Identifying Independent Predictors of Short-Term Postoperative Morbidity in Patients Undergoing Cranioplasty.

BACKGROUND: The present study intends to identify independent predictors of short-term postoperative complications and health utilization in patients undergoing cranioplasty. METHODS: Demographic, clinical, and intraoperative characteristics were collected for each patient undergoing cranioplasty in the National Surgery Quality Improvement Program database from 2011 to 2020. The 30-day outcomes analyzed were medical complications, wound complications, return to the operating room, extended hospital stay, and non-home discharge. Bivariate analyses were initially used to identify variables that yielded a P value less than 0.2 which were subsequently analyzed in a multivariate logistic regression to identify independent predictors of the aforementioned outcomes. RESULTS: In total, 2316 patients undergoing cranioplasty were included in the analysis. Increased operative time and totally dependent functional status significantly increased odds of returning to the operating room. Increased age, operative time, cranioplasty size >5 cm, and various comorbidities were associated with increased odds of non-home discharge. Bleeding disorders were independently associated with increased odds of wound complications. Increased age, operative time, cranioplasty size >5 cm, and several medical history features predisposed to medical complications. Demographic characteristics, including age and race, along with various operative and medical history characteristics were associated with increased odds of extended length of stay. CONCLUSIONS: Identification of risk factors can help guide preoperative risk management in cranioplasty.

Synthesis of 12-Membered Tetra-aza Macrocyclic Pyridinophanes Bearing Electron-Withdrawing Groups.

The number of substituted pyridine pyridinophanes found in the literature is limited due to challenges associated with 12-membered macrocycle and modified pyridine synthesis. Most notably, the electrophilic character at the 4-position of pyridine in pyridinophanes presents a unique challenge for introducing electrophilic chemical groups. Likewise, of the few reported, most substituted pyridine pyridinophanes in the literature are limited to electron-donating functionalities. Herein, new synthetic strategies for four new macrocycles bearing the electron-withdrawing groups CN, Cl, NO2, and CF3 are introduced. Potentiometric titrations were used to determine the protonation constants of the new pyridinophanes. Further, the influence of such modifications on the chemical behavior is predicted by comparing the potentiometric results to previously reported systems. X-ray diffraction analysis of the 4-Cl substituted species and its Cu(II) complex are also described to demonstrate the metal binding nature of these ligands. DFT analysis is used to support the experimental findings through energy calculations and ESP maps. These new molecules serve as a foundation to access a range of new pyridinophane small molecules and applications in future work.

Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules.

Alzheimer's and other neurodegenerative diseases are chronic conditions affecting millions of individuals worldwide. Oxidative stress is a consistent component described in the development of many neurodegenerative diseases. Therefore, innovative strategies to develop drug candidates that overcome oxidative stress in the brain are needed. To target these challenges, a new, water-soluble 12-membered tetraaza macrocyclic pyridinophane L4 was designed and produced using a building-block approach. Potentiometric data show that the neutral species of L4 provides interesting zwitterionic behavior at physiological pH, akin to amino acids, and a nearly ideal isoelectric point of 7.3. The copper(II) complex of L4 was evaluated by X-ray diffraction and cyclic voltammetry to show the potential modes of antioxidant activity derived, which was also demonstrated by 2,2-diphenyl-1-picrylhydrazyl and coumarin carboxylic acid antioxidant assays. L4 was shown to have dramatically enhanced antioxidant activity and increased biological compatibility compared to parent molecules reported previously. L4 attenuated hydrogen peroxide (H2O2)-induced cell viability loss more efficiently than precursor molecules in the mouse hippocampal HT-22 cell model. L4 also showed potent (fM) level protection against H2O2 cell death in a BV2 microglial cell culture. Western blot studies indicated that L4 enhanced the cellular antioxidant defense capacity via Nrf2 signaling activation as well. Moreover, a low-cost analysis and high metabolic stability in phase I and II models were observed. These encouraging results show how the rational design of lead compounds is a suitable strategy for the development of treatments for neurodegenerative diseases where oxidative stress plays a substantial role.

A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress.

Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

A novel BRAF::PTPRN2 fusion in meningioma: a case report.

