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Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = −0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs.

Several non-verbal cognitive and behavioral tests have been developed to assess learning deficits in humans with Down syndrome (DS). Here we used rodent touchscreen paradigms in adult male mice to investigate visual discrimination (VD) learning and inhibitory control in the Dp(16)1/Yey (C57BL/6J genetic background), Ts65Dn (mixed B6 X C3H genetic background) and Ts1Cje (C57BL/6J genetic background) mouse models of DS. Dp(16)1/Yey and Ts1Cje models did not exhibit motivation or learning deficits during early pre-training, however, Ts1Cje mice showed a significant learning delay after the introduction of the incorrect stimulus (late pre-training), suggesting prefrontal cortex defects in this model. Dp(16)1/Yey and Ts1Cje mice display learning deficits in VD but these deficits were more pronounced in the Dp(16)1/Yey model. Both models also exhibited compulsive behavior and abnormal cortical inhibitory control during Extinction compared to WT littermates. Finally, Ts65Dn mice outperformed WT littermates in pre-training stages by initiating a significantly higher number of trials due to their hyperactive behavior. Both Ts65Dn and WT littermates showed poor performance during late pre-training and were not tested in VD. These studies demonstrate significant learning deficits and compulsive behavior in the Ts1Cje and Dp(16)1/Yey mouse models of DS. They also demonstrate that the mouse genetic background (C57BL/6J vs. mixed B6 X C3H) and the absence of hyperactive behavior are key determinants of successful learning in touchscreen behavioral testing. These data will be used to select the mouse model that best mimics cognitive deficits in humans with DS and evaluate the effects of future therapeutic interventions.

Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive diagnostic procedures like amniocentesis for genetic disorders. Nonetheless, emergency care remains the only option for complications like preeclampsia and preterm birth, two of the most prevalent obstetrical syndromes. Advances in noninvasive prenatal testing expand the scope of precision medicine in obstetric care. In this review, we discuss advances, challenges, and possibilities toward the goal of providing proactive, personalized prenatal care. The highlighted advances focus mainly on cell-free nucleic acids; however, we also review research that uses signals from metabolomics, proteomics, intact cells, and the microbiome. We discuss ethical challenges in providing care. Finally, we look to future possibilities, including redefining disease taxonomy and moving from biomarker correlation to biological causation. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Prematurity remains a major cause of morbidity and mortality. Research to prevent preterm birth and improve treatments for preterm infants involves both intramural and extramural research, not just at the National Institute of Child Health and Human Development, but across many institutes and centers at the National Institutes of Health.

Neurodegenerative disorders are characterized by neuronal loss, usually in late life. But recently, abnormalities of proteins implicated in neurodegenerative disorders have been identified in disorders of childhood, raising the possibility that clues to susceptibility to and prevention of neurodegenerative disorders may be identifiable before symptoms of disease arise. This review leverages these new and evolving findings to test our hypothesis, first proposed in 2010, that proteins implicated in neurodegenerative disorders play important roles in brain development by examining evidence in the peer-reviewed literature published in the past five years for the relevance of these proteins in normal and disease-associated brain development.

Despite many successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome (DS), translation to humans has failed. This raises critical questions about the appropriateness of the Ts65Dn mouse as the “gold standard” for DS research given that it carries, in addition to Mmu16 orthologous genes, triplication of 50 Mmu17 non-orthologous genes that might contribute to the observed brain and behavioral phenotypes. We used the novel Ts66Yah mouse that carries both an extra mini chromosome and the identical segmental Mmu16 trisomy as Ts65Dn, but in which the Mmu17 non-orthologous region was removed using CRISPR/Cas9 technology. We demonstrate that the Ts65Dn exhibits a more severe phenotype throughout the lifespan compared to the Ts66Yah mouse. Several Mmu17 non-orthologous genes were uniquely overexpressed in Ts65Dn embryonic forebrain; this produced major differences in dysregulated genes and pathways. Despite these genome-wide differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in several commonly dysregulated disomic genes and pathways. During the neonatal period, delays in motor development, communication and olfactory spatial memory were observed in both Ts66Yah and Ts65Dn pups but were more pronounced in Ts65Dn. Adult Ts66Yah mice showed working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. Like the neonates, adult Ts66Yah mice exhibited fewer and milder behavioral deficits when compared to Ts65Dn mice. Our findings suggest that trisomy of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may be one major reason why preclinical trials that used this model have unsuccessfully translated to human therapies.

New fetal therapies offer important prospects for improving health. However, having to consider both the fetus and the pregnant woman makes the risk-benefit analysis of fetal therapy trials challenging. Regulatory guidance is limited, and proposed ethical frameworks are overly restrictive or permissive. We propose a new ethical framework for fetal therapy research. First, we argue that considering only biomedical benefits fails to capture all relevant interests. Thus, we endorse expanding the considered benefits to include evidence-based psychosocial effects of fetal therapies. Second, we reject the commonly proposed categorical risk and/or benefit thresholds for assessing fetal therapy research (e.g., only for life-threatening conditions). Instead, we propose that the individual risks for the pregnant woman and the fetus should be justified by the benefits for them and the study’s social value. Studies that meet this overall proportionality criterion but have mildly unfavorable risk-benefit ratios for pregnant women and/or fetuses may be acceptable.

ispartof: PRENATAL DIAGNOSIS vol:40 issue:13 pages:1627-1635 ispartof: location:England status: published

Objective To understand the evolution of the field of prenatal diagnosis over the past four decades. Method We analyzed the publications in the journal Prenatal Diagnosis from its inception in 1980 to 2019 using Medical Subject Headings (MeSH) to examine the major research topics and trends. The results were analyzed by 10-year intervals. Results Publications on prenatal cytogenetics, congenital anomalies and fetal imaging predominated during the first three decades, with a steady increase in molecular genetics over time. Publications on NIPT did not appear until the most recent decade and are likely under-counted because there was no MeSH term for NIPT until 2020. Conclusion The topics covered in Prenatal Diagnosis articles have evolved considerably over the past four decades and reflect a response to advances in technology and widespread incorporation of prenatal screening and diagnosis into standard obstetric care. The strengths of this analysis are its objective nature, its use of the standard MeSH terms used for coding, and application of a novel cluster analysis to visualize trends. The analysis also pointed out the fact that MeSH terms in this sub-specialty area are often inconsistent due to manually coding based on individual subject matter expertise.

OBJECTIVE: Fetal therapy trials pose complex ethical challenges because risks and benefits to both fetuses and pregnant persons must be considered. Existing regulatory guidance is limited and many proposed ethical frameworks have unnecessarily restrictive criteria that would block the development and implementation of important new fetal therapies. We aimed to develop a new ethical framework for assessing the risks and benefits of fetal therapy trials. METHODS: We reviewed existing regulatory and ethical guidance on fetal therapy trials. We used conceptual analysis to design a new ethical framework, which is grounded in general ethical principles for clinical research. RESULTS: We propose a new framework for assessing the risks and benefits of fetal therapy trials. We suggest that the potential benefits of a fetal therapy trial – for the fetus, the pregnant person, and society – should outweigh the risks for the fetus and the pregnant person. Furthermore, the risk-benefit profile for just the fetus and the risk-benefit profile for just the pregnant person should be appropriate. CONCLUSIONS: We hope that this new framework will permit important studies while protecting pregnant persons and fetuses from disproportionate harms.

Down syndrome (DS) is the most common genetic cause of developmental disabilities. Advanced analysis of brain magnetic resonance imaging (MRI) has been used to find brain abnormalities and their relationship to neurocognitive impairments in children and adolescents with DS. Because genetic factors affect brain development in early fetal life, there is a growing interest in analyzing brains from living fetuses with DS. In this study, we investigated regional sulcal folding depth as well as global cortical gyrification from fetal brain MRIs. Nine fetuses with DS (29.1 ± 4.24 gestational weeks [mean ± standard deviation]) were compared with 17 typically developing [TD] fetuses (28.4 ± 3.44). Fetuses with DS showed lower whole-brain average sulcal depths and gyrification index than TD fetuses. Significant decreases in sulcal depth were found in bilateral Sylvian fissures and right central and parieto-occipital sulci. On the other hand, significantly increased sulcal depth was shown in the left superior temporal sulcus, which is related to atypical hemispheric asymmetry of cortical folding. Moreover, these group differences increased as gestation progressed. This study demonstrates that regional sulcal depth is a sensitive marker for detecting alterations of cortical development in DS during fetal life, which may be associated with later neurocognitive impairment.

