248 results on '"Diana W. Bianchi"'
Search Results
2. The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry
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Marisa E. Schwab, Billie R. Lianoglou, Dawn Gano, Juan Gonzalez Velez, Isabel E. Allen, Regina Arvon, Ahmet Baschat, Diana W. Bianchi, Melissa Bitanga, Anne Bourguignon, Richard N. Brown, Bruce Chen, May Chien, Shareece Davis-Nelson, Monique W. M. de Laat, Supachai Ekwattanakit, Yvonne Gollin, Greigh Hirata, Angie Jelin, Jennifer Jolley, Paul Meyer, Jena Miller, Mary E. Norton, Keith K. Ogasawara, Tachjaree Panchalee, Erica Schindewolf, Steven W. Shaw, Tammy Stumbaugh, Alexis A. Thompson, Dena Towner, Pai-Jong Stacy Tsai, Vip Viprakasit, Emmanuel Volanakis, Li Zhang, Elliott Vichinsky, and Tippi C. MacKenzie
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Pediatric ,Pediatric Research Initiative ,Infant ,Gestational Age ,Reproductive health and childbirth ,Hematology ,Perinatal Period - Conditions Originating in Perinatal Period ,Newborn ,Brain Disorders ,Rare Diseases ,alpha-Thalassemia ,Pregnancy ,Clinical Research ,Humans ,Edema ,Blood Transfusion ,Female ,Intrauterine - Abstract
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.
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- 2023
3. The NIH Climate Change and Health Initiative and Strategic Framework: addressing the threat of climate change to health
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Richard P, Woychik, Diana W, Bianchi, Gary H, Gibbons, Roger I, Glass, Joshua A, Gordon, Eliseo J, Pérez-Stable, and Shannon N, Zenk
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Climate Change ,Humans ,Public Health ,General Medicine - Published
- 2022
4. World Prematurity Day: it takes an NIH village to prevent preterm birth and improve treatments for preterm infants
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Diana W. Bianchi, Andrew A. Bremer, Roberto Romero, Jagteshwar Grewal, and Rohan Hazra
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Adult ,Pulmonary and Respiratory Medicine ,Pregnancy ,medicine.medical_specialty ,Physiology ,business.industry ,Extramural ,Obstetrics ,Infant, Newborn ,Pneumonia ,Cell Biology ,Global Health ,medicine.disease ,Pulmonary Disease, Chronic Obstructive ,Bronchopulmonary dysplasia ,Physiology (medical) ,medicine ,Humans ,Premature Birth ,Female ,Child ,business ,Perspectives - Abstract
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.
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- 2021
5. Neurodevelopmental Clues to Neurodegeneration
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Nina F. Schor and Diana W. Bianchi
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Brain development ,business.industry ,Disease mechanisms ,Neurodegeneration ,Neurodegenerative Diseases ,Disease ,medicine.disease ,Developmental Neuroscience ,Neurology ,Neurodevelopmental Disorders ,Pediatrics, Perinatology and Child Health ,Animals ,Humans ,Medicine ,Neurology (clinical) ,business ,Neuroscience - Abstract
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.
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- 2021
6. A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials
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David Wasserman, Benjamin E. Berkman, David Wendler, Diana W. Bianchi, Christine Grady, and S Hendriks
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Value (ethics) ,medicine.medical_specialty ,Proportionality (mathematics) ,0603 philosophy, ethics and religion ,Article ,Fetus ,Social Justice ,Pregnancy ,medicine ,Humans ,Ethics, Medical ,Permissive ,Intensive care medicine ,Ethical framework ,Fetal therapy ,Fetal Therapies ,Research ethics ,business.industry ,Health Policy ,Abortion, Induced ,06 humanities and the arts ,Issues, ethics and legal aspects ,embryonic structures ,Female ,Pregnant Women ,060301 applied ethics ,business ,Psychosocial - Abstract
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.
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- 2021
7. Right or wrong? Looking through the retrospectoscope to analyse predictions made a decade ago in prenatal diagnosis and fetal surgery
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Alessandro Ghidini, Jan Deprest, Lyn S. Chitty, Diana W. Bianchi, Brynn Levy, Tim Van Mieghem, and Lisa Hui
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Fetal Therapies ,medicine.medical_specialty ,Fetal surgery ,business.industry ,General surgery ,medicine.medical_treatment ,MEDLINE ,Obstetrics and Gynecology ,Prenatal diagnosis ,Cytogenetics ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,Female ,business ,Cell-Free Nucleic Acids ,Biomarkers ,Genetics (clinical) ,Forecasting - Abstract
ispartof: PRENATAL DIAGNOSIS vol:40 issue:13 pages:1627-1635 ispartof: location:England status: published
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- 2020
8. Trends in prenatal diagnosis: An analysis of 40 years of Medical Subject Heading ( <scp>MeSH</scp> ) terms in publications
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Diana W. Bianchi and Ya-Ling Lu
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0301 basic medicine ,medicine.medical_specialty ,Abstracting and Indexing ,Noninvasive Prenatal Testing ,MEDLINE ,Prenatal diagnosis ,030105 genetics & heredity ,Article ,Obstetric care ,Medical Subject Headings ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,Medical physics ,Genetics (clinical) ,030219 obstetrics & reproductive medicine ,Mesh term ,Obstetrics and Gynecology ,Subject (documents) ,Prenatal cytogenetics ,Prenatal screening ,Bibliometrics ,Fetal imaging ,Female ,Periodicals as Topic ,Psychology - Abstract
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.
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- 2020
9. A new ethical framework to determine acceptable risks in fetal therapy trials
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Saskia Hendriks, Christine Grady, David Wasserman, David Wendler, Diana W. Bianchi, and Benjamin Berkman
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Fetus ,Pregnancy ,Obstetrics and Gynecology ,Humans ,Female ,Prenatal Care ,Risk Assessment ,Genetics (clinical) ,Article - Abstract
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.
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- 2022
10. Regional Alterations in Cortical Sulcal Depth in Living Fetuses with Down Syndrome
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Juan David Perez, Diana W. Bianchi, J Alejandro Valdés, Neel Madan, P. Ellen Grant, Tomo Tarui, Patricia Sosa, Rie Kitano, Shizuko Akiyama, Kiho Im, Brian G. Skotko, Henry A. Feldman, and Hyuk Jin Yun
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Adult ,Down syndrome ,Brain development ,Adolescent ,Cognitive Neuroscience ,Gestational Age ,Neuroimaging ,Fetal brain ,Fetal Development ,Young Adult ,Cellular and Molecular Neuroscience ,Fetus ,Gestational Weeks ,Image Processing, Computer-Assisted ,Humans ,Medicine ,Gyrification ,Cerebral Cortex ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,Anatomy ,medicine.disease ,Magnetic Resonance Imaging ,nervous system ,Original Article ,Down Syndrome ,business ,Neurocognitive ,Maternal Age - Abstract
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.
