Citations

BACKGROUND. Dementia is a rapidly expanding public health problem with major socio-economic burden. Insulin resistance (IR) is a prevalent but modifiable risk factor for dementia, yet its effects on brain structure, functional connectivity, and metabolism remain incompletely understood. METHODS. Regional brain glucose uptake (PET), volumes (MRI), functional connectivity (fMRI), and cognition (NIH Toolbox) was measured in 72 adults with or without markers of IR. To evaluate reversibility of IR-associated brain deficits, forty older adults with IR were randomized to forty weeks of metformin or placebo, and brain measures were repeated. As a proof-of-concept experiment, we developed a conditional brain-specific insulin receptor knockout mouse and assessed brain mitochondrial function and cognition. RESULTS. In older adults with markers of IR is associated with diminished total and regional brain volumes in areas critical for neuronal connectivity, memory, and learning, including cerebral white matter and the hippocampus. Reduced functional connectivity between brain regions detrimental for cognition was also noted. Further, we demonstrated that ATP production, essential for neuronal connectivity, was diminished in neuron-specific insulin receptor knockout mice accompanied by deficits in hippocampal- and prefrontal-dependent tasks. Forty weeks of metformin improved systemic insulin sensitivity concurrent to preserved brain glucose uptake, volume, and functional connectivity within specific regions central to decision-making and learning. Metformin was also associated with an improved composite measure of processing speed and working memory. CONCLUSION. These findings highlight IR as a key regulator of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.

The bone marrow immune microenvironment (BMME) is a critical factor in multiple myeloma (MM) pathogenesis. Despite higher incidence of MM among self-identified African Americans, the relationship between African genetic similarity and the BMME remains unclear. We present the largest analysis to date assessing the impact of Ancestry on the BMME in myeloma (N=320, including 64 with ≥50% African genetic similarity, AFR-High) leveraging our recently generated Immune Atlas. AFR-High was associated with enrichment of late T-effector cells, driven by rare cytotoxic CD4⁺ T cells, suggesting a distinct adaptive BMME. AFR-High exhibited expansion of late-differentiated adaptive NK cells with high cytotoxic GNLY and GZMH expression. AFR-High depicted reduced CD14⁺ monocytes, increased CD16⁺ non-classical monocytes, and expansion of macrophage-like monocyte populations with enrichment of metabolic adaptation, efferocytosis and phagocytic clearance programs, and immunoregulatory pathways. These findings reveal a shift from an innate inflammatory immune landscape toward adaptive cytotoxic and immunoregulatory remodeling associated with African genetic similarity in MM.

Abstract Background Immune checkpoint inhibitors (ICIs) directed against PD-1, PD-L1, and CTLA-4 augment antitumor immune responses but may also induce unintended immune activation, resulting in immune-related adverse events (irAEs). Cutaneous manifestations of irAEs are among the most common, ranging from mild eruptions to severe autoimmune blistering disorders (AIBDs). Although bullous pemphigoid (BP) is the most reported ICI-related autoimmune bullous disorder (irAIBD), data on the spectrum, and management of other ICI-associated AIBDs remain limited. Understanding these reactions is crucial to managing treatment interruptions and influencing oncologic outcomes. Objective This study aims to comprehensively characterize ICI-associated irAIBDs by examining demographics, clinical presentation, disease severity, therapeutic approaches, treatment responses, clinical outcomes, and mortality. Methods A single-institution retrospective chart review was conducted, using a text-based database search from 2011–2023. Adult patients (≥18 years) with biopsy-confirmed AIBDs attributed to ICIs were included. Demographic, oncologic, and immunotherapy details, as well as clinical, histopathologic, and immunofluorescence characteristics of AIBDs, were reviewed. Treatment approaches, outcomes, and mortality data were analyzed. Results Forty-four patients with irAIBDs were identified, predominantly representing males (29, 65.9%) with a mean age of 70.4 years (range: 62-80 years). Lung carcinoma (12, 27.2%) and melanoma (9, 20.4%) were the most frequent underlying malignancies, and pembrolizumab (25, 56.8%) was the most common agent. Bullous pemphigoid (BP) accounted for most cases (36, 81.8%), followed by lichen planus pemphigoides (LPP) (6, 13.6%), with one case each of mucous membrane pemphigoid (MMP) and linear IgA bullous dermatosis (LABD). Pruritus was reported in most (42, 9%) patients, and upper (36, 81.8%), lower (32, 72.2%) extremities and the chest (34, 77.2%) were most often involved. Eosinophilic infiltration was present in most (23, 81.8%) of BP cases, and linear IgG and C3 deposition were the predominant immunofluorescence patterns in BP. Most patients received topical (34, 77.2%) and/or systemic corticosteroids (32, 72.7%), while 16 required at least temporary ICI discontinuation. Four BP (4, 9.1%) patients were treated with dupilumab. Other systemic agents used included doxycycline (22, 50%), intravenous immunoglobulin (IVIG) (5, 11.3%), rituximab (6, 13.6%), dapsone (1, 2.2%), mycophenolate mofetil (1, 2.2%), methotrexate (1, 2.2%), and colchicine (1, 2.2%). Three cases with Grade 3 severity necessitated permanent ICI discontinuation. Clinical stabilization (24, 54.5%) or remission of the irAIBD (16, 36.3%) was achieved in most cases. One death (2.2%) was attributed to sepsis in a patient with severe irAIBD. Conclusion ICI-associated AIBDs are uncommon but clinically significant complications. Most patients in our cohort continued ICI therapy during management of their irAIBD, while others required temporary or permanent interruption. These findings highlight the importance of prompt recognition and multidisciplinary management of these uncommon toxicities.

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.

ABSTRACT Background Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal‐derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored. Objective We investigate whether archaic alleles influence PBC risk. Design Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235 592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE‐mc and temporal haplotype dynamics were assessed using ancient DNA data from Europe and Asia. Results A Neanderthal‐derived variant in TNPO3 (rs12531711), previously reported by Cordell et al. showed strong association in CANUK ( p = 2.04 × 10 −26 ) and replicated across all validation cohorts. This variant functions as an eQTL, upregulating IRF5 and downregulating TNPO3 in blood. It is rare in African populations but common both in Europeans and Asians. Temporal analysis of the haplotype carrying rs12531711 revealed frequency increased substantially during the Bronze Age (5000–3000 BP), rising from 2.0% to 7.7% in Europe and 3.4% to 17.4% in Asia, before stabilizing. Despite this strong single‐variant association, the heritability explained by NIMs was not significantly different from that of non‐NIM variants. Conclusion A Neanderthal‐derived variant contributes to PBC risk and its frequency increased in the Bronze Age, possibly due to pathogen‐driven selection. Archaic introgression overall has limited influence on PBC heritability. Functional studies are needed to elucidate the role of rs12531711.

Odontogenic myxoma (OM) is an uncommon, locally aggressive odontogenic neoplasm with characteristic histologic and clinico-radiographic features but with potential for histologic overlap with other odontogenic and non-odontogenic entities and a non-specific immunoprofile. Widespread loss of heterozygosity (LOH) has been recently described in rare cases of OM. The aim of this study was to determine whether widespread LOH represents a recurrent molecular signature that can be leveraged for clinical decision-making. Allele-specific copy number variation data from chromosomal microarray were generated from 7 OM, comprising a combined prospective and retrospective cohort. Four tumors arose in the mandible and 3 in the maxilla in patients ranging in age from 18 to 94 years (median: 44), with tumor size ranging from 2.2 to 13.0 cm. Variable amounts of fibrous stroma (odontogenic “fibromyxoma”) were present in 4/7 OM, and hypercellularity not typically appreciated in conventional OM was present in 3/7 cases. All OM (7/7) demonstrated widespread LOH, with 5 cases showing a near-haploid/low hypodiploid genomes (multiple monosomies) and 2 cases showing evidence of pseudo-hyperdiploidy due to probable endoreduplication. Both pseudo-hyperdiploid cases were ≥10 cm in size; 1 represented local recurrence. Chromosomes 1 to 3, 6, 9, 11, 13, 15, and 22 demonstrated LOH in ≥75% of cases (chromosomes 1 to 3, 6, and 9 in 100% of cases), while chromosomes 5, 12, 19, and 20 universally retained heterozygosity. Altogether, widespread LOH is a recurrent event in OM and a novel finding in odontogenic pathology, and allele-specific copy number variation analysis can serve as a diagnostic adjunct in challenging cases.