University of California, San Francisco

BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

Second generation antipsychotics (SGAs) are widely used clinical tools; yet, they often cause negative side effects and take weeks to become effective, leading to poor patient compliance. The effect/side effect profile of individual SGAs is highly variable, and the mechanisms that underlie this variability are not well understood. Here, we identify a role of type 3 dopamine receptor (D3R) neurons in the Nucleus Accumbens (NAc) that mimics the aversive effects of quetiapine. Using single-nucleus RNA sequencing, we show that D3R is expressed in a subpopulation of D1R neurons and defines a distinct NAc cell type. We found that both clozapine and quetiapine cause acute conditioned place aversion in mice, but aversion subsides only after 21 days of treatment with quetiapine, a drug characterized as an arrestin-biased agonist at D3R. We provide evidence at both the cellular and population level that quetiapine inhibits D3R-expressing neurons in the lateral shell (LatSh) of the NAc. We also demonstrate that local injection of quetiapine into LatSh NAc is sufficient to cause place aversion. Selective optogenetic inhibition of D3R-neurons in the LatSh produces real time place aversion in mice, correlating this cell type to the aversive effects of quetiapine. These findings suggest a cell-type-specific mechanism underlying quetiapine-induced aversion and its potential attenuation with chronic treatment, offering insight into the cell types and circuitry that shape the quetiapine side effect profile.

The use of prophylactic subgaleal vancomycin powder for preventing surgical site infections (SSI) has gained traction among cranial surgeons. However, its broad application remains controversial as the studies supporting its use are skewed toward high infection risk pathologies and have significant limitations. This study aimed to evaluate the efficacy of vancomycin powder in reducing SSIs in a cohort of patients with nonmalignant cranial pathologies. A retrospective chart review was conducted for 987 patients who underwent cranial surgeries for nonmalignant pathologies between July 2021 and June 2024 at a major academic center. Patients were divided into 2 groups: those who received prophylactic vancomycin powder (682 patients) and those who did not (305 patients). Data on demographics, comorbidities, procedure types, and SSI occurrences were collected. Established infection risk characteristics were nonsignificantly different between groups. There was no significant SSI difference when comparing patients not receiving vancomycin vs those who received the antibiotic (0.3% vs 0.7%, P = .578). There were 6 infections in total, 3/6 (50%) occurred with atypical meningiomas, 2/6 (33%) occurred with schwannomas, and 1/6 (17%) occurred with an amoebic abscess. Supratentorial craniotomies (odds ratio 0.95, P = .810) and posterior fossa craniotomies (odds ratio 1.18, 0.545) were the most common procedures and were nonsignificantly different between the cohorts. Meningiomas represented the largest portion of pathologies and were equally represented in both groups. This study suggests that the routine use of prophylactic vancomycin powder in nonmalignant cranial surgeries may be unnecessary, given an overall low incidence and lack of significant difference in SSIs between groups. These findings advocate for a more tailored approach to antibiotic prophylaxis, weighing the potential benefits against the known risks.

Avoidant/restrictive food intake disorder (ARFID) involves restrictive eating driven by sensory sensitivity, low interest in food, or fear of negative consequences of eating. ARFID affects males and females equally and presents across the weight spectrum. Leptin, an anorexigenic hormone linked to adiposity, may contribute to low hunger and early satiety in ARFID. Prior findings indicate low leptin levels in low-weight females with ARFID; however, the role of leptin in ARFID across weight status and sex remains unknown. We hypothesized that youth with full/subthreshold ARFID, including a subgroup of low-weight males, would exhibit lower fasting leptin levels than healthy controls (HCs). We explored cross-sectional and longitudinal associations between leptin and clinical characteristics. Participants were youth aged 10-23 years (BMI percentile M [SD] = 41.4 (33.6)) with full/subthreshold ARFID (n = 95; 49.5% female) and HCs (n = 28; 50.0% female). At baseline, participants completed questionnaires, a fasted blood draw, and a diagnostic interview for ARFID, readministered at 1- and 2year follow-ups. Leptin levels did not differ between ARFID and HC groups. Low-weight ARFID males had significantly lower leptin than HC males (η 2 = 0.258); however, this difference was nonsignificant after adjusting for BMI percentile. Leptin showed medium-to-large positive associations with age, BMI, and anxiety but not appetite or ARFID severity. Baseline leptin did not predict symptom or weight changes longitudinally. Hypoleptinemia was only evident in low-weight ARIFD and strongly correlated with BMI percentile. However, relationships with anxiety may suggest additional roles of leptin in underlying ARFID psychopathology. Findings should be replicated in larger, more representative samples.

SummaryDespite redundant cellular pathways to minimize translational errors, errors in protein synthesis are common. Pathways and mechanisms to minimize errors are classified as pre-ribosomal or ribosomal. Pre-ribosomal pathways are primarily concerned with the appropriate charging of tRNAs with their cognate amino acid. By contrast, the ribosomal decoding centre is considered ‘blind’ to mischarged tRNAs since these have cognate codon•anti-codon pairing. Here, we identified that in mycobacteria, deletion of the 16S ribosomal RNA methyltransferase gidB led to increased ribosomal discrimination of mischarged tRNAs. Discrimination only occurred in mycobacteria enriched from environments or genetic backgrounds with high rates of mistranslation. GidB deletion was necessary but not sufficient for reducing mistranslation due to misacylation. Analysis of new cryoEM structures of the M. smegmatis ribosomes derived from wild-type and gidB-deleted strains point to the interaction between the base methylated by GidB on the 16S RNA and an asparagine on the ribosomal S12 protein that when mistranslated to aspartate may be involved in altering translational fidelity. Our data suggest a mechanism by which mycobacterial ribosomes can discriminate mischarged tRNAs and that 16S rRNA differential methylation by GidB may act to prevent catastrophic translational error.