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- 2020
11. Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome
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Faycal Guedj, Sarah E. Lee, Diana W. Bianchi, Sabina Khantsis, and Monica Duran-Martinez
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Pluripotent Stem Cells ,0301 basic medicine ,Down syndrome ,Chromosomes, Human, Pair 21 ,Bioinformatics ,Article ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Intervention (counseling) ,medicine ,Animals ,Humans ,Molecular Biology ,business.industry ,Brain ,Translation (biology) ,medicine.disease ,Clinical trial ,Disease Models, Animal ,Phenotype ,030104 developmental biology ,Molecular Medicine ,Down Syndrome ,Cognition Disorders ,business ,030217 neurology & neurosurgery - Abstract
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.
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- 2020
12. In case you missed it: The Prenatal Diagnosis editors bring you the most significant advances of 2019
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Brynn Levy, Diana W. Bianchi, Lyn S. Chitty, T. Van Mieghem, Alessandro Ghidini, Jan Deprest, and Lisa Hui
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Publishing ,medicine.medical_specialty ,business.industry ,Genetic Diseases, Inborn ,Obstetrics and Gynecology ,Prenatal diagnosis ,United Kingdom ,Machine Learning ,Fetal Diseases ,Artificial Intelligence ,Pregnancy ,Prenatal Diagnosis ,Exome Sequencing ,medicine ,Humans ,Female ,Intensive care medicine ,business ,Cell-Free Nucleic Acids ,Genetics (clinical) - Abstract
ispartof: PRENATAL DIAGNOSIS vol:40 issue:3 pages:287-293 ispartof: location:England status: published
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- 2020
13. An Examination of Child and Adolescent Neurodevelopment Through National Institutes of Health Studies
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Diana W. Bianchi, Eliseo J. Pérez-Stable, Gary H. Gibbons, George F. Koob, Walter J. Koroshetz, Janine A. Clayton, Nora D. Volkow, William T. Riley, Linda S. Birnbaum, Joshua A. Gordon, and Robert T. Croyle
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Aging ,medicine.medical_specialty ,Adolescent ,Substance-Related Disorders ,media_common.quotation_subject ,Twins ,MEDLINE ,Child and adolescent ,Executive Perspective ,Pregnancy ,medicine ,Humans ,Longitudinal Studies ,Child ,Psychiatry ,media_common ,business.industry ,Addiction ,Infant, Newborn ,Public Health, Environmental and Occupational Health ,Brain ,Infant ,Opioid-Related Disorders ,United States ,National Institutes of Health (U.S.) ,Child, Preschool ,Prenatal Exposure Delayed Effects ,Female ,business - Published
- 2020
14. Fetal fraction and noninvasive prenatal testing: What clinicians need to know
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Diana W. Bianchi and Lisa Hui
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0301 basic medicine ,medicine.medical_specialty ,DNA Copy Number Variations ,Reproductive Techniques, Assisted ,Noninvasive Prenatal Testing ,Gestational Age ,030105 genetics & heredity ,Body weight ,Article ,Crown-Rump Length ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Need to know ,Humans ,Pregnancy-Associated Plasma Protein-A ,Medicine ,Standard test ,Chorionic Gonadotropin, beta Subunit, Human ,Fraction (mathematics) ,Medical physics ,Genetics (clinical) ,030219 obstetrics & reproductive medicine ,Human blood ,Mosaicism ,business.industry ,Body Weight ,Anticoagulants ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Obstetrics and Gynecology ,General Medicine ,Heparin, Low-Molecular-Weight ,Aneuploidy ,Triploidy ,Pregnancy Complications ,Clinical Practice ,Cell-free fetal DNA ,Female ,Pregnancy, Multiple ,business ,Cell-Free Nucleic Acids ,Algorithms ,Maternal Age - Abstract
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.
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- 2019
15. Building the Evidence for Safe Return to School During the COVID-19 Pandemic
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Sonia Lee, Diana W. Bianchi, and Alison N. Cernich
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2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,COVID-19 ,medicine.disease ,United States ,Return to School ,COVID-19 Testing ,Pediatrics, Perinatology and Child Health ,Pandemic ,Communicable Disease Control ,medicine ,Humans ,Supplement Article ,Medical emergency ,business ,Pandemics - Published
- 2021
16. Importance of research in reducing maternal morbidity and mortality rates
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C. Lamar, Diana W. Bianchi, Juanita J. Chinn, Nahida Chakhtoura, Katherine L. Grantz, Shavon Artis Dickerson, and Esther Eisenberg
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Pregnancy ,Biomedical Research ,Social Determinants of Health ,business.industry ,Mortality rate ,MEDLINE ,Obstetrics and Gynecology ,Maternal morbidity ,Health Status Disparities ,medicine.disease ,United States ,Article ,Pregnancy Complications ,Maternal Mortality ,Risk Factors ,Environmental health ,Humans ,Medicine ,Female ,Social determinants of health ,business - Published
- 2019
17. Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome
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Ellen Grant, Hyuk Jin Yun, Tomo Tarui, Diana W. Bianchi, Rie Kitano, Neel Madan, Allie Schwartz, Shizuko Akiyama, Christianne Sharr, Kiho Im, Steven J. Ralston, Brian G. Skotko, and Rajeevi Madankumar
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Down syndrome ,Pathology ,medicine.medical_specialty ,Brain development ,Cognitive Neuroscience ,Gestational Age ,Fetal Development ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neuroimaging ,Prenatal Diagnosis ,Intellectual disability ,Parenchyma ,medicine ,Humans ,030304 developmental biology ,Brain Mapping ,0303 health sciences ,Fetus ,business.industry ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Brain growth ,Gestation ,Original Article ,Down Syndrome ,business ,030217 neurology & neurosurgery - Abstract
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
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- 2019
18. Involving Pregnant Individuals in Clinical Research on COVID-19 Vaccines
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Alison N. Cernich, Diana W. Bianchi, and Lisa Kaeser
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medicine.medical_specialty ,2019-20 coronavirus outbreak ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,MEDLINE ,Article ,Government regulation ,Pregnancy ,medicine ,Humans ,Lactation ,Pregnancy Complications, Infectious ,Intensive care medicine ,Clinical Trials as Topic ,business.industry ,COVID-19 ,General Medicine ,medicine.disease ,Therapeutic Human Experimentation ,Human development (humanity) ,Vaccination ,Clinical research ,Government Regulation ,Female ,business - Published
- 2021
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19. Forever Connected: The Lifelong Biological Consequences of Fetomaternal and Maternofetal Microchimerism
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Keelin O'Donoghue, Kiarash Khosrotehrani, Diana W. Bianchi, Ingeborg M. Bajema, Sing Sing Way, and Tippi C. MacKenzie
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0301 basic medicine ,Male ,Clinical Biochemistry ,Prenatal diagnosis ,Disease ,Bioinformatics ,Chimerism ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Fetus ,Pregnancy ,Prenatal Diagnosis ,medicine ,Animals ,Humans ,Maternal-Fetal Exchange ,030219 obstetrics & reproductive medicine ,business.industry ,Mechanism (biology) ,Biochemistry (medical) ,Genetic Diseases, Inborn ,Microchimerism ,medicine.disease ,Fetal Blood ,030104 developmental biology ,Female ,Stem cell ,business - Abstract
Background Originally studied as a mechanism to understand eclampsia-related deaths during pregnancy, fetal cells in maternal blood have more recently garnered attention as a noninvasive source of fetal material for prenatal testing. In the 21st century, however, intact fetal cells have been largely supplanted by circulating cell-free placental DNA for aneuploidy screening. Instead, interest has pivoted to the ways in which fetal cells influence maternal biology. In parallel, an increasing appreciation of the consequences of maternal cells in the developing fetus has occurred. Content In this review, we highlight the potential clinical applications and functional consequences of the bidirectional trafficking of intact cells between a pregnant woman and her fetus. Fetal cells play a potential role in the pathogenesis of maternal disease and tissue repair. Maternal cells play an essential role in educating the fetal immune system and as a factor in transplant acceptance. Naturally occurring maternal microchimerism is also being explored as a source of hematopoietic stem cells for transplant in fetal hematopoietic disorders. Summary Future investigations in humans need to include complete pregnancy histories to understand maternal health and transplant success or failure. Animal models are useful to understand the mechanisms underlying fetal wound healing and/or repair associated with maternal injury and inflammation. The lifelong consequences of the exchange of cells between a mother and her child are profound and have many applications in development, health, and disease. This intricate exchange of genetically foreign cells creates a permanent connection that contributes to the survival of both individuals.
