandmother were present during that time. This resulted in 161 calves  from 95 mothers and 83 grandmothers. These calves were born during 1965–2000 and come from 29 logging locations (grandmothers from 32 locations) within 8 larger geographic regions  in Myanmar: Ayeyarwady, Bago, Chin, Kachin, Magway, Mandalay, Sagaing and Shan. All selected mothers and calves were captive-born with known birth date, but 87 of these calves had a grandmother which was captive born and 74 a grandmother with wild origin (and thus with estimated age only at the time of capture). There are no ethical issues related to the demographic data on Asian elephants because it is historical and no experimental protocols were used in collecting the dataset.p = 0.05) and when possible, we also used AIC criterion for model fit to the data.All statistical analyses were conducted using SAS . Final models were determined using backward elimination technique and terms dropped if they failed to reach statistical significance (n = 31) and one grandcalf (n = 26) alive in the same location. The 112 calves which lived in a different location to their grandmothers were born to 61 grandmothers (and 66 mothers), the grandmothers having 1–4 grandcalves in different locations to themselves. Of the 161 calves, 31 died before 5 years, 103 were successfully followed until age 5 (independence), and 27 were censored before age 5 due to being alive at the end of the study period. This is in line with the observed overall calf mortality in the population at around 25% of calves dying before age 5All 161 live-born calves in our sample had a living grandmother at the time of their birth, with 112 having a grandmother living in a different logging location to themselves and 49 a grandmother living in the same location. The 49 calves which lived in the same location as their grandmother were born to 33 grandmothers (and 35 mothers), the grandmothers having 1–6 grandcalves in the same location. However, most grandmothers had only one daughter (n = 161) and the main term of interest was grandmaternal proximity in the same (n = 49) or another logging location (n = 112) compared to the grandcalf. We also controlled for calf sex, birth cohort  and larger geographic region , birth order , previous interbirth-interval , maternal age , grandmaternal age , maternal survival , grandmaternal survival  and grandmother’s origin . Birth cohort is known to affect survival12 = 0.050, Adjusted p = 0.81), for the maternal age  and for the interaction between grandmother proximity and maternal age . The results of this analysis and the effect of the grandmother are corroborated by a more detailed analysis  where we only included calves whose grandmother was known to be alive and in the same (n = 33) or another location (n = 75) until the calf died or reached age 5. This analysis confirmed the effect of the grandmaternal and maternal age being similar and significant .First we investigated whether the grandmother presence in the same location vs. another location at the time the grandcalf was born affected calf survival until age 5 by using Cox proportional hazards model. In this analysis all calves were included (n = 5). Only birth intervals after live-born calves and during which the grandmother was known to be alive were included. This resulted in 75 birth intervals with the grandmother in the same (n = 17) or another location (n = 58). The 17 intervals  during which the grandmother lived in the same location were from 10 grandmothers and 11 mothers and the 58 intervals during which the grandmother lived in a separate location were from 41 grandmothers and 42 mothers. We investigated the effect of grandmaternal proximity on inter-birth intervals using Glimmix procedure in SAS with gamma distribution and log-link. In this analysis Chin, Kachin and Shan were again grouped together when adjusting for large-scale variation across Myanmar because of low sample size and their location on mountainous regions. Also, Ayeyarwady and Mandalay were grouped with Bago because of low sample size and location on lowland regions. This resulted in a total of four geographic regions across Myanmar. Calf survival is known to affect inter-birth intervals12 = 1.09, p = 0.15).Second we investigated whether grandmother presence in the same location vs. another location at the time the grandcalf was born affected her daughter’s next birth interval length. This next birth interval was, on average, 4.97 ± 1.91 years (median = 4.6). Lastborn offspring and those offspring without siblings were excluded from this analysis. Elephant pregnancy lasts around 22 months and birth intervals <1.8 and >12.4 years  were therefore excluded as erroneous or outliers. Inter-birth intervals where the grandmother/ mother had changed location between the births of the first and second calf  were excluded to avoid contrasting grandmother effects (n = 49). The grandmother’s reproductive status was coded as whether the grandmother had given birth within 3 years of the birth of the grandoffspring (before or after) as this can be seen as the most dependent period of calf care12 = 0.97, Adjusted p = 0.30). The mortality hazard was proportional for the previous number of calves born to the grandmother , for the maternal age  and for the grandmother’s reproductive status variable .Third we investigated how the grandmother’s reproductive status or previous number of calves at the time the grandcalf was born affected her grandcalf survival until age 5 by using Cox proportional hazards model. We only included calves with the grandmother in the same location n = . The graF1,76 = 19.42, p < 0.0001), origin Est. (captive born) = 0.30 ± 0.18; , lifespan Est. = − 0.0077 ± 0.0093; , whether the grandmother was still alive or not Est. (censored) = − 1.34 ± 0.74; , and interaction between lifespan and being alive or not Est. (censored) = 0.024 ± 0.014; . The results from this model should be interpreted with knowledge that the overall numbers of grandoffspring and the effects of lifespan on this outcome are under-estimates due to several females (and their daughters) still being alive and reproductively active.Finally we also tested whether being resident alongside at least one young (<20 years) daughter had an effect on the total number of grandoffspring born as compared to females which were not resident alongside any of their daughters, or were only resident alongside their older (>20) daughters. We investigated this by using Glimmix procedure in SAS with negative binomial distribution and log-link. In this analysis we used all grandmothers included in the grandcalf dataset, 83 grandmothers. Of these grandmothers 43 were known to be already dead, whereas 40 were still alive at the time of censoring, and this was controlled for in the analysis. Of these grandmothers, 25 were known to be in the same location with at least one young reproductive daughter and 58 were in another location or resident with only older daughters. The mean number of grandcalves for the grandmothers was 3.01 ± 1.98 (1–11). In this analysis Kachin and Shan were grouped together when adjusting for large-scale variation across Myanmar because of low sample size and their location on mountainous regions. Also, Mandalay was grouped with Bago because of low sample size and location on lowland regions. Other living areas in the analysis were Magway and Sagaing. We also controlled for birth cohort of the grandmother ), grandmother’s origin , age at first reproduction , lifespan at death or at censoring , number of reproductive daughters  and age at last reproduction . Terms included in the final model were the residence near the <20 year old daughter, number of reproducing daughters Est. (1 reproducing daughter) = − 0.67 ± 0.15; .


