bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMOD-23. LENTIVIRAL-INDUCED BRAIN GLIOMAS IN RAT MODEL
Authors: Zhang Michelle , Lakhina Yuliya , Yonk Marybeth , Poth Kelly , Neill Stewart , Zhang Zhaobin , Assed Hemza , Tora Muhibullah , Donsante Anthony , Federici Thais , Lei Kecheng , Boulis Nicholas 
Published: November 2024

Abstract
High-grade gliomas are the most common type of malignant intracranial tumor with dismal five-year prognostic outcomes despite developments in chemoradiotherapy and surgical intervention. Distinct oncogenes associated with tumorigenesis and progression have been identified, providing targets for potential therapeutic interventions and modeling efforts. In this study, we evaluated the efficacy of vectors targeting EGFR and PTEN, individually and in combination to produce high-grade brain gliomas. Four groups of rats underwent intracranial stereotaxic injection of lentiviral vector into the forceps minor of the corpus callosum. All animals were weighed and monitored for behavioral deficits three times per week for 90 days. Upon signs of clinical morbidity or at 90 days post-inoculation, tissues were harvested and analyzed using hematoxylin and eosin and immunohistochemical staining. Rats injected with the combination of the EGFR and the sh-PTEN vectors exhibited declines in weight, survival, and motor function compared to the control. The combination of the EGFR and sh-PTEN vectors was the only condition to induce tumorigenesis with histopathological confirmation of high-grade identity as confirmed by immunohistochemistry showing the most positivity for GFAP and SOX2 compared to the control. Significant increases in Ki-67 characterized combination tumors as highly proliferative. Increased oxidative stress and angiogenesis were supported by significant increases in 4HNE, SMA, and HIF-1α in the tumors compared to other treatment groups. Thus, the present model of high-grade rat brain glioma provides a potential model to assess pathogenic pathways and evaluate therapeutic strategies.
TMOD-25. UTILIZING PRIMARY MACROPHAGES AS AN IMPROVED SERUM-FREE IN VITRO MODEL OF TUMOR-ASSOCIATED MACROPHAGES IN GLIOBLASTOMA
Authors: Alrefai Hasan , Elkholy Amr , Lin Benjamin , Kumar Manoj , Schanel Taylor , Nassour-Caswell Lauren , Anderson Joshua , Hicks Patricia , Ahn Erin , Miller C Ryan , Willey Christopher 
Published: November 2024

Abstract

BACKGROUND
Tumor-associated macrophages (TAMs) account for up to 40% of tumor mass in glioblastoma and over 70% of the immune cells contained therein. TAMs influence glioblastoma (GBM) growth, invasion, and resistance to therapy. Unfortunately, in vitro macrophage models typically employ immortalized cell lines, such as THP-1, which require serum for their growth and maintenance, and are often stimulated with IL-4/13 to mimic TAM function in vitro. Unfortunately, THP-1-derived macrophages do not readily adopt the M2 state and may be poor TAM models.

METHODS
The buffy coat from peripheral blood was isolated from healthy donor blood and plated in RPMI 1640 supplemented with 10% human serum and 50ng/mL of M-CSF. 25 ng/mL of M-CSF was added on day 3. The macrophages were washed, lifted, and plated in serum-free X VIVO-15 supplemented with M-CSF. Afterwards macrophages were left in an M0 (resting) state, or polarized towards an M1(pro-inflammatory) by stimulating with LPS/IFNγ, M2 (anti-inflammatory) by polarizing with IL-4/13, or TAM state by co-culturing with GBM patient-derived xenolines. Macrophage polarization was characterized through cytokine arrays, invasion, angiogenesis, and phagocytosis assays, comparing them to M0, M1, and M2 macrophages.

