Citations

Background The management of osteochondral lesions of the talus (OLT) is challenging, with 2 main options being conservative and surgical management. Orthobiologic therapies come to bridge the gap between these 2 options; however, inconsistencies in indication, composition, and heterogeneous evidence limit clinical decision-making. To address these challenges, 3 International Congress Meetings on Cartilage Repair of the Ankle were convened in Pittsburgh, USA (2017), Dublin, Ireland (2019), and New York, USA (2025) to establish agreement on the role of conservative management and injectable orthobiologic strategies in the treatment of OLT. Methods Seventy-five multidisciplinary experts from over 25 countries and 1 territory participated in a structured Delphi-based consensus process. Blinded surveys, structured questionnaires, and in-person discussions were used to develop and refine statements, supported by literature review and graded evidence (A1–E). Consensus strength was defined as consensus (51%-74%), strong consensus (75%-99%), or unanimous (100%) Results In total, 29 consensus statements were achieved across the 3 meetings. Strong agreement was reached regarding indications and expected outcomes of conservative management, including the role of immobilization and appropriate timing for surgical intervention. Orthobiologic injections, including platelet-rich plasma, concentrated bone marrow aspirate, and hyaluronic acid, were considered appropriate in select patients with persistent symptoms, although no superiority was demonstrated among formulations, preparation methods, or injection strategies. When used as adjuncts to surgical procedures, orthobiologics may improve radiological outcomes, with limited evidence for improvement in clinical outcomes. Technical considerations, including preferred harvest sites and a lack of standardized preparation protocols, were identified, along with key principles for patient counseling Conclusion These international consensus statements establish a standardized framework for the conservative management and use of injectable orthobiologic therapies in OLT. By clarifying indications, technical considerations, and current limitations, this work aims to improve consistency in clinical practice, guide treatment decision-making, and inform future research.

Abstract Objective Pediatric epilepsy surgery is well established, but contemporary global data on referral and presurgical evaluation practices are lacking. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Task Force study provides an updated overview of current trends and regional differences. Methods Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) across 29 countries and six continents, identified through ILAE networks, and included all children and adolescents treated in 2023 who underwent presurgical evaluation/epilepsy surgery. Results Group‐level data were available for 2427 patients. Mean age at surgery was 9.1 ± 4.9 years; mean epilepsy duration was 5.3. At surgery, 3.2% were <1 year old (highest in Oceania: 5.1%), and 6.1% were nonpharmacoresistant (highest in Europe: 15.0%). Prior neurosurgery was reported in 14.2% (highest in North America: 28.8%), including 8.0% resections (6.1% for epilepsy, 1.5% for tumors; highest in Oceania: 16.5%), 2.3% disconnections (1.3% corpus callosotomy; highest in South America: 4.7%), and 4.2% neuromodulation (3.7% vagal nerve stimulation, .2% responsive neurostimulation, one deep brain stimulation; highest in North America: 12.2%). Developmental and epileptic encephalopathies (DEEs) at surgery included Lennox–Gastaut syndrome (7.4%), infantile epileptic spasms syndrome (5.1%), and DEE with spike–wave activation in sleep (1.5%). Presurgical investigations included fluorodeoxyglucose positron emission tomography (52.6%; highest in Oceania: 79.7%), genetic testing (46.8%; highest in Asia: 54.3%), magnetic resonance imaging (MRI) postprocessing (32.4%; highest in South America: 53.0%), functional MRI (fMRI; 15.2%; highest in North America: 40.3%), magnetoencephalography (11.9%; highest in North America: 39.3%), single photon emission computed tomography (9.6%; highest in North America: 22.2%), high‐density electroencephalography (EEG; 1.9%; highest in Europe: 4.7%), source localization (1.6%; highest in Oceania: 7.6%), Wada test (1.2%; highest in North America: 3.5%), and EEG‐fMRI (.5%; highest in Europe: 1.1%). Significance Despite some early surgeries, including in infancy and before pharmacoresistance, mean epilepsy duration before surgery remains >5 years. Reoperations are common, with resection more frequent than neuromodulation. Genetic testing in nearly half of patients reflects its growing relevance, and the high rate of DEEs underscores the complexity of surgical candidates.

Abstract The sections in this article are: Wave‐Speed Flow‐Limiting Mechanism Viscous Flow Limitation Relation Between Wave‐Speed and Viscous Flow‐Limiting Mechanisms Comments on Modeling

In pathologies of the heart, blood vessels, and airways, and in cancer as well, the ultimate therapeutic target is often modulation of cellular contractile force. For discovering new therapies, drug screening technologies typically use biochemical or structural surrogates for contractile force rather than contractile force itself. Because such approaches are indirect, some hits are false while other potential hits could be missed. To fill this gap, we developed a new high‐throughput method that utilizes cellular contractile force directly as the reporter ‐‐called contractile force screening (CFS)‐‐ and established feasibility of CFS in the context of drug discovery in asthma. During an acute asthma attack, contractile forces generated by airway smooth muscle cells act to constrict the airway and thus obstruct airflow. To dilate constricted airways, asthma patients use bronchodilators to reduce these contractile forces and thus allow the airway to open more fully, but currently available bronchodilator medications often fail to relax that muscle sufficiently, especially in severe asthma. To address this unmet need for more effective bronchodilator medications, we implemented CFS to evaluate 10,000 small molecule compounds selected randomly from the Chembridge DIVERset® library. Acrylamide gels were made in 96‐well plates and fluorescent markers and collagen were coated onto gel surfaces. Upon each gel we cultured primary human airway smooth muscle (HASM) cells to near confluence. Drug effects were quantified as the ‘force response ratio’, namely, the ratio of the contractile forces before and after drug addition. By screening mixtures of 8 compounds simultaneously, we were able to evaluate 2000 compounds per week in quadruplicate. After retesting individual compounds from initially positives, we identified 2 individual compounds that relaxed HASM cells in a dose‐dependent and a non‐toxic manner. The mechanism of action is still under investigation but we found that these compounds work independent of cAMP. CFS provides a convenient, rapid, and inexpensive platform for drug discovery based upon a physiological endpoint, namely, cell contractile force. Furthermore, CFS technology has the potential to become a new high‐content assay for drug discovery in any disease process in which cellular contractile force plays a central role. Support or Funding Information NIH P50HL107171 (CADET phase I), R01EY019696 (Eye BRP), NRF GRN (NRF‐2013S1A2A2035518)

