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22q11.2 deletion syndrome, or 22q11.2DS, is a genetic syndrome associated with high rates of schizophrenia and autism spectrum disorders, in addition to widespread structural and functional abnormalities throughout the brain. Experimental animal models have identified neuronal connectivity deficits, e.g., decreased axonal length and complexity of axonal branching, as a primary mechanism underlying atypical brain development in 22q11.2DS. However, it is still unclear whether deficits in axonal morphology can also be observed in people with 22q11.2DS. Here, we provide an unparalleled in vivo characterization of white matter microstructure in participants with 22q11.2DS (12-15 years) and those undergoing typical development (8-18 years) using a customized magnetic resonance imaging scanner which is sensitive to axonal morphology. A rich array of diffusion MRI metrics are extracted to present microstructural profiles of typical and atypical white matter development, and provide new evidence of connectivity differences in individuals with 22q11.2DS. A recent, large-scale consortium study of 22q11.2DS identified higher diffusion anisotropy and reduced overall diffusion mobility of water as hallmark microstructural alterations of white matter in individuals across a wide age range (6-52 years). We observed similar findings across the white matter tracts included in this study, in addition to identifying deficits in axonal morphology. This, in combination with reduced tract volume measurements, supports the hypothesis that abnormal microstructural connectivity in 22q11.2DS may be mediated by densely packed axons with disproportionately small diameters. Our findings provide insight into the in vivo white matter phenotype of 22q11.2DS, and promote the continued investigation of shared features in neurodevelopmental and psychiatric disorders.
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Síndrome de DiGeorge , Esquizofrenia , Sustancia Blanca , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Síndrome de DiGeorge/genética , Imagen de Difusión Tensora/métodos , EncéfaloRESUMEN
BACKGROUND: The risk of suicide is complex and often a result of multiple interacting factors. Understanding which groups of the population are most at risk of suicide is important to inform the development of targeted public health interventions. METHODS: We used a novel linked dataset that combined the 2011 Census with the population-level mortality data in England and Wales. We fitted generalized linear models with a Poisson link function to estimate the rates of suicide across different sociodemographic groups and to identify which characteristics are independent predictors of suicide. RESULTS: Overall, the highest rates of suicide were among men aged 40-50 years, individuals who reported having a disability or long-term health problem, those who were unemployed long term or never had worked, and those who were single or separated. After adjusting for other characteristics such as employment status, having a disability or long-term health problem, was still found to increase the incidence of suicide relative to those without impairment [incidence rate ratio minimally adjusted (women) = 3.5, 95% confidence interval (CI) = 3.3-3.6; fully adjusted (women) 3.1, 95% CI = 3.0-3.3]. Additionally, while the absolute rate of suicide was lower in women compared with men, the relative risk in people reporting impairments compared with those who do not was higher in women compared with men. CONCLUSIONS: The findings of this work provide novel population-level insights into the risk of suicide by sociodemographic characteristics in England and Wales. Our results highlight several sociodemographic groups who may benefit from more targeted suicide prevention policies and practices.
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Suicidio , Adulto , Femenino , Humanos , Masculino , Estudios de Cohortes , Inglaterra/epidemiología , Incidencia , Gales/epidemiología , Persona de Mediana EdadRESUMEN
Facial expression and body posture recognition have protracted developmental trajectories. Interactions between face and body perception, such as the influence of body posture on facial expression perception, also change with development. While the brain regions underpinning face and body processing are well-defined, little is known about how white-matter tracts linking these regions relate to perceptual development. Here, we obtained complementary diffusion magnetic resonance imaging (MRI) measures (fractional anisotropy [FA], spherical mean Sµ ), and a quantitative MRI myelin-proxy measure (R1), within white-matter tracts of face- and body-selective networks in children and adolescents and related these to perceptual development. In tracts linking occipital and fusiform face areas, facial expression perception was predicted by age-related maturation, as measured by Sµ and R1, as well as age-independent individual differences in microstructure, captured by FA and R1. Tract microstructure measures linking posterior superior temporal sulcus body region with anterior temporal lobe (ATL) were related to the influence of body on facial expression perception, supporting ATL as a site of face and body network convergence. Overall, our results highlight age-dependent and age-independent constraints that white-matter microstructure poses on perceptual abilities during development and the importance of complementary microstructural measures in linking brain structure and behaviour.
