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Severe Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth. However, delaying BCG vaccination can be detrimental to the population in tuberculosis-endemic regions. Early diagnosis of SCID through newborn screening followed by pre-emptive treatment with anti-mycobacterial therapy may be an alternative strategy to delaying routine BCG vaccination. We report the results of the first year of newborn SCID screening in Singapore while continuing routine BCG vaccination at birth. Newborn screening using a T-cell receptor excision circle (TREC) assay was performed in dried blood spots received between 10 October 2019 to 9 October 2020 using the Enlite Neonatal TREC kit. Patients with low TREC had lymphocyte subset analysis and full blood count performed to determine the severity of lymphopenia and likelihood of SCID to guide further management. Of the 35888 newborns screened in 1 year, no SCID cases were detected, while 13 cases of non-SCID T-cell lymphopenia (TCL) were picked up. Using a threshold for normal TREC to be >18 copies/μL, the retest rate was 0.1% and referral rate to immunologist was 0.04%. Initial low TREC correlated with low absolute lymphocyte counts (ALC), and subsequent normal ALC corresponded with increases in TREC, thus patients with normal first CD3+ T cell counts were considered to have transient idiopathic TCL instead of false positive results. 7/13 (54%) had secondary TCL (from sepsis, Trisomy 21 with hydrops and stoma losses or chylothorax, extreme prematurity, or partial DiGeorge Syndrome) and 6/13 (46%) had idiopathic TCL. No cases of SCID were diagnosed clinically in Singapore during this period and for 10 months after, indicating that no cases were missed by the screening program. 8/9 (89%) of term infants with abnormal TREC results received BCG vaccination within the first 6 days of life when TREC and ALC were low. No patients developed BCG complications after a median follow-up of 17 months. Newborn screening for SCID can be implemented while continuing routine BCG vaccination at birth. Patients with transient TCL and no underlying primary immunodeficiency are able to tolerate BCG vaccination.

Abstract Background Circuit-induced hemolysis is relatively common in extracorporeal membrane oxygenation (ECMO) patients. Intravascular release of cell-free hemoglobin can lead to complications and requires timely recognition. Validation of plasma free hemoglobin (PFH) measurement using a direct spectrophotometric method is presented. Methodology We evaluated a method modified from Kahn et al. (Ann Clin Lab Sci 1981;11:126–31) on a stand-alone spectrophotometer (Cary 60) and compared its performance to the semiquantitative H-index on an Abbott Alinity c, including precision, linearity, recovery, reference interval verification, interference, and stability. Method comparison was performed relative to the H-index and the same method on a different spectrophotometer (Beckman DU 720). Lipemia interference was performed on the Cary 60, Cary 3500, and Beckman DU 720. Surrogate biomarkers for hemolysis detection were also investigated in ECMO patients. Results The PFH method on the Cary 60 demonstrated imprecision ranging from 1% (96.0 mg/dL) to 4% (3.0 mg/dL), linearity to 100 mg/dL, and recovery >80% for values >2 mg/dL hemoglobin-spiked plasma. Dilution expanded the reportable range to the maximum dilution tested (1000 mg/dL). Lipemia interfered with PFH measurement by the direct method, but the same method on the Cary 3500 was resistant to lipemia. Bilirubin did not cause significant interference. Direct and H-index methods were comparable with a mean difference of 5.03 mg/dL (95% CI −1.38, 11.44). Lactate dehydrogenase was the most reliable surrogate biomarker for hemolysis. with AUC of 0.921 (0.894, 0.949) at >50 mg/dL. Conclusion PFH measurement by a direct spectrophotometric method is more precise and sensitive compared to the H-index; however, PFH measurement is susceptible to lipemia unless performed on a high-end spectrophotometer.

