Citations

ABSTRACT Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end‐organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin‐driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)‐protein associated with a clonal plasma or B‐cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein–induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M‐protein‐mediated mechanisms; however, direct evidence implicating the M‐protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M‐proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence‐based management strategies for this clinically important group of disorders.

Background: Diffuse axonal brain injury (DABI) is a major component of traumatic brain injury, but the optimal timing of magnetic resonance imaging and histologic assessment after isolated DABI remains unclear. Because each method captures a different phase of injury, defining time-dependent diagnostic windows may improve experimental design and reduce animal use. Methods: Sixty-four Sprague-Dawley rats were randomized to moderate DABI or sham operation. Neurological Severity Score (NSS), 3 T diffusion tensor imaging (DTI), and histologic assessment were performed at early and late time points. Hippocampal fractional anisotropy (FA) was measured at 48 h and 1 month. β-amyloid precursor protein (β-APP) immunohistochemistry assessed acute axonal injury at 48 h, and hematoxylin and eosin (H&E) staining quantified hippocampal neuronal density at 1 month. Results: At 48 h, DABI rats had higher NSS, lower hippocampal FA, and greater β-APP-positive axonal accumulation than sham-operated rats. By 1 month, NSS and hippocampal FA no longer differed between groups, whereas hippocampal neuronal density remained significantly reduced in DABI rats, indicating persistent structural injury. Conclusions: In this rat model of isolated DABI, hippocampal FA and β-APP immunohistochemistry identified acute axonal pathology at 48 h, whereas conventional histology detected a persistent reduction in neuronal density at 1 month. These findings support a time-optimized diagnostic strategy using early DTI for noninvasive injury detection and late histology for long-term structural assessment.

Background and Aims: Liver fibrosis and cirrhosis are major global health burdens with limited treatments. Activated HSCs drive fibrosis through increased proliferation, migration, collagen deposition and glycolysis. The aim of this study is to elucidate the signaling events that lead to enhanced glycolysis, subsequent HSC activation, and liver fibrosis. Approach and Results: Utilizing a phospho-kinase array, we identified with no lysine kinase 1 (WNK1) as a new kinase in primary human HSCs activated by the profibrotic PDGF-B. PDGF-mediated glycolysis in HSCs was attenuated by the WNK1 selective inhibitor, WNK-IN-11, as measured by live-cell metabolic assay, Glifon-300 fluorescence, Glucose-Glo assay, and glucose transporter 1 immunofluorescence. To understand how WNK1 promotes glycolysis, we employed chemical genetics where an engineered WNK1 carrying threonine 301 to glycine mutation (WNK1 T301G ) mutant with a modified ATP pocket accommodated a specific ATP-γ-S analogue to thio-phosphorylate its substrates. Thio-phosphorylated proteins were analyzed by mass spectrometry, which identified the glycolytic protein, triosephosphate isomerase 1 (TPI1), as a novel WNK1 direct substrate. TPI1 interacted with WNK1 in condensates, membrane-less phase separation structures. Condensate disruption and knockdown of TPI1 or WNK1 reduced HSC proliferation and migration in vitro. In vivo, pharmacological or genetic WNK1 inhibition significantly attenuated liver fibrosis in carbon tetrachloride and high-fat, choline-deficient, L -amino acid diet mouse models. Finally, WNK1 inhibition reduced fibrogenesis ex vivo in human precision-cut liver slices. Conclusions: These findings identify WNK1 as a previously unrecognized kinase that promotes HSC activation and liver fibrosis via TPI1-mediated glycolysis, highlighting the WNK1-TPI1 axis as a potential therapeutic target.

Abstract Introduction: Erythromelalgia is a descriptive term for burning pain and erythema in distal extremities, often worsened by heat and improved by cold. Inherited erythromelalgia has been primarily linked to gain-of-function variants in SCN9A , encoding voltage-gated sodium channel NaV1.7. However, approximately 65% to 85% of patients with erythromelalgia do not have pathogenic SCN9A variants. Objectives: The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia. Methods: With IRB approval and informed consent, probands and families with erythromelalgia underwent next-generation sequencing. A list of genes of interest was produced based on Mendelian inheritance models. Selected gene candidates were assessed using the Sequence Kernel Association Test-Optimal (SKAT-O). Results: Sixty-two probands with erythromelalgia and their relatives were included in Mendelian analysis, which identified variants in PR domain zinc finger protein 12 ( PRDM12 ) and dihydropyrimidinase-like protein 2 ( DPYSL2 ). In a targeted 12-gene rare-variant set analysis using SKAT-O, zinc finger homeobox protein 2 ( ZFHX2 ) showed evidence of association ( P = 6.9 × 10 −4 ), surpassing Bonferroni correction for 12 tests (α = 4.17 × 10 −3 ), whereas KIF1B showed only a nominal association signal ( P = 0.03) that did not survive multiple-testing correction. Conclusion: Genes associated with both increased and decreased pain sensitivity are of considerable interest for elucidating pain mechanisms and analgesic development. As rare variants in PRDM12 and DPYSL2 were identified in a pediatric erythromelalgia cohort and a gene-based rare-variant association signal for ZFHX2 was identified, replication and functional validation are needed.

Sex and gender influence disease mechanisms and outcomes, yet their integration into medical curricula remains limited. Faculty knowledge and confidence are essential for effective incorporation. This study assessed baseline sex- and gender-specific health (SGSH) knowledge, attitudes, and comfort among medical school educators and delivered a multi-format faculty development intervention. A survey adapted from prior SGSH assessments was distributed to medical school block leaders before the intervention, measuring SGSH knowledge, comfort differentiating sex and gender, awareness of SGSH resources, and readiness to integrate SGSH content. The intervention included virtual and in-person grand rounds, distribution of How Sex and Gender Impact Clinical Practice , and a screening of Ms. Diagnosed . Of the 103 invited to participate, 68 educators (66% response rate) completed the baseline survey. Forty percent reported no prior SGSH training, and only 13.2% felt very comfortable with SGSH concepts. Although 94.1% correctly identified gender as a social construct and sex assignment at birth, 22% remained uncomfortable distinguishing the two. More than 80% were neutral or uncomfortable identifying SGSH resources. Comfort with curriculum integration varied: 45.6% felt comfortable, 32.4% neutral, and 22.1% uncomfortable, with differences observed across specialties. These findings reveal significant gaps in medical educators’ SGSH knowledge and comfort regardless of experience, with SGSH content narrowly confined to reproductive health topics. Simply providing resources is insufficient; educators need structured guidance on integration. By outlining baseline gaps and an intervention model, this study offers a framework for institutions seeking to enhance SGSH integration through interactive, longitudinal, multi-format faculty development approaches.

OBJECTIVE Dysphagia has been shown to have an adverse effect on patient quality of life following cervical spine surgery, but its impact on patients’ ability to return to work (RTW) and return to physical activities (RTA) has never been investigated. This study aimed to evaluate the impact of postoperative dysphagia on patients’ ability to RTW and RTA after surgery. METHODS A prospectively maintained multi-institutional spine registry of patients who underwent cervical spine surgery between 2016 and 2023 was retrospectively reviewed. An Eating Assessment Tool-10 (EAT-10) score ≥ 3 was used to quantify preoperative and 12-month postoperative dysphagia. Prolonged dysphagia was defined as new dysphagia present at 12 months among patients without baseline dysphagia. RTW and RTA were assessed at baseline and 12 months postoperatively. Mixed-effects logistic regressions were used to evaluate the effect of dysphagia on RTW and RTA. RESULTS Of the 1208 patients meeting inclusion criteria, 240 (20%) experienced prolonged dysphagia, of whom 208 (87%) underwent anterior surgery. Preoperatively, 709 (59%) patients were fully employed or on short-term leave, 307 (25%) were retired, and 191 (16%) were otherwise unemployed. At the 12-month follow-up, RTW and RTA status were collected for 629 (95%) of the 664 employed patients who planned to RTW after surgery and 1127 (93%) of the total cohort, respectively. Significantly lower rates of RTW (86% vs 96%, p < 0.001) and RTA (62% vs 79%, p < 0.001) were observed in patients with prolonged dysphagia. Multivariable analysis identified dysphagia as being independently associated with lower odds of RTW (OR 0.35, 95% CI 0.14–0.86; p = 0.022) and RTA (OR 0.44, 95% CI 0.31–0.63; p < 0.001). CONCLUSIONS Prolonged postoperative dysphagia—defined as a new EAT-10 score ≥ 3 at 12 months—was associated with substantially lower odds of returning to work and physical activities after cervical spine surgery, underscoring the importance of dysphagia prevention and management in postoperative care.

OBJECTIVE Cognard type V dural arteriovenous fistulas (dAVFs), defined by spinal perimedullary venous drainage, represent a rare and aggressive neurovascular pathology. Comprehensive multicenter data remain scarce. The authors present the largest multicenter analysis to date, characterizing presentation, radiology, treatment, complications, and functional outcomes of Cognard type V dAVFs. METHODS The authors retrospectively analyzed patients with angiographically confirmed Cognard type V dAVFs from the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR), spanning 16 academic centers. Patient demographics, imaging features, treatment strategies, procedural complications, and modified Rankin Scale (mRS) scores were recorded. RESULTS Among 1077 patients with dAVFs, 37 (3%) had Cognard type V lesions. The mean patient age was 57 years, and 59.5% of patients were male. Most presented with nonhemorrhagic neurological deficits (68%), while 14% had hemorrhage. The most common location was the foramen magnum (32%). Embolization was the primary treatment in 67% of cases, complete obliteration was achieved in 71% of cases. Upfront microsurgery was performed in 22% of patients (obliteration rate 88%), and radiosurgery in 14% (success rate 40%). Salvage treatment further improved obliteration outcomes. Temporary complications occurred in 8% of patients (3/37): 2 with transient neurological deficits postembolization and 1 with transient hydrocephalus after surgery. Permanent complications were observed in 3% (1/37) due to treatment-related hemorrhage. At the last follow-up (mean 2.4 years), 69% (24/35) of patients maintained or improved to an mRS score ≤ 2. No deaths occurred. Functional improvement was seen in 29% (10/35), while mRS decline was in 40% of patients (14/35), all unrelated to the dAVF itself. CONCLUSIONS Cognard type V dAVFs carry a high risk of neurological morbidity. However, favorable functional outcomes are achievable with timely, multimodal intervention. Complication rates remain low, with most being transient. These data support aggressive but tailored management to prevent permanent disability in this high-risk population.

Abstract Tissue-mimicking phantoms play a crucial role in evaluating new imaging modalities, simulating clinical scenarios, and ensuring the quality and reliability of imaging systems. Styrene–ethylene/butylene–styrene (SEBS) is an extremely stable and versatile material that has been recently used in ultrasound, elastography, and photoacoustic imaging across diverse applications. Despite its extensive use, a systematic viscoelastic characterization of different SEBS-based formulations reported in the literature, particularly using shear wave elastography (SWE), remains limited. To address this gap, this study investigates the viscoelastic properties of tissue-mimicking phantoms composed of SEBS, glycerol dispersions in SEBS gels, and mixtures of SEBS with low-density polyethylene (LDPE) in mineral oil, using gelatin phantoms as a reference for comparison. Viscoelastic parameters were estimated from shear wave velocity and attenuation dispersion curves using a Kelvin–Voigt model, based on SWE measurements with acoustic radiation force (ARF) excitation, shear plane-wave excitation, and complementary mechanical testing. SEBS-based phantoms exhibited broad, composition-dependent viscoelastic tunability. Increasing SEBS or LDPE content led to stiffer and more viscous responses, while glycerol primarily modulated viscosity and, at higher concentrations, also affected stiffness. Consistent and concordant values were obtained using both ARF and plane wave SWE techniques. The resulting stiffness (2–22 kPa) and viscosity (0.01–1.24 Pa⋅s) overlaps with the mechanical properties of several biological soft tissues, supporting use of these phantoms for SWE validation.

Marketing authorizations for oncology drugs are often based on single‐arm trials (SATs), and real‐world data‐based external comparator cohorts (ECCs) are increasingly explored to contextualize results. In retrospective studies, comparators may be identified by time of diagnosis but included based on time of relapse; such sampling strategies can introduce bias, potentially leading to erroneous efficacy conclusions. Simulated diffuse large B‐cell lymphoma (DLBCL) cohorts were generated using published time‐to‐relapse and post‐relapse survival distributions. Three ECC sampling strategies were evaluated: naïve (screening and inclusion periods coincide), delayed (inclusion period extends beyond screening), and displacement (screening and inclusion periods shifted relative to each other). Different sampling strategies caused significant changes in the time‐to‐relapse distribution in the ECC and, by proxy, the estimated 2‐year post‐relapse overall survival (22.5–52.2%). Naïve sampling consistently resulted in oversampling of early relapses, though bias was reduced with extended inclusion periods; in hypothetical trials, it produced inflated Type I errors (10.5–84.9%) despite α = 0.025. Delayed sampling reduced bias when the inclusion period was sufficiently extended to capture late relapses, yielding unbiased estimates under long delays (Type I error of 2.5% at a 6‐year delay). Displacement sampling depended strongly on the degree of shift: moderate shifts minimized bias, whereas long displacements introduced substantial distortion (Type I error of 2.7% and 0.0% at displacements of 2 and 5, respectively). Real‐world data‐based ECCs in relapsed/refractory oncology are susceptible to selection bias from sampling strategies, particularly through distortions in time‐to‐relapse, leading to erroneous efficacy conclusions; similar bias may occur in non‐oncology settings where time‐to‐treatment initiation is prognostic.