Responsiveness of the Patient-Reported Outcome Measure for Vascular Malformation Questionnaire in Patients with Low-Flow Vascular Malformations.

PURPOSE: To assess the responsiveness, defined as the ability to detect change in a patient's health or function, of the Patient-Reported Outcome Measure for Vascular Malformation (PROVAM) questionnaire in a cohort of patients with low-flow vascular malformations (VMs). MATERIALS AND METHODS: PROVAM was previously developed to assess symptoms, functional limitations, and social/emotional effects experienced by patients with VMs. This is a prospective cohort study of 56 patients with venous and lymphatic VMs who completed at least 2 PROVAM questionnaires, of whom 43 had undergone treatment with sclerotherapy in the interim between questionnaires. External responsiveness was assessed using a receiver operating characteristic (ROC) curve to ascertain whether a change in the total PROVAM score predicts whether patients reported symptom improvement and by correlating the change in the total PROVAM score and change in symptoms reported during clinic visit. Internal responsiveness was evaluated using Wilcoxon signed rank test, Cohen d effect size (ESp), and standard response mean difference (SRM). RESULTS: The total PROVAM score demonstrated excellent discrimination for symptom improvement with an area under the ROC curve of 0.856. There was a statistically significant, moderate positive correlation between the change in the total PROVAM score and the change in patient symptoms as determined from clinical visits (Spearman correlation coefficient [rs] = 0.67, P < .001). The total PROVAM score and all subdomain scores improved significantly after treatment (all P < .05). ESp and SRM were 0.80 and 0.83, respectively. CONCLUSIONS: PROVAM is responsive to improvement after treatment and may be useful to assess health-related quality of life in patients treated for VMs.

Contralateral approach for clipping of bilateral anterior circulation aneurysms.

Patients with bilateral anterior circulation aneurysms present a management challenge. These lesions may be treated in a staged manner or alternatively, for select patients, a contralateral approach may be utilized to treat bilateral aneurysms with a single surgery. In this narrated video illustration, we present the case of a 57-year-old woman with incidentally discovered bilateral aneurysms (left middle cerebral artery [MCA], left anterior choroidal artery and right MCA). A contralateral approach through a left pterional craniotomy was performed formicrosurgical clipping of all three aneurysms. The techniques of pterional craniotomy, contralateral approach, microsurgical clipping and intraoperative angiography are reviewed. The authors are grateful to Wuyang Yang, M.D. for his assistance. The video can be found here: http://youtu.be/MlPIu3hQZkg.

Computational and experimental investigation of constitutive behavior in AraC.

Many mutations in the N-terminal arm of AraC result in constitutive behavior in which transcription of the araBAD genes occurs even in the absence of arabinose. To begin to understand the mechanism underlying this class of mutations, we used molecular dynamics with self-guided Langevin dynamics to simulate (1) wild-type (WT) AraC, (2) known constitutive mutants resulting from alterations in the regulatory arm, particularly alanine and glycine substitutions at residue 8 because P8G is constitutive, whereas P8A behaves like wild type, and (3) selected variant AraC proteins containing alterations in the dimerization core. In all of the constitutive arm mutants, but not the WT protein, residues 37-42, which are located in the core of the dimerization domain, became restructured. This raised the question of whether or not these structural changes are an obligatory component of constitutivity. Using molecular dynamics, we identified alterations in the core that produced a similar restructuring. The corresponding mutants were constructed and their ara constitutivity status was determined experimentally. Because the core mutants were not found to be constitutive, we conclude that restructuring of core residues 37-42 does not, itself, lead to constitutivity of AraC. The available data lead to the hypothesis that the interaction of the N-terminal arm with something other than the front lip is the primary determinant of the inducing versus repressing state of AraC.

Significant head accelerations can influence immediate neurological impairments in a murine model of blast-induced traumatic brain injury.

