Citations

Abstract Advancements in understanding H3 K27-altered diffuse midline glioma (DMG) biology have not yet translated into effective therapies for these tumors likely due to delivery challenges across the blood-brain barrier (BBB) and variable tumor genetics. This study systematically probes convective-enhanced delivery (CED) as a means to administer small molecule drugs directly to DMG tumors, circumventing constraints imposed by the BBB. Our findings emphasize the necessity of strategic drug selection and pharmacokinetic analysis in refining CED approaches, advocating for precision medicine techniques specialized for DMG. We demonstrate that while most small molecule drugs are rapidly cleared from the brain following CED, their retention and effectiveness are substantially improved by co-administration of systemic efflux transporter (ET) inhibitors such as everolimus. The synergistic potential of combining everolimus with topotecan or ponatinib offers a novel therapeutic pathway, advocating for further investigation into this DMG management strategy.

Abstract Purpose The purpose of this article is to explore the potential of digital twin technologies in orthopaedics and to evaluate how their integration with artificial intelligence (AI) and deep learning (DL) can improve orthopaedic evaluation and treatment. This review addresses key applications of digital twins, including surgical planning, patient‐specific outcome prediction, augmented reality‐assisted surgery and simulation‐based surgical training. Methods Existing studies on digital twins in various domains, including engineering, biomedical and orthopaedics are reviewed. We also reviewed advancements in AI and DL relevant to digital twins. We focused on identifying key benefits, challenges and future directions for the implementation of digital twins in orthopaedic practice. Results The review highlights that digital twins offer significant potential to revolutionise orthopaedic care by enabling precise surgical planning, real‐time outcome prediction and enhanced training. Digital twins can model patient‐specific anatomy using advanced imaging techniques and dynamically update with real‐time data, providing valuable insights during surgery and postoperative care. However, challenges such as the need for large‐scale data sets, technological limitations and integration issues must be addressed to fully realise these benefits. Conclusion Digital twins represent a promising frontier in orthopaedic research and practice, with the potential to improve patient outcomes and enhance surgical precision. To enable widespread adoption, future research must focus on overcoming current challenges and further refining the integration of digital twins with AI and DL technologies. Level of Evidence Level V.

AbstractPurposeTo systematically review the literature regarding machine learning in leg length discrepancy (LLD) and to provide insight into the most relevant manuscripts on this topic in order to highlight the importance and future clinical implications of machine learning in the diagnosis and treatment of LLD.MethodsA systematic electronic search was conducted using PubMed, OVID/Medline and Cochrane libraries in accordance with Preferred Reporting Items for Systematic Review and Meta‐Analysis guidelines. Two observers independently screened the abstracts and titles of potential articles.ResultsA total of six studies were identified in the search. All measurements were calculated using standardized anterior‐posterior long‐leg radiographs. Five (83.3%) of the studies used measurements of the femoral length, tibial length and leg length to assess LLD, whereas one (16.6%) study used the iliac crest height difference to quantify LLD. The deep learning models showed excellent reliability in predicting all length measurements with intraclass correlation coefficients ranging from 0.98 to 1.0 and mean absolute error (MAE) values ranging from 0.11 to 0.45 cm. Three studies reported measurements of LLD, and the convolutional neural network model showed the lowest MAE of 0.13 cm in predicting LLD.ConclusionsMachine learning models are effective and efficient in determining LLD. Implementation of these models may reduce cost, improve efficiency and lead to better overall patient outcomes.Clinical RelevanceThis review highlights the potential of deep learning (DL) algorithms for accurate and reliable measurement of lower limb length and leg length discrepancy (LLD) on long‐leg radiographs. The reported mean absolute error and intraclass correlation coefficient values indicate that the performance of the DL models was comparable to that of radiologists, suggesting that DL‐based assessments could potentially be used to automate the measurement of lower limb length and LLD in clinical practice.Level of EvidenceLevel IV.

