Citations

ABSTRACTIdiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder classified into three recognized clinical subtypes—idiopathic plasmacytic lymphadenopathy (IPL), TAFRO, and NOS. Although clinical criteria are available for subtyping, diagnostically challenging cases with overlapping histopathological features highlight the need for an improved classification system integrating clinical and histopathological findings. We aimed to develop an objective histopathological subtyping system for iMCD that closely correlates with the clinical subtypes. Excisional lymph node specimens from 94 Japanese iMCD patients (54 IPL, 28 TAFRO, 12 NOS) were analyzed for five key histopathological parameters: germinal center (GC) status, plasmacytosis, vascularity, hemosiderin deposition, and “whirlpool” vessel formation in GC. Using hierarchical clustering, we visualized subgroups and developed a machine learning‐based decision tree to differentiate the clinical subtypes and validated it in an external cohort of 12 patients with iMCD. Hierarchical cluster analysis separated the IPL and TAFRO cases into mutually exclusive clusters, whereas the NOS cases were interspersed between them. Decision tree modeling identified plasmacytosis, vascularity, and whirlpool vessel formation as key features distinguishing IPL from TAFRO, achieving 91% and 92% accuracy in the training and test sets, respectively. External validation correctly classified all IPL and TAFRO cases, confirming the reproducibility of the system. Our histopathological classification system closely aligns with the clinical subtypes, offering a more precise approach to iMCD subtyping. It may enhance diagnostic accuracy, guide clinical decision‐making for predicting treatment response in challenging cases, and improve patient selection for future research. Further validation of its versatility and clinical utility is required.

SUMMARY Tau aggregates propagate through the brain in a prion-like manner in Alzheimer’s disease (AD) and other tauopathies, but the molecular identity and functional partners of the seeding-competent Tau species remain poorly defined. Here, we present an unbiased proteomic profiling of a high-molecular-weight (HMW) Tau-seed isolated from AD patient brains. We contrast this interactome with that of a biochemically similar, seeding-incompetent HMW-Tau species from age-matched healthy controls. Despite comprising less than 5% of total Tau in the brain, Tau-seed associates with a distinct set of proteins enriched in synaptic, mitochondrial, and vesicle-trafficking functions. Cross-species functional screening in Drosophila and mouse models identifies interactors that modulate Tau toxicity and seeding. Spatially resolved analysis of postmortem AD brains reveals heterogenous co-deposition of these proteins with Tau aggregates, suggesting functionally distinct Tau-seed complexes. Together, this dataset provides a framework for understanding selective Tau-seed toxicity and identifies candidate regulators of Tau propagation with therapeutic potential.

Endothelial progenitor cells (EPCs) constitute a promising focus for research in regenerative medicine. These cells originate from the bone marrow and other circulating hematopoietic cells and regulate tissue regeneration and vascular integrity. EPC mobilization serves for neovascularization and re-endothelialization after injury in multiple organ systems, including the renal and cardiovascular systems. Both their number and function may vary in disease states such as CKD, depending on severity, comorbid conditions, and other factors. Therefore, circulating EPC count and function have been proposed as markers for vascular health, and their mobilization or replenishment may offer a potential therapy. Delivery of EPCs has shown success in repairing injured kidneys in animal models of both chronic and AKIs. This approach may be limited by EPC heterogeneity and incomplete characterization that may be addressed by standardization, engineering, or combination with other therapies. The aim of this article was to review the current state and recent advances in our understanding of the role of EPCs in homeostasis and conditions that may lead to their dysregulation in kidney diseases.

Objective To determine the clinical features that identify patients with suspected rapidly progressive dementia (RPD) who will develop RPD. Methods Patients with suspected RPD were enrolled and followed at Mayo Clinic (Jacksonville, FL; January 2020 to October 2023) and Washington University (Saint Louis, MO; June 2016 to December 2019). Two dementia specialists independently reviewed clinical data and assigned diagnoses. Patients were diagnosed with RPD if they developed dementia within 1 year or incapacitation within 2 years of symptom onset. The associations between clinical features and causes and outcomes were explored via univariate and multivariate comparisons. Results Of 248 patients with suspected RPD, 185 (74.6%) met criteria for RPD. Patients with RPD were older (62.6 ± 14.5 vs 55.2 ± 18.1 years; p < 0.001), and more frequently diagnosed with Alzheimer's disease or related dementias (OR 3.13, 95% CI 1.40, 7.31) or Creutzfeldt–Jakob disease (OR 4.67, 95% CI 1.38, 15.75). Visual agnosia (15/183; 8.2%), substantial brain atrophy (27/182; 14.8%), and periodic epileptiform discharges (11/151; 7.3%) were exclusively detected in patients with RPD. After controlling for age, intensive care unit admission (OR 4.77, 95% CI 1.61, 14.12), lack of seizures (OR 2.47, 95% CI 1.15, 5.31), abnormal brain magnetic resonance imaging (OR 2.01, 95% CI 0.997, 4.05), and cerebrospinal fluid white blood cell count ≤5 cells/mm 3 (OR 3.30, 95% CI 1.60, 6.82) were also independently associated with RPD. Patients with RPD were more likely to die or develop severe dementia (mean time to outcome, 36.1 months; 95% CI 31.2–41.0). Interpretation Selected clinical features may identify patients with suspected RPD who are likely to continue to decline. Early recognition of these features may improve diagnostic accuracy and inform prognosis. ANN NEUROL 2025;98:764–776

