Citations

Gliomas are diffusely infiltrative, requiring accurate and sensitive diagnostic tools during surgical resection. Mutations in isocitrate dehydrogenase enzyme (IDH) alter its normal activity and result in accumulation of a unique oncometabolite, 2-hydroxyglutarate (2HG), in tumor cells. However, IDH-wild-type (IDH-wt) gliomas are more common and typically more aggressive. Here, 86 human brain samples were analyzed by syringe touch spray mass spectrometry to evaluate molecular alterations in gliomas. Tandem mass spectrometry (MS/MS) experiments were performed to minimize isobaric and isomeric interferences, and a ratiometric approach (using only signals for endogenous compounds) was employed to improve reliability of the measurements. Multiple ratios for pairs of metabolite signal intensities were found to differentiate tumor samples from nontumor tissue and they stratified glioma subtypes by IDH mutation status and by tumor grade, with several ratios showing 100% agreement with independent clinical assignments ( P < 0.0001, Mann–Whitney U test). Increased carnitine relative abundances were found across all glioma subtypes. Importantly, α-aminoadipate was significantly elevated in grade 4 glioma, which may correlate with increased tumor malignancy. Grade 3 gliomas showed markedly higher 2HG abundance than grade 4 samples. In addition, a selection of ratios showed a linear trend with varying tumor cell percentage. Overall, the multiple metabolic ratio alterations indicate a high degree of heterogeneity among glioma subtypes. Furthermore, there are metabolites that can differentiate glioma from nontumor tissue and this measurement can be made by a simple ratiometric method which has potential to be used intraoperatively for margin assessment without diverging from standard of care.

Giant cell arteritis (GCA) is the most common primary systemic vasculitis of older adults and has traditionally been framed as an ophthalmologic emergency. Its most serious consequences, however, occur in the cardiovascular system, often years after inflammatory markers have normalized. In contemporary matched population cohorts, patients with GCA carry an approximately two-fold excess risk of aortic aneurysm; the historical Olmsted County cohort reported a 17-fold excess of thoracic aortic aneurysm with wide confidence limits, and the characteristic latency to aneurysm is five to ten years. Patients also face elevated risks of aortic dissection, myocardial infarction, stroke, venous thromboembolism, and heart failure that cluster within the first year of diagnosis, when vascular inflammation is most active. This narrative review, based on a structured search of PubMed/MEDLINE and Google Scholar through September 2026 with independent verification of every cited estimate, synthesizes current evidence on the full spectrum of cardiac and aortic complications of GCA, including aortitis, aneurysm and dissection, coronary arteritis, valvular disease, pericarditis, myocarditis, and conduction disease. We trace their common origin to the immunopathology of the arterial wall, where dendritic cell activation, Th1/Th17 polarization, and maladaptive vascular remodeling produce occlusion in medium-sized arteries and dilation in the aorta. We examine current diagnostic modalities, from the ultrasound-based fast-track clinic, which has reduced permanent visual loss by half or more in observational cohorts, to FDG-PET/CT, in which aortic uptake at diagnosis is associated with subsequent aortic dilation. We review treatment after the GiACTA and SELECT-GCA trials in the light of the 2025 European Alliance of Associations for Rheumatology (EULAR) recommendations, the unresolved role of antiplatelet and statin therapy, and the surgical and endovascular management of GCA-related aortopathy. We suggest that the organization of care, as well as the limitations of drug therapy, may contribute to the residual mortality of GCA, a hypothesis that has not been tested; distinguish recommendations that are supported by current guidelines from those that are our own proposals; and outline a cardio-rheumatology pathway in which baseline vascular phenotyping informs individualized aortic surveillance. GCA is a disease whose natural history often begins in the rheumatology clinic and ends in the cardiac operating room without prior surveillance.

