In Utero Exposure to Maternal COVID-19 Vaccination and Offspring Neurodevelopment at 12 and 18 Months.

Importance: Uptake of COVID-19 vaccines among pregnant individuals was hampered by safety concerns around potential risks to unborn children. Data clarifying early neurodevelopmental outcomes of offspring exposed to COVID-19 vaccination in utero are lacking. Objective: To determine whether in utero exposure to maternal COVID-19 vaccination was associated with differences in scores on the Ages and Stages Questionnaire, third edition (ASQ-3), at 12 and 18 months of age. Design, Setting, and Participants: This prospective cohort study, Assessing the Safety of Pregnancy During the Coronavirus Pandemic (ASPIRE), enrolled pregnant participants from May 2020 to August 2021; follow-up of children from these pregnancies is ongoing. Participants, which included pregnant individuals and their offspring from all 50 states, self-enrolled online. Study activities were performed remotely. Exposure: In utero exposure of the fetus to maternal COVID-19 vaccination during pregnancy was compared with those unexposed. Main Outcomes and Measures: Neurodevelopmental scores on validated ASQ-3, completed by birth mothers at 12 and 18 months. A score below the established cutoff in any of 5 subdomains (communication, gross motor, fine motor, problem solving, social skills) constituted an abnormal screen for developmental delay. Results: A total of 2487 pregnant individuals (mean [SD] age, 33.3 [4.2] years) enrolled at less than 10 weeks' gestation and completed research activities, yielding a total of 2261 and 1940 infants aged 12 and 18 months, respectively, with neurodevelopmental assessments. In crude analyses, 471 of 1541 exposed infants (30.6%) screened abnormally for developmental delay at 12 months vs 203 of 720 unexposed infants (28.2%; χ2 = 1.32; P = .25); the corresponding prevalences at 18 months were 262 of 1301 (20.1%) vs 148 of 639 (23.2%), respectively (χ2 = 2.35; P = .13). In multivariable mixed-effects logistic regression models adjusting for maternal age, race, ethnicity, education, income, maternal depression, and anxiety, no difference in risk for abnormal ASQ-3 screens was observed at either time point (12 months: adjusted risk ratio [aRR], 1.14; 95% CI, 0.97-1.33; 18 months: aRR, 0.88; 95% CI, 0.72-1.07). Further adjustment for preterm birth and infant sex did not affect results (12 months: aRR, 1.16; 95% CI, 0.98-1.36; 18 months: aRR, 0.87; 95% CI, 0.71-1.07). Conclusions and Relevance: Results of this cohort study suggest that COVID-19 vaccination was safe during pregnancy from the perspective of infant neurodevelopment to 18 months of age. Additional longer-term research should be conducted to corroborate these findings and buttress clinical guidance with a strong evidence base.

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma.

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.

Altered Urine Microbiome in Male Children and Adolescents with Attention-Deficit Hyperactivity Disorder.

While interest in developing the human microbiome as a biomarker for attention-deficit hyperactivity disorder (ADHD) is increasing, there has been limited exploration in utilizing urine samples. In this study, we analysed urine microbiome profiles by extracting 16S ribosomal DNA from purified bacteria-derived extracellular membrane vesicles obtained from urine samples. Sequencing libraries were constructed by amplifying V3-V4 hypervariable regions sequenced using Illumina MiSeq. Profiles of male Korean children and adolescents with ADHD (n = 33) were compared with healthy sex-matched controls (n = 39). Statistically controlling for age, we found decreased alpha diversity in the urine bacteria of the ADHD group, as evidenced by reduced Shannon and Simpson indices (p < 0.05), and significant differences in beta diversity between the two groups (p < 0.001). The phyla Firmicutes and Actinobacteriota, as well as the genera Ralstonia and Afipia, were relatively more abundant in the ADHD group. The phylum Proteobacteria and the genera Corynebacterium and Peptoniphilus were more abundant in the control group. Notably, the genus Afipia exhibited significant correlations with the Child Behavior Checklist Attention Problems score and DSM-oriented ADHD subscale. This study is the first to propose the urine microbiome as a potential biomarker for pediatric ADHD.

Hybrid Lateral Closed-Wedge High Tibial Osteotomy Showed Similar Accuracy in Angular Correction and Reduction of Posterior Tibial Slope Compared to Opening-Wedge High Tibial Osteotomy: A Correction Angle Matched Cohort Study.