While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS. We emphasize the importance of using these cell models to screen for therapeutic molecules, followed by validating them in the most suitable animal models prior to initiating human clinical trials.

ispartof: PRENATAL DIAGNOSIS vol:40 issue:3 pages:287-293 ispartof: location:England status: published

The fetal fraction (FF) is a function of both biological factors and bioinformatics algorithms used to interpret DNA sequencing results. It is an essential quality control component of noninvasive prenatal testing (NIPT) results. Clinicians need to understand the biological influences on FF to be able to provide optimal post-test counseling and clinical management. There are many different technologies available for the measurement of FF. Clinicians do not need to know the details behind the bioinformatics algorithms of FF measurements, but they do need to appreciate the significant variations between the different sequencing technologies used by different laboratories. There is no universal FF threshold that is applicable across all platforms and there have not been any differences demonstrated in NIPT performance by sequencing platform or method of FF calculation. Importantly, while FF should be routinely measured, there is not yet a consensus as to whether it should be routinely reported to the clinician. The clinician should know what to expect from a standard test report and whether reasons for failed NIPT results are revealed. Emerging solutions to the challenges of samples with low FF should reduce rates of failed NIPT in the future. In the meantime, having a "plan B" prepared for those patients for whom NIPT is unsuccessful is essential in today's clinical practice.

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P

In some parts of the world, prenatal screening using analysis of circulating cell-free (cf) DNA in the plasma of pregnant women has become part of routine prenatal care with limited professional guidelines and without significant input from the Turner syndrome community. In contrast to the very high positive predictive values (PPVs) achieved with cfDNA analysis for trisomy 21 (91% for high-risk and 82% for low-risk cases), the PPVs for monosomy X are much lower (~26%). This is because the maternal plasma sample contains both maternal cfDNA and placental DNA, which is a proxy for the fetal genome. Underlying biological mechanisms for false positive monosomy X screening results include confined placental mosaicism, co-twin demise, and maternal mosaicism. Somatic loss of a single X chromosome in the mother is a natural phenomenon that occurs with aging; this could explain many of the false positive cfDNA results. There is also increased awareness of women who have constitutional mosaicism for 45, X who are fertile. It is important to recognize that a positive cfDNA screen for 45, X does not mean that the fetus has Turner syndrome. A follow-up diagnostic test, either amniocentesis or neonatal karyotype/chromosome microarray, is recommended. Research studies on cell-free mRNA in second trimester amniotic fluid, which is almost exclusively fetal, demonstrate consistent dysregulation of genes involved in the hematologic, immune, and neurologic systems. This suggests that some of the pathophysiology of Turner syndrome occurs early in fetal life and presents novel opportunities for consideration of antenatal treatments.

Maternal mortality and severe maternal morbidity are urgent issues in the United States. It is important to establish priority areas to address these public health crises. On April 8, 2019, and May 2 to 3, 2019, the Eunice Kennedy Shriver National Institute of Child Health and Human Development organized and invited experts with varied perspectives to 2 meetings, a community engagement forum and a scientific workshop, to discuss underlying themes involved in the rising incidence of maternal mortality in the United States. Experts from diverse disciplines reviewed current data, ongoing activities, and identified research gaps focused on data measurement and reporting, obstetrical and health system factors, social determinants and disparities, and the community perspective and engagement. Key scientific opportunities to reduce maternal mortality and severe maternal morbidity include improved data quality and measurement, understanding the populations affected as well as the numerous etiologies, clinical research to confirm preventive and interventional strategies, and engagement of community participation in research that will lead to the reduction of maternal mortality in the United States. This article provides a summary of the workshop presentations and discussions.