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- 2021
20. Maternal Morbidity and Mortality
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Diana W. Bianchi, Samia Noursi, Dorothy Fink, and Janine A. Clayton
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Pregnancy ,medicine.medical_specialty ,Introduction ,business.industry ,MEDLINE ,Maternal morbidity ,General Medicine ,medicine.disease ,Pregnancy Complications ,Text mining ,Maternal Mortality ,Medicine ,Humans ,Female ,Morbidity ,business ,Intensive care medicine - Published
- 2020
21. Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model
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Fatimah Alsebaa, Lauren J. Massingham, Diana W. Bianchi, Umadevi Tantravahi, Faycal Guedj, Ashley E Siegel, and Jeroen L. A. Pennings
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0301 basic medicine ,Male ,Vascular Endothelial Growth Factor A ,PAX6 Transcription Factor ,Down syndrome ,medicine.disease_cause ,Hippocampus ,Nestin ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Neurotrophic factors ,Pregnancy ,Genetics (clinical) ,Spatial Memory ,0303 health sciences ,Stem Cells ,Gene Expression Regulation, Developmental ,3. Good health ,trisomy 21 ,Interleukin 10 ,In utero ,Apigenin ,Female ,Neurogenesis ,Primary Cell Culture ,Prenatal diagnosis ,prenatal treatment ,Article ,Andrology ,03 medical and health sciences ,Fetus ,Sex Factors ,In vivo ,Genetics ,medicine ,Animals ,Humans ,030304 developmental biology ,apigenin ,business.industry ,Interleukin-7 ,SOXB1 Transcription Factors ,medicine.disease ,Amniotic Fluid ,cytokines ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Ki-67 Antigen ,chemistry ,inflammation ,Exploratory Behavior ,Trisomy ,business ,transcriptome ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. Prenatal diagnosis provides a potential opportunity to begin treatment in utero. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with DS and mouse models we can discover novel targets for therapy. Here, we tested the safety and efficacy of apigenin (4’, 5, 7-trihydroxyflavone), identified using this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. The experiments compared treated to untreated results in T21 and euploid cells, as well as in Ts1Cje mice and their wild-type littermate controls. T21 cells cultured with apigenin (2µM) had significantly reduced oxidative stress and improved antioxidant defense response in vitro. Apigenin (333-400 mg/kg/day), mixed with chow, was initiated prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, with males showing significantly more improvement than females. Global gene expression analyses demonstrated that apigenin targets similar signaling pathways through common upstream regulators both in vitro and in vivo. These studies provide proof-of-principle that apigenin has therapeutic effects in preclinical models of Down syndrome.ONE SENTENCE SUMMARYAs a candidate prenatal treatment for Down syndrome, apigenin improved oxidative stress/antioxidant capacity imbalance and reduced pathways associated with inflammation in human cells while improving aspects of behavior in the Ts1Cje mouse model.
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- 2020
22. Cherchez la femme: maternal incidental findings can explain discordant prenatal cell-free DNA sequencing results
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Diana W. Bianchi
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0301 basic medicine ,Aneuploidy ,Chromosome Disorders ,030105 genetics & heredity ,Bioinformatics ,Article ,Ultrasonography, Prenatal ,Fetal Development ,03 medical and health sciences ,Fetus ,0302 clinical medicine ,Pregnancy ,Prenatal Diagnosis ,Placenta ,medicine ,Humans ,Sex Chromosome Aberrations ,Genetics (clinical) ,Incidental Findings ,030219 obstetrics & reproductive medicine ,business.industry ,High-Throughput Nucleotide Sequencing ,Obstetrics and Gynecology ,Chromosome ,Karyotype ,DNA ,Sequence Analysis, DNA ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Cell-free fetal DNA ,Karyotyping ,Etiology ,Female ,Differential diagnosis ,business ,Cell-Free Nucleic Acids ,Cholestasis of pregnancy - Abstract
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.
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- 2018
23. The conception of the ABCD study: From substance use to a broad NIH collaboration
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William T. Riley, Antonio Noronha, Gayathri J. Dowling, Diana W. Bianchi, Joshua A. Gordon, Walter J. Koroshetz, Glen D. Morgan, Eliseo J. Pérez-Stable, Kevin P. Conway, Susan R.B. Weiss, Robert T. Croyle, John A. Matochik, Katia D. Howlett, Kenneth R. Warren, George F. Koob, Michele Bloch, Catherine Y. Spong, Eric M. Wargo, Margaret M. Murray, Bethany Griffin Deeds, Nora D. Volkow, and Steven Grant
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0301 basic medicine ,Value (ethics) ,Longitudinal study ,medicine.medical_specialty ,Adolescent ,Substance-Related Disorders ,Cognitive Neuroscience ,Brain Structure and Function ,Neuroimaging ,Article ,Developmental psychology ,03 medical and health sciences ,0302 clinical medicine ,Cognition ,medicine ,Cognitive development ,Humans ,Longitudinal Studies ,Public health ,lcsh:QP351-495 ,Brain ,Adolescent Development ,Mental illness ,medicine.disease ,Mental health ,United States ,030104 developmental biology ,lcsh:Neurophysiology and neuropsychology ,National Institutes of Health (U.S.) ,Informatics ,Female ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day. Keywords: Adolescent, Brain development, Neuroimaging, Longitudinal, Substance use, Mental health
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- 2018
24. Biological explanations for discordant noninvasive prenatal test results: Preliminary data and lessons learned
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Eliza Cerveira, Charles Lee, Adam Mil-homens, Chengsheng Zhang, Honey V. Reddi, Qihui Zhu, Diana W. Bianchi, Mallory Ryan, and Louise Wilkins-Haug
- Subjects
Down syndrome ,medicine.medical_specialty ,Biospecimen ,Colorectal cancer ,Karyotype ,Polymerase Chain Reaction ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Humans ,Medicine ,Digital polymerase chain reaction ,030212 general & internal medicine ,Confined placental mosaicism ,Genetics (clinical) ,Vanishing twin ,030219 obstetrics & reproductive medicine ,business.industry ,Obstetrics ,Maternal Serum Screening Tests ,Obstetrics and Gynecology ,medicine.disease ,Female ,Down Syndrome ,business ,Cell-Free Nucleic Acids - Abstract
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.