BACKGROUND: We aimed to compare the accuracy of applied correction angle between hybrid lateral closed wedge high tibial osteotomy (hybrid HTO) and medial open wedge high tibial osteotomy (OWHTO), and verify previous reports on hybrid HTO by matching correction angle between groups. Change in various radiological parameters including union rate were also compared. METHODS: A total of 50 OWHTO patients were selected for 2:1 propensity matching with 25 hybrid HTO patients. Rate of correction error was calculated by dividing the difference between the change in medial proximal tibial angle and preoperatively planned correction angle (PRD) by planned correction angle. Accuracy of angular correction was assessed using PRD and correction error rates. Hip-knee-ankle axis, mechanical lateral distal femoral angle, medial proximal tibial angle, joint line convergence angle, and length of the entire lower limb and tibia were measured. The Caton-Deschamps index (CDI) was used to assess change in patellar height. Serial postoperative radiographic analysis was performed to assess the union rate. RESULTS: The discrepancy between planned correction angle and real correction angle was 0.8 ± 2.3° in hybrid HTO and 1.1 ± 3.4° in OWHTO (P > .05), and the rate of error in osteotomy was similar between the groups approximately 6%. Postoperatively, posterior tibial slope (PTS) (P < .001), tibia length, and CDI (P < .001) were significantly different between groups. The amount of change in PTS (P < .001), tibia length in hybrid HTO (P < .001), and CDI (P < .001) were significantly different between groups. Union rate of osteotomy site was significantly faster in hybrid HTO than in OWHTO (P < .001). CONCLUSION: Hybrid HTO showed similar accuracy in angular correction compared to correction angle-matched OWHTO. Reduction in PTS, tibial shortening, maintained patellar height relative to the proximal tibia, and faster osteotomy site union were also confirmed in hybrid HTO.

Advancing ecological validity and clinical utility in virtual reality-based continuous performance test: exploring the effects of task difficulty and environmental distractors.

Introduction: Researchers have highlighted concerns regarding the limited diagnostic utility and ecological validity of the Continuous Performance Test (CPT). Recent advancements in VR-based CPTs have attempted to address these concerns by simulating real-life scenarios and enhancing attention deficit hyperactivity disorder (ADHD) diagnosis; however, certain areas require improvement for obtaining reliable data from both healthy individuals and those with ADHD. To tackle these issues, we developed an enhanced VR-based CPT program featuring four distinct difficulty levels, advancing toward home-based assessment. Method: Our feasibility study involved subjects without ADHD to establish a normative profile for VR-based CPT before extending it to ADHD assessment. Our sample included 20 Korean adults. They received a VR device with the VR-based CPT program installed and were asked to perform 1-2 blocks per day at home. Participants were instructed to complete 12 blocks over the subsequent 2 weeks. Psychological assessments and electroencephalograms (EEGs) were administered before and after the program. Post-study usability measures were also collected. Result: Higher commission errors were notably evident in the "very high" difficulty level which featured complex stimuli and increased distraction. A notable correlation emerged between the overall distraction level and CPT accuracy, along with a significant link between intensity scores and commission errors. No significant differences were found in psychological assessment and there were no significant changes in the Theta-Beta Ratio (TBR) index before and after the program. The usability of our program was fair. Discussion: The study reveals that the newly designed VR-CPT program, simulating diverse real-life environments and offering varying task difficulty levels, proved acceptable and feasible. The key point of our study was that the adjustment and segmentation of difficulty levels in the VR-based CPT were achieved, and that this effort was validated by examining the impact of different levels of difficulty on CPT measures. Implementing this experimental setup in a home-based environment increased ecological validity, as well as clinical utility. Limitations and suggested directions for further investigation are described in detail.

Evaluating attention deficit hyperactivity disorder symptoms in children and adolescents through tracked head movements in a virtual reality classroom: The effect of social cues with different sensory modalities.

Background: Attention deficit hyperactivity disorder (ADHD) is clinically diagnosed; however, quantitative analysis to statistically analyze the symptom severity of children with ADHD via the measurement of head movement is still in progress. Studies focusing on the cues that may influence the attention of children with ADHD in classroom settings, where children spend a considerable amount of time, are relatively scarce. Virtual reality allows real-life simulation of classroom environments and thus provides an opportunity to test a range of theories in a naturalistic and controlled manner. The objective of this study was to investigate the correlation between participants' head movements and their reports of inattention and hyperactivity, and to investigate how their head movements are affected by different social cues of different sensory modalities. Methods: Thirty-seven children and adolescents with (n = 20) and without (n = 17) ADHD were recruited for this study. All participants were assessed for diagnoses, clinical symptoms, and self-reported symptoms. A virtual reality-continuous performance test (VR-CPT) was conducted under four conditions: (1) control, (2) no-cue, (3) visual cue, and (4) visual/audio cue. A quantitativecomparison of the participants' head movements was conducted in three dimensions (pitch [head nods], yaw [head turns], and roll [lateral head inclinations]) using a head-mounted display (HMD) in a VR classroom environment. Task-irrelevant head movements were analyzed separately, considering the dimension of movement needed to perform the VR-CPT. Results: The magnitude of head movement, especially task-irrelevant head movement, significantly correlated with the current standard of clinical assessment in the ADHD group. Regarding the four conditions, head movement showed changes according to the complexity of social cues in both the ADHD and healthy control (HC) groups. Conclusion: Children and adolescents with ADHD showed decreasing task-irrelevant movements in the presence of social stimuli toward the intended orientation. As a proof-of-concept study, this study preliminarily identifies the potential of VR as a tool to understand and investigate the classroom behavior of children with ADHD in a controlled, systematic manner.

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives.

Mitochondrial diseases are a group of rare, heterogeneous diseases caused by gene mutations in both nuclear and mitochondrial genomes that result in defects in mitochondrial function. They are responsible for significant morbidity and mortality as they affect multiple organ systems and particularly those with high energy-utilizing tissues, such as the nervous system, skeletal muscle, and cardiac muscle. Virtually no effective treatments exist for these patients, despite the urgent need. As the majority of these conditions are monogenic and caused by mutations in nuclear genes, gene replacement is a highly attractive therapeutic strategy. Adeno-associated virus (AAV) is a well-characterized gene replacement vector, and its safety profile and ability to transduce quiescent cells nominates it as a potential gene therapy vehicle for several mitochondrial diseases. Indeed, AAV vector-based gene replacement is currently being explored in clinical trials for one mitochondrial disease (Leber hereditary optic neuropathy) and preclinical studies have been published investigating this strategy in other mitochondrial diseases. This review summarizes the preclinical findings of AAV vector-based gene replacement therapy for mitochondrial diseases including Leigh syndrome, Barth syndrome, ethylmalonic encephalopathy, and others.

MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.

Mechanisms of targeted therapy resistance in a pediatric glioma driven by ETV6-NTRK3 fusion.

Chromosomal rearrangements of the NTRK genes generate kinase fusions that are targetable oncogenic drivers in diverse adult and pediatric malignancies. Despite robust clinical response to targeted NTRK inhibition, the emergence of therapeutic resistance poses a formidable clinical challenge. Here we report the characterization of an ETV6-NTRK3 fusion-driven pediatric glioma that progressed through NTRK-targeted treatments with entrectinib and selitrectinib. Genetic analysis of multifocal recurrent/resistant lesions identified a previously uncharacterized NTRK3 p.G623A and a known p.G623E resistance mutation, in addition to other alterations of potential pathogenic impact. Functional studies using heterologous reconstitution model systems and patient-derived tumor cell lines establish that NTRK3G623A and NTRK3G623E mutated kinases exhibit reduced sensitivity to entrectinib and selitrectinib, as well as other NTRK inhibitors tested herein. In summary, this genetic analysis of multifocal recurrent/resistant glioma driven by ETV6-NTRK3 fusion captured a cross section of resistance-associated alterations that, based on in vitro analysis, likely contributed to resistance to targeted therapy and disease progression.

Hammock plating for comminuted inferior sleeve avulsion fractures of the patella: A surgical technique and clinical results.

Comminuted inferior sleeve avulsion fractures of the patella is a surgical challenge owing to the lack of directly purchasable bone fragments and the vulnerable patellar tendon below the displaced lip fragments. Despite the reports of various techniques to treat this fracture, still there is need for a new surgical technique to improve the reduction construct. The purpose of this article is to introduce Hammock plating, which is a surgical technique for comminuted inferior sleeve avulsion patella fractures that utilizes synthetic suture and a low-profile mini plate. The reduction construct provides an indirect reduction of the inferior sleeve fragments to form a hammock-like construct that embraces and lifts the lip fragments upward altogether that enables a firm bone-to-bone union. The advantages also include relatively simple and easy procedure with less injury to the fractured bone fragments and patellar tendon.

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma.

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma.

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-ß receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.

Measure Twice: Promise of Liquid Biopsy in Pediatric High-Grade Gliomas.

PURPOSE: To review and critique the current state of liquid biopsy in pHGG. MATERIALS AND METHODS: Published literature was reviewed for articles related to liquid biopsy in pediatric glioma and adult glioma with a focus on high-grade gliomas. RESULTS: This review discusses the current state of liquid biomarkers of pHGG and their potential applications for liquid biopsy development. CONCLUSIONS: While nascent, the progress toward identifying circulating analytes of pHGG primes the field of neuro-oncoogy for liquid biopsy development.

Correction: Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide.

The original version of this Article contained an error in the spelling of the author David Solow-Cordero, which was incorrectly given as David Solow-Codero. This has now been corrected in both the PDF and HTML versions of the Article.

Corrigendum to "Anterolateral Approach in the Treatment of Femoroacetabular Impingement of the Hip".

[This corrects the article on p. 337 in vol. 11, PMID: 31475056.].

Anterolateral Approach in the Treatment of Femoroacetabular Impingement of the Hip.

Background: Ganz surgical hip dislocation via a posterior (Kocher-Langenbeck) approach is a popular procedure in the management of femoroacetabular impingement (FAI). We report the results of surgery performed through an anterolateral (Watson-Jones) approach in the management of anterolateral FAI. Methods: Twenty-one hips in 20 patients (mean age at the time of operation, 17.3 years) were treated surgically using an anterolateral approach: 12 hips with Legg-Calvé-Perthes disease, three septic hips, three hips with avascular necrosis (combined with slipped capital femoral epiphysis [SCFE], femoral neck fracture, and developmental dislocation of the hip), two hips with epiphyseal dysplasia, and one hip with SCFE. All patients had anterolateral FAI. Surgical hip dislocation was performed in four hips with trochanteric osteotomy. Combined osteotomies were for neck lengthening in 11 hips, varus or valgus osteotomy in the proximal femur in four hips, and pelvic osteotomy in four hips. Clinical results were evaluated using a modified Harris hip score (mHHS). Results: Range of hip flexion and abduction showed statistically significant improvement after surgery; however, the improvement in mean mHHS was not statistically significant. Conclusions: An anterolateral approach can be used as an alternative to a posterior approach in the management of anterolateral FAI with or without hip dislocation while safely preserving the blood supply to the femoral head and allowing simultaneous procedures in the proximal femur.

Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Since surviving patients experience severe neurocognitive disabilities, better and more effective treatments are needed to enhance their quality of life. Casein kinase 2 (CK2) is known to regulate cell growth and survival in multiple cancers; however, the role of CK2 in MB is currently being studied. In this study, we verified the importance of CK2 in MB tumorigenesis and discovered that inhibition of CK2 using the small molecule inhibitor, CX-4945, can sensitize MB cells to a well-known and tolerated chemotherapeutic, temozolomide (TMZ). To study the role of CK2 in MB we modulated CK2 expression in multiple MB cells. Exogenous expression of CK2 enhanced cell growth and tumor growth in mice, while depletion or inhibition of CK2 expression decreased MB tumorigenesis. Treatment with CX-4945 reduced MB growth and increased apoptosis. We conducted a high-throughput screen where 4000 small molecule compounds were analyzed to identify compounds that increased the anti-tumorigenic properties of CX-4945. TMZ was found to work synergistically with CX-4945 to decrease cell survival and increase apoptosis in MB cells. O-6-methylguanine-DNA methyltransferase (MGMT) activity is directly correlated to TMZ sensitivity. We found that loss of CK2 activity reduced ß-catenin expression, a known MGMT regulator, which in turn led to a decrease in MGMT expression and an increased sensitivity to TMZ. Our findings show that CK2 is important for MB maintenance and that treatment with CX-4945 can sensitize MB cells to TMZ treatment.