In order to provide juvenile idiopathic arthritis (JIA) patients with better pre-conceptional and prenatal counselling, we investigated the obstetrical and neonatal outcomes among women with Asian descent.Through the linkage of Taiwan National Health Insurance database and National Birth Registry, we established a population-based birth cohort in Taiwan between 2004 and 2014. In a case control study design, first children born to mothers with JIA are identified and matched with 5 non-JIA controls by maternal age and birth year. Conditional logistic regression was used to calculate odds ratios for maternal and neonatal outcomes crude and with adjustment.Of the 2,100,143 newborn, 778 (0.037%) were born to JIA mothers. Among them, 549 first-born children were included in this research. Our result suggested that babies born to mothers with JIA were more likely to have low birth body weight, with an adjusted OR of 1.35(95% CI: 1.02 to 1.79) when compared to babies born to mothers without. No differences were observed in other perinatal complications between women with and without JIA including stillbirth, prematurity, or small for gestational age. The rate of adverse obstetrical outcomes such as caesarean delivery, preeclampsia, gestational diabetes, postpartum hemorrhage and mortality were also similar between the two.Adverse obstetrical and neonatal outcomes were limited among Asian mothers with JIA. Intensive care may not be necessary for JIA mothers and their newborns. Juvenile idiopathic arthritis (JIA) is the most prevalent debilitating rheumatic disease of childhood . It compIncreasing attentions have been raised on reproduction related issues in patients with rheumatic diseases , 9. DespStudies investigating the risk of JIA related pregnancy morbidities have been reported –16. HoweAimed to provide mothers suffered from JIA with a better pre-conceptional and prenatal counselling, we took advantage of the NHI database and National Birth Registry in Taiwan. We examined the pregnancy outcomes as well as perinatal complications of neonate born to mothers with JIA in a population-based cohort incorporating patients with Asian origin exclusively.This study was approved of by the Institutional Review Board of the Chang Gung Memorial Hospital (201800358B0) and the data holders of the NHI database and the National Birth Registry in Taiwan. Patient consent was exempted since all study subjects were de-identified and completely anonymoused.The primary data sources were the NHI database and the National Birth Registry. With the help from the NHI administration, we linked the two databases by using the national identification number which is unique to each resident of Taiwan. Since the NHI database contain registration and claims data of the entire population, respective data for the mothers and their children were extracted. The linkage of mother-child relationships was ascertained using the National Birth Registry. The traceable data were encrypted by the data holder to prevent confidentiality break.The Taiwan NHI database was established in 1996, and contains the health data on approximately 99.5% of all Taiwanese population . The heaThe National Birth Registry records information of live births and stillbirths of neonate above 500 g of weight or elder than 20 weeks in gestation. It contains data of infants’ gender, birth order, birth body weight and height, Apgar scores, gestational age and neonatal abnormalities. The neonatal outcome and maternal outcome documented in the National Birth Registry have been proven to be a valid source for researchers .In Taiwan, JIA was diagnosed according to the International League of Associations for Rheumatology (ILAR) classification criteria by the pediatric rheumatologists . MothersPregnancies among JIA patients were identified and the cases with gaps between two deliveries less than 6 months or longer than 20 years were excluded from another. A total number of 2,100,143 pregnancies and 1,468,318 mothers were identified during the period of 2004 to 2014. The total pregnancy population is divided into two groups: women with JIA and those without. A total of 778 babies were born to 549 mothers with JIA. To avoid possible confounding factors and for case control selection, only the first child from either group was included for further analysis. In addition, considering maternal age as a potential confounding factor and to bypass the possible bias resulted from case selection, we matched 5 non-JIA cases as controls to one JIA cases by maternal age and birth year for further investigation .Neonatal and maternal outcomes were both examined. Neonatal outcomes include low birth weight (< 2500 g), SGA, large for gestational age (LGA) , apgar score at 1 and 5 min, prematurity (< 37 weeks), stillbirth, fetal distress and fetal abnormalities including central nervous system malformations and chromosome abnormalities. Small and large for gestational age were calculated according to the nomogram summarizing data collected from all livebirths in the National Birth Registry between 2004 and 2014.Maternal outcomes include death (death within 30 days post-partum), pregnancy-related hypertension, antepartum hemorrhage, severe postpartum hemorrhage, chorioamnionitis, caesarean delivery, preeclampsia, and gestational diabetes. Maternal deaths were verified by utilizing the National Death Registry in Taiwan. It kept records on the causes of death for all deceased citizens. The accuracy of the coding has previously been validated , 28.Maternal age, country of origin, place of residence, income level, occupation, obstetric history, and Charlson comorbidity index were included as maternal covariates. The place of residence was based on the urbanization of 369 towns and districts in Taiwan, which was divided into 3 categories: urban, suburban, or rural. Income levels were estimated by the business income for employers and the payrolls for the employees. It was categorized into 5 quintiles of which the first quintile being the highest paid. Occupations were classified into 5 categories: (1) dependents (2) civil servants, teachers and military personnel/veterans; (3) professionals and non-manual workers; (4) manual workers; and (5) others. Charlson comorbidity index is a summary measure scored on a number of medical conditions including diabetes, chronic renal diseases and cardiovascular diseases..etc., with an integer weighted score from one to six . SubstitThe rate of each outcome was compared between groups of mothers with and without JIA using a conditional logistic regression to estimate the odds ratio (OR) and the corresponding 95% confidence intervals (CI). A model adjusted for potential confounders including: infant sex, residence, income, occupation and Charlson comorbidity index was performed. Two-sided test with 5% level of significance was used for all statistical hypotheses. All analyses were performed using SAS v. 9.4 .P < 0.05) . Furthermore, no difference was found in other neonatal outcomes, including still birth, prematurity, small or large for gestational age, apgar score < 7 at 1 and 5 min, fetal distress and fetal abnormalities.According to the World Health Organization definition, infants born to mothers with JIA were more likely to be low in birth weight < 2500 g) as compared to those born to mothers without . As shown in Table 500 g as Maternal outcomes between women with and without JIA were shown in Table To our knowledge, this is the first study to investigate JIA related pregnancy outcomes and perinatal complications focus on women with Asian origin. Using a nationwide population-based cohort of which the data were extracted from the Taiwan NHI database and the National Birth Registry, we recruited 549 JIA mother-and-neonate pairs accommodating single ethnicity. As compared to previous study analyzing less than 10 Asian cases, the relatively large sample size in the present study provided sufficient statistical power to detect differences in the risk of adverse birth outcomes and pregnancy morbidities comparing women with and without JIA .Wallenius et al. among women with JIA [Physical and psycho-social stress resulted from chronic disease and the fear of neonatal and pregnancy related complications can potentially influence the willingness of women to give birth to children. In fact, a decrease in pregnancy rate has been reported by with JIA . Althougwith JIA . FurtherChen and Remaeus, however, failed to observe significant effects of maternal JIA on the risk of SGA, low Apgar score or severe neonatal morbidity [Ringold et al. analyze the Childhood Arthritis and Rheumatology Research Alliance Registry and found a more favorable outcome among Asians suffering JIA as compared to those white and black children [Unlike previous studies which have shown an increased risk of caesarean section (CS), pre-eclampsia, postpartum hemorrhage, preterm labor, miscarriages and abortion in JIA mothers, none of the analyzed adverse obstetrical outcomes were notable in the present study –16.. Furorbidity , 15. Theorbidity . While porbidity –20. In aorbidity , 5. Conschildren . The disconception and the relative low risk of serious infections during and after gestation, no study so far have discussed the risk of biologics solely in JIA mothers. Instead, results gather from women with various autoimmune diseases have recently found that the use of biologics during pregnancy is not associated with higher risks of maternal infections but may potentially impact neonatal outcome due to its ability to cross placenta [According to the previous study, 97.4% of the JIA patients received non-steroidal anti-inflammatory drug (NSAID), 26.7% received intra-articular steroid injection, 73.3% received conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and 12.8% received biological DMARDs (bDMARDs) during the period of 1995–2010 in Taiwan . Since tplacenta , 36. FurJIA patients were under the age of 16 during the period of 2004 to 2014 to meet the diagnostic criteria and be recruited as study subjects in the present study. Therefore, most of the women with JIA were still below 30 years old at time data analysis. This explained why the average maternal age of delivery is lower than the reported age of motherhood in Taiwan . In addiSeveral limitations deserved to be mentioned. First, the database uses the ICD-9 coding system provided by the clinical physicians for diagnosis. Despite a comprehensive inclusion and exclusion criteria, misclassification may still occur. Second, long-term outcomes and treatment responses have been shown to vary between different JIA subtypes , 40. WitIn conclusion, adverse obstetrical and neonatal outcomes were limited among pregnancies of JIA mothers with Asian origin. JIA mothers and their babies should be advice to follow routine obstetric care without over worrying. Future studies exploring the association between adverse pregnancy outcomes with the subtypes and severity of JIA as well as medications taken during pregnancy are also warranted.