Although blast-induced traumatic brain injury (bTBI) is well recognized for its significance in the military population, the unique mechanisms of primary bTBI remain undefined. Animate models of primary bTBI are critical for determining these potentially unique mechanisms, but the biomechanical characteristics of many bTBI models are poorly understood. In this study, we examine some common shock tube configurations used to study blast-induced brain injury in the laboratory and define the optimal configuration to minimize the effect of torso overpressure and blast-induced head accelerations. Pressure transducers indicated that a customized animal holder successfully reduced peak torso overpressures to safe levels across all tested configurations. However, high speed video imaging acquired during the blast showed significant head accelerations occurred when animals were oriented perpendicular to the shock tube axis. These findings of complex head motions during blast are similar to previous reports [Goldstein et al., 2012, "Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model," Sci. Transl. Med., 4(134), 134ra160; Sundaramurthy et al., 2012, "Blast-Induced Biomechanical Loading of the Rat: An Experimental and Anatomically Accurate Computational Blast Injury Model," J. Neurotrauma, 29(13), pp. 2352-2364; Svetlov et al., 2010, "Morphologic and Biochemical Characterization of Brain Injury in a Model of Controlled Blast Overpressure Exposure," J. Trauma, 69(4), pp. 795-804]. Under the same blast input conditions, minimizing head acceleration led to a corresponding elimination of righting time deficits. However, we could still achieve righting time deficits under minimal acceleration conditions by significantly increasing the peak blast overpressure. Together, these data show the importance of characterizing the effect of blast overpressure on head kinematics, with the goal of producing models focused on understanding the effects of blast overpressure on the brain without the complicating factor of superimposed head accelerations.

Acute axillary lymphadenopathy detected shortly after COVID-19 vaccination found to be due to newly diagnosed metastatic melanoma.

As the administration of COVID-19 vaccines continues to increase, so too does awareness of the associated ipsilateral axillary lymphadenopathy. This has created a diagnostic challenge in the field of radiology, in particular among patients with cancer, as post-vaccination reactive adenopathy has been reported to be mistakenly interpreted as malignancy. As radiology departments improve their protocols for obtaining vaccine-related patient history, and radiologists become acclimated to attributing axillary lymphadenopathy to recent COVID-19 vaccination, there is a risk of the pendulum swinging too far and under-diagnosing true oncologic disease. This report describes an otherwise healthy 53-year-old man who presented with discomfort due to ipsilateral axillary lymphadenopathy shortly after receiving a COVID-19 vaccine. Fine needle aspiration performed within 2 months of receiving the vaccine revealed metastatic melanoma and subsequent 18F-FDG PET/CT demonstrated intensely avid axillary and supraclavicular adenopathy without visualization of a primary lesion. This case serves as a cautionary report to remind clinicians to remain suspicious of possible underlying malignancy with the presence of axillary adenopathy, despite a history of recent COVID-19 vaccination.

Does Intraprocedural CT Improve the Success Rate of Adrenal Venous Sampling? A Systematic Review and Meta-Analysis of Data from 809 Patients.

PURPOSE: To perform a systematic review and meta-analysis to quantify the technical success rate of adrenal venous sampling (AVS) with and without intraprocedural computed tomography (CT). METHODS: A systematic search of the Medline, Scopus, EMBASE, and Web of Science databases for comparative studies using intraprocedural CT was undertaken. More than 1,000 records were screened using titles and abstracts. Full texts of 121 studies were reviewed and 14 eligible studies were identified. Nine studies had adequate comparative data and were included in the meta-analysis. RESULTS: A research synthesis was performed and data from 809 patients were pooled in multiple random effect models. Overall success rate of AVS without and with intraprocedural CT was 72.7% (59.3-83.0%) and 92.5% (86.6-95.9), respectively. The addition of intraprocedural CT increased the technical success rate by 19.8% (P < 0.001), with an odds ratio (OR) of 5.5 (3.3-9.2; P < 0.01). In meta-regression, odds of success with intraprocedural CT was associated with younger age (beta: 0.16 ± 0.05; P:0.001), higher body mass index (BMI; beta:0.08 ± 0.03; P:0.002), and higher selectivity index (defined as the ratio of cortisol in the adrenal vein to that in the inferior vena cava; beta:0.35 ± 0.08, P < 0.001). We found a linear inverse association between operator's success without CT and improved success with intraprocedural CT (R2: 0.86). CONCLUSIONS: Intraprocedural CT is not required for every case, but can be performed in difficult cases or when operators' success is limited. The benefit was more pronounced in younger patients with higher BMI, female gender, and with higher selectivity. LEVEL OF EVIDENCE: III Systematic review and meta-analysis of non-randomized clinical trials.

Trends in Intraoperative Assessment of Spinal Alignment: A Survey of Spine Surgeons in the United States.