Background: The purpose of this study was to validate the Foot and Ankle Outcome Score (FAOS) for osteochondral lesions of the talus (OLTs). We hypothesize that the FAOS will meet all 4 psychometric criteria for validity in this patient population. Methods: From 2008 to 2014, a total of 208 patients with OLTs were included in the construct validity portion of the study. All patients completed FAOS and 12-Item Short-Form Health Survey (SF-12) scores. Twenty additional patients were prospectively recruited and were asked to complete questionnaires to determine the relevance of each of the FAOS questions as it related to their OLT. Forty-four patients completed the FAOS 1 month after the first FAOS to assess reliability via Spearman correlation coefficient. Responsiveness of the FAOS was assessed with 54 patients who had both preoperative and postoperative FAOS scores via Student paired t test with significance determined as P < .05. In total, 229 unique patients were included in this study. Results: Statistically significant associations were found between all FAOS and SF-12 subscales ( P < .01). The FAOS symptoms subscale demonstrated the lowest correlation with the SF-12 physical health domains. No floor or ceiling effects were identified. Weak correlations were calculated between the 5 FAOS subscales and the SF-12 mental component summary score. All FAOS domains met the threshold for acceptable content validity (score > 2.0). All FAOS subscales demonstrated acceptable test-retest reliability, with ICC values ranging from 0.81 (ADL) to 0.92 (Pain). Conclusion: This study demonstrates the acceptable yet moderate construct and content validity, reliability, and responsiveness of the FAOS for patients with OLTs of the ankle joint. We endorse the use of the FAOS in evaluating ankle OLTs in both the research and clinical setting and consider it a useful patient-reported, self-administered instrument following surgical intervention. Level of Evidence: Level IV, retrospective case study.

Abstract Background The histologic assessment of inflammatory bowel disease (IBD) relies on qualitative grading methods. Although widely accepted, these instruments are time consuming, require specialized training, and suffer from inter-rater disagreement. For these reasons there is a need for more consistent and less biased methods to assess IBD histology. Methods The algorithm was initially developed using hematoxylin and eosin (H&E) stained whole slide images of colon biopsies (238 ulcerative colitis [UC], 30 Crohn’s Disease [CD], and 28 endoscopically normal adjacent [ENA]). The first two stages implement convolutional neural networks (CNN) which segment 11 key anatomical features (Figure 1). The third stage extracts the features and models them for prediction. Results The first stage of the algorithm was validated on an independent test dataset by calculating the intersection-over-union (IoU) for the ground truth and prediction masks, resulting in a value of 0.97. A preliminary validation for stage 2 was performed by randomly selecting 30 unique biopsy sections from the test dataset and applying a 150um x 150um counting frame. An expert gastrointestinal pathologist confirmed correct cell identification by the algorithm for three of the primary inflammatory cell types: plasma cells, eosinophils, and neutrophils which resulted in a sensitivity/specificity of 0.76/0.99, 0.78/1.00, and 1.00/0.98 respectively. The final stage predicts RHI grades which could be directly compared to pathologist reads (Figure 2, 3, and 4). Conclusion This is the first study to demonstrate the value of machine learning to assess histologic activity in IBD. These methods lay the foundations for future work, and we believe stages 1 and 2 can be explored independently to statistically characterize the histologic changes of IBD, enabling the improvement of preexisting grading systems.

Fredberg, J. J., K. A. Jones, M. Nathan, S. Raboudi, Y. S. Prakash, S. A. Shore, J. P. Butler, and G. C. Sieck. Friction in airway smooth muscle: mechanism, latch, and implications in asthma. J. Appl. Physiol. 81(6): 2703–2712, 1996.—In muscle, active force and stiffness reflect numbers of actin-myosin interactions and shortening velocity reflects their turnover rates, but the molecular basis of mechanical friction is somewhat less clear. To better characterize molecular mechanisms that govern mechanical friction, we measured the rate of mechanical energy dissipation and the rate of actomyosin ATP utilization simultaneously in activated canine airway smooth muscle subjected to small periodic stretches as occur in breathing. The amplitude of the frictional stress is proportional to ηE, where E is the tissue stiffness defined by the slope of the resulting force vs. displacement loop and η is the hysteresivity defined by the fatness of that loop. From contractile stimulus onset, the time course of frictional stress amplitude followed a biphasic pattern that tracked that of the rate of actomyosin ATP consumption. The time course of hysteresivity, however, followed a different biphasic pattern that tracked that of shortening velocity. Taken together with an analysis of mechanical energy storage and dissipation in the cross-bridge cycle, these results indicate, first, that like shortening velocity and the rate of actomyosin ATP utilization, mechanical friction in airway smooth muscle is also governed by the rate of cross-bridge cycling; second, that changes in cycling rate associated with conversion of rapidly cycling cross bridges to slowly cycling latch bridges can be assessed from changes of hysteresivity of the force vs. displacement loop; and third, that steady-state force maintenance (latch) is a low-friction contractile state. This last finding may account for the unique inability of asthmatic patients to reverse spontaneous airways obstruction with a deep inspiration.