RAGE ablation attenuates glioma progression and enhances tumor immune responses by suppressing galectin-3 expression.

BACKGROUND: Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas. METHODS: As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry. RESULTS: Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade. CONCLUSIONS: We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.

Ontology-based feature engineering in machine learning workflows for heterogeneous epilepsy patient records.

Biomedical ontologies are widely used to harmonize heterogeneous data and integrate large volumes of clinical data from multiple sources. This study analyzed the utility of ontologies beyond their traditional roles, that is, in addressing a challenging and currently underserved field of feature engineering in machine learning workflows. Machine learning workflows are being increasingly used to analyze medical records with heterogeneous phenotypic, genotypic, and related medical terms to improve patient care. We performed a retrospective study using neuropathology reports from the German Neuropathology Reference Center for Epilepsy Surgery at Erlangen, Germany. This cohort included 312 patients who underwent epilepsy surgery and were labeled with one or more diagnoses, including dual pathology, hippocampal sclerosis, malformation of cortical dysplasia, tumor, encephalitis, and gliosis. We modeled the diagnosis terms together with their microscopy, immunohistochemistry, anatomy, etiologies, and imaging findings using the description logic-based Web Ontology Language (OWL) in the Epilepsy and Seizure Ontology (EpSO). Three tree-based machine learning models were used to classify the neuropathology reports into one or more diagnosis classes with and without ontology-based feature engineering. We used five-fold cross validation to avoid overfitting with a fixed number of repetitions while leaving out one subset of data for testing, and we used recall, balanced accuracy, and hamming loss as performance metrics for the multi-label classification task. The epilepsy ontology-based feature engineering approach improved the performance of all the three learning models with an improvement of 35.7%, 54.5%, and 33.3% in logistics regression, random forest, and gradient tree boosting models respectively. The run time performance of all three models improved significantly with ontology-based feature engineering with gradient tree boosting model showing a 93.8% reduction in the time required for training and testing of the model. Although, all three models showed an overall improved performance across the three-performance metrics using ontology-based feature engineering, the rate of improvement was not consistent across all input features. To analyze this variation in performance, we computed feature importance scores and found that microscopy had the highest importance score across the three models, followed by imaging, immunohistochemistry, and anatomy in a decreasing order of importance scores. This study showed that ontologies have an important role in feature engineering to make heterogeneous clinical data accessible to machine learning models and also improve the performance of machine learning models in multilabel multiclass classification tasks.

Deep brain stimulation of the posterior subthalamic area as an alternative strategy for management of Holmes tremor: A case report and review of the literature.

Background: Holmes tremor is often refractory to medical treatment and deep brain stimulation of the ventralis intermedius nucleus of the thalamus (VIM-DBS) is the intervention of choice in controlling the tremor. Herein, we present a beneficial alternative strategy for the management of such situations, considering the posterior subthalamic area (PSA) as the target of stimulation. Case Description: We report a 57-year-old male with the right-sided tremor following a traumatic brain injury 20 years ago. He had been diagnosed with Holmes tremor that was not responsive to nonsurgical therapeutic options. When refractoriness confirmed, he became a candidate for VIM-DBS. During the operation, by performing macrostimulation with a maximum of 2 mA of amplitude, the tremor had no response to the stimulation of different tracts, and severe right hemi-body paresthesia occurred; therefore, we modified our approach and targeted the PSA, which resulted in satisfactory control of the tremor. The permanent lead was implanted into the left side PSA. At 1-year follow-up, the right side tremor was under complete control. Conclusion: Our case and other similar pieces of evidence are consistently indicating the potential regulatory effects of PSA-DBS in controlling the Holmes tremor as a feasible alternative strategy when VIM-DBS does not provide a satisfactory response. However, further studies with larger sample size are required to evaluate the long-term response and its possible long-term stimulation-related effects.

Launching Awake Craniotomy Technique in a Resource-Limited Center: New Insights into the Patient Experience, Costs, and Long-Term Outcomes and a Narrative Review of the Literature.