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Sustancia Blanca , Niño , Adolescente , Humanos , Sustancia Blanca/diagnóstico por imagen , Expresión Facial , Imagen de Difusión Tensora/métodos , Encéfalo/patología , Imagen de Difusión por Resonancia Magnética , Percepción , AnisotropíaRESUMEN
Neuroanatomical changes to the cortex during adolescence have been well documented using MRI, revealing ongoing cortical thinning and volume loss with age. However, the underlying cellular mechanisms remain elusive with conventional neuroimaging. Recent advances in MRI hardware and new biophysical models of tissue informed by diffusion MRI data hold promise for identifying the cellular changes driving these morphological observations. This study used ultra-strong gradient MRI to obtain high-resolution, in vivo estimates of cortical neurite and soma microstructure in sample of typically developing children and adolescents. Cortical neurite signal fraction, attributed to neuronal and glial processes, increased with age (mean R2 fneurite=.53, p<3.3e-11, 11.91% increase over age), while apparent soma radius decreased (mean R2 Rsoma=.48, p<4.4e-10, 1% decrease over age) across domain-specific networks. To complement these findings, developmental patterns of cortical gene expression in two independent post-mortem databases were analysed. This revealed increased expression of genes expressed in oligodendrocytes, and excitatory neurons, alongside a relative decrease in expression of genes expressed in astrocyte, microglia and endothelial cell-types. Age-related genes were significantly enriched in cortical oligodendrocytes, oligodendrocyte progenitors and Layer 5-6 neurons (pFDR<.001) and prominently expressed in adolescence and young adulthood. The spatial and temporal alignment of oligodendrocyte cell-type gene expression with neurite and soma microstructural changes suggest that ongoing cortical myelination processes contribute to adolescent cortical development. These findings highlight the role of intra-cortical myelination in cortical maturation during adolescence and into adulthood.
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The emergence of the COVID-19 vaccination has been critical in changing the course of the COVID-19 pandemic. To ensure protection remains high in vulnerable groups booster vaccinations in the UK have been targeted based on age and clinical vulnerabilities. We undertook a national retrospective cohort study using data from the 2021 Census linked to electronic health records. We fitted cause-specific Cox models to examine the association between health conditions and the risk of COVID-19 death and all-other-cause death for adults aged 50-100-years in England vaccinated with a booster in autumn 2022. Here we show, having learning disabilities or Down Syndrome (hazard ratio=5.07;95% confidence interval=3.69-6.98), pulmonary hypertension or fibrosis (2.88;2.43-3.40), motor neuron disease, multiple sclerosis, myasthenia or Huntington's disease (2.94, 1.82-4.74), cancer of blood and bone marrow (3.11;2.72-3.56), Parkinson's disease (2.74;2.34-3.20), lung or oral cancer (2.57;2.04 to 3.24), dementia (2.64;2.46 to 2.83) or liver cirrhosis (2.65;1.95 to 3.59) was associated with an increased risk of COVID-19 death. Individuals with cancer of the blood or bone marrow, chronic kidney disease, cystic fibrosis, pulmonary hypotension or fibrosis, or rheumatoid arthritis or systemic lupus erythematosus had a significantly higher risk of COVID-19 death relative to other causes of death compared with individuals who did not have diagnoses. Policy makers should continue to priorities vulnerable groups for subsequent COVID-19 booster doses to minimise the risk of COVID-19 death.
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COVID-19 , Neoplasias de la Boca , Adulto , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Pandemias , Estudios Retrospectivos , Inglaterra/epidemiología , Cirrosis HepáticaRESUMEN
Background: The diagnosis of a severe physical health condition can cause psychological distress and lead to severe depression. The association between severe physical health conditions and the risk of suicide, and how the risk of suicide changes in the months following diagnosis, are not clear. Methods: We estimated whether a diagnosis of severe physical health conditions is associated with an increase in the risk of death by suicide using a dataset based on the 2011 Census linked to hospital records and death registration records covering 47,354,696 people alive on 1 January 2017 in England. Patients diagnosed with a low-survival cancer, chronic ischaemic heart disease, chronic obstructive pulmonary disease, or degenerative neurological condition were matched to individuals using socio-demographic characteristics from the Census. Using the Aalen-Johansen estimator, we estimated the cumulative incidence of death by suicide occurring between 1 January 2017 and 31 December 2021 (registered by 31 December 2021) in patients and matched controls, adjusted for other potential confounders using inverse probability weighting. Findings: Diagnosis of severe conditions was associated with an increased risk of dying by suicide. One year after diagnosis, the rate of suicide was 21.6 (95% confidence intervals: 14.9-28.4, number of events (N): 39) per 100,000 low-survival cancer patients compared to 9.5 (5.6-14.6, N:16) per 100,000 matched controls. For COPD patients, the one-year suicide rate was 22.4 (19.4-25.5, N:208) per 100,000 COPD patients (matched controls: 10.6, 8.3-13.0, N:85), for ischaemic heart disease 16.1 (14.1-18.2, N:225) per 100,000 patients (matched controls: 8.8, 7.1-10.4, N:128), for degenerative neurological conditions 114.5 (49.6-194.7, N:11) per 100,000 patients. The increase in risk was more pronounced in the first six months after diagnosis or first treatment. Interpretation: A diagnosis of severe physical illness is associated with higher suicide risk. The interaction of physical and mental illness emphasises the importance of collaborative physical and mental health care in these patients. Funding: The Office for National Statistics. KES is the Laing Galazka chair in palliative care at King's College London, funded by an endowment from Cicely Saunders International and the Kirby Laing Foundation.
