Impact of socioeconomics and race on clinical follow-up and trial enrollment and adherence in cerebral cavernous malformation.

OBJECTIVES: Cerebral cavernous malformation (CCM) affects more than a million Americans but advanced care for symptomatic lesions and access to research studies is largely limited to referral academic centers MATERIALS AND METHODS: A cohort of CCM patients screened for research studies at an accredited center of excellence for CCM was analyzed. Demographics, lesion location, history of hemorrhage, insurance type and area of deprivation index (ADI) were collected. Primary outcomes were clinical follow-up within a year from initial evaluation, and enrollment and adherence in clinical trials among eligible subjects RESULTS: A majority (52.8%) of CCM patients evaluated had a high socioeconomic status (SES) (ADI 1-3), and only 11.5% were African American. Patients who had a symptomatic bleed were more likely to follow-up (p=0.01), and those with brainstem lesion were more likely to enroll/adhere in a clinical trial (p=0.02). Rates of clinical follow-up were similar across different ADI groups, insurance coverage and race. Patients who were uninsured/self-paying, and African Americans were more likely to decline/drop from clinical trials (OR 2.4, 95% CI 0.46-10.20 and OR 2.2, 95% CI 0.33-10.75, respectively), but differences were not statistically significant CONCLUSIONS: Access of disadvantaged patients to center of excellence care and research remains limited despite geographic proximity to their community. Patients with lower SES and African Americans are as likely to follow-up clinically, but there were trends of differences in enrollment/adherence in clinical trials. Mitigation efforts should target systemic causes of low access to specialized care among uninsured and African American patients.

Cerebrovascular Complications in Early Survivors of Civilian Penetrating Brain Injury.

BACKGROUND: This study investigates the presence of cerebrovascular injuries in a large sample of civilian penetrating brain injury (PBI) patients, determining the prevalence, radiographic characteristics, and impact on short-term outcome. METHODS: We retrospectively reviewed patients with PBI admitted to our institution over a 2-year period. Computed tomography head scans, computer tomography angiograms and venograms of the intracranial vessels were evaluated to determine the wound trajectory, intracranial injury characteristics, and presence of arterial (AI) and venous sinus (VSI) injuries. Demographics, clinical presentation, and treatment were also reviewed. Discharge disposition was used as surrogate of short-term outcome. RESULTS: Seventy-two patients were included in the study. The mechanism of injury was gunshot wounds in 71 patients and stab wound in one. Forty-one of the 72 patients (60%) had at least one vascular injury. Twenty-six out of 72 patients suffered an AI (36%), mostly pseudoaneurysms and occlusions, involving the anterior and middle cerebral arteries. Of the 72 patients included, 45 had dedicated computed tomography venograms, and of those 22 had VSI (49%), mainly manifesting as superior sagittal sinus occlusion. In a multivariable regression model, intraventricular hemorrhage at presentation was associated with AI (OR 9.9, p = 0.004). The same was not true for VSI. CONCLUSION: Acute traumatic cerebrovascular injury is a prevalent complication in civilian PBI, frequently involving both the arterial and venous sinus systems. Although some radiographic features might be associated with presence of vascular injury, assessment of the intracranial vasculature in the acute phase of all PBI is essential for early diagnosis. Treatment of vascular injury remains variable depending on local practice.

An overview of meningiomas.

Meningiomas are the most common primary intracranial tumor. Important advances are occurring in meningioma research. These are expected to accelerate, potentially leading to impactful changes on the management of meningiomas in the near and medium term. This review will cover the histo- and molecular pathology of meningiomas, including recent 2016 updates to the WHO classification of CNS tumors. We will discuss clinical and radiographic presentation and therapeutic management. Surgery and radiotherapy, the two longstanding primary therapeutic modalities, will be discussed at length. In addition, data from prior and ongoing investigations of other treatment modalities, including systemic and targeted therapies, will be covered. This review will quickly update the reader on the contemporary management and future directions in meningiomas. [Formula: see text].

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1.

Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.

Analysis of the process of representing clinical statements for decision-support applications: a comparison of openEHR archetypes and HL7 virtual medical record.