BACKGROUND: Awake craniotomy (AC) with brain mapping is a standard surgical technique for the excision of lesions located in eloquent areas. We aimed to assess the clinical challenges, patient experience, costs, and long-term outcomes of AC in a resource-limited setting. METHODS: In this cross-sectional study, electronic documents of 12 patients who underwent AC with functional brain mapping were prospectively collected from August 2017 to October 2020. Patient characteristics, surgical specifications, hospitalization period, intraoperative and postoperative events, functional outcome, patients' satisfaction, costs, and survivals were collected and analyzed. RESULTS: Twelve patients with a median age of 42.5 (interquartile range, 13.5) were enrolled, of whom 8 were male (66.7%), and 9 (75%) were harboring grade 2 glioma. Of the patients, 8.34%, 33.34%, and 58.33% had partial, subtotal, and gross total excision of the tumors, respectively. The intraoperative seizure was the only complication and occurred in 2 cases (16.67%). At 1 year follow-up, none of the patients experienced any neurologic deficit. Eleven patients (91.6%) had a satisfactory opinion about reappearing in the AC. At 38 months follow-up, mortality was 8% for AC group and 25% among the historically matched controls who had surgery under general anesthesia (P = 0.27). Most costs belonged to the neurosurgery team (43%), and the overall expenses were reduced by 13% compared with a putatively well-equipped setting in our country. CONCLUSIONS: In carefully selected individuals, AC with brain mapping for excision of gliomas could be a safe, effective, and affordable strategy in a resource-limited setting and can be successfully performed with satisfactory outcomes.

Aneurysmal subarachnoid haemorrhage-cerebral vasospasm and prophylactic ibuprofen: a randomised controlled pilot trial protocol.

INTRODUCTION: Cerebral vasospasm (CVS) is the leading cause of mortality and morbidity following aneurysmal subarachnoid haemorrhage (aSAH). One of the recently implicated underlying mechanisms of CVS is inflammatory cascades. Specific feasibility objectives include determining the ability to recruit 30 participants over 24 months while at least 75% of them comply with at least 75% of the study protocol and being able to follow 85% of them for 3 months after discharge. METHODS AND ANALYSIS: This is a feasibility study for a randomised controlled trial. Eligible participants are adult patients who are 18 years of age and older with an aSAH confirmed by a brain CT scan, and CT angiography, or magnetic resonance angiography, or digital subtraction angiography who admitted to the emergency department within 12 hours of the ictus. Eligible subjects will be randomised 1:1 for the administration of either ibuprofen or a placebo, while both groups will concomitantly be treated by the standard of care for 2 weeks. Care givers, patients, outcome assessors and data analysts will be blinded. This will be the first study to investigate the preventive effects of a short-acting non-steroidal anti-inflammatory drug on CVS and the key expected outcome of this pilot study is the feasibility and safety assessment of the administration of ibuprofen in patients with aSAH. The objectives of the definitive trial would be to assess the effect of ibuprofen relative to placebo on mortality, CVS, delayed cerebral ischaemia, and level of disability at 3-month follow-up. ETHICS AND DISSEMINATION: This study is approved by Mashhad University of Medical Sciences ethical committee (IR.MUMS.MEDICAL.REC.1398.225). Results from the study will be submitted for publication regardless of whether or not there are significant findings. TRIAL REGISTRATION NUMBER: ISRCTN14611625.

Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials. METHODS: We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence. RESULTS: We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio [OR],0.73 [95% CI, 0.53-1.00]; moderate certainty; absolute risk reduction (ARR), -3.35%). Nimodipine (OR, 1.46 [95% CI, 1.07-1.99]; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 [95% CI, 1.14-12.18]; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 [95% CI, 0.22-0.68]; high certainty; ARR, -16.65%), nicardipine (OR, 0.48 [95% CI, 0.24-0.94]; moderate certainty; ARR, -13.70%), fasudil (OR, 0.55 [95% CI, 0.31-0.98]; moderate certainty; ARR, -11.54%), and magnesium (OR, 0.66 [95% CI, 0.46-0.94]; high certainty; ARR, -8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia. CONCLUSIONS: Nimodipine and cilostazol are likely the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019122183.

Seizure Clusters, Seizure Severity Markers, and SUDEP Risk.