To evaluate the feasibility of differentiating between hepatocellular carcinomas (HCC) and healthy liver using diffusion tensor imaging (DTI).2) and various diffusion-encoding directions using two way ANOVA analysis. Eighteen Patients with HCC underwent DTI scans with the optimized parameters. Fractional anisotropy(FA) and average apparent diffusion coefficient (ADC) values were measured. The differences of FA and ADC values between liver healthy region and HCC lesion were compared through paired t tests.All subjects underwent an abdominal examination on a 3.0T MRI scanner. Two radiologists independently scored the image quality (IQ). An optimal set of DTI parameters was obtained from a group of fifteen volunteers with multiple b-values , whereas the liver IQ and FA/ADC values decreased significantly with increased b-values(P <0.05). Good IQ, acceptable scan time and reasonable FA/ADC values were acquired using NED = 9 with b-value of  s/mm2. Using the optimized DTI sequence, ADC value of the tumor lesion was significantly lower than that of the healthy liver region , whereas the mean FA value of the tumor lesion (0.42 ± 0.11) was significantly higher than the normal liver region (0.32 ± 0.10) (P = 0.004).There were no significant changes in liver IQ and FA/ADC values with increased NED(Either FA or ADC value from DTI can be used to differentiate HCC from healthy liver. HCC lead to higher FA value and lower ADC value on DTI than healthy liver. Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most frequent cause of death amongst oncological patients. Alone, Diffusion tensor imaging (DTI) is a MRI technique that reveals microstructural characteristics of biological tissue, which can detect the degree of diffusion in multiple dimensions by using additional gradients, 9.CompaDTI has been used predominantly for brain imaging to characterize the healthy and diseased tissues in brain white matter–20. A feAs we know, b-value is the key factor in DW images, which will affect imaging quality and ADC values. Diffusion-encoding directions (NED) are the number of diffusion-encoding gradient directions, which is the other important factor in DTI acquisition. As NED increases, more DW images are used for the calculation of diffusion tensor, resulting in more accurate diffusion tensor estimation and a higher signal-to-noise ratio (SNR), but at the expense of a longer scan time . HoweverThe study was approved by the ethics committee of Affiliated Hospital of North Sichuan Medical College. Healthy volunteers were asked to voluntarily participate in this study, there was no specific protocol or methodology on the selection of the participants of this study as this was a convenience sample. However, a verbal informed consent regarding the goals of the study and the willingness to participate was taken by the HCC participants as the study qualified as involving only “minimal risks" to participants and the procedure was approved by the ethics committee of Affiliated Hospital of North Sichuan Medical College.15 healthy volunteers  without any history of liver disease or significant alcohol consumption and 18 consecutive patients  with histopathologic diagnosis of HCC through biopsy were included in this study.All examinations were performed on a 3.0 T MR scanner with a 50 mT/m maximum gradient length and 200 T/m/s maximum slew rate  using a 32-channel body array coil with sixteen anterior and sixteen posterior elements. All examinations were implemented in the supine position.After a gradient echo localizer, DTI was acquired on the 15 healthy volunteers in axial orientation with breath-hold fat saturated single spin echo planar imaging with the following parameters: TR 2500 ms; TE 70.1 ms; bandwidth 250 Hz; section thickness = 7 mm; intersection gap = 0 mm; matrix = 256×192; NEX = 1; and FOV = 28–34 cm, Auto shim: on. Slices number:18.2 respectively. Acquisition of more encoding directions leads to an extended scan time with the same scan range. Encoding directions  correspond to total acquisition time of 16s, 22s, 28s. A maximum of 12 diffusion encoding directions were chosen in this study to limit patient’s breath hold period to within a comfortable range (28s).The DTI acquisitions were repeated twelve times with NED = 6, 9 and 12 and b = values of , , , and  s/mm18 HCC patients underwent the following routine upper abdominal MR sequences and the optimized DTI sequence:A FRFSE T2-weighted sequence in axial orientation. The parameters were: TE = 90–100 ms, the TR was determined by the frequency of respiration; matrix = 256×192 NEX = 3; FOV = 26–33 cm; section thickness = 5 mm; intersection gap = 0.5 mm.A 3D LAVA-Flex MR performed during one breath-hold with the following parameters: TR/TE = 4.2 ms/2.6 ms, 1.3 ms; matrix = 320×384×224; FOV = 26–33 cm; section thickness = 5 mm; intersection gap = 0mm; fat suppression technique: two-point Dixon method[A dynamic enhanced image performed with axial 3D LAVA–Flex sequencing. Gadolinium chelate  was administered intravenously (0.2 mmol/L per kilogram of body weight) at approximately 3.5 mL/s using a double tube high-pressure injector  and was followed by a 20 mL saline solution flushed at the same speed. From the beginning of the injection, two arterial phase images were created in 19 seconds; two portal vein phase images were created in 60 seconds and one equilibrium phase image was obtained within 180 seconds.The DTI data were acquired after those conventional T2WI (a), T1WI (b) sequences and before dynamic enhanced image (c).Image quality of liver DTIs was evaluated independently by two radiologists .The two radiologists were blinded to the b-value of the DTIs. Overall DTI image quality for parenchyma structure discrimination, distortion, susceptibility artifacts and motion artifacts was assessed. Visual a. Definitions of DTI Indices: An average diffusion coefficient along each direction was derived from the DW images, as follows[S(i) is the signal intensity (SI) measured on the ithb-value image and bi is the corresponding b-value. S0 is the exact SI for a b-value = 0s/mm2.s follows:S(i)=S0λ1, λ2, λ3.The primary eigenvalue λ1  was the largest restricted diffusivity and the secondary and tertiary eigenvalues  (and their average) reflect lower restricted diffusion orthogonal to V1 [From all diffusion-weighted images, the general diffusion tensor was first diagonalized, and the yielded scalar invariants of the tensor, including diffusion eigenvalues iffusion).The indeefined asλ¯=λ1+λ2The range of FA value is from 0 to 1. FA value = 1 means those structures allowing diffusion restricted only along a single direction, whereas structures allowing completely free or isotropically diffusion should result in a FA of 0.b. Measurements in normal subjects: All the original MRI data were loaded onto a workstation .The signal-to-noise ratio (SNR) of liver and contrast-to-noise ratio between liver and spleen (CNR(ls)) were calculated to quantitatively analyze IQ. By placing three circular 20 mm2 region-of-interests (ROIs) over the right lobe of the liver and spleen porta slice on signal intensity images with b = 0 with the aid of the T2-weighted images, then the three ROIs were mapped to the FA and ADC map , but the main effect of b-values  was significant such that the scores of the image quality of liver reduced with increased b-values  = 25.36, P = 0.00) (2 with NED = 9 as the set of new parameters could gain a similar higher score. = 0.00) .From ana = 0.00) , choosinF  = 3.21, P = 0.03), but there was no statistically significant difference in SNR with different NED   = 0.73, P = 0.48)  . By stud = 0.48) , we founF = 0.93, P = 0.39), while the main effect of b-values on SNR was significant such that the SNR significantly reduced with increased b-values  = 17.49, P = 0.00). Moreover, there were no statistically significant differences in CNR(sl) with different NED and b-values = 0.24, P = 0.86),  = 1.98, P = 0.15), respectively).In the spleen region of the DTI, the main effect of NED on SNR was not significant as well = 22.86, P = 0.00; F  = 90.17, P = 0.00respectively). However, there was no statistically significant difference in liver ADC values with different NED  = 0.29, P = 0.75)    . From th highest  Fig 6B)F 2) on among IQ, FA and ADC values of liver DTI was significant such that the qualitative scores, SNR, ADC and FA of liver reduced with increased b-values . The ADC values of HCC lesions and normal right liver were 1.30±0.34×10−3mm2/s vs 1.52± 0.27×10−3mm2/s, also demonstrating a significant difference (P = 0.013). .The mean FA value of HCC lesions (0.42 ± 0.11) was significantly higher than that of normal right liver (0.32 ± 0.10) ( 0.013).  Fig 9)..P = 0.00P >0.05).2)The liver IQ and FA/ADC values decreased significantly with increased b-values(P <0.05). 3) Among acquisition time, resulting image quality and reasonable FA/ADC values seems to be the application of 9 encoding directions with b-values of 300 s/mm2 as a set of parameters for liver DTI on GE 3.0 T. 4)DTI with FA and ADC values can be used to different HCC from healthy liver.An optimal set of MRI acquisition parameters is critical for clinical diagnosis since it significantly affects the MRI quality and acquisition time. The major findings of this study are: 1) There were no significant changes in liver IQ and FA/ADC values with increased NED(P>0.05). It is notable that we chose smaller NEDs than the above referenced works. Large NEDs (>12) are suitable for brain DTI scans since no breath holding technique is required. However, for moving organs like liver, a breath holding technique should be adopted, especially because a respiratory gating technique is not allowed to use in liver DTI on 3.0T GE and when patient breathing pattern is irregular. Moreover, irregularities in breathing may lead to increased motion artifacts and mis-registration in liver DTI. Therefore, only NED of 6 (16sec), 9 (22sec) and 12 (28sec) were considered in our study. Although the main effect of NED  on imaging quality and FA/ADC values of liver DTI was not significant, our statistical interaction analysis indicated a combination of NED = 9 (22sec) with b-value = 100, 300 s/mm2 gain a higher qualitative score and a higher SNR of the liver DTI which was the main reason for us to pick NED = 9 as the optimized DTI scan parameter. It is well recognized that sequences scanned with higher b-values are considered to be more diffusion-weighted than sequences with lower b-values, while at an expense of a lower SNR[2).However, overly low b-values might result in an overestimation of FA/ADC values due to perfusion effects when applying higher b-values; the faster spin ensembles are already dephased and cannot contribute to the signal[2.Considering both quantitative and qualitative aspects, b-value = 300s/mm2 was picked as the optimized value for our patient liver DTI scans to gain better image quality without overestimation of FA/ADC values.The diffusion induced signal attenuation in DTI was measured for water displacement along at least six non collinear directions. Xia et lower SNR. Our finlower SNR–36 that he signal. B Chuckhe signalproved inR = 0.75). Sugita et al[DTI provides more accurate ADC calculation than DWI. Low ADCita et al demonstrita et al claimed Through thoroughly investigating the effect of NED, b value to image quality and FA/ADC value, we presented an optimal parameter setting for clinical DTI liver scan. In addition, FA/ADC values were found to be great indicators for HCC diagnosis which exhibits great value to clinical practice. Future work will focus on grading of HCC based on FA/ADC values. However, a small number of HCC patients in this study may introduce a slightly biased conclusion for further analysis. A large scale study is underway to evaluate the feasibility of grading HCC using FA/ADC values from liver DTIs.2 as the set of new parameters for liver DTI. FA and ADC from DTI could be used as indexes to differentiate HCC from healthy liver.The best compromise among acquisition time, resulting image quality and reasonable FA/ADC values is NED = 9 with b-values of 300s/mmS1 FigThree same ROIs placement of liver and spleen in signal intensity image (a), FA map (b) and ADC map(c).(PDF)Click here for additional data file.S2 FigThree same ROIs placement over the most homogeneous part of each lesion and on the right liver lobe on the signal intensity image (a), FA map (b) and ADC map(c).(PDF)Click here for additional data file.S3 Fig2 with NED = 9 could gain the higher score.The main effect of b-values and NED on qualitative scores of liver DTI (a) showed that the main effect of NED on qualitative scores of liver DTI was not significant, but the scores of the image quality of liver reduced with increased b-values. The interaction between b-values and NED on qualitative scores of liver DTI (b) showed that choosing b-value = 100, 300 s/mm(PDF)Click here for additional data file.S4 Fig2 lead to higher SNR of the liver DTI.The main effect of b-values and NED on liver SNR (a) showed that the liver SNR reduced with increased b-values, but the differences had no significant with increased NED. The interaction between b-values and NED on liver SNR(b) showed that selected NED = 9 and b‑values range between 100 and 300s/mm(PDF)Click here for additional data file.S5 Fig2 no matter what values the NED were, the liver ADC values were the highest.The main effect of b-values and NED on liver A DC (a) showed that the main effect of NED on liver ADC value was not significant, but liver ADC value reduced with increased b-values. The interaction between b-values and NED on liver ADC (b) showed that choosing b-value = 100s/mm(PDF)Click here for additional data file.S6 Fig(PDF)Click here for additional data file.S7 FigNED = 6 (a), NED = 9(b) and NED = 12(c) show equally good image quality (five points).(PDF)Click here for additional data file.S8 Fig2, it was difficult to discriminate the boundry of vascular structures in left liver.Both readers judged that the liver signal intensity was markedly reduced and the noise was significantly increased with increased B values, especially b-value = 800s/mm(PDF)Click here for additional data file.S9 Fig−3mm2/s and a FA value of 0.33, respectively.The tumor appeared hyperintense on DTI image (a). On dynamic gadolinium-enhanced imaging it showed markedly inhomogeneous enhancement at arterial phase (b). Surgical histopathologic diagnosis (c) confirmed it HCC. The tumor had an ADC value of 1.27×10(PDF)Click here for additional data file.S10 Fig(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file.


