The key regulators of inflammation underlying ventilator‐induced lung injury (VILI) remain poorly defined. Long noncoding RNAs (lncRNAs) have been implicated in the inflammatory response of many diseases; however, their roles in VILI remain unclear. We, therefore, performed transcriptome profiling of lncRNA and messenger RNA (mRNA) using RNA sequencing in lungs collected from mice model of VILI and control groups. Gene expression was analyzed through RNA sequencing and quantitative reverse transctiption polymerase chain reaction. A comprehensive bioinformatics analysis was used to characterize the expression profiles and relevant biological functions and for multiple comparisons among the controls and the injury models at different time points. Finally, lncRNA‐mRNA coexpression networks were constructed and dysregulated lncRNAs were analyzed functionally. The mRNA transcript profiling, coexpression network analysis, and functional analysis of altered lncRNAs indicated enrichment in the regulation of immune system/inflammation processes, response to stress, and inflammatory pathways. We identified the lncRNA Gm43181 might be related to lung damage and neutrophil activation via chemokine receptor chemokine (C‐X‐C) receptor 2. In summary, our study provides an identification of aberrant lncRNA alterations involved in inflammation upon VILI, and lncRNA‐mediated regulatory patterns may contribute to VILI inflammation. We performed transcriptome profiling of long noncoding RNA (lncRNA) and messenger RNA using RNA sequencing in lungs collected from mice model of the ventilator‐induced lung injury (VILI) and control groups. Our study provides an identification of aberrant lncRNA alterations involved in inflammation upon VILI, and lncRNA‐mediated regulatory patterns may contribute to VILI inflammation. We aimed to screen the dysregulated lncRNAs in the lung during early and relatively late time intervals of lung inflammation of VILI to provide new insight into the lncRNA‐mediated regulatory network of inflammation progression.22.1n = 8 per group). The VILI mouse model was established using MV with a high tidal volume (20 ml/kg) for 4 hours as reported.2O, FiO2 = 0.21. Anesthesia was maintained by administering the mixture of ketamine and xylazine; muscle relaxation was implemented and maintained with pancuronium (2 mg·kg−1·h−1). The control group comprised of intubated and nonventilated mice. A heating pad was used to maintain normothermia at 37°C throughout MV. Mice were allowed to recover and were exsanguinated under anesthesia at 0, 3, 6, 24 hours following 4 hours MV or control procedure. We cut the carotid artery and collected blood for the arterial blood gas analysis  at the indicated time points. All animal procedures were approved by the Animal Ethics Committee of the China‐Japan Friendship Hospital (no. 13007). Experiments were performed in accordance with the National Guidelines of Laboratory Animal Care principles.Male C57BL/6 mice at 6 to 8 weeks  maintained under a standard environment were randomly divided into five groups  was collected.2.3Mouse lungs were minced to single cell suspensions and filtered through 70‐μm cell strainers  as previously described.2.4+CD48−) in lungs were purified by staining with anti‐mouse Gr‐1‐PE and CD48‐APC antibody (BD Biosciences) from VILI 6 hours, VILI 0 hours, and control groups using fluorescence‐activated cell sorter (FACS) Aria II flow cytometer (BD Biosciences). The purity of the neutrophils was more than 95%.For functional analysis, neutrophils  under the accession number GSE120080.Total RNA was extracted from the lung samples using TRIzol  according to the manufacturer's instructions. RNA purity, concentration, and integrity were determined using a NanoPhotometer spectrophotometer , Qubit RNA Assay Kit in a Qubit 2.0 Fluorometer , and an RNA Nano 6000 Assay Kit of the Bioanalyzer 2100 system , respectively. Whole transcriptome libraries and deep sequencing were performed by Novogene Bioinformatics Technology Cooperation . Briefly, a total of 3 μg RNA per sample was used as input material. Sequencing libraries were generated using rRNA‐depleted RNA by following manufacturer's instructions for the NEBNext Ultra Directional RNA Library Prep Kit for Illumina . The Agilent Bioanalyzer 2100 system was used to evaluate the purity and quantity of the products. RNA‐Seq was performed on an Illumina HiSeq. 2500 platform and 125‐bp paired‐end reads were generated. The RNA‐seq data set was deposited in Gene Expression Omnibus . The mapped reads of each sample were assembled by both Scripture 2.8P < 0.05 were determined as being differentially expressed.Cuffdiff  provided fragments per kilobase of exon per million fragments (FPKM) calculations of both lncRNAs and coding genes in each sample.2.9P < 0.05 were considered significantly enriched.Gene Ontology (GO) annotations of differentially expressed genes were performed by the GOseq R package and the corrected 2.10The differentially expressed genes were mapped to the STRING database  to construct a protein‐protein interactions (PPI) network and were visualized by Cytoscape software .2.11cis and trans. We searched for potential cis mRNAs within 100 kb upstream and downstream of each lncRNA. The coexpressed mRNAs of lncRNAs with the Pearson correlation coefficients over 0.95 or under −0.95, and beyond 100 kb in genomic distance from the lncRNA or located on different chromosomes were defined as the trans‐regulated genes. The coexpression network was constructed based on the screening of lncRNAs‐mRNAs gene pairs  using Cytoscape software. The dysregulated lncRNAs were annotated by GO term and pathway analysis.The target genes of lncRNAs were predicted based on functional annotations of the associated mRNAs in 2.122−ΔΔCt method.Total RNA was extracted from lung samples or neutrophils using TRIzol reagent (Invitrogen), and a high‐capacity RNA‐to‐cDNA Kit (Invitrogen) was used to synthesize the complementary DNA using manufacturer's instructions. The quantitative real‐time polymerase chain reaction (qRT‐PCR) for the expression of selected lncRNAs and mRNAs was performed in triplicate with SYBR Green Master Mix (Invitrogen). lncRNA and mRNAs expression was quantified relative to glyceraldehyde 3‐phosphate dehydrogenase expression as fold change using the 2.13P < 0.05.Statistical analysis was performed using GraphPad Prism 7 software . Kolmogorov‐Smirnov test was used to test the normality of the data. Data analysis were performed using one‐way analysis of variance (ANOVA) or Kruskal‐Wallis ANOVA on ranks with the Bonferroni test to estimate the parameters for multiple comparisons. The correlations were assessed using the Pearson correlation test. Data are reported as mean ± standard deviation (SD) for normally distributed data or as median (interquartile range). For all comparisons, statistical significance was defined as 33.1Blood gas assessments demonstrated hypoventilation in the control group, which are mostly due to ventilation without the animal ventilator Table . The micThe quantification of BALF protein was also found to peak at VILI 6 hours post‐MV Figure C. Furthe3.2To identify novel molecular features of VILI, high‐throughput RNA‐Seq was carried out in a mouse model of VILI. We extracted and sequenced the total lung RNA from three VILI 0 hours mice (mice killed immediately after MV), three VILI 6 hours mice , and three control mice, during early and relatively late time intervals of lung inflammation. Low‐quality reads and rRNA were depleted and the total clean reads were uniquely mapped to the genome (Table S1).P < 0.05. Overall, 1976 mRNA transcripts in VILI 0 hours vs control, 2061 mRNAs in VILI 6 hours vs control, and 1219 mRNAs in VILI 6 hours vs VILI 0 hours, were found to be differentially expressed . A heat map of the differentially expressed mRNAs is displayed in Figure We generated volcano plots to visualize the differential expression profiles of genes with the statistical significance threshold set at Importantly, many lncRNAs were found to be dysregulated. We identified 82 differentially expressed lncRNAs in VILI 0 hours vs control, 58 lncRNAs in VILI 6 hours vs control, and 32 lncRNAs in VILI 6 hours vs VILI 0 hours , and molecular function (MF) of differentially expressed transcripts. For the differentially expressed mRNAs between VILI 0 hours and the control, the most significantly upregulated and downregulated GO terms included the following BP terms: response to stress, immune system process, intracellular signal transduction, and regulation of the cellular metabolic process. The dysregulated mRNAs were associated with the adherens junction (CC), while MF terms included cytokine binding and kinase activator activity . In VILI 6 hours vs control, the significantly overrepresented terms are depicted in Figure S1C and S1D. For BP analysis, the most‐enriched terms included response to stress, response to cytokine stimulus, immune system process, and cellular metabolic process; the most‐enriched CC terms included adherens junction and anchoring junction, and overrepresented MF terms included cytokine receptor activity. Comparing VILI 6 vs VILI 0 hours, results of the GO annotations collectively implicated response to stress, intracellular signal transduction, and metabolic process (BP); adherens junction, anchoring junction, cell‐cell adherens junction, and cell junction (CC); and cytokine receptor binding (MF) .We next considered these differentially expressed genes for KEGG pathway analysis, and the top‐20 pathways are summarized. In VILI 0 hours vs control, the forkhead box O (FoxO) signaling pathway, adherens junction, nuclear factor‐κB (NF‐κB) signaling pathway, and the tumor necrosis factor (TNF) signaling pathway were the most enriched Figure A and 4B.Figure 4Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on mRNAs. A,B, Top‐20 of the upregulated and downregulated KEGG pathways in VILI 0 hours vs control. C,D, The predominant top‐20 upregulated and downregulated signaling pathways enriched in VILI 6 hours vs control. E,F, The increased and decreased pathways of top‐20 between VILI 6 and VILI 0 hours are exhibited, respectively. mRNA, messenger RNA; VILI, ventilator‐induced lung injury3.4The altered genes in the VILI 0 hours group overlapped with genes in the VILI 6 hours group when compared with the control group. We, therefore, explored the common mRNAs obtained from these two comparisons to better determine the pathophysiological features of VILI. As indicated, we observed 677 commonly dysregulated mRNAs of the 1976 VILI 0 hours and 2061 VILI 6 hours compared