* Abbreviation: NIH — : National Institutes of Health The National Institutes of Health (NIH) has a special interest group on childhood screening that is staffed jointly by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Disease Prevention in the Office of the NIH Director. After a series of internal meetings, the special interest group decided that the most compelling issue to tackle was the lack of an evidence base to support screening recommendations for exposures, behaviors, and conditions that are part of current routine pediatric care. To stimulate methodologic innovation to address this problem, the NIH convened an in-person workshop in Bethesda, Maryland, on May 9–10, 2019, entitled “Methods for Assessing the Impact of Screening in Childhood on Health Outcomes.” Workshop objectives included (1) conceptualizing the universe of child health outcomes pertinent to screening; (2) identifying methodologic challenges in assessing child health outcomes; (3) discussing novel and rigorous approaches to assessing these outcomes; … Address correspondence to Diana W. Bianchi, MD, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 31, Room 2A03, 31 Center Dr, Bethesda, MD 20892. E-mail: diana.bianchi{at}nih.gov

Humans with Down syndrome (DS) exhibit hippocampal learning deficits in the Cambridge Neuropsychological Test Automated Battery (CANTAB). Here we translated the CANTAB Visual Discrimination (VD) and Extinction tasks to investigate hippocampal learning and cortical inhibitory control in the Dp(16)1/Yey, Ts65Dn and Ts1Cje mouse models of DS. No food or water restriction was used prior to testing. The number of days to reach 70% correct answers and percent of correct responses were analyzed. All Dp(16)1/Yey, Ts1Cje and WT mice reached Stage 5 of pre-training. No differences between genotypes were found in percent of correct responses. Five Ts65Dn and one WT animals reached Stage 5 and only one Ts65Dn mouse reached VD. Ts1Cje mice took longer (17.86±3.19 days) to move to VD vs. WT (11.44±1.96 days, P=0.09). There were no differences between Dp(16)1/Yey and WT mice. At VD, the average percent of correct answers was significantly lower in Dp(16)1/Yey (22.70±1.93%) and Ts1Cje (34.39±1.98%) compared to WT littermates (32.18±1.49% and 41.11±1.45%, respectively, Pad libitum access to food and water. In conclusion, we were able to apply human cognitive tests to evaluate hippocampal learning and cortical inhibitory control in three mouse models of DS. These studies demonstrate significant cognitive differences between strains. Future experiments will evaluate whether food restriction and/or pre- and postnatal therapy decreases the time intervals to achieve training mile.

Circulating DNA fragments in a pregnant woman's plasma derive from three sources: placenta, maternal bone marrow, and fetus. Prenatal sequencing to noninvasively screen for fetal chromosome abnormalities is performed on this mixed sample; results can therefore reflect the maternal as well as the fetoplacental DNA. Although it is recommended that pretest counseling include the possibility of detecting maternal genomic imbalance, this seldom occurs. Maternal abnormalities that can affect a prenatal screening test result include disorders that affect the size and metabolism of DNA, such as B12 deficiency, autoimmune disease, and intrahepatic cholestasis of pregnancy. Similarly, maternal tumors, both benign and malignant, can release DNA fragments that contain duplications or deletions. Bioinformatics algorithms can subsequently interpret the raw sequencing data incorrectly, resulting in false-positive test reports of fetal monosomies or test failures. Maternal sex-chromosome abnormalities, both constitutional and somatic, can generate results that are discordant with fetal ultrasound examination or karyotype. Maternal copy-number variants and mosaicism for autosomal aneuploidies can also skew interpretation. A maternal etiology should therefore be considered in the differential diagnosis of prenatal cell-free DNA test failures, false-positive and false-negative sequencing results. Further study is needed regarding the clinical utility of reporting maternal incidental findings.

Objective Maternal plasma cell-free DNA (cfDNA) analysis is a powerful screening tool for Down syndrome. In a pilot series, we examined biologic causes of discordance between the cfDNA test results and the fetal karyotype. We also explored the feasibility of obtaining trio biospecimens by using parental engagement. Methods A convenience sample of women with discordant cfDNA results were recruited by their care providers. We provided shipping materials and instructions for biospecimen collection. Maternal, newborn, and placental samples were examined with droplet digital PCR. Results Thirteen of 15 women successfully had biospecimens obtained remotely. High-quality DNA was extracted in 12 of 13 women. Presumed biologic etiologies for discordance were identified in 7 of 12 women: 3 cases from additional clinical review (male renal transplant, vanishing twin, and colon cancer) and 4 cases from additional laboratory investigation using droplet digital PCR (3 with confined placental mosaicism and 1 with true fetal mosaicism). Conclusions Understanding the biology behind cfDNA-fetal karyotype discordancy is useful for follow-up clinical care. Our study suggests that most cases could be resolved by using a trio biospecimen protocol and parental involvement. To improve accuracy, additional sequencing of biospecimens will be required.