Expectant parents of very preterm infants, physicians, and policy makers require estimates for chances of survival and survival without morbidity. Such estimates should derive from a large, reliable, and contemporary data base of easily available items known at birth.To determine short-term outcome and risk factors in very-low-birth-weight preterm infants based on administrative data.Anonymized routine data sets transmitted from hospital administrations to statutory health insurance companies were used to assess survival and survival free of major morbidities in a large cohort of preterm infants in Germany.After exclusion of infants with lethal malformations, there were 13,147 infants with a birth weight below 1,500 g admitted to neonatal care 2008–2012, of whom 1,432 infants (10.9%) died within 180 days. Estimated 180 days survival probabilities were 0.632  for infants with 250–499 g birth weight, 0.817 (0.799–0.834) for 500–749 g, 0.931 (0.920–0.940) for 750–999 g, 0.973 (0.967–0.979) for 1,000–1,249 g, and 0.985 (0.981–0.988) for 1,250–1,499 g. Estimated probabilities for survival without major morbidity  were 0.433 (0.384–0.481) for 250–499 g, 0.622 (0.600–0.643) for 500–749 g, 0.836 (0.821–0.849) for 750–999 g, 0.938 (0.928–0.946) for 1,000–1,249 g, and 0.969 (0.964–0.974) for 1,250–1,499 g, respectively. Prediction of survival and survival without major morbidities was moderately improved by adding sex, small for gestational age, and severe or moderate congenital malformation, increasing receiver operating characteristic areas under the curve from 0.839 (0.827–0.850) to 0.862 (0.852–0.874)  and from 0.827 (0.822–0.842) to 0.852 (0.846–0.863) , respectively.The present analysis encourages attempts to use administrative data to investigate the association between risk factors and outcome in preterm infants. Kaplan–Meier analysis was used to describe survival up to 180 days and survival without major neonatal morbidity, with strata being compared by the log-rank test. The impact of predictor variables was assessed with adjusted odds ratios (OR) in multiple logistic regression analyses. To describe the power to predict survival and survival without major neonatal morbidity, receiver operating characteristics (ROC) curves were generated, and the areas under the curve with 95% confidence intervals were calculated.The study received institutional review board approval . No consent was required as this is a retrospective analysis of anonymized data collected according to federal law.n = 17; lethal malformations: n = 128, twins with identical numbers: n = 17). The characteristics of the 13,147 patients included are given in Table p = 0.0216) and small-for-gestational-age babies  in infants with a birth weight of 250–749 g, as compared to infants of 750–1,499 g, while the opposite was observed for multiples .A total of 13,303 infants covered by the regional statutory health insurance companies were born between January 1, 2008 and December 31, 2012 with a birth weight between 250 and 1,499 g. Of these, 156 were excluded  in the total group, and 22%  in infants below 1,000 g birth weight  infants. Estimated probabilities of 180 days survival without major morbidity were 0.433 (0.384–0.481) for 250–499 g, 0.622 (0.600–0.643) for 500–749 g, 0.836 (0.821–0.849) for 750–999 g, 0.938 (0.928–0.946) for 1,000–1,249 g, and 0.969 (0.964–0.974) for 1,250–1,499 g, respectively , sex, small for gestational age, multiple gestation, moderate, and severe congenital malformations, on survival and survival without major morbidity , and 0.827 (0.822–0.842) when only birth weight was used  and 0.852 (0.846-0.863) taking the 2–0.874 aThis analysis reports an overall 180 days survival rate of preterm infants with a birth weight <1,500 g admitted to neonatal intensive care units in Germany 2008–2012 of 89.1%, with 14.1% of deaths occurring between 30 and 180 days of life. Surgically treated major morbidities were observed in 7.7% of all very-low-birth-weight infants, and 7.8% of survivors, respectively. Rates of survival strongly declined alongside decreasing birth weight, from 97.9% in 1,250–1,499 g birth weight infants to 38% in infants below 500 g birth weight, while the rates of surgically treated major morbidities in survivors increased from 1.7 to 32%.We compared our data with published data of a cohort of 2,207 infants below 1,500 g birth weight without lethal malformations treated in 2010 in a network of 46 tertiary care neonatal units in Germany . The puba priori selected variables on death and death and major morbidity combined was remarkably similar. Multiple gestation was not linked to poor outcome, an observation made for recent cohorts also in Australia and New Zealand . This drawback is to be balanced against the risk of recruitment bias in prospective clinical trials, especially those that require antenatal parental consent , the risOur investigation was based on data from patients rather than cases, whereas events occurring after discharge or transfer to another hospital are being missed in unit-based network and quality improvement data sets. In contrast to other studies, the 180 days window allowed to take events after discharge or transfer to another hospital into account, unless there was a change in the company providing health care insurance. Late deaths are an important issue, especially in very small infants, with 13.3% of deaths occurring after 30 days of life in infants below 1,000 g birth weight. For comparison, 17.3 and 19.8% of all deaths occurred beyond 28 days of life in the American NICHD , respectAs a major weakness, some variables of great interest to clinicians are missing, particularly gestational age at birth, antenatal steroids, mode of delivery, and inborn/outborn status. A merger of the anonymized infant administrative data sets, as used in this study, with maternal records is being hampered by current rules governing privacy protection. The variable “small for gestational age” partly made up for the missing variable “gestational age at birth,” also avoiding the multicollinearity problem when birth weight and gestational age are entered simultaneously as continuous measures. The variable “antenatal steroids” has lost statistical impact as a result of the high rates of antenatal steroids and exogenous surfactant replacement therapy . As dataHigh-grade IVH, high-grade ROP, and NEC requiring surgery have been shown to be strong predictors of long-term neurodevelopmental impairment , 28–35. Data entered into any type of registry are liable to inadvertent mistakes, biased coding, or even wilful deceit. When estimating the risk of false entries, there are several questions to be addressed: (1) How reliable is the information given to the person who enters the data? (2) How likely are errors based on negligence? (3) Are there incentives for up-coding, down-coding, or omission of data? For these reasons, we chose to not include bronchopulmonary dysplasia as an outcome variable in this analysis, as it lacks an unambiguous marker to disassociate mild from severe forms unless strict definitions are being employed. Some degree of disordered lung development is common in very preterm infants, and it largely depends on the exact criteria used whether or not infants are classified as having bronchopulmonary dysplasia . For morAdministrative data have been used successfully for as diverse purposes as to estimate live delivery rates after tubal sterilization reversal , to compEJ, AB, CG, TB, GH, HH, and CB all contributed to the conception and design of this analysis. EJ, AB, and CG provided the statistical analysis, EJ and CB drafted the first manuscript that was revised by AB, CG, TB, GH, and HH and finally approved by all authors.The authors declare that this work was done in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A case of ileal atresia in association with duplication of terminal ileum is being reported here. Jejuno-ileal atresias and jejuno-ileal duplication cysts are uncommon gastrointestinal malformations. The association of these two malformations is extremely rare with very few reports in English literature [1-9]. We report a case of ileal atresia in association with ileal duplication cyst in a neonate. The relevant literature pertaining to the etiology of these lesions is discussed.A term female baby weighing 3130 grams was born by normal delivery to a second gravida mother in our hospital. Mother had a previous history of abortion at 2 months of gestation. At 36 weeks of gestation, antenatal sonogram revealed a massively dilated bowel loop; no other