Rationale: Seizure clusters may be related to Sudden Unexpected Death in Epilepsy (SUDEP). Two or more generalized convulsive seizures (GCS) were captured during video electroencephalography in 7/11 (64%) patients with monitored SUDEP in the MORTEMUS study. It follows that seizure clusters may be associated with epilepsy severity and possibly with SUDEP risk. We aimed to determine if electroclinical seizure features worsen from seizure to seizure within a cluster and possible associations between GCS clusters, markers of seizure severity, and SUDEP risk. Methods: Patients were consecutive, prospectively consented participants with drug-resistant epilepsy from a multi-center study. Seizure clusters were defined as two or more GCS in a 24-h period during the recording of prolonged video-electroencephalography in the Epilepsy monitoring unit (EMU). We measured heart rate variability (HRV), pulse oximetry, plethysmography, postictal generalized electroencephalographic suppression (PGES), and electroencephalography (EEG) recovery duration. A linear mixed effects model was used to study the difference between the first and subsequent seizures, with a level of significance set at p < 0.05. Results: We identified 112 GCS clusters in 105 patients with 285 seizures. GCS lasted on average 48.7 ± 19 s (mean 49, range 2-137). PGES emerged in 184 (64.6%) seizures and postconvulsive central apnea (PCCA) was present in 38 (13.3%) seizures. Changes in seizure features from seizure to seizure such as seizure and convulsive phase durations appeared random. In grouped analysis, some seizure features underwent significant deterioration, whereas others improved. Clonic phase and postconvulsive central apnea (PCCA) were significantly shorter in the fourth seizure compared to the first. By contrast, duration of decerebrate posturing and ictal central apnea were longer. Four SUDEP cases in the cluster cohort were reported on follow-up. Conclusion: Seizure clusters show variable changes from seizure to seizure. Although clusters may reflect epilepsy severity, they alone may be unrelated to SUDEP risk. We suggest a stochastic nature to SUDEP occurrence, where seizure clusters may be more likely to contribute to SUDEP if an underlying progressive tendency toward SUDEP has matured toward a critical SUDEP threshold.

Role of RAGE and Its Ligands on Inflammatory Responses to Brain Tumors.

Gliomas, the most common form of brain cancer, can range from relatively slow-growing low-grade to highly aggressive glioblastoma that has a median overall survival of only 15 months despite multimodal standard therapy. Although immunotherapy with checkpoint inhibitors has significantly improved patient survival for some cancers, to date, these agents have not shown consistent efficacy against malignant gliomas. Therefore, there is a pressing need to better understand the impact of host inflammatory responses on the efficacy of emerging immunotherapy approaches for these resistant tumors. RAGE is a multi-ligand pattern recognition receptor that is activated in various inflammatory states such as diabetes, Alzheimer's disease, cystic fibrosis, and cancer. Low levels of RAGE can be found under normal physiological conditions in neurons, immune cells, activated endothelial, and vascular smooth muscle cells, but it is over-expressed under chronic inflammation due to the accumulation of its ligands. RAGE binds to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA which mediate downstream cellular responses that promote tumor growth, angiogenesis, and invasion. Both in vitro and in vivo studies have shown that inhibition of RAGE signaling can disrupt inflammation and cancer progression and metastasis. Here, we will review our current understanding of the role of RAGE pathway on glioma progression and how it could be exploited to improve the efficacy of immunotherapy approaches.

"Infection prevention and control idea challenge" contest: a fresh view on medical education and problem solving.

BACKGROUND: Healthcare-associated infections (HAIs) challenge modern medicine. Considering their high prevalence in Iran, we aimed to provide knowledge on the subject, and to teach about the importance of infection prevention and control (IPC) to a broad audience of pre-graduate healthcare professionals, focusing on education as the cornerstone of IPC. MAIN BODY: We invited Iranian medical students to present ideas on "how to reduce HAIs." Projects were eligible if being original and addressing the call. Accepted projects were quality assessed using a scoring system. Forty-nine projects were submitted, of which 37 met the inclusion criteria. They had a mean score of 69.4 ± 18.3 out of the maximum possible score of 115. Four reviewers assessed the 37 projects for clinical applicability, impact on patient safety, and innovation, and selected the best 12 to compete at the 2nd International Congress on Prevention Strategies for Healthcare-associated Infections, Mashhad, Iran, 2018. The competition took place in three rounds. The selected teams presented their projects in the first round and debated one by one in a knockout manner, while the jury reviewed their scientific content and presentation skills. In the second round, the top 5 projects competed for reaching the final stage, in which the teams presented their ideas in front of a panel of international IPC experts to determine the first three ranks. At the end of the contest, the participants gained valuable criticisms on how to improve their ideas. Moreover, by its motivating atmosphere, the contest created an excellent opportunity to promote IPC in medical schools. CONCLUSIONS: Using innovation contests in pre-graduates is an innovative education strategy. It sensitizes medical students to the challenges of IPC and antimicrobial resistance and drives them to think about solutions. By presenting and defending their innovations, they deepen their understanding on the topic and generate knowledge transfer in both ways, from students to teachers and vice versa.

