Common health conditions in childhood and adolescence, school absence, and educational attainment: Mendelian randomization study

Good health is positively related to children’s educational outcomes, but relationships may not be causal. Demonstrating a causal influence would strongly support childhood and adolescent health as important for education policy. We applied genetic causal inference methods to assess the causal relationship of common health conditions at age 10 (primary/elementary school) and 13 (mid-secondary/mid-high school) with educational attainment at 16 and school absence at 14–16. Participants were 6113 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Exposures were symptoms of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, asthma, migraines and BMI. Genetic liability for these conditions and BMI was indexed by polygenic scores. In non-genetic, multivariate-adjusted models, all health conditions except asthma and migraines were associated with poorer attainment and greater school absence. School absence substantially mediated effects of BMI (39.9% for BMI at 13) and migraines (72.0% at 10), on attainment with more modest mediation for emotional and neurodevelopmental conditions. In genetic models, a unit increase in standardized BMI at 10 predicted a 0.19 S.D. decrease (95% CI: 0.11, 0.28) in attainment at 16, equivalent to around a 1/3 grade lower in all subjects, and 8.7% more school absence (95% CI:1.8%,16.1%). Associations were similar at 13. Genetic liability for ADHD predicted lower attainment but not more absence. Triangulation across multiple approaches supports a causal, negative influence on educational outcomes of BMI and ADHD, but not of ASD, depression, asthma or migraine. Higher BMI in childhood and adolescence may causally impair educational outcomes

Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants

OBJECTIVES: To investigate whether physicians' prescribing preferences were valid instrumental variables for the antidepressant prescriptions they issued to their patients. STUDY DESIGN AND SETTING: We investigated whether physicians' previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom. RESULTS: Prior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.7 percentage points (95% CI, 26.7, 28.8) more likely to prescribe paroxetine, to their next patient. Physicians' previous prescriptions were less strongly associated with patients' baseline characteristics than actual prescriptions. We found no evidence that the estimated association of TCAs with self-harm/suicide using instrumental variable regression differed from conventional regression estimates (P-value = 0.45). CONCLUSION: The main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants

Distributed ice thickness and glacier volume in southern South America

South American glaciers, including those in Patagonia, presently contribute the largest amount of meltwater to sea level rise per unit glacier area in the world. Yet understanding of the mechanisms behind the associated glacier mass balance changes remains unquantified partly because models are hindered by a lack of knowledge of subglacial topography. This study applied a perfect-plasticity model along glacier centre-lines to derive a first-order estimate of ice thickness and then interpolated these thickness estimates across glacier areas. This produced the first complete coverage of distributed ice thickness, bed topography and volume for 617 glaciers between 41°S and 55°S and in 24 major glacier regions. Maximum modelled ice thicknesses reach 1631 m ± 179 m in the South Patagonian Icefield (SPI), 1315 m ± 145 m in the North Patagonian Icefield (NPI) and 936 m ± 103 m in Cordillera Darwin. The total modelled volume of ice is 1234.6 km3 ± 246.8 km3 for the NPI, 4326.6 km3 ± 865.2 km3 for the SPI and 151.9 km3 ± 30.38 km3 for Cordillera Darwin. The total volume was modelled to be 5955 km3 ± 1191 km3, which equates to 5458.3 Gt ± 1091.6 Gt ice and to 15.08 mm ± 3.01 mm sea level equivalent (SLE). However, a total area of 655 km2 contains ice below sea level and there are 282 individual overdeepenings with a mean depth of 38 m and a total volume if filled with water to the brim of 102 km3. Adjusting the potential SLE for the ice volume below sea level and for the maximum potential storage of meltwater in these overdeepenings produces a maximum potential sea level rise (SLR) of 14.71 mm ± 2.94 mm. We provide a calculation of the present ice volume per major river catchment and we discuss likely changes to southern South America glaciers in the future. The ice thickness and subglacial topography modelled by this study will facilitate future studies of ice dynamics and glacier isostatic adjustment, and will be important for projecting water resources and glacier hazards

Low tropical diversity during the adaptive radiation of early land plants.

