Tibial tubercle osteotomy (TTO): A review of impactful papers in the literature.

Background: Tibial tubercle osteotomy (TTO) is a procedure that can be used as an alternative to total knee arthroplasty (TKA) or to address patellar instability in patients experiencing dislocation events. The purpose of this paper is to systematically evaluate the most cited articles pertaining to TTO through bibliometric analysis. Methods: A search using the Web of Science database with keywords pertaining to TTO was conducted in April 2024. Articles with the most citations that met all inclusion criteria were analyzed to determine information such as level of evidence (LoE), article topic, journal of publication, year published, country of origin, and institution of origin. Results: The average number of citations was 79 (range of 42-334). The decade with the most publications was from 2010 to 2019 (n = 26; 52%). Clinical Orthopaedics and Related Research was the journal with the largest number of published articles (n = 9, 18%). The United States (US) (n = 25; 50%) and France (n = 4; 8%) were the two countries with the most publications. Mayo Clinic (n = 3, 6 %), Ohio State University (n = 3, 6%), and Rush University (n = 3, 6%) were the institutions contributing the most articles. The LoE most reported was level 4 (n = 22; 44%). Topics were primarily related to clinical outcomes (n = 38; 76%). Conclusion: This analysis revealed that most articles were related to clinical outcomes and have been published since 2000. By analyzing the characteristics of the most cited articles, an understanding of current research and identification of areas for further exploration can be determined for TTO. Study Design: Cross-sectional study. Level of Evidence: III.

Time to Publication in Medical Education Journals: An Analysis of Publication Timelines During COVID-19 (2019-2022).

Introduction: COVID-19 changed scholarly publishing. Yet, its impact on medical education publishing is unstudied. Because journal articles and their corresponding publication timelines can influence academic success, the field needs updated publication timelines to set evidence-based expectations for academic productivity. This study attempts to answer the following research questions: did publication timelines significantly change around the time of COVID-19 and, if so, how? Methods: We conducted a bibliometric study; our sample included articles published between January 2018, and December 2022, that appeared in the Medical Education Journals List-24 (MEJ-24). We clustered articles into three time-based groups (pre-COVID, COVID-overlap, and COVID-endemic), and two subject-based groups (about COVID-19 and not about COVID-19). We downloaded each article's metadata from the National Library of Medicine and analyzed data using descriptive statistics, analysis of variance, and post-hoc tests to compare mean time differences across groups. Results: Overall, time to publish averaged 300.8 days (SD = 200.8). One-way between-groups ANOVA showed significant differences between the three time-based groups F (2, 7473) = 2150.7, p < .001. The post-hoc comparisons indicated that COVID-overlap articles took significantly longer (n = 1470, M= 539; SD = 210.6) as compared to pre-COVID (n = 1281; M = 302; SD = 172.5) and COVID-endemic articles (n = 4725; M = 226; SD = 136.5). Notably, COVID-endemic articles were published in significantly less time than pre-pandemic articles, p < .001. Discussion: Longer publication time was most pronounced for COVID-overlap articles. Publication timelines for COVID-endemic articles have shortened. Future research should explore how the shift in publication timelines has shaped medical education scholarship.

The Role of Bone Grafting vs. Bone Cement in the Treatment of Giant Cell Tumor of Bone: A Systematic Review and Meta-Analysis on the Risk of Recurrence in 1,454 Patients.

BACKGROUND: Giant cell tumor of bone (GCTB) presents a challenge in management due to its invasive nature and propensity for local recurrence. While either bone grafting (BG) or bone cement (BC) can be utilized to fill defects after intralesional curettage, the optimal treatment remains contested. The purpose of this study was to examine the impact of defect filling with BC compared with BG on recurrence rates in patients with GCTB following intralesional curettage. METHODS: A random-effects model binary outcome meta-analysis was performed utilizing recurrence rate for the BC and BG groups to evaluate the risk ratio (p < 0.05 considered significant). There were 1,454 patients included. RESULTS: Intralesional curettage with BG had a recurrence risk ratio of 1.68 (95% confidence interval [CI], 1.22-2.31, p = 0.001) when compared with BC. The overall rate of recurrence for GCTB after intralesional curettage with BC was 20.05% vs. 29.74% with BG (95% CI, 0.17-0.23 vs. 0.26-0.33, p < 0.001). CONCLUSION: Intralesional curettage with BC for the treatment of GCTB demonstrated lower recurrence rates than intralesional curettage with BG. However, the rates of recurrence remain substantial for both groups, necessitating careful consideration of the benefits and potential pitfalls associated with BC vs. BG when considering salvage options after recurrences. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

