アレキサンダー病

PURPOSE: Calcified chondroid mesenchymal neoplasm (CCMN) is a recently described and evolving entity that predominantly arises in the distal extremities andtemporomandibular joint (TMJ) region. CCMN is characterized by FN1 and PDGFRA gene fusions. In the TMJ region, most cases previously described as tophaceous pseudogout (i.e., mass-forming calcium pyrophosphate deposition disease) are now being increasingly recognized as CCMN. There is considerable morphologic overlap between CCMN and tophaceous pseudogout (TPG), and the detection of FN1 and PDGFRA gene rearrangements is critical in distinguishing CCMN from TPG. We aim to identify, from our archival records, cases of CCMN that were previously diagnosed as TPG. METHODS: We retrospectively reviewed clinical history and histopathology slides of three cases of TMJ region masses initially diagnosed as TPG, and submitted all three cases for targeted RNA sequencing. RESULTS: Case 1 harbored a canonical FN1::FGFR2 fusion. Case 2 failed targeted RNA sequencing. Case 3 harbored a canonical PDGFRA::USP8 fusion. None of the three cases had clinical history of pseudogout. All three cases were subsequently reclassified as CCMN on review. CONCLUSION: CCMN should be considered as a differential diagnosis in first presentations of 'tophaceous pseudogout' associated with chondroid metaplasia, with targeted molecular testing done as part of the diagnostic process.

CONTEXT: In the SOUL trial (NCT03914326), oral semaglutide reduced risk of major adverse cardiovascular (CV) events (MACE) by 14%. Whether baseline or changes in HbA1c or BMI are associated with these CV benefits is not known. OBJECTIVE: We evaluated whether CV benefits of oral semaglutide are associated with baseline or in-trial reductions in HbA1c or BMI. DESIGN: Post hoc analysis of SOUL, a double-blind, placebo-controlled trial (2019‒2024). SETTING: International, 444 sites. PARTICIPANTS: Adults aged ≥50 years, with type 2 diabetes and atherosclerotic CV disease and/or chronic kidney disease. INTERVENTION(S): Oral semaglutide or placebo. MAIN OUTCOME MEASURES: 3-point MACE (CV death, nonfatal myocardial infarction, or nonfatal stroke) analyzed by baseline and in-trial changes in HbA1c and BMI (Weeks 13; 52). RESULTS: 9650 adults randomized 1:1 to oral semaglutide or placebo were followed for 47.5 months. Median (IQR) age was 66 (61-72) years, mean (±SD) HbA1c 8.0 (1.1)% (63.5±12.5 mmol/mol) and BMI 31.1 (5.8) kg/m2. MACE benefits from oral semaglutide were significantly different across baseline HbA1c categories (P-interaction = .04), suggesting greater risk reduction at higher baseline HbA1c, but were consistent across baseline BMI categories. Greater in-trial HbA1c reductions were associated with larger decreases in MACE risk with oral semaglutide at 13 and 52 weeks (P-interactions .005 and < .001, respectively), whereas BMI changes showed consistency (P-interactions .88 and .64, respectively). CONCLUSIONS: In SOUL, CV benefits of oral semaglutide appeared more pronounced among participants with higher baseline HbA1c and greater HbA1c reductions, but were consistent across baseline or changes in BMI.

BACKGROUND: To evaluate comparative effectiveness of methotrexate (MTX), calcineurin inhibitors (CNI), Janus kinase inhibitors (JAKi), and biologics for the first-line therapies in adult-onset Still's disease (AOSD) in real-world settings. METHODS: Two AOSD cohorts were retrospectively analysed. First, effectiveness of first-line biological versus non-biologic modulator was validated using overlap weighting of propensity scores in the Shanghai AOSD cohort. To compare AOSD treatment strategies (MTX, CNI, JAKi, biologics), we pooled data from the Shanghai and Erlangen cohorts, emulated a target trial, and applied doubly robust weighted regression to adjust for demographic and clinical confounders. The primary outcome was sustained event-free remission over 12 and 72 weeks. RESULTS: 124 AOSD patients were analyzed, 96 from the Shanghai and 28 from Erlangen cohort. In overlap-weighted analyses of Shanghai cohort, biologic was associated with higher sustained event-free remission and event-free state than non-biologic immune modulators (P = 0.0065 and P = 0.0096). In the pooled analysis, biologics were linked to higher likelihood of event-free state and sustained event-free remission at weeks 12 and 72 (all P < 0.05). Pairwise comparisons confirmed the advantage of biologics over CNI (sustained event-free remission at week 72 OR 0.11, p = 0.001), with significant benefits over MTX (OR 0.12, p = 0.002) and JAKi (OR 0.14, p = 0.008) emerging at week 72 for sustained event-free remission, and more frequent glucocorticoid discontinuation than MTX and CNI (both p < 0.05). CONCLUSIONS: First-line biological treatment is associated with improved sustained event-free remission compared to non-biologic treatments, such as MTX, CNI and JAKi and associated with more favorable long-term outcomes in AOSD.

Chimeric antigen receptor (CAR)-expressing cells bear a great potential for the treatment of autoimmune diseases. While numerous challenges persist, recent technological developments have demonstrated the potential for CAR cells to reset dysfunctional immune systems and transform care for patients with autoimmune disease.

The incidence of disseminated gonococcal infection (DGI) has remained low since the advent of antibiotics; however, a recent surge in DGI has inexplicably emerged during the past decade. In an effort to understand whether Neisseria gonorrhoeae that cause disseminated disease can be differentiated from non-invasive strains, we have performed a phenotypic and genotypic analysis on a selection of isolates obtained from invasive and uncomplicated infections in Canada. The increase in DGI was initially associated with a single antibiotic-susceptible gonococcal lineage, but later cases have been caused by diverse strains. Phenotypic analysis of a matched subset of 20 isolates obtained since 2013 found that these varied in their capacity to aggregate in suspension and in their association with serum complement proteins; however, these interactions did not discriminate between the invasive and mucosal isolates. Sequence typing of 360 Canadian isolates revealed that two variant porBa alleles are significantly associated with the DGI strains, one of these being present throughout the past decade, whereas the other emerged more recently. A PopNet-based population dynamics analysis, which instead establishes relationships based upon variance among discrete chromosomal segments, revealed that DGI isolates were restricted to distinct subpopulations within their phylogenetic distribution, implying a genetically linked potential to cause invasive disease. Consistent with this, a large number of genetic determinants are enriched in the DGI strains, making these enticing candidates to explain the increased capacity of N. gonorrhoeae to cause systemic infection and/or reduce the presentation of clinical symptoms from localized infection so that it remains untreated.IMPORTANCEThe re-emergence of disseminated gonococcal infections (DGIs) has raised concern that the virulence of some strains has increased due to their acquisition of a new capacity to remain asymptomatic during uncomplicated mucosal infection and/or to invade the bloodstream and persist upon establishing colonization at distal tissue sites. The molecular epidemiology of a very large incidence of DGI in Canada, which began from a single strain but then diversified with time, provided an opportunity to understand whether the invasive isolates were either phenotypically or genotypically related. While classical phenotypic analysis did not discriminate between mucosal and invasive isolates, a population dynamics-based approach established that the DGI isolates are present within distinct subpopulations of Neisseria gonorrhoeae and reveals genetic determinants that are linked to this phenotype. This suggests that the DGI phenotype emerged multiple times independently and/or the genetic features responsible have been transmitted among the populations.