Monoclonal gammopathy of renal significance (MGRS) encompasses renal lesions caused by nephrotoxic monoclonal immunoglobulins produced by small B-cell or plasma cell clones that do not meet criteria for overt hematologic malignancy. Diagnosis may be challenging when immune deposits are masked on routine immunofluorescence. We report a 63-year-old woman with hypertension, chronic kidney disease, peripheral neuropathy, venous thromboembolism, and progressive proteinuria who underwent kidney biopsy for worsening urinary abnormalities. Routine immunofluorescence on frozen tissue was negative; however, repeat immunofluorescence on protease-digested paraffin-embedded tissue demonstrated focal and segmental granular staining for IgG and kappa light chain with essentially negative lambda staining, consistent with proliferative glomerulonephritis with masked IgG-kappa dominant deposits. Congo red stain was negative. Bone marrow biopsy subsequently showed approximately 8% plasma cells with an abnormal kappa-excess plasma cell population, and serum immunofixation identified IgG-kappa monoclonal protein, supporting MGRS. Due to baseline peripheral neuropathy, bortezomib-based therapy was deferred, and the patient was treated with daratumumab, lenalidomide, and dexamethasone. Kidney function remained preserved, and proteinuria improved markedly from nephrotic-range level of 8.5–0.22 g/g. This case highlights the diagnostic importance of paraffin immunofluorescence when MGRS is suspected despite negative routine studies and illustrates that early clone-directed therapy can produce substantial renal response in masked monoclonal proliferative glomerulonephritis.

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.

Purpose To describe whether subspecialty training, specifically arthroscopic fellowship training, influences intraoperative range‐of‐motion (ROM) gains, postoperative ROM retention, and lysis of adhesions (LOA) complication rates. Methods Between August 1989 and May 2025, all patients who underwent arthroscopic LOA for stiffness after primary total knee arthroplasty (TKA) at a single multisite academic institution with a minimum follow‐up of 3 months were reviewed. Cases were stratified by the surgeon's training: 1 group with arthroscopic fellowship training and another with nonarthroscopic or no fellowship training. Primary outcomes were intraoperative ROM change and postoperative ROM retention compared with intraoperative and pre‐TKA baseline values. Revision and periprosthetic joint infection rates were also collected. Results A total of 94 LOA cases were identified, where 48 (51.1%) were performed by nonarthroscopically trained surgeons. Intraoperative ROM improvements were similar between groups in both knee flexion (35.2° arthroscopic vs 31.1° nonarthroscopic, P = .130) and extension (2.43° vs 3.91°, P = .079). Compared with the intraoperative ROM, procedures performed by arthroscopically trained surgeons showed significantly better long‐term retention of both flexion (loss of 4.85° vs 15.98°, P = .006) and extension (gain of 0.50° vs loss of 1.58°, P = .036) at postoperative follow‐up. When compared with preprimary TKA baseline ROM, flexion at follow‐up was slightly improved in the arthroscopic group but declined significantly in the nonarthroscopic group (gain of 1.66° vs loss of 21.76°, P < .001). Eight revision TKAs (8.51%) occurred after LOA, 6 of which involved nonarthroscopic surgeons, and 1 periprosthetic joint infection case was reported. Conclusions LOA performed by arthroscopic fellowship‐trained surgeons results in significantly better retention of postoperative ROM than nonfellowship‐trained surgeons when used for arthrofibrosis after TKA. Level of Evidence Level III, retrospective comparative study.

Purpose To determine the incidence of cystoid macular edema (CME) within the first 6 months after endothelial keratoplasty (EK) in eyes that had previously undergone vitrectomy versus those without prior vitrectomy. Design Retrospective cohort study. Methods A retrospective cohort analysis of the TriNetX database was performed by querying all patients who underwent EK (Descemet stripping automated endothelial keratoplasty or Descemet membrane endothelial keratoplasty) with ≥ 6 months of follow-up between January 1, 2004, and August 30, 2024. Patients with a previous history of diabetic macular edema, uveitis, or retinal vascular occlusion were excluded. Cohorts were stratified based on a history of prior vitrectomy. Propensity score matching (PSM) between cohorts was conducted for age at index, sex, race, ethnicity, and diagnosis of Fuchs endothelial dystrophy. The outcome assessed was the incidence of postoperative CME within 6 months after EK in both groups. Odds ratios were calculated between cohorts. Results The final analysis included 1044 patients, divided into those with (n = 522) and without (n = 522) prior vitrectomy before EK. Patients who had undergone vitrectomy prior to EK were found to develop postoperative CME within 6 months at a significantly higher rate (32 of 522) compared to those who had not undergone vitrectomy (17 of 522) (P = 0.0282; OR 1.94, 95% CI 1.063–3.539). Conclusion Prior vitrectomy appears to be associated with a greater incidence of postoperative CME after EK.