- Published
- 2018
25. In case you missed it: The Prenatal Diagnosis editors bring you the most significant advances of 2017
- Author
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Alessandro Ghidini, Brynn Levy, Tim Van Mieghem, Lyn S. Chitty, Jan Deprest, and Diana W. Bianchi
- Subjects
Heart Defects, Congenital ,medicine.medical_specialty ,Autism Spectrum Disorder ,MEDLINE ,Prenatal diagnosis ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Fetus ,0302 clinical medicine ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetics (clinical) ,Chromosome Aberrations ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,Obstetrics ,business.industry ,Brain ,Infant ,Obstetrics and Gynecology ,Magnetic resonance imaging ,medicine.disease ,Magnetic Resonance Imaging ,Fetal Diseases ,Child, Preschool ,Fetus surgery ,Female ,Periodicals as Topic ,business ,Sequence Analysis - Published
- 2018
26. Nine patients with chronic granulomatous disease having selective neck dissection for severe cervical lymphadenitis
- Author
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Diana W. Bianchi, C. Van Waes, K. Hauck, Michael S. Hu, Harry L. Malech, B. Driscoll, J. Liu, S.M. Holland, L.R. Wingfield, and John I. Gallin
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Surgical strategy ,Adolescent ,medicine.medical_treatment ,Disease ,Granulomatous Disease, Chronic ,Article ,Young Adult ,03 medical and health sciences ,Chronic granulomatous disease ,Lymphadenitis ,medicine ,Humans ,Child ,Head and neck ,Retrospective Studies ,Surgical approach ,business.industry ,Cervical lymphadenitis ,medicine.disease ,Selective neck dissection ,Surgery ,Treatment Outcome ,030104 developmental biology ,Otorhinolaryngology ,Lymph Node Excision ,Neck Dissection ,Female ,Lymphadenectomy ,business ,Neck - Abstract
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.
- Published
- 2017
27. Disorganized Patterns of Sulcal Position in Fetal Brains with Agenesis of Corpus Callosum
- Author
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Rudolph Pienaar, Neel Madan, Borjan Gagoski, Vidya Iyer, Kiho Im, Caitlin K. Rollins, Tomo Tarui, Diana W. Bianchi, Cynthia M. Ortinau, Asye Ceren Tanritanir, Nabgha Farhat, George Graham, Alexa Craig, P. Ellen Grant, and Rie Kitano
- Subjects
Male ,0301 basic medicine ,Cognitive Neuroscience ,Neuroimaging ,Biology ,Corpus callosum ,White matter ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Fetus ,Imaging, Three-Dimensional ,0302 clinical medicine ,Image Interpretation, Computer-Assisted ,medicine ,Humans ,Agenesis of the corpus callosum ,Gyrification ,Cerebral Cortex ,Original Articles ,Anatomy ,medicine.disease ,Magnetic Resonance Imaging ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Cerebral cortex ,Agenesis ,Female ,Agenesis of Corpus Callosum ,psychological phenomena and processes ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2017
28. Noninvasive Prenatal DNA Testing: The Vanguard of Genomic Medicine
- Author
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Lisa Hui and Diana W. Bianchi
- Subjects
Health Knowledge, Attitudes, Practice ,medicine.medical_specialty ,DNA Mutational Analysis ,Prenatal diagnosis ,Prenatal care ,Human genetic variation ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Prenatal Diagnosis ,medicine ,Vanguard ,Data Mining ,Humans ,Genetic Testing ,030212 general & internal medicine ,Social Change ,Intensive care medicine ,Genetic testing ,Chromosome Aberrations ,Pregnancy ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,business.industry ,Genomics ,General Medicine ,medicine.disease ,Intellectual Property ,Biotechnology ,Cell-free fetal DNA ,Personalized medicine ,business ,Cell-Free Nucleic Acids - Abstract
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.
- Published
- 2017
29. The Impact of an Institutional Grant Program on the Economic, Social, and Cultural Capital of Women Researchers
- Author
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Diana W. Bianchi, Rebecca D. Blanchard, and Reva Kleppel
- Subjects
Program evaluation ,Biomedical Research ,Faculty, Medical ,020205 medical informatics ,Inequality ,media_common.quotation_subject ,Distribution (economics) ,Qualitative property ,02 engineering and technology ,Cultural capital ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,0202 electrical engineering, electronic engineering, information engineering ,Medicine ,Humans ,030212 general & internal medicine ,media_common ,Medical education ,business.industry ,Financing, Organized ,General Medicine ,Original Articles ,Focus group ,Research Personnel ,Work (electrical) ,Capital (economics) ,Social Capital ,Female ,business ,Program Evaluation - Abstract
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.