RESULTS
M1-polarized THP-1 macrophages displayed an increase in M1-associated markers, such as CD80 and HLA-DR (p&lt;0.0001); however, M2-polarized THP-1 macrophages did not display an increase in the M2-associated surface marker, CD206 (p = 0.6167). Interestingly, M1-polarized peripheral blood mononuclear cell (PBMC)-derived macrophages displayed increases in the M1-associated markers, CD80 and CD369 (p&lt; 0.01). Additionally, M2-polarized PBMC-derived macrophages displayed increases in CD206 (p&lt;0.0001). Interestingly, TAMs derived from either THP-1s or PBMCs did not closely align with either polarization state using cell-surface markers, dPCR, or cytokine arrays.

CONCLUSIONS
We have demonstrated a serum-free method of generating a TAM model by polarizing primary macrophages towards a GBM-supportive phenotype that differs molecularly and functionally from M0, M1, and M2 macrophages.
TMOD-28. MODELING MICROENVIRONMENTAL DYNAMICS: A NOVEL 3D GLIOMA-NEURON FUSION MODEL
Authors: Oten Sena , Krishna Saritha , Picart Thiebaud , Daniel Andy , Gonzales Cesar Nava , Lu Katie 
Published: November 2024

Abstract
Gliomas engage in bidirectional interactions with their microenvironment, wherein neuronal activity influences glioma proliferation and gliomas induce neuronal hyperexcitability. Although various models elucidate this complex interplay, a preference for a three-dimensional (3D) cell culture model has emerged to mimic intra-tumoral heterogeneity and microenvironmental interactions influencing glioma invasion, resistance, and recurrence. This study introduces an in vitro, self-assembled, scaffold-free, neuron-glioma spheroid fusion model to investigate the electrophysiological and functional interplay between glioma and its microenvironment. Primary mouse cortical neurons (MCN) were isolated from prenatal brain tissues and were cultured at 500,000 cells/spheroid on ultra-low attachment plates. Glioma organoids (WHO Grade 2-4) were developed from primary patient-derived tissue samples and were allowed to self-assemble for at least two weeks. After spontaneous spiking activity was detected in MCN spheroids, they were combined with glioma organoids in culture and allowed to fuse. A multielectrode array (MEA) was used to characterize the electrophysiological properties of the fusion model. Structural and functional characterizations were performed using immunofluorescence staining of proliferation, microglial, astrocytic, synaptic, and tumor markers. Additionally, the electrophysiological effects of the dual-IDH-mutant inhibitor, Vorasidenib, were assessed in WHO grade 2-4 IDH-mutant gliomas. Electrophysiological analysis of glioma-neuron co-cultures using MEA demonstrated a significantly increased network synchrony and firing rate in the fusion model when compared with the neuron-only condition, consistent with 2D models in the past. In correlation, the fusion model also demonstrated a significant increase in the Ki67 proliferation index across WHO grade 2-4 gliomas when compared to the glioma organoid-only condition. Vorasidenib treatment decreased neuronal firing rate and synchrony. Together, these results offer a high-throughput 3D model for recapitulating the tumor-brain microenvironment for both low and high-grade gliomas. Future studies will focus on the use of this model for drug screening and the exploration of malignant transformation in gliomas.
TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS
Authors: Zadeh Arman T , Crooks Elliot J , Volovetz Josephine , Sloan Anthony R , Lathia Justin D , Dhawan Andrew 
Published: November 2024

Abstract
Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.
TMOD-34. GENERATION OF BRAIN-VESSEL-GBM ASSEMBLOIDS USING PATIENT-DERIVED GLIOBLASTOMA TISSUE
Authors: ha Taehyeong , Hwang Kihwan , Nam Kyung Mi , Ji So Young , Kang Ho , Han Jung Ho , Kim Chae-Yong 
Published: November 2024