Purpose: Birth weight has a profound long-term impact on individual’s predisposition to various diseases at adulthood—a hypothesis commonly referred to as the fetal origins of adult diseases. However, it is not fully clear to what extent the fetal origins of adult diseases hypothesis holds and it is also not completely known what types of adult diseases are causally affected by birth weight.Materials and methods: Mendelian randomization using multiple genetic instruments associated with birth weight was performed to explore the causal relationship between birth weight and adult diseases. The causal relationship between birth weight and 21 adult diseases as well as 38 other complex traits was examined based on data collected from 37 large-scale genome-wide association studies with up to 340,000 individuals of European ancestry. Causal effects of birth weight were estimated using inverse-variance weighted methods. The identified causal relationships between birth weight and adult diseases were further validated through extensive sensitivity analyses, bias calculation, and simulations.Results: Among the 21 adult diseases, three were identified to be inversely causally affected by birth weight after the Bonferroni correction. The measurement unit of birth weight was defined as its standard deviation , and one unit lower birth weight was causally related to an increased risk of coronary artery disease (CAD), myocardial infarction (MI), type 2 diabetes (T2D), and BMI-adjusted T2D, with the estimated odds ratios of 1.34 [95% confidence interval (CI) 1.17–1.53], 1.30 (95% CI 1.13–1.51), 1.41 (95% CI 1.15–1.73), and 1.54 (95% CI 1.25–1.89), respectively. All these identified causal associations were robust across various sensitivity analyses that guard against various confounding due to pleiotropy or maternal effects as well as reverse causation. In addition, analysis on 38 additional complex traits did not identify candidate traits that may mediate the causal association between birth weight and CAD/MI/T2D.Conclusions: The results suggest that lower birth weight is causally associated with an increased risk of CAD, MI, and T2D in later life, supporting the fetal origins of adult diseases hypothesis. The EGGp < 5.00E−8)  (p < 5.00E−8) recorded in the Phenoscanner (We first selected 47 independent index SNPs Table 1 5.00E−8)  to exclu0.05/47) . In thisoscanner  and NHGRoscanner  databaseF statistic to ensure strong instrument , we mostly followed the practical recommendations of other Mendelian randomization and performed them only when a significant causal association between birth weight and an adult disease  was detected.F statistic based on the EGG GWAS discovery sample of birth weight following . These three diseases include CAD , we choose to mainly present our results from the random-effects IVW analysis, which properly accounts for causal effect heterogeneity.We examined the causal relationship between birth weight and 21 adult diseases through MR analysis using the selected instruments. Across 21 diseases, we displayed the causal effects of lude CAD , MI ; a unit lower birth weight is also causally associated with an increased T2D risk, with an estimated OR of 1.41  for the original T2D, and with an estimated OR of 1.54  for the BMI-adjusted T2D . These causal associations are also supported by the results generated using the smaller set of instruments from For each of the three diseases, we compute the odds ratio (OR) of the disease for one unit decrease of birth weight, where the unit is defined as the standard deviation of birth weight, estimated to be 488 g across 35 studies in the original meta-analysis . We founConsistent with the fetal origins of adult diseases hypothesis, the causal effects of lower birth weight on most of the diseases investigated are estimated to be positive ; and ii) among all identified loci associated with birth weight, 93% SNPs exhibit larger fetal effects than maternal effects. Nevertheless, despite the strong evidence, we acknowledge that we do not have access to individual-level genotype information in the present study and that the data sets we have analyzed here do not contain mother–child pairs. Accurate disentangling of maternal and offspring effects on adult outcomes in the absence of child–mother pairs and/or individual-level genotype information is challenging and remains an active area of research . TherefoOur analysis results are not without limitations. First, we acknowledge that there was a small overlap between individuals used in the EGG GWAS for birth weight  and can Our results suggest that lower birth weight is causally associated with an increased risk of CAD, MI, and T2D in later life, supporting the fetal origins of adult diseases hypothesis.All datasets generated for this study are included in the manuscript and the supplementary files.PZ and XZ conceived the idea for the study. PZ obtained the genetic data. PZ and XZ developed the study methods. PZ performed the data analyses. PZ and XZ interpreted the results of the data analyses. PZ and XZ wrote the manuscript.This study was supported by the National Institutes of Health (R01HG009124 and R01GM126553 to XZ), the National Science Foundation (DMS1712933 to XZ), Youth Foundation of Humanity and Social Science funded by Ministry of Education of China (18YJC910002 to PZ), the Natural Science Foundation of Jiangsu (BK20181472 to PZ), the project funded by China Postdoctoral Science Foundation (2018M630607 and 2019T120465 to PZ), the Project funded by Postdoctoral Science Foundation of Xuzhou Medical University (to PZ), QingLan Research Project of Jiangsu for Outstanding Young Teachers (to PZ), the National Natural Science Foundation of China (81402765 to PZ),the Statistical Science Research Project from National Bureau of Statistics of China (2014LY112 to PZ), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University (to PZ).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To evaluate the relationship between cyst characteristics and macular and peripheral ischemia in diabetic macular edema (DME).We retrospectively reviewed eyes with DME and included those with clinically significant macular edema as defined by ETDRS (Early Treatment Diabetic Retinopathy Study) and cystoid spaces in optical coherence tomography scans in this study. Central subfield thickness (CSFT), horizontal and vertical diameters of the largest cyst, cyst area, and the remaining retinal thickness outside the cyst were determined. The presence and number of hyperreflective foci in the cyst wall and the internal reflectivity of the cyst were analyzed. Outer retinal damage was graded. Fluorescein angiography was used to determine the areas of macular and peripheral ischemia, which were graded as mild or severe. Correlations between macular and peripheral ischemia and cyst-related measurements and structural changes in the retina were evaluated.This retrospective study included 250 eyes of 186 patients with DME. Mean CSFT was significantly greater in eyes with macular ischemia (510.4±144.7 μm) compared to eyes without macular ischemia (452.1±114.6 μm) (p=0.001). Horizontal and vertical diameter of the largest cyst increased with the presence and severity of macular ischemia . Remaining retinal thickness increased with the presence and severity of peripheral ischemia (p=0.009). There was a statistically significant relationship between the number of the hyperreflective foci in the cyst wall and internal reflectivity of the cyst (p=0.007). Patients with greater CSFT had a 1.04-times higher odds of having macular ischemia and 0.25-times higher odds of having outer retinal damage.The likelihood of macular ischemia increases with larger cyst diameter, CSFT, and extent of outer retinal damage. Thickness of the noncystic area is increased in the presence of peripheral ischemia. The enlargement of the foveal avascular zone (FAZ) can be described as diabetic macular ischemia (DMI).4 This definition includes occlusion of retinal capillaries in the macula and obliteration of precapillary arterioles.4 DMI is associated with poor visual prognosis.6The most common cause of visual loss in people with diabetes is diabetic macular edema (DME).7 Vascular endothelial growth factor (VEGF), which is the most significant factor in the pathogenesis of DR, is released from ischemic areas.8 Neovascularization and increased permeability of the vascular structures occur with the activation of VEGF, which was found in patients with DME.10A remarkable association was found between the extent of peripheral nonperfused areas and the degree of DME.11 In the process of cyst formation, fluid accumulates in the intercellular space in the acute phase. Later, in the chronic stage, fluid begins to form in the intracellular space. Thus, this accumulation leads to large cystoid cavities.12 Cystoid spaces at the fovea and enlarged FAZ were found to be related to each other.13 Besides the common pathogenesis of cyst and ischemia, cyst presence has been linked to decreased retinal sensitivity.14 To date, there has been no description in the literature of quantitative and qualitative cyst features associated with retinal ischemia as a part of the degenerative process.Cystoid macular edema (CME) is one of the morphological patterns of DME on optical coherence tomography (OCT).The aim of this study was to investigate the relationship between cyst formation and related OCT features and both macular and peripheral retinal ischemia.In this retrospective cross-sectional study, medical records of patients who were followed up with the diagnosis of cystic DME at Gazi University Department of Ophthalmology between November 2011 and March 2015 were evaluated for inclusion. The study was approved by the local ethics committee of Gazi University.Eyes with clinically significant macular edema as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS), cystoid spaces in OCT scans, and high-quality fluorescein angiography (FA) and spectral domain images were included in the study. Eyes with macular edema due to other causes such as uveitis; retinal vein occlusion; concurrent macular degeneration; macular hole; visually significant cataract or any other pathology causing visual loss such as amblyopia, corneal opacity, significant vitreous hemorrhage, and optic atrophy were excluded from the study. Eyes that had undergone cataract surgery within the last 6 months were also excluded from the study to exclude Irvine-Gass syndrome.The demographic features of the patients  and stage and duration of DR were recorded. The records of patients were reviewed for best corrected visual acuity (BCVA), DR findings in fundus examination, OCT and FA evaluation. BCVA was converted to LogMAR for statistical analysis. All OCT scans and FA investigations were performed with Heidelberg Spectralis OCT . All images were obtained by the same experienced technician. In OCT, 25-line raster scans were obtained for each eye after pupil dilation and the average thickness in the central 1000-µm diameter circle of the ETDRS grid was accepted as central subfield thickness (CSFT).11 In the analyses of cysts in OCT, we used the largest cystoid space in the area within 1000 µm of the foveal center as representative of degenerative status. The horizontal and vertical diameters of the largest cyst, the area of the cyst (product of the diameters), and the remaining retinal thickness outside the cyst were determined