Siberian snow forcing in a dynamically bias-corrected model

We investigate the effect of systematic model biases on teleconnections influencing the Northern Hemisphere wintertime circulation. We perform a two-step nudging and bias-correcting scheme for the dynamic variables of the ECHAM6 atmospheric model to reduce errors in the model climatology relative to ERA-Interim. One result is a significant increase in the strength of the Northern Hemisphere wintertime stratospheric polar vortex, reducing errors in the December–February mean zonal stratospheric winds by up to 75%. The bias corrections are applied to the full atmosphere or the stratosphere only. We compare the response of the bias-corrected and control runs to an increase in Siberian snow cover in October—a surface forcing that, in our experiments, weakens the stratospheric polar vortex from October to December. We find that despite large differences in the vortex strength the magnitude of the stratospheric weakening is similar among the different climatologies, with some differences in the timing and length of the response. Differences are more pronounced in the stratosphere–troposphere coupling, and the subsequent surface response. The snow forcing with the stratosphere-only bias corrections results in a stratospheric response that is comparable to control, yet with an enhanced surface response that extends into early January. The full-atmosphere bias correction’s snow response also has a comparable stratospheric response but a somewhat suppressed surface response. Despite these differences, our results show an overall small sensitivity of the Eurasian snow teleconnection to the background climatology

Lessons for major system change: centralization of stroke services in two metropolitan areas of England

OBJECTIVES: Our aim was to identify the factors influencing the selection of a model of acute stroke service centralization to create fewer high-volume specialist units in two metropolitan areas of England (London and Greater Manchester). It considers the reasons why services were more fully centralized in London than in Greater Manchester. METHODS: In both areas, we analysed 316 documents and conducted 45 interviews with people leading transformation, service user organizations, providers and commissioners. Inductive and deductive analyses were used to compare the processes underpinning change in each area, with reference to propositions for achieving major system change taken from a realist review of the existing literature (the Best framework), which we critique and develop further. RESULTS: In London, system leadership was used to overcome resistance to centralization and align stakeholders to implement a centralized service model. In Greater Manchester, programme leaders relied on achieving change by consensus and, lacking decision-making authority over providers, accommodated rather than challenged resistance by implementing a less radical transformation of services. CONCLUSIONS: A combination of system (top-down) and distributed (bottom-up) leadership is important in enabling change. System leadership provides the political authority required to coordinate stakeholders and to capitalize on clinical leadership by aligning it with transformation goals. Policy makers should examine how the structures of system authority, with performance management and financial levers, can be employed to coordinate transformation by aligning the disparate interests of providers and commissioners

Structural basis for complement factor H-linked age-related macular degeneration

This is the final version of the article. Available from the publisher via the DOI in this record.Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to approximately 50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance-monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG-FH complex.B. Prosser is funded by the Wellcome Trust Structural Biology Training Program (075415/Z/04/Z). S. Johnson and P. Roversi were funded by grants to S.M. Lea from the Medical Research Council (MRC) of the United Kingdom (grants G0400389 and G0400775). D. Uhrin and P.N. Barlow were funded by the Wellcome Trust (078780/ Z/05/Z). S.J. Clark was funded by an MRC Doctoral Training Account (G78/7925), and R.B. Sim and A.J. Day were funded by MRC core funding to the MRC Immunochemistry Unit

Rapid Quantification of Molecular Diversity for Selective Database Acquisition

There is an increasing need to expand the structural diversity of the molecules investigated in lead-discovery programs. One way in which this can be achieved is by acquiring external datasets that will enhance an existing database. This paper describes a rapid procedure for the selection of external datasets using a measure of structural diversity that is calculated from sums of pairwise intermolecular structural similarities

Genetic evidence for different adiposity phenotypes and their opposing influence on ectopic fat and risk of cardiometabolic disease

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants, one with ‘adverse’ metabolic effects (UFA) and the other with, paradoxically, ‘favourable’ metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, higher fat in subcutaneous and visceral adipose tissue, liver and pancreas for UFA; and a favourable metabolic profile, lower risk of disease, higher CRP, higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for risk-increasing effect of UFA and protective effect of FA on type 2 diabetes, heart disease, hypertension, stroke, non-alcoholic fatty liver disease and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat, and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting and treating of cardiometabolic diseases

Mechanical thrombectomy in patients with proximal occlusions and low NIHSS: Results from a large prospective registry

Background: Mechanical thrombectomy is now standard of care for treatment of acute ischemic stroke secondary to large vessel occlusion in the setting of high NIHSS. We analysed a large nationwide registry focusing on patients with large vessel occlusion and low NIHSS on admission to evaluate the efficacy and safety of thrombectomy in this patient population Methods: 2826 patients treated with mechanical thrombectomy were included in a multicentre registry from January 1, 2011 to December 31, 2015. We included patients with large vessel occlusion and NIHSS ≤ 6 on admission. Baseline characteristics, imaging, clinical outcome, procedure adverse events and positive and negative outcome predictors were analysed. Results: 134 patients were included. 90/134 had an anterior circulation and 44 a posterior circulation stroke. One patient died before treatment. Successful revascularization (mTICI 2b-3) was achieved in 73.7% (98/133) of the patients. Intraprocedural adverse event was observed in 3% (4/133) of cases. Symptomatic intracranial haemorrhage rate was 5.3% (7/133). At three months, 70.9% (95/134) of the patients had mRS score 0-2, 15.7% (21/134) mRS 3-5 and 13.4% (18/134) mRS 6. Age and successful recanalization were significant predictors of a good clinical outcome on both univariate (p= 0.005 and p=0.007) and multivariable (p=0.0018 and p=0.009 [nat log]) analysis. Absence of vessel recanalization and symptomatic intracranial hemorrhage were independent predictors of poor outcome (p=0.021). Conclusions: Our study suggests that patients with large vessel occlusion and low NIHSS score on admission can benefit from mechanical thrombectomy. Randomized trials are warranted