Search

Autism spectrum disorder and intellectual disability are associated with psychiatric comorbidities, yet a 2009 study of US child and adolescent psychiatry program directors indicated that psychiatry residents receive insufficient training in autism spectrum disorder/intellectual disability. This follow-up study surveyed child and adolescent psychiatry and general psychiatry program directors to assess (1) the current extent of residency training in autism spectrum disorder/intellectual disability, (2) program director perceptions of educational topics and resident competency in autism spectrum disorder/intellectual disability, and (3) preferred resources to strengthen autism spectrum disorder/intellectual disability training. As in 2009, many child and adolescent psychiatry program directors reported few lecture hours, although current child and adolescent psychiatry residents saw slightly more patients with autism spectrum disorder but not intellectual disability. General psychiatry program directors reported fewer lecture hours in autism spectrum disorder/intellectual disability and fewer patients with autism spectrum disorder than child and adolescent psychiatry program directors. Both child and adolescent psychiatry and general psychiatry program directors recognized the importance of a range of educational topics in autism spectrum disorder/intellectual disability. Child and adolescent psychiatry program directors reported higher resident competency, and lecture hours and patients seen moderately correlated with resident competency. Program directors indicated that online videos and other resources would help improve autism spectrum disorder/intellectual disability training in their programs. Collectively, these findings suggest minimal improvements in autism spectrum disorder/intellectual disability training over the past decade and highlight the urgent need to advance psychiatry training in this field through dissemination of resources. Lay abstract Children, adolescents, and adults with autism spectrum disorder and intellectual disability experience high rates of co-occurring psychiatric conditions throughout their lifetime. However, there is a shortage of psychiatrists to treat these populations. We evaluated how much education psychiatrists-in-training receive on how to care for individuals with autism spectrum disorder/intellectual disability. We found that in many psychiatry programs, residents receive limited training experiences in autism spectrum disorder/intellectual disability involving lectures and patient contact and that psychiatry program directors would benefit from more resources to strengthen education in autism spectrum disorder/intellectual disability.

ImportanceAssociations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding.ObjectiveTo assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months.Design, Setting, and ParticipantsThis cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants.ExposuresMaternal symptomatic or asymptomatic SARS-CoV-2 infection.Main Outcomes and MeasuresInfant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language.ResultsAmong 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (β = 0.31; 95% CI, −2.97 to 3.58), gross motor (β = 0.82; 95% CI, −1.34 to 2.99), fine motor (β = 0.36; 95% CI, −0.74 to 1.47), expressive language (β = −1.00; 95% CI, −4.02 to 2.02), or receptive language (β = 0.45; 95% CI, −2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores.Conclusions and RelevanceIn this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

IMPORTANCE: Associations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown. OBJECTIVE: To examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months. DESIGN, SETTING, AND PARTICIPANTS: A cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses. EXPOSURES: Maternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic. MAIN OUTCOMES AND MEASURES: Outcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months. RESULTS: Of 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, −5.63; 95% CI, −8.75 to −2.51; F(1,267) = 12.63; P

The intrauterine environment strongly influences development. Neurodevelopmental effects of in utero exposure to maternal SARS-CoV-2 infection are widely speculated but currently unknown. The COVID-19 Mother Baby Outcomes (COMBO) initiative was established at Columbia University Irving Medical Center (CUIMC) in New York City to prospectively study the health and wellbeing of infants with and without in utero exposure to maternal SARS-CoV-2 infection. We report findings on 6-month neurodevelopmental outcomes using the parental-report Ages & Stages Questionnaire, 3rd Edition (ASQ-3), from 107 in utero exposed and 131 unexposed full-term infants born between March and December, 2020. We compare these infants to a historical cohort comprised of 62 infants born at CUIMC at least two months prior to the onset of the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with differences on any ASQ-3 subdomain regardless of infection timing or severity, however, infants born during the pandemic had significantly lower scores on gross motor, fine motor, and personal-social subdomains when compared to the historical cohort. Infants born to women who were in the first trimester of pregnancy during the peak of the pandemic in NYC had the lowest personal-social scores. Birth during the pandemic, but not maternal SARS-CoV-2 infection, was associated with differences in neurodevelopmental outcomes at 6-months. These early findings suggest significantly higher public health impact for the generation born during the COVID-19 pandemic than previously anticipated.

