Neurodevelopmental delay in children exposed to maternal SARS-CoV-2 in-utero.

It is unclear if SARS CoV-2 infection during pregnancy is associated with adverse neurodevelopmental repercussions to infants. We assessed pediatric neurodevelopmental outcomes in children born to mothers with laboratory-confirmed SARS CoV-2 infection during pregnancy. Neurodevelopmental outcomes of in-utero exposed children were compared to that of pre-pandemic control children in Los Angeles (LA), CA, USA and Rio de Janeiro, Brazil. Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), the gold standard tool for evaluating neurodevelopment until 36 months of age and Ages and Stages Questionnaires (ASQ-3), a frequently used screening instrument for evaluating neurodevelopment in this same age group were the assessment tools used. Developmental delay (DD) was defined as having a score < - 2 SD below the norm (< 70) in at least one of three Bayley-III domains, (cognitive, motor or language) or a score below the cut-off (dark zone) in at least one of five ASQ-3 domains (communication, gross motor, fine motor, problem solving, personal-social). Exposed children were born between April 2020 and December 2022 while control children were born between January 2016 to December 2019. Neurodevelopmental testing was performed in 300 children total: 172 COVID-19 exposed children between 5-30 months of age and 128 control children between 6-38 months of age. Bayley-III results demonstrated that 12 of 128 exposed children (9.4%) had DD versus 2 of 128 controls (1.6%), p = 0.0007. Eight of 44 additional exposed children had DD on ASQ-3 testing. Fully, 20 of 172 exposed children (11.6%) and 2 of 128 control children (1.6%), p = 0.0006 had DD. In Rio, 12% of exposed children versus 2.6% of controls, p = 0.02 had DD. In LA, 5.7% of exposed children versus 0 controls, p = 0.12 had DD. Severe/critical maternal COVID-19 predicted below average neurodevelopment in the exposed cohort (OR 2.6, 95% CI 1.1-6.4). Children exposed to antenatal COVID-19 have a tenfold higher frequency of DD as compared to controls and should be offered neurodevelopmental follow-up.

Prophylactic Unfractionated Heparin in Antepartum Hospitalizations: A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of gestational age-based dosing of unfractionated heparin (UFH) compared with standard dosing of UFH for thromboprophylaxis on an elevated serum activated partial thromboplastin time (aPTT) during prolonged antepartum hospitalizations. METHODS: This was a randomized trial of pregnant persons who were admitted in the antepartum period for at least 72 hours. Participants were randomly allocated to the standard dose of UFH (5,000 units subcutaneously every 12 hours) or the gestational age-based dose of UFH (first trimester [less than 14 weeks]: 5,000 units subcutaneously every 12 hours; second trimester [14-27 6/7 weeks]: 7,500 units subcutaneously every 12 hours; third trimester (28 weeks or more): 10,000 units subcutaneously every 12 hours). The primary outcome was the proportion of antepartum patients who had an elevated serum aPTT value above the normal range (more than 36.2 seconds) 6 hours after an UFH dose. Secondary outcomes included the development of venous thromboembolism (VTE) and reported side effects of heparin administration. RESULTS: Between December 15, 2020, and April 1, 2022, 97 patients with antepartum hospitalizations were screened and 46 were randomized: 22 allocated to standard dosing and 24 allocated to gestational age-based dosing of UFH. A significantly greater proportion of antepartum patients who received gestational age-based dosing had an abnormal elevation in aPTT compared with those who received standard dosing (33.3% vs 4.8%, P=.02). Gestational age-based dosing resulted in higher maximum [interquartile range] aPTT (30.4 [27.4, 37.5] vs 26.6 [23.0, 29.6], P=.01) and anti-Xa levels (0.09 [0.09, 0.11] vs 0.09 [0.09, 0.09], P=.04). There was no significant difference in VTE between groups (P=.47). CONCLUSION: Gestational age-based dosing of UFH for thromboprophylaxis of antepartum hospitalizations was associated with significantly increased rates of elevated coagulation parameters compared with standard fixed dosing. This study suggests a need for close monitoring if higher doses of UFH during pregnancy are used later in gestation. The efficacy of gestational age-based dosing compared with standard dosing for UFH to prevent thromboembolic events remains an area for future investigation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04635839.

Respiratory distress in SARS-CoV-2 exposed uninfected neonates followed in the COVID Outcomes in Mother-Infant Pairs (COMP) Study.

Respiratory distress (RD) has been reported in SARS-CoV-2 exposed uninfected (SEU) term neonates. Prior studies suggest that prenatal exposure to Coronavirus Disease 19 (COVID-19) may activate an inflammatory cascade in the newborn airway. In this study, we examine the relationship between maternal COVID-19 vaccination and neonatal RD using a longitudinal cohort of mother-infant pairs in Los Angeles, CA. Two-hundred and twenty-one mothers with laboratory confirmed SARS-CoV-2 during pregnancy and 227 exposed fetuses are enrolled in our study. Maternal disease severity and neonatal RD variables were defined based on current accepted clinical criteria. To explore the multifactorial associations between maternal COVID-19 parameters and infant RD, we utilize a multivariable logistic regression model and a proteomic sub-analysis to propose a pathway for the development of RD following in utero exposure to SARS-CoV-2. Unusually high rates of RD are observed in SEU infants (17%). The odds ratio of RD is 3.06 (95% CI:1.08-10.21) in term neonates born to unvaccinated individuals versus those born to individuals vaccinated prior to maternal infection. Proteomic analysis reveals a robust inflammatory response associated with ciliary dysregulation and enhanced IgE production among SEU neonates with RD. Maternal vaccination against COVID-19 reduces the frequency of neonatal RD.

Understanding the multifaceted role of miRNAs in Alzheimer's disease pathology.

Small non-coding RNAs (miRNAs) regulate gene expression by binding to mRNA and mediating its degradation or inhibiting translation. Since miRNAs can regulate the expression of several genes, they have multiple roles to play in biological processes and human diseases. The majority of miRNAs are known to be expressed in the brain and are involved in synaptic functions, thus marking their presence and role in major neurodegenerative disorders, including Alzheimer's disease (AD). In AD, amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs) are known to be the major hallmarks. The clearance of Aß and tau is known to be associated with miRNA dysregulation. In addition, the ß-site APP cleaving enzyme (BACE 1), which cleaves APP to form Aß, is also found to be regulated by miRNAs, thus directly affecting Aß accumulation. Growing evidences suggest that neuroinflammation can be an initial event in AD pathology, and miRNAs have been linked with the regulation of neuroinflammation. Inflammatory disorders have also been associated with AD pathology, and exosomes associated with miRNAs are known to regulate brain inflammation, suggesting for the role of systemic miRNAs in AD pathology. Several miRNAs have been related in AD, years before the clinical symptoms appear, most of which are associated with regulating the cell cycle, immune system, stress responses, cellular senescence, nerve growth factor (NGF) signaling, and synaptic regulation. Phytochemicals, especially polyphenols, alter the expression of various miRNAs by binding to miRNAs or binding to the transcriptional activators of miRNAs, thus control/alter various metabolic pathways. Awing to the sundry biological processes being regulated by miRNAs in the brain and regulation of expression of miRNAs via phytochemicals, miRNAs and the regulatory bioactive phytochemicals can serve as therapeutic agents in the treatment and management of AD.

Clinical implications of crown-rump length discordance at 11 to 14 weeks in dichorionic twins.

BACKGROUND: Crown-rump length discordance, defined as ≥10% discordance, has been investigated as an early sonographic marker of subsequent growth abnormalities and is associated with an increased risk of fetal loss in twin pregnancies. Previous studies have not investigated the prevalence of fetal aneuploidy or structural anomalies in twins with discordance or the independent association of crown-rump length discordance with adverse perinatal outcomes. Moreover, data are limited on cell-free DNA screening for aneuploidy in dichorionic twins with discordance. OBJECTIVE: This study aimed to evaluate whether crown-rump length discordance in dichorionic twins between 11 and 14 weeks of gestation is associated with a higher risk of aneuploidy, structural anomalies, or adverse perinatal outcomes and to assess the performance of cell-free DNA screening in dichorionic twin pregnancies with crown-rump length discordance. STUDY DESIGN: This was a secondary analysis of a multicenter retrospective cohort study that evaluated the performance of cell-free DNA screening for the common trisomies in twin pregnancies from December 2011 to February 2020. For this secondary analysis, we included live dichorionic pregnancies with crown-rump length measurements between 11 and 14 weeks of gestation. First, we compared twin pregnancies with discordant crown-rump lengths with twin pregnancies with concordant crown-rump lengths and analyzed the prevalence of aneuploidy and fetal structural anomalies in either twin. Second, we compared the prevalence of a composite adverse perinatal outcome, which included preterm birth at <34 weeks of gestation, hypertensive disorders of pregnancy, stillbirth or miscarriage, small-for-gestational-age birthweight, and birthweight discordance. Moreover, we assessed the performance of cell-free DNA screening in pregnancies with and without crown-rump length discordance. Outcomes were compared with multivariable regression to adjust for confounders. RESULTS: Of 987 dichorionic twins, 142 (14%) had crown-rump length discordance. The prevalence of aneuploidy was higher in twins with crown-rump length discordance than in twins with concordance (9.9% vs 3.9%, respectively; adjusted relative risk, 2.7; 95% confidence interval, 1.4-4.9). Similarly, structural anomalies (adjusted relative risk, 2.5; 95% confidence interval, 1.4-4.4]) and composite adverse perinatal outcomes (adjusted relative risk, 1.2; 95% confidence interval, 1.04-1.3) were significantly higher in twins with discordance. A stratified analysis demonstrated that even without other ultrasound markers, there were increased risks of aneuploidy (adjusted relative risk, 3.5; 95% confidence interval, 1.5-8.4) and structural anomalies (adjusted relative risk, 2.7; 95% confidence interval, 1.5-4.8) in twins with CRL discordance. Cell-free DNA screening had high negative predictive values for trisomy 21, trisomy 18, and trisomy 13, regardless of crown-rump length discordance, with 1 false-negative for trisomy 21 in a twin pregnancy with discordance. CONCLUSION: Crown-rump length discordance in dichorionic twins is associated with an increased risk of aneuploidy, structural anomalies, and adverse perinatal outcomes, even without other sonographic abnormalities. Cell-free DNA screening demonstrated high sensitivity and negative predictive values irrespective of crown-rump length discordance; however, 1 false-negative result illustrated that there is a role for diagnostic testing. These data may prove useful in identifying twin pregnancies that may benefit from increased screening and surveillance and are not ascertained by other early sonographic markers.

Dissuasion in women surgical trainees pursuing cardiothoracic surgery.

BACKGROUND: The reasons for persistent gender disparity in cardiothoracic surgery (CTS) are multifaceted. The objective of this paper is to understand if and why women surgical trainees are dissuaded from pursuing CTS. METHODS: A survey was sent to self-identified women participating in Women in Thoracic Surgery speed mentoring. Statistical analysis was performed to determine dissuasion rates. Open-ended responses describing examples of dissuasion were characterized and categorized. RESULTS: Of all participants, 76 â€‹% (163/215) reported dissuasion from a CTS career. Third- and fourth-year medical students experienced the highest rate by training (81 â€‹%, 48/59) and those interested in Congenital CTS experienced the highest rate based on subspecialty interest (94 â€‹%, 17/18). The most cited dissuasion examples included work/life balance, lifestyle with children, and gender. CONCLUSIONS: Most women surveyed had been dissuaded from pursuing a career in CTS. Examples of dissuasion provided are heavily associated with traditional gender roles, supporting the presence of continued gender bias in CTS.

Clinical pharmacology and pharmacogenomics for implementation of personalized medicine.

With the aim of integrating clinical pharmacology with pharmacogenomics and providing a platform to gather clinicians, academicians, diagnostic laboratory personnel and scientists from related domains, the International Conference on Clinical Pharmacology and Pharmacogenomics 2023 (ICCPP 2023) was jointly organized by the Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, India and the CANSEARCH research platform in Pediatric Oncology and Hematology, University of Geneva, Geneva, Switzerland. The conference was held on 31 August and 1 September 2023, as a continued Indo-Swiss scientific exchange event series. In this report we describe the proceedings of this conference for the benefit of peers who could not attend the conference but are interested in knowing about the scientific program in detail.

Understanding the neuronal synapse and challenges associated with the mitochondrial dysfunction in mild cognitive impairment and Alzheimer's disease.

Synaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating the damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (ψ) gradient exists and is highest in the somal region. Lower ψ in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (Aß) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD.

Prenatal detection of congenital heart disease: Recent experience across the state of Arizona.

OBJECTIVE: To determine the prenatal detection rate (PDR) of congenital heart disease (CHD) in Arizona as well as describe various factors that may influence detection rates. METHODS: This was a retrospective chart review using the Society of Thoracic Surgeons and Phoenix Children's Fetal Cardiology databases. We included all cases of CHD requiring surgery <1 year of age between 2013 and 2018. A total of 1137 patients met the criteria, and various demographic, socioeconomic, and patient outcome data were collected. RESULTS: The overall PDR was 58% with an improving detection rate over the course of our study, with the final year having a PDR of 67%. Over time, PDR improved in urban communities, but this was not seen in rural communities. Rural address, public insurance, and Native American ethnicity were associated with lower PDR. Postnatal outcomes, including Apgars, initial pH, and lactate, did not differ with the presence of a prenatal diagnosis. Diagnoses typically identified with the outflow tract and 3-vessel views on the fetal echocardiogram were less likely to be detected prenatally. CONCLUSIONS: The PDR of CHD continues to improve with evolving technologies and guidelines. We highlight a discrepancy between urban, rural, and Native American populations. Additionally, by supplying descriptors of missed diagnosis and associated echocardiography views, we hope to provide data for future interventions.

Can prenatal ultrasound predict adverse neonatal outcomes in SARS-CoV-2-affected pregnancies?

BACKGROUND: On the basis of available data, at least 1 ultrasound assessment of pregnancies recovering from SARS-CoV-2 infection is recommended. However, reports on prenatal imaging findings and potential associations with neonatal outcomes following SARS-CoV-2 infection in pregnancy have been inconclusive. OBJECTIVE: This study aimed to describe the sonographic characteristics of pregnancies after confirmed SARS-CoV-2 infection and assess the association of prenatal ultrasound findings with adverse neonatal outcomes. STUDY DESIGN: This was an observational prospective cohort study of pregnancies diagnosed with SARS-CoV-2 by reverse transcription polymerase chain reaction between March 2020 and May 2021. Prenatal ultrasound evaluation was performed at least once after diagnosis of infection, with the following parameters measured: standard fetal biometric measurements, umbilical and middle cerebral artery Dopplers, placental thickness, amniotic fluid volume, and anatomic survey for infection-associated findings. The primary outcome was the composite adverse neonatal outcome, defined as ≥1 of the following: preterm birth, neonatal intensive care unit admission, small for gestational age, respiratory distress, intrauterine fetal demise, neonatal demise, or other neonatal complications. Secondary outcomes were sonographic findings stratified by trimester of infection and severity of SARS-CoV-2 infection. Prenatal ultrasound findings were compared with neonatal outcomes, severity of infection, and trimester of infection. RESULTS: A total of 103 SARS-CoV-2-affected mother-infant pairs with prenatal ultrasound evaluation were identified; 3 cases were excluded because of known major fetal anomalies. Of the 100 included cases, neonatal outcomes were available in 92 pregnancies (97 infants); of these, 28 (29%) had the composite adverse neonatal outcome, and 23 (23%) had at least 1 abnormal prenatal ultrasound finding. The most common abnormalities seen on ultrasound were placentomegaly (11/23; 47.8%) and fetal growth restriction (8/23; 34.8%). The latter was associated with a higher rate of the composite adverse neonatal outcome (25% vs 1.5%; adjusted odds ratio, 22.67; 95% confidence interval, 2.63-194.91; P<.001), even when small for gestational age was removed from this composite outcome. The Cochran Mantel-Haenszel test controlling for possible fetal growth restriction confounders continued to show this association (relative risk, 3.7; 95% confidence interval, 2.6-5.9; P<.001). Median estimated fetal weight and birthweight were lower in patients with the composite adverse neonatal outcome (P<.001). Infection in the third trimester was associated with lower median percentile of estimated fetal weight (P=.019). An association between placentomegaly and third-trimester SARS-CoV-2 infection was noted (P=.045). CONCLUSION: In our study of SARS-CoV-2-affected maternal-infant pairs, rates of fetal growth restriction were comparable to those found in the general population. However, composite adverse neonatal outcome rates were high. Pregnancies with fetal growth restriction after SARS-CoV-2 infection were associated with an increased risk for the adverse neonatal outcome and may require close surveillance.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function.

Deficiency of iron­sulfur (FeS) clusters promotes metabolic rewiring of the endothelium and the development of pulmonary hypertension (PH) in vivo. Joining a growing number of FeS biogenesis proteins critical to pulmonary endothelial function, recent data highlighted that frataxin (FXN) reduction drives Fe-S-dependent genotoxic stress and senescence across multiple types of pulmonary vascular disease. Trinucleotide repeat mutations in the FXN gene cause Friedreich's ataxia, a disease characterized by cardiomyopathy and neurodegeneration. These tissue-specific phenotypes have historically been attributed to mitochondrial reprogramming and oxidative stress. Whether FXN coordinates both nuclear and mitochondrial processes in the endothelium is unknown. Here, we aim to identify the mitochondria-specific effects of FXN deficiency in the endothelium that predispose to pulmonary hypertension. Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells had increased vasoconstrictor production (EDN1) and decreased nitric oxide synthase expression (NOS3). These data were observed in primary pulmonary endothelial cells after pharmacologic inhibition of FXN, mice carrying a genetic endothelial deletion of FXN, and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study indicates FXN is an upstream driver of pathologic aberrations in metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction in vivo, prompting future studies to investigate available and novel PH therapies in contexts of FXN deficiency.

Cell-free DNA screening for trisomy 21 in twin pregnancy: a large multicenter cohort study.

BACKGROUND: Analysis of cell-free DNA from maternal blood provides effective screening for trisomy 21 in singleton pregnancies. Data on cell-free DNA screening in twin gestations are promising although limited. In previous twin studies, cell-free DNA screening was primarily performed in the second trimester and many studies did not report chorionicity. OBJECTIVE: This study aimed to evaluate the screening performance of cell-free DNA for trisomy 21 in twin pregnancies in a large, diverse cohort. A secondary aim was to evaluate screening performance for trisomy 18 and trisomy 13. STUDY DESIGN: This was a retrospective cohort study of twin pregnancies from 17 centers for which cell-free DNA screening was performed from December 2011 to February 2020 by one laboratory using massively parallel sequencing technology. Medical record review was conducted for all newborns and data on the birth outcome, the presence of any congenital abnormalities, phenotypic appearance at birth, and any chromosomal testing that was undertaken in the antenatal or postnatal period were extracted. Cases with a possible fetal chromosomal abnormality with no genetic test results were reviewed by a committee of maternal-fetal medicine geneticists. Cases with a vanishing twin and inadequate follow-up information were excluded. A minimum of 35 confirmed cases of trisomy 21 was required to capture a sensitivity of at least 90% with a prevalence of at least 1.9% with 80% power. Test characteristics were calculated for each outcome. RESULTS: A total of 1764 samples were sent for twin cell-free DNA screening. Of those, 78 cases with a vanishing twin and 239 cases with inadequate follow-up were excluded, leaving a total of 1447 cases for inclusion in the analysis. The median maternal age was 35 years and the median gestational age at cell-free DNA testing was 12.3 weeks. In total, 81% of the twins were dichorionic. The median fetal fraction was 12.4%. Trisomy 21 was detected in 41 of 42 pregnancies, yielding a detection rate of 97.6% (95% confidence interval, 83.8-99.7). There was 1 false negative and no false positive cases. Trisomy 21 was detected in 38 out of 39 dichorionic twin pregnancies, yielding a detection rate of 97.4% (95% confidence interval, 82.6-99.7). Trisomy 18 was detected in 10 of the 10 affected pregnancies. There was 1 false positive case. Trisomy 13 was detected in 4 of the 5 cases, yielding a detection rate of 80% (95% confidence interval, 11.1-99.2). There was one false negative and no false positive cases. The nonreportable rate was low at 3.9 %. CONCLUSION: Cell-free DNA testing is effective in screening for trisomy 21 in twin gestations from the first trimester of pregnancy. Detection of trisomy 21 was high in dichorionic and monochorionic twins, and the nonreportable result rates were low. This study included high numbers of cases of trisomy 18 and 13 when compared with the current literature. Although screening for these conditions in twins seems to be promising, the numbers were too small to make definitive conclusions regarding the screening efficacy for these conditions. It is possible that cell-free DNA testing performance may differ among laboratories and vary with screening methodologies.

Acute Treatment of Migraine in Adolescents: Real-World Analysis of Remote Electrical Neuromodulation (REN).

Nearly 10% of children and adolescents in the United States experience migraine. Pharmacologic treatment of migraine in adolescents is limited due to only few US Food and Drug Administration (FDA)-approved medications, limited efficacy, or lack of tolerability. Remote Electrical Neuromodulation (REN) is a nonpharmacologic abortive treatment for migraine, cleared by the FDA for patients aged 12 years and above. This study evaluated real-world efficacy of REN in adolescents aged 12 to 17 years. Real-world data were collected from patients aged 12 to 17 years treated with the REN device (Nerivio) from January 1, 2021, to May 31, 2022. Study's end points included consistent efficacy two hours after treatment, use of REN as a standalone versus as an adjunct therapy, treatment intensity, and safety. Of 1629 adolescents included in the study, consistent response in at least 50% of treatments at two hours posttreatment was achieved by 60.3% of patients for pain relief, 26.3% for pain freedom, 66.3% for functional disability relief, and 41.2% for functional disability freedom. Of 2365 treatments in which medication usage was reported, REN was used as standalone therapy in 64.4% of the treatments, REN was combined with over-the-counter medications in 18.6%, and it was combined with prescription medications in 17%. Mean treatment intensity from 13,716 treatments was 28.5% (±13.6%) of the max stimulator output. Only three device-related adverse events were reported, all minor. This real-world analysis demonstrates the persistent efficacy of REN for abortive treatment of migraine in adolescents, extending findings of prior clinical trials in adolescents and real-world studies in adults.

Single Nucleotide Polymorphism rs9277336 Controls the Nuclear Alpha Actinin 4-Human Leukocyte Antigen-DPA1 Axis and Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension.

Background Pulmonary arterial hypertension (PAH) is a complex, fatal disease where disease severity has been associated with the single nucleotide polymorphism (SNP) rs2856830, located near the human leukocyte antigen DPA1 (HLA-DPA1) gene. We aimed to define the genetic architecture of functional variants associated with PAH disease severity by identifying allele-specific binding transcription factors and downstream targets that control endothelial pathophenotypes and PAH. Methods and Results Electrophoretic mobility shift assays of oligonucleotides containing SNP rs2856830 and 8 SNPs in linkage disequilibrium revealed functional SNPs via allele-imbalanced binding to human pulmonary arterial endothelial cell nuclear proteins. DNA pulldown proteomics identified SNP-binding proteins. SNP genotyping and clinical correlation analysis were performed in 84 patients with PAH at University of Pittsburgh Medical Center and in 679 patients with PAH in the All of Us database. SNP rs9277336 was identified as a functional SNP in linkage disequilibrium (r2>0.8) defined by rs2856830, and the minor allele was associated with decreased hospitalizations and improved cardiac output in patients with PAH, an index of disease severity. SNP pulldown proteomics showed allele-specific binding of nuclear ACTN4 (alpha actinin 4) protein to rs9277336 minor allele. Both ACTN4 and HLA-DPA1 were downregulated in pulmonary endothelium in human patients and rodent models of PAH. Via transcriptomic and phenotypic analyses, knockdown of HLA-DPA1 phenocopied knockdown of ACTN4, both similarly controlling cell structure pathways, immune pathways, and endothelial dysfunction. Conclusions We defined the pathogenic activity of functional SNP rs9277336, entailing the allele-specific binding of ACTN4 and controlling expression of the neighboring HLA-DPA1 gene. Through inflammatory or genetic means, downregulation of this ACTN4-HLA-DPA1 regulatory axis promotes endothelial pathophenotypes, providing a mechanistic explanation for the association between this SNP and PAH outcomes.

Neuromotor repertoires in infants exposed to maternal COVID-19 during pregnancy: a cohort study.

