Citations

The kinesin-5 motor protein KIF11 is crucial for mitotic spindle assembly, driving the separation of spindle poles through microtubule sliding. Src-family kinases phosphorylate KIF11 at multiple tyrosine residues within its motor domain, but the mechanistic consequences of these modifications remain unclear. Here, we dissect the role of phosphorylation at Y211 using phospho-mimetic (Y211E) and nonphosphorylatable mutants (Y211F) in biochemical, biophysical, and cellular assays. Optical trapping and Förster resonance energy transfer analyses reveal that Y211 phosphorylation slows neck-linker docking, reducing motor velocity and force generation under load. In human cells, Y211E expression impairs bipolar spindle formation and decreases spindle pole separation velocity, while Y211F shortens steady-state spindle length. Fluorescence recovery after photobleaching analyses show that Y211E accelerates motor turnover on spindle microtubules, consistent with the mutant motor’s heightened load sensitivity. Together, these findings support a model in which Src-mediated phosphorylation at Y211 acts as a rheostat to tune KIF11 mechanochemistry and spindle assembly dynamics, linking cancer-relevant kinase signaling to mitotic force generation.

Background: Whether robot-assisted cholecystectomy reduces bile duct injury compared with laparoscopic cholecystectomy remains uncertain because prior studies have inadequately accounted for disease severity and have rarely classified injury severity using standardized criteria. This study compared perioperative outcomes after robot-assisted and laparoscopic cholecystectomy across a large healthcare system while adjusting for operative complexity. Study Design: Adults undergoing robot-assisted or laparoscopic cholecystectomy within the Mayo Clinic Enterprise (2014–2025) were retrospectively evaluated. Propensity score weighting adjusted for demographics, surgeon case volume, learning curve, and disease severity using the Tokyo Guidelines and Parkland grading system in patients with acute cholecystitis. The primary outcome was bile duct injury; secondary outcomes included general and procedure-specific complications. Results: Among 23,513 patients (19,998 laparoscopic; 3,515 robotic), robot-assisted cholecystectomy was used more frequently for Parkland grade ≥3 disease. Overall, 227 bile duct injuries occurred (204 laparoscopic; 23 robotic), corresponding to absolute risks of 1.02% and 0.65%, respectively (absolute risk difference −0.37%, 95% CI −0.72% to −0.02%; number needed to treat, 273). Robot-assisted cholecystectomy was associated with lower odds of conversion to open surgery, 30-day readmission, and mortality, shorter hospital stay (β −0.56, 95% CI −0.66 to −0.45; P<0.001), and a 5-minute longer median operative time. In acute cholecystitis, robot-assisted cholecystectomy was associated with lower adjusted odds of bile duct injury (aOR 0.29, 95% CI 0.07–0.78; P=0.011). Conclusions: After adjustment for disease severity and surgeon-related factors, robot-assisted cholecystectomy was associated with lower odds of bile duct injury in acute cholecystitis and improved perioperative outcomes, including shorter hospitalization and lower conversion rates, despite greater use in more complex cases.

Abstract Background Bevacizumab is a treatment for radiation necrosis; the optimal dosing remains inadequately studied. Methods Retrospective review of adult patients with primary central nervous system (CNS) tumors or brain metastasis treated with bevacizumab for radiation necrosis from 6/29/2021 to 7/31/2024. Primary outcome was to compare edema response with two different bevacizumab doses: 7.5 mg/kg and 10 mg/kg. Edema response was classified according to the following groups: (1) increase of edema, &gt;105% of baseline; (2) constant edema, 75%-105% of baseline; (3) slight decrease of edema, 25%-75% of baseline; (4) large decrease of edema, &lt;25% of baseline. Results 104 patients were evaluated (median age 59 years, 56% male); 53 patients in the 7.5 mg/kg group and 51 patients in the 10 mg/kg group. Tumor type varied significantly across dosing groups (p &lt; 0.001). In the 7.5 mg/kg group, tumor type was primary CNS (n = 23, 43%), lung (n = 14, 26%), breast (n = 8, 15%), melanoma (n = 4, 8%) and other (n = 4, 8%). In the 10 mg/kg group, tumor type was primary CNS (n = 43, 84%), lung (n = 2, 4%), melanoma (n = 2, 4%) and other (n = 4, 8%). Median number of bevacizumab doses administered was 4. There was a statistically significant difference in distribution of edema response across all response levels favoring bevacizumab 10 mg/kg (p = 0.032). When edema response was dichotomized (large decrease vs other), the difference remained statistically significant (p = 0.015). Conclusion Bevacizumab 10 mg/kg was more efficacious in terms of edema response; this result is impacted by the significantly higher incidence of primary CNS tumors in the 10 mg/kg dosing group.