Delivering patient-specific decision-support based on computer-interpretable guidelines (CIGs) requires mapping CIG clinical statements (data items, clinical recommendations) into patients' data. This is most effectively done via intermediate data schemas, which enable querying the data according to the semantics of a shared standard intermediate schema. This study aims to evaluate the use of HL7 virtual medical record (vMR) and openEHR archetypes as intermediate schemas for capturing clinical statements from CIGs that are mappable to electronic health records (EHRs) containing patient data and patient-specific recommendations. Using qualitative research methods, we analyzed the encoding of ten representative clinical statements taken from two CIGs used in real decision-support systems into two health information models (openEHR archetypes and HL7 vMR instances) by four experienced informaticians. Discussion among the modelers about each case study example greatly increased our understanding of the capabilities of these standards, which we share in this educational paper. Differing in content and structure, the openEHR archetypes were found to contain a greater level of representational detail and structure while the vMR representations took fewer steps to complete. The use of openEHR in the encoding of CIG clinical statements could potentially facilitate applications other than decision-support, including intelligent data analysis and integration of additional properties of data items from existing EHRs. On the other hand, due to their smaller size and fewer details, the use of vMR potentially supports quicker mapping of EHR data into clinical statements.

The Time Burden of Office Visits in Contemporary Pituitary Care, 2016 to 2019.

BACKGROUND: The concept of "time toxicity" has emerged to address the impact of time spent in the healthcare system; however, little work has examined the phenomenon in the field of otolaryngology. OBJECTIVE: To validate the use of Evaluation and Management (E/M) current procedural terminology codes as a method to assess time burden and to pilot this tool to characterize the time toxicity of office visits associated with a diagnosis of pituitary adenoma between 2016 and 2019. METHODS: A retrospective cohort study of outpatient office visits quantified differences between timestamps documenting visit length and their associated E/M code visit length. The IBM MarketScan database was queried to identify patients with a diagnosis of pituitary adenoma in 2016 and to analyze their new and return claims between 2016 and 2019. One-way ANOVA and two-sample t-tests were used to examine claim quantity, time in office, and yearly visit time. RESULTS: In the validation study, estimated visit time via E/M codes and actual visit time were statistically different (P < 0.01), with E/M codes underestimating actual time spent in 79.0% of visits. In the MarketScan analysis, in 2016, 2099 patients received a primary diagnosis of pituitary adenoma. There were 8490 additional-related claims for this cohort from 2016 to 2019. The plurality of new office visits were with endocrinologists (n = 857; 29.3%). Total time spent in office decreased yearly, from a mean of 113 min (2016) to 69 min (2019) (P < 0.001). CONCLUSIONS: E/M codes underestimate the length of outpatient visits; therefore, time toxicity experienced by pituitary patients may be greater than reported. Further studies are needed to develop additional assessment tools for time toxicity and promote increased efficiency of care for patients with pituitary adenomas.

A review of AI and Data Science support for cancer management.

INTRODUCTION: Thanks to improvement of care, cancer has become a chronic condition. But due to the toxicity of treatment, the importance of supporting the quality of life (QoL) of cancer patients increases. Monitoring and managing QoL relies on data collected by the patient in his/her home environment, its integration, and its analysis, which supports personalization of cancer management recommendations. We review the state-of-the-art of computerized systems that employ AI and Data Science methods to monitor the health status and provide support to cancer patients managed at home. OBJECTIVE: Our main objective is to analyze the literature to identify open research challenges that a novel decision support system for cancer patients and clinicians will need to address, point to potential solutions, and provide a list of established best-practices to adopt. METHODS: We designed a review study, in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, analyzing studies retrieved from PubMed related to monitoring cancer patients in their home environments via sensors and self-reporting: what data is collected, what are the techniques used to collect data, semantically integrate it, infer the patient's state from it and deliver coaching/behavior change interventions. RESULTS: Starting from an initial corpus of 819 unique articles, a total of 180 papers were considered in the full-text analysis and 109 were finally included in the review. Our findings are organized and presented in four main sub-topics consisting of data collection, data integration, predictive modeling and patient coaching. CONCLUSION: Development of modern decision support systems for cancer needs to utilize best practices like the use of validated electronic questionnaires for quality-of-life assessment, adoption of appropriate information modeling standards supplemented by terminologies/ontologies, adherence to FAIR data principles, external validation, stratification of patients in subgroups for better predictive modeling, and adoption of formal behavior change theories. Open research challenges include supporting emotional and social dimensions of well-being, including PROs in predictive modeling, and providing better customization of behavioral interventions for the specific population of cancer patients.