Objective To compare cochlear implant (CI) speech perception outcomes in patients with sporadic vestibular schwannoma (VS) managed with observation, radiosurgery, or microsurgery. Study Design Retrospective review. Setting Eleven tertiary academic medical centers. Patients One hundred patients with sporadic VS who received an ipsilateral CI. Interventions Ipsilateral cochlear implantation. Main Outcome Measures Pure-tone thresholds, monosyllabic speech perception testing scores, and rates of open-set speech acquisition. Results Of the 100 patients studied, 54 underwent microsurgery, 26 underwent radiosurgery, 19 continued observation, and 1 underwent multimodal therapy. Among all patients, the median post-implantation pure-tone average was 31 dB (interquartile range [IQR] 25–39 dB) and the median monosyllabic speech perception score was 30% (IQR 0–60%) at a median of 12 months (IQR 5–25 months) post-implantation. Patients who were managed with microsurgery (median speech perception score 11%, IQR 0–52%) exhibited poorer implant outcomes overall compared with those managed with observation (median speech perception score 52%, IQR 40–72%) or radiosurgery (median speech perception score 30%, IQR 16–60%). Open-set speech perception was achieved in 61% of patients managed with microsurgery, 100% with observation, and 80% with radiosurgery. In a multivariable setting, those managed with observation (p = 0.02) or who underwent radiosurgery (p = 0.04) were significantly more likely to achieve open-set speech perception compared with patients who underwent microsurgery. Conclusions Cochlear implants offer benefit in selected patients with sporadic VS. Although achieved in over half of people after microsurgery, open-set speech perception is more reliably attained in patients who are treated with observation or radiosurgery compared with microsurgical resection. These data may inform patient counseling and VS tumor management in people who may benefit from implantation.

AbstractBackgroundFlow cytometry protocols for counting fresh CD34+ cell samples are not ideal for cryopreserved products due to cryoprotectant cytotoxicity. For cryopreserved samples, often large volumes of hypotonic solutions, which can cause cell death, are used to remove the cryoprotectant with a post‐thaw wash. We recently developed a novel multistep dilution method with subsequent flow cytometry analysis to allow for accurate and reproducible results. The previous method involved washing steps which invalidate the ability to enumerate cell recovery, and success had to be gauged solely on viability. The new method allows for assessment of total cell recovery and viable cell recovery.Study Design and MethodsApheresis products were cryopreserved in 10% DMSO at a target WBC concentration of 300 × 106/mL. Cryovials from these products were thawed at 37°C, and samples were diluted 1:2 by three additions of 1/3 sample volume using 1%‐Human Albumin in Dextran 40 (10% Low Molecular Weight Dextran in 0.9% NaCl) separated by 5 min between each addition. A 1:10 dilution was performed to obtain the correct cell concentration for flow cytometric analysis resulting in a 1:20 dilution. End WBC concentrations were ~15 × 106/mL with DMSO diluted to 0.5%.ResultsFifty‐two samples were tested with this new method. Total and viable cell recoveries were calculated based on pre‐cryopreservation data. Median total cell recoveries for CD34 and CD3 were >85%, while median viable cell recoveries were >75%.DiscussionCryopreserved samples can be reliably prepared for flow cytometric testing using a step‐wise dilution to preserve cell integrity and robust recoveries.