in the quantitative analyses part of the study. Remaining retinal thickness outside the cyst was calculated by subtracting the vertical diameter of the cyst from the CSFT. All measurements were performed by the same investigator (N.G.Y.) with a manual caliper.Cystic space was defined as round or oval-shaped low reflective intraretinal spaces separated by hyperreflective septa.15 The internal reflectivity of the cysts was classified as isoreflective when similar to the retinal layers, hyporeflective when similar to the vitreous, or heterogeneous (as described in an earlier study).16 Accompanying outer retinal damage in the ellipsoid zone was also determined and any loss of continuity of either the external limiting membrane (ELM) or inner segment/outer segment (IS/OS) band in the central 0.1 mm of the fovea was noted as outer retinal damage.17In the qualitative examination of the cyst, the presence and the number of hyperreflective foci in the cyst wall and the internal reflectivity of the cyst were analyzed. Hyperreflective foci were defined as the hyperreflective dots less than 30 µm in thickness and having the same reflectivity of clustered hard exudates, as described by Bolz et al.18 The severity of macular ischemia was graded according to disruption of the FAZ outline. If the ischemic area affected less than half of the FAZ outline, it was evaluated as mild; further disruption was graded as severe  or presence of capillary nonperfusion within one disc diameter (DD) from the foveal center.s severe .19 Periprections . This cuData obtained from the study were recorded using Excel for Windows  and statistical analyses were performed using the Statistical Package for the Social Sciences for Windows . The statistical level of significance was set to p>0.05. Kolmogorov-Smirnov test, histograms, and P-P plots were used to test continuous variables for conformity to normal distribution. One-way ANOVA and LSD test for post-hoc analyses were used for the comparison of three or more groups if the variables were normally distributed. The Kruskal-Wallis test was used for the comparison of three or more groups if the variables were not normally distributed. Mann-Whitney U test with Bonferroni correction was used for post-hoc analysis if the result revealed a significant difference. Pearson chi-square or Yate’s corrected chi-square tests were used for categorical variables. Binary logistic regression analyses were done.A total of 250 eyes of 186 patients met the inclusion criteria. There were 64 patients (34.4%) with bilateral involvement and 122 patients (65.6%) with unilateral DME. One hundred ninety-four eyes (77.6%) had received prior intravitreal injection and/or laser therapy. Other demographic features of the cases are shown in Macular ischemia was present in 110 eyes (44%). Seventy-two eyes (28.8%) had mild macular ischemia and 38 eyes (15.2%) had severe macular ischemia. The relationship between DR stage and ischemia is shown in Peripheral ischemia was present in 192 eyes (76.8%). Half of these eyes  had mild peripheral ischemia and the other half  had severe peripheral ischemia. The mean BCVA was 0.43±0.35 LogMAR in eyes without peripheral ischemia and 0.52±0.39 LogMAR in eyes with peripheral ischemia (p=0.076). The mean CSFT was 483.91±138.7 µm in eyes with peripheral ischemia and 457.31±103.5 µm in eyes without peripheral ischemia (p=0.36). Severity of peripheral ischemia and related OCT features are given in Hyperreflective foci in the cyst wall were detected in 170 eyes (68%). Most of these hyperreflective foci  were in the outer retinal layers. The median number of the foci was 1 (0-14) in the cyst wall and 1 (0-8) in outer retinal layers. The number of the hyperreflective foci did not change significantly with the severity of macular or peripheral ischemia (p>0.05).Internal reflectivity of the cyst did not differ significantly between eyes with and without ischemia (p>0.05). Eighty-two eyes (33%) had hyporeflective cysts and 60 (24%) had isoreflective cysts. Heterogeneous internal reflectivity was observed in 108 eyes (43%). The number of hyperreflective foci in the cyst wall was significantly higher in the isoreflective internal reflectivity group than the others (p=0.007) .In binary logistic regression analyses, only CSFT and outer retinal damage status were statistically significant for macular ischemia. No significant risk factor for peripheral ischemia was identified in binary logistic regression analyses .6 Hyperpermeability and ischemia are different components of DME and also the main outcomes of the distorted vascular network. In an earlier study, the presence of a cyst was associated with decreased retinal sensitivity independent of IS/OS damage and increased retinal thickness.14 In this study, we focused on the impact of diabetic cystic changes on the ischemic process.Pericyte loss and autoregulatory dysfunction play an important role in the pathophysiology of DR. Thus, weakening and destruction of retinal vessels occur.23 In the present study, severe peripheral retinal ischemia was more prevalent in eyes with proliferative DR, as expected. However, no statistically significant difference was observed in the prevalence of macular ischemia between the groups according to the severity of DR or peripheral retinal ischemia.Enlargement of the FAZ and perifoveal intercapillary area and disruption of macular circulation have already been demonstrated in conjunction with the progression of DR and visual disturbance.27 Also, similar to our study, disorganization and loss of retinal capillaries was observed more precisely in the deep plexus with more severe DME in OCTA images.28 Although enlargement of the cyst in both planes seems to be associated with macular ischemia, vertical enlargement and retinal thickness had a greater impact on the ischemic process. However, we believe that the horizontal enlargement of the cyst is associated with degeneration of Muller cells. In contrast to this hypothesis, a study that classified diabetic CME based on the ratio of vertical size of the largest cyst to the maximum macular thickness showed that disruption of the cystic septa occurred in the most advanced stage.29 In a previously published study, vascular hyperpermeability and ischemia were shown to cause necrosis and apoptosis in the neuroglia cells, resulting in large cystoid cavities. A vicious circle ensues, with the enlargement of the cystoid spaces causing enlarged FAZ and increased foveal ischemia.13 In the same study, sponge-like retinal thickening and larger FAZ were more common in CME cases than in serous foveal detachment.Macular ischemia was found to be more prevalent in eyes with larger macular cysts and CSFT. Larger FAZ areas have been observed in the superficial, deep, and summated capillary plexus in diabetic patients in several studies using OCT angiography (OCTA), which is one of the current retinal imaging methods and allows construction of microvascular flow maps.31 The presence of macular cystoid spaces was found to be predictive of visual deterioration, with larger cystoid spaces being more disruptive than small ones.32 In light of this information and the findings in this study, larger cysts may have a damaging effect that triggers or exacerbates the ischemic state. Regression analyses more clearly demonstrated the association between CSFT and outer retinal disruption and macular ischemia. Patients with more severe DME had a 1.04-fold greater chance of having macular ischemia, and those with outer retinal damage had a 0.25-fold greater chance of having macular ischemia. Furthermore, outer retinal damage was observed more frequently in severe macular ischemia.We hypothesized that the disruption of retinal structures and the ischemic process as a part of the degeneration occur together in the chronic stage of DME. The damaging effect of cyst formation on ganglion and bipolar cells has been suggested in previously published studies.33 demonstrated a negative correlation between BCVA and cystoid DME groups . Both macular ischemia and cyst size affect visual acuity.We have shown that as a result of the degenerative process, BCVA decreased gradually with increasing severity of ischemia. Similarly, Koleva-Georgieva and SivkovaIn our study, qualitative parameters such as the presence and number of hyperreflective foci in the cyst wall and internal reflectivity of the cyst were not associated with macular or peripheral ischemia.15 were suggested to be subclinical characteristics of lipoprotein extravasation and an early manifestation of DME. Hyperreflective foci that can be found scattered throughout all retinal layers have also been detected in the cystoid space. They were correlated with modest fluorescein pooling and heterogeneous reflectivity.34 In the current study, we studied hyperreflective foci in the cyst wall and hypothesized that they may be associated with the early period of degenerative process and ischemia. Although not associated with ischemia, we found a significant relationship between the number of hyperreflective foci in the cyst wall and the internal reflectivity of the cyst. It was hypothesized that internal reflectivity of cysts was related with degeneration; in the early period, the cyst is usually isoreflective, then becomes heterogeneous due to the debris accumulation resulting from degeneration, and finally, the degenerated cyst becomes hyporeflective in the chronic stage. Our findings supported this hypothesis in that there were more hyperreflective foci in the isoreflective cysts.Hyperreflective foci defined by Bolz et al.35 In contrast to these findings, Wessel et al.7 claimed that the risk of having DME increases 3.75 times in the presence of ischemia. However, in the same study there was no relationship between degree of ischemia and DME. Similar to this study, peripheral ischemia was shown to be associated with greater degree of DME in a study using ultra-wide-field angiography (UWFA).36 In the current study, there was a statistically significant relationship between the noncystoid retinal tissue and peripheral ischemia. Noncystoid retinal thickness increased with the presence and severity of ischemia in the peripheral retina. This may be explained by a diffuse thickening of the macula outside the cyst due to increased VEGF load in the presence of peripheral ischemia.The relationship between macular edema and peripheral ischemia was inconclusive. We failed to show any relationship between the presence and severity of the peripheral ischemia and CSFT. Similarly, the severity of DME was not found to be correlated with the global nonperfusion area in the DAVE study.The retrospective design is the main limitation of our study. Other limitations include unavailability of current retinal imaging methods that can be used for ischemia such as OCTA and UWFA in our clinic and the lack of image analysis software for the measurement of nonperfusion areas and calculation of ischemic index.In conclusion, the possibility of macular ischemia increases when the diameter of the cyst increases. The main factors increasing the probability of ischemia were increased CSFT and the presence of outer retinal damage. In cystoid DME, greater CSFT is associated with larger cyst, more outer retinal damage, and higher likelihood of macular ischemia findings in FA. In addition, the presence of peripheral ischemia seems to increase retinal thickening in the noncystic retinal area.


