Citations

Abstract Current standard of care for IDH-wildtype glioblastoma (GBM) includes maximal safe resection, adjuvant radiation, and chemotherapy with the alkylating agent temozolomide. A subset of gliomas treated with temozolomide develop somatic hypermutation with a predominance of C>T transitions due to the alkylation effects on DNA. However, the frequency of occurrence, clinical ramifications, and predictive biomarkers for developing temozolomide-induced hypermutation (TMZ-HM) in GBM are unknown. Here we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Seven patients (7%) developed hypermutation at time of first recurrence, while an additional five patients (5%) developed hypermutation at a subsequent recurrence. Patients who developed TMZ-HM had a significantly longer interval between initial surgery and first recurrence (27.8 vs. 9.9 months, p<0.001). In contrast to IDH-mutant gliomas where TMZ-HM is associated with poor prognosis, those patients with IDH-wildtype GBM who developed TMZ-HM had significantly longer overall survival from both initial surgery (67.9 vs. 20.3 months, p<0.001) and from time of recurrence after development of hypermutation (30.9 vs. 9.5 months, p=0.001). There was no difference in oncogenic alteration frequency in initial GBM that subsequently developed TMZ-HM. However, 4 specific CpG sites out of 12 total interrogated sites in the promoter region of MGMT (a DNA repair enzyme) and 5 specific CpG sites in the promoter region of KCNQ1DN (a negative regulator of c-Myc) were significantly more hypermethylated in those GBM that developed TMZ-HM. We then generated a weighted risk score across these CpG sites that can be used to prospectively identify GBM likely to develop TMZ-HM associated with favorable survival. In summary, patients with GBM that develop TMZ-HM follow a more favorable clinical course, and specific MGMT and KCNQ1DN promoter hypermethylation patterns could serve as a biomarker to identify these patients who may potentially benefit from extended alkylating chemotherapy treatment.

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.