Impact of Perinatal Exposure to SARS-CoV-2 Infection on Early Health Outcomes among Infants Born from 2020 to 2021 in British Columbia, Canada.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has impacted healthcare services and outcomes. We aimed to investigate healthcare resource utilization and early health outcomes of infants born to mothers with perinatal SARS-CoV-2 infection. Methods: The study included all infants born alive between February 1, 2020, and April 30, 2021, in British Columbia. We used linked provincial population-based databases including data on COVID-19 testing, birth, and health information for up to one year from birth. Perinatal COVID-19 exposure for infants was defined being born to mothers with a positive test for SARS-CoV-2 infection during pregnancy or at delivery. Cases of COVID-19-exposed infants were matched with up to four non-exposed infants by birth month, sex, birthplace, and gestational age in weeks. Outcomes included hospitalizations, emergency department visits, and in-/outpatient diagnoses. Outcomes were compared between groups using conditional logistic regression and linear mixed effects models including effect modification by maternal residence. Results: Among 52,711 live births, 484 infants had perinatal exposure to SARS-CoV-2, an incidence rate of 9.18 per 1000 live births. Exposed infants (54.6% male) had a mean gestational age of 38.5 weeks, and 99% were born in hospital. Proportions of infants requiring at least one hospitalization (8.1% vs. 5.1%) and at least one emergency department visit (16.9% vs. 12.9%) were higher among the exposed vs. unexposed infants, respectively. Among infants from the urban area, those with exposure were more likely to have respiratory infectious diseases (odds ratio: 1.74; 95% confidence intervals: 1.07, 2.84), compared with those without exposure. Interpretation. In our cohort, infants born to mothers with SARS-CoV-2 infection have increased healthcare demands in their early infancy, which warrants further investigation.

Coffin-Lowry syndrome in Chinese.

Coffin-Lowry syndrome (CLS) is a well-described syndrome characterized by intellectual disability, growth retardation, recognizable dysmorphic features, and skeletal changes. It is an X-linked syndrome where males are more severely affected and females have high variability in clinical presentations. This case series reports nine molecularly confirmed Chinese CLS patients from six unrelated families (three with familial variants and three with de novo variants). There is a wide genotypic spectrum with five novel variants in RPS6KA3 gene. Clinical phenotype and facial features of these Chinese CLS patients are comparable to what has been described in other ethnicities.

Risk of Child Maltreatment in Chinese Teenage and Young Mothers With Rapid Repeat Pregnancy: The Moderating Role of Family Cohesion and Support From Friends.

Rapid repeat pregnancy (RRP) often occurs in teenage and young mothers. Mothers with a history of RRP are more likely to experience high stress increasing their risk of child maltreatment. Despite these challenges, some mothers can continue to cope adaptively. Social support may play a role in empowering these mothers to overcome the childbearing difficulties. Although the protective effects of social support are well recognized, there has been little evidence on the relative importance of sources of support. For example, whether support from family and friends is equally important in relieving parenting stress remains unanswered. RRP, a social phenomenon encompassing various adverse living and parenting issues, provides an ideal research context to investigate the role of family and friends in preventing child maltreatment. This study examined whether family cohesion and friends' support moderated the association between RRP and child maltreatment in young mothers. We recruited 392 Chinese teenage and young mothers from a population-based integrated young mothers supporting program in Hong Kong. Questionnaires on pregnancy history, family cohesion, social support, and risk of child maltreatment were administered. Moderation analysis was conducted to examine the effect of RRP on child maltreatment as a function of family cohesion or friend support. Results showed that RRP was associated with a higher risk of child neglect (adjusted odds ratio [aOR] = 1.72, p < .05) and physical maltreatment (aOR = 1.91, p < .01), and that family cohesion was more important than friend support in mitigating the risk of child maltreatment for mothers with a history of RRP. Our findings suggest that interventions for young mothers, particularly those with a history of RRP, should be family-based so the whole family can be empowered to tackle the childrearing burden.

Disentangling the Effects of Exposure to Maternal Substance Misuse and Physical Abuse and Neglect on Child Behavioral Problems.