anomaly was detected. After birth, she developed features of low intestinal obstruction as evidenced by bilious nasogastric aspirates and air-fluid levels on plain X-ray abdomen. Post-natal ultrasonogram revealed a cyst in the right abdomen measuring 1.5 x 1.3 cm. Con-trast enhanced abdominal CT scan revealed grossly dilated bowel loops and a small retroperitoneal cyst of the same dimensions as above, adjacent to the right kidney . Contrast enema demonstrated a microcolon . A preoperative diagnosis of intestinal atresia was made. The unusual location of the abdominal cyst ruled out the possibility of it being a cyst of ovarian, mesenteric or choledochal origin; the diagnosis that was considered at this stage was ‘incidental’ bowel duplication cyst that was unrelated to the bowel atresia.The neonate was taken up for laparotomy at 28 hours of age and intestinal atresia was confirmed at surgery. However, the ileum distal to the atresia had formed a cocoon due to adhesions and was full of soft meconium pellets which were obstructing the free flow of saline into the caecum. There were tell-tale signs of a vascular event at the site of atresia with evidence of resorption of a bowel segment with a separate vessel supplying it. There was a non-communicating duplication cyst within the leaves of the bowel mesentery and sharing a common wall as well as blood supply with the terminal ileum, 7cm proximal to the ileocecal valve . Since the cyst could not be separated from the bowel wall, two resection anastomoses were done at the site of excised duplication cyst and ileal atresia . The bowel distal to atresia was gently flushed with saline till all the meconium pellets were washed out prior to the anastomoses.Postoperatively, the neonate was kept on total parenteral nutrition and continuous nasogastric suction for 10 days. Gradual enteral feeding was started thereafter and built up to full feeds. The baby was discharged on 15th postoperative day. The biopsy report was consistent with ileal duplication cyst. The cyst wall showed ulceration and chronic inflammation. The excised segment of atretic bowel showed marked bowel submucosal fibrosis and focal calcification. The excised intervening bowel segment was filled with necrotic and focally calcific material. The mucosa was replaced by granulation. Submucosa showed dense inflammation with organising exudate and foreign body giant cell reaction to hemosiderin. The surrounding muscularis showed focal thinning with serosal fibrosis. The child has been followed up for 1 year and is thriving well.The incidence of bowel duplication cysts in patients with jejuno-ileal atresias has been quoted as 0-4.7% . Conversely, the incidence of jejuno-ileal atresias in series of jejuno-ileal duplications has been reported to be 10% [3].Various eitiopathogenetic mechanisms have been proposed to explain the development of intestinal atresia and duplications and their unusual concurrence . Mellish and Koop [1] suggested that environmental factors such as trauma or hypoxia in early fetal development were likely to be responsible when multiple duplications are found in association with anomalies such as malrotation or atresia. A mesenteric vascular accident has been implicated as a causative factor for both intestinal atresia and completely isolated duplication cyst . This was supported by Favara et al. [2] who postulated that antenatal vascular accidents can result in four types of lesions depending on the severity of the accident and the subsequent healing: short bowel, intestinal stenosis, intestinal atresia, and enteric duplication. They also speculated that enteric duplication can occur when a segment of intestine is spared from necrosis and is nourished by the blood supply from the neighbouring inflamed intestine. Al Salem found evidence of ischemic insult in the form of intra¬abdominal calcification in a baby with multiple atresias and bowel duplication [13]. Similarly, Ratan et al suggested that differential healing of a segment of intestine affected by an antenatal vascular accident probably resulted in the simultaneous formation of intestinal atresia and a duplication cyst [7]. Sinha et al [6] suggested that atresias arise as a result of volvulus caused by the pre-existing duplication. As such intrauterine volvulus has been known to co-exist in as many 1/4th of all jejuno-ileal atresias [11]. Peterson et al described ileal intus-susception caused by an ileal duplication cyst, which may be one of the mechanisms of bowel duplica¬tion causing atretic changes in the adjacent bowel [14]. We believe that an antenatal vascular accident could be the aetiology of this association in our case as evidenced by presence of calcification.Surgical management is straight forward. If the site of intestinal atresia is far away from the site of duplication, two separate resection-anastomoses are required as was done in this case.Source of Support: NilConflict of Interest: None declared


VT) before, during, and after a sigh are influenced by gestational age at birth and lung disease  in former preterm infants and healthy term controls measured at equivalent postconceptional age (PCA). We performed tidal breathing measurements in 143 infants during quiet natural sleep at a mean (SD) PCA of 44.8 (1.3) weeks. A total of 233 sighs were analyzed using multilevel, multivariable regression. Sigh frequency in preterm infants increased with the degree of prematurity and severity of BPD, but was not different from that of term controls when normalized to respiratory rate. After a sigh, VT decreased remarkably in all infants (paired t-test: P < 0.001). There was no major effect of prematurity or BPD on various indices of sigh morphology and changes in VT prior to or after a sigh. Short-term variability in VT modestly increased with maturity at birth and infants with BPD showed an earlier return to baseline variability in VT following a sigh. In early infancy, sigh-induced changes in breathing pattern are moderately influenced by prematurity and BPD in preterm infants. The major determinants of sigh-related breathing pattern in these infants remain to be investigated, ideally using a longitudinal study design.Sighs are thought to play an important role in control of breathing. It is unclear how sighs are triggered, and whether preterm birth and lung disease influence breathing pattern prior to and after a sigh in infants. To assess whether frequency, morphology, size, and short-term variability in tidal volume ( VT) of the preceding breaths, have been associated with various physiological and pathophysiological mechanisms. Sighs play an important role in the plastoelastic stretching of lung tissue and breathing muscles, which may result in improvement of lung compliance, reduction in airway resistance and recruitment of lung volume  at birth, and presence and severity of BPD in former preterm and healthy term control infants.We thus hypothesized that the frequency, morphology, and short-term variability in tidal breathing differ between healthy term infants and preterm infants with BPD when measured at the same corrected age. We further hypothesized that differences in those outcomes are mainly influenced by the degree of prematurity at birth and severity of BPD. Thus, we aimed to assess whether frequency, morphology, and short-term variability of This is a retrospective analysis of data obtained from a prospective birth cohort study conducted in Bern, Switzerland (BILD cohort study)  born at <37 weeks GA and healthy term control infants (n = 86). Preterm infants were assessed for presence of BPD based on their duration of supplemental oxygen requirement at 36 weeks GA. Mild, moderate, and severe BPD was defined based on the National Institutes of Child Health Consensus definition  as described previously .Detailed measurement set up has been published previously  of average VT of preceding breaths , and sighs were automatically identified by software script according to the following criteria: (1) Sigh The following parameters were then analyzed for all measurements containing at least one sigh that met inclusion criteria:All measurements lasting at least 10 min were used for the analysis of sigh frequency. Respiratory rate (mean over 10 min), number of sighs within 10 min, and extrapolated value of sighs expected in 1000 breaths were defined.VI,max) and maximal expiration  during a sigh , and the ratio of VE,max/VI,max were calculated to describe the morphology of a sigh.Maximal inspiration , the last 30 breaths as baseline after the sigh . The five breaths just after the sigh were