While neural networks are powerful approximators used to classify or embed data into lower dimensional spaces, they are often regarded as black boxes with uninterpretable features. Here we propose Graph Spectral Regularization for making hidden layers more interpretable without significantly impacting performance on the primary task. Taking inspiration from spatial organization and localization of neuron activations in biological networks, we use a graph Laplacian penalty to structure the activations within a layer. This penalty encourages activations to be smooth either on a predetermined graph or on a feature-space graph learned from the data via co-activations of a hidden layer of the neural network. We show numerous uses for this additional structure including cluster indication and visualization in biological and image data sets.

Analysis of de novo mutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWAS) strongly suggests that variants important to human diseases often lie in non-coding regions. Extending DNM-based approaches to non-coding sequences is, however, challenging because the functional significance of non-coding mutations is difficult to predict. We propose a new statistical framework for analyzing DNMs from whole-genome sequencing (WGS) data. This method, TADA-Annotations (TADA-A), is a major advance of the TADA method we developed earlier for DNM analysis in coding regions. TADA-A is able to incorporate many functional annotations such as conservation and enhancer marks, learn from data which annotations are informative of pathogenic mutations and combine both coding and non-coding mutations at the gene level to detect risk genes. It also supports meta-analysis of multiple DNM studies, while adjusting for study-specific technical effects. We applied TADA-A to WGS data of ∼300 autism family trios across five studies, and discovered several new autism risk genes. The software is freely available for all research uses.

We tested the hypothesis that progesterone (P(4)) withdrawal is the primary mechanism by which intrauterine bacteria induce preterm labor in mice. CD-1 mice on Day 14.5 of a 19- to 20-day gestation were subjected to one of four treatments: 1) intrauterine injection of sterile medium, 2) intrauterine injection of 10(6) heat-killed Escherichia coli bacteria, 3) intrauterine injection of 10(9) heat-killed E. coli, or 4) ovariectomy. Mice were then killed at four time points from 0.75 to 11 h after surgery for serum collection. Separately, animals were pretreated either with s.c. P(4) or with vehicle 2 h before ovariectomy or high-dose bacterial inoculation. Ovariectomy led to a rapid fall in serum P(4) levels of 60% by 1 h and 81% by 8 h compared with levels in controls (P < 0.001). In contrast, intrauterine inoculation with 10(9) bacteria led to a more modest decline in P(4) of only 28% by 8 h (P = 0.24, which was no different from that of 10(6) bacteria, an inoculum below the threshold for preterm delivery). Despite significantly lower levels of P(4) in the ovariectomy group, time to delivery was significantly shorter with 10(9) bacteria intrauterine (24 +/- 5.6 h vs. 19 +/- 3.6 h, P = 0.03). Pretreatment with 1.5 mg P(4) per mouse prolonged the interval to delivery following both ovariectomy and high-dose bacteria, in association with pharmacologically elevated serum P(4) levels. In contrast, physiologic P(4) supplementation (0.375 mg/mouse) prolonged gestation only in the ovariectomy group. We conclude that withdrawal of endogenous P(4) is not the primary cause of labor following intrauterine bacterial inoculation in mice.

OBJECTIVE: We tested the hypothesis that intrauterine bacterial inoculation induces labor via expression of the inflammatory cytokine interleukin-1 (IL-1) in a murine model. STUDY DESIGN: Pregnant mice on day 14.5 of a 19-20 day gestation were inoculated with killed Escherichia coli or sterile media into either (a) the right uterine horn, (b) the right uterine horn following its surgical isolation from the contralateral horn and cervix, or (c) the kidney. Cytokine levels in gestational tissues and maternal serum were determined by use of enzyme-linked immunosorbent assay (ELISA). In a separate experiment, bacterially induced preterm delivery was compared between mice lacking a functional IL-1 receptor and wild-type control litter mates. RESULTS: Killed E coli induced delivery within 48 hours with similar dose-response curves regardless of inoculation site (intact uterine horn, isolated uterine horn, or kidney). Bacterial inoculation of an isolated right horn caused dramatic increases in local expression of IL-1 and IL-6. However, delivery occurred from the uninjected horn without corresponding upregulation of cytokines, with the exception of a modest rise within fetal membranes. Mice lacking a functional IL-1 receptor were no different from wild-type mice in their susceptibility to bacterially induced delivery. CONCLUSION: Bacterially induced labor in the murine model does not require IL-1 signaling. (Am J Obstet Gynecol 2002;186:523-30.)

