Autism in England: assessing underdiagnosis in a population-based cohort study of prospectively collected primary care data

Background: Autism has long been viewed as a paediatric condition, meaning that many autistic adults missed out on a diagnosis as children when autism was little known. We estimated numbers of diagnosed and undiagnosed autistic people in England, and examined how diagnostic rates differed by socio-demographic factors. / Methods: This population-based cohort study of prospectively collected primary care data from IQVIA Medical Research Data (IMRD) compared the prevalence of diagnosed autism to community prevalence to estimate underdiagnosis. 602,433 individuals registered at an English primary care practice in 2018 and 5,586,100 individuals registered between 2000 and 2018 were included. / Findings: Rates of diagnosed autism in children/young people were much higher than in adults/older adults. As of 2018, 2.94% of 10- to 14-year-olds had a diagnosis (1 in 34), vs. 0.02% aged 70+ (1 in 6000). Exploratory projections based on these data suggest that, as of 2018, 463,500 people (0.82% of the English population) may have been diagnosed autistic, and between 435,700 and 1,197,300 may be autistic and undiagnosed (59–72% of autistic people, 0.77%–2.12% of the English population). Age-related inequalities were also evident in new diagnoses (incidence): c.1 in 250 5- to 9-year-olds had a newly-recorded autism diagnosis in 2018, vs. c.1 in 4000 20- to 49-year-olds, and c.1 in 18,000 people aged 50+. / Interpretation: Substantial age-related differences in the proportions of people diagnosed suggest an urgent need to improve access to adult autism diagnostic services

Modeling the Shape and Evolution of Normal-Fault Facets

Facets formed along the footwalls of active normal-fault blocks display a variety of longitudinal profile forms, with variations in gradient, shape, degree of soil cover, and presence or absence of a slope break at the fault trace. We show that a two-dimensional, process-oriented cellular automaton model of facet profile evolution can account for the observed morphologic diversity. The model uses two dimensionless parameters to represent fault slip, progressive rock weathering, and downslope colluvial-soil transport driven by gravity and stochastic disturbance events. The parameters represent rock weathering and soil disturbance rates, respectively, scaled by fault slip rate; both can be derived from field-estimated rate coefficients. In the model's transport-limited regime, slope gradient depends on the ratio of disturbance to slip rate, with a maximum that represents the angle of repose for colluvium. In this regime, facet evolution is consistent with nonlinear diffusion models of soil-mantled hillslope evolution. Under the weathering-limited regime, bedrock becomes partly exposed but microtopography helps trap some colluvium even when facet gradient exceeds the threshold angle. Whereas the model predicts a continuous gradient from footwall to colluvial wedge under transport-limited behavior, fully weathering-limited facets tend to develop a slope break between footwall and basal colluvium as a result of reduced transport efficiency on the rocky footwall slope. To the extent that the model provides a reasonable analogy for natural facets, its behavior suggests that facet profile morphology can provide useful constraints on relative potential rates of rock weathering, soil disturbance, and fault slip.</p

Estimating life expectancy and years of life lost for autistic people in the UK: a matched cohort study

Background: Previous research has shown that people who have been diagnosed autistic are more likely to die prematurely than the general population. However, statistics on premature mortality in autistic people have often been misinterpreted. In this study we aimed to estimate the life expectancy and years of life lost experienced by autistic people living in the UK.// Methods: We studied people in the IQVIA Medical Research Database with an autism diagnosis between January 1, 1989 and January 16, 2019. For each participant diagnosed autistic, we included ten comparison participants without an autism diagnosis, matched by age, sex, and primary care practice. We calculated age- and sex-standardised mortality ratios comparing people diagnosed autistic to the reference group. We used Poisson regression to estimate age-specific mortality rates, and life tables to estimate life expectancy at age 18 and years of life lost. We analysed the data separately by sex, and for people with and without a record of intellectual disability. We discuss the findings in the light of the prevalence of recorded diagnosis of autism in primary care compared to community estimates.// Findings: From a cohort of nearly 10 million people, we identified 17,130 participants diagnosed autistic without an intellectual disability (matched with 171,300 comparison participants), and 6450 participants diagnosed autistic with an intellectual disability (matched with 64,500 comparison participants). The apparent estimates indicated that people diagnosed with autism but not intellectual disability had 1.71 (95% CI: 1.39–2.11) times the mortality rate of people without these diagnoses. People diagnosed with autism and intellectual disability had 2.83 (95% CI: 2.33–3.43) times the mortality rate of people without these diagnoses. Likewise, the apparent reduction in life expectancy for people diagnosed with autism but not intellectual disability was 6.14 years (95% CI: 2.84–9.07) for men and 6.45 years (95% CI: 1.37–11.58 years) for women. The apparent reduction in life expectancy for people diagnosed with autism and intellectual disability was 7.28 years (95% CI: 3.78–10.27) for men and 14.59 years (95% CI: 9.45–19.02 years) for women. However, these findings are likely to be subject to exposure misclassification biases: very few autistic adults and older-adults have been diagnosed, meaning that we could only study a fraction of the total autistic population. Those who have been diagnosed may well be those with greater support needs and more co-occurring health conditions than autistic people on average

First do no harm: extending the debate on the provision of preventive tamoxifen

The Breast Cancer Prevention Trial (BCPT-P-1) demonstrated that tamoxifen could reduce the risk of invasive breast cancer in high-risk women by 49%, but that it could also increase the risk of endometrial cancer, vascular events and cataracts. This paper provides an estimate of the net health impacts of tamoxifen administration on high-risk Canadian women with no prior history of breast cancer. The results of the BCPT-P-1 were incorporated into the breast cancer and other modules of Statistics Canada’s microsimulation POpulation HEalth Model (POHEM). While the main intervention scenario conformed as closely as possible to the eligibility criteria for tamoxifen in the BCPT-P-1 protocol, 3 additional scenarios were simulated. Predicted absolute risks of breast cancer at 5 years of 1.66%, 3.32% and 4.15% were calculated for women 35 to 70 years of age. When the BCPT-P-1 results were incorporated into the simulation model, the analysis suggests no increase in life expectancy in this risk group. Tamoxifen appeared to be beneficial for women with a 5-year predicted risk of 3.32% or greater. The results of these simulations are particularly sensitive to the reduction in mortality observed in the BCPT-P-1, as well as being sensitive to other characteristics of the simulation model. Overall, the analysis raises questions about the use of tamoxifen in otherwise healthy women at high risk of breast cancer. © 2001 Cancer Research Campaig

New Constraints (and Motivations) for Abelian Gauge Bosons in the MeV-TeV Mass Range

We survey the phenomenological constraints on abelian gauge bosons having masses in the MeV to multi-GeV mass range (using precision electroweak measurements, neutrino-electron and neutrino-nucleon scattering, electron and muon anomalous magnetic moments, upsilon decay, beam dump experiments, atomic parity violation, low-energy neutron scattering and primordial nucleosynthesis). We compute their implications for the three parameters that in general describe the low-energy properties of such bosons: their mass and their two possible types of dimensionless couplings (direct couplings to ordinary fermions and kinetic mixing with Standard Model hypercharge). We argue that gauge bosons with very small couplings to ordinary fermions in this mass range are natural in string compactifications and are likely to be generic in theories for which the gravity scale is systematically smaller than the Planck mass - such as in extra-dimensional models - because of the necessity to suppress proton decay. Furthermore, because its couplings are weak, in the low-energy theory relevant to experiments at and below TeV scales the charge gauged by the new boson can appear to be broken, both by classical effects and by anomalies. In particular, if the new gauge charge appears to be anomalous, anomaly cancellation does not also require the introduction of new light fermions in the low-energy theory. Furthermore, the charge can appear to be conserved in the low-energy theory, despite the corresponding gauge boson having a mass. Our results reduce to those of other authors in the special cases where there is no kinetic mixing or there is no direct coupling to ordinary fermions, such as for recently proposed dark-matter scenarios.Comment: 49 pages + appendix, 21 figures. This is the final version which appears in JHE

Low bone mineral density is related to male gender and decreased functional capacity in early spondylarthropathies

The objective of this study was to determine the prevalence and risk factors of low bone mineral density (BMD) in patients with spondylarthropathies (SpA) at an early stage of disease. In this cross-sectional study, the BMD of lumbar spine and hips was measured in 130 consecutive early SpA patients. The outcome measure BMD was defined as (1) osteoporosis, (2) osteopenia, and (3) normal bone density. Logistic regression analyses were used to investigate relations between the following variables: age, gender, disease duration, diagnosis, HLA-B27, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), extra-spinal manifestations and medication, with outcome measure low BMD (osteopenia and/or osteoporosis). The SpA population had a median time since diagnosis of 6.6 months and a disease duration of 6.3 years. In total, 9% of the early SpA patients had osteoporosis, 38% osteopenia, and 53% normal BMD. On univariate analyses, male gender, diagnosis of ankylosing spondylitis, increased CRP, high BASFI, and high BASMI were significantly associated with low BMD. Factors showing a relation with low BMD in the multivariate model were male gender (OR 4.18, 95% confidence interval (CI) 1.73–10.09), high BASMI (OR 1.54, 95% CI 1.14–2.07), and high BASFI (OR 1.18, 95% CI 1.00–1.39). In early SpA patients, a high frequency (47%) of low BMD in femur as well as in lumbar spine was found. Low BMD was associated with male gender and decreased functional capacity. These findings emphasize the need for more alertness for osteoporosis and osteopenia in spondylarthropathy patients at an early stage of the disease