The latitudinal biodiversity gradient, with tropical regions acting as 'evolutionary cradles', is a cornerstone of current biogeographical and ecological theory1. In the modern world floral biodiversity and biomass are overwhelmingly concentrated in the tropics, and it is often assumed that the tropics were evolutionary cradles throughout land plant evolutionary history. For example, the origination and diversification of angiosperms is believed to have taken place in the Cretaceous tropics2 and modern gymnosperms in the Permian tropics3. Here, we show that during the first major diversification of land plants, in the Late Silurian-Early Devonian, land plant biodiversity was much lower at the equator compared to medium-high southern latitudes. Throughout this crucial interval of plant evolution, tropical vegetation remained depauperate and of very low taxonomic biodiversity, although with similar morphological disparity to the more diverse higher latitude floras. Possible explanations for this low tropical floral biodiversity include palaeocontinental configuration or adverse palaeotropical environmental conditions. We discount the possibility that it was simply a fortuitous feature of the biogeographical spread of the earliest vascular land plants.National Geographi

The Relative Orientation of Nuclear Accretion and Galaxy Stellar Disks in Seyfert Galaxies

We use the difference (delta) between the position angles of the nuclear radio emission and the host galaxy major axis to investigate the distribution of the angle (beta) between the axes of the nuclear accretion disk and the host galaxy disk in Seyfert galaxies. We provide a critical appraisal of the quality of all measurements, and find that the data are limited by observational uncertainties and biases, such as the well known deficiency of Seyfert galaxies of high inclination. There is weak evidence that the distribution of delta for Seyfert 2 galaxies may be different (at the 90% confidence level) from a uniform distribution, while the Seyfert 1 delta distribution is not significantly different from a uniform distribution or from the Seyfert 2 delta distribution. The cause of the possible non-uniformity in the distribution of delta for Seyfert 2 galaxies is discussed. Seyfert nuclei in late-type spiral galaxies may favor large values of delta (at the ~96% confidence level), while those in early-type galaxies show a more or less random distribution of delta. This may imply that the nuclear accretion disk in non-interacting late-type spirals tends to align with the stellar disk, while that in early-type galaxies is more randomly oriented, perhaps as a result of accretion following a galaxy merger. We point out that biases in the distribution of inclination translate to biased estimates of beta in the context of the unified scheme. When this effect is taken into account, the distributions of beta for all Seyferts together, and of Seyfert 1's and 2's separately, agree with the hypothesis that the radio jets are randomly oriented with respect to the galaxy disk. The data are consistent with the expectations of the unified scheme, but do not demand it.Comment: To appear in the Astrophysical Journal, Vol 516 #1, May 1, 1999. Corrected figure placement within pape

Dealing with the deluge of historical weather data: the example of the TEMPEST database

People have long been interested in the history of weather, particularly extremes, and chronologies of past events drawing on information from written records, have been compiled and published throughout history. In recent years, concern over current and future weather and climate has triggered a new level of interest in past weather events and their impacts. This interest, alongside the development of digital humanities research methods has resulted in a rapid growth in the number of online databases relating to historic weather and climate around the world. This paper reviews this expansion with reference to a range of examples, before documenting the design and creation of one such database, TEMPEST, an online repository for extreme weather history in the UK. TEMPEST has been created as the major output of the AHRC funded project ?Spaces of Experience and Horizons of Expectation: Extreme Weather in the UK, Past, Present and Future? (2013-2016). Unlike the majority of existing databases that rely on published materials, TEMPEST?s records are drawn from primary research into original documentary sources held in archives around the UK. The c. 18,000 records that TEMPEST currently contains offer personalised and geo-referenced insights into the relationship between society and extreme weather in the UK spanning a period of over 400 years. We conclude this paper by outlining some potential applications for TEMPEST, and suggesting directions for future research and resources in historical weather. We also consider broader issues for the digital humanities.publishersversionPeer reviewe

Varenicline Versus Nicotine Replacement Therapy for Long-Term Smoking Cessation:An Observational Study Using the Clinical Practice Research Datalink