Electrical Stimulation-Induced Seizures and Breathing Dysfunction: A Systematic Review of New Insights Into the Epileptogenic and Symptomatogenic Zones.

Objective: Electrical stimulation (ES) potentially delineates epileptogenic cortex through induction of typical seizures. Although frequently employed, its value for epilepsy surgery remains controversial. Similarly, ES is used to identify symptomatogenic zones, but with greater success and a long-standing evidence base. Recent work points to new seizure symptoms such as ictal central apnea (ICA) that may enhance presurgical hypotheses. The aims of this review are 2-fold: to determine the value of ES-induced seizures (ESIS) in epilepsy surgery and to analyze current evidence on ICA as a new surrogate of symptomatogenic cortex. Methods: Three databases were searched for ESIS. Investigators independently selected studies according to pre-specified criteria. Studies reporting postoperative outcome in patients with ESIS were included in a meta-analysis. For ES-induced apnea, a thorough search was performed and reference list searching was employed. Results: Of 6,314 articles identified for ESIS, 25 were considered eligible to be reviewed in full text. Fourteen studies were included in the qualitative synthesis (1,069 patients); six studies were included in the meta-analysis (530 patients). The meta-analysis showed that favorable outcome is associated with ESIS prior to surgery (OR: 2.02; 95% CI: 1.332-3.08). In addition, the overall estimation of the occurrence of favorable outcome among cases with ESIS is 68.13% (95% CI: 56.62-78.7). On the other hand, recent studies have shown that stimulation of exclusively mesial temporal lobe structures elicits central apnea and represents symptomatogenic anatomic substrates of ICA. This is in variance with traditional teaching that mesial temporal ES is non-symptomatogenic. Conclusions: ES is a tool highly likely to aid in the delineation of the epileptogenic zone, since ESIS is associated with favorable postoperative outcomes (Engel I). There is an urgent need for prospective evaluation of this technique, including effective stimulation parameters and surgical outcomes, that will provide knowledge base for practice. In addition, ES-induced apnea studies suggest that ICA, especially when it is the first or only clinical sign, is an important semiological feature in localizing the symptomatogenic zone to mesial temporal lobe structures, which must be considered in SEEG explorations where this is planned, and in surgical resection strategies.

Rate and Risk Factors of Early Ventriculoperitoneal Shunt Revision: A Five-Year Retrospective Analysis of a Referral Center.

BACKGROUND: Cerebral shunts are the mainstay treatment of hydrocephalus. Because most previous studies have focused on factors related to long-term outcomes of shunt surgery, we aimed to assess the rates and causes of 30-day ventriculoperitoneal shunt (VPS) failure in a single referral center over 5 years in both adult and pediatric patients. METHODS: Patients who underwent VPS surgery from February 2012 to February 2017 in Ghaem Teaching Hospital, Mashhad, Iran were evaluated retrospectively through clinical history, operative reports, imaging studies, and follow-up notes. Data of 12 possible factors related to shunt failure were collected comprising age, gender, household income, level of education, cause of hydrocephalus, causes of revision, type of failure, anatomic site, duration of operation, time of surgery, surgeons' level of expertise, and Glasgow Coma Scale (GCS) score. RESULTS: Among 403 VPS placements, 121 VPS revisions were performed, and 82 eligible patients were included in the study (57.3% male and 42.7% female). The 30-day shunt failure rate was 24.4% among all revisions. Obstruction and malposition were the most common causes of early revisions. Six factors were statistically significant in the univariate analysis. After adjustment in a logistic regression model, 2 factors, namely surgeons' level of expertise (odds ratio, 10.33; 95% confidence interval, 1.08-98.80) and anatomic site of the shunt (odds ratio, 10.28; 95% confidence interval, 1.21-87.35) were associated with early shunt revision. CONCLUSIONS: Shunt surgeries performed by junior residents and shunts placed in the frontal site were associated with early shunt failure.