OBJECTIVE: To evaluate neuromotor repertoires and developmental milestones in infants exposed to antenatal COVID-19. DESIGN: Longitudinal cohort study. SETTING: Hospital-based study in Los Angeles, USA and Rio de Janeiro, Brazil between March 2020 and December 2021. PARTICIPANTS: Infants born to mothers with COVID-19 during pregnancy and prepandemic control infants from the Graz University Database. INTERVENTIONS: General movement assessment (GMA) videos between 3 and 5 months post-term age were collected and clinical assessments/developmental milestones evaluated at 6-8 months of age. Cases were matched by gestational age, gender and post-term age to prepandemic neurotypical unexposed controls from the database. MAIN OUTCOME MEASURES: Motor Optimality Scores Revised (MOS-R) at 3-5 months. Presence of developmental delay (DD) at 6-8 months. RESULTS: 239 infants were enrolled; 124 cases (83 in the USA/41 in Brazil) and 115 controls. GMA was assessed in 115 cases and 115 controls; 25% were preterm. Median MOS-R in cases was 23 (IQR 21-24, range 9-28) vs 25 (IQR 24-26, range 20-28) in controls, p<0.001. Sixteen infants (14%) had MOS-R scores <20 vs zero controls, p<0.001. At 6-8 months, 13 of 109 case infants (12%) failed to attain developmental milestones; all 115 control infants had normal development. The timing of maternal infection in pregnancy (first, second or third trimester) or COVID-19 disease severity (NIH categories asymptomatic, mild/moderate or severe/critical) was not associated with suboptimal MOS-R or DD. Maternal fever in pregnancy was associated with DD (OR 3.7; 95% CI 1.12 to 12.60) but not suboptimal MOS-R (OR 0.25; 95% CI 0.04 to 0.96). CONCLUSIONS: Compared with prepandemic controls, infants exposed to antenatal COVID-19 more frequently had suboptimal neuromotor development.

Global multi-center and multi-modal magnetic resonance imaging study of obsessive-compulsive disorder: Harmonization and monitoring of protocols in healthy volunteers and phantoms.

OBJECTIVES: We describe the harmonized MRI acquisition and quality assessment of an ongoing global OCD study, with the aim to translate representative, well-powered neuroimaging findings in neuropsychiatric research to worldwide populations. METHODS: We report on T1-weighted structural MRI, resting-state functional MRI, and multi-shell diffusion-weighted imaging of 140 healthy participants (28 per site), two traveling controls, and regular phantom scans. RESULTS: Human image quality measures (IQMs) and outcome measures showed smaller within-site variation than between-site variation. Outcome measures were less variable than IQMs, especially for the traveling controls. Phantom IQMs were stable regarding geometry, SNR, and mean diffusivity, while fMRI fluctuation was more variable between sites. CONCLUSIONS: Variation in IQMs persists, even for an a priori harmonized data acquisition protocol, but after pre-processing they have less of an impact on the outcome measures. Continuous monitoring IQMs per site is valuable to detect potential artifacts and outliers. The inclusion of both cases and healthy participants at each site remains mandatory.

Longitudinal Evaluation of Antibody Persistence in Mother-Infant Dyads After Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Pregnancy.

BACKGROUND: There are limited data on how coronavirus disease 2019 (COVID-19) severity, timing of infection, and subsequent vaccination impact transplacental transfer and persistence of maternal and infant antibodies. METHODS: In a longitudinal cohort of pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, maternal/infant sera were collected at enrollment, delivery/birth, and 6 months. Anti-SARS-CoV-2 spike immunoglobulin (Ig)G, IgM, and IgA were measured by enzyme-linked immunosorbent assay. RESULTS: Two-hundred fifty-six pregnant women and 135 infants were enrolled; 148 maternal and 122 neonatal specimens were collected at delivery/birth; 45 maternal and 48 infant specimens were collected at 6 months. Sixty-eight percent of women produced all anti-SARS-CoV-2 isotypes at delivery (IgG, IgM, IgA); 96% had at least 1 isotype. Symptomatic disease and vaccination before delivery were associated with higher maternal IgG at labor and delivery. Detectable IgG in infants dropped from 78% at birth to 52% at 6 months. In the multivariate analysis evaluating factors associated with detectable IgG in infants at delivery, significant predictors were 3rd trimester infection (odds ratio [OR] = 4.0), mild/moderate disease (OR = 4.8), severe/critical disease (OR = 6.3), and maternal vaccination before delivery (OR = 18.8). No factors were significant in the multivariate analysis at 6 months postpartum. CONCLUSIONS: Vaccination in pregnancy post-COVID-19 recovery is a strategy for boosting antibodies in mother-infant dyads.