Citations

Objective Hospitalization, particularly for surgery, represents a period of heightened stress. We evaluated how frailty attenuates the association of rheumatoid arthritis (RA) with negative health outcomes after elective noncardiac surgery. Methods We conducted a cross‐sectional study using the National Inpatient Sample (2018 to 2020), including adults (aged ≥18 years) with elective hospitalizations with noncardiac surgery. Frailty was measured using the Hospital Frailty Risk Score (HFRS). Surgeries were categorized by risk level. Outcomes included discharge health resources need (DHRN), composite adverse clinical events (CACE), and death. Results Among 8,800,359 hospitalizations (2.14% among patients with RA), 73.36% underwent intermediate‐risk surgery and 62.25% had HFRS above 0. DHRN occurred in 28.9%, CACE occurred in 0.93%, and all‐cause mortality occurred in 0.17%. A 10‐point increase in HFRS was associated with a 3.8‐fold increased DHRN, 8.5‐fold increased CACE, and 22.8‐fold increased mortality. RA was not independently associated with CACE (adjusted odds ratio [aOR] 0.91; 95% confidence interval [CI] 0.82–1.01; P = 0.08) or death (aOR 0.90; 95% CI 0.71–1.15; P = 0.41) but was significantly associated with DHRN (aOR 1.28, 95% CI 1.25–1.31; P < 0.001) after adjusting for confounders and frailty. In sensitivity analysis, RA had 10% higher relative odds of DHRN following orthopedic (aOR 1.10; 95% CI 1.07–1.13; P < 0.001) but not nonorthopedic intermediate‐risk surgery (aOR 1.10; 95% CI 0.98–1.23; P = 0.11). Conclusion RA was associated with higher odds of DHRN after orthopedic intermediate‐risk surgery but not CACE or inpatient mortality. Moreover, HFRS was associated with DHRN, CACE, and death. These findings underscore the need for disease‐specific clinical considerations and highlight the potential utility of HFRS in discharge planning.

T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor classically studied in T cells and natural killer (NK) cells. Recent evidence demonstrates that TIGIT is also expressed on distinct B cell subsets exhibiting potent immunoregulatory properties. TIGIT + B cells are proposed to contribute to immune homeostasis through anti-inflammatory cytokine secretion, modulation of antigen-presenting cell function, regulation of T cell differentiation, and bidirectional crosstalk with regulatory T cells and myeloid populations. The strongest direct evidence for a role of TIGIT + B cells in autoimmune pathogenesis exists in multiple sclerosis and type 1 diabetes, where these cells display regulatory activity and may help limit disease progression. In contrast, evidence in systemic lupus erythematosus, rheumatoid arthritis, and transplantation tolerance remains more limited and largely indirect, often inferred from broader regulatory B cell (Breg) biology, TIGIT studies in other immune cell types, or systemic pharmacologic interventions. This review summarizes the biology, phenotype, and proposed functions of TIGIT + B cells. It also discusses emerging insights into their roles in autoimmunity and transplantation tolerance by explicitly distinguishing direct experimental findings from broader TIGIT-related data, and finally explores therapeutic strategies targeting TIGIT signaling, highlighting key challenges and opportunities for future research and clinical applications.

Abstract Objective This study was conducted to review and synthesize current evidence on anti‐calcitonin gene‐related peptide (CGRP) therapies in women with menstrual‐related migraine, during pregnancy and lactation, and while using hormonal contraception. Background Migraine disproportionately affects women, with prevalence peaking during reproductive years when hormonal fluctuations modulate neurovascular and nociceptive pathways, including CGRP signaling, that contribute to migraine susceptibility. Despite the established efficacy of anti‐CGRP therapies—including monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and gepants (ubrogepant, rimegepant, atogepant, and zavegepant)—evidence regarding their use across critical reproductive health contexts remains limited. Methods A systematic search of MEDLINE and Embase was conducted using MeSH terms and keywords related to migraine, CGRP‐targeted therapies, and reproductive health contexts. Studies were screened independently by two reviewers. Data were extracted using standardized forms and synthesized narratively by clinical domain. Results Sixteen studies met inclusion criteria. For menstrual‐related migraine, post hoc analyses and observational studies demonstrate that CGRP monoclonal antibodies reduce migraine frequency both during and outside the perimenstrual window (galcanezumab: −5.1 vs. −3.2 days, p < 0.001), although the perimenstrual period remains a time of relatively higher headache burden despite treatment. Pregnancy data are limited to pharmacovigilance analyses and case reports of unintended exposures, which have not identified specific patterns of maternal, fetal, or neonatal toxicity. Phase 1 pharmacokinetic studies demonstrate minimal gepant transfer into breast milk (relative infant doses, 0.04%–0.19%), well below the 10% safety threshold, although no human lactation data exist for CGRP monoclonal antibodies. No studies specifically evaluated anti‐CGRP therapies in women using hormonal contraceptives. Conclusion Substantial evidence gaps exist across all reproductive health contexts examined. Prospective trials in menstrual‐related migraine, pregnancy registries, lactation studies assessing infant outcomes, and research examining interactions with hormonal contraceptives are needed to optimize migraine care for women.

This Perspective discusses the misalignment physicians face between their professionalism-based values and the conditions of practice that are influenced by pressures from market, managerial, and platform logics, and offers suggestions to align practice conditions and professional identity.

Objective This study aimed to compare longitudinal cephalometric growth, speech outcomes, and secondary surgeries after 1-stage versus 2-stage palatoplasty in patients with non-syndromic unilateral cleft lip and palate (UCLP). Design Retrospective single-institution cohort study. Setting Tertiary academic craniofacial center. Patients/Participants Sixty-eight patients with non-syndromic UCLP treated between 1992 and 2015 who underwent primary palatal repair and had long-term clinical and radiographic follow-up. Forty-eight underwent 1-stage palatoplasty, and 20 underwent 2-stage palatoplasty. Interventions One-stage palatoplasty versus staged palatoplasty with initial soft palate repair followed by delayed hard palate closure. Main Outcome Measures Longitudinal cephalometric measurements at approximately 10 and 16 years, speech outcomes at 5, 10, 13, and 16 years, oronasal fistula, velopharyngeal insufficiency surgery, and need for continued speech follow-up after age 10. Results Mean follow-up was 15.2 ± 4.4 years. Linear fixed-effects modeling showed significant age-related worsening in sagittal skeletal relationships in both groups, including decreases in sella-nasion-A point angle (SNA), A point-nasion-B point angle (ANB), and Wits appraisal, without significant effects of palatoplasty strategy or age-by-strategy interaction for key sagittal outcomes. Speech outcomes were comparable between groups across all timepoints, including hypernasality, nasal emission, compensatory articulation, intelligibility, and Cleft Audit Protocol for Speech-Augmented (CAPS-A) scores. Rates of secondary velopharyngeal surgery and continued speech follow-up after age 10 did not differ significantly. Oronasal fistula occurred more frequently after 2-stage palatoplasty than 1-stage palatoplasty (30% vs 9%, P = .02). Conclusion One-stage and 2-stage palatoplasty demonstrated similar long-term growth and speech outcomes through adolescence. Two-stage repair was associated with a higher oronasal fistula rate but not greater secondary velopharyngeal or speech burden.

Abstract Mismatch repair (MMR) deficiency contributes to temozolomide (TMZ) resistance in a subset of isocitrate dehydrogenase 1/2 mutant (IDH mut ) gliomas, creating a need for therapies that retain activity despite MMR loss. We evaluated the novel interstrand crosslinking agent KL-50, alone and in combination with the histone deacetylase inhibitor belinostat, in patient-derived IDH mut glioma models. MSH6 knockout or constitutive expression established four matched MMR-proficient and MMR-deficient culture models. Drug responses were assessed using live cell count and cytotoxicity assays, and KL-50 monotherapy was tested in intracranial BT142 orthotopic xenografts. LOEWE synergy analysis, RNA sequencing, and a genome-wide CRISPR knockout screen assessed combination activity and potential mechanisms. MMR deficiency increased TMZ GI ₅₀ values 2.2- to 30.4-fold, whereas KL-50 retained antiproliferative activity and showed enhanced cytotoxicity in selected MMR-deficient models. In TMZ-naïve, MMR-proficient BT142 xenografts, KL-50 increased median survival from 107.5 to 194 days. Two of eight treated mice had no histologically detectable residual tumor after 220 days post-engraftment. KL-50 and belinostat exhibited synergistic cytotoxicity in BT142, 905, and TS603 IDH mut glioma cultures. Transcriptomic gene ontology analyses identified downregulation of DNA repair pathways following histone deacetylase inhibition, including terms for homologous recombination and double-strand break repair. The CRISPR screen identified depletion of PKMYT1-targeting gRNAs during KL-50 treatment, implicating this mitotic checkpoint kinase as a candidate determinant of drug sensitivity. PKMYT1 expression was also reduced by histone deacetylase inhibition. These findings support further preclinical development of KL-50, alone and in combination with belinostat, for IDH mut gliomas including tumors with MMR-associated TMZ resistance.

ABSTRACT The novel HLA‐DQA1*01:217 allele differs from DQA1*01:01:01:12 by a single non‐synonymous change in exon 3′.