Molecular basis for antiviral activity of pediatric neutralizing antibodies targeting SARS-CoV-2 Spike receptor binding domain

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV- 2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC-evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here we elucidate the structural basis and mode of action for two potent SARS-CoV-2 Spike (S) neutralizing monoclonal antibodies CV3-1 and CV3-25 that remained effective against emerging variants of concern in vitro and in vivo. CV3-1 bound to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the "RBD-up" position and triggered potent shedding of the S1 subunit. In contrast, CV3-25 inhibited membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among {beta}-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

Ineffectual AEC1 Differentiation from KRT8hi Transitional Cells without Fibrosis Associated with Fatal Acute Respiratory Failure in COVID-19 ARDS

ARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis.

Tuberculosis in pregnant women and neonates: A meta-review of current evidence.

Pregnant women and their infants are a vulnerable but neglected population in tuberculosis (TB) control efforts. Recent advances in TB prevention, diagnosis and treatment have implications for their care, despite their frequent exclusion from research. We have conducted a meta-review of current evidence and clinical guidelines for TB prevention, diagnosis and management in pregnant women and neonates, focusing on review articles published since 2010. The actual burden of TB in pregnancy is unmeasured, but has been estimated at 216,500 cases per year. Although the effect of pregnancy on TB risk is uncertain and controversial, two large whole-of-population studies found that pregnancy was associated with a two- to three-fold increase in risk of TB. Congenital TB is rare but extremely serious. Neonates exposed to TB after delivery will be at high risk of disease, and preventive therapy is recommended once disease has been ruled out. At present, there is limited evidence regarding the performance of different screening strategies for pregnant women, appropriate drug dosing for either pregnant women or neonates, and the safety of most second-line drugs in pregnancy. High quality evidence on these topics is needed, as are detailed guidelines to inform efforts by TB control programs and clinicians working with pregnant women and their infants.

Dose-response relationship between maternal thyroid hormones in the first twenty weeks and physical and neuropsychological development of infants: A prospective cohort study in China / 中华流行病学杂志

Objective: To study the dose-response relationship between maternal thyroid hormone levels in the first twenty weeks of pregnancy and the infant physical and neuropsychological development. Methods: In this prospective cohort study, a total of 945 women and their children were included. Maternal serum samples during first half of the pregnancy were collected and analyzed for levels of thyroid hormones by using the electro-chemiluminescence immunoassay. Maternal social demographic information was collected by using the a self-administered questionnaire. Physical measurements of newborns and neuropsychological evaluation of infants were performed by doctors of maternal and child health care. Results: The differences in newborns' birth length and head circumference were significant among the newborns of mothers with different percentiles of maternal serum (thyroid-stimulating hormone, TSH) levels (P<0.05). Newborns with maternal TSH level ≥P(95) or <P(5) had significantly lower birth length and birth head circumference, compared with the newborns with maternal TSH level between P(25)-P(75) (P<0.05). Newborns' birth head circumferences showed an inverted U-shaped association with maternal serum TSH level (Y=33.940+0.003X-0.109X(2), F=4.685, P=0.009). The difference in mental development index (MDI) of the infants at 18-30 months were significant among the infants of mothers with different percentiles of maternal serum TSH level (P<0.05). Infants with maternal TSH level ≥P(90) showed lower MDI (6.39, 95%CI: 2.29-10.49, P=0.002) compared with the infants with maternal TSH level between P(25)-P(75). Infant's MDI at 18- 30 months also showed an inverted U-shaped association with maternal serum TSH level (Y=103.249-1.524X-0.939X(2), F=6.616, P=0.001). Conclusions: Maternal TSH level was associated with newborn's birth length, birth head circumference and infant's MDI at 18-30 months. Newborn's birth head circumference and infant's MDI at 18-30 months showed an inverted U-shaped association with maternal serum TSH-Z score.

Exposure to bisphenol A during maternal pregnancy and the emotional and behavioral impact on their preschool children / 中华流行病学杂志

Objective: To explore the long-term effects of maternal pregnancy bisphenol A (BPA) exposure on emotional and behavioral problems appeared in their preschool children. Methods: The study sample was a subset of the China-Anhui Birth Cohort Study (C-ABCS). A unified questionnaire was used to collect basic information on both pregnant women and their children. Free BPA concentration in maternal serum was determined by high-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS). The parent-report version of the Strengths and Difficulties Questionnaire (SDQ) was used to estimate the emotional and behavioral problems in preschool children. A total of 1 713 pairs of mothers and children were included in this study. Association between BPA exposure during pregnancy and the emotional and behavioral problems in preschool children was evaluated with multinomial logistic regression model. Results: Prevalence rates in 1 713 preschool children appeared as: 6.48% of emotional problems, 8.11% for conduct problems, 8.35% for hyperactivity/inattention, 2.86% for peer problems, 11.38% for prosocial behaviors and 7.94% for total difficulties. Subjects were divided according to the degrees of exposure and the results showed as: low exposure group (≤0.120 ng/ml), medium exposure group (0.120<BPA<0.400 ng/ml) and high exposure group (≥0.400 ng/ml) according to the serum BPA concentration in tertile. Results from the multivariate logistic regression analysis showed that high level of maternal BPA exposure appeared a risk factor on children's abnormal conducts (OR=1.876, 95% CI: 1.161-3.029), more obvious in boys (OR=2.291, 95%CI: 1.126-4.661). Conclusion: Maternal exposure to high level of BPA during pregnancy might increase the detrimental effects of abnormal conducts in their preschool children, more obviously seen in boys.

