The health and care of children with Down Syndrome

Down Syndrome (DS) affects ~10,500 children in the UK. Individuals with DS continue to have poorer health outcomes compared with the general population, and other forms of intellectual disability. By systematically mapping two decades of paediatric DS literature, I found a general decline in the number of publications, since 2014. The majority of publications utilised observational methodologies, with few interventional (5.6%) or qualitative/mixed-method studies (4.3%). Most publications focused on development & cognition, oncology and neurology; relatively few looked at the prevalence of morbidities and health surveillance. Using a large electronic health record dataset I determined the prevalence of morbidities among individuals with DS (N=4,648, age range 0-75 years), and compared with matched controls. The most prevalent morbidities in the DS cohort were hypothyroidism (30.4%), congenital cardiac disease (27.8%), epilepsy (21.9%) and hearing impairment (19.2%). We also found an increased risk of autism (aOR 7.7), chronic kidney disease (aOR 2.3), inflammatory bowel disease (aOR 2.4), non-accidental injury (aOR 1.9), sleep disordered breathing (SDB) (aOR 6.6) and vitamin-D deficiency (aOR 3.1). Finally, I explored current practice with regard to the routine health surveillance of children with DS, in paediatric departments across the UK. Sixty four departments returned a copy of their local health surveillance protocol. Practice was compared across departments, and with three national guidelines. For congenital cardiac disease, hypothyroidism and hearing/visual impairment, practice appeared to be consistent and compliant with national guidelines. However, in other areas (echocardiogram at transition, SBD, vitamin-D deficiency & renal/liver function), practice was patchy and inconsistent. The findings highlight a need for ongoing research in the field of paediatric DS, targeted at areas of greatest need, and those morbidities which are prevalent in the DS cohort. Furthermore, our findings highlight a need a single, evidence based guideline for the health surveillance of children with DS, to promote high quality, consistent care

Increased household financial strain, the Great Recession and child health-findings from the UK Millennium Cohort Study.

Background: There is a growing body of evidence associating financial strain (FS) with poor health but most of this research has been cross-sectional and adult-focused. During the ‘Great Recession’ many UK households experienced increased FS. The primary aim of this study was to determine the impact of increased FS on child health. Methods: We analysed the Millennium Cohort Study, a longitudinal study of children born in the UK between 2000 and 2002. Surveys at 7 years (T1, 2008) and 11 years (T2, 2012) spanned the ‘Great Recession’. Three measures of increased FS were defined; ‘became income poor’ (self-reported household income dropped below the ‘poverty line’ between T1 and T2); ‘developed difficulty managing’ ( parental report of being ‘financially comfortable’ at T1 and finding it ‘difficult to manage’ at T2); ‘felt worse off’ ( parental report of feeling financially ‘worse off’ at T2 compared with T1). Poisson regression was used to estimate risk ratios (RR), adjusted risk ratios (aRR) and 95% CIs for six child health outcomes: measured overweight/obesity, problematic behaviour as scored by parents and teachers, and parental reports of fair/poor general health, long-standing illness and bedwetting at T2 (N=13 112). In subanalyses we limited our sample to those who were above the poverty line at T2. Results: Compared with those who were not financially strained at both time points, children in households which experienced increased FS were at an increased risk of all unhealthy outcomes examined. In most cases, these increased risks persisted after adjustment for confounding and when limiting the sample to those above the poverty line. Conclusions: FS is associated with a range of new or continued poor child health outcomes. During times of widespread economic hardship, such as the ‘Great Recession’, measures should be taken to buffer children and their families from the impact of FS, and these should not be limited to those who are income poor

Financial strain, parental smoking, and the great recession: an analysis of the UK Millennium Cohort Study

Introduction: During the recent “Great Recession,” many families in the United Kingdom experienced increased financial strain (FS). The aim of this study was to determine if increases in FS, occurring over the period of the “Great Recession,” were associated with increased risks of persistent and relapsed tobacco use among parents. Methods: We analyzed the Millennium Cohort Study, a longitudinal study of 18819 children born in the United Kingdom between 2000 and 2002. Surveys at 7 (T1, 2008) and 11 years (T2, 2012) spanned the “Great Recession.” Three measures of increased FS were defined; “became income poor” (self-reported household income dropped below the “poverty line” between T1 and T2); “developed difficulty managing” (parental report of being “financially comfortable” at T1 and finding it “difficult to manage” at T2); “felt worse off” (parental report of feeling financially “worse off” at T2, compared to T1). Poisson regression was used to estimate risk ratios (RR), adjusted RRs (aRR), and 95% confidence intervals for three outcomes: “persistent tobacco use,” “new reported tobacco use,” and “relapsed tobacco use.” Results: Parents in households which “became income poor” over the period of the “Great Recession” were significantly more likely to report “persistent tobacco use” (aRR = 2.17 [1.83–2.57]) or “new reported tobacco use” (aRR = 1.72 [1.04–2.83]). Ninety-five percent of “new reported tobacco users” had evidence of prior tobacco use suggesting the majority were “relapsed tobacco users.” Similar patterns were seen for those who “developed difficulty managing” and “felt worse off.” Conclusions: Increased tobacco use among financially strained families has the potential to widen inequalities and undermine the public health policies that have had positive impacts on tobacco consumption in the United Kingdom

Mapping Two Decades of Paediatric Down Syndrome Research Literature

BACKGROUND: While research has led to significant advancements in the health and life expectancy of children with Down Syndrome (DS), there remains a significant burden of disease and health inequity. Further research, focused on areas of greatest need, is imperative to address this. An understanding of what research has been undertaken, and any existing gaps, helps to guide future academic efforts. METHODS: We utilised an epistemological approach to summarise two decades of paediatric DS literature. Publications were categorised according to the country of origin, methodology, primary health themes and subcategory research themes. RESULTS: Across 5,800 paediatric DS publications we demonstrate a general increase in the number of publications in this field between 2000 and 2014, with a trending decline thereafter. The majority of publications were affiliated with Institutions based in Western countries. The majority of studies utilised a cross-sectional methodology (33.3%), while relatively few were interventional (5.6%), qualitative (2.7%) or mixed-method studies (1.6%). Most publications focused on development & cognition (13.1%), neurology (9.9%) and oncology (9.8%), with fewer focusing on genitourinary health (0.9%), growth (0.9%), mortality (0.9%) and child protection (0.2%). CONCLUSION: These findings highlight areas of relative paucity within the paediatric DS literature which may warrant increased academic attention

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine