Distinctive patterns of sequential platelet counts following blunt traumatic brain injury predict outcomes.

OBJECTIVE: To determine the role of platelet counts in the context of the decision to treat patients with non-compounded, non-surgically-treated blunt traumatic brain injury (NCNS-bTBI) with anticoagulants/antiaggregants. METHODS: A retrospective analysis of 141 anticoagulants/antiaggregants-naïve patients with NCNS-bTBI. Changes in PT-INR and prolonged aPTT were examined and correlated with Marshall and Rotterdam scores, clinical and neuroradiological outcomes. RESULTS: Three groups of platelet counts were identified. Group 1 (83% of patients) had normal platelet counts (150,000-450,000 platelets/mm3) from admission to discharge. Group 2 (13%) developed transient thrombocytopenia (<150,000 platelets/mm3) 2-3 days post-trauma. Group 3 (4%) developed extreme thrombocytosis > 1,000,000/mm3 platelets 6-9 days post-trauma. Neither acute coagulopathy of trauma nor progressive hemorrhagic insults followed NCNS-bTBI. Moreover, while patients with thrombocytosis/extreme thrombocytosis presented with a worse Glasgow coma score (GCS) on admission (8.8 ± 2.9 vs. 13 ± 2, p < 0.01) and had longer hospitalization (13.5 ± 10.4 vs. 4.5 ± 2.1 days), their improvement at discharge was the highest (delta GCS, 4 ± 2.8 vs. 1.2 ± 2.1, p = 0.05). Traumatic subarachnoid hemorrhage was associated with isolated thrombocytosis and 'best improvement.' No thromboembolic or hemorrhagic complications occurred. CONCLUSION: NCNS-bTBI, thrombocytosis was correlated with better outcomes and was not associated with an increased risk for developing thromboembolism or hemorrhage, precluding the immediate need for any additional antiaggregates.

Image Synthesis Pipeline for CNN-Based Sensing Systems.

The rapid development of machine learning technologies in recent years has led to the emergence of CNN-based sensors or ML-enabled smart sensor systems, which are intensively used in medical analytics, unmanned driving of cars, Earth sensing, etc. In practice, the accuracy of CNN-based sensors is highly dependent on the quality of the training datasets. The preparation of such datasets faces two fundamental challenges: data quantity and data quality. In this paper, we propose an approach aimed to solve both of these problems and investigate its efficiency. Our solution improves training datasets and validates it in several different applications: object classification and detection, depth buffer reconstruction, panoptic segmentation. We present a pipeline for image dataset augmentation by synthesis with computer graphics and generative neural networks approaches. Our solution is well-controlled and allows us to generate datasets in a reproducible manner with the desired distribution of features which is essential to conduct specific experiments in computer vision. We developed a content creation pipeline targeted to create realistic image sequences with highly variable content. Our technique allows rendering of a single 3D object or 3D scene in a variety of ways, including changing of geometry, materials and lighting. By using synthetic data in training, we have improved the accuracy of CNN-based sensors compared to using only real-life data.

Comparative immunogenicity and efficacy of thermostable (lyophilized) and liquid formulation of anthrax vaccine candidate AV7909.

The anthrax vaccine candidate AV7909 is being developed as a next-generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the anthrax vaccine adsorbed (AVA) (Emergent BioSolutions Inc., Lansing, MI) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. Emergent has produced a thermostable (lyophilized) formulation of AV7909 vaccine utilizing drying technology. The purpose of the study described here was to assess the immunogenicity and efficacy of the lyophilized formulation of the AV7909 vaccine candidate as compared with the liquid formulation in the guinea pig general-use prophylaxis (GUP) model. The study also provides initial information on the relationship between the immune response induced by the thermostable formulation of the vaccine, as measured by the toxin neutralization assay (TNA), and animal survival following lethal anthrax aerosol challenge. Results demonstrated that there were no significant differences in the immunogenicity or efficacy of lyophilized AV7909 against lethal anthrax spore aerosol challenge in the guinea pig model as compared to liquid AV7909. For both vaccine formulations, logistic regression modeling showed that the probability of survival increased as the pre-challenge antibody levels increased.

Combined treatment approach to cerebral arteriovenous malformation in pediatric patients: stereotactic radiosurgery to partially Onyx-embolized AVM.

PURPOSE: Treatment of cerebral arteriovenous malformations (AVM)-the most common cause of stroke in the pediatric population-can be challenging due to the complexity of size, morphology, and location. There is a significant risk in comparison to AVM treatment among adults. Thus, AVM treatment in the pediatric population imposes unique challenges. Recent improvements include optimized catheter techniques and better embolization materials, such as Onyx, a non-adhesive liquid embolic agent used in the adult population. These improvements have increased the success rate of total and near-total obliteration of cerebral AVM. However, the use of Onyx causes significant distortion of the MR and CT images, which must be accounted for in any radiation treatment planning predicated on CT and MRI. These image distortions impact on the actual delivered dose to the nidus and behoove heterogeneity correction. Our group has previously shared a solution for heterogeneity correction in the adult population. The purpose of this study is to show our experience in this unique group of pediatric patients. METHODS: This is a retrospective review of pediatric patients, who were undergoing combined endovascular embolization followed by SRS. The cohort consists of 14 patients undergoing SRS treatment in our institute between November 2006 and December 2012 with a mean follow-up of 49.9 months. Within this cohort, we retrospectively reviewed 12 consecutive pediatric patients who underwent a combined endovascular and SRS approach with a mean follow-up of 52.1 months and two patients receiving SRS-only treatment were excluded. RESULTS: In our cohort of 14 patients, 7 (50%) were male, with a mean age of 17.3 years (12.0-22.9) at the time of radiosurgery treatment. Mean age of beginning the combined modality treatment was 15.3 years (8.4-20). The median time from diagnosis to SRS was 24.3 months (11.1-64.4 months) in the complete cohort and 25.6 months (11.1-64.4) in the multimodality group. The overall median follow-up period was 49.9 months (range 12.8-118.8 months) in the complete cohort and 52.1 months (range 12.8-118.8 months) in the multimodality group. Eleven (78.6%) patients had at least one episode of hemorrhage prior to treatment. Spezler-Martin grades at baseline ranged from 2 to 5 (mean 3.2). Fifty percent had grade IV and V. Patients underwent a median of 2 (range 1-5) embolization procedures. The radiosurgical treatment dose to the margin of the angiography-based nidus: median prescription dose of 21.49 Gy (14.39-27.51) with a median max dose of 27.77 Gy (18.93-32.52). The median treatment volume was 0.6 cm3 (0.1-7.3 cm3). The Onyx embolization reduced the nidus target volume by a median of 66.7% (12.0-92.7%). We confirmed 10/14 (71%) complete closures. In 2/14 (14.2%) additional patients, a significant flow reduction was noted. In 1/14 (7.1%) patients, no significant change was noted during the observation period and two (14.2%) patients were without follow-up information. In two patients, post-treatment edema was noted; however, none was clinically significant and resolved without additional intervention or treatment. CONCLUSIONS: This cohort comprises the largest combined Onyx-SRS pediatric experience in the literature. In conjunction with our adult group study, we show that the use of Onyx reduces the SRS treatment target volume significantly. Importantly, we implemented the heterogeneity correction to avoid increased radiation exposure to normal surrounding brain tissue. The combined approach appears to be safe provided that the above-mentioned corrections are implemented.

Impact of Onyx Embolization on Radiosurgical Management of Cerebral Arteriovenous Malformations: Treatment and Outcome.

BACKGROUND: Stereotactic radiosurgery (SRS) is a well-established treatment modality for cerebral arteriovenous malformations (AVMs). The main limiting factor in the radiosurgical treatment of AVMs is the volume of the nidus, with high-grade lesions often requiring combined treatment to reduce the SRS target volume. To overcome this limitation, we have been using a combined treatment approach consisting of endovascular embolization with Onyx followed by SRS. OBJECTIVE: To evaluate our clinical experience for safety and feasibility of this multimodality treatment approach. METHODS: This is a retrospective review of all adult patients with cerebral AVMs who received SRS treatment to their AVM after endovascular embolization with Onyx between June 2007 and June 2014. RESULTS: Thirty-five consecutive patients were identified. The mean follow-up period was 52.4 ± 22.6 months (range 18-97 months). We confirmed 18 (51.4%) complete nidus closures at a median time of 49.5 months (range 6.5-81 months) from SRS. High-resolution Magnetic resonance imaging/magnetic resonance angiography was performed routinely in all patients until closure of the nidus. Digital subtraction angiography was performed to confirm complete obliteration in 5 of the patients (28%); 13 patients are either planned for digital subtraction angiography or have refused it. In 6 patients (17%) a significant flow reduction was noted after a mean of 32 ± 16 months. No significant improvement was observed in 9 patients (26%) during the follow-up period. Two patients were lost to follow-up. CONCLUSIONS: The multimodality treatment of cerebral AVMs using embolization with Onyx followed by SRS is feasible and safe. The use of Onyx significantly reduced the SRS treatment target volume.

Critical appraisal of endovascular treatment of brain arteriovenous malformation using Onyx in a series of 92 consecutive patients.

BACKGROUND: The introduction of Onyx has led us to adopt a new treatment approach for brain arteriovenous malformation (AVM), using endovascular embolization with Onyx as the first line treatment with a curative intent. The aim of the present report is to evaluate our results using this strategy, with special emphasis on angiographic characteristics affecting treatment risks and success rates. METHODS: From October 2006 to December 2009, 92 consecutive patients harboring brain AVM were treated with Onyx during 177 procedures. RESULTS: Endovascular treatments were completed in 68 out of 92 patients. Median number of procedures was two. Complete obliteration using embolization exclusively was achieved in 25 patients, resulting in a 37 % cure rate in patients who concluded treatments (25/68), and 27 % in the cohort. In Spetzler-Martin grades 1 & 2 AVMs, complete obliteration was achieved in 48 % of the cases. Complete obliteration rates were significantly higher in lesions with superficial big feeding arteries. There were 15 bleeding complications during 177 embolization sessions (8.4 % per procedure); seven cases resolved in less than 3 months. Permanent disability rate was 6.5 %; mortality rate was 2.2 %. Bleeding was related to the use of the microcatheter/guidewire in six cases and to the use of the embolization material in nine, the amount of Onyx injected was significantly higher in those nine cases. CONCLUSIONS: Embolization of brain AVM using Onyx and detachable tip microcatheters results in a relatively high rate of complete obliteration. Angioarchitecture of the lesion can predict treatment success. Higher amounts of Onyx injected per session increase the bleeding risk.

Transcutaneous immunization with Intercell's vaccine delivery system.

Transcutaneous immunization (TCI) has become an attractive alternate route of immunization due to increase understanding of the skin immune system and to recent technical innovations in skin patch delivery systems. Basic principles of TCI have been demonstrated in animal and human studies, covering a variety of bacterial, viral, and cancer diseases. At Intercell, we have advanced two major platforms of TCI: 1) a needle-free vaccine delivery patch (VDP) and 2) a vaccine enhancement patch (VEP). Simplified, the VDP contains an antigen with or without an adjuvant that is administered on the skin; while the VEP contains only the adjuvant and is used in combination with an injected vaccine. In many of our TCI studies, the VDP or VEP is routinely applied on pretreated skin, in which the stratum corneum has been partially removed by mild abrasion. Recently, we have achieved technical breakthroughs in formulating and stabilizing vaccines in a dry patch format. For instance, a microplate-based screening process has been implemented to rapidly identify excipients, singularly or in combination, to stabilize biological macromolecules in patch blend formulations. A second technical innovation is our nonwoven (patch) disc matrix-supported drying technology, which allows efficient drying of our patch formulation blend to produce dry stable dosage forms of VDP or VEP. The low cost and the facileness in the manufacturing of VDP (or VEP) combined with the development of thermostable dry patches should improve the supply chain efficiency and reduce the dependence on cold chain.