Coagulopathy as a Surrogate of Severity of Injury in Penetrating Brain Injury.

Penetrating brain injury (PBI) is the most devastating type of traumatic brain injury. Development of coagulopathy in the acute setting of PBI, though common, remains of unclear significance as does its reversal. The aim of this study is to investigate the relationship between coagulopathy and clinical presentation, radiographical features, and outcome in civilian patients with PBI. Eighty-nine adult patients with PBI at a Level I trauma center in Chicago, Illinois who survived acute resuscitation and with available coagulation profile were analyzed. Coagulopathy was defined as international normalized ratio [INR] >1.3, platelet count <100,000 /µL, or partial thromboplastin time >37 sec. Median age (interquartile range; IQR) of our cohort was 27 (21-35) years, and 74 (83%) were male. The intent was assault in 74 cases (83%). The mechanism of PBI was gunshot wound in all patients. Forty patients (45%) were coagulopathic at presentation. In a multiple regression model, coagulopathy was associated with lower Glasgow Coma Scale (GCS)-Motor score (odds ratio [OR], 0.67; confidence interval [CI], 0.48-0.94; p = 0.02) and transfusion of blood products (OR, 3.91; CI, 1.2-12.5; p = 0.02). Effacement of basal cisterns was the only significant radiographical features associated with coagulopathy (OR, 3.34; CI, 1.08-10.37; p = 0.04). Mortality was found to be significantly more common in coagulopathic patients (73% vs. 25%; p < 0.001). However, in our limited sample, reversal of coagulopathy at 24 h was not associated with a statistically significant improvement in outcome. The triad of coagulopathy, low post-resuscitation GCS, and radiographical effacement of basal cisterns identify a particularly ominous phenotype of PBI. The role, and potential reversal of, coagulopathy in this group warrants further investigation.

Cranial Vault Reconstruction and Evacuation of Hemorrhage After a Bifrontal Gunshot Wound to the Brain.

Civilian gunshot wounds to the brain are associated with high overall mortality; however, outcomes can vary significantly depending on bullet trajectory. This report details the outcome of a patient who sustained a bifrontal gunshot wound with multiple associated calvarial and frontal sinus fractures. Although surgery for penetrating brain injury is most frequently employed for relief of mass effect and decompression of vital structures, this case report describes a more comprehensive technique involving duroplasty, obliteration of the frontal sinus, and cranial vault reconstruction with the aim of decreasing the rate of cerebrospinal fluid leak, infection, reoperation, and readmission.

Management of civilians with penetrating brain injury: A systematic review.

PURPOSE: There has been a dramatic increase in penetrating gunshot-inflicted civilian penetrating brain injuries (cvPBI). We undertook a systematic review with exclusive focus on the management of cvPBI. METHODS: We explored: (1) cervical spine immobilization, (2) seizure incidence and prophylaxis, (3) infection incidence and antibiotic prophylaxis, (4) coagulopathy (5) vascular complications, and (6) surgical management. We searched PubMed, EMBASE, and Cochrane (1985-2019). The PRISMA guidelines were followed. The Newcastle-Ottawa Scale was employed for qualitative assessment; risk of bias was evaluated based upon the RTI item bank. The full protocol was registered to PROSPERO (CRD42019118877). RESULTS: The literature is scant, and of overall low quality and high risk of bias. Incidence of c-spine injury with no direct trauma is low; incidence of seizures does not appear to be different from non-penetrating mechanisms; there is no robust data for prophylactic antibiotics; coagulopathy is prevalent and has been independently associated with outcome; there is a high incidence of vascular injuries with traumatic intracranial aneurysms the most common sequelae; neurosurgical decision-making appears largely influenced by operator's assessment of salvageability. Surgery has been associated with decreased mortality. CONCLUSIONS: Limited amount of published work is clinically meaningful; this systematic review identified key knowledge gaps.

Tau 6D and 6P isoforms inhibit polymerization of full-length tau in vitro.