Background In human fetuses with Down syndrome, placental pathology, structural anomalies and growth restriction are present. There is currently a significant lack of information regarding the early life span in mouse models of Down syndrome. Objective The objective of this study was to examine embryonic day 18.5 and placental phenotype in the 3 most common mouse models of Down syndrome (Ts65Dn, Dp(16)1/Yey, Ts1Cje). Based on prenatal and placental phenotyping in 3 mouse models of Down syndrome, we hypothesized that one or more of them would have a similar phenotype to human fetuses with trisomy 21, which would make it the most suitable for in utero treatment studies. Study Design Here, C57BL6J/6 female mice were mated to Dp(16)1/Yey and Ts1Cje male mice and Ts65Dn female mice to C57BL/B6Eic3Sn.BLiAF1/J male mice. At embryonic day 18.5, dams were euthanized. Embryos and placentas were examined blindly for weight and size. Embryos were characterized as euploid or trisomic, male or female by polymerase chain reaction. A subset of embryos (34 euploid and 34 trisomic) were examined for malformations. Results The Ts65Dn mouse model showed the largest differences in fetal growth, brain development, and placental development when comparing euploid and trisomic embryos. For the Dp(16)1/Yey mouse model, genotype did not impact fetal growth, but there were differences in brain and placental development. For the Ts1Cje mouse model, no significant association was found between genotype and fetal growth, brain development, or placental development. Euploid mouse embryos had no congenital anomalies; however, 1 mouse embryo died. Hepatic necrosis was seen in 6 of 12 Dp(16)1/Yey (50%) and 1 of 12 Ts1Cje (8%) mouse embryos; hepatic congestion or inflammation was observed in 3 of 10 Ts65Dn mouse embryos (30%). Renal pelvis dilation was seen in 5 of 12 Dp(16)1/Yey (42%), 5 of 10 Ts65Dn (50%), and 3 of 12 Ts1Cje (25%) mouse embryos. In addition, 1 Ts65Dn mouse embryo and 1 Dp(16)1/Yey mouse embryo had an aortic outflow abnormality. Furthermore, 2 Ts1Cje mouse embryos had ventricular septal defects. Ts65Dn mouse placentas had increased spongiotrophoblast necrosis. Conclusion Fetal and placental growth showed varying trends across strains. Congenital anomalies were primarily seen in trisomic embryos. The presence of liver abnormalities in all 3 mouse models of Down syndrome (10 of 34 cases) is a novel finding. Renal pelvis dilation was also common (13 of 34 cases). Future research will examine human autopsy material to determine if these findings are relevant to infants with Down syndrome. Differences in placental histology were also observed among strains.

Women’s health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation—a fast, scarless healing process in healthy individuals—will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, “Menstruation: Science and Society” with an aim to “identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field.” Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration—and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids—to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent “menstrual equity” and “period poverty” movements spreading across high-income countries.

Chronic Granulomatous Disease (CGD) is a rare, inherited disorder due to an X-linked or autosomal genetic defect, in which patients experience a high rate of lymphadenitis. To date, no studies have examined the best treatment for severe lymphadenitis in this patient population. We present a nine CGD patient retrospective case series, examining surgical treatment of cervical lymphadenitis. Our evolving surgical strategy shows that an initially more aggressive surgical approach (selective neck dissection) can help prevent recurrent infection. The results found within this patient population may be relevant to other multi-nodal disease, including cancers of the head and neck region, while preserving functional and cosmetically acceptable outcomes. This article is protected by copyright. All rights reserved.

Fetuses with isolated agenesis of the corpus callosum (ACC) are associated with a broad spectrum of neurodevelopmental disability that cannot be specifically predicted in prenatal neuroimaging. We hypothesized that ACC may be associated with aberrant cortical folding. In this study, we determined altered patterning of early primary sulci development in fetuses with isolated ACC using novel quantitative sulcal pattern analysis which measures deviations of regional sulcal features (position, depth, and area) and their intersulcal relationships in 7 fetuses with isolated ACC (27.1 ± 3.8 weeks of gestation, mean ± SD) and 17 typically developing (TD) fetuses (25.7 ± 2.0 weeks) from normal templates. Fetuses with ACC showed significant alterations in absolute sulcal positions and relative intersulcal positional relationship compared to TD fetuses, which were not detected by traditional gyrification index. Our results reveal altered sulcal positional development even in isolated ACC that is present as early as the second trimester and continues throughout the fetal period. It might originate from altered white matter connections and portend functional variances in later life.