How Often Does Technology Fail in Robotic-Assisted Arthroplasty? A Comprehensive Analysis of a United States Food and Drug Administration Database.

BACKGROUND: Robotic-assisted arthroplasty is a growing alternative to conventionally instrumented arthroplasty; however, the incidence of adverse events (AEs) associated with this technology reported to the United States Food and Drug Administration (FDA) remains poorly quantified. The objective of this study was to categorize AEs associated with robotic-assisted arthroplasty and calculate their annual incidence as reported to the FDA. METHODS: The FDA's Manufacturer and User Facility Device Experience database was queried for AEs from January 1, 2017 to December 31, 2021 associated with the most prevalent robotic-arthroplasty system. The AEs were calculated using national surgical numbers provided by the manufacturer and grouped by total hip arthroplasty (THA), total knee arthroplasty (TKA), or partial knee arthroplasty (PKA). RESULTS: There were 1,710 unique AEs across the study period, with 436 THA, 1,005 TKA, and 269 PKA, representing incidence rates of 0.37, 0.30, and 0.40%, respectively. All procedures demonstrated lower rates of AEs in the final year of the study, compared to the first year. Most complications were related to mechanical problems, not software issues. Surgical delays due to AEs occurred in THA (0.13% cumulative incidence, 14.0 minutes average delay), TKA (0.13%, 20.6 minutes), and PKA (0.22%, 19.4 minutes). No cases were canceled due to AEs in THA, though a few TKA (0.003%) and PKA (0.02%) cases were not performed. Patient injuries occurred in 0.05, 0.05, and 0.08% of THA, TKA, and PKA, respectively. Surgical reintervention was necessary in 0.004, 0.003, and 0.01% of THA, TKA, and PKA, respectively. CONCLUSIONS: Robotic-assisted arthroplasty has a small number and relatively low rate of AEs reported to the FDA as measured through the Manufacturer and User Facility Device Experience database, with rates steadily decreasing over the study period. Patient injury, case delay, and reoperation represent only a small fraction of the already rare AEs in the database.

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms.

Acyl-CoA binding domain-containing proteins (ACBDs) perform diverse but often uncharacterised functions linked to cellular lipid metabolism. Human ACBD4 and ACBD5 are closely related peroxisomal membrane proteins, involved in tethering of peroxisomes to the ER and capturing fatty acids for peroxisomal ß-oxidation. ACBD5 deficiency causes neurological abnormalities including ataxia and white matter disease. Peroxisome-ER contacts depend on an ACBD4/5-FFAT motif, which interacts with ER-resident VAP proteins. As ACBD4/5-like proteins are present in most fungi and all animals, we combined phylogenetic analyses with experimental approaches to improve understanding of their evolution and functions. Notably, all vertebrates exhibit gene sequences for both ACBD4 and ACBD5, while invertebrates and fungi possess only a single ACBD4/5-like protein. Our analyses revealed alterations in domain structure and FFAT sequences, which help understanding functional diversification of ACBD4/5-like proteins. We show that the Drosophila melanogaster ACBD4/5-like protein possesses a functional FFAT motif to tether peroxisomes to the ER via Dm_Vap33. Depletion of Dm_Acbd4/5 caused peroxisome redistribution in wing neurons and reduced life expectancy. In contrast, the ACBD4/5-like protein of the filamentous fungus Ustilago maydis lacks a FFAT motif and does not interact with Um_Vap33. Loss of Um_Acbd4/5 resulted in an accumulation of peroxisomes and early endosomes at the hyphal tip. Moreover, lipid droplet numbers increased, and mitochondrial membrane potential declined, implying altered lipid homeostasis. Our findings reveal differences between tethering and metabolic functions of ACBD4/5-like proteins across evolution, improving our understanding of ACBD4/5 function in health and disease. The need for a unifying nomenclature for ACBD proteins is discussed.