Most studies have revealed that the incidence of morbidity and mortality of preterm male infants is greater than that of preterm female infants. Recently, conflicting outcomes have been reported regarding mixed-gender twins. The aim of this study was to estimate the association between gender and outcome in newborn twins of different gender.We conducted a retrospective review of mixed-gender twins weighing < 1500 g that were born at Shamir Medical Center (Assaf Harofeh) between the years 1995 and 2016 (158 newborns). The incidence of morbidity and mortality until discharge from the hospital were evaluated while looking at gender differences.No significant differences were found in neonatal mortality or morbidity between females and males from different-gender twins. Even after considering confounding variables  in linear and logistic regression models, no significant differences were found between the genders.Our study suggests that there are no significant differences in neonatal mortality or morbidity among different-gender twins. Our results support the need for further studies. Prematurity and low birth weight is a major risk factor for neonatal morbidity and mortality . PrematuStudies revealed that the prognosis of males who are part of a male-male pair relative to a female-female pair is less favorable –12. ThisRecently two studies were published on comparisons between males and females in cases of mixed gender twins. Zhao et al.  showed tDue to the conflicting data, we conducted a study based on our population. Since very low birth weight premature neonates are the most vulnerable , we chosWe conducted a retrospective review of all the premature mixed gender twins that were born at Shamir Medical Center (Assaf Harofeh) between the years 1995 and 2016 (158 newborns). Inclusion criteria: birth weight of less than 1500 g. Exclusion criteria: twins who were born dead and babies with severe structural and/or chromosomal abnormalities. Details of the perinatal and post-natal course until the discharge date or death were recorded. Medical data in regard to morbidity and mortality was collected. A comparative evaluation was done between the male and female groups. The study was approved by the Institutional Ethics Committee at Shamir Medical Center (Assaf Harofeh) (Ref: 0073–17-ASF).In each group, complications of prematurity and post-neonatal complications were examined until discharge from the neonatal intensive care unit. The data includes: delivery room information ; and Neonatal Intensive Care Unit information .Since the comparison was made between the twins, it was possible to overcome confounding factors related to genetics, exposures during pregnancy and birth, and social and demographic factors.Weight Z score was presented by Fenton growth charts. PH levels refer to the umbilical cord blood pH levels. The need for resuscitation refers to the need for resuscitation in the delivery room. Invasive ventilation refers to mechanical ventilation via an endotracheal tube. Noninvasive ventilation refers to continuous positive airway pressure (CPAP) induced through a mask. Early/late onset of sepsis refers to sepsis presenting before/after the first 72 h of life. Outcome score is a calculated score between 0 and 6 and based on six parameters  with a weighted value of 0–1 .P < 0.05 was considered as statistically significant.Categorical variables were described using frequency and percentage, and sequential variables were described using mean and standard deviation. Continuous variables were calculated using a t-test. The difference between the two groups dependent on categorical variables was performed using the McNemar’s test. The difference between the two groups dependent on ordinal variables was performed using the Wilcoxon test. For dichotomous variables, data was analyzed using mixed model logistic regression, which took into account the dependence between twins in order to predict the probability of mortality and complications. For sequential variables, data were analyzed using mixed linear models that took into account the dependence of the twins, and the explanatory variables were the subjects’ sex, the birth week, the Z score of the twin weights, and birth order. Data analysis was performed with the statistical software IBM SPSS statistics 24. The value of Data on 162 premature mixed gender twins was collected, from them 2 twin pairs were excluded, due to death at birth and chromosomal abnormalities. There were 158 twins included in the final study, divided into 2 equal groups . The characteristics of the participants are illustrated in Table Table P < 0.015, CI 0.214–0.845). No significant relationship was found between the newborn’s gender and the specific complications.Multivariate analysis, using a mixed regression model, took into account the dependence between the twins in order to predict the risk of death and complications such as RDS, BPD, ROP, PVH/IVH, NEC, and PVL. The explanatory variables were the gender of the subjects, gestational age, the Z score of the twin weights, and the birth order. A significant association was found between the Z scores of birth weight and ROP; for each unit increase in Z score there was a 0.425 reduction in risk for ROP  and length of oxygen supplement treatment Table . In a miOur study suggests that there are no significant differences in neonatal and post neonatal mortality and morbidity among different gender preterm twins with birth weight less than 1500 g. Birth weight was found to be significantly higher in males; however, in the calculation of Z score for weight depending on gender and gestational week at birth, there was no significant difference between males and females. In the logistic regression model, a significant association was found between the Z score of the weight and ROP. For each increase in standard deviation in the Z score, the odds of ROP decreased. In addition, a significant correlation was found between the week of birth and most of the prognosis variables examined ; with each additional gestational week at birth reducing the risk of the detailed prognosis variables and increasing the Apgar score at 1 and 5 min.Zhao et al.  reportedSimilar to our study, a recent study found no differences in mortality rates between males and females in cases of mixed gender twins . It was Birth order was also studied as a variable. Armson et al.  studied One of the findings in our study was the inverse association between the week of gestational age at birth and neonatal and postnatal complications among twins of opposite gender. The higher the gestational week at birth, the lower the chance of death and complications, regardless of gender. Similar findings on the relationship between the week of birth and neonatal complications were discussed in a previous study . In our The limitations of our study are the retrospective nature and the low number of participants. However, it presents our experience among preterm mixed gender twins and reinforces the assumption of no gender differences in the outcome, when comparing between mixed gender twins.Our study suggests that there are no significant differences in neonatal and post neonatal mortality and morbidity among different gender twins with very low birth weight. Our results support the need for further studies.


Electrophorus electricus) made it one of the first model species in science. It was pivotal for understanding animal electricity in the 1700s, was investigated by Humboldt and Faraday in the 1800s, was leveraged to isolate the acetylcholine receptor in the 20th century, and has inspired the design of new power sources and provided insights to electric organ evolution in the 21st century. And yet few studies have investigated the electric eel’s behavior. This review focuses on a series of recently discovered behaviors that evolved alongside the eel’s extreme physiology. Eels use their high-voltage electric discharge to remotely control prey by transcutaneously activating motor neurons. Hunting eels use this behavior in two different ways. When prey have been detected, eels use high-voltage to cause immobility by inducing sustained, involuntary muscle contractions. On the other hand, when prey are hidden, eels often use brief pulses to induce prey twitch, which causes a water movement detected by the eel’s mechanoreceptors. Once grasped in the eel’s jaws, difficult prey are often subdued by sandwiching them between the two poles (head and tail) of the eel’s powerful electric organ. The resulting concentration of the high-voltage discharge, delivered at high-rates, causes involuntary fatigue in prey muscles. This novel strategy for inactivating muscles is functionally analogous to poisoning the neuromuscular junction with venom. For self-defense, electric eels leap from the water to directly electrify threats, efficiently activating nociceptors to deter their target. The latter behavior supports a legendary account by Alexander von Humboldt who described a battle between electric eels and horses in 1800. Finally, electric eels use high-voltage not only as a weapon, but also to efficiently track fast-moving prey with active electroreception. In conclusion, remarkable behaviors go hand in hand with remarkable physiology.The remarkable physiology of the electric eel ( You might say that electric eels need no introduction. Most people have heard of them and are aware of their unusual ability to generate powerful electrical discharges for offense and defense. But it would probably come as some surprise to many readers that electric eels played a pivotal role in the early development of the science of physiology and their anatomy helped inspire Volta to develop the battery, which he called an artificial electric organ similar to the electric eel’s  is much lower than that of an eel (400–600 volts) it was very difficult to obtain a gap-crossing spark from the former. In 1775, John Walsh experimented with eels and succeeded in demonstrating the spark repeatedly to colleagues and visitors  on nearby animals. This research began simply as a photography project but turned into a multi-year scientific investigation.Electric eels provide an informative example of strongly electric fish because they uniquely emit two different types of EOD  used for human muscle therapy Sweeney, .This mechanism for incapacitating prey suggested that new insights might be gained by considering the eel’s volley from the perspective of prey motor neurons. For example, Alternatively, because eel electrocytes are derived from muscles and innervated by motor neurons, the eel’s motor neuron output (and therefore its EOD) might be constrained in a manner similar to that of a wide range of neuromuscular systems. Put another way, the similarity between the beginning of an eel’s EOD and the optimal motor neuron train found for maximal muscle activation could reflect a constraint on both systems at peak power output. And yet this seems unlikely, given the incredible variation in the form and rate of EOD’s exhibited by a diversity of electric fish. Moreover, electric eels have another way of remotely controlling prey that also seems to make use of an optimal strategy.In 1979 the results of Bauer’s investigation of electric eel hunting behavior and EOD were posthumously published . Electric eels are extremely sensitive to water movements and often respond with a high-voltage volley and strike. In addition, eels hunting live prey in a complex environment (or when prey were under an agarose barrier) sometimes gave off a doublet, resulting in prey twitch, followed (20–40 ms later) by the eel’s full, tetanus inducing high-voltage volley and suction feeding strike .Determining whether eels use doublets to detect induced prey movements required a paradigm in which the prey’s response was under the control of the experimenter. This was achieved using a variation of the pithed fish preparation . In thisThe first question to be addressed was the latency of the eel’s response to fish twitch. If eel’s were responding to fish twitch in their natural doublet-hunting behavior, then their reaction time would have to be in the 20–40 ms range. This was, in fact, found to be the case. When the eels were close to the fish preparation and the investigator trigger the stimulator, eels responded to the twitch with a high-voltage volley and strike toward the preparation with a delay of 20–40 ms.When eels gave off doublets near the fish preparation, but no fish twitch was triggered, no attack was elicited. Moreover, eels never gave off doublets, followed by a full volley, in the absence of fish twitch. However, the key experiment was to configure the data acquisition unit to immediately trigger fish twitch when the eel gave of a doublet. When this was arranged, the natural doublet-hunting behavior was recreated . Eels gaThe remarkable conclusion from these experiments is that eels have dual modes of prey remote control. When a nearby fish is detected, a full volley of high-voltage impulses causes rapid and powerful muscle contractions preventing escape. When prey are hidden, or their identity is uncertain, eels can induce involuntary twitch, revealing their approximate location . In esseThe Gymnotus appears to be sensible when he has shocked an animal, being made conscious of it, probably, by the mechanical impulses he receives, caused by the spasms into which he is thrown” . The explanation was not available until Lissmann  showed tLissmann’s discovery of active electroreception provided the missing, functional intermediate needed to explain the evolution of strongly electric species. Thus for electric eels, the evolutionary trajectory was easy to envision. Their ancestors presumably used an electric organ for navigation, and this was progressively enlarged to provide an electrical weapon . The