with the control group, indicating their potential implications in VILI Figure A‐C. Furt3.5PPI networks were constructed to analyze protein interactions between the dysregulated protein‐coding genes. The PPI network consisted of 787 nodes and 2059 edges in VILI 0 hours vs control Figure A and 8393.6trans and in cis, contributing to their possible regulatory mechanisms. We consequently explored the target genes of the differentially expressed lncRNAs identified in this study. To identify potential target genes, we set a threshold of colocation as 100 kb upstream and 100 kb downstream of each lncRNA. Some mRNAs were found that could be potentially affected by the modified lncRNAs in cis, but there were very few significant enriched GO terms detected.Importantly, lncRNAs play a role in regulating mRNA expression in trans‐regulated mRNAs for the altered lncRNAs were predicted. lncRNA‐mRNA pairs were built to facilitate their internal relationship. This coexpression network encompassed 81 lncRNA nodes, 835 mRNA nodes, and 2636 edges in VILI 0 hours vs control , and 1637 edges linking 55 lncRNA nodes, 655 mRNA nodes in the network of VILI 6 hours vs control . The lncRNA‐mRNA coexpression networks could help better integrate the coexpressed mRNAs with the regulatory functions of lncRNAs.Next, the Next, the dysregulated lncRNAs were analyzed functionally. Based on the GO analysis of the coexpressed genes, a variety of biological terms correlated with the lncRNAs in VILI 0 hours vs control  and VILI 6 hours vs control , including response to stress, inflammatory response, cellular response to cytokine stimulus, intracellular signal transduction, and immune system process (BP); extracellular space (CC); and cytokine activity and chemokine activity (MF). Simultaneously, the altered lncRNAs were enriched by pathway analysis, and the most‐enriched pathways ranked according to their enrichment scores are represented in Figure 3.7Notably, comparison of lncRNAs profiles from VILI 0 and VILI 6 hours uncovered 25 shared lncRNAs when compared with the control Figure A‐C. We, Figure 8P < 0.05 represents a significant difference. CXCR2, chemokine receptor chemokine (C‐X‐C) receptor 2; lncRNA, long noncoding RNA; qRT‐PCR, quantitative real‐time polymerase chain reaction; VILI, ventilator‐induced lung injuryFunction predictions of the lncRNA Gm43181. A, Coexpression networks of the shared lncRNAs and mRNAs with fold change greater than two in both comparisons of VILI 0 hours vs control and VILI 6 hours vs control. The mRNAs are shown with green circles, lncRNAs are shown with red diamonds, and the lines denote the correlational relationship. The size represents the node degree. B, The top‐10 common lncRNAs with fold change greater than two. C,D, The coexpressed mRNAs with lncRNA Gm43181 in VILI 0 hours vs control and VILI 6 hours vs control, respectively. E,F, Gene Ontology (GO) annotations of lncRNA Gm43181 and the coexpressed mRNAs in VILI 0 hours vs control, and VILI 6 hours vs control. G, The correlation analysis between lncRNA Gm43181 expression and the lung injury score determined through qRT‐PCR. The correlation analysis between lncRNA Gm43181 and CXCR2 expression levels in lung samples determined using RNA‐Seq (H) and qRT‐PCR (I), respectively. J, Expression levels of lncRNA Gm43181 and CXCR2 in neutrophils quantified using qRT‐PCR. K, A scatterplot of lncRNA Gm43181 and CXCR2 expression levels in neutrophils determined by qRT‐PCR. trans‐regulated target chemokine receptor chemokine (C‐X‐C) receptor 2 (CXCR2) determined by RNA‐Seq data    , which was not only overexpressed but also had a relatively high node degree in the subnetwork. We, therefore, established a coexpression subnetwork between lncRNA Gm43181 and the coexpressed genes . Despite these differences, the list of differentially expressed lncRNAs in our study along with the data from Xu et al lead to the conclusion that a subset of these lncRNAs might have regulatory functions in the progression of VILI inflammation.Our present results identified the transcriptome profiles including mRNAs and lncRNAs using RNA‐Seq, which was a useful method for detecting novel genes and transcripts that may not have been identified using a microarray technique. Unlike previous microarray analyses concentrating on protein‐coding genes,In our analysis, we focus on a lncRNA named Gm43181 that was overexpressed with the highest fold change in the common lncRNAs. Moreover, CXCR2 was identified as one of the coexpressed genes of this lncRNA with high expression levels both in VILI 0 hours and VILI 6 hours groups. Interestingly, the GO term annotations linked the lncRNA Gm43181 to the bioprocess of neutrophil activation. CXCR2 is a chemokine receptor belonging to CXCR chemokine family that is activated by chemokine (C‐X‐C motif) ligand 1 and 2/3 (CXCL1 and CXCL2/3), and it is expressed on neutrophils, where its activation could lead to neutrophil recruitment.Despite the significance of our findings, our study also had some limitations. On one hand, our sample size was relatively small with only three mice in each group. Further, being largely a descriptive study, we could not ascertain whether the identified lncRNAs were causing the inflammation in VILI. Moreover, as the lncRNAs' functions were determined based on bioinformatics predictions, the RNA‐Seq data should be confirmed with direct evidence from subsequent in vivo experiments. The short lifespan of neutrophils restricted the study of the role of lncRNA Gm43181. Nonetheless, these observations provide a basis for the transcriptome signatures in the lung inflammation during VILI progression.Collectively, our study might set the stage for better understanding the pathogenesis and precise manipulation of VILI as it relates to lncRNAs, and further studies are needed to help delineate the mechanism of lncRNAs in regulating inflammation during VILI.The authors declare that there are no conflict of interests.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.Supplementary informationClick here for additional data file.


Prior studies have shown that there is an inverse association between birth weight and stroke in adulthood; however, whether such association is causal remains yet known and those studies cannot distinguish between the direct fetal effect and the indirect maternal effect. The aim of the study is to untangle such relationship using novel statistical genetic approaches.n = 264,498 for birth weight and 446,696 for stroke). We further validated the MR results with extensive sensitivity analyses.We first utilized linkage disequilibrium score regression (LDSC) and Genetic analysis incorporating Pleiotropy and Annotation (GPA) to estimate the overall genetic correlation between birth weight and stroke. Then, with a set of valid birth-weight instruments which had adjusted fetal and maternal effects, we performed a two-sample Mendelian randomization (MR) to evaluate its causal effect on stroke based summary statistics from large scale genome-wide association study (GWAS) . The maternal ORs of birth weight on three subtypes of stroke including cardioembolic stroke (CES), large artery stroke (LAS) and small vessel stroke (SVS) were 1.16 (95% CI 0.93–1.43), 1.50 (95% CI 1.14–1.96) and 1.47 (95% CI 1.15–1.87), respectively. In contrast, no fetal causal associations were found between birth weight and stroke or the subtypes. Those results were robust against extensive sensitivity analyses, with Egger regression ruling out the possibility of pleiotropy and multivariable MR excluding the likelihood of confounding or mediation effects of other risk factors of stroke.This study provides empirically supportive evidence on the fetal developmental origins of stroke and its subtypes. However, further investigation is warranted to understand the pathophysiological role of low birth weight in developing stroke. The brain can be directly modulated due to the sparing adaptation in restricted fetal growth  or intracerebral hemorrhage (ICH) with a neurological deficit of sudden onset , and it dulthood  – a hypodulthood . This hyl growth . Such reHowever, it remains unclear whether the observed association between birth weight and stroke in prior studies uncover a truly causal association, or only a spurious correlation due to confounding emerging during the prenatal/postnatal life  or due tIn the past few years, several large scale genome-wide association studies (GWASs) have been performed and have greatly advanced our understanding of the genetic architecture for birth weight  and stron = ∼300,000 for birth weight   and Mendh weight  and ∼447h weight ].1  and offspring  birth weights after controlling covariates . To distinguish the fetal and maternal genetic components of genotypes on birth weight, an efficient structural equation model (SEM) was implemented up to 264,498 individuals who reported their own birth weight and 179,360 individuals who reported their offspring birth weight (p < 5.00E-8) reported in We initially obtained summary association statistics for birth weight from the Early Growth Genetics (EGG) Consortium1 . The assh weight , generath weight . The sep2 (We next yielded summary association statistics for any ischaemic stroke (AIS) at the MEGASTROKE Consortium2 . In addiz statistics of two traits against the LD scores that are computed from the 1000 Genomes project phase III   or π11/(π01+π11) are estimated, representing the proportion of SNPs associated with one phenotype that are also associated with the other and indicating the extent of common biological pathways to which the two phenotypes may share  , which cay share . As compay share  based onay share : indep-pWe first aligned to birth weight-increasing allele with that of stroke. Then the causal effect of birth weight on stroke was estimated with inverse-variance weighted (IVW) MR methods  based on3. Details of power calculation and the multivariable MR analysis are shown in To assess whether MR model assumptions were violated in our analysis and to assess the robustness of the results, we performed several complementary and sensitivity analyses for the causal effect estimation of birth weight on stroke: (1) weighted median-based method to estimate the causal effect when some of the instrument variables of birth weight are likely invalid ; (2) leaBrion et al. (2013)rg = −0.176, p = 1.10E-3), in contrast to the positive but non-significant fetal genetic correlation . However, due to the small sample size that leads to negative estimates of heritability for the stroke subtypes, we cannot acquire a valid estimate for maternal