Functional Electrical Stimulation and Brain-Machine Interfaces for Simultaneous Control of Wrist and Finger Flexion.

Brain-machine interface (BMI) controlled functional electrical stimulation (FES) is a promising treatment to restore hand movements to people with cervical spinal cord injury. Recent intracortical BMIs have shown unprecedented successes in decoding user intentions, however the hand movements restored by FES have largely been limited to predetermined grasps. Restoring dexterous hand movements will require continuous control of many biomechanically linked degrees-of-freedom in the hand, such as wrist and finger flexion, that would form the basis of those movements. Here we investigate the ability to restore simultaneous wrist and finger flexion, which would enable grasping with a controlled hand posture and assist in manipulating objects once grasped. We demonstrate that intramuscular FES can enable monkeys with temporarily paralyzed hands to move their fingers and wrist across a functional range of motion, spanning an average 88.6 degrees at the metacarpophalangeal joint flexion and 71.3 degrees of wrist flexion, and intramuscular FES can control both joints simultaneously in a real-time task. Additionally, we demonstrate a monkey using an intracortical BMI to control the wrist and finger flexion in a virtual hand, both before and after the hand is temporarily paralyzed, even achieving success rates and acquisition times equivalent to able-bodied control with BMI control after temporary paralysis in two sessions. Together, this outlines a method using an artificial brain-to-body interface that could restore continuous wrist and finger movements after spinal cord injury.

Effects of voluntary exercise and electrical muscle stimulation on reaction time in the Go/No-Go task.

INTRODUCTION: Acute exercise improves cognitive performance. However, it remains unclear what triggers cognitive improvement. Electrical muscle stimulation (EMS) facilitates the examination of physiological changes derived from peripheral muscle contraction during exercise. Thus, we compared the effects of EMS and voluntary exercise at low- or moderate-intensity on reaction time (RT) in a cognitive task to understand the contribution of central and peripheral physiological factors to RT improvement. METHODS: Twenty-four young, healthy male participants performed a Go/No-Go task before and after EMS/exercise. In the EMS condition, EMS was applied to the lower limb muscles. In the low-intensity exercise condition, the participants cycled an ergometer while maintaining their heart rate (HR) at the similar level during EMS. In the moderate-intensity exercise condition, exercise intensity corresponded to ratings of perceived exertion of 13/20. The natural log-transformed root mean square of successive differences between adjacent inter-beat (R-R) intervals (LnRMSSD), which predominantly reflects parasympathetic HR modulation, was calculated before and during EMS/exercise. RESULTS: RT improved following moderate-intensity exercise (p = 0.002, Cohen' d = 0.694), but not following EMS (p = 0.107, Cohen' d = 0.342) and low-intensity exercise (p = 0.076, Cohen' d = 0.380). Repeated measures correlation analysis revealed that RT was correlated with LnRMSSD (Rrm(23) = 0.599, p = 0.002) in the moderate-intensity exercise condition. CONCLUSION: These findings suggest that the amount of central neural activity and exercise pressor reflex may be crucial for RT improvement. RT improvement following moderate-intensity exercise may, at least partly, be associated with enhanced sympathetic nervous system activity.

Evaluation of Porcine-Derived Collagen Membranes for Soft Tissue Augmentation in the Oral Cavity: An In Vivo Study.

The use of porcine-derived collagen membranes (PDCM) to improve intraoral soft tissue rehabilitation remains under investigation. Different degrees of crosslinking have yielded differences in resorption time and inflammation surrounding collagen membranes. The aim of this study was to evaluate the in vivo performance of bilayered PDCMs with varying degrees of crosslinking for the regeneration of oral soft tissue defects. Bilateral split-thickness oral mucosa defects were created in mandibles of beagles (n=17) and assigned to one of the following: bilayer PDCM (high crosslinking porcine dermis in sheet form-H-xlink) and (low crosslinking porcine dermis in sheet form-L-xlink), bilayer PDCM (non-crosslinked predicate collagen membrane in spongy form-Ctrl), or negative control (Sham) and compared with positive control (unoperated). Animals were euthanized after 4-, 8-, or 12-weeks of healing to evaluate soft tissue regeneration and remodeling through histomorphometric analyses. H-xlink membranes presented delayed healing with a poorly developed epithelial layer (analogous to the sham group) across time points. Relative to Ctrl at 8 and 12 weeks, defects treated with H-xlink presented no difference in semiquantitative scores ( P > 0.05), while L-xlink exhibited greater healing ( P = 0.042, P = 0.043, at 8 and 12 weeks, respectively). Relative to positive control, L-xlink exhibited similar healing at 8 weeks and greater healing at 12 weeks ( P = 0.037) with a well-developed epithelial layer. Overall, groups treated with L-xlink presented with greater healing relative to the positive control after 12 weeks of healing and may serve as an alternative to autologous grafts for intraoral soft tissue regeneration.

E-learning Interventions for Quality Improvement Continuing Medical Education-A Scoping Review.

INTRODUCTION: Improving health care quality and patient safety are top priorities for the medical field. Robust continuing medical education (CME) programs represent major interventions to effectively teach quality improvement (QI) principles to practicing physicians. In particular, eLearning, a term describing online and distance learning interventions using digital tools, provides a means for CME interventions to reach broader audiences. Although there has been a focus on CME addressing QI, no knowledge synthesis has focused specifically on eLearning interventions. The purpose of this review was to examine the current landscape of eLearning interventions in QI-focused CME. METHODS: We conducted a scoping review using the framework developed by Arksey and O'Malley as revised by Levac. We searched five databases and identified 2467 prospective publications, which two authors independently screened for inclusion. From each included article, two authors independently extracted data on the instructional modalities and QI tools used and met regularly to achieve consensus. RESULTS: Twenty-one studies were included. Most studies used blended instruction (n = 12) rather than solely eLearning interventions. Salient findings included the importance of coaching from QI experts and institutional support for planning and implementing eLearning interventions. Lack of protected time and resources for participants were identified as barriers to participation in CME activities, with small practices being disproportionately affected. DISCUSSION: Partnerships between CME developers and sponsoring organizations are vital in creating sustainable eLearning interventions for QI-focused CME. Remote coaching can be an effective strategy to provide ongoing support to geographically separated learners.

Deconstructing Intratumoral Heterogeneity through Multiomic and Multiscale Analysis of Serial Sections.

Tumors may contain billions of cells, including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that are consistently expressed by astrocytoma truncal clones, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors.

Combined effects of electrical muscle stimulation and cycling exercise on cognitive performance.

The purpose of this study was to investigate whether a combination of electrical muscle stimulation (EMS) and cycling exercise is beneficial for improving cognitive performance. Eighteen participants (7 females and 11 males) performed a Go/No-Go task before and 2 min after i) cycling exercise (EX), ii) a combination of EMS and cycling (EMS + EX) and iii) a control (rest) intervention in a randomized controlled crossover design. In the EX intervention, the participants cycled an ergometer for 20 min with their heart rate maintained at ∼120 beats·min-1. In the EMS + EX intervention, the participants cycled an ergometer simultaneously with EMS for 20 min, with heart rate maintained at ∼120 beats·min-1. In the Control intervention, the participants remained at rest while seated on the ergometer. Cognitive performance was assessed by reaction time (RT) and accuracy. There was a significant interaction between intervention and time (p = 0.007). RT was reduced in the EX intervention (p = 0.054, matched rank biserial correlation coefficient = 0.520). In the EMS + EX intervention, RT was not altered (p = 0.243, Cohen's d = 0.285) despite no differences in heart rate between the EX and EMS + EX interventions (p = 0.551). RT was increased in the Control intervention (p = 0.038, Cohen's d = -0.529). These results indicate that combining EMS and cycling does not alter cognitive performance despite elevated heart rate, equivalent to a moderate intensity. The present findings suggest that brain activity during EMS with cycling exercise may be insufficient to improve cognitive performance when compared to exercise alone.