Gene fusion events have been linked to oncogenesis in many cancers. However, gene fusions in meningioma are understudied compared to somatic mutations, chromosomal gains/losses, and epigenetic changes. Fusions involving B-raf proto-oncogene, serine/threonine kinase (BRAF) are subtypes of oncogenic BRAF genetic abnormalities that have been reported in certain cases of brain tumors, such as pilocytic astrocytomas. However, BRAF fusions have not been recognized in meningioma. We present the case of an adult female presenting with episodic partial seizures characterized by déjà vu, confusion, and cognitive changes. Brain imaging revealed a cavernous sinus and sphenoid wing mass and she underwent resection. Histopathology revealed a World Health Organization (WHO) grade 1 meningioma. Genetic profiling with next generation sequencing and microarray analysis revealed an in-frame BRAF::PTPRN2 fusion affecting the BRAF kinase domain as well as chromothripsis of chromosome 7q resulting in multiple segmental gains and losses including amplifications of cyclin dependent kinase 6 (CDK6), tyrosine protein-kinase Met (MET), and smoothened (SMO). Elevated pERK staining in tumor cells provided evidence of activated mitogen-activated protein kinase (MAPK) signaling. This report raises the possibility that gene fusion events may be involved in meningioma pathogenesis and warrant further investigation.

Adolescent Idiopathic Scoliosis and Pregnancy.

Objective This study examined the interaction between adolescent idiopathic scoliosis (AIS) and pregnancy, focusing on pregnancy outcomes, changes in back pain, and anesthesia use. Methods A retrospective analysis was conducted on adult patients with AIS who gave birth at our institution between 2006 and 2022. Results A total of 163 AIS patients with 263 pregnancies were included. The median age at delivery was 33 (range 18 to 50) years. Among 157 patients with information on prior scoliosis treatment, 66.9% had not received treatment, 20.4% had undergone spinal fusion, and 12.7% had received bracing. Of the 260 pregnancies with available data, 90.4% were delivered at term and 8.5% were preterm. Of the 257 pregnancies with information on anesthesia type, 35.0% received epidural anesthesia, 17.9% received spinal anesthesia, 37.7% received combined spinal and epidural anesthesia, 8.2% received no anesthesia, and 1.2% received intravenous or general anesthesia. Difficulty administering neuraxial anesthesia was reported in 6.1% of cases, and these patients were less likely to receive combined spinal and epidural anesthesia (6.3% versus 39.8%, p = 0.0123). Among 116 cases with recorded back pain during pregnancy, 67.2% reported increased pain, 31.9% reported similar pain, and one patient reported decreased pain. Of the 16 patients with pre and postpartum radiographs, eight showed a Cobb angle increase ≥ 3°, with five patients having an increase ≥ 5°. Conclusions Pregnancy can exacerbate back pain and pose challenges for neuraxial anesthesia in some AIS patients. Further large-scale, multi-institutional studies with standardized data collection are needed to fully understand the impact of pregnancy on AIS.

Post-Surgical Prognosis of Patients with Pineoblastoma: A Systematic Review and Individual Patient Data Analysis with Trends over Time.

Most of the literature on pineoblastoma consists of case reports and single-institution series. The goal of this systematic review and individual patient data (IPD) analysis was to summarize the existing literature, identify factors associated with overall survival (OS), and provide a contemporary update on prognosis for patients with pineoblastoma. Forty-four studies were identified with 298 patients having IPD. Kaplan-Meier analyses were used to report survival outcomes based on age, tumor metastases, extent of resection (EOR), adjuvant therapy, and publication year. Cox regression was performed to identify independent predictors of time to mortality. Multivariable recursive partitioning analysis was used to identify the most important subgroups associated with mortality. Patients were classified based on publication year before and after the last systematic review on this topic (pre-2012 and 2012 onwards) and compared using univariate and multivariable analyses. This study demonstrates that EOR less-than-gross total resection, metastatic presentation, adjuvant chemotherapy without radiation, and tumor presentation in children less than three years old are associated with poorer prognosis. Since 2012, the 5-year actuarial OS has improved from 32.8% to 56.1%, which remained significant even after accounting for EOR, age, and adjuvant therapy. Pineoblastoma remains a severe rare disease, but survival outcomes are improving.