or fetal genetic correlations between birth weight and the subtypes of stroke  and the proportion of SNPs that are associated with birth weight are also associated with stroke  or π11/(π01 + π11)) are consistently larger for the maternal specific effect of birth weight compared with those for the fetal specific effect of birth weight , the random-effects IVW method was thus utilized. We find the maternal causal effect of birth weight on stroke is 1.13 (p = 0.040), indicating a 13% (95% CI 0–27%) increase of stroke risk for every 488 g decrease in birth weight (p = 0.182), 1.49 , and 1.46 , respectively, again implying lower birth weight is associated with an increased risk of stroke subtypes. However, no statistically significant fetal causal associations are identified between birth weight and stroke or the three subtypes . The LOO analysis shows no single instrument substantially influences the estimated maternal casual effect. For example, after removing rs45446698 , the OR is estimated to be 1.11 ; after removing rs139429176 (located within gene P2RX7/HNF1A and had the largest effect size on stroke with beta = −0.155), the OR is estimated to be 1.12 . Like the LOO analysis, MR-PRESSO also demonstrates no maternal instrumental outliers at the significance level of 0.05. The intercept of the MR-Egger regression is 5.08E-4 , indicating horizontal pleiotropy unlikely biases the estimated maternal causal effect. Nevertheless, we screened the EBI website4 and removed 50 instruments that were associated with other relevant traits and diseases .We next performed multiple sensitivity analyses to evaluate the robustness of this inversely maternal association between birth weight and stroke above , S3. Thediseases , and stip = 1.88E-3) although the duration of gestation is a major determinant of birth weight and is highly correlated with birth weight  cases is the same as that given in Finally, we calculated the statistical power for our MR analysis and supposed the true fetal or maternal causal OR of lower birth weight on stroke was 1.20 , the proportion of variance explained by instrumental variables was equal to 2% . In view of the increasing survival rate of fetus with low birth weight today, our result therefore has important implications on the early predictor of stroke in adulthood. In addition, the present analysis also further confers the significance to unmask the fetal and maternal contributions respectively to birth weight as an exposure (or outcome) in genetic studies.Our analysis provides new supportive evidence on the maternal molecular genetic overlap between birth weight and stroke, and further offers robust evidence showing lower birth weight, by maternal rather than fetal genome, is causally associated with stroke and its subtypes in later life. Furthermore, such effect is independently of many other possible risk factors of stroke. In contrast, our analysis does not support the fetal genetic correlation and the direct fetal causal effect of birth weight on stroke or its subtypes, further demonstrating the separate maternal influence. rg = −0.27 for T2D and −0.30 for T2D) (We now compare our results with those displayed in previous work . Our finfor T2D) . The caufor T2D) , a retrofor T2D) , a histofor T2D)  as well for T2D) . Howeverfor T2D) . In contfor T2D)  and thusOur study, at least in part, provides answers for several previous unsolved questions. First, our analysis showed the shared maternal genetic foundation between birth weight and stroke cannot fully explain the observed inverse association, partly resolving the question proposed in a priori hypothesis concerning sex differences in the effect of birth weight on stroke exists, it was shown that there may be gender specific causal effects of birth weight on stroke with the effect of lower birth weight on stroke slightly higher in females compared with in males (First, due to the small sample sizes for the subtypes of stroke and relying on summary association results, we cannot determine the fetal or maternal genetic correlation between birth weight and stroke subtypes. Investigations with much larger sample size for stroke subtypes are warranted. Second, like most other MR applications, we assumed a linear relationship between birth weight and stroke. It is certainly possible that there may be a non-linear relationship. However, as most of the individuals had their birth weights within in the normal range, the linearity assumption in our MR is likely reasonable . Third, in males . Howeverhttps://egg-consortium.org/; "https://strokegenetics.org/.Publicly available datasets were analyzed in this study. This data can be found here: PZ, ZT, SH, and JZ conceived the idea for the study. PZ and TW obtained the genetic data. PZ, XY, YG, and TW performed the data analyses. PZ, TW, XY, FG, CL, and SH interpreted the results of the data analyses. All the authors wrote the manuscript.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.


With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3 months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone.For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements. To find an effective treatment for COVID-19 several existing drugs have been assessed and approved for clinical trials through accelerated procedures worldwide . These dEvidence suggests that males are more severely affected by the ongoing pandemic irrespective of age  and therWe aimed to investigate the safety of COVID-19 drugs taken by fathers prior to conception to assess for adverse birth outcomes. A few recent studies have shown adverse effects of drugs, including chloroquine, on gametes –6, raisiThe Danish Birth Registry (MFR)  records The Danish National Patient Registry (DNPR)  providesThe Danish Birth Registry can be linked to the Danish National Prescription Registry (LMDB)  through Our two primary outcomes were odds of pre-term birth (birth at less than 37 weeks of gestation) and of having at least one major birth defect in offspring (as per EUROCAT Guide 1.4 ).mice (version 3.6.1) using predictive mean matching for the numeric variables and polytomous regression for the categorical variables. We performed logistic regression on each of the medications separately, adjusting for birth year, the age of both parents, smoking status of the mother, and education and income of the father. In addition, the regressions of major birth defects were adjusted for gestation age. We also performed logistic regression with all medications as independent variables simultaneously. The statistical significance threshold for all tests is set at two-side 0.05 level.All analyses were carried out at the secure server of Statistics Denmark in R (version 3.6.1) . ConceptThe average age of fathers was 32.3 years, while mothers were on average 29.7 years old. Of the mothers, 84.1% did not smoke at conception, 2.6% quit during pregnancy and 13.3% smoked during pregnancy. Of the fathers, 79.9% had at least upper secondary education, of which 11.8% had at least a masters degree.Medications taken by a large number of fathers (> 100 fathers) were chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone, and prednisone.The overall birth defect rate was 3.2%, while 7.4% of all births were preterm.None of the investigated drugs taken by men up to three months before conception was statistically associated with pre-term birth or congenital malformations at 5% significant level Table . IncludiFor hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). For azithromycin and naproxen, large numbers of offspring were exposed > 1800), and we found no association with adverse birth outcomes with 95% confidence interval of odds ratios given in Table 800, and Using a nationwide cross-sectional study with data over 20 years in Denmark, we found no statistical evidence of association between the COVID-19 drugs under study, taken by men up to three months before conception, and pre-term birth or major birth defects in offspring. Evidence of drugs safety before paternal conception is limited. Our findings suggest that azithromycin and naproxen can be considered safe with respect to pre-term birth and major birth defects. For chloroquine, losartan and dexamethasone, our study was more constrained in size, while for hydroxychloroquine and prednisone we would be able only to find very large effects. While reassuring, given the limitations of the current report, continued surveillance of parental exposure to experimental COVID-19 treatments remains prudent.The prescription registry does not include prescription diagnosis. It was therefore not possible to separate the effect of the medication from the effect of the disease for which the medication was given. This study will therefore tend to overestimate, but not underestimate any effect. This might (partly) explain odds ratios larger than one for chloroquine and losartan. In addition, medications that can be obtained over the counter (e.g. naproxen) may be misclassified biasing results toward the null.


In-utero progress of fetal development is normally assessed through manual measurements taken from ultrasound images, requiring relatively expensive equipment and well-trained personnel. Such monitoring is therefore unavailable in low- and middle-income countries (LMICs), where most of the perinatal mortality and morbidity exists. The work presented here attempts to identify a proxy for IUGR, which is a significant contributor to perinatal death in LMICs, by determining gestational age (GA) from data derived from simple-to-use, low-cost one-dimensional Doppler ultrasound (1D-DUS) and blood pressure devices. A total of 114 paired 1D-DUS recordings and maternal blood pressure recordings were selected, based on previously described signal quality measures. The average length of 1D-DUS recording was 10.43 ± 1.41 min. The min/median/max systolic and diastolic maternal blood pressures were 79/102/121 and 50.5/63.5/78.5 mmHg, respectively. GA was estimated using features derived from the 1D-DUS and maternal blood pressure using a support vector regression (SVR) approach and GA based on the last menstrual period as a reference target. A total of 50 trials of 5-fold cross-validation were performed for feature selection. The final SVR model was retrained on the training data and then tested on a held-out set comprising 28 normal weight and 25 low birth weight (LBW) newborns. The mean absolute GA error with respect to the last menstrual period was found to be 0.72 and 1.01 months for the normal and LBW newborns, respectively. The mean error in the GA estimate was shown to be negatively