Objective: We propose that elucidation of the pathophysiology of preterm labor can be achieved with genome-scale analyses of differential gene expression. Study Design: CD-1 mice on day 14.5 of a 19- to 20-day gestation were assigned to one of 4 treatment groups modeling different clinical conditions (n = 5 per group): group A, infection with labor (intrauterine injection of 10 10 heat-killed Escherichia coli , which causes delivery within an average of 20 hours); group B, infection without labor (intrauterine injection of 10 7 heat-killed E coli , which leads to normal delivery at term); group C, labor without infection (ovariectomy, which causes delivery within an average of 27 hours); and group D, no infection and no labor (intrauterine injection of vehicle). Total pooled myometrial RNA was prepared 3.5 hours after surgery for groups A, B, and D and 5 hours after surgery for group C. The relative expression of 4963 genes was assayed in these pools by using DNA microarrays. Transcripts specifically involved in infection-induced labor were identified by subtracting from the list of differentially regulated genes in group A those with common expression in groups B and C. Results: In group A 68 differentially expressed transcripts (≥2-fold upregulation or downregulation) were identified. Among these are 39 characterized genes. Fourteen (45%) are involved in inflammatory responses, 7 (18%) are involved in growth-differentiation-oncogenesis, and 3 (8%) are involved in apoptosis. Subtraction identified 13 gene products most likely to be important for bacterially induced labor, as opposed to labor without infection or bacterial exposure without labor. Conclusion: This study demonstrates the potential of the subtractive DNA microarray technique to identify transcripts important specifically for bacterially induced preterm labor. (Am J Obstet Gynecol 2001;185:716-24.)

Normal mammalian growth and development are highly dependent on the regulation of the expression and activity of the Myc family of transcription factors. Mxi1-mediated inhibition of Myc activities requires interaction with mammalian Sln3A or Sin3B proteins, which have been purported to act as scaffolds for additional co-repressor factors. The identification of two such Sin3-associated factors, the nuclear receptor co-repressor (N-CoR) and histone deacetylase (HD1), provides a basis for Mxi1/Sin3-induced transcriptional repression and tumour suppression.

We tested the hypothesis that progesterone (P(4)) withdrawal is the primary mechanism by which intrauterine bacteria induce preterm labor in mice. CD-1 mice on Day 14.5 of a 19- to 20-day gestation were subjected to one of four treatments: 1) intrauterine injection of sterile medium, 2) intrauterine injection of 10(6) heat-killed Escherichia coli bacteria, 3) intrauterine injection of 10(9) heat-killed E. coli, or 4) ovariectomy. Mice were then killed at four time points from 0.75 to 11 h after surgery for serum collection. Separately, animals were pretreated either with s.c. P(4) or with vehicle 2 h before ovariectomy or high-dose bacterial inoculation. Ovariectomy led to a rapid fall in serum P(4) levels of 60% by 1 h and 81% by 8 h compared with levels in controls (P0.001). In contrast, intrauterine inoculation with 10(9) bacteria led to a more modest decline in P(4) of only 28% by 8 h (P = 0.24, which was no different from that of 10(6) bacteria, an inoculum below the threshold for preterm delivery). Despite significantly lower levels of P(4) in the ovariectomy group, time to delivery was significantly shorter with 10(9) bacteria intrauterine (24 +/- 5.6 h vs. 19 +/- 3.6 h, P = 0.03). Pretreatment with 1.5 mg P(4) per mouse prolonged the interval to delivery following both ovariectomy and high-dose bacteria, in association with pharmacologically elevated serum P(4) levels. In contrast, physiologic P(4) supplementation (0.375 mg/mouse) prolonged gestation only in the ovariectomy group. We conclude that withdrawal of endogenous P(4) is not the primary cause of labor following intrauterine bacterial inoculation in mice.

Silencing of gene transcription involves local chromatin modification achieved through the local recruitment of large multiprotein complexes containing histone deacetylase (HDAC) activity. The mammalian corepressors mSin3A and mSin3B have been shown to play a key role in this process by tethering HDACs 1 and 2 to promoter-bound transcription factors. Similar mechanisms appear to be operative in yeast, in which epistasis experiments have established that the mSin3 and HDAC orthologs (SIN3 and RPD3), along with a novel protein, SDS3, function in the same repressor pathway. Here, we report the identification of a component of the mSin3-HDAC complex that bears homology to yeast SDS3, physically associates with mSin3 proteins in vivo, represses transcription in a manner that is partially dependent on HDAC activity, and enables HDAC1 catalytic activity in vivo. That key physical and functional properties are also shared by yeast SDS3 underscores the central role of the Sin3-HDAC-Sds3 complex in eukaryotic cell biology, and the discovery of mSds3 in mammalian cells provides a new avenue for modulating the activity of this complex in human disease.