Background: Facial aberrant reinnervation syndrome is characterized by aberrant facial muscle reinnervation after facial nerve injury producing facial synkinesis, hypertonicity, and muscle spasm. Objective: To systematically review the surgical treatments for facial aberrant reinnervation syndrome and assess their effectiveness as measured by patient-reported outcomes, physician-graded outcomes, or computer-automated grading systems. Methods: We conducted a systematic review using PubMed, Embase, and Cochrane CENTRAL in accordance with PRISMA guidelines. Texts reporting outcomes of any surgical treatment for facial aberrant reinnervation syndrome from 2003 to 2023 were included. Results: After screening, 25 studies with 731 patients were included. Surgical procedures included selective neurectomy (SN), selective myectomy (SM), cross-facial nerve graft, masseter nerve transfer, and gracilis muscle transfer. All surgical techniques and combinations showed significant improvement in at least one clinical outcome measure from baseline ( p < 0.05), although one study found no significant improvement. Thirty different outcome measures were used, the most common being the FaCE and eFACE scales (seven studies each). Conclusions: All surgical procedures in this review yield improved clinical outcome measures for facial aberrant reinnervation syndrome, with SN and SM being the dominant surgical treatments. Standardized outcome assessment and more nuanced patient evaluation are necessary to determine the most effective surgical treatments.

AbstractObjectivesTo examine heterogeneity in physician batch ordering practices and measure the associations between a physician's tendency to batch order imaging tests on patient outcomes and resource utilization.Study Setting and DesignIn this retrospective study, we used comprehensive EMR data from patients who visited the Mayo Clinic of Arizona Emergency Department (ED) between October 6, 2018 and December 31, 2019. Primary outcomes are patient length of stay (LOS) in the ED, number of diagnostic imaging tests ordered during a patient encounter, and patients' return with admission to the ED within 72 h. The association between outcomes and physician batch tendency was measured using a multivariable linear regression controlling for various covariates.Data Sources and Analytic SampleThe Mayo Clinic of Arizona Emergency Department recorded approximately 50,836 visits, all randomly assigned to physicians during the study period. After excluding rare complaints, we were left with an analytical sample of 43,299 patient encounters.Principal FindingsFindings show that having a physician with a batch tendency 1 standard deviation (SD) greater than the average physician was associated with a 4.5% increase in ED LOS (p < 0.001). It was also associated with a 14.8% (0.2 percentage points) decrease in the probability of a 72‐h return with admission (p < 0.001), implying that batching may lead to more comprehensive evaluations, reducing the need for short‐term revisits. A batch tendency 1SD greater than that of the average physician was also associated with an additional 8 imaging tests ordered per 100 patient encounters (p < 0.001), suggesting that batch ordering may be leading to tests that would not have been otherwise ordered had the physician waited for the results from one test before placing their next order.ConclusionsThis study highlights the considerable impact of physicians' diagnostic test ordering strategies on ED efficiency and patient care. The results also highlight the need to develop guidelines to optimize ED test ordering practices.

SUMMARYDelirium frequently occurs among hospital in-patients, with significant attributable healthcare costs. It is associated with long-term adverse outcomes, including an eightfold increased risk of subsequent dementia. The purpose of this article is to inform clinicians of the best practices for spotting, stopping and treating delirium and provide guidance on common challenging clinical dilemmas. For spotting delirium, suggested screening tools are the 4 ‘A's Test (in general medical settings) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Prevention is best achieved with multicomponent interventions and targeted strategies focusing on: (a) avoiding iatrogenic causes; (b) brain optimisation by ensuring smooth bodily functioning; (c) maintaining social interactions and normality. Non-pharmacological approaches are the first line for treatment; they largely mirror prevention strategies, but the focus of empirical evidence is on prevention. Although sufficient evidence is lacking for most pharmacological approaches, an antipsychotic at low doses for short durations may be of utility for highly distressing or high-risk situations, particularly in hyperactive delirium, but only as a last resort.

Purpose To evaluate the available literature on the relationship between knee bony morphology and medial meniscus posterior root tears (MMPRTs) to determine which tibiofemoral morphologic risk factors may predispose the development of MMPRTs. Methods Embase, MEDLINE, and PubMed databases were searched to identify all relevant human clinical studies investigating knee morphologic features and MMPRTs. Shape features were compared between control groups and patients with MMPRTs. The methodological index for nonrandomized studies (MINORS) instrument was utilized to assess the methodological quality of included studies. Results Thirteen level III evidence studies and 1 level IV evidence study were included in this review (n = 2,181), with 895 patients in the MMPRT group and 1,286 in the control group. Tibial morphology features associated with an increased risk for MMPRTs included an increased medial tibial slope (6 studies), increased tibial torsion (1 study), increased medial meniscal slope (1 study), and shallower medial tibial plateau concavity (1 study). Varus mechanical alignment was found to increase the risk for MMPRTs (4 studies). Femoral morphology features associated with an increased risk for MMPRTs included an A‐type intercondylar notch (1 study), increased medial femoral condyle (MFC) angle (1 study), narrower intercondylar distance (1 study), narrower intercondylar notch width (1 study), shorter MFC distal offset distance (1 study), increased MFC width (1 study), increased MFC to medial tibial condyle width ratio (1 study), greater distance between the medial tibial eminence and MFC (1 study), and smaller femoral offset ratios of both the medial and lateral condyles (1 study). Conclusions Multiple tibiofemoral shape features, including a steeper slope of the medial tibial plateau, greater varus alignment, and a narrower intercondylar distance and notch width, were found to be predictive factors for MMPRTs. Level of Evidence Level IV, systematic review of Level III and IV studies.

Abstract Introduction: Immune checkpoint inhibitors (ICI) are an essential systemic therapy for advanced melanoma. However, most melanomas develop resistance to ICI. Tumor-derived soluble PD-L1 (sPD-L1) and other soluble immunosuppressive factors drive checkpoint inhibitor resistance and correlate with inferior survival. We previously showed that therapeutic plasma exchange (TPE) removes sPD-L1 from circulation. Thus, we hypothesized that TPE-mediated removal of sPD-L1 and other immunosuppressive factors could overcome immunotherapy resistance in refractory melanoma. Methods: In this clinical trial (NCT04581382), we prospectively enrolled eighteen (18) patients with widely metastatic melanoma with progression despite anti-PD-1 ICI and elevated sPD-L1 by ELISA (≥1.7ng/mL). Each patient received radiotherapy to between one and three metastatic lesions (at least two unirradiated lesions) followed by three TPE sessions on consecutive days and re-challenge with checkpoint inhibitor. The primary safety and efficacy endpoints of the study were adverse events (AEs) and sPD-L1 reduction by TPE, respectively. Secondary endpoints included RECIST-based response in unirradiated lesions and overall survival. Correlative studies included kinetics of sPD-L1 and soluble immonsuppressive factors and dynamics of peripheral immune cell phenotypes. Results: Mean age was 62 (SD 13) and seven of eighteen (39%) were female. Mean baseline sPD-L1 was 26.31 ng/mL (40.01). The treatment was well-tolerated with one (6%) patient with grade 3 and 4 adverse events from a central line infection after TPE. Levels of sPD-L1 were significantly reduced by TPE (mean 80.2% reduction, p<0.0001). Two patients (11.1%) experienced complete response (CR), one (5.6%) partial response, three (16.7%) stable disease, and 12 (66.7%) progressive disease. In one case, immunotherapy was discontinued after two years due to no detectable lesions. Changes in tumor-reactive (TTR) GZMB+/CX3CR1+/CD11ahigh and other peripheral immune cell populations predicted overall survival in this cohort. In addition to sPD-L1, other soluble mediators of ICI resistance were also reduced by TPE and predicted overall survival in this cohort. Summary/Conclusion: sPD-L1 and other soluble immunoregulatory signaling molecules are important mediators of ICI resistance. SBRT and TPE can resensitize ICI-refractory melanoma by removing these factors. Patients with persistently elevated or rapid rebound of sPD-L1 following TPE experienced poor response and overall survival. Serial monitoring of sPD-L1 may predict response to ICI and multiple courses of TPE may be necessary. Our findings may apply in other ICI-resistant cancers with elevated sPD-L1. ClinicalTrials.gov registration: NCT04581382, ReCIPE-M1 (Rescuing Cancer Immunotherapy with Plasma Exchange in Melanoma 1).