correlated with the birth weight. Thus, if the estimated GA is lower than the (remembered) GA calculated from last menstruation, then this could be interpreted as a potential sign of IUGR associated with LBW, and referral and intervention may be necessary. The assessment system may, therefore, have an immediate impact if coupled with suitable intervention, such as nutritional supplementation. However, a prospective clinical trial is required to show the efficacy of such a metric in the detection of IUGR and the impact of the intervention. Estimation of fetal gestational age (GA) provides important information throughout pregnancy, such as delivery scheduling, growth disorder detection, and preterm newborns management , in which a 28-days menstrual cycle is assumed. Although previous studies have criticized LMP due to the inconsistency in the menstrual cycle length  in centimeters should correspond to the number of weeks of gestation ±2 cm. When Lsfh < N − 2, where N is the number of weeks since the last menstrual period, the fetus is suspected to be IUGR , which has a prevalence varying between 9 and 11% in LMICs  indexes and maternal hemodynamics derived from one-dimensional Doppler ultrasound (1D-DUS) and maternal blood pressure, respectively. Data were acquired during routine perinatal check-up visits by traditional birth attendants using a low-cost Doppler transducer and a self-inflating blood pressure device  . In the trial, traditional birth attendants were trained to use a mobile mHealth system to record perinatal information during approximately monthly visits during the second and third trimesters. More details on the design and implementation of the mobile mHealth system, and the training of the traditional birth attendants can be found in Stroux et al.  and registered on x et al.  and Martx et al. , 2018. AThe perinatal care program included both prenatal and post-partum visits. In the prenatal visits, traditional birth attendants recorded GA in months by counting the number of whole months since the last menstrual period. The GA was recorded in months instead of weeks to reduce measurement errors since usually patients attended in this project forgot the specific date of their last menstrual period, and very few received an early obstetrical ultrasound for more accurate dating  or small-for-gestational-age. However, in LMICs, around 60% of LBW newborns are small-for-gestational-age  was estimated auto-correlation (AC)-based method using an open source code written in Matlab , previously introduced in .The baseline was determined using an algorithm proposed by Andersson , which iFollowing the work of Andersson , accelers and at least one sample was 15 BPM or more above the baseline. Similarly, a deceleration was defined where the FHR remained below the baseline FHR for at least 15 s, and at least one sample was 15 BPM below the baseline. More details of the algorithm can be found in Andersson . Since the RR-interval sequence is necessary to estimate fHRV metrics, the FHR series was converted into a interbeat sequence as:S(i) is the FHR at the i − th second.where The maternal systolic blood pressure (SBP), diastolic blood pressure (DBP), and the maternal heart rate (MHR) measurements from the blood pressure device were used as features. Since the SBP, DBP, and MHR were taken for both patient's arms, these values were averaged. The averaged SBP, DBP, MHR were used to generate seven additional hemodynamics formulas, which have been reported to vary throughout pregnancy  was applied in order to test whether there were statistically significant differences between the training and test sets for all the values of the 37 features .The training set comprised 104 newborns, from which 95 had one visit, eight had two visits, and one had three visits, giving a total of 114 visits. For the test set there were a total of 25 normal birth weight newborns, for which 22 had one visit and three had two visits, giving a total of 28 visits. The training and validation procedure was performed using a 5-fold cross validation with 50 trials (repetitions). At each trial, the patients were randomly assigned to different folds, ensuring that visit features corresponding to the same patient were in the same folder. Thus, at each iteration, ~20% of the training data was used for validation (held-out fold). By using 50 trials the variability of the models for estimating the GA could be measured, and confidence intervals could be estimated.Since folds were class unbalanced , at each iteration of the 5-fold cross-validation, the number of visits per GA was balanced on the training folds before constructing a model. To that end, we used the Adaptive Synthetic Sampling (ADASYN) method, which has been reported to overcome the class imbalance problem in support vector machine models , and Gradient Boosting Tree (GBT). At each iteration of the cross-validation, the training folds were used to select the most relevant features for the SVR and GBT models. For the SVR, features were selected using the maximum relevance and minimum redundancy (mRMR) algorithm  and the margin of tolerance (ϵ) were defined as: C ∈ {2−3, 2−1, ..., 28} and ϵ ∈ {2−10, 2−9, ..., 2−5}. The Gaussian radial basis function parameter (γ) was analytically estimated as reported in Caputo et al. }; where S is the total number of visits of the training folds.GBT. The grid search for the learning rate was defined as {0.1, 0.25, 0.5, 1} and the number of trees was defined as {100, 150, 200, ..., 500, 550}. The number of maximum splits (tree height) was defined as {1, 2, ..., The 50 trial 5-fold cross-validation resulted in 50 median absolute error (MAE) vectors, and 250 selected feature vectors. From the 50 MAE vectors, the median, interquantile range, and the lower and upper 95% confidence interval for the median were determined. The median MAEs were compared to select which regression model  to use in the test stage.From the 250 selected feature vectors, the top twenty most relevant features were identified. To that end, the features were ranked at each feature vectors, and the mean rank was determined by averaging the ranking of each feature over the 250 feature vectors. This simple aggregation technique was used as it has shown to be effective to combine different features sets in the medical application field  was calculated to discriminate between LBW and NBW newborns. The AUROC was calculated using the difference between LMP-based GA and the estimated GA. As we hypothesized that LBW newborns are likely to result in underestimations (LMP-based GA > estimated GA), a newborn was considered LBW if the difference between the LMP and SVR estimates of the GA was greater than the thresholds used in the AUROC analysis.For newborns with more than one visit, NBW = 1.85−0.60wNBW. For the low weight newborns, the fitted line was δLBW = 0.82−0.23wLBW. For all the newborns, the fitted line was δ = 1.12−0.35w.The AUROC using the estimation difference between NBW and LBW resulted in 0.55. However, as in The results presented in this work indicate that it is possible to provide a proxy for screening fetal growth retardation in a resource-constrained setting by using the difference between GA estimated by LMP and the GA estimated from features extracted from an inexpensive Doppler transducer and a blood pressure device.This proxy fetal assessment relies on the GA estimation approach introduced in this work, which using a pregnancy conversion factor of d et al.  and Marzd et al.  of 2.7–5d et al. , our word et al. .The higher GA estimation errors for the LBW newborns indicate that this type of patient has different patterns in the 1D-DUS and maternal blood pressure features than normal birth weight newborns of the same GA. We note that this difference is related to the birth weight as the AUROC between very low birth weight (<2.3 kg) and normal birth weight indicated acceptable discrimination. Therefore, assuming that LBW is a consequence of IUGR . Presumably, premature and IUGR newborns behave similarly, and there is overlap between these two groups , and use a more accurate dating method, such as expert-driven ultrasound imaging.Future research should also evaluate the efficacy of the proxy presented here on confirmed diagnoses of IUGR. This evaluation would allow a full end-to-end assessment of how 1D-DUS and maternal blood pressure can contribute to detection fetal growth abnormalities.Moreover, future research should ensure the collection of multiple visits during the course of pregnancy , so that a longitudinal analysis can be performed that incorporates the individual dynamics into the model.This work introduced a proxy to detect possible cases of IUGR for constrained-resource environments in which ultrasound imaging is not available, and current low-cost methods are prone to error. The potential IUGR cases are detected by comparing GA based on the last menstrual period with estimates obtained 1D-DUS and maternal blood pressure recordings collected with inexpensive devices, usable with little training. The method is valuable to endow non-medically trained operators with an objective metric to identify cases that need to be referred to further medical assistance. The assessment system may, therefore, have an immediate impact if coupled with suitable intervention, such as nutritional supplementation. However, a prospective clinical trial is required to show the efficacy of such metrics and intervention.The datasets generated for this study will not be made publicly available. The data was collected in Guatemala rural community, including recordings of a vulnerable indigenous population. We need to obtain permission from the ethical committee before making the dataset publicly available.ClinicalTrials.gov (identifier NCT02348840). The patients/participants provided their written informed consent to participate in this study.The studies involving human participants were reviewed and approved by the Institutional Review Boards of Emory University, the Wuqu' Kawoq|Maya Health Alliance, and Agnes Scott College  and registered on GC, RH-C, and PR conceived of the study and acquired the funding. RH-C and PR coordinated the data collection process in the Guatemalan rural community. CV, FM, and GC contributed to the development of techniques and analysis tools. The data was analyzed by CV, FM, and GC. CV implemented the methods presented here for estimating gestational age. CV, FM, PR, and GC contributed to the writing of the manuscript. All authors reviewed and approved the final manuscript.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.