Abstract
Glioblastoma (GBM) is the most common malignant brain tumor of the central nervous system and has a significantly low survival rate of approximately 15 months. Current preclinical GBM models are limited by the lack of a normal human microenvironment and the inability of many tumor cell lines to accurately reproduce GBM biology. To address these limitations, we describe a detailed procedure to generate brain-vessel- GBM assembloids, which are fusions of glioblastoma organoids (GBOs) from resected patient tumor tissue and cerebral and vessel organoids derived from human pluripotent stem cells. The proposed methodology will be used to detect and treat brain tumors, which will enable personalized treatment for brain tumor diseases. By universalizing the methodology we present, we aim to encourage other scientists to further develop existing models for studying these lethal tumors.
TMOD-36. NANOGLIOS: A MINIATURIZED PATIENT AVATAR ENABLING RAPID AND HIGH-THROUGHPUT PHENOTYPIC SCREENING FOR GLIOMAS
Authors: Wang Zhaohui , Huang Wei , Kawakita Satoru , Bustamante Francisco , Larios Rene , Jiang Chongming , Lekovic Gregory P , Everson Richard G , Liau Linda M , Lai Albert , Wang Zhaohui 
Published: November 2024

Abstract

BACKGROUND
Establishing pre-clinical patient derived orthtopical xenograft models for IDH-mutant and H3K27M-mutant gliomas has presented significant histological challenges. There is increasing interest in developing faithful patient-derived ex vivo 3D models to replicate these type of gliomas, aiming to accelerate drug screening efforts.

METHOD
We developed a rapid approach for establishing nanoliter-sized miniature glioma organoids, termed NanoGlios, by leveraging emulsion microfluidics. We tested the robustness of NanoGlios for neurosphere culture, glioma xenografts, and primary patient samples, focusing on H3K27M-mutant diffuse midline gliomas (DMGs) and IDH-mutant gliomas. We compared the morphological features of NanoGlios to their counterparts using high-content imaging, H&E staining, and histological analysis. Additionally, we evaluated the mutation and gene expression profiles of NanoGlios relative to their counterparts. Furthermore, we conducted proof-of-concept drug screening of NanoGlios with various inhibitors and established an AI-enhanced high-throughput phenotypic imaging-based screening platform.

RESULTS
We successfully established NanoGlios from various sample sources, including neurospheres, xenografts, and primary tissues harboring H3K27M or IDH1/2 mutations. NanoGlios derived from xenografts or primary tissues captured more heterogeneous patterns as compared to the neuropsheres. We were able to generate thousands of NanoGlios and perform drug assays for hundreds of conditions at passage 0 within two weeks from both resected glioma tissues and xenografts. The AI phenotypic screening enabled us to identify differential responses of NanoGlios to ONC-201 treatment and drug responses to mutant IDH inhibitors Vorasidenib and Ivosidenib, which was not able to be detected by conventional cell viability bulk assays.
Radiation dose assessment during dental cone beam computed tomography procedures in Sri Lanka towards establishing a dose reference level
Authors: Nissanka Madumali , Satharasinghe Duminda , Jeyasugiththan Jeyasingam , Bandara Wikum , Wijayasinghe Wasundara , Weerapperuma Indika , Jayasuriya Nadeena , Jayasinghe Ruwan 
Published: November 2024

Abstract
This study assesses radiation doses in cone beam computed tomography (CBCT) procedures in Sri Lanka, with the goal of establishing initial diagnostic reference levels (DRLs). Data from 1162 retrospective scans across four institutions were analyzed, and the medians of the pooled dose distribution for seven clinical indication categories were presented as the DRL values. The proposed DRLs based on clinical indications are 1013 mGy·cm2 for pathological conditions including cysts, tumors, and lesions, 1307 mGy·cm2 for implant planning, 1266 mGy·cm2 for presurgery assessment, and 1585 mGy·cm2 for evaluation of sinus and nasal pathology, temporomandibular disorder, and facial trauma. Considerable variability in doses across facilities was observed, driven by differences in equipment and imaging practices. Therefore, this study recommends adopting suggested DRL values as benchmarks, standardizing protocols to reduce dose variability, and implementing a national framework for regular updates of DRL values.
Deciphering the accelerated expansion of China’s NEV sector post-2020: a cross-system analysis using multi-level perspective
Authors: Tsou Cheng-Ting , Kim Dong-Hyu 
Published: November 2024