STUDY DESIGN: Survey. OBJECTIVES: To characterize national practices of and shortcomings surrounding intraoperative assessments of spinal alignment. METHODS: Spine surgeons in the US were surveyed to analyze their experience with assessing spinal alignment intraoperatively. RESULTS: 108 US spine surgeons from 77 surgical centers with an average of 19.2 + 8.8 years of surgical experience completed the survey. To assess alignment intraoperatively, 84% (91/108) use C-arm or spot radiographs, 40% (43/108) use full-length radiographs, and 20% utilize the T-bar (22/108). 88% of respondents' surgical centers (93/106) possessed a navigation camera and 63% of respondents (68/108) report using surgical navigation for 40% of their deformity cases on average. Reported deterrents for using current technology to assess alignment were workflow interruption (54%, 58/108), expense (33%, 36/108), and added radiation exposure (26%, 28/108). 87% of respondents (82/94) reported a need for improvement in current capabilities of making intraoperative assessments of spinal alignment. CONCLUSIONS: Corrective surgery for spinal deformity is a complex procedure that requires a high level of expertise to perform safely. The majority of surveyed surgeons primarily rely on radiographs for intraoperative assessments of alignment. Despite the majority of surveyed surgical practices possessing navigation cameras, they are utilized only for a minority of spinal deformity cases. With the majority of surveyed surgeons reporting a need for improvement in technology to assess spinal alignment intraoperatively, 3 of the top design considerations should include workflow interruption, expense, and radiation exposure.

Implementation of a Standardized Multimodal Postoperative Analgesia Protocol Improves Pain Control, Reduces Opioid Consumption, and Shortens Length of Hospital Stay After Posterior Lumbar Spinal Fusion.

BACKGROUND: Multimodal analgesia regimens have been suggested to improve pain control and reduce opioid consumption after surgery. OBJECTIVE: To institutionally implement an evidence-based quality improvement initiative to standardize and optimize pain treatment following neurosurgical procedures. Our goal was to objectively evaluate efficacy of this multimodal protocol. METHODS: A retrospective cohort analysis of pain-related outcomes after posterior lumbar fusion procedures was performed. We compared patients treated in the 6 mo preceding (PRE) and 6 mo following (POST) protocol execution. RESULTS: A total of 102 PRE and 118 POST patients were included. The cohorts were well-matched regarding sex, age, surgical duration, number of segments fused, preoperative opioid consumption, and baseline physical status (all P > .05). Average patient-reported numerical rating scale pain scores significantly improved in the first 24 hr postoperatively (5.6 vs 4.5, P < .001) and 24 to 72 hr postoperatively (4.7 vs 3.4, P < .001), PRE vs POST, respectively. Maximum pain scores and time to achieving appropriate pain control also significantly improved during these same intervals (all P < .05). A concomitant decrease in opioid consumption during the first 72 hr was seen (110 vs 71 morphine milligram equivalents, P = .02). There was an observed reduction in opioid-related adverse events per patient (1.31 vs 0.83, P < .001) and hospital length of stay (4.6 vs 3.9 days, P = .03) after implementation of the protocol. CONCLUSION: Implementation of an evidence-based, multimodal analgesia protocol improved postoperative outcomes, including pain scores, opioid consumption, and length of hospital stay, after posterior lumbar spinal fusion.

Evaluation of select biocompatible markers for labelling peripheral nerves on 11.7 T MRI.

BACKGROUND: Peripheral nerve injury is often followed by a highly variable recovery process with respect to both rapidity and efficacy. Identifying post-nerve injury phenomena is key to assessing the merit and timing of surgery as well as to tracking nerve recovery postoperatively. Diffusion Tensor Imaging (DTI) has been investigated in the clinical and research settings as a noninvasive technique to both assess and monitor each patient's unique case of peripheral nerve damage. NEW METHOD: We identify a MRI-suitable marker for tracking the exact site of either nerve injury or coaptation following surgical repair to aid with DTI analysis. RESULTS: Due to artefact and disruption of tractography, silver wire and microvascular clips were not suitable markers. AxoGuard®, 4-0 vicryl suture, and 10-0 polyamide suture, although detectable, did not produce a signal easily distinguished from post-surgical changes. Silicone was easily identifiable and stable in both the acute and delayed time points, exhibited negligible impact on DTI parameters, and possessed geometry to prevent nerve strangulation. COMPARISON WITH EXISTING METHOD: Prior studies have not assessed the efficacy of other markers nor have they assessed silicone for potential artefact with DTI parameter analysis. Furthermore, this work demonstrates the reliability and compatibility of silicone in the delayed postoperative time period and includes its unique imaging appearance on high-resolution 11.7 MRI. CONCLUSION: Semi-cylindrical silicone tubing can be used as a safe, reliable, and readily available radiological marker to visualize and monitor a region of interest on a rodent's peripheral nerve for aiding assessments with diffusion tensor imaging.