Coordinate transformation (CT) theory has shown great potentials in manipulating both time-varying and static fields for different physics ranging from electromagnetism and acoustics to electrostatic and thermal science. Nevertheless, as inhomogeneous and anisotropic materials are required to be realized for the implementation of CT-based devices, the applicability of this method is restricted due to difficulties in the fabrication process. In this paper, based on transformation electrostatic (TE) methodology, the design principle of an arbitrary shape dc electric concentrator is established which yields the enhancement of static electric fields in a predefined region with only one homogeneous conductivity, named as dc null medium (DNM). It is shown that one constant DNM is sufficient for localizing steady electric current in any arbitrary shape region, which in turn obviates the tedious mathematical calculations that conventional methods suffer from. In other words, the same DNM can be used for different concentrators regardless of their cross-section geometries, which makes the presented approach suitable for scenarios where reconfigurability is of utmost importance. Several numerical simulations are performed in order to demonstrate the capability of the proposed dc electric concentrator in localizing steady electric fields into the desired region. Moreover, by utilizing the analogy between electrically conducting materials and resistor networks, the attained DNM is realized with low-cost resistors and then exploited for fabricating a square shape dc electric concentrator on a printed circuit board (PCB). It is demonstrated that the measurement results agree well with the theoretical predictions and numerical simulations, which corroborate the effectiveness of the propounded method. The presented idea of this paper could find applications in scenarios where highly confined electric fields/currents are of critical importance such as electronic skin devices and electrical impedance tomography. Although static fields play a significant role in several applications such as in electric impedance tomography (EIT)8, electrostatic spraying systems9, and photocopy machines, most of TO devices were designed and fabricated in time-varying EM fields. In 2007, Wood et al., exploited coordinate transformation in static potentials and cloaking for the static magnetic field was then propounded based on transformation electrostatic (TE) methodology11. Besides cloak, dc electric concentrators13, which are devices that can concentrate static fields in a given region while the external fields keep undisturbed has attracted a lot of attention due to its potential applications in scenarios where uniform enhanced current density is of critical importance including electronic skin (e-skin) devices14. Sensors play a crucial role in tactile sensing which is necessary to enable skin-like functionality14. In particular, these sensors can be used to evaluate human motion, and vital signs such as heart rate, respiration, and body temperature for health monitoring. However, for a sensor to function accurately, the electric current is of critical importance. That is, a local well enhanced electric current density plays a crucial role to avoid malfunctions in e-skin devices. This can be achieved by utilizing dc electric concentrators as they can localize steady electric field and current in the predefined region of interest. In addition to e-skin devices, the core idea of dc electric concentrators have potential applications in electrical impedance tomography (EIT), which are noninvasive type of medical imaging systems that are used to form a tomographic image of the human body8. As most of the EIT systems apply electric currents for their measurement, local enhanced current densities that do not distort the voltage equipotential lines of the background medium are of utmost importance. However, typical applied currents in EIT are relatively small and certainly below the threshold at which they would result in severe nerve stimulation. Therefore, the potential use of electric concentrators in EIT systems is for applying a well-enhanced current while the background external fields and voltage equipotential lines are not distorted. However, to date, all the proposed TE-based dc concentrators are limited to circular cross-section geometries, which in turn limit the applicability of the designed devices for more general cases where there is a prerequisite to focus static electric field in an arbitrary domain. Besides the geometry problem, the main drawback of TE-based concentrators is their inhomogeneous and anisotropic conductivities, which are of paramount difficulty for the fabrication process. In addition to the realization procedure, the obtained materials from TE methodology possess a high dependency on the applied transformation function. That is, if the mapping function is changed , the necessitating conductivities must be recalculated and redesigned. That is why an arbitrary shape dc electric concentrator has never been demonstrated experimentally in time-varying and static fields23.Controlling electromagnetic (EM) fields to render an object invisible has been a long-standing dream for many scientists over decades. The seminal work of Pendry et al, named as transformation optics (TO), which was based on the form invariant of Maxwell’s equations exhibit great potentials to manipulate EM wave propagation arbitrarily25. However, to the authors’ best knowledge, no systematic works for extending the concept of ONM/ANM into static fields have been performed. Therefore, following our previous theoretical works, in this paper, we will outline a new design principle to achieve arbitrary shape dc electric concentrators based on null transformation methodology, which leads to a new material that is named as dc null medium (DNM). It will be shown that the proposed DNM is independent of the concentrator geometries. That is, if the device shape is changed, one can still use the same DNM without the demand for recalculating a new material. Several numerical simulations are carried out to verify the validity of the proposed theoretical investigations. To authenticate the concept, with the aid of analogy between electrically conducting materials and resistor networks, which was reported previously by Yang et al.26, we have realized the DNM with low-cost resistors and exploited it to implement a square shape dc electric concentrator. To the authors’ best knowledge, it is the first time that an arbitrary shape dc electric concentrator is being realized with feasible material. It is observed that the experimental results exhibit good agreement with the theoretical predictions and numerical simulation results, which indicates the generality and effectiveness of the proposed designing method. We emphasize that in this work, our main concern is to point out the novel capability of DNM in manipulating electrostatic fields as well as demonstrating the electric field concentration in an arbitrary region. However, with the expeditious growth in technology and material science, it is expected that the presented idea of this work finds applications in scenarios where compactness is of critical importance such as non-destructive sensors and energy harvest devices.Recently, novel approaches for achieving arbitrary shape time-varying fields concentrators have been proposed that are based on new materials which named as optic null medium (ONM) and acoustic null medium (ANM)The goal is to construct an electrostatic device that is competent in concentrating steady electric current density in an arbitrary region without influencing the potential distributions of the outside of the concentrator. Since in e-skin devices, the more the electric currents are enhanced, the more device sensitivity increases, which gives rise to better and accurate functionality, dc electric concentrator could have potential applications in e-skins as it is shown schematically in Fig. c and s represent the compressed  and the electric field distribution have been obtained and analyzed with COMSOL MULTIPHYSICS solver. Afterwards, a square shape dc electric concentrator has been realized with the aid of low-cost resistor network. To examine the performance of the implemented dc electric concentrator, we have used Advanced Design System (ADS) solver. In particular, in the ADS solver, we have established a resistor network that its topology is shown in Fig.


Neuroglial  cyst is a rare congenital tumor of the central nervous system usually found in childhood. It can be isolated or associated with other brain malformations. Magnetic resonance imaging is the technique of choice for making the diagnosis. We report the case of a 10-year-old child who presented with epileptic seizures revealing a neuroglial cyst and dysgenesis of the corpus callosum. The neuroglial cyst, also called the glioependymal cyst, is a benign cystic tumor rarely described in the literature. It is seen mainly in children but also in adults.The mode of revelation is variable depending on its location in the central nervous system. These lesions are sometimes associated with an abnormality in the development of the corpus callosum.A 10-year-old child, with no particular history, presented for a year with intermittent chronic headaches without visual disturbances with the notion of three spaced generalized tonic-clonic seizures requiring the prescription of an antiepileptic treatment. The neurological examination was normal.Cerebral magnetic resonance imaging showed an interhemispheric cystic formation, with smooth and well-defined contours, with fluid content in low signal on T1-weighted image signal  and highThis cystic formation compresses the interventricular foramen responsible for ventriculomegaly of the left lateral ventricle Figures . On the The cyst was treated by endoscopic fenestration with good clinical outcomes.Neuroglial cyst is a rare brain tumor also called the glioependymal cyst. It can develop intraparenchymal, in the ventricles, in the subarachnoid space, and rarely in the spinal cord . This tyMacroscopically, this tumor is surrounded by a thin translucent membrane with a fluid content having a composition very close to that of cerebrospinal fluid (CSF). Its wall is composed of an internal layer made of ependymal cells with secretory activity explaining the progressive growth of the cyst .The clinical symptoms depend on the size and location of the tumor. It can manifest as seizures, motor deficit, chronic headache, psychomotor delay, or macrocephaly in infants . In addiOn imaging, the typical appearance of a neuroglial cyst is that of a large periventricular or interhemispherical lesion with a density and signal identical to CSF on computed tomography and magnetic resonance imaging. In some cases, with the T2 sequence, the fluid content may have a higher signal than that of the CSF (indicating a fluid rich in proteins). The wall of the cyst does not enhance after injection of gadolinium .The diagnosis can be made during the prenatal period by morphological ultrasound  4], all, all4], Histopathological analysis of the tumor is not necessary to make the diagnosis because the MRI radiological semiology of the lesion and its association with the abnormalities of the corpus callosum are sufficient to make this diagnosis .Arachnoid cyst typically presents as an unilocular extra-axial cystic lesion which has the same signal as CSF, its outlines are sharp and smooth, and it can displace or deform adjacent brain or adjacent calvarium . The arachnoid cyst does not enhance Epidermoid cysts appear as lobulated CFS-like mass that fills and expand CSF spaces and exerts a gradual mass effect, insinuating between structures and encasing adjacent nerves and vessels. Calcification is present in 10%–25% of cases, and a thin enhancement around the periphery may sometimes be seen .Ependymal cysts are rare benign neuroepithelial cysts lined by ependymal cells, typically nonenhancing periventricular lesion Porencephalic cyst is a rare condition of CSF accumulation within the brain parenchyma that communicates directly with the ventricular system. It appears as a CFS-like lesion lined by white matter, without mass effect on the adjacent parenchyma or enhancement with contrast  8]8]The differential diagnoses of neuroglial cysts are arachnoid cyst, epidermoid cyst, ependymal cyst, and porencephalic cyst :ArachnoiFor symptomatic patients, treatment is surgical. There are many methods used: a cysto-peritoneal or cysto-ventricular bypass, partial or total resection . Neuroen


Here, we describe the case of an 80-year-old woman who presented with cranial dermoid cyst causing orbital disfigurement. The cyst was treated successfully with ethanol sclerotherapy and has shown no growth for 1 year. Dermoid cysts are benign subcutaneous tumors, which may be present at birth and develop gradually over time. Most periorbital dermoid cysts are easily detected and the patient presents for surgery for cosmetic reasons in childhood or adolescence. We describe herein an extremely rare case of dermoid cyst in an 80-year-old woman, causing orbital compression and treated by sclerotherapy.An 80-year-old woman was referred to our department with a 50-year history of a slow-growing, painless cyst in the right lateral orbital region. The cyst had been aspirated at regular intervals by previous physicians, but always re-expanded shortly thereafter. Examination revealed a single, well-defined, elastic hard mass fixed to the orbit, with normal-appearing surrounding skin . MechaniMagnetic resonance imaging (MRI) demonstrated a round mass measuring 45 × 43 × 45 mm superolateral to the right orbit, showing low intensity on T1-weighted imaging and high intensity on T2-weighted imaging with no enhancement by gadolinium . ComputeOn the basis of these findings, we diagnosed the lesion as dermoid cyst, and proposed surgical removal of the cyst and boney reconstruction with hydroxyapatite paste. However, the patient firmly declined such an operation and wished to continue periodic aspiration.Aspiration was performed 3 times within the 3 years after her first visit. The aspirated fluid was dark-brown and serous in nature, without debris or contamination, and fluid volumes were 34, 30, and 37 mL, respectively . The fluThe cyst was punctured with an 18-G needle under local anesthesia and fluid was completely aspirated. After the cyst cavity was washed with 10 mL of saline, 10 mL of 1% lidocaine containing 1:100,000 epinephrine was instilled and left in place for 2–3 min. Next, the lidocaine was aspirated completely, and 10 mL of absolute ethanol was instilled and left in place for 1 min. The ethanol was then completely aspirated, and the cavity was washed again with 10 mL of saline.Three months after the first sclerotherapy, the cyst had decreased in size and 15 mL of clear, yellow fluid was aspirated. Second and third sclerotherapies were performed in the same manner, at intervals of 3 months.Six months after the last sclerotherapy, the cyst had shrunk in size to 26 × 15 × 35 mm . HoweverDermoid cysts are benign, soft-tissue tumors that develop from entrapment of surface ectoderm along the lines of embryonic fusion and have a capacity to grow. Eighty-four percent of dermoid cysts reportedly occur in the head or neck , with thIn the present case, the origin was assumed to be the frontosphenoidal suture because of the full-thickness bony erosion at that site. Located deep to the temporalis muscle, the patient might have been unaware of the cyst until her 30 s. Through the 80 years of enlargement, not only full-thickness bone erosion, but orbital disfigurement was noted.To the best of our knowledge, only two reports have described sclerotherapy for dermoid cyst ,7. GoldeEthanol sclerotherapy is widely performed for cystic masses. Baker’s cyst, branchial cleft cyst, thyroglossal duct cyst , and serEven though all 7 cases (including the present case) were treated successfully, various limitations of sclerotherapy for dermoid cyst should be recognized. One is that the material within the dermoid cyst must be aspiratible through the needle or catheter. The contents of dermoid cysts, comprising substances such as keratin, sebum, and fat, is often pultaceous and difficult to aspirate. Although the exact ratio of dermoid cysts for which sclerotherapy can be applied has remained unknown, Pushker et al.  stated tAs shown in our histological examinations, despite cyst reduction, the dermal component of the cyst wall still existed after sclerotherapy. This implies a risk of cyst re-expansion, representing another limitation of sclerotherapy. Furthermore, most dermoid cysts are detected early enough to be extirpated safely with low invasiveness during the first decade of life. These limitations and benefit of surgical extirpation seem to be why only very small numbers of case reports have described sclerotherapy for dermoid cysts.Sclerotherapy may not eradicate dermoid cysts, but has potential to decrease cyst size. This treatment can thus be adopted for patients who cannot undergo operation for whatever reason, or as preoperative therapy to reduce the tumor volume.While long-term follow-up is warranted, this case suggests the feasibility of sclerotherapy for dermoid cyst, but underlines the importance of early diagnosis and cyst removal without delay.Long-term development of cranial dermoid cyst can cause bone erosion and facial disfigurement. Although sclerotherapy was effective in this case, surgical extirpation during the early stage is currently preferred to prevent sequelae.