A Self-Made, Reusable, and Adjustable Device for Making Burr Hole Bone Plugs: Doing More with Less.

BACKGROUND: Burr hole craniotomy is a daily procedure in neurosurgery. Defects after burr hole craniotomies will not spontaneously heal and can result in skin dents and cosmetic dissatisfaction. We have introduced a self-made, reusable, and adjustable bone plug packer to use in the repair of burr holes via packing of autologous bone dust. Our bone plug packer is free of charge and can be readily available in neurosurgical operating rooms. METHODS: We have produced a stainless steel bone packer device that can be assembled without the use of a special wrench. The instrument consists of a container plate and a main cylinder for packing, in which an adjustable airtight piston is placed to compress the bone dust and create a bone plug of the desired dimensions. RESULTS: Some recent studies have shown that burr holes filled by autologous bone dust will result in good cosmetic and osteogenic outcomes. Although we did not perform a long-term follow-up assessment of the burr holes filled with bone plugs, in the short term, we have not seen any local reactions or infections in our patients. The autologous bone plug is a more affordable and available option with no technical or clinical complications in the short term. CONCLUSION: We have introduced a practical, convenient, and cost-effective bone packer device. Bone plugs formed using our device can be a potential substitute for expensive covering materials in countries with limited access to other repair options. Providing proper evidence will require the performance of large studies to assess our suggested method in the long term and, possibly, compare it with the usual options in controlled studies.

Association of Opium Addiction with Rupture of Intracranial Aneurysms: A Case-Control Study.

BACKGROUND: Disorders related to opioid use account for the most substantial burden of disease attributable to drug use disorders. We aimed to justify if there is an association between either opium consumption or addiction and rupture of intracranial aneurysms. METHODS: In this case-control study, we enrolled 50 cases with ruptured intracranial aneurysms and 43 control subjects with an incidental finding of an intracranial aneurysm without history of subarachnoid hemorrhage (SAH). Four major risk factors of rupture including age, sex, size, and site of aneurysm were matched among both groups. All participants were asked about cigarette smoking state, opium addiction, opium consumption, and duration and route of opium consumption. Eight other trigger factors were assessed in the period soon before SAH (hazard period). The odds ratio (OR) of all factors was calculated separately, and then a logistic regression for the factors with significant odds was calculated. RESULTS: Sixty-two percent of cases and 32.6% of control subjects were addicted to opium. The OR for opium consumption in the hazard period was 8.1 (95% confidence interval [CI], 2.2-30.1) and for opium addiction was 3.3 (95% CI, 1.4-7.9). Of those trigger factors, cola consumption was included in the logistic regression model. After adjustment, results demonstrated an OR of 9.2 (95% CI, 2.4-34.7) for opium consumption in the hazard period. CONCLUSIONS: There is an association between opium addiction and opium consumption in the hazard period with the occurrence of aneurysmal SAH. Replication of the study with a larger sample size and conduction of prospective studies is suggested.

Giant Tarlov Cyst of Infancy.

We report an 8-month-old female infant with complaints of irritability and recent inability to sit in a stable position. On physical examination, a palpable mass in the left upper quadrant of her abdomen was evident. Sonography and magnetic resonance imaging showed a giant cyst, consisting of 2 communicating compartments: dorsal and ventrolateral. The dorsal part compressed the conus medullaris, and the ventrolateral part compressed the left kidney. Partial cyst wall resection and imbrication for the dorsal pouch were done, and diagnosis of Tarlov cyst was confirmed via the visualization of the endocystic nerve root during surgery. Familiarizing physicians with this unusual presentation of Tarlov cyst may help them in early recognition of this lesion, and subsequent surgery might be considered to prevent clinical sequela. To our knowledge, a lumbar Tarlov cyst presenting as a giant abdominal cyst in an infant has not been reported in the English-language literature.