"Hiker's feet": a novel cutaneous finding in the inflammatory myopathies.

Mechanic's hands is a well-characterized manifestation of select idiopathic inflammatory myopathy (IIM) syndromes. Less well characterized is the hyperkeratosis of the toes and plantar surface of the feet that can also accompany these disorders. We aim to describe common pedal signs in the context of IIM, and suggest that it may be another key feature in the presentation of these syndromes. A cohort of 2145 myositis patient charts gathered since 2003 were retrospectively reviewed using the key search terms "mechanic's feet" and/or "mechanic's foot." Charts that included either phrase were further reviewed for clinical characteristics. Nine patients were identified with documentation describing "mechanic's feet" or "mechanic's foot." All nine affected individuals carried a diagnosis of DM, seven of whom also met criteria for antisynthetase syndrome. In eight patients (89%), it presented in conjunction with mechanic's hands. Six (67%) presented with anti-Jo-1 antibodies, and three (33%) were seronegative. Although the term "mechanic's feet" has been used to describe this clinical finding in patients in our myositis cohort, we propose the term "hiker's feet," given that the presentation resembles a callousing pattern more typical of avid hikers or long-distance walkers. Prevalence data are not yet known but should be considered for further study. If the presenting signs of IIM are expanded to include hiker's feet, it could aid in not only diagnosis and management but also provide insights into the pathophysiology of these diseases.

HIF-1α- Targeting Acriflavine Provides Long Term Survival and Radiological Tumor Response in Brain Cancer Therapy.

Tumor progression, limited efficacy of current standard treatments, and the rise in patient mortality are associated with gene expression caused by the synergistic action of intratumoral hypoxia and HIF-1α activation. For this reason, recent investigations have focused on HIF-targeting therapeutic agents, with encouraging preclinical and clinical results in solid tumors. Here we describe the efficacy of a HIF-1α inhibitor, Acriflavine, and demonstrate its potency against brain cancer. This safe antibacterial dye induces cell death and apoptosis in several glioma cell lines, targets HIF-1α-mediated pathways, and decreases the level of PGK1, VEGF and HIF-1α in vitro and in vivo. Administered locally via biodegradable polymers, Acriflavine provides significant benefits in survival resulting in nearly 100% long term survival, confirmed by MRI and histological analyses. This study reports preclinical evidence that this safe, small molecule can contribute to brain tumor therapy and highlights the significance of HIF-1α-targeting molecules.

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies.

Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the impedance of the blood brain barrier (BBB), and the lack of therapeutic agents that can selectively target the intracranial tumor environment. To overcome such barriers, a number of chemotherapeutic agents and nucleic acid-based therapies are rapidly being synthesized and tested as new brain tumor-targeted delivery strategies. Novel carriers include liposomal and polymeric nanoparticles, wafers, microchips, microparticle-based nanoplatforms and cells-based vectors. Strong preclinical results suggest that these nanotechnologies are set to transform the therapeutic paradigm for brain tumor treatment. In addition to new tumoricidal agents, parallel work is also being conducted on the BBB front. Preclinical testing of chemical and physical modulation strategies is yielding improved intracranial concentrations. New diagnostic and therapeutic imaging techniques, such as high-intensity focused ultrasound and MRI-guided focused ultrasound, are being used to modulate the BBB in a more precise and non-invasive manner. This review details some of the tremendous advances that are being explored in current brain tumor targeted therapies, including local implant development, nanobiotechnology-based delivery strategies, and techniques of BBB manipulation.

Polylactic acid (PLA) controlled delivery carriers for biomedical applications.

Polylactic acid (PLA) and its copolymers have a long history of safety in humans and an extensive range of applications. PLA is biocompatible, biodegradable by hydrolysis and enzymatic activity, has a large range of mechanical and physical properties that can be engineered appropriately to suit multiple applications, and has low immunogenicity. Formulations containing PLA have also been Food and Drug Administration (FDA)-approved for multiple applications making PLA suitable for expedited clinical translatability. These biomaterials can be fashioned into sutures, scaffolds, cell carriers, drug delivery systems, and a myriad of fabrications. PLA has been the focus of a multitude of preclinical and clinical testing. Three-dimensional printing has expanded the possibilities of biomedical engineering and has enabled the fabrication of a myriad of platforms for an extensive variety of applications. PLA has been widely used as temporary extracellular matrices in tissue engineering. At the other end of the spectrum, PLA's application as drug-loaded nanoparticle drug carriers, such as liposomes, polymeric nanoparticles, dendrimers, and micelles, can encapsulate otherwise toxic hydrophobic anti-tumor drugs and evade systemic toxicities. The clinical translation of these technologies from preclinical experimental settings is an ever-evolving field with incremental advancements. In this review, some of the biomedical applications of PLA and its copolymers are highlighted and briefly summarized.