Clinical diagnostic laboratories are producing next-generation sequencing-based test results that are becoming increasingly incorporated into patient care. Whole genome and exome sequencing on fetal material derived from amniocytes, chorionic villi, or products of conception is starting to be offered clinically in specialized centers, but it has not yet become routine practice. The technical, interpretation, and ethical challenges are greatest in the area of prenatal medicine because the fetus has a limited health history, and the physical examination is only indirectly available via prenatal sonography. Here, we provide an overview of these challenges and highlight the clinical utility, reporting, and counseling issues associated with prenatal DNA sequencing. Future considerations are also discussed. © 2017 John Wiley & Sons, Ltd.

22q11.2 deletion, the most common microdeletion syndrome within the general population, is estimated to have a prevalence of 1 in 3000 to 6000. Non-invasive prenatal testing has recently expanded to include screening for several microdeletions including 22q11.2. Given the expansion of prenatal screening options to include microdeletions, it is important to understand the limits of this technology and the variety of reasons that a discordant positive result can occur. Here, we describe a case of a pregnant woman who received a positive non-invasive prenatal maternal plasma screen for 22q11.2 deletion. Maternal and postnatal neonatal peripheral blood cytogenetic, PCR, and fluorescence in situ hybridization studies were normal, but the placenta was mosaic for 22q11.2 deletion in two of three biopsy sites. This case illustrates both the complexities of pre- and post-test counseling for microdeletion screening and the potential for a discordant positive microdeletion result because of confined placental mosaicism. © 2017 John Wiley & Sons, Ltd.

Background Parallel to recent advances in prenatal screening for Down syndrome (DS), therapies for different aspects of the condition have become available. As intellectual disability is a key aspect, this is an active area for research. Several groups have hypothesized that prenatal interventions will give better chances at improving cognitive functioning in persons with DS than postnatal treatment. Clinical trials are being developed. Method We first discuss the ethical pros and cons of trying to improve cognitive functioning in persons with DS to see if there are categorical objections to the general idea, and then move on to explore ethically relevant aspects of the prospect of developing fetal therapy for DS (FTDS). Results Only on the basis of a one-dimensional emphasis on the social model of disability would (fetal) therapy aimed at cognitive improvement be inherently problematic. Conclusions Inviting pregnant women to participate in FTDS-research should be based on adequate pre-clinical trials, as well as information aimed at avoiding the so-called ‘therapeutic misconception’. Should FTDS be proven to be effective and safe, women carrying a fetus with trisomy 21 who have decided to continue the pregnancy may have a moral obligation to make use of this option. © 2016 John Wiley & Sons, Ltd.

Noninvasive prenatal DNA testing is the vanguard of genomic medicine. In only four years, this screening test has revolutionized prenatal care globally and opened up new prospects for personalized medicine for the fetus. There are widespread implications for increasing the scope of human genetic variation that can be detected before birth, and for discovering more about maternofetal and placental biology. These include an urgent need to develop pretest education for all pregnant women and consistent post-test management recommendations for those with discordant test results. The reduction in invasive testing has had downstream effects on specialist training and caused many countries to re-examine their national approaches to prenatal screening. Finally, the accumulating datasets of genomic information on pregnant women and their fetuses raise ethical issues regarding consent for future data mining and intellectual property.

Introduction: Early funding can have significant impact on a researcher's career. However, funding is not equal for men and women. Not only do female researchers apply for fewer grants than men, but they also experience a lower success rate when they do. The Zucker Grant Program (ZGP) was established in 2000 to promote the early success of women researchers. The purpose of this evaluation is to support other institutions hoping to grow the research careers of women scientists. Methods: This program evaluation reviewed the first 16 years of the program's history. Our mixed-methods, outcomes-based evaluation had four phases: (I) interviews with key stakeholders, (II) development and distribution of a survey to ZGP recipients, (III) focus groups and interviews with ZGP recipients, (IV) document analysis from the ZGP Center and the Tufts University School of Medicine (TUSM) Development Office. This article reports on the qualitative data collection and analysis. Results: Between 2000 and 2016, US$377,050 was awarded for 142 recipients. Qualitative data revealed how grant funding was critical to support pilot data in awardees' research to inform extramural grant applications. However, the program evaluation also identified effects on awardees' confidence as researchers and connection to a community. Conclusion: Outcomes are interpreted through the framework of Bourdieu's three forms of capital, including economic, social, and cultural capital. Viewed through this framework, they provide a critical infrastructure to the development and success of early career female investigators. This work offers other institutions a framework to consider when establishing intramural funding and support programs for their early career investigators.