retention of the low-voltage EOD for active electrolocation seemed to fit well with such a functional bifurcation: low voltage for electrolocation and high-voltage for offense and defense. In the author’s view (prior to 2015) a remaining question was how the eel’s sensitive electroreceptors dealt with the high-voltage volleys, the presumption being that the electric sense was shut down completely during the high-voltage EOD. Recent data show this is not the case.Recall the electric eels did not grasp the electrically insulated prey in the course of doublet hunting experiments described above. Instead, the strikes were aborted without a final “bite.” This was obvious because electric eels are air-breathers and they hold air in their mouths between breaths. As a result, their suction feeding is accompanied by sudden expulsion of air from the operculum. This was fortuitous because it made the absence of the final component of the strike more obvious during experiments. Before describing the next experiments, it is import to re-emphasize that electric eel predatory strikes occur in conjunction with the high-voltage volley; there are no low-voltage EOD’s emitted during the strike. Thus evidence of ongoing active electroreception during the strike must be attributed to the high-voltage EOD.As a preliminary test for the possibility that electric eels were using the high-voltage EOD for active electroreception, a conductive carbon rod was placed next to the electrically isolated fish preparation . The fish was made to twitch by activating the stimulator and the eel then gave off its high-voltage volley and struck toward the electrically isolated fish as previously described. But this time, the eel altered course, moved over the conductor, broke through the agarose barrier, and sucked the conductive rod into its jaws , territoriality, or communication. Assunção and Schwassmann  were ablSo far the predatory behavior of electric eels has been described and illustrated as it typically occurs when feeder goldfish are provided to an eel in an aquarium. But electric eels live in the Amazon, which includes a wide diversity of fish species and other potential prey. Surprisingly little is known about the diets of electric eels in their natural habitat, but it is obvious that feeder goldfish are not their most challenging prey. Moreover, juvenile eels have much smaller, weaker electric organs and can have difficulty handling even small fish.In cases where difficult prey are encountered, electric eels are uniquely suited for a strategy that increases the intensity of their attack. This is because, unlike strongly electric rays or catfish, the eel’s electric organ is linear and extends through its long, thin body. This means the positive and negative poles  are widely separated in space. During a typical predatory attack, the eel’s electrical discharge forms a (roughly) dipole field around the eel. The positive pole is the region around the eel’s head and the negative poll is the region around the tail . A fish This would change drastically, however, if the eel were to curl and bring its tail behind and close to the prey. In such a case, the effect of the tail (the negative pole) would be additive (because the prey would be sandwiched between the two poles) and strong (because the negative pole would be close), rather than subtractive and weak. The theoretical effect of such a curling move would be to double the intensity of the electric field experienced by prey, at virtually no cost to the eel.In fact, electric eels commonly engage in this curling behavior when handling difficult prey Catania, . JuvenilMeasuring the changing intensity of an electric field experienced by prey during an eel’s attack would seem daunting. The common method of monitoring electric fish EOD’s, with electrodes stationary in the aquarium, cannot provide data about the local field strength in and around prey. Nor can an investigator chase a hunting eel with electrodes and hope to get useful data. This problem was solved by leveraging the eel’s aggressive predatory attack.To measure the electric field within prey, the pithed fish preparation was again used. However, in this case, the fish was impaled on a custom-made, plastic electrode holder . The recWhen this preparation was introduced to a hungry eel, it was attacked, sucked into the eel’s mouth, and gripped very tightly . This coThe preparation provided data from numerous eels, showing that the intensity of the electric field experienced by prey often more than doubled when the eel curled . Recall,It might seem surprising that, in many cases, the field strength within prey more than doubled when the eel curled. This likely occurred because the tail, containing the negative pole, can be brought very close to the prey , whereas the positive pole of the electric organ is situated at some distance behind the front of the eel’s head . Therefore the negative pole (with an effect that is added to the positive pole) may have a greater effect, based on proximity, than the positive pole during the curling behavior.What benefit does this behavior provide the eel? Although it intensifies the electric field through prey, a large electric eel would seem to have enough power from just the positive pole. This appeared to be the case when an eel was offered goldfish. But when an electric eel was offered large crayfish, the eel’s initial attack sometimes failed and the crayfish executed the appropriate escape response . ClearlyRecall that high-voltage EOD’s from electric eels activate motor neuron efferents, and hence muscles in nearby prey. In the pithed-fish preparation, this was measured based on whole-body fish tension. Crayfish provide a different window into this effect because many of their paired muscles are asymmetric: the muscles that close their claws are more powerful than the muscles that open them. As a result, the effect of repeated high-voltage volleys from the eel electrifying a crayfish was readily apparent. Unlike the situation in fish, where contraction of symmetric muscle groups resulted in total immobility, in crayfish it was possible to watch the claws open and close with repeated high voltage volleys  in muscle physiology labs to investigate fatigue.To investigate this outcome a stimulator was first used to mimic the effects of an electric eel on prey muscle preparations . Muscle These experiments demonstrate the predictable, fatiguing effect of repeated bouts of high-frequency muscle stimulation. The half-second, post-bout testing time for muscle fatigue was chosen because after electric eels engage in this form of behavior while curled, they then reposition the prey for swallowing within a half-second. Thus they need only cause a short period of muscle inactivation to reposition and swallow helpless prey.To provide more data regarding the effect of eel curling behavior, an additional more elaborate experiment was designed. In this case, the stimulator was configured to be driven by an eel’s high voltage EOD while the eel curled around the previously described fish-electrode preparation . Thus thFinally, although this was not explicitly investigated for eels, the oral region of most animals is very sensitive. Electric eels are holding the prey in their mouth while they engage in the curling behavior, so there is every reason to suggest the eel can monitor the contractile force of the prey’s muscles during the curl. This would explain, for example, why eels sometimes electrify the crayfish, while in the curled position, for over a minute Catania, . This isTo summarize these results, electric eels have a strategy for inactivating the muscles of difficult, struggling prey that have been grasped but not subdued. In these cases, the eels concentrate the electric field by sandwiching the prey between the two poles of their long electric organ. This likely ensures activation of the motor neuron efferents in prey that might have more resistive skin or cutical or in the case of juvenile eels, prey might simply not be affected by the output of their weaker electric organ in a linear configuration. Once curled to amplify the local field through the prey, the eels give off repeated volleys. The resulting effect on prey muscles is remarkably similar to the application of a paralyzing agent, such as curare, that blocks the neuromuscular junction. There is a precipitous drop in muscle function. In essence, the eels have a new method for inactivating muscles, through the induction of involuntary fatigue. The strategy is analogous to the use of paralyzing venom, but it takes effect more rapidly.In March of 1800, Alexander von Humboldt supposedly observed an extraordinary encounter between electric eels and horses. He had been traveling in South America and one of his goals was to experiment with electric eels. The first eels that fishermen had brought to him had been poisoned with plant roots and they were “much enfeebled” and useless for experiments . On many occasions, when the metal net was brought toward a large eel, the eel transitioned from a retreat to an explosive attack targeting the metal part of the net. The eel rapidly approached, followed the metal rim to where it exited the water, and then leaped upward while pressing its lower jaw to the metal handle. In coordination with the upward leap, the eel gave off long volleys of its high-voltage EOD. The behavior was particularly surprising because at no other time were electric eels observed leaping upward from the aquarium. Moreover, the unexpected leap was clearly directed toward the metal handle, and therefore coincidently toward the investigator’s hand. Although the rubber glove afforded protection from the eel’s EOD, it was easy to imagine the consequences had there been no glove. The behavior gave the impression of a formidable, electrical attack.As was the case for experiments measuring the effect of curling, it was possible to leverage the eel’s behavior to further investigate this novel attack. This was accomplished using two flat metal plates attached to a plastic handle. The lower plate was submerged most of the way in the water, separated from the upper plate (which was entirely above the water) by a thin insulator. A voltmeter was then connected between the two plates. When the eels attacked the apparatus, they emerged from the water pressing their lower jaw against the lower plate while giving off their high-voltage volleys. As they rose higher, they crossed from the lower plate to the upper plate, and thus variations in the electrical potential could be recorded as the eels ascended .As might be predicted, the electrical potential (voltage) increased dramatically as the eels ascended to greater heights. This is best appreciated by considering the equivalent circuit that is thought to develop . When fuAnother way to think about this dynamic is to consider the flow of electricity being “pushed” by the eel’s electrocytes. The increasing resistance of the return path along the eel means that more current would be “pushed” through the target . In other words, the higher the eel leaps, the less pleasant the experience for the target.The experiment and observations described above seem to support Humboldt’s story. Yet it was not entirely clear how similar the behavior described above might be to what Humboldt observed. He reported that the eels emerged from the mud and attacked, with at least some eels pressing themselves against the horses . The analysis begins with a determination of the (EMF in volts) and internal resistance (r) for each eel. These variables are unique for any given eel at a particular stage of development. As the eel grows and adds electrocytes, its internal resistance and EMF change . Previous investigations of eels Brown,  and otheOne way this can be done is to measure the current (I) that flows for a “short circuited” eel and then measure voltage (V) directly from the skin of an eel that has been removed from the water. Then the resistance (r) can be determined from Ohm’s law (r = V/I). But a more accurate method is to add a variable resistor to the circuit and measure V and I (during each high-voltage EOD) as the resistance is varied. When this is done, a plot of V vs. I yields a straight line with a slope equivalent to the negative of the internal resistance (r). The details of the method are given in Catania . Using tMany insights can be gained about the dynamics of the electric circuit from the parameters shown in Target resistance was therefore determined using the small eel illustrated in The results of these recent investigations show that electric eels have behaviors that are far more sophisticated than previously thought (at least by the author). The conception of this species as a “one trick pony”—having a powerful weapon that provided the advantage of brute force, without the need for complex behaviors, could not be further from the truth. As is often the case, this seems obvious in retrospect when one considers the eel’s anatomy and physiology in an evolutionary context. Clearly, the electric eel has been strongly selected for electrical power. Electrocytes make up an astonishing proportion of its long body. But there is more than one way to increase power. The first is to add electrocytes. The second is to apply the power from existing electrocytes more efficiently. The second option is arguably less costly than expending many resources to develop, maintain, and power more electrocytes. The curling behavior provides the most obvious example—an eel can literally double the power communicated to prey by simply reorienting its tail. Consider the difference in “cost” between evolving this behavior or, alternatively, doubling the number of electrocytes. A similar argument can be made for the leaping defense. In short, it seems inevitable the strong