Primary blast injury causes cognitive impairments and hippocampal circuit alterations.

Blast-induced traumatic brain injury (bTBI) and its long term consequences are a major health concern among veterans. Despite recent work enhancing our knowledge about bTBI, very little is known about the contribution of the blast wave alone to the observed sequelae. Herein, we isolated its contribution in a mouse model by constraining the animals' heads during exposure to a shockwave (primary blast). Our results show that exposure to primary blast alone results in changes in hippocampus-dependent behaviors that correspond with electrophysiological changes in area CA1 and are accompanied by reactive gliosis. Specifically, five days after exposure, behavior in an open field and performance in a spatial object recognition (SOR) task were significantly different from sham. Network electrophysiology, also performed five days after injury, demonstrated a significant decrease in excitability and increase in inhibitory tone. Immunohistochemistry for GFAP and Iba1 performed ten days after injury showed a significant increase in staining. Interestingly, a threefold increase in the impulse of the primary blast wave did not exacerbate these measures. However, we observed a significant reduction in the contribution of the NMDA receptors to the field EPSP at the highest blast exposure level. Our results emphasize the need to account for the effects of primary blast loading when studying the sequelae of bTBI.

Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival.

There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than Lipofectamine™ 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell-based cancer-targeting therapies.

Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo.

Biodegradable polymeric nanoparticles have the potential to be safer alternatives to viruses for gene delivery; however, their use has been limited by poor efficacy in vivo. In this work, we synthesize and characterize polymeric gene delivery nanoparticles and evaluate their efficacy for DNA delivery of herpes simplex virus type I thymidine kinase (HSVtk) combined with the prodrug ganciclovir (GCV) in a malignant glioma model. We investigated polymer structure for gene delivery in two rat glioma cell lines, 9L and F98, to discover nanoparticle formulations more effective than the leading commercial reagent Lipofectamine 2000. The lead polymer structure, poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-modified with 1-(3-aminopropyl)-4-methylpiperazine, is a poly(ß-amino ester) (PBAE) and formed nanoparticles with HSVtk DNA that were 138 ± 4 nm in size and 13 ± 1 mV in zeta potential. These nanoparticles containing HSVtk DNA showed 100% cancer cell killing in vitro in the two glioma cell lines when combined with GCV exposure, while control nanoparticles encoding GFP maintained robust cell viability. For in vivo evaluation, tumor-bearing rats were treated with PBAE/HSVtk infusion via convection-enhanced delivery (CED) in combination with systemic administration of GCV. These treated animals showed a significant benefit in survival (p = 0.0012 vs control). Moreover, following a single CED infusion, labeled PBAE nanoparticles spread completely throughout the tumor. This study highlights a nanomedicine approach that is highly promising for the treatment of malignant glioma.

An open-source toolbox for automated phenotyping of mice in behavioral tasks.

Classifying behavior patterns in mouse models of neurological, psychiatric and neurodevelopmental disorders is critical for understanding disease causality and treatment. However, complete characterization of behavior is time-intensive, prone to subjective scoring, and often requires specialized equipment. Although several reports describe automated home-cage monitoring and individual task scoring methods, we report the first open source, comprehensive toolbox for automating the scoring of several common behavior tasks used by the neuroscience community. We show this new toolbox is robust and achieves equal or better consistency when compared to manual scoring methods. We use this toolbox to study the alterations in behavior that occur following blast-induced traumatic brain injury (bTBI), and study if these behavior patterns are altered following genetic deletion of the transcription factor Ets-like kinase 1 (Elk-1). Due to the role of Elk-1 in neuronal survival and proposed role in synaptic plasticity, we hypothesized that Elk-1 deletion would improve some neurobehavioral deficits, while impairing others, following blast exposure. In Elk-1 knockout (KO) animals, deficits in open field, spatial object recognition (SOR) and elevated zero maze performance after blast exposure disappeared, while new significant deficits appeared in spatial and associative memory. These are the first data suggesting a molecular mediator of anxiety deficits following bTBI, and represent the utility of the broad screening tool we developed. More broadly, we envision this open-source toolbox will provide a more consistent and rapid analysis of behavior across many neurological diseases, promoting the rapid discovery of novel pathways mediating disease progression and treatment.