There is inconsistent evidence on the association between prenatal substance exposure and child behavioral problems. Children affected by maternal substance misuse are vulnerable to physical abuse and neglect. Few studies have examined factors contributing to internalizing and externalizing problems in these children. This study, with a focus on children with prenatal substance exposure, investigated whether family characteristics (the duration of maternal substance misuse postpartum or the existence of a sibling) moderated the association between adverse exposure (physical abuse or neglect) and behavior (internalizing or externalizing problems). We recruited 54 Hong Kong Chinese mothers with registered records of substance misuse during pregnancy and their children (2-9 years). Mothers completed questionnaires on drug use patterns during pregnancy and postpartum, abusive and neglectful parenting behaviors in the preceding year, and children's current behavioral problems. Moderated regression analyses tested whether abusive and neglectful parenting behavior interacted with family characteristics to affect child behavioral problems. The existence of a sibling moderated the relationship between neglect experience and internalizing problems, with a positive relationship observed only among single children (adjusted B [95% confidence interval] = 3.70 [0.98, 6.41], p = .012). The duration of maternal substance misuse postpartum moderated the relationship between physical abuse experience and externalizing problems, with a positive relationship observed only among children of mothers abusing substances beyond the child's infancy period (adjusted B [95% confidence interval] = 6.86 [2.34, 11.38], p = .008). The results show that the impact of physical abuse and neglect experiences depend on the type of behavior assessed and family and child characteristics. Positive sibling relationship and early detoxification in the mother can foster healthy behavioral development for children exposed prenatally to maternal substance misuse.

Basement membrane protein nidogen-1 shapes hippocampal synaptic plasticity and excitability.

The basement membrane (BM) is a specialized form of extracellular matrix (ECM) underlying epithelia and endothelia and surrounding many types of mesenchymal cells. Nidogen, along with collagen IV and laminin, is a major component of BMs. Although certain ECM proteins such as laminin or reelin influence neuronal function via interactions with cell-surface receptors such as integrins, behavioral neurological impairments due to deficits of BM components have been recognized only recently. Here, alterations in neuronal network function underlying these behavioral changes are revealed. Using nidogen-1 knockout mice, with or without additional heterozygous nidogen-2 knockout (NID1(-/-)/NID2(+/+) or NID1(-/-)/NID2(+/-)), we demonstrate that nidogen is essential for normal neuronal network excitability and plasticity. In nidogen-1 knockouts, seizurelike behavior occurs, and epileptiform spiking was seen in hippocampal in vivo EEG recordings. In vitro, hippocampal field potential recordings revealed that lack of nidogen-1, while not causing conspicuous morphological changes, led to the appearance of spontaneous and evoked epileptiform activity, significant increase of the input/output ratio of synaptically evoked responses in CA1 and dentate gyrus, as well as of paired pulse accentuation, and loss of perforant-path long-term synaptic potentiation. Nidogen-1 is thus essential for normal network excitability and plasticity.

Altered thalamocortical rhythmicity in Ca(v)2.3-deficient mice.

Voltage-gated calcium channels (VGCCs) are key regulators of neuronal excitability and important factors in epileptogenesis and neurodegeneration. Recent findings suggest a novel, important proictogenic and proneuroapoptotic role of the Ca(v)2.3 E/R-type VGCCs in convulsive generalized tonic-clonic and hippocampal seizures. Though Ca(v)2.3 is also expressed in key structures of the thalamocortical circuitry, their functional relevance in non-convulsive absence seizure activity remains unknown. To this end, we investigated absence specific spike-wave discharge (SWD) susceptibility in control and Ca(v)2.3-deficient mice by systemic administration of gamma-hydroxybutyrolactone (GBL, 70 mg/kg i.p.), followed by electrocorticographic radiotelemetric recordings, behavioral analysis and histomorphological characterization. Based on motoric studies, SWD and power-spectrum density (PSD) analysis, our results demonstrate that Ca(v)2.3(-/-) mice exhibit increased absence seizure susceptibility and altered absence seizure architecture compared to control animals. This study provides evidence for the first time that Ca(v)2.3 E/R-type Ca2+ channels are important in modulating thalamocortical hyperoscillation exerting anti-epileptogenic effects in non-convulsive absence seizures.

Prevalence of Child Maltreatment and Its Association with Parenting Style: A Population Study in Hong Kong.

Previous studies point to a link between parenting style and child maltreatment, but evidence from a Chinese context is lacking. We investigated the association between parenting style and child maltreatment in Hong Kong, and examined whether family socio-economic status and child gender moderate this relationship. Using stratified random sampling, 7585 children in Grade 1 to Grade 3 of 51 schools in Hong Kong were recruited and their parents were invited to complete the questionnaire. The past year weighted prevalence for minor physical abuse, severe/very severe physical abuse, psychological abuse, and neglect were 63.9%, 23.4%, 84.1%, and 23.2%, respectively. Authoritarian parenting was associated with all types of child maltreatment (prevalence ratio (PR) range: 1.10⁻1.53; p < 0.001), whereas authoritative parenting was associated with a lower risk of all types of child maltreatment (PR range: 0.89⁻0.97; p < 0.001). Child maltreatment is prevalent in Hong Kong and is strongly associated with parenting style. The association was significantly stronger among girls and those with higher family socioeconomic status. Education to empower parenting skills may alleviate the burden of child maltreatment.

