Kilometer-scale climate models: Prospects and challenges

Currently major efforts are underway toward refining the horizontal resolution (or grid spacing) of climate models to about 1 km, using both global and regional climate models (GCMs and RCMs). Several groups have succeeded in conducting kilometer-scale multiweek GCM simulations and decadelong continental-scale RCM simulations. There is the well-founded hope that this increase in resolution represents a quantum jump in climate modeling, as it enables replacing the parameterization of moist convection by an explicit treatment. It is expected that this will improve the simulation of the water cycle and extreme events and reduce uncertainties in climate change projections. While kilometer-scale resolution is commonly employed in limited-area numerical weather prediction, enabling it on global scales for extended climate simulations requires a concerted effort. In this paper, we exploit an RCM that runs entirely on graphics processing units (GPUs) and show examples that highlight the prospects of this approach. A particular challenge addressed in this paper relates to the growth in output volumes. It is argued that the data avalanche of high-resolution simulations will make it impractical or impossible to store the data. Rather, repeating the simulation and conducting online analysis will become more efficient. A prototype of this methodology is presented. It makes use of a bit-reproducible model version that ensures reproducible simulations across hardware architectures, in conjunction with a data virtualization layer as a common interface for output analyses. An assessment of the potential of these novel approaches will be provided

International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor–Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome

Objective: Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). Methods: PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de‐identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. Results: A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute‐phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8‐year delay in FMF patients. An equal proportion of TRAPS patients first received anti–interleukin‐1 (anti‐IL‐1) and anti–tumor necrosis factor (anti‐TNF) biologic agents, whereas IL‐1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti‐TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. Conclusion: Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real‐world treatment assessment supports the need for further refinement of treatment practices

In silico validation of the autoinflammatory disease damage index

Introduction Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. Methods The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an â observer-nested-within-subject\u27 design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach\u27s alpha. Results The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. Conclusion The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies

Development of the autoinflammatory disease damage index (ADDI)

OBJECTIVES: Autoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in clinical studies. Currently, there is no such tool. Our objective was to develop a common autoinflammatory disease damage index (ADDI) for familial Mediterranean fever, cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic fever syndrome and mevalonate kinase deficiency. METHODS: We developed the ADDI by consensus building. The top 40 enrollers of patients in the Eurofever Registry and 9 experts from the Americas participated in multiple rounds of online surveys to select items and definitions. Further, 22 (parents of) patients rated damage items and suggested new items. A consensus meeting was held to refine the items and definitions, which were then formally weighted in a scoring system derived using decision-making software, known as 1000minds. RESULTS: More than 80% of the experts and patients completed the online surveys. The preliminary ADDI contains 18 items, categorised in the following eight organ systems: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular and musculoskeletal damage. The categories renal/amyloidosis and neurological damage were assigned the highest number of points, serosal damage the lowest number of points. The involvement of (parents of) patients resulted in the inclusion of, for example, chronic musculoskeletal pain. CONCLUSIONS: An instrument to measure damage caused by autoinflammatory diseases is developed based on consensus building. Patients fulfilled a significant role in this process

In silico validation of the Autoinflammatory Disease Damage Index

INTRODUCTION: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. METHODS: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha. RESULTS: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. CONCLUSION: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies

Anthropogenic intensification of short-duration rainfall extremes

Short- duration (1-3 h) rainfall extremes can cause serious damage to societies through rapidly developing (flash) flooding and are determined by complex, multifaceted processes that are altering as Earth's climate warms. In this Review, we examine evidence from observational, theoretical and modelling studies for the intensification of these rainfall extremes, the drivers and the impact on flash flooding. Both short- duration and long- duration (\textgreater1 day) rainfall extremes are intensifying with warming at a rate consistent with the increase in atmospheric moisture (~7% K-1), while in some regions, increases in short- duration extreme rainfall intensities are stronger than expected from moisture increases alone. These stronger local increases are related to feedbacks in convective clouds, but their exact role is uncertain because of the very small scales involved. Future extreme rainfall intensification is also modulated by changes to temperature stratification and large- scale atmospheric circulation. The latter remains a major source of uncertainty. Intensification of short- duration extremes has likely increased the incidence of flash flooding at local scales and this can further compound with an increase in storm spatial footprint to considerably increase total event rainfall. These findings call for urgent climate change adaptation measures to manage increasing flood risks

Boundaries between familial Mediterranean fever and juvenile spondyloarthritis: Analysis of three French retrospective cohorts.

Children with Familial Mediterranean fever may suffer from musculoskeletal involvement, somewhat difficult to distinguish from juvenile spondyloarthritis. The association of these two diseases has been scarcely reported in children. Objective of this work was to define the association of familial Mediterranean fever and juvenile spondyloarthritis in France. Three cohorts of children with familial Mediterranean fever, juvenile spondyloarthritis, familial Mediterranean fever related juvenile spondyloarthritis, were retrospectively identified in the French reference center of auto-inflammatory diseases. Familial Mediterranean fever was defined according to Tel-Hashomer or Turkish pediatric criteria with at least one exon-10 MEFV-gene mutation. Juvenile spondyloarthritis was defined according to ILAR criteria. Patients with familial Mediterranean fever or juvenile spondyloarthritis were respectively compared to familial Mediterranean fever related juvenile spondyloarthritis patients. Sixteen children were identified as having familial Mediterranean fever related juvenile spondyloarthritis. The male/female-ratio was 0.6, with median age at spondyloarthritis onset of 7.5years (3-16years). All carried at least one M694V variant in MEFV gene; 16.7% were HLA-B27-carriers. Compared to 83 familial Mediterranean fever patients, familial Mediterranean fever related juvenile spondyloarthritis patients had less frequently fever (P&lt;0.01) and more frequently arthritis (P&lt;0.05), enthesitis (P&lt;0.001), inflammatory back pain (P&lt;0.001), inadequate response to colchicine (P&lt;0.05). Compared to 20 juvenile spondyloarthritis patients, familial Mediterranean fever related juvenile spondyloarthritis patients less often received non-steroidal anti-inflammatory drugs (P&lt;0.01) and anti-tumor necrosis factor drugs (P&lt;0.001). Familial Mediterranean fever may be associated with typical pattern of juvenile spondyloarthritis. These patients, with less response to colchicine, should be diagnosed earlier and treated as for jSpA