selection for electrical power would act on both physiology and behavior.Torpedo marorata might serve to startle prey. Similarly, Belbenoit et al.  and identified frequent pre-volley activity; the investigators specifically suggested these might serve to startle immobile prey. If so, these would be remarkable examples of convergent hunting strategies. Do other strongly electric species also use high-voltage for active electroreception? What are the parallels, from the perspective of sensory processing, between the high rate of an eel’s attack volley and the high rate of a bat’s feeding buzz while echolocating? What kinds of electroreceptors might mediate sensory transduction of high-voltage? What is the composition of an eel’s diet in the wild? Do electric eels specifically target other electric fish (Stoddard, In addition to revealing a number of new behaviors, these studies raise many additional questions for future study. Perhaps the most obvious questions relate to other strongly electric species. Are electric rays and catfish activating the motor neurons in nearby prey? If so, do they use the same strategies for inducing or arresting prey movement? Belbenoit and Bauer  suggestet et al.  recordedThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Peptide-based supramolecular hydrogels, as a new type of biological nanoarchitectonic structure, hold great promise for a wide range of biomedical and nanotechnological applications, such as tissue engineering, drug delivery, and electronic and photonic energy storage. In this work, a cyclic dipeptide (CDP) cyclo-(Trp-Tyr) (C-WY), which has exceptional structural rigidity and high stability, is selected as a hydrogelator for the formation of supramolecular hydrogels. The unique hydrogen bonding in C-WY endows a high propensity for self-assembly and the resulting hydrogels are revealed to be crystalline. The crystalline hydrogels possess excellent mechanical capacity and superior tolerance to various harsh conditions, including in the presence of charged biopolymers, extreme acid/base environments, and changing thermal conditions. Such high tolerance enables the crystalline hydrogels to be applied in the complex and harsh environments of electrochemistry. In addition, this study demonstrates that the self-assembly of cyclic dipeptides results in highly robust hydrogels which can be applied for electrochemical applications such as electrochemical supercapacitors. On account of their high water content and highly tunable mechanical properties, hydrogels as soft nanoarchitectonics and soft matter are well-suited in extensive applications, such as tissue engineering, drug delivery, and electronic and photonic energy storage –10. SelfCyclic dipeptides (CDPs), which are based on the basic structures of heterocyclic 2,5-diketopiperazines, are a special kind of dipeptides. They are the smallest cyclic peptides and contain six-membered heterocyclic lactam ring cores. CDPs exhibit exceptional structural rigidity, stability, as well as biological activity as compared to their linear counterparts –41. TherGels prepared by CDP self-assembly integrate the advantages of low molecular weight gels, including the multiple functionalities, adjustable performance, and dynamic features. CDP-based gels have been developed as smart soft materials for a multitude of applications. However, most of the attention is focused on the amorphous assemblies in organic solvents and ionic liquids –46. AlthHerein, we investigate the self-assembly and application of a CDP, cyclo-(Trp-Tyr) (C-WY) . C-WY co−1 of the unimolecular C-WY, the hydrogel has a red-shifted amide N–H stretching band located at 3317 cm−1, indicating the formation of strong hydrogen bonds between C-WY molecules in the hydrogel  with water 480 μL) . The hydhydrogel . Furtherhydrogel ,D. The f0 μL . ThThe fibrillar structure and three-dimensional fibrous network of the C-WY hydrogel were further investigated by confocal laser scanning microscopy (CLSM) . Thiofla−1). Under a high magnitude strain (500%), the modulus of G’’ values exceeded G’ values, indicating the breaking of the hydrogel  curves of the hydrogel at different scan rates ranging from 10 to 40 mV were studied . Typicaltability . These rIn summary, we demonstrated that C-WY peptides can self-assemble into well-ordered fibrous networks based mainly on the inherent intermolecular hydrogen-bonding interactions. The hydrogel has a crystalline structure, excellent rheological properties, superior stability, and ideal robustness under various conditions, such as acidic or basic environments, or in the presence of charged biopolymers. Given its excellent electrochemical stability, the highly stable hydrogel was successfully demonstrated as an electrochemical supercapacitor. This study demonstrates that hydrogels based on self-assembly of CDPs can be valuable candidates for applications in harsh environments.File 1Experimental section and additional figures.


More than 20 million infants were born with low birth weight in worldwide. Low birth weight contributes more than 80 percent of all the neonatal mortality. In Ethiopia, studies have shown that there is a high prevalence of low birth weight among newborns. Thus, this study was aimed to determine the magnitude and associated factors with low birth weight among newborns delivered at term in Kambata-Tembaro zone, Southern Ethiopia, 2018.Institution based cross-sectional study design was used. The sample size was proportionally allocated to each hospital. The total of 341 study participants was enrolled using systematic random sampling techniques. Data were collected by interview-administered questionnaire and entered using Epi-Info version-7 and exported to SPSS version 20 for analysis. Multivariate logistic regression analysis was carried out to identify associated factors with the low birth weight.The prevalence of low birth weight was 18% and significantly associated with the mothers’ non-employment , residing in the rural , unintended pregnancy , not attending antenatal care , mothers with greater than three births , birth interval less than or equal to two years  and intimate partner violence during pregnancy [aOR=2.1:95% CI: 1.1-3.9].The study finding shown that the prevalence of low birth weight among newborn was high (18%) in the study. Preventing of low birth weight is an important intervention to reduce neonatal death. Therefore, maximizing women economic status, providing quality family planning services, enabling pregnant women to use antenatal care and preventing intimate partner violence during pregnancy via launching women empowering strategies in the community level is highly recommend. Low birth weight is defined as a weight of newborns at birth less than 2500 gram by World Health Organization. More than 20 million infants are born with low birth weight in worldwide , 2. Low Low birth weight is not only a predictor of prenatal morbidity and mortality, but studies have found that it also increases the risk for non-communicable diseases such as diabetes mellitus and cardiovascular diseases in later life , 8. StudTo prevent low birth weight World Health Organization recommended evidence-based maternal health care interventions like women empowerment, women education attainment, appropriate perinatal care, adequate nutrition for adolescent girls, prevention of malaria during pregnancy, birth spacing, antenatal care interventions for all women, iron and folic acid supplements for women during pregnancy daily, interventionist care in severe pre-eclampsia before term and improve linkage and referral for facility births , 17. As Study design and period: institution-based cross- sectional study was conducted from May 1-30, 2018.Source population: all newborns in the governmental hospitals in Kembata-Tembaro Zone, southern Ethiopia.Study population: all selected newborns in the governmental hospitals in Kembata-Tembaro Zone, southern Ethiopia.Inclusion criteria: all singleton newborns delivered at term, without congenital anomalies were included and newborns from mothers who had diagnosed medical illness during pregnancy were excluded.Sample size determination: the sample size was determined by a single population formula considering the prevalence of low birth weight in Kersa, southern Ethiopia (p=28%) . Mothers who had unintended pregnancy were two times more likely to have low birth weight as compared to planned pregnancy . Mothers who had a history of intimate partner violence during pregnancy were two times more likely to have low birth weight babies as compared to that of mother didn’t have violence during pregnancy  (1.1-3.9] .In this study, the prevalence of low birth weight was found to be 18%. This study finding is comparable with study finding Northwest Ethiopia the prevalence of low birth weight 17.8%  and in SIn contrast, the study finding was higher as compared to other studies result; study done in Northern and southwestern Ethiopia the prevalence of low birth weight was found to be 14.6% and 11.02% respectively , 27. StuIn this study, mother occupation was significantly associated with low birth weight of newborns. Those mothers who didn’t employed were five times more likely to have low birth weighted babies as compared to mothers who are employed . This might lead housewives to be economically and psychologically dependent on their husbands and affect their health care seeking behavior timely. This woman’s financial dependency is the major hiders of health care seeking behavior in the community.In this study, mothers residence was found to be significantly associated with low birth weight, meaning mothers residing in the rural area were five times more likely to have low birth weighted babies as compared to mothers from Urban area . This finding is consistent with other studies findings  and   and aOR. This isIn this study, mothers who have had unintended pregnancy were two times more likely to have low birth weighted babies as compared to mother with planned pregnancy . This study finding is consistent with the study finding in the Axum, North Ethiopia with  . This miIn this study, the mothers who didn’t attend antenatal care follow up during pregnancy were two times more likely to have low birth weighed babies as compared to mothers who have ANC follow up . This study finding was supported by study done in the Ethiopia, low birth weight was significantly associated with non-attending antenatal care follow up  ; aOR=.2, and stuIn this study, the number of birth was significantly associated with the low birth weight of babies delivered at term. Mothers who had number of birth greater than three were nearly two times more likely to have low birth weighted babies at term delivery . This finding is in line with finding of study in Mekelle Hospital, Ethiopia and Republic of Indonesia , 21. ButIn this study, mother who gave birth with birth interval less or equal to two year were two times more likely to have low birth weighed babies as compared to those who have three years and above . This is because, if the birth interval is short; it might increase the life risk for mothers related to pregnancy and delivery complications. It might directly or indirectly affects mothers’ health, economic and social status during pregnancy.In this study, mother who had suffered any act intimate partner violence during pregnancy were two times more likely to have low birth weighed babies as compared to mothers who didn’t have any violence [aOR=2.1: 95% CI: 1.1-3.9]. This study finding is supported by result of study done on intimate partner violence during pregnancy and low birth weight, Southeast Ethiopia  , 34.Intimate partner violence might be physical, sexual and psychological which has negative impact on birth weight of newborn. Violence during pregnancy potentially hinders mothers’ health care seeking behaviors, health service utilization and decision making on their all aspects of life. This obviously might lead to have low birth weighted babies.The prevalence of low birth weight among newborn was 18% in the study. Prevention of low birth weight is an important intervention to reduce neonatal death. Therefore, to prevent low birth weight among newborns; encouraging women by means of accessing income generating enterprise to maximize their economic status in the community, providing quality and client choose based family planning services, enabling all mothers to use antenatal care during pregnancy by continues and consistent awareness creation and preventing intimate partners violence during pregnancy via empowering women in the community is greatly recommended.In this study, contextual and individual life styles factors that affects weight of newborns didn’t addressed. We recommend other researchers to do follow up study to come up with finds shown that what effects each covariates have by controlling all potential confounders.Maternal socio-demographic characteristics like education and age already known factors that associated with low birth weight in most of the studies;Maternal medical illness during pregnancy, preterm, multiple pregnancy were already well known associated factors with the low birth weight at birth in most of the studies.In this study, intimate partner violence during pregnancy was significantly associated with the low birth weight among newborns; this was not much revealed by other studies;The finding of this study supplemented that appropriate family planning service utilization prevent unintended pregnancy and helps to space birth interval. As result of this study showed unintended pregnancy and short birth interval was significantly associated with low birth weight of newborn. Thus, quality family planning service has great contribution to prevent low birth weight among newborns.The authors declare no competing interests.


