Accumulation of Self-Reactive Naive and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sjogren's Syndrome

This work was funded by grants number 18237 and 20089 from Arthritis Research UK (http://www.arthritisresearchuk.org) to MB and the William Harvey Research Foundation. EC was recipient of short-term travel fellowships from EMBO (ASTF 318-2010) and EFIS-IL

LEGaTO: first steps towards energy-efficient toolset for heterogeneous computing

LEGaTO is a three-year EU H2020 project which started in December 2017. The LEGaTO project will leverage task-based programming models to provide a software ecosystem for Made-in-Europe heterogeneous hardware composed of CPUs, GPUs, FPGAs and dataflow engines. The aim is to attain one order of magnitude energy savings from the edge to the converged cloud/HPC.Peer ReviewedPostprint (author's final draft

C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation

Intronic GGGGCC (G4C2) hexanucleotide repeat expansion within the human C9orf72 gene represents the most common cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of repeat-containing C9orf72 RNA results in the production of neurotoxic dipeptide-repeat proteins (DPRs). Here, we developed a high-throughput drug screen for the identification of positive and negative modulators of DPR levels. We found that HSP90 inhibitor geldanamycin and aldosterone antagonist spironolactone reduced DPR levels by promoting protein degradation via the proteasome and autophagy pathways respectively. Surprisingly, cAMP-elevating compounds boosting protein kinase A (PKA) activity increased DPR levels. Inhibition of PKA activity, by both pharmacological and genetic approaches, reduced DPR levels in cells and rescued pathological phenotypes in a Drosophila model of C9ALS/FTD. Moreover, knockdown of PKA-catalytic subunits correlated with reduced translation efficiency of DPRs, while the PKA inhibitor H89 reduced endogenous DPR levels in C9ALS/FTD patient-derived iPSC motor neurons. Together, our results suggest new and druggable pathways modulating DPR levels in C9ALS/FTD

Low arthroplasty survival after treatment for proximal humerus fracture sequelae: 3,245 shoulder replacements from the Nordic Arthroplasty Register Association

Background and purpose - Proximal humerus fractures (PHF) may result in sequelae indicating arthroplasty. We report cumulative survival rates and reasons for revision after arthroplasty for proximal humerus fracture sequelae (PHFS). Patients and methods - Data were derived from the Nordic Arthroplasty Register Association. The Kaplan-Meier method was used to illustrate survival rates. A scaled Schoenfeld residual plot was used to report the risk of revision for men relative to women in patients who were treated with reverse shoulder arthroplasty (RSA). Revision was defined as removal or exchange of any component or the addition of a glenoid component. Results - 30,190 primary arthroplasties were reported from 2004 to 2016, of which 3,245 were for PHFS. The estimated 1-, 5-, and 10-year cumulative survival rates (95% CI) were 96% (95-97), 90% (89-92), and 86% (83-88) for stemmed hemiarthroplasty and 94% (92-95), 89% (87-91), and 86% (82-90) for RSA with a median time to revision of 18 months (IQR 9-44) and 3 months (IQR 0-17). The risk of revision for men relative to women in patients who were treated with RSA was 3.2 (1.9-5.1) 0-1 year after surgery and 1.9 (0.9-4.1) 1-8 years after surgery. The estimated 1-, 5-, and 10-year cumulative survival rates (95% CI) were 94% (92-96), 88% (85-90), and 80% (75-86) for men and 95% (94-96), 86% (84-89), and 81% (77-84) for young patients. Interpretation - Shoulder arthroplasty for PHFS was associated with lower survival rates, compared with previously published results of shoulder arthroplasty for acute PHF. The low arthroplasty survival rates for men and young patients especially are worrying

Low risk of revision after reverse shoulder arthroplasty for acute proximal humeral fractures

Background: Reverse shoulder arthroplasty (RSA) has gained popularity in the treatment of proximal humeral fractures (PHFs), especially in elderly patients. The purpose of this study was to investigate the use of RSA implants for acute PHFs and risk of revision, as well as risk factors for revision.Methods: RSA implants for acute PHFs were identified from the Nordic Arthroplasty Register Association registry data from 2004 to 2016. Kaplan-Meier survival analysis was used to calculate implant survival. Cox multiple regression analysis was used to calculate the adjusted revision rate for sex, age, country of operation, and year of surgery.Results: The study included 1523 RSA implants for PHFs (84% women; average age, 77 years; average follow-up time, 2.5 years). The 5-year cumulative implant survival rate was 97% (confidence limits, 95.5% and 98%). Revision was performed for 33 implants (2%). The most common reason for revision was instability, occurring in 11 cases (0.7%), followed by fracture, occurring in 6 (0.4%), and infection, occurring in 5 (0.3%). Four different arthroplasty brands were used in this cohort, with the Delta Xtend in two-thirds of cases (n = 1025). Age younger than 60 years and male sex were associated with slightly higher rates of revision; however, these differences did not reach statistical significance (hazard ratio of 2.02 with P = .075 and hazard ratio of 3.23 with P = .057, respectively).Conclusion: The use of RSA for acute PHFs is increasing in the Nordic countries. The short-term risk of revision is low. The main reason for revision of RSA for this indication is instability.</p

The Bankart repair versus the Putti-Platt procedure: A randomized study with WOSI score at 10-year follow-up in 62 patients

Background and purpose This randomized study compared clinical results after surgery for posttraumatic shoulder instability with either an anatomical repair or an older, less anatomical but commonly used method. The less anatomical procedure has been considered quicker and less demanding, but it has been questioned regarding the clinical result. We therefore wanted to compare the clinical outcome of the two different procedures. Our hypothesis was that the anatomical repair would give less residual impairment postoperatively