Abstract
This article investigates the rapid expansion of China’s new energy vehicle market in the challenging context of global economic uncertainties and the pandemic, highlighting its significant growth since 2020. By delving deeper into the sectoral and geographical scope of the multi-level perspective concept, this study explores the interactions among various sociotechnical systems that have accelerated the development of China’s automotive electrification. The research offers a deep dive into the factors driving this sector’s growth using a mixed-methods approach, including participatory observation, expert interviews, and secondary data analysis. The findings provide a detailed examination of the NEV market’s evolution and offer a methodological blueprint for analysing the intricate progression of automotive electrification in China, serving as a resource for policymakers and industry stakeholders. This work enhances the discourse on sociotechnical transitions, equipping decision makers with critical insights for steering the industry’s future direction.
Perioperative pain management for cardiac surgery
Authors: Yakubi Masseh , Curtis Sam , Anwar Sibtain 
Published: November 2024

Purpose of review
Acute postsurgical pain after cardiac surgery is challenging to treat. Adverse effects related to the high dose opioids which have traditionally been used perioperatively in cardiac surgery have led to the adoption of alternative analgesic strategies. This review aims to highlight current evidence-based approaches to managing pain after cardiac surgery

Recent findings
Current evidence and international guidelines support the use of multimodal analgesics for managing perioperative pain after cardiac surgery. Regional anaesthesia in the form of fascial plane blocks, such as the erector spinae plane and parasternal intercostal plane blocks, are effective and safe techniques for anticoagulated cardiac surgery patients. Transitional pain services are multidisciplinary programmes that bridge the gap between inpatient and outpatient care for these patients.

Summary
This paper reviews advancements in perioperative pain management for cardiac surgery patients, emphasising the shift from high-dose opioids to multimodal analgesia and regional anaesthetic techniques, and highlighting the role of multidisciplinary transitional pain services.
Perioperative risk scores: prediction, pitfalls, and progress
Authors: Bedford Jonathan P. , Redfern Oliver C. , O’Brien Benjamin , Watkinson Peter J. 
Published: November 2024

Purpose of review
Perioperative risk scores aim to risk-stratify patients to guide their evaluation and management. Several scores are established in clinical practice, but often do not generalize well to new data and require ongoing updates to improve their reliability. Recent advances in machine learning have the potential to handle multidimensional data and associated interactions, however their clinical utility has yet to be consistently demonstrated. In this review, we introduce key model performance metrics, highlight pitfalls in model development, and examine current perioperative risk scores, their limitations, and future directions in risk modelling.

Recent findings
Newer perioperative risk scores developed in larger cohorts appear to outperform older tools. Recent updates have further improved their performance. Machine learning techniques show promise in leveraging multidimensional data, but integrating these complex tools into clinical practice requires further validation, and a focus on implementation principles to ensure these tools are trusted and usable.

Summary
All perioperative risk scores have some limitations, highlighting the need for robust model development and validation. Advancements in machine learning present promising opportunities to enhance this field, particularly through the integration of diverse data sources that may improve predictive performance. Future work should focus on improving model interpretability and incorporating continuous learning mechanisms to increase their clinical utility.
Neurodevelopmental Outcomes after Multiple General Anesthetic Exposures before 5 Years of Age: A Cohort Study
Authors: Xin Annie , Grobler Anneke , Bell Graham , de Graaff Jurgen C. , Dorris Liam , Disma Nicola , McCann Mary Ellen , Withington Davinia E. , Davidson Andrew J. 
Published: November 2024

Background:
The general anaesthesia or awake-regional anaesthesia in infancy (GAS) trial demonstrated evidence that most neurodevelopmental outcomes at 2 and 5 yr of age in infants who received a single general anesthetic for elective inguinal herniorrhaphy were clinically equivalent when compared to infants who did not receive general anesthesia. More than 20% of the children in the trial had at least one subsequent anesthetic exposure after their initial surgery. Using the GAS database, this study aimed to address whether multiple (two or more) general anesthetic exposures compared to one or no general anesthetic exposure in early childhood were associated with worse neurodevelopmental outcomes at 5 yr.