Background Smoking is the leading avoidable cause of illness and premature mortality. The first-line treatments for smoking cessation are nicotine replacement therapy and varenicline. Meta-analyses of experimental studies have shown that participants allocated to the varenicline group were 1.57 times (95% confidence interval 1.29 to 1.91 times) as likely to be abstinent 6 months after treatment as those allocated to the nicotine replacement therapy group. However, there is limited evidence about the effectiveness of varenicline when prescribed in primary care. We investigated the effectiveness and rate of adverse events of these medicines in the general population. Objective To estimate the effect of prescribing varenicline on smoking cessation rates and health outcomes. Data sources Clinical Practice Research Datalink. Methods We conducted an observational cohort study using electronic medical records from the Clinical Practice Research Datalink. We extracted data on all patients who were prescribed varenicline or nicotine replacement therapy after 1 September 2006 who were aged ≥ 18 years. We investigated the effects of varenicline on smoking cessation, all-cause mortality and cause-specific mortality and hospitalisation for: (1) chronic lung disease, (2) lung cancer, (3) coronary heart disease, (4) pneumonia, (5) cerebrovascular disease, (6) diabetes, and (7) external causes; primary care diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression, or prescription for anxiety; weight in kg; general practitioner and hospital attendance. Our primary outcome was smoking cessation 2 years after the first prescription. We investigated the baseline differences between patients prescribed varenicline and patients prescribed nicotine replacement therapy. We report results using multivariable-adjusted, propensity score and instrumental variable regression. Finally, we developed methods to assess the relative bias of the different statistical methods we used. Results People prescribed varenicline were healthier at baseline than those prescribed nicotine replacement therapy in almost all characteristics, which highlighted the potential for residual confounding. Our instrumental variable analysis results found little evidence that patients prescribed varenicline had lower mortality 2 years after their first prescription (risk difference 0.67, 95% confidence interval –0.11 to 1.46) than those prescribed nicotine replacement therapy. They had similar rates of all-cause hospitalisation, incident primary care diagnoses of myocardial infarction and chronic obstructive pulmonary disease. People prescribed varenicline subsequently attended primary care less frequently. Patients prescribed varenicline were more likely (odds ratio 1.46, 95% confidence interval 1.42 to 1.50) to be abstinent 6 months after treatment than those prescribed nicotine replacement therapy when estimated using multivariable-adjusted for baseline covariates. Patients from more deprived areas were less likely to be prescribed varenicline. However, varenicline had similar effectiveness for these groups. Conclusion Patients prescribed varenicline in primary care were more likely to quit smoking than those prescribed nicotine replacement therapy, but there was little evidence that they had lower rates of mortality or morbidity in the 4 years following the first prescription. There was little evidence of heterogeneity in effectiveness across the population

Thymus transplantation for complete DiGeorge syndrome: European experience

Background: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods: Twelve patients with cDGS were transplanted with allogeneic cultured thymus. Objective: To confirm and extend the results previously obtained in a single centre. Results: Two patients died of pre-existing viral infections without developing thymopoeisis and one late death occurred from autoimmune thrombocytopaenia. One infant suffered septic shock shortly after transplant resulting in graft loss and the need for a second transplant. Evidence of thymopoeisis developed from 5-6 months after transplantation in ten patients. The median (range) of circulating naïve CD4 counts (x10663 /L) were 44(11-440) and 200(5-310) at twelve and twenty-four months post-transplant and T-cell receptor excision circles were 2238 (320-8807) and 4184 (1582 -24596) per106 65 T-cells. Counts did not usually reach normal levels for age but patients were able to clear pre-existing and later acquired infections. At a median of 49 months (22-80), eight have ceased prophylactic antimicrobials and five immunoglobulin replacement. Histological confirmation of thymopoeisis was seen in seven of eleven patients undergoing biopsy of transplanted tissue including five showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator (AIRE) expression was also demonstrated. Autoimmune complications were seen in 7/12 patients. In two, early transient autoimmune haemolysis settled after treatment and did not recur. The other five suffered ongoing autoimmune problems including: thyroiditis (3); haemolysis (1), thrombocytopaenia (4) and neutropenia (1). Conclusions: This study confirms the previous reports that thymus transplantation can reconstitute T cells in cDGS but with frequent autoimmune complications in survivors

Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study

OBJECTIVE: To examine antiseizure medication (ASM) prescription during pregnancy. DESIGN: Population-based drug utilisation study. SETTING: UK primary and secondary care data, 1995-2018, from the Clinical Practice Research Datalink GOLD version. POPULATION OR SAMPLE: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. METHODS: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. MAIN OUTCOME MEASURES: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. RESULTS: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non-epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. CONCLUSIONS: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics