Improving Benefit-harm Assessment of Therapies from the Patient Perspective: OMERACT Premeeting Toward Consensus on Core Sets for Randomized Controlled Trials

Objective: Outcome Measures in Rheumatology (OMERACT) convened a premeeting in 2018 to bring together patients, regulators, researchers, clinicians, and consumers to build upon previous OMERACT drug safety work, with patients fully engaged throughout all phases. Methods: Day 1 included a brief introduction to the history of OMERACT and methodology, and an overview of current efforts within and outside OMERACT to identify patient-reported medication safety concerns. On Day 2, two working groups presented results; after each, breakout groups were assembled to discuss findings. Results: Five themes pertaining to drug safety measurement emerged. Conclusion: Current approaches have failed to include data from the patient’s perspective. A better understanding of how individuals with rheumatic diseases view potential benefits and harms of therapies is essential

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Plant functional groups mediate drought resistance and recovery in a multi-site grassland experiment

1.Climate change predictions suggest that summer droughts will become more intense and recurrent in Europe. While drought‐induced reductions in grassland primary productivity are well documented, the drivers behind drought resistance (the capacity to withstand change) and recovery (the capacity for recovery of function) of above‐ and belowground biomass remain poorly understood. 2.Across eight grasslands differing in plant community productivity (CP) we investigated the effects of summer drought on plant and soil microbial variables, plant nutrient content and soil nitrogen (N) availability. We examined the linkages between community productivity, soil N, drought responses of plant and microbial communities and relative drought responses of plant and microbial biomass. Plant and microbial variables were recorded at the end of a three‐month rainfall exclusion period. Plant variables were also assessed during a 10‐month drought recovery period. 3.Experimental drought decreased plant biomass and increased plant C:N ratios, but had no effect on total microbial biomass across sites. Instead, drought caused shifts in plant and microbial community structures as well as an increase in arbuscular mycorrhiza fungi biomass. Overall, plant biomass drought resistance was unrelated to community productivity or microbial community structure but was positively related to drought resistance of forbs. 4.In the month after rewetting, soil N availability increased in droughted plots across sites. Two months post‐rewetting, droughted plots had higher plant N concentration, but lower plant N use efficiency. The short‐term drought recovery of plant biomass was unrelated to community productivity or soil N availability, but positively related to the response of grass biomass, reflecting incomplete recovery at high community productivity. Ten months after rewetting, drought effects on plant biomass and plant N content were no longer apparent. 5.Synthesis. Our results suggest that drought resistance and recovery are more sensitive to plant community composition than to community productivity (CP). Short‐term recovery of plant biomass may also benefit from increased soil N availability after drought and from a high abundance of soil fungi in low productivity sites. Our findings underline the importance of plant functional groups for the stability of permanent grasslands in a changing climate with more frequent drought

Data from: Plant functional groups mediate drought resistance and recovery in a multi-site grassland experiment

1. Climate change predictions suggest that summer droughts will become more intense and recurrent in Europe. While drought-induced reductions in grassland primary productivity are well documented, the drivers behind drought resistance (the capacity to withstand change) and recovery (the capacity for recovery of function) of above- and belowground biomass remain poorly understood. 2. Across eight grasslands differing in plant community productivity (CP) we investigated the effects of summer drought on plant and soil microbial variables, plant nutrient content and soil nitrogen (N) availability. We examined the linkages between community productivity, soil N, drought responses of plant and microbial communities and relative drought responses of plant and microbial biomass. Plant and microbial variables were recorded at the end of a three-month rainfall exclusion period. Plant variables were also assessed during a 10-month drought recovery period. 3. Experimental drought decreased plant biomass and increased plant C:N ratios, but had no effect on total microbial biomass across sites. Instead, drought caused shifts in plant and microbial community structures as well as an increase in arbuscular mycorrhiza fungi biomass. Overall, plant biomass drought resistance was unrelated to community productivity or microbial community structure but was positively related to drought resistance of forbs. 4. In the month after rewetting, soil N availability increased in droughted plots across sites. Two months post-rewetting, droughted plots had higher plant N concentration, but lower plant N use efficiency. The short-term drought recovery of plant biomass was unrelated to community productivity or soil N availability, but positively related to the response of grass biomass, reflecting incomplete recovery at high community productivity. Ten months after rewetting, drought effects on plant biomass and plant N content were no longer apparent. 5. Synthesis. Our results suggest that drought resistance and recovery are more sensitive to plant community composition than to community productivity (CP). Short-term recovery of plant biomass may also benefit from increased soil N availability after drought and from a high abundance of soil fungi in low productivity sites. Our findings underline the importance of plant functional groups for the stability of permanent grasslands in a changing climate with more frequent drought

Extreme drought impacts have been underestimated in grasslands and shrublands globally.

Climate change is increasing the frequency and severity of short-term (~1 y) drought events-the most common duration of drought-globally. Yet the impact of this intensification of drought on ecosystem functioning remains poorly resolved. This is due in part to the widely disparate approaches ecologists have employed to study drought, variation in the severity and duration of drought studied, and differences among ecosystems in vegetation, edaphic and climatic attributes that can mediate drought impacts. To overcome these problems and better identify the factors that modulate drought responses, we used a coordinated distributed experiment to quantify the impact of short-term drought on grassland and shrubland ecosystems. With a standardized approach, we imposed ~a single year of drought at 100 sites on six continents. Here we show that loss of a foundational ecosystem function-aboveground net primary production (ANPP)-was 60% greater at sites that experienced statistically extreme drought (1-in-100-y event) vs. those sites where drought was nominal (historically more common) in magnitude (35% vs. 21%, respectively). This reduction in a key carbon cycle process with a single year of extreme drought greatly exceeds previously reported losses for grasslands and shrublands. Our global experiment also revealed high variability in drought response but that relative reductions in ANPP were greater in drier ecosystems and those with fewer plant species. Overall, our results demonstrate with unprecedented rigor that the global impacts of projected increases in drought severity have been significantly underestimated and that drier and less diverse sites are likely to be most vulnerable to extreme drought

The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes

Niemann-Pick type C1 disease (NPC1) is an autosomal recessive lysosomal storage disorder characterized by neonatal jaundice, hepatosplenomegaly, and progressive neurodegeneration. The present study provides the lipid profiles, mutations, and corresponding associations with the biochemical phenotype obtained from NPC1 patients who participated in the National NPC1 Disease Database. Lipid profiles were obtained from 34 patients (39%) in the survey and demonstrated significantly reduced plasma LDL cholesterol (LDL-C) and increased plasma triglycerides in the majority of patients. Reduced plasma HDL cholesterol (HDL-C) was the most consistent lipoprotein abnormality found in male and female NPC1 patients across age groups and occurred independent of changes in plasma triglycerides. A subset of 19 patients for whom the biochemical severity of known NPC1 mutations could be correlated with their lipid profile showed a strong inverse correlation between plasma HDL-C and severity of the biochemical phenotype. Gene mutations were available for 52 patients (59%) in the survey, including 52 different mutations and five novel mutations (Y628C, P887L, I923V, A1151T, and 3741_3744delACTC). Together, these findings provide novel information regarding the plasma lipoprotein changes and mutations in NPC1 disease, and suggest plasma HDL-C represents a potential biomarker of NPC1 disease severity