Association between pregnancy-related anxiety of pregnant women and autism-like behavior in their offspring at 18 months of age / 中华流行病学杂志

Objective: To investigate the relationship of pregnancy-related anxiety of pregnant women in second/third trimesters and autism-like behaviors in their offspring at 18 months of age. Methods: Based on a prospective cohort study design, we evaluated the situation of pregnancy-related anxiety of women during second and third trimesters through a Pregnancy-Related Anxiety Questionnaire. Subjects under study were classified into three groups, 1) those with pregnancy- related anxiety during both trimesters, 2) those with pregnancy-related anxiety at one trimester and 3) those without pregnancy-related anxiety in either trimester. When their children were 18 months, autism-like behaviors (ALB) were evaluated, using the part A of Checklist for Autism in Toddlers-23, and then classified into three groups as non-ALB group, minor ALB group and major ALB group. Multi-nominal logistic Regression was used to analyze the relationship of pregnancy-related anxiety with autism-like behaviors. Results: Compared with non-ALB group, children whose mother with pregnancy-related anxiety during both trimesters presented significant higher risk on ALB than children whose mother without pregnancy-related anxiety in these two periods (relative risk, RR=2.43, 95% CI: 1.21-4.86, P=0.012), major factors as pregnant women's IQ and gestational diabetes mellitus, premature delivery and education levels of fosterers on these pregnant women were under control. Our results from the stratified analysis showed: when in the subgroup that mother was the main fosterer of the child, there was an significant increase of risk in children whose mothers with pregnancy-related anxiety during both trimesters (RR=4.22, 95%CI: 1.73-10.32, P=0.002). Conclusion: The association between pregnancy-related anxiety and autism-like behavior was not strong but influenced by the fosterer of the child.

Study on the relationship of thallium exposure and outcomes of births / 中华流行病学杂志

Objective: To investigate the relationship of thallium exposure and outcomes of births. Methods: A total of 3 236 mothers who had visited in Ma'anshan Maternal and Child Health-Care Hospital between May 2013 and September 2014 were included in this study and their thallium concentrations measured from samples of maternal and umbilical cord blood by inductively coupled plasma mass spectrometry. The results were correlated and evaluated with birth outcomes of the infants, using the multiple linear regression method. Results: The median (P(25)-P(75)) of thallium levels in first trimester, second trimester and umbilical cord blood were 61.7 (50.8-77.0), 60.3 (50.8-75.2) and 38.5 (33.6-44.1) ng/L, respectively. After adjustment for potential confounders, the thallium levels showed an inversely significant association with birth head circumference (unstandardized β coefficient=-0.41, 95%CI: -0.76- -0.06) in the first trimester blood, and associated with reduced birth length (unstandardized β coefficient=-0.65, 95%CI: -1.25- -0.05) in umbilical cord blood. However, there appeared no significantly associations with birth weight, length and head circumference (P>0.05) in second trimester. On stratification by sex, in girls but not in boys, the thallium levels were adversely associated with birth head circumference (unstandardized β coefficient=-0.53, 95%CI: -1.05--0.01) in the first trimester and were associated with decreased birth weight (unstandardized β coefficient=-277.08, 95%CI: -485.13- -69.03) and length (unstandardized β coefficient=-1.39, 95%CI: -2.26- -0.53) in umbilical cord blood thallium. Conclusions: Thallium exposure appeared a gender difference in newborn birth outcomes. In the first trimester, it was negatively associated with the birth head circumference, in the umbilical cord blood, and reduced birth weight and length in girls.

Pregnancy-related anxiety associated with small-for-gestational-age infants / 中华流行病学杂志

Objective: To investigate the second or third trimester pregnancy-related anxiety on small-for-gestational-age infants. Methods: This study was based on Ma'anshan Birth Cohort Study (MABC), with 3 040 maternal-singleton pairs finally selected for data analysis, from May 2013 to September 2014. The psychological state of pregnancy was evaluated according to a self-developed 'anxiety scale for gestation'. Small-for-gestational-age was defined as 'having birth weight below the 10(th) percentile at a particular gestational week', while large-for-gestational-age infants was defined as 'having birth weight above the 90(th) percentile'. Birth weight between the 10(th) and 90(th) percentile was classified as appropriate-for-gestational age infants. χ(2) test was used to compare the distribution of characteristics in pregnancy among three groups with different birth weights. Multivariate logistic regression models were conducted to evaluate the associations between third trimester pregnancy- related anxiety and birth weight. Results: The incidence rates of small- and large-gestational-age infants were 9.6% and 16.6%, respectively. Difference between women with only one of the second or third trimester pregnancy-related anxiety syndromes and small-for-gestational-age infants showed no statistical significance. Women with both second and third trimester pregnancy-related anxieties might increase the risk of small-for-gestational-age infants (OR=1.39, 95%CI: 1.04-1.87). However, there was no significant difference between pregnancy-related anxiety and large-for- gestational-age infants (OR=1.05, 95%CI: 0.81-1.35) noticed. Conclusion: Women with second and third trimester pregnancy-related anxiety appeared a risk factor for small-for-gestational-age infants.