Nidogens-Extracellular matrix linker molecules.

Nidogens/entactins are a family of highly conserved, sulfated glycoproteins. Biochemical studies have implicated them as having a major structural role in the basement membrane. However despite being ubiquitous components of this specialized extracellular matrix and having a wide spectrum of binding partners, genetic analysis has shown that they are not required for the overall architecture of the basement membrane. Rather in development they play an important role in its stabilization especially in tissues undergoing rapid growth or turnover. Nidogen breakdown has been implicated as a key event in the basement membrane degradation occurring in mammary gland involution. A number of studies, most compellingly those in C. elegans, demonstrated that nidogens may have other nonstructural roles and be involved in axonal pathfinding and synaptic transmission.

A synaptic nidogen: developmental regulation and role of nidogen-2 at the neuromuscular junction.

BACKGROUND: The skeletal neuromuscular junction is a useful model for elucidating mechanisms that regulate synaptogenesis. Developmentally important intercellular interactions at the neuromuscular junction are mediated by the synaptic portion of a basal lamina that completely ensheaths each muscle fiber. Basal laminas in general are composed of four main types of glycosylated proteins: laminins, collagens IV, heparan sulfate proteoglycans and nidogens (entactins). The portion of the muscle fiber basal lamina that passes between the motor nerve terminal and postsynaptic membrane has been shown to bear distinct isoforms of the first three of these. For laminins and collagens IV, the proteins are deposited by the muscle; a synaptic proteoglycan, z-agrin, is deposited by the nerve. In each case, the synaptic isoform plays key roles in organizing the neuromuscular junction. Here, we analyze the fourth family, composed of nidogen-1 and -2. RESULTS: In adult muscle, nidogen-1 is present throughout muscle fiber basal lamina, while nidogen-2 is concentrated at synapses. Nidogen-2 is initially present throughout muscle basal lamina, but is lost from extrasynaptic regions during the first three postnatal weeks. Neuromuscular junctions in mutant mice lacking nidogen-2 appear normal at birth, but become topologically abnormal as they mature. Synaptic laminins, collagens IV and heparan sulfate proteoglycans persist in the absence of nidogen-2, suggesting the phenotype is not secondary to a general defect in the integrity of synaptic basal lamina. Further genetic studies suggest that synaptic localization of each of the four families of synaptic basal lamina components is independent of the other three. CONCLUSION: All four core components of the basal lamina have synaptically enriched isoforms. Together, they form a highly specialized synaptic cleft material. Individually, they play distinct roles in the formation, maturation and maintenance of the neuromuscular junction.

COL10A1 nonsense and frame-shift mutations have a gain-of-function effect on the growth plate in human and mouse metaphyseal chondrodysplasia type Schmid.

Missense, nonsense and frame-shift mutations in the collagen X gene (COL10A1) result in metaphyseal chondrodysplasia type Schmid (MCDS). Complete degradation of mutant COL10A1 mRNA by nonsense-mediated decay in human MCDS cartilage implicates haploinsufficiency in the pathogenesis for nonsense mutations in vivo. However, the mechanism is unclear in situations where the mutant mRNA persist. We show that nonsense/frame-shift mutations can elicit a gain-of-function effect, affecting chondrocyte differentiation in the growth plate. In an MCDS proband, heterozygous for a p.Y663X nonsense mutation, the growth plate cartilage contained 64% wild-type and 36% mutant mRNA and the hypertrophic zone was disorganized and expanded. The in vitro translated mutant collagen X chains, which are truncated, were misfolded, unable to assemble into trimers and interfered with the assembly of normal alpha1(X) chains into trimers. Unlike Col10a1 null mutants, transgenic mice (FCdel) bearing the mouse equivalent of a human MCDS p.P620fsX621 mutation, displayed typical characteristics of MCDS with disproportionate shortening of limbs and early onset coxa vara. In FCdel mice, the degree of expansion of the hypertrophic zones was transgene-dosage dependent, being most severe in mice homozygous for the transgene. Chondrocytes in the lower region of the expanded hypertrophic zone expressed markers uncharacteristic of hypertrophic chondrocytes, indicating that differentiation was disrupted. Misfolded FCdel alpha1(X) chains were retained within the endoplasmic reticulum of hypertrophic chondrocytes, activating the unfolded protein response. Our findings provide strong in vivo evidence for a gain-of-function effect that is linked to the activation of endoplasmic reticulum-stress response and altered chondrocyte differentiation, as a possible molecular pathogenesis for MCDS.