defined as immediate postsigh period . We then calculated the difference in mean VT,pre − VT,post as a measure of changes in VT upon a sigh . We further calculated the number of breaths that deviated from VT,pre in excess of 2 SD within the periods 15 breaths before and 15 breaths after a sigh, and discriminated between the number of high  and low  values.The first 30 breaths of the tidal breathing measurement were used as baseline before the sigh  of VT (CVVT) was obtained from windows of 11 breaths. The window was shifted by one breath four times in four predefined regions of the tidal breathing measurement . This approach resulted in four consecutive windows per region. Baseline CVVT was calculated at the beginning (CVpre) and at the end (CVend) of a measurement. Also, CVVT was calculated just prior to the sigh (CVprior) and immediately after a sigh (CVpost). CVdiff (CVpost − CVpre) describes the change from baseline to postsigh period. We further calculated changes in CVVT (CVpost_slope) by subtracting the value of the second moving window just after the sigh from the first one just after the sigh, normalized for individual CVpre. Sample tidal breathing traces including a graphical overview on outcomes related to changes in VT and variability in VT are displayed in FigureShort-term variability in VI,max and VE,max (sigh morphology); size of tidal volume before and after a sigh (changes in VT), and coefficient of variation in VT (Short-term variability in VT).Our main outcome parameters, as described above, were number of sighs (sigh frequency); VT, variability in VT) and potential predicting factors. Considered predictors included degree of prematurity (GA), BPD , body size at test (weight), intrauterine growth restriction (birth weight z-score), gender, and maternal smoking during pregnancy. We used multilevel modeling to allow clustering on the individual level given that some measurements incorporated more than one sigh. Model building included exploring associations of all considered predictors with sigh characteristics in univariable regression analysis where P < 0.1 was considered to indicate potential relevance of a predictor. We then built multilevel, multivariable linear regression models for each outcome and did stepwise backward elimination of predictors that were not significantly associated with the outcome . Lastly, we defined a best model depending on the coefficient of determination of the model (R2). Statistical analysis was done using Stata software .We performed linear regression analyses to assess associations between sigh characteristics  showed at least one sigh during their tidal breathing measurement and were included in this study. A total of 233 sighs met inclusion criteria and were used for further analysis  and negatively associated with GA (P = 0.001), body weight (P = 0.076), and birth weight z-score (P = 0.004). Eighty-six out of 223 term infants (39%), 35 out of 87 preterm infants without BPD (40%), and 22 out of 89 preterm infants with BPD (25%) had at least one sigh during their tidal breathing measurement. The number of sighs over a 10 min measurement period was associated with BPD (P = 0.059), but not GA (P = 0.12)  was not associated with any predictor when corrected for baseline VT. In contrast, maximal expiratory volume of the sigh  was positively associated with BPD (P = 0.038) and negatively with maternal smoking (P = 0.006) after correcting for VT at baseline. Additionally, the ratio of VE,max/VI,max was negatively associated with GA (P < 0.001) and maternal smoking (P = 0.078), and positively associated with BPD (P < 0.001). In multivariable analysis, VE,max/VI,max remained weakly associated with BPD after adjusting for maternal smoking (R2 = 0.09)  and sex (P = 0.007). VT,diff was positively associated with GA (P = 0.023), body weight (P = 0.022), and birth weight z-score (P = 0.062), and negatively associated with BPD (P = 0.024). VT,post was smaller than VT,pre . VT,high after the sigh was negatively associated with BPD (P = 0.028). There were no associations between major deviation from VT,pre  and GA or BPD.In univariable analyses, both T,pre (R2 = 0.40) and VT,end (R2 = 0.40) with GA, but not BPD after adjusting for body weight and sex , but not BPD and a negative association with male sex (P < 0.001). CVprior was not associated with any tested predictor. CVpost was positively associated with GA (P < 0.001) and negatively associated with BPD (P < 0.001), male sex (P = 0.043), and maternal smoking in pregnancy (P = 0.085). CVend showed a positive association with GA (P = 0.041) and birth weight z-score (P < 0.001), and a negative association with BPD (P = 0.043) and male sex (P = 0.003). CVdiff as a marker of changes in CV of VT from baseline to immediately after a sigh was positively associated with GA (P = 0.010), and negatively associated with BPD (P = 0.015) and maternal smoking (P = 0.022). CVpost_slope as a marker of how fast variability in VT after a sigh returns down to baseline, was negatively associated with GA (P < 0.001) and positively associated with BPD .In univariable analyses, CVpost with GA, but not BPD after adjusting for sex and maternal smoking (R2 = 0.16). Similarly, CVend was significantly associated with GA, but not BPD after adjusting for sex and birth weight z-score (R2 = 0.16). CVdiff was associated with GA after adjusting for maternal smoking in pregnancy (R2 = 0.07). Figurepre, CVprior, CVpost, and CVend for the subgroups of healthy term infants, preterm infants without BPD, and preterm infants with BPD.Multivariable analysis Table establisVT during a sigh despite their known restrictive lung disease  and experimental conditions  might explain the discrepancy to our results as breathing pattern of preterm infants measured in left lateral and prone position differs from that obtained in supine position . This suggests that both immaturity at birth and residual lung disease accelerate an infant’s return to baseline breathing pattern after a sigh. However, the effect size of both preterm birth and BPD is small indicating that unmeasured factors substantially influence those outcomes.To the best of our knowledge, this is the first study examining sigh-related breathing pattern during quiet sleep in former preterm and term healthy control infants measured at equivalent PCA shortly after term corrected age. Qureshi et al.  comparedAll measurements were conducted according to American Thoracic Society/European Respiratory Society standards for infant lung function testing. Infants were studied at a comparable PCA and were assessed in unsedated quiet sleep using modern, miniaturized lung function equipment. Limitations of our study include a recruitment period of over 7 years, potentially introducing observer bias as several investigators conducted the measurements. Nevertheless, all personnel followed standard operating instructions and we did not find any trends in outcomes over time, that is, observer-dependent effects as origin of our findings are unlikely. A general methodological difficulty lies in the precise quantification of residual lung disease in preterm infants as the clinical definition of BPD is entirely based on duration, and level of oxygen supplementation and respiratory support during neonatal intensive care stay  of preterm infants was comparable to that of their term peers although these infants have restrictive lung disease (Thunqvist et al. VT. These observations are consistent with the hypothesis that although sighs play an important role in restoring lung volume in preterm infants (Poets et al. The specific mechanisms that trigger sighs in human infants are essentially unknown (Alvaro and Rigatto We conclude that breathing pattern following a sigh is moderately influenced by the degree of prematurity and residual lung disease in preterm and term infants measured at equivalent corrected age shortly after the expected date of delivery. The precise mechanisms triggering sighs, and the major determinants of breathing pattern prior to and after a sigh in preterm infants remain to be investigated in future studies. Whether or not sigh architecture is a predictive marker of later respiratory morbidity should ideally be investigated in future longitudinal studies. Such studies should potentially include measurement of long-range memory of control of breathing given that the latter provided novel insights into breathing dynamics in term healthy infants.We thank Nitin Kumar for his assistance in computer programming and Karine Landgren-Hugentobler for reviewing of the manuscript.None declared.


