Objective To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Methods This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta‐regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi‐criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. Results The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE‐specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. Conclusion These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

ObjectiveTo develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).MethodsThis international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects.ResultsThe 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.ConclusionThese new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.

The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulinindependent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKα2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle.LKB1 | Akt Substrate of 160 kDa | TBC1D1 | exercise

NA interference (RNAi) therapeutics use an endogenous mechanism whereby short interfering RNAs (siRNAs) direct the RNA-induced silencing complex (RISC) to sequence matched target transcripts for knockdown 1 . Both lipid nanoparticles and N-acetylgalactosamine (GalNAc) conjugates are clinically validated and approved delivery strategies for liver targets [2][3][4][5][6][7][8] . Building on nearly 2 decades of siRNA design and chemistry optimization [9][10][11][12] , we demonstrate here that, with suitable delivery solutions, the RNAi pathway can be harnessed in extrahepatic tissues, such as the central nervous system (CNS), eye and lung. Multiple CNS diseases, representing some of the highest unmet medical needs and greatest therapeutic challenges, have been associated with dominant gain-of-function mutations, making them suitable candidates for an RNAi-based silencing approach. As such, chemically modified siRNAs have demonstrated potent and sustained silencing in rodents and non-human primates (NHPs); however, using an invasive intracerebroventricular (ICV) administration approach 13 that is not suitable for repeated dosing in humans. Furthermore, technologies enabling siRNA delivery across the blood-brain barrier following a less challenging systemic administration are similarly being explored [14][15][16][17] , which are, however, still in early stages of discovery. In the eye, intravitreal (IVT) dosing of siRNAs has been evaluated in late-stage clinical studies, with few safety concerns, but did not advance further due to lack of efficacy 18 . Recently, the Coronavirus Disease 2019 (COVID-19) pandemic has highlighted the importance of optimizing siRNA delivery to the lung for the treatment of emergent viral respiratory diseases. Although earlier programs have already shown potential clinical benefits of siRNA-based therapeutics in the lung 19 , 2′-O-hexadecyl (C16) conjugates demonstrate enhanced delivery and siRNA uptake into the alveolar and bronchiolar epithelium. Taken together, this work highlights that the combination of a C16 lipophilic modification with our fully chemically modified, metabolically stable siRNAs achieves efficient delivery to the CNS, eye and lung, resulting in a robust and durable gene silencing in rodents and NHPs, with a favorable safety profile. We think that these advances have the potential to generate multiple candidates for investigating clinical safety and efficacy in humans. ResultsOptimization of the siRNA conjugate design. Lipophilic moieties represent one of the earliest approaches to improve cellular uptake and delivery of antisense oligonucleotides (ASOs) and siRNAs to the liver and various other organ systems 20 , including the CNS [21][22][23] . We reasoned that, by carefully optimizing the lipophilicity of chemically modified siRNAs, we could enhance intracellular delivery without compromising broad biodistribution, potency and safety. We used the 2′ position of the ribose sugar backbone to introduce