Comparative evidence for a link between Peyer's patch development and susceptibility to transmissible spongiform encephalopathies

BACKGROUND: Epidemiological analyses indicate that the age distribution of natural cases of transmissible spongiform encephalopathies (TSEs) reflect age-related risk of infection, however, the underlying mechanisms remain poorly understood. Using a comparative approach, we tested the hypothesis that, there is a significant correlation between risk of infection for scrapie, bovine spongiform encephalopathy (BSE) and variant CJD (vCJD), and the development of lymphoid tissue in the gut. METHODS: Using anatomical data and estimates of risk of infection in mathematical models (which included results from previously published studies) for sheep, cattle and humans, we calculated the Spearman's rank correlation coefficient, r(s), between available measures of Peyer's patch (PP) development and the estimated risk of infection for an individual of the corresponding age. RESULTS: There was a significant correlation between the measures of PP development and the estimated risk of TSE infection; the two age-related distributions peaked in the same age groups. This result was obtained for each of the three host species: for sheep, surface area of ileal PP tissue vs risk of infection, r(s )= 0.913 (n = 19, P < 0.001), and lymphoid follicle density vs risk of infection, r(s )= 0.933 (n = 19, P < 0.001); for cattle, weight of PP tissue vs risk of infection, r(s )= 0.693 (n = 94, P < 0.001); and for humans, number of PPs vs risk of infection, r(s )= 0.384 (n = 46, P = 0.008). In addition, when changes in exposure associated with BSE-contaminated meat were accounted for, the two age-related patterns for humans remained concordant: r(s )= 0.360 (n = 46, P = 0.014). CONCLUSION: Our findings suggest that, for sheep, cattle and humans alike there is an association between PP development (or a correlate of PP development) and susceptibility to natural TSE infection. This association may explain changes in susceptibility with host age, and differences in the age-susceptibility relationship between host species

DNA Barcoding in the Cycadales: Testing the Potential of Proposed Barcoding Markers for Species Identification of Cycads

Barcodes are short segments of DNA that can be used to uniquely identify an unknown specimen to species, particularly when diagnostic morphological features are absent. These sequences could offer a new forensic tool in plant and animal conservation—especially for endangered species such as members of the Cycadales. Ideally, barcodes could be used to positively identify illegally obtained material even in cases where diagnostic features have been purposefully removed or to release confiscated organisms into the proper breeding population. In order to be useful, a DNA barcode sequence must not only easily PCR amplify with universal or near-universal reaction conditions and primers, but also contain enough variation to generate unique identifiers at either the species or population levels. Chloroplast regions suggested by the Plant Working Group of the Consortium for the Barcode of Life (CBoL), and two alternatives, the chloroplast psbA-trnH intergenic spacer and the nuclear ribosomal internal transcribed spacer (nrITS), were tested for their utility in generating unique identifiers for members of the Cycadales. Ease of amplification and sequence generation with universal primers and reaction conditions was determined for each of the seven proposed markers. While none of the proposed markers provided unique identifiers for all species tested, nrITS showed the most promise in terms of variability, although sequencing difficulties remain a drawback. We suggest a workflow for DNA barcoding, including database generation and management, which will ultimately be necessary if we are to succeed in establishing a universal DNA barcode for plants

Characterization of Serum Proteins Associated with IL28B Genotype among Patients with Chronic Hepatitis C

Introduction: Polymorphisms near the IL28B gene (e.g. rs12979860) encoding interferon lambda 3 have recently been associated with both spontaneous clearance and treatment response to pegIFN/RBV in chronic hepatitis C (CHC) patients. The molecular consequences of this genetic variation are unknown. To gain further insight into IL28B function we assessed the association of rs12979860 with expression of protein quantitative traits (pQTL analysis) generated using open-platform proteomics in serum from patients

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal