Citations

This study found that inhibiting TrkB kinase activity decreases the extent of neuromuscular transmission failure during repetitive stimulation at low frequency while increasing failure with high-frequency stimulation. The frequency-dependent effect of 1NMPP1 treatment suggests that the role of TrkB signaling in maintaining neuromuscular transmission during repetitive stimulation may differ between motor unit types (slow-twitch, fatigue-resistant vs. fast-twitch, fatigable) and likely reflect effects at the presynaptic terminal without major effects on the muscle itself.

Background: Despite guideline support for plain radiography (XR) in low-risk pediatric blunt trauma, CT remains the predominant imaging modality for cervical spine evaluation, increasing radiation exposure. We evaluated contemporary XR utilization and its diagnostic performance in children meeting consensus criteria for XR-first imaging. Study Design: We performed a prospective, multicenter observational study of 19,995 children enrolled in the Western Pediatric Cervical Spine Study across 72 U.S. trauma centers (2022–2025). Children appropriate for XR screening (Glasgow Coma Scale score >13, asymptomatic, non-obtunded) were identified using consensus criteria. XR utilization, sensitivity, and negative predictive value (NPV) were assessed, and multivariable logistic regression identified predictors of XR use. Results: XR was performed in 39% of patients overall and varied significantly by trauma center type (pediatric 48% vs adult 14% vs mixed 15%; p<0.001), whereas CT was used in 60%. Among XR-appropriate children (n=12,650), an estimated 7,705 CT examinations could potentially have been replaced with XR. In the overall cohort, XR sensitivity for any cervical spine injury was 30.3% (95% CI 26.2–34.6%) with an NPV of 95.2% (95% CI 94.7–95.7%). In XR-appropriate children, only two clinically significant cervical spine injuries were missed, yielding a sensitivity of 75.0% (95% CI 34.9–96.8%) and an NPV of 99.9% (95% CI 99.9%–100.0%). Conclusions: Plain radiography is substantially underutilized in children meeting consensus criteria for XR-first imaging. In appropriately selected patients, XR demonstrated an NPV of 99.9% for clinically significant cervical spine injury, supporting broader implementation of XR-first imaging strategies to reduce CT utilization and pediatric radiation exposure.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-associated bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of male mouse femurs. In studies done in male mice, following three preclinical radiotherapy regimens of 30Gy (5 x 6Gy), 60Gy (5 x 12Gy) and a single dose of 24Gy, suppression of SASP by JAKi was efficacious in suppressing radiation-induced bone damage. In comparison and as shown before, the senolytic combination of D+Q was also able to alleviate radiation-associated bone loss. Early and intermittent suppression of SASP using JAK inhibitors in male mice alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression and reduced bone-marrow adiposity. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

ABSTRACT Prolonged operative time is associated with increased surgical complications, resource utilization, and cost. While factors such as surgeon experience and patient habitus are well recognized, the impact of anatomical anomalies and variations remains poorly quantified. This systematic review evaluates the influence of abdominal structural anomalies and anatomical variations on operative time. Following PRISMA 2020 guidelines, a search of PubMed (2000–2025) identified 82 eligible studies. Operative‐time impact was assessed using added operative time relative to reference benchmarks. The unit of analysis was the procedure‐level observation. Observations were stratified by procedure category and surgical complexity and summarized using median added operative time and range. Among procedure‐level observations with available benchmarks, 13 of 14 (92.9%) structural anomalies, 48 of 54 (88.9%) situs inversus cases, and 10 of 11 (90.9%) other anatomical variants demonstrated increased operative time relative to baseline. Structural anomalies were associated with larger median increases, particularly in colorectal procedures, whereas anatomical variations demonstrated a more heterogeneous effect across procedural systems. Higher‐complexity procedures, including pancreatic operations, showed greater absolute increases in operative time. Preoperative identification of anatomical differences was associated with attenuation of operative delays. Structural anomalies are frequently associated with increased operative duration, whereas anatomical variations demonstrate a more variable and context‐dependent effect. The magnitude of operative time impact is influenced by procedural complexity and preoperative planning. Incorporating anatomical variability into surgical planning may reduce avoidable operative delays and improve operative efficiency.

Abstract Standard of care RPT may result in dose-limiting side effects of the salivary glands include sialadenitis and xerostomia that are inconsistent with outcomes from external beam for equivalent ADs. This work develops a parametrizable ‘Macro-to-Micro’ (M2μ) model that demonstrates the consideration of small-scale dosimetry in comparison to conventional methods that typically assume uniform voxel or organ-level uptake. Anatomical features of the salivary gland are represented by annular structures (a centralized branching network of ducts, including excretory, lobar, interlobular) and small-scale voxels (intralobular ducts and acinar cells) with dimensions set to reproduce ex-vivo murine histopathology measurements and scaled up in size for extrapolation to humans. Simulations were performed by scoring and recording S-value histograms to the target ductal and acinar cells, for two beta emitters (177Lu, 131I) and one alpha emitter (225Ac). Four idealized activity distributions were created to assign activity to surface and volumes of the annuli, and GEANT4 v11 was used for radiation transport calculations. Comparisons against whole gland uniform spherical self-dose S-value calculations were conducted to validate the radiation transport and to highlight differences between M2μ and conventional dosimetry approaches. Analyses for both models showed greater S-value variation in comparison to the homogeneously distributed activity S-value calculation. The most notable result was that the calculated S-values differed between different branches, depending on the geometric size of the annuli. For the surrounding acinar cells, S-values from ductal cells decreased as a function of distance from the branching structures. High variability of S-values, depending on ductal cell dimensions as well as within the acinar cell distribution of the salivary gland highlights the potential clinical utility of small-scale approaches to RPT salivary gland dosimetry, contingent on clinical translation and validation. To this end, future work should further refine the model and incorporate small-scale activity distributions from pre-clinical and translational studies.

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.

Health care–related out‐of‐pocket and indirect costs may create financial barriers to initial and/or continued receipt of care among patients with cancer, and subsequent financial toxicity is associated with worse oncologic and quality of life outcomes. Recognition and mitigation of risk factors for financial toxicity are essential to the provision of equitable, high‐quality care.

Abstract Primary angiitis of the central nervous system is an extremely rare diagnosis, with an incidence of 2.4 cases per 1,000,000 person-years. The exact cause of PACNS remains unknown, and typically cases present with a long prodrome. It is a diagnosis of exclusion, and various infectious, autoimmune, and malignant processes must be excluded prior to final diagnosis. Given the rarity of this condition, there is often a delay in diagnosis that can range from 6 to 23 months. It is imperative that all clinical providers be aware of this diagnosis when managing patients who present with insidious and non-specific neurological symptoms. We present a case of PACNS that responded well to a therapeutic regimen of high-dose steroids and cyclophosphamide.

Abstract Objective. Proton minibeam radiation therapy (pMBRT) is a novel spatially fractionated radiation therapy technique that offers improved tumor control and reduced normal tissue toxicity. However, its clinical translation has been hindered in part by limited field sizes, low dose rates, and complex manufacturing. This work describes the design, manufacturing, and commissioning of a novel divergent pMBRT collimator along with accessory components to maximize its versatility and facilitate clinical implementation. Approach. The dosimetric outcomes for pMBRT collimator geometry, including slit width, center-to-center (CTC) spacing, thickness, divergence, and field size, were evaluated using TOPAS Monte Carlo (MC) to maximize surface peak-to-valley dose ratio (PVDR) while maintaining uniform target coverage. The collimator was constructed using brass plates held by aluminum side holders. Commissioning measurements with a PTW Bragg peak chamber and EBT4 radiochromic film were compared to TOPAS and an in-house fast GPU-based MC simulation. Ancillary equipment consisting of lead foils, range shifters, custom apertures, and secondary pMBRT collimators were characterized in tandem. Main results. An optimized divergent pMBRT collimator with 0.5 mm slit width, 2.0 mm CTC distance, and 40 mm thickness produced a surface PVDR of 4.8 while preserving quasi-homogeneous dose in the 6–14 cm depth region. Measured dose profiles demonstrated valley dose agreement within 3% for both TOPAS and GPU-based MC predictions after the simulated collimator geometry was refined to match Bragg-peak chamber average dose measurements. The onset of the quasi-homogeneous dose region was shifted toward shallower depths by using thin lead foils, without significantly impacting entrance PVDR. Apertures sharpened penumbra and enhanced peripheral PVDR. A dual collimator approach produced 2D pinhole dose arrays that resulted in valley doses from MC simulations and film measurements agreeing within ∼5%. Significance. We demonstrated a practical low-cost, large-area divergent physical pMBRT collimation system with validated MC modeling. In addition, we introduce complementary accessories that substantially expand system versatility to facilitate clinical implementation.

Importance Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by sterile ulcerative skin lesions. Multiple comorbidities and clinical features have been associated with PG, but no standardized guidelines exist for classifying PG phenotypes. Objective To develop an expert-established classification framework for PG phenotypes to inform treatment guidelines and future research endeavors. Evidence Review In this modified Delphi consensus study that included 23 board-certified dermatologists and Medical Dermatology Society members with expertise in PG, panelists completed 5 rounds of anonymous, iterative online surveys that were administered from December 2023 through July 2025. Before the beginning of the consensus exercise, a literature review was performed by nonvoting researchers to summarize existing data on PG clinical associations and comorbidities. A PubMed search from inception to September 2023 identified observational studies, narrative reviews, systematic reviews, and meta-analyses describing PG clinical associations and comorbidities that were published in English. Experts indicated their agreement with proposed PG phenotypes and disease modifiers with a consensus threshold of 70% or greater. Anonymous comments and aggregated results were presented in each subsequent round. In the final round, a framework of PG phenotypes and disease modifiers was proposed for agreement. Findings Twenty-three board-certified dermatologists and Medical Dermatology Society members with expertise in PG completed 5 rounds of iterative surveys. Consensus was reached on the final set of PG phenotypes and disease modifiers, with 83% of experts in agreement. PG phenotypes were overall classified into 2 major groups: PG with autoinflammatory syndromes and nonsyndromic PG. Nonsyndromic PG included 4 phenotypes: inflammatory bowel disease–associated PG, PG in association with hematologic cancers and blood dyscrasias, drug-induced PG, and other (including idiopathic) PG. Disease modifiers of PG phenotype presentations included involvement of special sites (head/neck, genitals, or peristomal skin) and extracutaneous manifestations. Conclusions and Relevance This expert-established, descriptive framework provides a standardized classification system for distinct PG phenotypes and its modifiers. This nomenclature may inform upcoming clinical guidelines and allow for consistency in reporting epidemiological research and outcomes among patients with PG.