The Home Literacy Environment as a Predictor of the Early Literacy Development of Children at Family-Risk of Dyslexia

The home literacy environment (HLE) predicts language and reading development in typically developing children; relatively little is known about its association with literacy development in children at family-risk of dyslexia. We assessed the HLE at age 4 years, precursor literacy skills at age 5, and literacy outcomes at age 6, in a sample of children at family-risk of dyslexia (n = 116) and children with no known risk (n = 72). Developmental relationships between the HLE and literacy were comparable between the groups; an additional effect of storybook exposure on phoneme awareness was observed in the family-risk group only. The effects of socioeconomic status on literacy were partially mediated by variations in the HLE; in turn, effects of the HLE on literacy were mediated by precursor skills (oral language, phoneme awareness, and emergent decoding) in both groups. Findings are discussed in terms of possible gene–environment correlation mechanisms underpinning atypical literacy development

Shared storybook reading with children at family risk of dyslexia

Background: Shared storybook reading is an important context for language learning and often constitutes young children's first encounter with the printed word. The quality of early shared reading interactions is a known predictor of language and reading development, but few studies have examined these interactions in children at family risk of dyslexia. Methods: This exploratory study describes the quality of shared storybook reading between mothers and their 3- to 4-year-old children at family risk of dyslexia (FR; n = 18) in comparison with dyads with no known risk (no-FR; n = 13). Mother–child interactions while sharing a familiar and an unfamiliar storybook were coded for type of extra-textual talk (meaning-related talk at the concrete and abstract levels; print-related talk) and affective quality. Maternal and child language and literacy skills were considered as potential correlates of shared reading quality. Results: The linguistic and affective quality of shared reading was broadly comparable across FR and no-FR dyads, particularly when sharing a book they knew well, with large within-group variation. Mothers contributed more concrete meaning-related talk when introducing an unfamiliar book to their children; children contributed more extra-textual talk overall when sharing a familiar book. Maternal language, but not reading, skills were related to the linguistic quality of shared reading. The affective quality of reading interactions was rated more highly in dyads where mothers and children had stronger language skills. Conclusions: These results suggest that the quality of shared reading does not vary systematically as a function of children's risk of dyslexia but is related to maternal language skills. This finding needs to be replicated in a larger sample in order to better understand the risk and protective factors associated with dyslexia. Highlights: What is already known about this topic The quality of extra-textual talk during shared reading between parents and preschoolers predicts later language and literacy outcomes in typically developing children. The affective quality of early shared reading predicts children's motivation to read independently in later childhood. Children at family risk of dyslexia are more likely than their peers with no family risk to have difficulty learning to read and may show weaknesses in oral language skills. What this paper adds. The linguistic and affective quality of shared reading between mothers and preschool children is broadly similar when children are at family risk of dyslexia compared with no family risk. The type and quantity of extra-textual talk contributed by mothers and children appears to differ according to the familiarity of the storybook, but replication of the findings in a larger sample is required. The linguistic and affective quality of shared reading is related to maternal language skills. Implications for theory, policy or practice. Shared storybook reading offers rich language learning opportunities for children at family risk of dyslexia. Maternal language skills may be an important determinant of the interactional quality of shared reading. The linguistic and affective quality of shared reading is not clearly associated with maternal reading difficulties

Hsa-mir183/EGR1-mediated regulation of E2F1 is required for CML stem/progenitor cell survival

Chronic myeloid leukemia (CML) stem/progenitor cells (SPC) express a transcriptional program characteristic of proliferation, yet can achieve and maintain quiescence. Understanding the mechanisms by which leukemic SPC maintain quiescence will help to clarify how they persist during long-term targeted treatment. We have identified a novel BCR-ABL1 protein kinase dependent pathway mediated by the up-regulation of hsa-mir183, the down-regulation of its direct target EGR1 and, as a consequence, up-regulation of E2F1. We show here that inhibition of hsa-mir183 reduced proliferation and impaired colony formation of CML SPC. Downstream of this, inhibition of E2F1 also reduced proliferation of CML SPC, leading to p53-mediated apoptosis. In addition, we demonstrate that E2F1 plays a pivotal role in regulating CML SPC proliferation status. Thus, for the first time, we highlight the mechanism of hsa-mir183/EGR1-mediated E2F1 regulation and demonstrate this axis as a novel, critical factor for CML SPC survival, offering new insights into leukemic stem cell eradication

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children