Environmental contaminants such as heavy metals are transported to the Arctic regions via atmospheric and ocean currents and enter the Arctic food web. Exposure is an important risk factor for health and can lead to increased risk of a variety of diseases. This study investigated the association between pregnant women’s levels of heavy and essential metals and the birth outcomes of the newborn child. This cross-sectional study is part of the ACCEPT birth cohort  and included 509 pregnant Inuit women ≥18 years of age. Data were collected in five Greenlandic regions during 2010–2015. Population characteristics and birth outcomes were obtained from medical records and midwives, respectively, and blood samples were analyzed for 13 metals. Statistical analysis included one-way ANOVA, Spearman’s rho, and multiple linear and logistic regression analyses. The proportion of current smokers was 35.8%. The levels of cadmium, chromium, and nickel were higher compared to reported normal ranges. Significant regional differences were observed for several metals, smoking, and parity. Cadmium and copper were significantly inversely related to birth outcomes. Heavy metals in maternal blood can adversely influence fetal development and growth in a dose–response relationship. Diet and lifestyle factors are important sources of toxic heavy metals and deviant levels of essential metals. The high frequency of smokers in early pregnancy is of concern, and prenatal exposure to heavy metals and other environmental contaminants in the Greenlandic Inuit needs further research. Environmental contaminants such as toxic heavy metals and persistent organic pollutants (POPs) are transported to the Arctic through long-range atmospheric and ocean currents ,5,6,7,8.Heavy metals is a general term that applies to metals and metalloids, which have a relatively high density and are considered to be toxic to living organisms and the environment in certain concentrations ,10,11.Metals and other elements occur naturally in the Earth’s crust. However, human and environmental exposure has increased with increasing use of heavy metals in industry, agriculture, technology, and medicine, as well as from domestic settings and workplaces ,10,11.Some metals and trace elements are essential nutrients for biochemical processes in the human organism. Insufficient or otherwise deviant blood concentrations of these essential metals and trace elements may result in various diseases ,11,16,17The severity of toxicity as well as organ systems affected depends on the heavy metal type, chemical form, whether it is single or mixtures of compounds, exposure dose and time, exposure route, physiologically based pharmacokinetic model, and the age of the exposed organisms, including humans ,20,21,22Exposure to heavy metals may lead to increased risks of cancer, allergies, neurological diseases, decreased cognition, and endocrine disorders ,25,26,27The developmental period of the fetus and the newborn is the most sensitive period in life, making them particularly vulnerable to exposure of heavy metals ,25,33. TThe traditional diet of the Greenlandic Inuit relies on marine food, such as seal, whale, and polar bears at the top of the food chain, and furthermore fish, and therefore, they are exposed to relatively higher levels of heavy metals ,12,28,34There are reports on a decreasing trend in blood levels of contaminants for some of the Arctic populations, indicating regulation through legislation as well as health interventions are working ,36,37. HThis cross-sectional study is nested in the birth cohort ACCEPT  . The oveData were collected from 2010–2015 in five regions of Greenland: North (RN), Disko Bay (DB), West (W), South (S), and East (E) .The criteria for inclusion were pregnant Inuit women ≥18 years of age who had lived more than 50% of their lives in Greenland.ACCEPT enrolled 614 pregnant women. Among them, 42 participants had not lived in Greenland for more than 50% of their lives, five participants were younger than 18 years of age, 33 women gave no information of life duration in Greenland, and 19 participants withdrew their consent to participate or had an early abortion and were excluded. Then, 509 women fulfilled the criteria for inclusion; however, of these, 12 participants had abortions or miscarriages, five participants had no birth outcome information, four twin pairs and two stillborn were excluded, and finally, 487 live born singletons were included in our study analysis .A Danish- and Greenlandic-speaking medical doctor recruited the participants in 2010–2011 and Greenlandic midwives and the study research team in 2013–2015. Enrolment and inclusion to the ACCEPT study have previously been reported ,27,28,34Samples of venous blood were collected from the pregnant women at inclusion to the study and stored at −80 °C until analysis.Prior to data collection, all participants received detailed descriptions of the objective of the project. Informed consent was obtained from all participants and data were anonymized after collection. In addition, participants were informed that participation was voluntary, and they could withdraw their consent at any time.This study was approved by the Ethical Committee for Scientific Investigations in Greenland (J.no. 011-0035-09/gope) as well as the Danish Data Protection Agency (J.no. 2011-41-6367) and conducted in accordance with the Helsinki II Declaration.Thirteen blood metals, including heavy metals mercury (Hg), lead (Pb), arsenic (As) and cadmium (Cd), chromium (Cr), manganese (Mn), and nickel (Ni), as well as essential metals, including selenium (Se), iron (Fe), copper (Cu), zinc (Zn), magnesium (Mg), and calcium (Ca), were measured using inductively coupled plasma mass spectrometry (ICP-MS) at the accredited element laboratory, Institute for Bioscience—Arctic Research Centre, Aarhus University, Denmark. The quality was ensured by repeated analyses and frequent analysis of certified reference material (Seronorm™), as well as by participation in the Quality Assurance of Information in Marine Environmental monitoring (QUASIMEME), an inter-laboratory comparison program . Unless Cotinine is a metabolite of nicotine and is therefore proportional to the amount of exposure to tobacco smoke and, thus, serves as a biomarker for recent exposure to tobacco smoke. The Calbiotech Cotinine Direct ELISA Kit from Calbiotech Inc., CA, USA was used to measure plasma cotinine at the Centre for Arctic Health and Molecular Epidemiology, Department of Public Health, Aarhus University, Denmark.The ratio between n-3 polyunsaturated fatty acids and n-6 fatty acids (n-3/n-6 ratio) is known to be a strong indicator for the consumption of marine food items vs. imported food items . Plasma The birth outcomes are basic measurements of the newborns : Birth wLow birth weight: Defined by the WHO as weight at birth less than 2500 g .Preterm birth: Defined by the WHO as babies born before 37 completed weeks of gestation .Low APGAR5: Defined as a score of less than 7 .Categorized outcomes have the following definitions:The APGAR score assesses the newborns and the need for intervention to establish breathing. The score is reported at one minute, five minutes and at five-minute intervals thereafter until 20 min for infants with scores below 7 . The metData were analyzed with IBM SPSS Statistics version 20.0  with a significance level of 5%, and 95% confidence intervals (95%CI) were calculated. Unless otherwise stated, only significant results are given in the text.Data distribution was checked by Q–Q plot and natural logarithmic transformed data made the distribution more symmetrical and improved the normality of data.One-way ANOVA was applied to compare the levels of metals in pregnant women from different Greenlandic regions. When ANOVA showed statistical significance, complementary multiple comparison post hoc tests were performed. A test for equal variances of variables was performed using Levene’s test. Fisher’s least-significant difference test was used if equal variance was observed; otherwise, Dunett’s T3 was used. One-way ANOVA was applied to compare birth outcomes for the quartiles of blood metals. Pearson’s chi-square was applied to check the regional difference of categorical variables. Student’s t-test was used to compare the levels of cotinine in smokers/nonsmokers, respectively. Spearman’s rho was applied to assess the bivariate correlation of the metals for all regions in total as well as stratified by region, and also to assess the correlation between metals and lifestyle factors.The association for the maternal levels of blood metals and the continuous birth outcome data was analyzed by multiple linear regression analysis and was stratified by gender. For the association between maternal blood metal concentrations and the categorical birth outcome data , logistic regression analysis was used. We built the models one element by one. The identification of potential confounders was based on literature knowledge and directed acyclic graphs (DAGs) supported by the “Change in estimate” method ,47. For 2. Primary school, secondary, and university education were 29.4%, 47.1%, and 23.5%, respectively, and 56.8% of the participants lived in the West region. More than a third (35.8%) of the women were current smokers at the beginning of their pregnancy. The proportions of smokers were statistically significant different among the regions with the highest frequency in East in the order: East (E) > South (S) > North (RN) > West (W) > Disko Bay (DB). No significant difference was found for plasma cotinine among the regions for smokers or nonsmokers; however, current smokers had significant higher plasma cotinine levels compared to nonsmokers .The study population included 509 pregnant women (18–43 years of age) with a median age of 27.0 years and median pre-pregnancy BMI of 24.3 kg/mp = 0.08) among the regions was found, possibly explained by only one person’s (from the North region) consumption of >2–3 times a month.A significant difference was found among the regions for parity, defined as a full-term pregnancy, with a higher median in the East region. No significant difference was found when parity was categorized into 0, 1–2 or ≥3 prior full-term pregnancies. The n-3/n-6 ratio was not significantly different among regions, although a slightly higher median value in the East region was observed.For alcohol consumption during pregnancy, a borderline significant difference  and cotinine , respectively. Smoking positively correlated with cotinine . Age positively correlated with the n-3/n-6 ratio  (not shown).Moreover, we found a negative correlation between age and smoking , Se , Pb , Cd , Cr , and Mn  in the order of Se > Cd > Hg > Pb > Mn > P-Se > Cr but negatively to Cu ; negative correlations were observed between plasma-Se and Cd , Cr  and Mn , and Cd and Cr . . The maternal blood level of Cd was negatively associated with birth weight both as raw data as well as upon adjustments. For Cu, the raw data were negatively associated with birth weight and upon core and region adjustment, whereas the inverse association for Ca disappeared upon further adjustments (ustments .p = 0.049), upon core adjustment , core adjustment plus gestational age at birth  and adjustment for core plus region   .p = 0.047) and Zn adjusted for core and gestation age   .p = 0.026), upon core adjustment  and adjustment for core plus region . Raw data Zn  and Mg  were weakly positive, while Ca were negatively associated with gestational age at birth , but upon adjustments, the associations disappeared  and lead (Pb) were relatively lower than in previously reported data for the Greenlandic population, indicating a decline over time ,39,50. MIn some regions, especially North and East, deviant levels of both essential metals and heavy metals and lifestyle factors were observed.Significant inverse relations were observed for birth weight and maternal levels of Pb, Cd, and Cu; birth length and maternal levels of Cd and Cu; head circumference and maternal levels of Pb and gestational age and maternal levels of Cu, As, and Cd.The population characteristics across regions were similar in general, but significant regional differences were found for smoking, alcohol consumption during pregnancy, and parity.A total of 35.8% of the participants were current smokers in their early pregnancy—we observed a decline compared to previous Greenlandic birth cohorts like the Disko Bay Birth Cohort (60%), INUENDO (56%), and IVAAQ (45%) ,34. HoweAlthough the smoking rate seems to have declined in some regions compared to previous reports, the high smoking rate is a major public health challenge in Greenland because of its high prevalence and related morbidity and mortality from a number of diseases. Lung cancer is the most common cancer in Greenland, amounting to 34% of cancer deaths during 2000–2014 .Smoking is a well-known source of heavy metals, affects growth and development of the fetus, and increases the risk of low birth weight and preterm birth and, thus, health risk in childhood and later in life ,53. Collp < 0.001) but not across the regions. Cotinine is a proportional marker for recent tobacco exposure and can support the smoking questionnaire that may be subject to reporting and/or recall bias [Significant differences in current smoking frequency were observed across the regions, being the highest in East (72.2%), followed by the South (40.9%), then the North (40.6%), then the West region (33.7%), and Disko Bay (32.2%). There was a significant difference in plasma cotinine level between smokers and nonsmokers  may mitigate the negative effects of some heavy metals in chronically exposed populations . FurtherNutrients and antioxidants such as Se and the n3/n6 ratio found in seafood are thought to be capable of attenuating the adverse effects of some environmental pollutants . FurtherA Canadian birth cohort study found that estimated Ca intake may be associated with lower maternal Cd, Pb, Mn, and Hg, as well as cord blood Pb . In suppSeveral metals correlated with lifestyle factors. Age was positively correlated with Pb, Se, and Fe but negatively with Cd and Ca . Cd and The fatty acids n-3/n-6 ratio correlated significantly positively with plasma-Se and whole blood selenium, respectively. This suggests that the traditional marine diet is an important source of this antioxidant. By contrast, the levels of Hg and Pb were also positively correlated with the n-3/n-6 ratio, suggesting the traditional marine diet was an important source of these heavy metals as well—a classic example of the so-called “Arctic dilemma”, describing the benefits and disadvantages of traditional food within the Arctic regions ,32,86.Metal-to-metal correlation analysis showed positive correlation between heavy metals such as Hg, Pb, As, and Cd, suggesting that the contamination from metals in the blood of the women may originate from the same exposure source . Cd may When stratified by region, these correlations showed some similarities and differences, suggesting different sources of exposure within the regions .No statistically significant differences were found for the birth outcome characteristics across regions, but a tendency for lower birth weight and shorter length was observed in the East. This might be explained by the higher frequency of smokers during pregnancy in the East . In the For the total study population, we found that Pb, Cd, and Cu levels were negatively related to birth outcomes. Moreover, the β estimates indicated that an increased level of Cu increases the risk of earlier delivery c. FurtheWhen stratified by gender, these associations showed clear differences in metal blood levels . For femGender differences were also reported for exposure to other environmental contaminants; e.g., the lipophilic POPs . The heap = 0.040) of Cd and low birth weight showed a higher risk of low birth weight upon exposure to Cd. Similar findings are previously described in the literature [The OR of 1.441   b, suggesAlthough weakly, the OR for preterm birth was positively associated with Cu c. This aThe strengths of the present study are the relatively large population compared to previous studies of the Arctic populations. Our results are the first to provide all included population data from the ACCEPT study. The relatively large number of measured metals of this study, compared to the typical analyses in the available literature, provides new insights into heavy metal effects on essential metals, e.g., Fe in the Greenlandic Inuit.This study has some limitations: Reference ranges of whole blood metal levels are nonexistent for Arctic populations. The reference population for normal ranges included in this study was non-Arctic, nonpregnant Nordic populations both male and female of various ages. No suitable whole blood references for Mg and Ca were found.Five newborns died within the first 24 hours; we reran the statistical analyses upon eliminating these five, and the statistically significant data given were not changed.Several non-expected estimates with APGAR5 were found, suggesting that the score improved with higher concentrations of toxic heavy metals, e.g., Cd and Cu, whereas increase in Cr lowered the APGAR5 scores. The effects of heavy metal exposure on the APGAR score is sparsely investigated in the literature, and the conclusions from the few studies that describe the matter differ on population, material, and statistical power and, thus, cannot be generalized to the present study ,93,94. OIn a quality control of the ACCEPT analyses, the number of samples eligible for analysis by ICP-MS was investigated. Some analyses of the metals did not exceed the detection limit and, thus, may influence the precision of the present study. Furthermore, 201 samples were not analyzed for Mg and Ca from 2013–2015 as well as 17 samples for Cu .Adjustments for POPs were not conducted in this study but should be considered for future studies. Adverse health effects associated with POPs in pregnant Inuit women, the fetus, and newborn are found in several studies ,99,100. When divided into five regions, the study population was relatively small. Consequently, some regions  had below 10% of the total study population included because of the relatively low proportion of residents in these regions, as reported in similar studies, and thus, the statistical power is low ,28,33,34Multiple hypothesis tests with an alpha error set to 0.05 were performed. In the present study, we measured 13 metals in maternal blood, analyzed, and estimated their association with birth outcomes. The ‘multiple testing problem’ should be addressed and chance findings cannot thus be ruled out ,102.The Greenlandic Inuit are exposed to high levels of heavy metals through a traditional diet. Previous ACCEPT studies reported a traditional food intake of 12–18% ,34, a deIt cannot be ruled out that socioeconomic status and food insecurity are factors for the consumption of heavy metal or POP-contaminated food items . In a poThe Arctic is an area of transition, both culturally with regards to lifestyle but also with respect to climate change and pollution. We believe this study elucidates important environmental issues to consider when assessing the human health of the Arctic.Our results may provide local governments and other stakeholders with information to base their decisions on regarding contaminants and public health. Elucidating the heavy metal effects on the Inuit population and their environment is essential for a complete health risk assessment and management of public health. Hence, continuous monitoring of changes in climate and culture is vital to interpret and understand the complex and synergistic effects between climate change, contaminants, and human health to reduce adverse health effects.This cross-sectional ACCEPT study investigated the association between blood metal concentration in Greenlandic pregnant Inuit women and their birth outcomes. High smoking frequency was observed, especially in the East region. For the East region, a tendency for lower birth weight and lower birth length were found compared to the other regions in Greenland. Maternal blood levels of Cd, Cr, and Ni were found to be higher than reported clinical references for nonpregnant, non-Inuit populations . Cd and