Through parenting, parents transmit different cultural values to their children, including how one should behave when becoming a parent. Therefore, it was hypothesized that intergenerational transmission of parenting could be one strong factor that contributes to parenting styles. While empirical evidence has been found to support this hypothesis in the West, few studies have been done on the question in Chinese culture. The lack of intergenerational parenting studies in Chinese cultural contexts could possibly be due to the fact that Chinese and other Asian populations are underrepresented in the psychology literature (Chang, Lansford, Schwartz, & Farver, 2004). Therefore, the primary purpose of this study was to fill this research gap in Chinese parenting studies to examine the intergenerational transmission of parenting in Hong Kong. The purpose of this study was threefold: first, to examine whether parenting would be transmitted from one generation to the next in the Hong Kong Chinese culture; second, to replicate Western intergenerational studies on parenting that have claimed that parenting in one generation direct predicts that in the next generation, and subsequent predicts children’s behaviours and third, to examined the mechanism through which parenting is transmitted from one generation to the next so that further insights on the relationship of intergeneration parenting can be derived. In this study, 261 mother-child dyads were recruited in this study through convenience sampling. All participants were asked to fill out the demographic information form and reported on their childhood experience. In addition, mothers were asked to report on their own parenting styles (G2) and their own mothers’ parenting styles (G1). Children were asked to self-report on their behaviour and emotional outcomes. Prior to the main analyses, preliminary analyses were conducted to provide descriptive details of the sample, and path analyses were used to examine the two major hypotheses of this study. Results of this study showed that parenting styles are transmitted across generations from mothers to daughters in all parenting dimensions. Daughters’ parenting permissiveness was found to be negatively associated with their children’s anxiety and externalizing behaviour, and positively with their children’s agreement and satisfaction with their parenting strategies in this sample. Further, it mothers’ parenting was found to affect daughters’ agreement and satisfaction to their mothers’ parenting and their experience of happiness and fulfillment during childhood, which subsequently affected daughters’ parenting during motherhood. The present study joins a growing body of evidence that supports the intergenerational transmission of parenting (Bailey et al., 2009; Belsky et al., 2005). Further, children had less agreement and satisfaction when mothers adopted parenting authoritarianism and consequently led to their less using of this same parenting strategy when being parent. When children felt happy and satisfied with their mothers’ parenting, they were more likely to be influenced by the Chinese traditional value on authoritarianism and adopt such parenting dimension with their own children. The present study also identified three directions for future intergenerational parenting studies and clinical considerations for counselling children and parents in Hong Kong.

Background Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified in both pediatric neurodevelopmental syndromes and as somatic variants in cancer. However, little is known about the extent of the shared disruption of signaling pathways by the same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 ( ASXL1 ), where truncating heterozygous variants cause Bohring-Opitz syndrome (BOS, OMIM #605039), a germline neurodevelopmental disorder, while somatic variants are driver events in acute myeloid leukemia (AML). No BOS patients have been reported to have AML. Methods This study explores common pathways dysregulated by ASXL1 variants in patients with BOS and AML. We analyzed whole blood transcriptomic and DNA methylation data from patients with BOS and AML with ASXL1 -variant (AML- ASXL1 ) and examined differential exon usage and cell proportions. Results Our analyses identified common molecular signatures between BOS and AML- ASXL1 and highlighted key biomarkers, including VANGL2 , GRIK5 and GREM2 , that are dysregulated across samples with ASXL1 variants, regardless of disease type. Notably, our data revealed significant de-repression of posterior homeobox A ( HOXA ) genes and upregulation of Wnt-signaling and hematopoietic regulator HOXB4 . While we discovered many shared epigenetic and transcriptomic features, we also identified differential splice isoforms in RUNX3 where the long isoform, p46, is preferentially expressed in BOS, while the shorter p44 isoform is expressed in AML- ASXL1. Conclusion Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1 , to an underlying stem-cell state in both early development and in malignancy. Key points • ASXL1-driven transcriptomic and DNA methylation dysregulation highlight upregulation of Wnt-signaling pathways and aberrant posterior HOX gene regulation. • Differential RUNX3 isoform usage between BOS and AML- ASXL1 distinguishes between normal, in BOS, and abnormal, in AML, hematopoiesis. • The ASXL1-centric approach demonstrates that ASXL1 variants affect some common pathways and mechanisms and highlight the potential for common therapeutic targets.

Background and Objectives: The usual recommended intake of vitamin D for healthy infants is 400 international unit (IU) daily. However, a high dose of vitamin D at 2000-3000 IU daily is needed for those with vitamin D deficiency (VDD). This study aimed to assess the natural history of a group of healthy infants with VDD and the associated factors for persistent VDD. Methods and Study Design: Healthy infants detected to have VDD (25OHD <25 nmol/L) in a population study were followed, and their demographics and clinical data were collected. Results: One hundred and thirty-one subjects (boys equivalent 66%) were included. Their first serum 25OHD was taken at a median age of 87.5 days. None were treated with high-dose vitamin D supplements, but some have been given vitamin D at 400 IU daily. They were assessed again at the median age of 252.5 days when 15 remained to have VDD and 26 were in the insufficient range (25 - 49.9nmol/L). All persistent VDD children were on exclusive breastfeeding. Exclusive breastfeeding and no vitamin D supplementation were significant risk factors for persistent vitamin D insufficiency (<50nmol/L). Conclusions: Persistent VDD is common among infants exclusively breastfeeding and those who did not receive vitamin D supplementation.

The mRNA-1273 vaccine is effective against SARS-CoV-2 and was granted emergency use authorization by the FDA. Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibits severe SARS-CoV-2 disease similar to that in hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and nonhuman primates, low-level virus replication in mRNA-1273-vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high-resolution analysis that is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a 2-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.