Trace elements are anessential nutritional component for humans and inadequate tissue-concentrations may have a significant effect on fetal size.To measure ten trace elements in blood samples from mothers and their newborns, and assess their association with anthropometric characteristics at birth. The effects of other factors on fetal growth, such as biologic characteristics of the infant and mother, were analysed.n = 54 paired samples). Infants were grouped according to birth weight: small for gestational age (SGA n = 11), appropriate (AGA n = 30), and large (LGA n = 13). Anthropometric and biologic characteristics of the infant and mother were recorded. Levels of ten essential elements: arsenic (As), barium (Ba), cobalt (Co), copper (Cu), chrome (Cr), iron (Fe), magnesium (Mg), manganese (Mn), selenium (Se) and zinc (Zn), in maternal and cord plasma samples were determined. Samples were obtained from the umbilical cord immediately after delivery and the samples of their mothers were drawn at 2–4 h after delivery.A cross-sectional study was conducted in the Hospital general, University of Valencia, Spain. Healthy pregnant women, and their full-term infants were selected (p = 0.009), maternal smoking during pregnancy , shorter gestational age , and female sex  were significantly associated with decreased birth weight. Maternal anaemia was positively associated with birth weight . No significant associations were found between maternal trace elements and birth weight in multivariate analysis.The analysis identified that cord blood Cu (p = 0.017) and maternal blood Ba and Mg  concentrations were significantly higher among SGA infants compared to AGA and LGA infants. A multiple linear regression analysis showed that increased umbilical cord Cu concentration  contains supplementary material, which is available to authorized users. The knowledge gained from several studies has demonstrated that intrauterine life plays a key role in the development of chronic disease in adulthood. The concept suggests that early life conditions can “program” the fetus for a spectrum of adverse health outcomes –6. FetalWhile trace elements are essential for humans, their specific roles are not well understood, especially in the prenatal period. Even though their quantities are very small in body tissue, they are involved in various biochemical pathways and are critical to the performance of certain functions that are necessary to sustain life . InadequIn previous studies different concentrations of trace elements such as arsenic (As), iron (Fe), manganese (Mn), selenium (Se), copper (Cu), and zinc (Zn), have been found in maternal blood, placenta or umbilical cord, showing an inconsistent association with the anthropometric characteristics of the newborns –20. SeveUp to now studies have focused on evaluating the effects of small number of trace elements on fetal growth , 20, 21.Newborns and their mothers from the area of the Hospital general Universitario de Valencia, Spain were enrolled in a cross-sectional study over 1 year. The inclusion criteria were newborns born at term  in the absence of perinatal illness. All mothers were healthy, and without risk factors that may determine the size of the newborn such as, hypertension, diabetes, infections, etc. Infants were excluded if chromosomal abnormalities and/or congenital malformations were detected during gestation. According to these criteria, 54 newborns and their mothers were selected.Birth weight, length and head circumference were registered at the time of birth by delivery room staff using standard anthropometric procedures, and data were registered in the medical record of the newborns. Gestational age was calculated based on last menstrual period, ultrasound examinations during pregnancy were extracted from the medical records, and ascertained according to the Ballard method by the neonatologist.Three groups of newborns were created based on the growth curve database of Alexander and associates : small fAnthropometric and biologic characteristics of the infants , and mothers , were collected from the medical records. The mothers did not receive any nutrient supplement or any other medication that could have influenced the concentration of trace elements. Mothers whose haemoglobin was <11 mg/dl were defined as anaemic, according to the criteria of the World Health Organization . The motBoth parents were required to sign informed consent in order to participate in the study. The study was approved by the Hospital’s review board and was carried out in accordance with the Declaration of Helsinki. Both of the samples , as well as the collected data, were stored according to the regulations dictated by the law of Biomedical Investigation of 2007 (Law 14/2007) and all applicable rules.g for 10 min at 4 °C, the plasma was collected, aliquoted in polypropylene tubes, and stored at −80 °C and thawed before use. Amounts of 0.5–1 mL were used for analysis.Umbilical cord blood samples were collected immediately after delivery. Blood samples from the newborns were obtained through venous puncture of the umbilical cord. The samples from their mothers were drawn at 2–4 h after delivery in non-fasting conditions, but with at least 8 h between the last meal and blood sampling. All samples were collected in EDTA tubes, centrifuged at 3000 All samples were analyzed simultaneously after the collection period and the plasmatic concentration of the ten essential elements, arsenic (As), barium (Ba), cobalt (Co), copper (Cu), chrome (Cr), iron (Fe), magnesium (Mg), manganese (Mn), selenium (Se) and zinc (Zn), were determined through inductively coupled plasma mass spectrometry .Concentrations of As, Ba, Co, Cr, Mg, Mn and Se were expressed as nM/L, and Cu, Fe and Zn were expressed as µM/L. Shapiro analysis was performed to test the normal distribution of the data. Concentrations of trace elements that were normally distributed were expressed as mean [±standard deviation (SD)] whereas those that failed to satisfy criteria for normal distribution were expressed as median [interquartile range (IQR)].p < 0.05 were considered statistically significant. Pearson’s correlation and Spearman rho coefficients were used to examine the relationships between birth weight, length and head circumference, as continuous variables, and trace element levels. Likewise, correlations of trace element concentrations between umbilical cord and maternal blood by group were analyzed. An outlier analysis was performed, and levels of trace elements deviating from the mean by more than 2.5 times the standard deviation were excluded. The results shown do not include outlier values. Values below the detection limit (LOD) were included in the analysis using the predetermined value of LOD.Trace element concentrations among groups were compared by the nonparametric Jonckheere’s trend test. Values of p values of <0.05 were considered statistically significant in the final multivariate model.A multivariate linear regression model was performed to identify trace elements in cord blood associated with birth weight. The relationship between maternal blood trace elements and birth weight was also analyzed. Only variables that differed with p < 0.10 in the correlation analysis were selected for multivariate linear regression analysis. All models were adjusted for known variables as predictors of fetal growth, which were determined a priori based on previous studies, including characteristics of the infants and their mothers, such as gestational age, sex, parity, maternal age, pregnancy-anaemia, and maternal smoking during pregnancy. Maternal age and gestational age were modelled as continuous variables. Other variables were modelled as binary. The A total of 54 newborns and their mothers were included in the study. Among the newborns, 11 (20.4 %) were qualified as SGA, 30 (55.6 %) as AGA and 13 (24.1 %) as LGA. Even though mothers of newborns regardless of birth weight were invited to participate in the study, those with infants SGA or LGA, were more interested in participating. This explains the birth weight distribution, which is not representative of the general population. The general characteristics of mothers and their newborns in the three groups are shown in Table In 54 samples of umbilical cord blood, ten elements were tested. Umbilical cord blood trace element concentrations of the study population are shown in Table p = 0.017). Likewise, when using an analysis model adjusted by sex, statistically significant differences were only observed in Cu levels (p = 0.039).The detection limits and the percentage below the LOD of ten trace elements are shown in Table p = 0.005; r = −0.25, p = 0017, respectively). Additionally length and head circumference were also inversely associated with cord blood Mn levels . Additional file Correlation coefficients were calculated between each of the ten cord blood trace elements and anthropometric characteristics in the newborns. The analysis identified an inverse association between birth weight and Mn and Cu levels , showing a decreasing trend . Length and head circumference were inversely associated with maternal blood Ba  and Mg . Additional file Correlations between each of the ten maternal blood elements and anthropometric characteristics of the newborns were calculated. An