- Published
- 2019
30. The power of human touch in the era of artificial intelligence
- Author
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Diana W, Bianchi
- Subjects
Artificial Intelligence ,Touch ,Humans - Published
- 2019
31. In case you missed it: The prenatal diagnosis editors bring you the most significant advances of 2018
- Author
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Lyn S. Chitty, Diana W. Bianchi, Alessandro Ghidini, Brynn Levy, Jan Deprest, and Tim Van Mieghem
- Subjects
Publishing ,medicine.medical_specialty ,business.industry ,Fetoscopy ,Obstetrics and Gynecology ,Prenatal diagnosis ,Congresses as Topic ,Obstetrics ,Gynecology ,Pregnancy ,Prenatal Diagnosis ,Medicine ,Humans ,Female ,business ,Intensive care medicine ,Diagnostic Techniques, Obstetrical and Gynecological ,Genetics (clinical) - Abstract
ispartof: PRENATAL DIAGNOSIS vol:39 issue:2 pages:61-69 ispartof: location:England status: published
- Published
- 2019
32. Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome
- Author
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Tarik F. Haydar, Jose Luis Olmos-Serrano, Joseph W. Goodliffe, Nadine M. Aziz, Diana W. Bianchi, Faycal Guedj, and Jeroen L. A. Pennings
- Subjects
Male ,0301 basic medicine ,Down syndrome ,Microcephaly ,Genotype ,Developmental Disabilities ,Neurogenesis ,Trisomy ,Biology ,Craniofacial Abnormalities ,Nestin ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Chromosome 16 ,medicine ,Animals ,Humans ,Muscle Strength ,Maze Learning ,Spatial Memory ,Neocortex ,General Neuroscience ,Age Factors ,Brain ,Articles ,Embryo, Mammalian ,medicine.disease ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,Synaptic plasticity ,Forebrain ,Exploratory Behavior ,Female ,Down Syndrome ,Chromosome 21 ,Neuroscience ,Chromosomes, Human, Pair 16 ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2016
33. The NIH Blueprint for Neuroscience Research Seeks Community Input on Future Neuroscience Investments
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Martha J. Somerman, Ann K. Cashion, David F. Owens, Joshua A. Gordon, Diana W. Bianchi, Paul A. Sieving, Jill Heemskerk, Christopher P. Austin, George F. Koob, William T. Riley, Nora D. Volkow, David B. Shurtleff, Meghan Mott, Richard J. Hodes, Walter J. Koroshetz, and Kathleen C. Anderson
- Subjects
Cognitive science ,Request for information ,Blueprint for Neuroscience ,National Institutes of Health (U.S.) ,General Neuroscience ,Research Support as Topic ,Neurosciences ,Commentary ,Humans ,Psychology ,Community-Institutional Relations ,United States - Abstract
The NIH Blueprint for Neuroscience Research, a group of 14 NIH Institutes, Centers, and Offices (ICOs) that support research on the nervous system, recently released a Request for Information ( ) on the Proposed Funding Priorities
- Published
- 2018
34. Neuroethics for the National Institutes of Health BRAIN Initiative
- Author
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Diana W. Bianchi, Paul A. Sieving, Jill Heemskerk, James D. Churchill, Nora D. Volkow, Khara M. Ramos, David B. Shurtleff, Joshua A. Gordon, George F. Koob, Judith A. Cooper, Richard J. Hodes, and Walter J. Koroshetz
- Subjects
0301 basic medicine ,General Neuroscience ,MEDLINE ,Neurosciences ,Library science ,Brain ,Brain research ,Ethical standards ,United States ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,National Institutes of Health (U.S.) ,Political science ,Commentary ,Humans ,Neuroethics ,030217 neurology & neurosurgery - Abstract
Background on the National Institutes of Health BRAIN Initiative and neuroethics The National Institutes of Health (NIH) works tirelessly to support the best science and ensure that its funded research adheres to the highest ethical standards. From its inception, the NIH Brain Research through
- Published
- 2018
35. Sequencing of Circulating Cell-free DNA during Pregnancy
- Author
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Rossa W.K. Chiu and Diana W. Bianchi
- Subjects
Male ,0301 basic medicine ,Sequence analysis ,MEDLINE ,Prenatal diagnosis ,030105 genetics & heredity ,medicine.disease_cause ,Bioinformatics ,DNA sequencing ,Article ,chemistry.chemical_compound ,03 medical and health sciences ,Fetus ,0302 clinical medicine ,Text mining ,Pregnancy ,Prenatal Diagnosis ,medicine ,Humans ,False Positive Reactions ,False Negative Reactions ,Chromosome Aberrations ,Mutation ,030219 obstetrics & reproductive medicine ,business.industry ,Chromosome ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,General Medicine ,medicine.disease ,Molecular biology ,Circulating Cell-Free DNA ,Cell-Free Nucleic Acids ,030104 developmental biology ,chemistry ,Female ,sense organs ,business ,DNA - Abstract
Sequence analysis of cell-free DNA (cfDNA) fragments that circulate in the blood of pregnant women, along with the translation of this method into screening for fetal chromosome abnormalities, is a success story of modern genomic medicine. In less than a decade, prenatal cfDNA testing has gone from small, proof-of-principle studies to a global transformation of prenatal care. As of late 2017, a total of 4 million to 6 million pregnant women had had DNA from their plasma analyzed to screen for fetal aneuploidy.(1) The exponential growth of the test has been a function of the role of the biotechnology industry in its development and marketing. Here we review what has been learned from the wide-scale implementation of this testing, how it has changed prenatal clinical care, and what ethical concerns have arisen, and we speculate about what lies ahead.
- Published
- 2018
36. The Inadvertent Discovery of Human Fetal Cell Microchimerism
- Author
-
Diana W. Bianchi
- Subjects
0301 basic medicine ,medicine.drug_class ,Clinical Biochemistry ,Physiology ,Monoclonal antibody ,Chimerism ,03 medical and health sciences ,0302 clinical medicine ,Fetus ,Antigen ,Pregnancy ,Medicine ,Humans ,030212 general & internal medicine ,Progenitor cell ,Maternal-Fetal Exchange ,business.industry ,Biochemistry (medical) ,Microchimerism ,medicine.disease ,Haematopoiesis ,030104 developmental biology ,Female ,Stem cell ,business - Abstract
Featured Article: Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci U S A 1996;93:705–8.2 “The data are the data” is a phrase often used in our laboratory. Our job as scientists is to interpret the data. In 1994, however, we were very unhappy with the data. As part of a comprehensive evaluation of monoclonal antibodies used to flow sort fetal cells from the blood of pregnant women, we found recurring evidence of circulating male cluster differentiation antigen (CD) 34+ cells when the fetus was female. At the time, the PCR technique was still relatively new; our initial interpretation of the data was that there was probable contamination of the laboratory or reagents with Y-chromosomal DNA. Knowing that fetal leukocytes had been shown to persist for up to a year in the blood of women who had given birth to a male infant (1), we hypothesized that the Y-chromosomal DNA could have originated from fetal hematopoietic stem cells from a prior pregnancy. To test this hypothesis, we recruited 8 women who were not currently pregnant, but had between 1 and 10 …
- Published
- 2018
37. Research on Underrepresented Populations-Reply
- Author
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Diana W. Bianchi and Catherine Y. Spong
- Subjects
Gerontology ,business.industry ,Research ,010102 general mathematics ,General Medicine ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Humans ,030212 general & internal medicine ,0101 mathematics ,business ,Minority Groups - Published
- 2018
38. Characterization of three ciliopathy pedigrees expands the phenotype associated with biallelic C2CD3 variants
- Author
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Lacey G. Benoit, Gavin R. Oliver, Diana W. Bianchi, Charles D. Madsen, Jie Na, Geoffrey J. Beek, Asha Nair, Nicole J. Boczek, Margot A. Cousin, Pavel N. Pichurin, Peter C. Harris, Daniel L. Kraft, Eric W. Klee, Katharina Hopp, and Patrick R. Blackburn
- Subjects
0301 basic medicine ,Adult ,Male ,Adolescent ,RNA Splicing ,Pedigree chart ,Disease ,Biology ,medicine.disease_cause ,Compound heterozygosity ,Ciliopathies ,Article ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Exome sequencing ,Mutation ,Infant ,Orofaciodigital Syndromes ,medicine.disease ,Phenotype ,Pedigree ,Ciliopathy ,030104 developmental biology ,Child, Preschool ,Aborted Fetus ,Female ,Microtubule-Associated Proteins - Abstract
Whole exome sequencing (WES) is utilized in diagnostic odyssey cases to identify the underlying genetic cause associated with complex phenotypes. Recent publications suggest that WES reveals the genetic cause in ~25% of these cases and is most successful when applied to children with neurological disease. The residual 75% of cases remain genetically elusive until more information becomes available in the literature or functional studies are pursued. WES performed on three families with presumed ciliopathy diagnoses, including orofaciodigital (OFD) syndrome, fetal encephalocele, or Joubert-related disorder, identified compound heterozygous variants in C2CD3. Biallelic variants in C2CD3 have previously been associated with ciliopathies, including OFD syndrome type 14 (OFD14; MIM: 615948). As three of the six identified variants were predicted to affect splicing, exon-skipping analysis using either RNA sequencing or PCR-based methods were completed to determine the pathogenicity of these variants, and showed that each of the splicing variants led to a frameshifted protein product. Using these studies in combination with the 2015 ACMG guidelines, each of the six identified variants were classified as either pathogenic or likely pathogenic, and are therefore likely responsible for our patients' phenotypes. Each of the families had a distinct clinical phenotype and severity of disease, extending from lethal to viable. These findings highlight that there is a broad phenotypic spectrum associated with C2CD3-mediated disease and not all patients present with the typical features of OFD14.