Objective We tested the hypothesis that FMR1 expansions would result in global gene dysregulation as early as the second trimester of human fetal development. Method Using cell-free fetal RNA obtained from amniotic fluid supernatant and expression microarrays, we compared RNA levels in samples from fetuses with premutation or full mutation allele expansions with control samples. Results We found clear signals of differential gene expression relating to a variety of cellular functions, including ubiquitination, mitochondrial function, and neuronal/synaptic architecture. Additionally, among the genes showing differential gene expression, we saw links to related diseases of intellectual disability and motor function. Finally, within the unique molecular phenotypes established for each mutation set, we saw clear signatures of mitochondrial dysfunction and disrupted neurological function. Patterns of differential gene expression were very different in male and female fetuses with premutation alleles. Conclusion These results support a model for which genetic misregulation during fetal development may set the stage for late clinical manifestations of FMR1-related disorders. © 2016 John Wiley & Sons, Ltd.

Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16.SIGNIFICANCE STATEMENTDown syndrome (DS) leads to intellectual disability. Several mouse models have increased our understanding of the neuropathology of DS and are currently being used to test therapeutic strategies. A new mouse model that contains an expanded number of DS-related genes, known as Dp(16)1Yey/+ (Dp16), has been generated recently. We sought to determine whether the extended triplication creates a better phenocopy of DS-related brain pathologies. We measured embryonic development, forebrain maturation, and perinatal/adult behavior and revealed an absence of prenatal phenotypes in Dp16 fetal brain, but specific cellular and behavioral deficits after the first 2 postnatal weeks. These results uncover important differences in prenatal phenotype between Dp16 animals and humans with DS and other DS mouse models.

Objectives To determine the underlying biological basis for noninvasive prenatal testing (NIPT) results of multiple aneuploidies or autosomal monosomies. Methods Retrospective analysis of 113,415 tests to determine the study cohort, consisting of 138 (0.12%) cases reported as a single autosomal monosomy (n = 65), single trisomy with a sex chromosome aneuploidy (n = 36), or with multiple aneuploidies (n = 37). Clinical outcome information was reviewed and stratified into eight categories according to whether the karyotype or sonographic information agreed or disagreed with sequencing results. Results Of 67 cases with fetal or neonatal karyotypes available, 16 (24%) were partially or fully concordant with the NIPT result, 4 (6%) had aneuploidy on a reference chromosome, and 47 (70%) had normal fetal chromosomes, in which 5/47 had maternal malignancies reported. One case of maternal mosaic trisomy 8 was also detected. Of cases with no fetal karyotype information, ten had an abnormal clinical outcome, one was a normal live birth, and one reported maternal malignancy. Conclusions Noninvasive prenatal test results of autosomal monosomy or multiple aneuploidies are rare but have a diversity of underlying biologic causes. Some reflect the fetal karyotype; some reflect the presence of other maternal or fetal chromosome abnormalities, and a small number are linked to maternal disease. © 2016 Illumina. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

The metaphor 'open kimono' has been applied in the business world to connote transparency via the release of all available data to an external party. Here, the author uses this term to discuss the relative advantages and disadvantages of reporting on the presence of rare autosomal aneuploidies detected by massively parallel sequencing of placental cell-free DNA in the plasma of pregnant women. Newly presented data sets from multiple laboratories suggest that autosomal aneuploidies such as trisomies 7, 15, 16, 22, and 8 are easily detectable and are potentially associated with fetal growth restriction, pregnancy loss, and maternal preeclampsia. Furthermore, they may explain false positive results for the common autosomal trisomies (13, 18, and 21) as well as test failures. Thus, release of this information may result in improved clinical utility. At the present time, however, professional societies in various parts of the world differ in their recommendations as to whether or not to release expanded autosomal aneuploidy results beyond the common trisomies. © 2016 John Wiley & Sons, Ltd.