Methods:
Children with multiple general anesthetic exposures and children with one or no general anesthetic exposure were identified from the GAS database. The primary outcome was the full-scale intelligence quotient on the Wechsler Preschool and Primary Scale of Intelligence (third edition) at 5 yr of age. Secondary outcomes included neurocognitive tests addressing all major developmental domains and caregiver-reported questionnaires assessing emotional and behavioral problems.

Results:
Complete assessment was available from a total of 90 children in the multiple general anesthetic group and 141 children in the no or one general anesthetic group. Compared with children with a single or no general anesthetic exposure, multiply exposed children scored on average almost 6 points lower (mean, −5.8; 95% CI, −10.2 to −1.4; P = 0.011) in the Wechsler Preschool and Primary Scale of Intelligence full-scale intelligence quotient. They also demonstrated lower verbal and performance IQ scores and more emotional, behavioral, and executive function difficulties. However, significant residual confounding cannot be excluded from the results due to the observational nature of this study.

Conclusions:
Multiple general anesthetic exposures before 5 yr of age were associated with reduced performance in general intelligence score and some domains of neurodevelopmental assessments. The clinical significance of this study’s results must be cautiously interpreted in light of several sources of limitations including small sample size and unadjusted residual confounding. This study illustrates the limitations of trial data sets that may not be fit for the purpose for the secondary analysis.
Are Drains Associated With Infection After Operative Fixation of High-Risk Tibial Plateau and Pilon Fractures?
Authors: Boissonneault Adam , O'Toole Robert V. , Hayda Roman , Reid J. Spence , Caroom Cyrus , Carlini Anthony , Dagal Arman , Castillo Renan , Karunakar Madhav , Matuszewski Paul E. , Hymes Robert , O'Hara Nathan N. ,   METRC
Published: November 2024

OBJECTIVES:
To determine the association between closed suction drainage and postoperative infection in patients with tibial plateau or pilon fractures. Secondarily, this study assessed whether intrawound vancomycin powder modified the association of closed surgical drains with infection.

METHODS:

Design:
Secondary analysis of the Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial (VANCO).

Setting:
Thirty-six academic trauma centers.

Patient Selection Criteria:
All patients with high-risk tibia fractures Orthopaedic Trauma Association/Arbeitsgemeinschaft fur Osteosynthesefragen (OTA/AO classification 41B/C or 43B/C) from the VANCO trial were considered. Closed suction drains were placed based on the treating surgeon's discretion. Patients were randomly assigned to receive 1-gram intrawound vancomycin powder in the surgical wound at definitive fixation or the standard infection prevention protocol at each center.

Outcome Measures and Comparisons:
Deep surgical site infection (SSI) within 6 months. Comparisons were made between patients treated with and without drains. Subgroup analysis also examined the effect of drains in patients with and without intrawound vancomycin powder.

RESULTS:
Of the 978 study patients, 197 (20%) were treated with drains. Deep infection rates did not significantly differ between patients with or without surgical drains (8% vs. 8%, P = 0.88). However, intrawound vancomycin powder significantly modified the association of surgical drains on deep SSI (interaction P = 0.048). Specifically, patients with drains but no vancomycin powder had the highest deep infection rate (13%; 95% confidence interval, 6%–19%). When vancomycin powder was used in addition to a drain, deep SSI rates were reduced by 10% (95% confidence interval, 2%–17%, P = 0.01).

CONCLUSIONS:
This study suggests that closed suction drains after operative fixation of high-risk tibia fractures may not be associated with deep infection in general. However, a secondary analysis raises the possibility that drains are associated with reduced deep infection rates if topical vancomycin powder is used but associated with increased infection rates if vancomycin powder is not used.

LEVEL OF EVIDENCE:
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.