Colonization mostly occurred between weeks 2 and 6 and displayed a high diversity requiring categorization. Analyses of deviance considering all relevant confounders revealed statistical significance solely for upper airway colonization with bacteria with pathogenic potential and moderate/severe BPD (p = 0.0043) while no link could be established to the Gram response or the gastrointestinal tract. Our data highlight that specific colonization of the upper airway poses a risk to the immature lung. These data are not surprising taking into account the tremendous impact of microbial axes on health and disease across ages. We suggest that studies on upper airway colonization using predefined categories represent a feasible approach to investigate the impact on the pulmonary outcome in ventilated and non-ventilated preterm infants.Bronchopulmonary dysplasia (BPD) is a multifactorial disease mainly provoked by pre- and postnatal infections, mechanical ventilation, and oxygen toxicity. In severely affected premature infants requiring mechanical ventilation, association of bacterial colonization of the lung and BPD was recently disclosed. To analyze the impact of bacterial colonization of the upper airway and gastrointestinal tract on moderate/severe BPD, we retrospectively analyzed nasopharyngeal and anal swabs taken weekly during the first 6 weeks of life at a single center in  Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants leading to life-long restrictions in lung function even in infants who do not fulfill the clinical criteria of BPD of dependency on mechanical ventilation or oxygen at a corrected age of 36 weeks of gestation ,2. BPD eFor a long time, the amniotic cavity has been considered a sterile environment and any bacterial penetration an agitator of inflammation in the fetus and preterm birth. In fact, physiologically the fetus is exposed to a changing microbiome in utero with reduced bacterial richness and diversity and increased bacterial biomass over time ,12,13,14The clinical measures of breast milk supply and reduction of antibiotic exposure are well known to have a positive impact on the gut microbiome development and to reduce the incidence of NEC. Breast milk supply increases microbial diversity and enhances immunologic properties while antibiotic therapy is a major cause of microbial dysbiosis. In the context of lung development and lung injury, meta-analyses of breast milk supply display a relevant reduction in the incidence of BPD ,22. FurtThe high throughput analysis of microbiomes by molecular barcoding is currently restricted to research projects and not standard of clinical routine. Due to these limitations, we used a classical culture-based approach to assess bacterial diversity of the upper airway and gastrointestinal tract on a weekly basis to identify preterm infants with a birth weight <1000 g and gestational age ≤32 + 0 weeks at special risk for BPD. The inclusion criteria were selected based on the particularly high vulnerability for BPD in this population of infants with lungs in the saccular stage of lung development ,31. The n = 146 inborn patients were eligible. n = 37 preterm infants were excluded due to death before 36 weeks of gestation (n = 28), severe congenital malformations of the heart, brain, gut, or urogenital tract (n = 7) or transfer to another center before 36 weeks of gestation (n = 2). Furthermore, all infants with severe gastrointestinal complications (n = 7) of necrotizing enterocolitis or focal intestinal perforation were excluded due to the high impact of prolonged ventilation periods and inflammatory episodes on the pulmonary outcome. Overall, n = 102 infants were included in the initial analyses. Two infants had to be excluded from further analyses due to missing information on more specific bacterial colonization.Preterm infants with a birth weight <1000 g and gestational age ≤32 + 0 weeks were analyzed within a retrospective cohort study at our tertiary perinatal center  between January 2014 and June 2017. Overall, The study was conducted following the rules of the Declaration of Helsinki of 1975, revised in 2013. The retrospective analysis was approved by the ethics committee of the Justus-Liebig-University Gießen (Az 97/14).According to the recommendations by the German Commission for Hospital Hygiene and Infectious Disease Prevention at the Robert Koch Institute (RKI) in 2013, bacterial colonization of the upper airway, and the gastrointestinal tract of all preterm infants were screened by nasopharyngeal and anal swabs, respectively, during routine clinical care at birth and weekly thereafter. Nasopharyngeal and anal swabs  were taken during daily routine by trained ward staff. Samples were promptly transferred to the microbiological laboratory. Swabs were routinely cultured on blood, chocolate, and MacConkey agar plates . Plates were incubated at 37° with 5% carbon dioxide. Cultures were analyzed after 16–22 h and again after 48 h of incubation. Bacteria were analyzed by MALDI-TOF technology . For our analysis, bacterial strains were categorized according to Gram staining. Additionally, twelve species were classified as potential pathogens based on published literature and datasets from the German National Reference Center for the Surveillance of Nosocomial Infections  for Microsoft Windows . The following baseline maternal and infant parameters as well as disease stages were recorded: gestational age, birth weight, gender, birth as singleton or multiple, antenatal steroid application, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and retinopathy of prematurity. Antenatal steroids were recorded as days before delivery or categorized as no completed course including four cases with no antenatal steroid application before birth (<24 h), delivery within 24 h and 7 days after the last application and provision of antenatal steroids >7 days before birth. Small for gestational age (SGA) status was defined as all three parameters of birth weight, length, and head circumference below the 10th percentile according to the percentiles from the German perinatal registry . Severit as CPAP ,38. Prov as CPAP . Furthern = 102) [p < 0.05.To dissect the impact of specific patterns of microbial colonization and BPD, we focused our analysis on preterm infants with a birth weight <1000 g and below 32 weeks of gestation that have the highest risks for relevant limitations in lung function (n = 102) . Baselinn = 67) and moderate/severe (n = 35) BPD.In our cohort, median gestational age was 26 + 3 (range 23 + 4 to 30 + 5) and median birth weight 795 g (range 320 to 995 g). As expected, most infants of the total cohort fulfilled any severity stage of BPD (82.4%) and about one third (34.3%) the criterion of moderate/severe BPD  infants from the total cohort never required invasive mechanical ventilation excluding tracheal aspirates as applicable microbiological source. Instead, swabs from the upper airway were analyzed. We suggest that the upper respiratory tract is at least partially shaped by the bacterial milieu of the lung via mucociliary clearance. The gut–lung axis has been described as another important contributor to pulmonary health and disease in pediatric and adult patients [Consideration of all bacterial strains for both localizations revealed low frequencies at birth but rapid colonization with frequencies approximating 80% in week 2 excluding a scientific approach A,B. TherAfter the first six weeks of life, most infants were colonized A–D. Due Similar to the published literature, infants in the moderate/severe BPD group were more immature, had a lower birth weight and displayed a higher frequency of male gender and small for gestational age status. Antenatal steroid exposure was not equally distributed between the groups . To compp = 0.0043, p = 0.0038). p = 0.0164) and a risk reduction from week 3 on (p = 0.0204) pointing towards an overall unfavorable impact of early occurrence.To elaborate a significant impact of each bacterial category on the severity of BPD, the confounder model was compared to the model with the respective germ category  included using analysis of deviance. Within all studied variations of upper airway and gut bacterial colonization, only the colonization of the upper respiratory tract with strains with pathogenic potential prevailed statistically significant  zero, leading to the equivalent models and same test results as described above (data not shown).p-values for the other covariates analyzed . As more than 90% of all children included in the study were fed with breast milk, there is too little variation in the covariate to see an effect in our analyses.As the provision of breast milk has a tremendous well recognized impact on the microbiota structures in the preterm infant, the impact of the addition of this covariate was analyzed separately. Extension of the confounder model for the provision of breast milk from the infants´ mother did not relevantly impact the In summary, the colonization with bacterial strains with pathogenic potential during the first six weeks of life showed a statistically significant, yet unstructured, effect on the risk of moderate/severe BPD in a study population at high risk for functional limitations in lung function.The microbiome has a tremendous impact on long-term health. Alterations of microbiome structures in the preterm infant are coming more and more into the focus of research. While the beneficial effects of a healthy bacterial composition are well-known for the gut, the impact of the pulmonary microbiome on the pulmonary outcome still awaits a detailed investigation ,15,16. OE. coli and Klebsiella species did not reduce the risk for BPD. On the other side, different bacterial strains display different inflammatory and immune system shaping properties. Gram-negative strains like E. coli and Klebsiella species are well known for their extensive activation of pro-inflammatory immune response during infection, but many other strains are also capable to do so including Ureaplasma species, which is frequently found in the newborn [It is well accepted that colonization of the lower respiratory tract with specific bacterial strains poses the preterm infant at increased risk for BPD ,15,16,17 newborn . TherefoDisease initiation and progression are broadly ascribed to the specific action of microbial axes especially from the gut including the gut–lung and gut–brain axes in many pediatric and adult diseases . Here, oThe complex signaling network in the lung comprises a tremendous overlap between inflammatory responses and lung growth promoting pathways. Abrogation of individual pathways revealed that the balanced equilibrium is a prerogative to preserve physiologic lung growth with NFκB taking center stage. Therefore, modulation of the inflammatory cytokine response and thereby NFκB in either direction puts the lung at risk for increased lung damage. BPD has been recently demonstrated to evolve from either inhibition or overstimulation of the pathways of classical pro-inflammatory cytokine response including TNF-α and IL-6 ,51,52,53E. coli, Enterobacterales, and Klebsiella species in contrast to other studies where one dominating germ was identified as the causative factor [n = 100/102), the comprehensive risk adjustment for all relevant baseline confounders and the constantly small statistical p-values for the major outcome (p < 0.01). The validity of our data is increased by continuous protocols with regard to antibiotic therapy and ventilation strategies, not adding a further confounder to the study. Furthermore, BPD rates did not change significantly over time. Our data await confirmation in independent and larger cohorts before delineation of future prospective studies with the aim to modify bacterial colonization in the lung as is already well-established for the gut [Limitations of our study comprise the restriction to an association and the single center approach in a restricted number of cases. On the other hand, the distribution of bacterial strains within our cohort is diverse and within the expected range with dominance of strains like Coagulase-negative staphylococci, e factor ,33,34,35 the gut .In summary, our data add evidence to another dimension of the multifactorial origins of BPD: the impact of bacterial colonization on the immature lung. It is not surprising that clinical routine measures like the provision of breast milk and the reduction of antibiotic exposure are able to reduce the burden of BPD considering the impact on microbiota structures ,24,25,56