- Published
- 2018
39. Unusual Prenatal Genomic Results Provide Proof-of-Principle of the Liquid Biopsy for Cancer Screening
- Author
-
Diana W. Bianchi
- Subjects
medicine.medical_specialty ,Clinical Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Neoplasms ,Cancer screening ,Morning sickness ,Medicine ,Humans ,Mass Screening ,Liquid biopsy ,Early Detection of Cancer ,Fetus ,030219 obstetrics & reproductive medicine ,Plasma samples ,business.industry ,Obstetrics ,Biochemistry (medical) ,Liquid Biopsy ,Cancer ,Genomics ,medicine.disease ,Predictive value ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,business - Abstract
A best-selling book, entitled, “What to Expect When You're Expecting,” has provided reassuring information to several generations of pregnant women (1). Filled with advice on topics such as nutrition and morning sickness, it lacks a chapter on being diagnosed with cancer during pregnancy. Why would it even have such a chapter? Pregnant women represent the epitome of good health and the promise of new life. No one expects to be diagnosed with cancer while pregnant. Yet, as Dharajiya and colleagues demonstrate in this issue of Clinical Chemistry (2), incidental detection of maternal neoplasia is possible while performing prenatal whole genome DNA sequencing to screen for fetal chromosomal aneuploidies. Not only is it possible, it is not uncommon. It is also creating new ethical and clinical dilemmas. These investigators described 55 maternal plasma samples sequenced over a 3-year period in a large-scale clinical laboratory that had altered genome profiles and were suspicious for maternal neoplasm. Of these, 43 of 55 (78.1%) had certain clinical follow-up information available. Forty of 43 had confirmed maternal neoplasms; half were due to uterine leiomyomas and half were due to a variety of malignant tumors. Of these, 7 of 20 were already diagnosed, but 13 women who were expecting information about their fetus instead received the worrisome news that their plasma DNA profile put them at risk for cancer. Starting in 2011, analysis of circulating cell-free DNA (cfDNA) in the blood of pregnant women began to be offered clinically as a prenatal screen for trisomies 13, 18, and 21 (3). Owing to its superior sensitivity and positive predictive values compared to serum biochemistry and ultrasound markers, the cfDNA test became rapidly incorporated into prenatal clinical care. By 2013, however, reports began to appear that described examples of false-positive test results (4). Experts questioned the methodologies used …
- Published
- 2017
40. New Perspectives for the Rescue of Cognitive Disability in Down Syndrome
- Author
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Diana W. Bianchi, Tarik F. Haydar, Mara Dierssen, Jean-Maurice Delabar, Carmen Martínez-Cué, Renata Bartesaghi, Bartesaghi, Renata, Haydar, Tarik F., Delabar, Jean Maurice, Dierssen, Mara, Martinez-Cué, Carmen, Bianchi, Diana W., and Universidad de Cantabria
- Subjects
medicine.medical_specialty ,Down syndrome ,Brain development ,Chromosomes, Human, Pair 21 ,Intellectual disability ,Genetic Condition ,Mouse model ,Mice ,Cognitive disabilities ,medicine ,Animals ,Humans ,Brain abnormalitie ,Effects of sleep deprivation on cognitive performance ,Psychiatry ,Neuroscience (all) ,General Neuroscience ,Symposium and Mini-Symposium ,medicine.disease ,Disease Models, Animal ,Cognition Disorders ,Preventive therapie ,Psychology ,Chromosome 21 ,Neurocognitive - Abstract
Down syndrome (DS) is a relatively common genetic condition caused by the triplication of human chromosome 21. No therapies currently exist for the rescue of neurocognitive impairment in DS. This review presents exciting findings showing that it is possible to restore brain development and cognitive performance in mouse models of DS with therapies that can also apply to humans. This knowledge provides a potential breakthrough for the prevention of intellectual disability in DS.
- Published
- 2015
41. The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome
- Author
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Leah C. Graham, Heather C. Wick, Faycal Guedj, Jeroen L. A. Pennings, Klaus A. Miczek, Donna K. Slonim, Diana W. Bianchi, and Millie A. Ferres
- Subjects
Male ,Down syndrome ,Neurogenesis ,Down-Regulation ,Biology ,Article ,Transcriptome ,Andrology ,Mice ,Fetus ,Pregnancy ,Gene expression ,Genetics ,medicine ,Animals ,Humans ,Genetics (clinical) ,Gene Expression Profiling ,Wild type ,Brain ,Embryo ,Anatomy ,medicine.disease ,Phenotype ,Up-Regulation ,Mice, Inbred C57BL ,Disease Models, Animal ,Female ,Down Syndrome - Abstract
Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3–21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition. © 2015 Wiley Periodicals, Inc.