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Several studies have reported associations between COVID-19 vaccination and risk of cardiac diseases, especially in young people; the impact on mortality, however, remains unclear. We use national, linked electronic health data in England to assess the impact of COVID-19 vaccination and positive SARS-CoV-2 tests on the risk of cardiac and all-cause mortality in young people (12 to 29 years) using a self-controlled case series design. Here, we show there is no significant increase in cardiac or all-cause mortality in the 12 weeks following COVID-19 vaccination compared to more than 12 weeks after any dose. However, we find an increase in cardiac death in women after a first dose of non mRNA vaccines. A positive SARS-CoV-2 test is associated with increased cardiac and all-cause mortality among people vaccinated or unvaccinated at time of testing.
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Prueba de COVID-19 , Vacunas contra la COVID-19 , COVID-19 , Causas de Muerte , SARS-CoV-2 , Vacunación , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Factores de Edad , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/mortalidad , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Registros Electrónicos de Salud , Inglaterra/epidemiología , Cardiopatías/epidemiología , Cardiopatías/mortalidad , Incidencia , Vacunas de ARNm/administración & dosificación , Vacunas de ARNm/efectos adversos , Medición de Riesgo , SARS-CoV-2/aislamiento & purificación , Factores Sexuales , Factores de Tiempo , Vacunación/efectos adversos , Niño , HospitalizaciónRESUMEN
Background: Hypertension is a leading cause of morbidity and mortality worldwide, yet a substantial proportion of cases are undiagnosed. Understanding the scale of undiagnosed hypertension and identifying groups most at risk is important to inform approaches to detection. Methods: In this cross-sectional cohort study, we used data from the 2015 to 2019 Health Survey for England, an annual, cross-sectional, nationally representative survey. The survey follows a multi-stage stratified probability sampling design, involving a random sample of primary sampling units based on postcode sectors, followed by a random sample of postal addresses within these units. Within each selected household, all adults (aged ≥16 years) and up to four children, were eligible for participation. For the current study, individuals aged 16 years and over who were not pregnant and had valid blood pressure data were included in the analysis. The primary outcome was undiagnosed hypertension, defined by a measured blood pressure of 140/90 mmHg or above but no history of diagnosis. Age-adjusted prevalence of undiagnosed hypertension was estimated across sociodemographic and health-related characteristics, including ethnicity, region, rural-urban classification, relationship status, highest educational qualification, National Statistics Socio-Economic Classification (NS-SEC), Body Mass Index (BMI), self-reported general health, and smoking status. To assess the independent association between undiagnosed hypertension and each characteristic, we fitted a logistic regression model adjusted for sociodemographic factors. Findings: The sample included 21,476 individuals, of whom 55.8% were female and 89.3% reported a White ethnic background. An estimated 30.7% (95% confidence interval 29.0-32.4) of men with hypertension and 27.6% (26.1-29.1) of women with hypertension were undiagnosed. Younger age, lower BMI, and better self-reported general health were associated with an increased likelihood of hypertension being undiagnosed for men and women. Living in rural areas and in regions outside of London and the East of England were also associated with an increased likelihood of hypertension being undiagnosed for men, as were being married or in a civil partnership and having higher educational qualifications for women. Interpretation: Hypertension is commonly undiagnosed, and some of the groups that are at the lowest risk of hypertension are the most likely to be undiagnosed. Given the high lifetime risk of hypertension and its strong links with morbidity and mortality, our findings suggest a need for greater awareness of the potential for undiagnosed hypertension, including among those typically considered 'low risk'. Further research is needed to assess the impact of extending hypertension screening to lower-risk groups. Funding: None.
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OBJECTIVE: To assess the risk of covid-19 death after infection with omicron BA.1 compared with delta (B.1.617.2). DESIGN: Retrospective cohort study. SETTING: England, United Kingdom, from 1 December 2021 to 30 December 2021. PARTICIPANTS: 1 035 149 people aged 18-100 years who tested positive for SARS-CoV-2 under the national surveillance programme and had an infection identified as omicron BA.1 or delta compatible. MAIN OUTCOME MEASURES: The main outcome measure was covid-19 death as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause specific Cox proportional hazard regression models (censoring non-covid-19 deaths) were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, index of multiple deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Interactions between variant and sex, age, vaccination status, and comorbidities were also investigated. RESULTS: The risk of covid-19 death was 66% lower (95% confidence interval 54% to 75%) for omicron BA.1 compared with delta after adjusting for a wide range of potential confounders. The reduction in the risk of covid-19 death for omicron compared with delta was more pronounced in people aged 18-59 years (number of deaths: delta=46, omicron=11; hazard ratio 0.14, 95% confidence interval 0.07 to 0.27) than in those aged ≥70 years (number of deaths: delta=113, omicron=135; hazard ratio 0.44, 95% confidence interval 0.32 to 0.61, P<0.0001). No evidence of a difference in risk was found between variant and number of comorbidities. CONCLUSIONS: The results support earlier studies showing a reduction in severity of infection with omicron BA.1 compared with delta in terms of hospital admission. This study extends the research to also show a reduction in the risk of covid-19 death for the omicron variant compared with the delta variant.