Cytokines are soluble factors that play vital roles in systemic function due to their ability to initiate and mediate cell-to-cell communication. Another important mechanism of intercellular communication that has gained significant attention in the past 10 years is the release of extracellular vesicles (EVs). EVs are released by all cells during normal physiology, in states of resting and activation, as well as during disease. Accumulating evidence indicates that cytokines may be packaged into EVs, and the packaging of cytokines into EVs, along with their ultimate secretion, may also be regulated by cytokines. Importantly, the repertoire of biomolecules packaged into EVs is shaped by the biological state of the cell  and the EV biogenesis pathway involved, thus providing mechanisms by which EV packaging and secretion may be modulated. Given the critical role of cytokines in driving acute and chronic inflammatory and autoimmune diseases, as well as their role in establishing the tumor immune microenvironment, in this review, we will focus on these disease settings and summarize recent progress and mechanisms by which cytokines may be packaged within and modulated by EVs, as a therapeutic option for regulating innate and adaptive immunity. Intercellular communication is an essential biological feature that is mediated through 1) cell-cell contact, 2) soluble factors  and (3) the more recently discovered extracellular vesicles (EVs) that carry cytosolic, nuclear and cell-surface proteins, lipids, nucleotides, microRNA, and metabolites  revealed that 9 cytokines—Interleukin 6 (IL6), IL8, IL13, IL16, IP10, MCP1, MIP1α, MIP1β, and MIP3α–were more often found in soluble form. Conversely, 11 cytokines—IL2, IL4, IL12p70, IL17, IL21, IL22, IL33, IFNγ, ITAC, TGFβ, and TNFα–were found in greater levels in EVs. An interesting aspect of this study that is relevant to disease was the finding that cytokines packaged into EVs are not detected by standard cytokine assays, such as ELISA or other multiplexed immunoassays, since they are hidden from antibody detection by the EV membrane. Thus, methods to determine cytokine production from EVs will be important for our understanding of their role(s) in health and disease  released by EVs into the microenvironment. For instance, Rana et al. reported that poly(I:C) could induce the release of both soluble and EV-secreted IL36γ from keratinocytes . The autin vivo microenvironments tended to release more cytokines in soluble form than were found in T cell or monocyte suspensions or in plasma. Indeed, a greater proportion of EV-associated cytokines were found from the cells and plasma. However, upon stimulation of cells, they found that the number and pattern of cytokines packaged in EVs changed depending on the stimulus, suggesting that the packaging of cytokines in EVs is not simply the property of a particular cytokine, but rather a tightly controlled biological process. For instance, stimulation of tonsillar explants with pokeweed mitogen resulted in a drastic change in the pattern of cytokine release with a shift toward more soluble secretion rather than EV-associated secretion. In contrast, human primary monocytes stimulated with either LPS or polyI:C resulted in more EVs being secreted with different patterns of cytokines associated with EVs; distinct patterns of soluble vs. EV-associated cytokine secretion were also detected between the two stimuli  induces the release of granule-associated mediators such as histamine, metabolites, and cytokines –26. Kand+ and CD4+ T cells, respectively . ResultAlthough EVs are released in resting cells, stimulating events, such as cell activation, leads to increased intracellular calcium levels, resulting in cellular membrane remodeling and enhanced EV secretion . Pharmacregs for the treatment of autoimmune disease (As our current understanding of the mechanisms that differentially regulate the packaging of cytokines in EVs from resting and activated cells expands, this knowledge may be also used to preferentially drive the packaging of distinct groups of cytokines into EVs for therapeutic use. For instance, DCs can be stimulated to secrete EVs that induce the differentiation of immunosuppressive T disease –116. The disease , 118. La disease ].a priori knowledge of the biogenesis pathway resulting in EV cargo loading and secretion. Alternatively, EVs may be targeted to specific cells via binding of EV surface cytokines to cells that express the specific cytokine receptor (in vitro and in vivo (in vivo (EV encapsulation of cytokines may facilitate their delivery and targeting to distant cells . Recent receptor . Sialic-receptor –129. Thureceptor . Here, w in vivo . The sec(in vivo .While technological advances in isolating, characterizing, and now engineering EVs to deliver therapeutic payloads and immune modulators are being made [recently reviewed in ], it is BB and CS planned and prepared the manuscript.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.


This study aimed to illustrate and account for immortal time bias in pregnancy observational investigations, using the relationship between late use of antibiotics and risk of preterm birth as an example. We conducted a population-based cohort study including 549,082 deliveries between 2007 and 2017 in Lombardy, Italy. We evaluated the risk of preterm births, low birth weight, small for gestational age, and low Apgar score associated with antibiotic dispensing during the third trimester of pregnancy. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of the outcomes, considering the use of antibiotics as time-fixed (with biased classification of exposure person-time) and time-varying (with proper classification of exposure person-time) exposure. There were 23,638 (4.3%) premature deliveries. There was no association between time-fixed exposure to antibiotics and preterm delivery  but an increased risk of preterm birth when time-varying exposure to antibiotics was considered . The same trend was found for low birth weight and low Apgar score. Immortal time bias is a common and sneaky trap in observational studies involving exposure in late pregnancy. This bias could be easily avoided with suitable design and analysis. Preterm delivery is estimated to affect 10.6% of all live births around the world, equating to about 15 million births each year ,4,5,6,7,Nevertheless, no association between third trimester exposure to macrolide antibiotics and the risk of preterm delivery or related outcomes  was reported by a large observational study , raisingImagine following a cohort of women from the start of the third trimester of pregnancy (week 27) until delivery and comparing the prevalence of preterm births  between those who use antibiotics and those who do not use them during this period . AccordiThe origin and implications of immortal time bias in the field of drug safety in pregnancy are reviewed in this paper. Data for a large cohort of women using antibiotics during the third trimester of pregnancy and their risk of adverse events , and low Apgar score) are used to illustrate how immortal time bias can be avoided using appropriate statistical tools and techniques.The data used for this study were retrieved from the healthcare use databases of Lombardy, a region of Italy that accounts for about 16%  of the national population. All Italian citizens have equal access to healthcare services as part of the National Health Service (NHS); in Lombardy, this is associated with an automated system of databases to collect a variety of information on residents who receive NHS assistance (NHS beneficiaries), diagnoses, procedures performed on inpatients in public or private hospitals , outpatient drugs dispensed in community pharmacies  codes), and specialist visits and diagnostic examinations reimbursable by the NHS. In addition, a database reporting the Certificates of Delivery Assistance (CeDAP) provides detailed information on the mother’s socioeconomic traits, as well as medical information on the pregnancy, childbirth, and child presentation at delivery. As a unique identification code is systematically used for all databases, record linkage provides a large and unselected birth cohort and enables the establishment of relevant traits of and care pathways for mothers and newborns. To preserve privacy, each identification code was automatically deidentified, the inverse process being allowed only to the Regional Health Authority on request from judicial authorities. Diagnostic, therapeutic, and procedural codes used for the current study are given in the The criteria for selecting the study cohort almost completely overlapped with those previously reported by our group ,22,23. BInformation on dispensed antibiotics was obtained from the outpatient drug-dispensing database. Accordingly, women were first classified as those for whom, starting from 27 weeks of gestation until delivery, antibiotics were dispensed at least once, and those who never received them.Users and non-users were compared with respect to sociodemographic features . Reproductive history any time before the last menstrual period (LMP) was also considered. Finally, medical morbidities , concomitant medications  and drugs for acid-related disorders), and use of healthcare services  from 1 year before the LMP until the end of the second trimester of pregnancy were considered. Sources were CeDAP, hospital discharge, and outpatient drug-dispensing databases as appropriate. Users and non-users were compared for each of these covariates using the standardized difference.The principal outcome of interest was preterm birth (less than 37 gestation weeks ). SecondCox proportional hazard models were fitted to estimate the hazard ratio (HR) with its 95% CI for a given outcome associated with the “fixed-time” exposure to antibiotics. Three types of models were fitted. In the first, unadjusted HRs were estimated from models including only exposure to antibiotics as a covariate. In the second, partially adjusted HRs were estimated from models also including reproductive history, medical morbidities, concomitant medications, and use of healthcare services as covariates. In the third, fully adjusted HRs were estimated from models also including sociodemographic traits. However, as sociodemographic data were missing for some women, only complete records were considered for this analysis .The basic design ignored the actual timing of antibiotic use; thus, person-weeks from the beginning of the third trimester of pregnancy until delivery entirely contributed to exposure classification . This prA model-based approach was subsequently used. As outcome rates were expected to vary considerably during the considered period, rather than fitting a Poisson regression model , Cox proportional hazard models were fitted to estimate the HR and 95% CI of a given outcome associated with the “time-varying” exposure to antibiotics. In other words, at each event time , prevalence of antibiotic use by mother with less than 37 weeks of gestation was compared with prevalence of antibiotic use during the same time frame by mothers who had not