- Published
- 2015
42. CSAX: Characterizing Systematic Anomalies in eXpression Data
- Author
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Andrea G. Edlow, Donna K. Slonim, Keith Noto, Heather C. Wick, Diana W. Bianchi, and Saeed Majidi
- Subjects
Adult ,Blood Platelets ,Feature vector ,Datasets as Topic ,Sample (statistics) ,Computational biology ,Biology ,Bioinformatics ,Fetus ,Pregnancy ,Databases, Genetic ,Genetics ,Humans ,Retinopathy of Prematurity ,Obesity ,Platelet activation ,Molecular Biology ,Research Articles ,Gene Expression Profiling ,Infant, Newborn ,Amniotic Fluid ,Platelet Activation ,Expression (mathematics) ,Gene expression profiling ,Oxidative Stress ,Computational Mathematics ,Phenotype ,Computational Theory and Mathematics ,Pregnancy Trimester, Second ,Modeling and Simulation ,Female ,Anomaly detection ,Transcriptome ,Algorithms ,Software ,Curse of dimensionality - Abstract
Methods for translating gene expression signatures into clinically relevant information have typically relied upon having many samples from patients with similar molecular phenotypes. Here, we address the question of what can be done when it is relatively easy to obtain healthy patient samples, but when abnormalities corresponding to disease states may be rare and one-of-a-kind. The associated computational challenge, anomaly detection, is a well-studied machine-learning problem. However, due to the dimensionality and variability of expression data, existing methods based on feature space analysis or individual anomalously expressed genes are insufficient. We present a novel approach, CSAX, that identifies pathways in an individual sample in which the normal expression relationships are disrupted. To evaluate our approach, we have compiled and released a compendium of public expression data sets, reformulated to create a test bed for anomaly detection. We demonstrate the accuracy of CSAX on the data sets in our compendium, compare it to other leading methods, and show that CSAX aids in both identifying anomalies and explaining their underlying biology. We describe an approach to characterizing the difficulty of specific expression anomaly detection tasks. We then illustrate CSAX's value in two developmental case studies. Confirming prior hypotheses, CSAX highlights disruption of platelet activation pathways in a neonate with retinopathy of prematurity and identifies, for the first time, dysregulated oxidative stress response in second trimester amniotic fluid of fetuses with obese mothers. Our approach provides an important step toward identification of individual disease patterns in the era of precision medicine.
- Published
- 2015
43. Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease
- Author
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William K. Seltzer, Diana W. Bianchi, Nicola Flowers, Meredith Halks-Miller, Mark D. Pertile, Catalin Barbacioru, Darcy Vavrek, and Sarah L. Kinnings
- Subjects
0301 basic medicine ,Adult ,Placenta Diseases ,Chorionic villus sampling ,Physiology ,Trisomy ,030105 genetics & heredity ,Biology ,Bioinformatics ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Risk Factors ,medicine ,Chromosomes, Human ,Humans ,Confined placental mosaicism ,Demography ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,Trisomy 16 ,Chromosome ,Karyotype ,General Medicine ,Sequence Analysis, DNA ,Placental disease ,medicine.disease ,Uniparental disomy ,Fetal Diseases ,Treatment Outcome ,Chorionic Villi Sampling ,Female ,Cell-Free Nucleic Acids - Abstract
Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare autosomal trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected “target” chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications.
- Published
- 2017
44. Prenatal DNA Sequencing: Clinical, Counseling, and Diagnostic Laboratory Considerations
- Author
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Ahmad N, Abou Tayoun, Nancy B, Spinner, Heidi L, Rehm, Robert C, Green, and Diana W, Bianchi
- Subjects
Whole Genome Sequencing ,Clinical Laboratory Techniques ,Pregnancy ,Prenatal Diagnosis ,Humans ,Female ,Genetic Counseling ,Article - Abstract
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 WileySons, Ltd.
- Published
- 2017
45. In case you missed it: the Prenatal Diagnosis editors bring you the most significant advances of 2016
- Author
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Tim, Van Mieghem, Diana W, Bianchi, Brynn, Levy, Jan, Deprest, Lyn S, Chitty, and Alessandro, Ghidini
- Subjects
Gene Editing ,Publishing ,Embryo Research ,Viral Tropism ,Mosaicism ,Pregnancy ,Fetoscopy ,Prenatal Diagnosis ,Humans ,Female ,Editorial Policies ,Mitochondrial Replacement Therapy - Published
- 2017
46. Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome
- Author
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Thomas M. Scholl, Donna K. Slonim, Heather C. Wick, Diana W. Bianchi, Kirby L. Johnson, and Lauren J. Massingham
- Subjects
DNA, Complementary ,Amniotic fluid ,Karyotype ,Down-Regulation ,Turner Syndrome ,Pilot Projects ,Biology ,Bioinformatics ,Article ,Transcriptome ,Pregnancy ,Turner syndrome ,Gene expression ,Genetics ,medicine ,Humans ,RNA, Messenger ,Gene ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Chromosomes, Human, X ,Gene Expression Profiling ,Gene Expression Regulation, Developmental ,Amniotic Fluid ,Aneuploidy ,medicine.disease ,Up-Regulation ,Gene expression profiling ,Phenotype ,Organ Specificity ,Case-Control Studies ,Female ,XIST - Abstract
Turner syndrome is a sex chromosome aneuploidy with characteristic malformations. Amniotic fluid, a complex biological material, could contribute to the understanding of Turner syndrome pathogenesis. In this pilot study, global gene expression analysis of cell-free RNA in amniotic fluid supernatant was utilized to identify specific genes/organ systems that may play a role in Turner syndrome pathophysiology. Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five euploid female fetuses matched for gestational age was extracted, amplified, and hybridized onto Affymetrix(®) U133 Plus 2.0 arrays. Significantly differentially regulated genes were identified using paired t tests. Biological interpretation was performed using Ingenuity Pathway Analysis and BioGPS gene expression atlas. There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (p < 0.0001); SHOX was not differentially expressed. One of the most highly represented organ systems was the hematologic/immune system, distinguishing the Turner syndrome transcriptome from other aneuploidies we previously studied. Manual curation of the differentially expressed gene list identified genes of possible pathologic significance, including NFATC3, IGFBP5, and LDLR. Transcriptomic differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction. Other genes identified with possible pathologic significance are associated with cardiac and skeletal systems, which are known to be affected in females with Turner syndrome. The discovery-driven approach described here may be useful in elucidating novel mechanisms of disease in Turner syndrome.