Alzheimer's disease and other tauopathies are characterized by the intracellular accumulation of insoluble filaments of the microtubule-associated protein tau. The six canonical tau isoforms in the adult brain consist of an N-terminal "projection" domain followed by a proline-rich region, a microtubule-binding repeat region, and a C-terminal tail. However, alternative splicing in exon 6 produces an additional set of tau isoforms, termed 6D and 6P, which contain only the N-terminus and part of the proline-rich region. We have previously shown that constructs representing N-terminal fragments of tau, which resemble the naturally occurring 6P and 6D isoforms, inhibit polymerization of the full-length protein in an in vitro filament formation assay and traced the inhibitory activity to amino acids 18-42. Here we report that 6P and 6D tau isoforms inhibit polymerization of full-length tau (hTau40) in a similar manner, likely by stabilizing full-length tau in a soluble conformation. The absence of exons 2 and 3 decreased the effectiveness of the 6D isoforms but not the 6P variants or the N-terminal tau fragments from our previous study, indicating that the 18-42 region is not the sole determinant of inhibitory ability. Finally, this paper demonstrates that inhibition is blocked by pseudophosphorylation of tyrosines 18 and 29, providing a potential link between tyrosine phosphorylation and disease progression. Taken together, these results indicate that the 6P/6D isoforms are potential endogenous inhibitors of tau filament formation and suggest a mechanism by which this ability may be disrupted in disease.

A possible link between astrocyte activation and tau nitration in Alzheimer's disease.

Alzheimer's disease (AD) pathology has been characterized, in part, by the self-assembly of the tau molecule into neurofibrillary tangles (NFT). While different post-translational modifications have been identified that accelerate tau aggregation, nitration at tyrosine residues prevents or slows tau filament formation in vitro. Of the five tyrosine residues within the molecule, nitration at the first tyrosine residue (Tyr 18) results in a profound inhibition of filament self-assembly. To determine whether nitration at Tyr 18 occurs in AD pathology, monoclonal antibodies were raised against a synthetic tau peptide nitrated at Tyr 18. A clone, termed Tau-nY18, reacts specifically with tau proteins nitrated at Tyr 18 and fails to cross-react with other nitrated tyrosine residues spanning the length of the molecule or with other proteins known to be nitrated in neurodegenerative diseases. In situ, Tau-nY18 sparsely labels the neuronal pathological hallmarks of the disease, including NFT and dystrophic neurites. Surprisingly however, Tau-nY18 robustly labels nitrated tau within activated, GFAP positive astrocytes intimately associated with amyloid plaques. Furthermore, this antibody detects nitrated tau in soluble preparations from both severe AD brains (Braak stage V, VI) and age-matched controls. Collectively, these findings suggest that nitration at Tyr 18 may be linked to astrocyte activation, an early event associated with amyloid plaque formation.

[Alveolar ridge augmentation with hip corticocancellous allogenic block graft prior to implant placement].

The use of autogenous block bone grafts in bone regeneration procedures for alveolar ridge augmentation can be limited by donor-site morbidity and complications. In this study, allogeneic block grafts were used for ridge augmentation prior to implant placement. Thirty six patients with severe ridge width and height deficiency underwent augmentation using an allogeneic corticocancellous iliac block bone graft. After rigid fixation of the graft, the site was covered with a freeze dried allogeneic dura mater membrane or restorable collagen membrane and then tension-free closure was performed. Implants were placed three to four months after surgery. Three to six months after implant placement, panoramic radiographs were taken and implants were uncovered for prosthetic restoration. Out of the 70 implants placed, one implant failed to integrate. Out of the 49 grafts placed one graft showed three millimeters of bone resorbtion at the superior buccal aspect of the graft. No other clinical problems were observed. The block grafts were clinically well integrated into the recipient site. The augmented bone remained stable throughout implant placement procedures. Clinical outcome evidence demonstrates that allogeneic block bone grafts in conjunction with G.B.R principles might be a viable alternative to autogenous grafts in selected patients with alveolar ridge deficiencies.

Combined petrosal approach.