yet given birth at that time . UnadjusAll analyses were performed using the Statistical Analysis System software . Statistical significance was set at 0.05, and p-values were two-sided.Finally, as shown in Immortal time bias is one of the sneakiest traps affecting observational studies in the field of pregnancy investigations. We showed how this bias might act by investigating the relationship between use of antibiotics during the third trimester of pregnancy and preterm birth and its correlates linked with neonatal health (birth weight and Apgar score). The rationale for using this example is as follows. Readers may verify that when investigating the association of interest by means of a conventional cohort study, i.e., by comparing users and non-users of antibiotics with respect to the occurrence of preterm birth, an unexpected independence or even protective action of antibiotics is systematically observed. This is quite strange, as use of antibiotics is thought of as a proxy for the onset of some kind of infection, which is one of the major causes of preterm births ,6,7,8,9.The limitations of our study include those that conventionally affect observational investigations based on healthcare use databases. It should, however, be emphasized that because antibiotic dispensing was assumed to be a surrogate for the occurrence of infection, the usual concern about the uncertainty of patients’ compliance with the drug treatment regimen should not be of interest in our example. Rather, the delay between infection onset and the date of drug dispensing could lead to misclassification of a certain number of person-weeks as currently exposed to infection, thus diluting the point estimates toward the null. In addition, antibiotics dispensed over the counter might also drag our estimates toward the null. Finally, as for all observational studies, there is some concern regarding residual confounding due to unmeasured factors. Some lifestyle factors, as well as drugs dispensed during hospitalization and the over the counter medications, are not recorded in our database, resulting in a loss of information. Therefore, because some drugs associated with reduced preterm delivery rates  were not taken into account in our study, further investigations are needed to better understand the causal model of preterm birth and its correlates.In conclusion, we described immortal time bias as a common and sneaky trap affecting observational studies investigating exposure during pregnancy and preterm births, or other outcomes associated with preterm birth. We showed that this bias could be easily avoided with suitable design and analysis.


In 2016, March of Dimes (MOD) launched its Prematurity Collaborative to engage a broad cross section of national experts to address persistent and widening racial disparities in preterm birth by achieving equity and demonstrated improvements in preterm birth. African-American and Native American women continue to have disproportionate rates of preterm birth and maternal death. As part of the Collaborative, MOD created the Health Equity Workgroup whose task was the creation of a scientific consensus statement articulating core values and a call to action to achieve equity in preterm birth utilizing health equity and social determinants of health frameworks.Health Equity Workgroup members engaged in-person and virtually to discuss key determinant contributors and resolutions for disparate maternal and birth outcomes. Workgroup members then drafted the Birth Equity Consensus Statement that contained value statements and a call to action. The birth equity consensus statement was presented at professional conferences to seek broader support. This article highlights the background and context towards arriving at the core values and call to action, which are the two major components of the consensus statement and presents the core values and call to action themselves.The result was the creation of a birth equity consensus statement that highlights risks and protections of social determinants based on the prevailing science, and identifies promising solutions for reducing preterm birth and eliminating racial disparities.The birth equity consensus statement provides a mandate, guiding the work of March of Dimes and the broader MCH community, for equity-based research, practice, and policy advocacy at local, state, and federal levels.This field report adds to the current knowledge base on racial and ethnic disparities in birth and maternal health outcomes. Research has documented the science behind eliminating health disparities. Scientists and practitioners should continue to explore in practice how the social determinants of birth and maternal health, which manifest historically and contemporarily, can be addressed. Building upon its past successes in eradicating polio, March of Dimes (MOD) shifted its focus in 2003 to prematurity, with the goal of decreasing the preterm birth rate by at least 15%. Between 2015 and 2017, the U.S. preterm birth rate increased from 9.6 to 9.8%. Preterm birth rates were 50% higher among non-Hispanic black/African-American women and 20% higher among American Indian/Alaska Native women compared to non-Hispanic white women  frameworks.Advance SDOH as the primary basis for disparities in maternal and birth outcomes;Articulate and advance core birth equity values to guide the work required to achieve the best possible maternal and birth outcomes for all mothers and babies;Create a call to action with equity-focused recommendations for work across and beyond the Collaborative, based upon the core values and the current science.The objectives for the Health Equity Workgroup were to:This document presents the work of the Health Equity Workgroup that resulted in a birth equity consensus statement on the key drivers of prematurity and maternal mortality disparities to prompt transformation and advancements in research, policy, and advocacy.The MOD Prematurity Collaborative Health Equity Workgroup is comprised of approximately 300 individuals who represent a cross-section of partners committed to maternal and child health. Members were invited or requested to join. Quarterly meetings were facilitated in-person and virtually and offered insight into best practices for reducing racial and ethnic disparities in birth outcomes. The initial effort of the Workgroup was to produce a set of guiding principles and glossary to achieve equity in preterm birth. Workgroup members discussed key determinant contributors and resolutions for disparate maternal and birth outcomes and convened to write the birth equity consensus statement to reinforce inquiry and action by the social sciences based on the equity and SDOH perspectives. Workgroup members then drafted the Birth Equity Consensus Statement that contained value statements and a call to action. The birth equity consensus statement was presented at professional conferences to seek broader support. This article specifically highlights the background and context towards arriving at the core values and call to action, which are the two major components of the consensus statement and presents the core values and call to action themselves.This work was conducted in accord with prevailing ethical principles and does not constitute human subjects research. The manuscript is not based upon clinical study or patient data.In the review of the literature we identified the following core areas: health care access, psychosocial conditions and economic inequality that were of interest to the Health Equity Workgroup participants, which led to generating a consensus agreement process of the Collaborative. The following sections provide support for the consensus statement components.Equity is a human right built upon the belief that all individuals are of equal worth and should be afforded respect, dignity, justice, and fairness. When applied to health, health equity means that all human beings must have every opportunity that is fair and just to achieve optimal health .We believe that ALL mothers and babies, regardless of race, ethnicity, culture, language and national origin; poverty and socioeconomic status; gender identity and sexual orientation; disability; and region and place  must have every opportunity for optimal maternal and birth outcomes.We embrace birth equity as a directive for confronting inaccessible and inadequate prenatal and maternal health care, while challenging the inequalities in the distribution of power, income, wealth and other related factors  that contribute to persistent, unfair conditions expectant mothers impacted by negative birth outcomes endure.We believe that undoing historical and contemporary patterns of racial and gender discrimination is imperative for disrupting implicit and explicit bias, miseducation and exclusionary customs and practices that can have dire health consequences for expectant mothers and babies that permeate systems of care; practice and treatment; education and research; public policies; communications; and access to funding and resources.We respect the authoritative knowledge and assets among affected women, families and communities and regard their intersectional perspectives as paramount for the conceptualization and conduct of equity-driven research and its translation into maternal, paternal and child health education, practices and policies that are just and fair.We believe that pursuit of explanations for racially disparate birth and maternal outcomes must employ social science disciplines and methods to best examine social and economic disadvantages as well as community and population assets for maternal mental and physical health.We believe that scientific examination of the biological, clinical, social and environmental contributors to prematurity and maternal mortality must be inclusive of an equity framework in order to accelerate and translate reproductive health research and medical breakthroughs into innovative and accessible health care practices and policies that are equitable and beneficial for ALL expectant mothers and their infants.We believe that the experience, expertise and leadership of researchers, practitioners and policymakers from historically underrepresented communities should be prioritized for birth equity solutions, including the provision of commensurate funding levels to advance equity for moms and babies.Health equity requires addressing equity not only in health care but in all human-made and modifiable determinants of health  of the lives and well-being of impacted women and children.Engaging in health systems reform, including re-educating providers to better serve high risk populations.Working to undo beliefs, perceptions and practices associated with racism and discrimination to ensure that every woman at risk receives the care and support they need.Empowering communities through inclusion, education, social activism, and advocacy with full participation in cross sector efforts to confront and change social policies that are detrimental to mothers, fathers, babies, families and communities, recognizing that positive discernible changes in SDOH are essential for birth equity.March of Dimes must exhibit the same collective will and dedicate needed resources that were instrumental for ending the polio epidemic to achieve birth equity. Following approaches to expand social determinant pathways for research, policy, and practice to promote health equity and thereby eliminating racial disparities in maternal and birth outcomes, we recommend:The birth equity consensus statement provides a mandate, guiding the work of March of Dimes and the broader MCH community, for equity-based research, practice, and policy advocacy at local, state and federal levels. March of Dimes’ focus on SDOH supports the ongoing quest for birth equity for all mothers and babies.