inverse relationship was observed between birth weight and Ba, Cu, Mg and Mn levels in maternal blood . There was no significant correlation in the LGA group, Fig. A positive correlation between Cu levels in the umbilical cord and maternal blood was observed , maternal smoking during pregnancy , shorter gestational age , and female sex  were significantly associated with decreased birth weight. Maternal anemia was positively associated with birth weight , see Table A multiple linear regression analysis showed that increased umbilical cord Cu concentration (adjusted β −146.4 g, 95 % CI −255 to −37.7; The associations between the different trace elements and birth length and head circumference were examined using univariate analysis, see Additional file The main finding of the present study was that Cu was the only trace element in umbilical cord blood found to be inversely and independently related to birth weight, the highest Cu concentrations were found in the SGA group. In addition, anthropometric parameters were inversely related with Mn, and no association with birth weight was observed for the other trace elements. In maternal blood, a significant trend in Ba and Mg levels, decreasing from SGA to LGA, was observed. The study is important due to the assessment of a large number of trace element levels in healthy pregnant women and their newborns, providing relevant information about their effects on birth weight and the potential adverse health outcomes later in life.Interestingly, Cu is a trace element that is involved in the function of several cuproenzymes that are essential for life, and their requirement increases during pregnancy . AlthougThe concentrations of Cu for adequate fetal development and a possible “safe level” are still unknown in humans. Copper toxicity during pregnancy and its effects on developmental outcome have been examined in considerable detail in animal models. Excess Cu has been reported to result in growth retardation in rat fetuses . A stronEven though the observed Cu in umbilical cord blood was the only independent factor related to birth weight, a positive relationship between Cu levels in umbilical cord and maternal blood was observed. The placenta is the essential interface between maternal and fetal circulation that normally maintains the proper balance of the metabolic needs of the fetus. However, it can be irreversibly damaged by oxidative stress, losing adequate functioning . The rolMore recently there has been a focus on the possible effects of Mn on fetal development and pregnancy outcome. Manganese is an essential mineral nutrient in humans and other animals and is required for normal amino acid, lipid, protein, and carbohydrate metabolism. However, Mn exposure also has the potential to produce toxicity , 31, 32.Studies have provided information concerning the relationship between Mn and birth weight , 20, 34.The results of the study demonstrate that Ba and Mg in maternal blood are inversely and significantly related to all the anthropometric parameters of the newborns. Higher concentrations of Mg in cord blood of infants with intrauterine growth retardation, as compared with normal weight-newborns were observed by Barbosa et al. . HoweverIn contrast, the association was practically non-existent between anthropometric parameters and the remaining trace elements, As, Co, Cr, Fe, Se, and Zn in both umbilical cord and maternal blood. In previous studies, the association varies widely between birth weight and trace elements such as Se, Zn, Fe, Cr and Mg, , 34–38. In the present research additional information is provided such as the effect of other factors on fetal growth, i.e. maternal smoking and female sex, and shorter gestational age, which were significantly associated with decreased birth weight. Conversely the presence of anemia was associated with increased weight in newborns.The findings of this study need to be interpreted within their strengths and limitations. Combining several trace elements in newborns and mothers, along with other variables of interest, the study analyses the association with anthropometric characteristics of the newborn, demonstrating the importance of Cu levels in umbilical cord. In spite of the fact that the exact toxicity limits of trace elements in the newborn are not exactly known, this study provides data on concentrations of Cu and its association with lower birth weight. This knowledge is important considering the known association between fetal growth and the development of chronic disease in adulthood , 3–6. ThThe results demonstrate the importance of Cu levels in the umbilical cord on birth weight. There may be many factors acting additively or synergistically to trigger the condition of low birth weight, and perhaps low birth weight acts merely as a marker of a number of biological insults. The findings of this study suggest that Cu could be one of these factors. Certainly, more research is needed in order to better assess the role of trace elements in fetal growth.


Renal cysts are common and most often are discovered incidentally, but may require intervention if associated with pain, hypertension, or hematuria. Minimally invasive treatment options are preferred with numerous modalities available, including renal cyst ablation. This case report of a 61-year-old female describes the effective percutaneous drainage and endoscopic ablation of a simple parapelvic renal cyst for management of symptomatic renal calculus. Current literature regarding this surgical intervention and alternative methods is discussed. The patient's surgical history included intestinal volvulus requiring bowel resection, bariatric abdominal surgery, and nephrolithiasis. Her CT imaging revealed a single 8 mm stone in the upper pole calix of the left kidney as well as a large 5.5 cm Bosniak-I cyst of the left central region of the kidney  and 2. TThe patient underwent initial 8F pigtail catheter insertion in the cyst cavity the morning of the surgery under CT guidance in the radiology department , and theOn follow-up at 3 and 5 months, there was no recurrence of the cyst on ultrasound imaging and the patient's symptoms were resolved.4 The natural history of a simple renal cyst is for progression in size and number. Symptomatic cysts, which are variously reported as accounting for between 2% to 4% and 6% to 8% of simple cysts, may be treated by a variety of modalities.5 Modern approaches to renal cyst management include percutaneous aspiration, with or without sclerotherapy, and excision or marsupialization using laparoscopic, single port laparoscopic, ureteroscopic, and percutaneous approaches. Open surgery is rarely performed.4–7Autopsy studies have suggested that more than 50% of persons older than 50 years of age have at least one simple renal cyst.4 Sclerotherapy using a variety of sclerosing agents, most commonly ethanol, has been used to reduce the rate of recurrence.5 Recurrence after aspiration and sclerosis, however, frequently occurs and is thought to be due to incomplete ablation of the cyst wall by the sclerosing agent. Surgical intervention of simple renal cysts has traditionally occurred using a transperitoneal or retroperitoneal laparoscopic approach depending on the cyst location.8 Laparoscopy has a success rate of 95% to 100% for managing simple renal cysts.5 Disadvantages of this technique include the requirement for multiple port sites, extensive dissection, and greater surgical experience relative to a percutaneous approach.7 A retrograde ureteroscopic approach has also been described.7 This offers a less invasive approach than laparoscopic and percutaneous management but lacks a robust body of evidence in support of its use. Its use is also limited to small cysts that are located near the collecting system.7. Surgical management of simple renal cysts using percutaneous access has previously been described in the literature.5 Techniques used using percutaneous access include ablation with cyst resection and percutaneous intrarenal marsupialization (endocystolysis).7Percutaneous cyst drainage alone is frequently undertaken but is associated with recurrence and reaccumulation of fluid in up to 80% of cases.In our case, the entire cyst wall was visualized, and the cyst wall was ablated using low-voltage diathermy without penetrating the cyst wall. This is the first time the authors have treated a cyst of this size (5.5 cm Bosniak-I cyst). The cyst was initially treated, which partly relieved the patient's symptoms. Having got the access to the stone, ureteroscopic management of the stone was performed, which completely resolved the patient's symptoms. The authors felt that the patient's pain was from the cyst and that ablating the cyst would resolve the pain. It only resolved the pain partially and it also made the subsequent ureteroscopy easier to perform.Renal cysts can distort the collecting system with segmental obstruction. Stones developing in these segments are difficult to manage. Although this technique is not new, it is not reported being used in such a large renal cyst with complete resolution on follow-up. And given that it also provided easy access to treat the upper pole calix stone, which helped relieve the patient's symptoms completely, this combined technique offers a solution to this difficult problem.