37 research outputs found

    Forcings, feedbacks and climate sensitivity in HadGEM3‐GC3.1 and UKESM1

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    Climate forcing, sensitivity and feedback metrics are evaluated in both the UK’s physical climate model HadGEM3-GC3.1at low (-LL) and medium(-MM) resolution and the UK’s Earth System Model UKESM1. The Effective Climate Sensitivity (EffCS)to a doubling of CO2 is 5.5K for HadGEM3.1-GC3.1-LL and 5.4 K for UKESM1. The transient climate response is 2.5K and 2.8K respectively. Whilst the EffCS is larger than that seen in the previous generation of models, none of the model’s forcing or feedback processes are found to be atypical of models, though the cloud feedback is at the high end. The relatively large EffCS results from an unusual combination of a typical CO2 forcing with a relatively small feedback parameter. Compared to the previous UK climate model, HadGEM3-GC2.0, the EffCS has increased from 3.2K to 5.5K due to an increase in CO2 forcing, surface albedo feedback and mid-latitude cloud feedback. All changes are well understood and due to physical improvements in the model.At higher atmospheric and ocean resolution(HadGEM3-GC3.1-MM), there is a compensation between increased marine stratocumulous cloud feedback and reduced Antarctic sea-ice feedback. In UKESM1 a CO2 fertilization effect induces a land surface vegetation change and albedo radiative effect. Historical aerosol forcing in HadGEM3-GC3.1-LL is -1.1 Wm-2. In HadGEM3-GC3.1-LL historical simulations cloud feedback is found to be less positive than in abrupt-4xCO2, in agreement with atmosphere-only experiments forced with observed historical sea-surface-temperature and sea-ice variations. However variability in the coupled model’s historical sea-ice trends hampers accurate diagnosis of the model’s total historical feedback

    A Medicinal Chemist’s Guide to Molecular Interactions

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    Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model

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    Summary Background Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal motor neuron disease with a variable natural history. There are no accurate models that predict the disease course and outcomes, which complicates risk assessment and counselling for individual patients, stratification of patients for trials, and timing of interventions. We therefore aimed to develop and validate a model for predicting a composite survival endpoint for individual patients with ALS. Methods We obtained data for patients from 14 specialised ALS centres (each one designated as a cohort) in Belgium, France, the Netherlands, Germany, Ireland, Italy, Portugal, Switzerland, and the UK. All patients were diagnosed in the centres after excluding other diagnoses and classified according to revised El Escorial criteria. We assessed 16 patient characteristics as potential predictors of a composite survival outcome (time between onset of symptoms and non-invasive ventilation for more than 23 h per day, tracheostomy, or death) and applied backward elimination with bootstrapping in the largest population-based dataset for predictor selection. Data were gathered on the day of diagnosis or as soon as possible thereafter. Predictors that were selected in more than 70% of the bootstrap resamples were used to develop a multivariable Royston-Parmar model for predicting the composite survival outcome in individual patients. We assessed the generalisability of the model by estimating heterogeneity of predictive accuracy across external populations (ie, populations not used to develop the model) using internal–external cross-validation, and quantified the discrimination using the concordance (c) statistic (area under the receiver operator characteristic curve) and calibration using a calibration slope. Findings Data were collected between Jan 1, 1992, and Sept 22, 2016 (the largest data-set included data from 1936 patients). The median follow-up time was 97·5 months (IQR 52·9–168·5). Eight candidate predictors entered the prediction model: bulbar versus non-bulbar onset (univariable hazard ratio [HR] 1·71, 95% CI 1·63–1·79), age at onset (1·03, 1·03–1·03), definite versus probable or possible ALS (1·47, 1·39–1·55), diagnostic delay (0·52, 0·51–0·53), forced vital capacity (HR 0·99, 0·99–0·99), progression rate (6·33, 5·92–6·76), frontotemporal dementia (1·34, 1·20–1·50), and presence of a C9orf72 repeat expansion (1·45, 1·31–1·61), all p<0·0001. The c statistic for external predictive accuracy of the model was 0·78 (95% CI 0·77–0·80; 95% prediction interval [PI] 0·74–0·82) and the calibration slope was 1·01 (95% CI 0·95–1·07; 95% PI 0·83–1·18). The model was used to define five groups with distinct median predicted (SE) and observed (SE) times in months from symptom onset to the composite survival outcome: very short 17·7 (0·20), 16·5 (0·23); short 25·3 (0·06), 25·2 (0·35); intermediate 32·2 (0·09), 32·8 (0·46); long 43·7 (0·21), 44·6 (0·74); and very long 91·0 (1·84), 85·6 (1·96). Interpretation We have developed an externally validated model to predict survival without tracheostomy and non-invasive ventilation for more than 23 h per day in European patients with ALS. This model could be applied to individualised patient management, counselling, and future trial design, but to maximise the benefit and prevent harm it is intended to be used by medical doctors only. Funding Netherlands ALS Foundation
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