Human dopaminergic system in the exercise-cognition link.

While the dopaminergic system is important for cognitive processes, it is also sensitive to the influence of physical activity (PA). We summarize current evidence on whether PA-related changes in the human dopaminergic system are associated with alterations in cognitive performance, discuss recent advances, and highlight challenges and opportunities for future research.

Describing the Landscape of Medical Education Preprints on MedRxiv: Current Trends and Future Recommendations.

PURPOSE: A preprint is a version of a research manuscript posted to a preprint server prior to peer review. Preprints enable authors to quickly and openly share research, afford opportunities for expedient feedback, and enable immediate listing of research on grant and promotion applications. In medical education, most journals welcome preprints, which suggests that preprints play a role in the field's discourse. Yet, little is known about medical education preprints, including author characteristics, preprint use, and ultimate publication status. This study provides an overview of preprints in medical education to better understand their role in the field's discourse. METHOD: The authors queried medRxiv, a preprint repository, to identify preprints categorized as "medical education" and downloaded related metadata. CrossRef was queried to gather information on preprints later published in journals. Data were analyzed using descriptive statistics. RESULTS: Between 2019 and 2022, 204 preprints were classified in medRxiv as "medical education," with most deposited in 2021 (n = 76; 37.3%). On average, preprint full-texts were downloaded 1,875.2 times, and all were promoted on social media. Preprints were authored, on average, by 5.9 authors. Corresponding authors were based in 41 countries, with 45.6% in the United States, the United Kingdom, and Canada. Almost half (n = 101; 49.5%) became published articles in predominantly peer-reviewed journals. Preprints appeared in 65 peer-reviewed journals, with BMC Medical Education (n = 9; 8.9%) most represented. CONCLUSIONS: Medical education research is being deposited as preprints, which are promoted, heavily accessed, and subsequently published in peer-reviewed journals, including medical education journals. Considering the benefits of preprints and the slowness of medical education publishing, it is likely that preprint depositing will increase and preprints will be integrated into the field's discourse. The authors propose next steps to facilitate responsible and effective creation and use of preprints.

Quantitative Assessment of Preanalytic Variables on Clinical Evaluation of PI3/AKT/mTOR Signaling Activity in Diffuse Glioma.

Biomarker-driven therapeutic clinical trials require the implementation of standardized, evidence-based practices for sample collection. In diffuse glioma, phosphatidylinositol 3 (PI3)-kinase/AKT/mTOR (PI3/AKT/mTOR) signaling is an attractive therapeutic target for which window-of-opportunity clinical trials could facilitate the identification of promising new agents. Yet, the relevant preanalytic variables and optimal tumor sampling methods necessary to measure pathway activity are unknown. To address this, we used a murine model for isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) and human tumor tissue, including IDH-wildtype GBM and IDH-mutant diffuse glioma. First, we determined the impact of delayed time-to-formalin fixation, or cold ischemia time (CIT), on the quantitative assessment of cellular expression of 6 phosphoproteins that are readouts of PI3K/AK/mTOR activity (phosphorylated-proline-rich Akt substrate of 40 kDa (p-PRAS40, T246), -mechanistic target of rapamycin (p-mTOR; S2448); -AKT (p-AKT, S473); -ribosomal protein S6 (p-RPS6, S240/244 and S235/236), and -eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1, T37/46). With CITs ≥ 2 hours, typical of routine clinical handling, all had reduced or altered expression with p-RPS6 (S240/244) exhibiting relatively greater stability. A similar pattern was observed using patient tumor samples from the operating room with p-4EBP1 more sensitive to delayed fixation than p-RPS6 (S240/244). Many clinical trials utilize unstained slides for biomarker evaluation. Thus, we evaluated the impact of slide storage conditions on the detection of p-RPS6 (S240/244), p-4EBP1, and p-AKT. After 5 months, storage at -80°C was required to preserve the expression of p-4EBP1 and p-AKT, whereas p-RPS6 (240/244) expression was not stable regardless of storage temperature. Biomarker heterogeneity impacts optimal tumor sampling. Quantification of p-RPS6 (240/244) expression in multiple regionally distinct human tumor samples from 8 patients revealed significant intratumoral heterogeneity. Thus, the accurate assessment of PI3K/AKT/mTOR signaling in diffuse glioma must overcome intratumoral heterogeneity and multiple preanalytic factors, including time-to-formalin fixation, slide storage conditions, and phosphoprotein of interest.

Physician educators' perceptions of experiences contributing to teaching.

INTRODUCTION: Physician educators are essential in training the next generation of physicians. However, physician educators' perspectives about what experiences they find beneficial to their teaching and the prevalence of these experiences remain unknown. Guided by social cognitive career theory (SCCT) and communities of practice (CoP), we explored what experiences physician educators perceive as beneficial in preparing them to teach. METHODS: In 2019, the Uniformed Services University School of Medicine in the United States surveyed its physician alumni to understand their education experiences during medical school, their current career path and what has contributed to their teaching role. Content analysis was applied to extract themes across the text response. Chi-square analysis was applied to examine if perceived contributing factors vary based on physician educators' gender, specialty and academic ranks. RESULTS: The five most prevalent contributing factors participants (n = 781) identified are (1) experiences gained during residency and fellowship (29.8%), (2) teaching as faculty member (28.9%) and (3) class experiences and peer interaction during medical school (26%). We organised three themes that reflected major avenues of how physician educators acquire teaching skills: reflection about quality teaching, journey as learners and learning by doing. Gender and clinical specialty were differentially associated with contributing factors such as faculty development and meta-reflection. CONCLUSION: The results are in line with theories of SCCT and CoP, in which we identified self-directed learning and regulation in shaping physician educators' teaching. The findings also revealed gaps and potential contexts for more formalised teaching practices to develop physician educators.

A rhPDGF-BB/bovine type I collagen/ß-TCP mixture for the treatment of critically sized non-union tibial defects: An in vivo study in rabbits.

Non-union during healing of bone fractures affects up to ~5% of patients worldwide. Given the success of recombinant human platelet-derived growth factor-B chain homodimer (rhPDGF-BB) in promoting angiogenesis and bone fusion in the hindfoot and ankle, rhPDGF-BB combined with bovine type I collagen/ß-TCP matrix (AIBG) could serve as a viable alternative to autografts in the treatment of non-unions. Defects (~2 mm gaps) were surgically induced in tibiae of skeletally mature New Zealand white rabbits. Animals were allocated to one of four groups-(1) negative control (empty defect, healing for 8 weeks), (2 and 3) acute treatment with AIBG (healing for 4 or 8 weeks), and (4) chronic treatment with AIBG (injection 4 weeks post defect creation and then healing for 8 weeks). Bone formation was analyzed qualitatively and semi-quantitatively through histology. Samples were imaged using dual-energy X-ray absorptiometry and computed tomography for defect visualization and volumetric reconstruction, respectively. Delayed healing or non-healing was observed in the negative control group, whereas defects treated with AIBG in an acute setting yielded bone formation as early as 4 weeks with bone growth appearing discontinuous. At 8 weeks (acute setting), substantial remodeling was observed with higher degrees of bone organization characterized by appositional bone growth. The chronic healing, experimental, group yielded bone formation and remodeling, with no indication of non-union after treatment with AIBG. Furthermore, bone growth in the chronic healing group was accompanied by an increased presence of osteons, osteonal canals, and interstitial lamellae. Qualitatively and semiquantitatively, chronic application of AI facilitated complete bridging of the induced non-union defects, while untreated defects or defects treated acutely with AIBG demonstrated a lack of complete bridging at 8 weeks.

Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.

Bibliometric Networks for Researchers in Health Professions Education.

Bibliometric network analysis is an analytical approach that enables researchers to visualize the relationships between a set of research items (e.g., journal articles, books). There are 3 types of bibliometric network analyses, and multiple tools to conduct the analysis and visualize results (e.g., VOSviewer , 1Gephi2 ). For health professions educators, bibliometric network analysis is valuable for discovering the field's emerging trends, popular topics, and multidisciplinary relationships. 3,4.