Abstract Keratoconus (KC) is a multifactorial corneal ectasia disorder that is influenced by genetic and environmental risk factors. The manner and degree to which any risk factor contributes mechanistically to KC pathogenesis is not fully understood, despite epidemiological associations. Likewise, the relationship between genetic and environmental risk factors and how they may interact or compound upon one another to precipitate KC is largely unknown. In this review, we discuss existing research surrounding the genetic and environmental risk factors for KC, as well as the probable mechanisms driving individual risk factors such as ultraviolet radiation exposure and eye-rubbing. Additionally, we discuss the interplay between underlying genetic susceptibility to KC and contributory environmental factors. This review highlights advances in existing research in vivo and in vitro, potential underlying mechanisms and avenues for future inquiry to elucidate the multifactorial aetiology of KC.

Importance The development of artificial intelligence (AI) models for atherosclerotic cardiovascular disease (ASCVD) risk prediction has rapidly accelerated. However, despite reports of high predictive accuracy, evidence supporting clinical implementation remains limited. Objective This study aimed to evaluate the methodological rigor of AI-based ASCVD prediction models and assess whether reported algorithmic discrimination is associated with prespecified reporting and translational-evidence gaps. Data sources and study selection A systematic search of PubMed, Embase, Web of Science, Scopus, and Cochrane CENTRAL was conducted for original studies published between 1 January 2020 and 27 March 2026. Studies reporting the development or validation of AI and machine learning prognostic models for adult ASCVD outcomes were included. Data extraction and synthesis Following the PRISMA guidelines, a structured methodological audit was performed. Five binary reporting and translational-evidence gaps were independently extracted: absent calibration assessment, lack of external validation, absent decision-analytic utility evaluation, undefined temporal prediction horizons, and lack of reproducibility or accessibility artifacts. A prespecified minimum evidence proxy for translational evaluation was defined. Main outcomes and measures The primary outcomes were the cumulative methodological gap burden (range, 0–5) and its association with the primary discrimination metric (area under the receiver operating characteristic curve [AUC] or C-index). Results Among 101 primary models evaluated, the median discrimination performance was 0.790 (IQR, 0.734–0.833). However, a substantial cumulative gap burden was observed, with only 6.9% of the models meeting the prespecified translational-readiness proxy. Reported discrimination was not associated with methodological completeness; top-quartile models (AUC ≥ 0.833) exhibited high gap burdens at rates comparable to lower-performing models. Reporting and translational-evidence gaps systematically co-occurred, predominantly driven by the simultaneous absence of external validation, calibration assessment, and reproducibility or accessibility artifacts. The use of advanced algorithmic architectures (e.g., deep learning) and multimodal data integration did not independently reduce the reporting gap burden. Conclusion and relevance In AI-based ASCVD risk prediction, reported algorithmic discrimination is a poor surrogate for clinical readiness. The literature features models with high discrimination but critical methodological deficits. These findings suggest that evaluation frameworks should consider incorporating calibration, external validation, and formal decision-analytic utility assessment alongside discrimination metrics.

ABSTRACT Background Patients with cardiovascular implantable electronic devices (CIEDs) who develop bacteremia require risk stratification for device infection. Although prediction scores exist for Staphylococcus aureus bacteremia, no comparable CIED‐specific tool exists for non– S. aureus bacteremia. Our study aimed to estimate the probability of definite CIED infection in adults with non– S. aureus bacteremia without pocket infection. Methods We performed a prediction‐model analysis of adults with CIEDs and non– S. aureus bacteremia, comprising gram‐negative bacteremia (GNB) and gram‐positive cocci other than S. aureus (GPC) bacteremia, at Mayo Clinic Rochester during 2012–2019. Patients with pocket infection were excluded. Definite CIED infection was classified using 2019 European Heart Rhythm Association criteria. Penalized logistic regression was used to construct two prediction models for definite infection: a full model with nine prespecified predictors, and a reduced model from which a point‐based risk score could be obtained. Results A total of 282 patients with CIEDs developed non– S. aureus bacteremia. Median age was 75 years; 69% were men. GPC bacteremia occurred in 156 patients (55%) and GNB in 126 (45%). Sixty patients (21%) had definite CIED infection. Both the full and reduced models demonstrated excellent predictive discrimination (apparent area under receiver operating characteristic curve 0.946 and 0.940). The reduced model retained four predictors: GPC bacteremia, persistent bacteremia, longer time to positivity, and unknown bacteremia source. Conclusion A four‐variable risk score incorporating organism category, persistent bacteremia, time to positivity, and unknown bacteremia source may guide early device‐focused evaluation, but external validation is required before clinical adoption.