- Published
- 2014
47. Prenatal treatment of Down syndrome
- Author
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Faycal Guedj, Diana W. Bianchi, and Jean-Maurice Delabar
- Subjects
Down syndrome ,DYRK1A ,Neurogenesis ,Mice, Transgenic ,Prenatal diagnosis ,Physical exercise ,Protein Serine-Threonine Kinases ,Bioinformatics ,Receptors, N-Methyl-D-Aspartate ,Catechin ,Choline ,Mice ,Neural Stem Cells ,Receptors, GABA ,Pregnancy ,Fluoxetine ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Apigenin ,Environmental enrichment ,business.industry ,Obstetrics and Gynecology ,Prenatal Care ,Cognition ,Protein-Tyrosine Kinases ,medicine.disease ,Disease Models, Animal ,Oxidative Stress ,Neuroprotective Agents ,Animals, Newborn ,Female ,Down Syndrome ,business ,Signal Transduction ,Stem Cell Transplantation ,medicine.drug - Abstract
Purpose of review Down syndrome affects more than 5 million people globally. During the last 10 years, there has been a dramatic increase in the research efforts focused on therapeutic interventions to improve learning and memory in Down syndrome. Recent findings This review summarizes the different functional abnormalities targeted by researchers in mouse models of Down syndrome. Three main strategies have been used: neural stem cell implantation; environmental enrichment and physical exercise; and pharmacotherapy. Pharmacological targets include the choline pathway, GABA and NMDA receptors, DYRK1A protein, oxidative stress and pathways involved in development and neurogenesis. Many strategies have improved learning and memory as well as electrophysiological and molecular alterations in affected animals. To date, eight molecules have been tested in human adult clinical trials. No studies have yet been performed on infants. However, compelling studies reveal that permanent brain alterations originate during fetal life in Down syndrome. Early prenatal diagnosis offers a 28 weeks window to positively impact brain development and improve postnatal cognitive outcome in affected individuals. Only a few approaches (Epigallocatechine gallate, NAP/SAL, fluoxetine, and apigenin) have been used to treat mice in utero; these showed therapeutic effects that persisted to adulthood. Summary In this article, we discuss the challenges, recent progress, and lessons learned that pave the way for new therapeutic approaches in Down syndrome.
- Published
- 2014
48. Integration of Noninvasive DNA Testing for Aneuploidy into Prenatal Care: What Has Happened Since the Rubber Met the Road?
- Author
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Diana W. Bianchi and Louise Wilkins-Haug
- Subjects
Gynecology ,Fetus ,medicine.medical_specialty ,Pregnancy ,Massive parallel sequencing ,Cell-Free System ,Obstetrics ,Biochemistry (medical) ,Clinical Biochemistry ,Aneuploidy ,Gestational age ,Prenatal diagnosis ,DNA ,Prenatal care ,Biology ,medicine.disease ,Article ,Prenatal Diagnosis ,medicine ,Humans ,False Positive Reactions ,Female ,Confined placental mosaicism - Abstract
BACKGROUNDOver the past 2 years, noninvasive prenatal testing (NIPT), which uses massively parallel sequencing to align and count DNA fragments floating in the plasma of pregnant women, has become integrated into prenatal care. Professional societies currently recommend offering NIPT as an advanced screen to pregnant women at high risk for fetal aneuploidy, reserving invasive diagnostic procedures for those at the very highest risk.CONTENTIn this review, we summarize the available information on autosomal and sex chromosome aneuploidy detection. Clinical performance in CLIA-certified, College of American Pathology–accredited laboratories appears to be equivalent to prior clinical validation studies, with high sensitivities and specificities and very high negative predictive values. The main impact on clinical care has been a reduction in invasive procedures. Test accuracy is affected by the fetal fraction, the percentage of fetal DNA in the total amount of circulating cell-free DNA. Fetal fraction is in turn affected by maternal body mass index, gestational age, type of aneuploidy, singleton vs multiples, and mosaicism. Three studies comparing NIPT to serum or combined screening for autosomal aneuploidy all show that NIPT has significantly lower false-positive rates (approximately 0.1%), even in all-risk populations. A significant number of the discordant positive cases have underlying biological reasons, including confined placental mosaicism, maternal mosaicism, cotwin demise, or maternal malignancy.SUMMARYNIPT performs well as an advanced screen for whole chromosome aneuploidy. Economic considerations will likely dictate whether its use can be expanded to all risk populations and whether it can be applied routinely for the detection of subchromosome abnormalities.
- Published
- 2014
49. Circulating Fetal Cell-Free DNA Fractions Differ in Autosomal Aneuploidies and Monosomy X
- Author
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Amy J. Sehnert, Richard P. Rava, Diana W. Bianchi, and Anupama Srinivasan
- Subjects
Male ,medicine.medical_specialty ,Monosomy ,Trisomy 13 Syndrome ,Clinical Biochemistry ,Turner Syndrome ,Aneuploidy ,Chromosome Disorders ,Trisomy ,Prenatal diagnosis ,Biology ,Sensitivity and Specificity ,Fetus ,Pregnancy ,Prenatal Diagnosis ,Internal medicine ,medicine ,Humans ,Genetic Testing ,Cell-Free System ,Chromosomes, Human, Pair 13 ,Biochemistry (medical) ,Gestational age ,Karyotype ,DNA ,medicine.disease ,Endocrinology ,Female ,Down Syndrome ,Chromosomes, Human, Pair 18 ,Trisomy 18 Syndrome - Abstract
BACKGROUND Noninvasive prenatal testing based on massively parallel sequencing (MPS) of cell-free DNA in maternal plasma has become rapidly integrated into clinical practice for detecting fetal chromosomal aneuploidy. We directly determined the fetal fraction (FF) from results obtained with MPS tag counting and examined the relationships of FF to such biological parameters as fetal karyotype and maternal demographics. METHODS FF was determined from samples previously collected for the MELISSA (Maternal Blood Is Source to Accurately Diagnose Fetal Aneuploidy) study. Samples were resequenced, analyzed blindly, and aligned to the human genome (assembly hg19). FF was calculated in pregnancies with male or aneuploid fetuses by means of an equation that incorporated the ratio of the tags in these samples to those of a euploid training set. RESULTS The mean (SD) FF from euploid male pregnancies was 0.126 (0.052) (n = 160). Weak but statistically significant correlations were found between FF and the maternal body mass index (r2 = 0.18; P = 2.3 × 10−8) and between FF and gestational age (r2 = 0.02; P = 0.047). No relationship with maternal ethnicity or age was observed. Mean FF values for trisomies 21 (n = 90), 18 (n = 38), and 13 (n = 16) and for monosomy X (n = 20) were 0.135 (0.051), 0.089 (0.039), 0.090 (0.062), and 0.106 (0.045), respectively. CONCLUSIONS MPS tag-count data can be used to determine FF directly and accurately. Compared with male euploid fetuses, the FF is higher in maternal plasma when the fetus has trisomy 21 and is lower when the fetus has trisomy 18, 13, or monosomy X. The different biologies of these aneuploidies have practical implications for the determination of cutoff values, which in turn will affect the diagnostic sensitivity and specificity of the test.
- Published
- 2014
50. Prenatal testing for neuropsychiatric disorders
- Author
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Alessandro, Ghidini and Diana W, Bianchi
- Subjects
Neurodevelopmental Disorders ,Pregnancy ,Prenatal Diagnosis ,Humans ,Female ,Genetic Testing - Published
- 2016
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