Study Design: Single-center retrospective cohort study. Objective: To determine if the 4-rod construct (4RC) is protective against the occurrence of rod fractures when compared with the 3-rod construct (3RC) in adult spinal deformity (ASD) patients with long fusions to the sacrum. Summary of Background Data: Past studies have explored the different outcomes in subjects with dual-rod versus multirod constructs. There is a lack of literature distinguishing the ramifications of 3RC versus 4RC, particularly in the prevalence of rod fractures and rod fractures requiring subsequent revision surgery as a result of pseudarthrosis. Methods: ASD patients undergoing long instrumented fusions to the sacrum were dichotomized between the 3RC and 4RC cohorts. Outcomes of interest include the occurrence of rod fractures (RFs) and RFs requiring revision (RFR). Two-tailed independent-sample t test with Welch's correction and χ 2 /Fisher exact test were used for continuous and categorical variables, respectively. Multivariable logistic regression analysis was performed to assess whether the 4RC is protective against rod fractures when compared with the 3RC. Results: One hundred forty-five patients with a minimum 2-year follow-up were included (3RC=57, 4RC=88). Four RC had a greater body mass index (BMI) ( P =0.002), longer operating room (OR) time ( P =0.002), greater estimated blood loss (EBL) ( P =0.002), total instrumented levels (TIL) ( P =0.028), and more 3-column osteotomies (3COs) performed ( P =0.028). Four RC had greater baseline coronal vertical axis (CVA) (28.2±24.9 vs. 18.5±16.9 mm, P =0.006) and sagittal vertical axis (SVA) (55.1±64.8 vs. 30.4±41.8 mm, P =0.006). Three RC had a greater rate of RF (28.1% vs. 14.8%, P =0.0506) and RFR (14.9% vs. 10.2%, P =0.486) when compared with 4RC, but these findings were not statistically significant. After controlling for BMI, the use of 3-column osteotomies, total instrumented levels, change in coronal alignment (∆CVA), change in sagittal alignment (∆SVA), use of bone morphogenetic protein, and number of interbody fusions, 3RC was associated with 4.93× greater odds of experiencing RFs ( P =0.0078). However, significance fell short when adjusting for the occurrence of RFR [OR=2.58 (0.60–11.19), P =0.2067]. Conclusion: ASD patients having long fusions to the sacrum with 4RC across the lumbosacral junction are shown to be at lesser risk of developing rod fractures but not revision surgery as compared with 3RC at 2-year follow-up.

Abstract Background Resident Doctors (RDs) in the UK must balance clinical training with non-clinical administrative tasks. Concerns increase over how these tasks impact their professional development, job satisfaction and patient care. The shift toward consultant-delivered care has led to a redistribution of responsibilities, increasing administrative burden on RDs. Aims This study aims to quantify how RDs allocate time between patient-facing and non-patient-facing tasks and assess impact on job satisfaction. Design National multicentre observational cohort study. Methodology The Time Allocation in Clinical Training study is a multicentre, observational cohort study conducted over seven months (January–July 2024) at secondary NHS centres. 137 RDs, from Foundation Year 1 to Specialty Training Year 8, were observed for 4-hour periods, with time tracked using stopwatches for five task categories. An optional survey assessed job satisfaction, rated on a five-point Likert scale. Results RDs spent 73.0% of their time on non-patient-facing tasks, and 17.9% on patient-facing activities. Women spent more time on non-patient-facing tasks compared to men (75.0% vs. 69.9%, P = 0.03). Junior RDs (Foundation years and Core trainees) spent significantly less time on patient-facing tasks compared to senior RDs (ST6-8) (38.4% vs. 17.8%; P = 0.004). Most RDs (62%) reported dissatisfaction with the administrative burden. Electronic health record users spent significantly more time on administrative tasks than paper-based record users (44.1% vs. 37.3%; P = 0.02). Conclusions The study reveals a significant imbalance between clinical and administrative tasks, with excessive administrative workload contributing to RD dissatisfaction. Streamlining administrative duties and integrating digital solutions is crucial for improving job satisfaction, clinical development and healthcare delivery in the NHS.