PURPOSE OF REVIEW: The combined petrosal approach to the lateral skull base merges a retrolabyrinthine-presigmoid posterior fossa craniotomy with an adjacent middle fossa craniotomy, which are rendered continuous by division of the tentorium. This is a hearing-preserving approach that affords wide access to the lateral aspect of the clivus, the prepontine space, and the cerebellopontine angle. RECENT FINDINGS: This article details the historical development of the combined petrosal approach alongside a description. In particular, the critically relevant anatomy is reviewed, including the course of the vein of Labbé, with a view toward avoiding the known complications associated with this approach. Outcomes for application of this approach as applied for various lesions are also reviewed as portrayed by the current literature. SUMMARY: The combined petrosal approach affords wide access to the lateral skull base in the middle and posterior fossa. The approach and the lesions addressed by this approach involve delicate and sensitive anatomy. We review the evolution of this approach and highlight advancements that have allowed the combined petrosal approach to be a safe addition to the surgeon's armamentarium.

Diagnostic Evaluation in Primary CNS Lymphoma.

The diagnosis of primary central nervous system lymphoma (PCNSL) may be fraught with difficulty. After initial imaging reveals enhancing intracranial mass lesions steroids are often initiated. This leads to a decreased diagnostic yield of tumor biopsies which may be associated with delay in treatment initiation. We review a case of PCNSL treated with a very brief steroid course. Initial nondiagnostic biopsy histopathology is juxtaposed against subsequent diagnostic pathology. Imaging before and after steroids is presented, as is imaging after tumor regrowth in a noncontiguous location. Elements in the clinical history and radiographic presentation which should raise suspicion for PCNSL are reviewed. Increased understanding of the potential pitfalls surrounding PCNSL diagnosis may limit their future occurrence.

The use of three-dimensional strut plates for the management of mandibular angle fractures: a retrospective analysis of 222 patients.

This study was performed to evaluate the use of three-dimensional (3D) strut plates for the surgical management of mandibular angle fractures and to determine the subsequent postoperative complication rate. Two hundred and twenty-two patients met the inclusion criteria for mandible angle fracture at the university hospital in Miami between 2009 and 2013 and were included in this study. The treatment protocol for mandibular angle fractures included open reduction and internal fixation with the utilization of a 3D strut plate. Patients were not placed in postoperative intermaxillary fixation. An evaluation of the cases revealed a complication rate of 15.3%, of which 6.8% were considered major complications requiring a surgical intervention. The 3D strut plate has been found to have many advantages over single miniplate techniques with respect to the stability of the fracture and the rate of complications. Based on the current data, 3D strut plates provide a predictable result in the treatment of mandibular angle fractures.

Complication Avoidance in Endoscopic Skull Base Surgery.

Endoscopic endonasal approaches to the skull base pathology have developed and evolved dramatically over the past 2 decades, particularly with collaboration between neurosurgery and otolaryngology physicians. These advances have increased significantly the use of such approaches beyond just resection of pituitary adenomas, including a variety of skull base pathologies. As the field has evolved, so has our understanding of the complications accompanying endoscopic skull base surgery, as well as techniques to both avoid and manage these complications. These are discussed here.

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive amnestic dementia that involves post-translational hyperphosphorylation, enzymatic cleavage, and conformational alterations of the microtubule-associated protein tau. The truncation state of tau influences many of its pathologic characteristics, including its ability to assume AD-related conformations and to assemble into filaments. Cleavage also appears to be an important marker in AD progression. Although C-terminal truncation of tau at D421 has recently been attributed to the apoptotic enzyme caspase-3, N-terminal processing of the protein remains mostly uncharacterized. Here, we report immunohistochemical staining in a cohort of 35 cases ranging from noncognitively impaired to early AD with a panel of three N-terminal anti-tau antibodies: Tau-12, 5A6, and 9G3-pY18. Of these three, the phosphorylation-independent epitope of 5A6 was the earliest to emerge in the pathological lesions of tau, followed by the appearance of the Tau-12 epitope. The unmasking of the Tau-12 epitope in more mature 5A6-positive tangles was not correlated with tau phosphorylation at tyrosine 18 (9G3-pY18). Still, later in the course of tangle evolution, the extreme N terminus of tau was lost, correlating temporally with the appearance of a C-terminal caspase-truncated epitope lacking residues 422-441. In addition, caspase-6 cleaved the N terminus of tau in vitro, preventing immunoreactivity with both Tau-12 and 5A6. Mass spectrometry confirmed that the in vitro caspase-6 truncation site is D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. Collectively, these results suggest a role for caspase-6 and N-terminal truncation of tau during neurofibrillary tangle evolution and the progression of Alzheimer's disease.