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 Objective Epilepsy duration is a modifiable risk factor in the outcome of definitive epilepsy surgery; however, an analogous effect in palliative procedures has not been shown. We reviewed the Pediatric Epilepsy Surgery Database data for an association between epilepsy duration and seizure reduction in palliative procedures. Methods Patients enrolled between January 2018 and April 2025 who underwent their first epilepsy surgery with palliative intent with 6 months of follow‐up were included. Procedures included neuromodulation, corpus callosotomy, hemispherotomy, lesionectomy, and lobectomy where surgical intent was not seizure freedom. Outcomes of seizure freedom, 90% seizure reduction, and 50% seizure reduction were considered at 6–12 months and >12 months from surgery. Duration from epilepsy onset to surgery was compared for patients above and below each outcome threshold at each time point. Logistic regression analysis for the association between epilepsy duration and seizure reduction adjusted for potential confounders including procedure type, etiology, and other clinical factors. Logistic regression analysis was performed on the overall cohort and subgroups of patients with each procedure. Results A total of 588 patients were included. Initial univariate analysis suggested that epilepsy duration at time of surgery was significantly associated with seizure freedom and 90% seizure reduction at both 6–12 months and >12 months. After adjusting for confounders, only seizure freedom at >12 months was significantly associated with duration of epilepsy. When individual procedures were considered, only lobectomy was sensitive to duration of epilepsy in multivariate analysis, with significant impacts on >50% and >90% seizure reduction at >12 months. Lesional epilepsy predicted seizure freedom at >12 months. Neuromodulation and corpus callosotomy were less likely to achieve seizure reduction than other procedures. Significance We did not find an association between early epilepsy surgery and seizure reduction. This reflects the heterogeneity of our population, including different types of surgical procedures and lesional and nonlesional epilepsies.

Abstract Background Existing formal feedback systems in graduate medical education often rely heavily on intangible Likert Scales linked to ACGME milestones as an end-of-rotation summative assessment. However, more frequent, actionable, formative feedback based on observations is essential to personal growth. Objective To evaluate the impact of changing from a milestone-based evaluation form to a brief narrative-based feedback form in a Pulmonary Disease and Critical Care Medicine (PCCM) fellowship as an exploratory pilot project. Our aim was to describe change in perception of feedback quality and the impact on Clinical Competency Committee (CCC) decisions. Methods We compared the quality of written rotation feedback before and after implementing a shorter feedback form on January 1, 2024 for 15 PCCM fellows at a single large academic institution using the Quality of Assessment for Learning (QuAL) score, (July 2023-December 2023 compared to January 2024-July 2024), fellow pre- and post-surveys (December 2023 and June 2024) and a CCC focus group (June 2024). Results Overall QuAL score improved significantly after narrative-based feedback form implementation (2.71 pre [n = 75] vs 3.70 post [n = 85], p &lt; 0.001). Surveys had 13/14 (92.8%) fellows respond pre-intervention and 8/14 (57.1%) post-intervention. There was significant improvement in the number of fellows indicating they could identify new learning goals based on written feedback after implementation of the new form (23.1% pre vs 75.0% post, p = 0.03). The CCC focus group with 5 of 8 eligible faculty participating described milestone decisions were better supported by more detailed narratives. Conclusions Implementing a brief narrative-based form improved feedback quality and the number of trainees able to create learning goals. The CCC identified that the new form provided better details to support milestone recommendations.

BMT CTN 1506 ("MORPHO") was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants transplanted &lt; 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = 0.001) in participants transplanted within 120 days from diagnosis and in those treated with a FLT3 inhibitor pre-HCT and transplanted within 120 days (P = 0.008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment pre-HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Abstract Introduction Distinct temperature patterns have long been recognized to correlate with fevers of differing etiologies. While the use of wearable sensors for high-frequency temperature monitoring (HFTM) on a near minute-by-minute basis has been shown to detect fevers earlier than standard-of-care nursing vital sign assessments in hospitalized patients, leveraging these high-resolution datasets to computationally identify unique digital signatures for real-time diagnosis of underlying fever etiology has not been widely explored. Diagnostic uncertainty is common in patients undergoing hematopoietic stem cell transplantation (HCT), with only 20–30% of febrile neutropenic episodes being microbiologically documented. We hypothesized that unique temperature patterns extracted from HFTM data collected during episodes of febrile neutropenia could be used to develop a supervised machine learning classifier capable of accurately predicting underlying fever etiology in HCT patients. Methods We analyzed 68 clinically independent fever episodes recorded in HCT patients (n=90) outfitted with an FDA-cleared wireless temperature sensor (TempTraq®, BlueSpark Technologies) that measured axillary temperature every 2 minutes throughout hospitalization. Time-series features were extracted from temperature traces spanning 1 hour before to 3 hours after fever onset and used to train a suite of machine-learning models to distinguish engraftment fevers from other fever etiologies. Model training and evaluation were performed using repeated stratified 5-fold patient-level cross-validation, yielding 100 train-test evaluations. Results Among all classification models, the logistic regression classifier provided the best overall performance and interpretability, achieving 94% specificity (95% CI, 0.84–1.0) for identifying engraftment fevers with a mean AUROC of 0.88 ± 0.10. Feature importance analysis demonstrated that both clinical variables and HFTM-derived temperature dynamics contributed to model performance, with a strong reliance on time-series features captured within the first 4 hours of fever onset. Conclusion Our study provides a demonstration that continuous temperature data collected from patients outfitted with wearable sensors can be leveraged not only for early fever detection but also for machine learning–based diagnosis of fever etiology. These findings suggest that dynamic temperature patterns contain clinically meaningful physiologic information that with further studies could support real-time diagnostic decision-making and guide safe de-escalation of empiric antibiotics during febrile neutropenia in patients undergoing intensive cancer therapy.

Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as PKD1 and PKD2 , expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell RNA sequencing atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Across models, single cell RNA sequencing (scRNAseq) data revealed increased Spp1 (osteopontin) expression and signaling from PKD-enriched clusters. Global deletion of Spp1 in Pkd1 RC/RC mice resulted in a modest reduction in cyst severity and improved kidney function. From these studies, we created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.