Medical findings and congenital anomalies in Vermeer's paintings.

The 17th century was a time of scientific discovery in Europe. Leading academic centers provided the general population with an opportunity to view anatomic dissections of human bodies. Rather than portray idealized versions of individuals, Dutch painters were committed to accurately representing their models. This was true for Johannes Vermeer. The 2023 exhibition of Vermeer's paintings at the Rijksmuseum in Amsterdam provided an unprecedented opportunity to observe 28 of his 37 existing paintings simultaneously in person. Here the authors suggest that in at least eight paintings a visibly pregnant woman is present. Vermeer's wife was pregnant or lactating most of the time during their 22-year marriage. Further, evidence of specific medical findings and congenital anomalies such as polydactyly, ectrodactyly, alopecia, kyphosis, and hyperthyroidism were observed in the paintings. These have not been previously reported in the medical or art history literature.

Embryonic statistical analyses reveal 2 growth phenotypes in mouse models of Down syndrome.

BACKGROUND: Down syndrome is associated with several comorbidities, including intellectual disability, growth restriction, and congenital heart defects. The prevalence of Down syndrome-associated comorbidities is highly variable, and intellectual disability, although fully penetrant, ranges from mild to severe. Understanding the basis of this interindividual variability might identify predictive biomarkers of in utero and postnatal outcomes that could be used as endpoints to test the efficacy of future therapeutic interventions. OBJECTIVE: The main objective of this study was to examine if antenatal interindividual variability exists in mouse models of Down syndrome and whether applying statistical approaches to clinically relevant measurements (ie, the weights of the embryo, placenta, and brain) could define cutoffs that discriminate between subgroups of trisomic embryos. STUDY DESIGN: Three commonly used mouse models of Down syndrome (Dp(16)1/Yey, Ts65Dn, and Ts1Cje) and a new model (Ts66Yah) were used in this study. Trisomic and euploid littermate embryos were used from each model with total numbers of 102 for Ts66Yah, 118 for Dp(16)1/Yey, 92 for Ts65Dn, and 126 for Ts1Cje. Placental, embryonic, and brain weights and volumes at embryonic day 18.5 were compared between genotypes in each model. K-mean clustering analysis was applied to embryonic and brain weights to identify severity classes in trisomic embryos, and brain and placental volumetric measurements were compared between genotypes and classes for each strain. In addition, Ts66Yah embryos were examined for malformations because embryonic phenotypes have never been examined in this model. RESULTS: Reduced body and brain weights were present in Ts66Yah, Dp(16)1/Yey, and Ts65Dn embyos. Cluster analysis identified 2 severity classes in trisomic embryos-mild and severe-in all 4 models that were distinguishable using a putative embryonic weight cutoff of <0.5 standard deviation below the mean. Ts66Yah trisomic embryos develop congenital anomalies that are also found in humans with Down syndrome, including congenital heart defects and renal pelvis dilation. CONCLUSION: Statistical approaches applied to clinically relevant measurements revealed 2 classes of phenotypic severity in trisomic mouse models of Down syndrome. Analysis of severely affected trisomic animals may facilitate the identification of biomarkers and endpoints that can be used to prenatally predict outcomes and the efficacy of treatments.

Addressing the Public Health Crisis of Maternal Mortality: A National Research Agenda.

This Viewpoint discusses the National Institutes of Health initiative that focuses on research that reduces preventable maternal mortality, decreases severe maternal morbidity, and promotes health equity.

Biometric magnetic resonance imaging analysis of fetal brain development in Down syndrome.

OBJECTIVES: To assess brain development in living fetuses with Down syndrome (DS) by biometric measurements on fetal brain magnetic resonance images (MRI). METHODS: We scanned 10 MRIs of fetuses with confirmed trisomy 21 at birth and 12 control fetal MRIs without any detected anomalies. Fetal brain MRIs were analyzed using 14 fetal brain and skull biometric parameters. We compared measures between DS and controls in both raw MRIs and motion-corrected and anterior-posterior commissure-aligned images. RESULTS: In the reconstructed images, the measured values of the height of the cerebellar vermis (HV) and anteroposterior diameter of the cerebellar vermis (APDV) were significantly smaller, and the anteroposterior diameter of the fourth ventricle (APDF) was significantly larger in fetuses with DS than controls. In the raw MRIs, the measured values of the right lateral ventricle were significantly larger in fetuses with DS than in controls. Logistic regression analyses revealed that a new parameter, the cerebellar-to-fourth-ventricle ratio (i.e., (APDV * Height of the vermis)/APDF), was significantly smaller in fetuses with DS than controls and was the most predictive to distinguish between fetuses with DS and controls. CONCLUSIONS: The study revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared to the controls.

Patients' perspectives on prenatal screening results that suggest maternal cancer: A qualitative analysis.

OBJECTIVE: To explore patient perspectives after receiving non-invasive prenatal testing (NIPT) results that suggest maternal cancer. METHODS: Individuals who received non-reportable or discordant NIPT results during pregnancy and enrolled in a study were interviewed prior to and after receiving the outcome of their clinical evaluation for cancer. Interviews were independently coded by two researchers and analyzed thematically. RESULTS: Forty-nine participants were included. Three themes were identified: 1) limited pre-test awareness of maternal incidental findings caused considerable confusion for participants, whose initial concerns focused on their babies; 2) providers' communication influenced how participants perceived their risk of cancer and the need to be evaluated; and 3) participants perceived value in receiving maternal incidental findings from NIPT despite any stress it caused during their pregnancy. CONCLUSION: Participants viewed the ability to detect occult malignancy as an added benefit of NIPT and felt strongly that these results should be disclosed. Obstetric providers need to be aware of maternal incidental findings from NIPT, inform pregnant people of the potential to receive these results during pre-test counseling, and provide accurate and objective information during post-test counseling. CLINICAL TRIAL REGISTRATION: Incidental Detection of Maternal Neoplasia Through Non-Invasive Cell-Free DNA Analysis (IDENTIFY), a Natural History Study, NCT4049604.

Noninvasive Prenatal Testing Using Circulating DNA and RNA: Advances, Challenges, and Possibilities.

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.

The Impact of Mmu17 Non-Hsa21 Orthologous Genes in the Ts65Dn Mouse Model of Down Syndrome: The Gold Standard Refuted.

BACKGROUND: Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome, translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the gold standard. We used the novel Ts66Yah mouse that carries an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-Hsa21 orthologous region. METHODS: Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Because male Ts66Yah mice are fertile, parent-of-origin transmission of the extra chromosome was studied. RESULTS: Forty-five protein-coding genes mapped to the Ts65Dn Mmu17 non-Hsa21 orthologous region; 71%-82% are expressed during forebrain development. Several of these genes are uniquely overexpressed in Ts65Dn embryonic forebrain, producing major differences in dysregulated genes and pathways. Despite these differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in commonly dysregulated disomic genes and pathways. Delays in motor development, communication, and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed milder working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. CONCLUSIONS: Our findings suggest that triplication of the non-Hsa21 orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies.

Visual discrimination and inhibitory control deficits in mouse models of Down syndrome: A pilot study using rodent touchscreen technology.

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.

The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry.

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.

A new ethical framework to determine acceptable risks in fetal therapy trials.

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.

A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials.

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.

World Prematurity Day: it takes an NIH village to prevent preterm birth and improve treatments for preterm infants.

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.

Neurodevelopmental Clues to Neurodegeneration.

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.