Radiosurgical treatment planning of AVM following embolization with Onyx: possible dosage error in treatment planning can be averted.

Treatment of arteriovenous malformations (AVM) of the brain is challenging due to the size and location of the nidus-proper and its proximity to the cerebrovascular circulation. Recent advances in catheter techniques and new embolization materials such as Onyx (a liquid agent that is less adhesive and slowly polymerizing) have increased the probability of achieving obliteration. When planning radiosurgical cases following such embolization, however, one must be cognizant of the distortions introduced by this novel substance on imaging studies. A sample of Onyx was irradiated to define the attenuation per mm thickness. The difference in attenuation compared to water was determined. Dose calculations were performed using 3 methods of inhomogeneity corrections. Homogeneous calculations were compared to "standard" heterogeneity corrections and to "modified" heterogeneity corrections by assigning individual electron densities to the normal brain and the Onyx. The difference between the attenuation of water in comparison to the Onyx was approximately 3% for beam energy of 6 MV. Best calculation results were achieved when using the modified inhomogeneity corrections which were based on the actual attenuation of the Onyx. The use of Onyx caused significant image artifact on MR and especially CT. As such, a correction must be manually introduced into the planning system to account for this potential error. Otherwise, dose calculation may be unreliable and could have dire consequences for patients receiving high doses of radiotherapy.

Domain formation in membranes caused by lipid wetting of protein.

Formation of rafts and other domains in cell membranes is considered as wetting of proteins by lipids. The membrane is modeled as a continuous elastic medium. Thermodynamic functions of the lipid films that wet proteins are calculated using a mean-field theory of liquid crystals as adapted to biomembranes. This approach yields the conditions necessary for a macroscopic wetting film to form; its thickness could also be determined. It is shown that films of macroscopic thicknesses form around large (tens nanometers in diameter) lipid-protein aggregates; only thin adsorption films form around single proteins or small complexes. The means by which wetting films can facilitate the merger of these aggregates is considered. It is shown that a wetting film prevents a protein from leaving an aggregate. Using experimentally derived values of elastic moduli and spontaneous curvatures as well as height mismatch between aggregates and bulk membrane, we obtained numerical results, which can be compared with the experimental data.

Transcutaneous delivery and thermostability of a dry trivalent inactivated influenza vaccine patch.

A patch containing a trivalent inactivated influenza vaccine (TIV) was prepared in a dried, stabilized formulation for transcutaneous delivery. When used in a guinea pig immunogenicity model, the dry patch was as effective as a wet TIV patch in inducing serum anti-influenza IgG antibodies. When the dry TIV patch was administered with LT as an adjuvant, a robust immune response was obtained that was comparable with or better than an injected TIV vaccine. When stored sealed in a nitrogen-purged foil, the dry TIV patch was stable for 12 months, as measured by HA content, under both refrigerated and room temperature conditions. Moreover, the immunological potency of the vaccine product was not affected by long-term storage. The dry TIV patch was also thermostable against three cycles of alternating low-to-high temperatures of -20/25 and -20/40 degrees C, and under short-term temperature stress conditions. These studies indicate that the dry TIV patch product can tolerate unexpected environmental stresses that may be encountered during shipping and distribution. Because of its effectiveness in vaccine delivery and its superior thermostable characteristics, the dry TIV patch represents a major advance for needle-free influenza vaccination.

Analysis of the thermal and pH stability of human respiratory syncytial virus.

Respiratory syncytial virus (RSV) was studied as a function of pH (3-8) and temperature (10-85 degrees C) by fluorescence, circular dichroism, and high-resolution second-derivative absorbance spectroscopies, as well as dynamic light scattering and optical density as a measurement of viral aggregation. The results indicate that the secondary, tertiary, and quaternary structures of RSV are both pH and temperature labile. Derivative ultraviolet absorbance and fluorescence spectroscopy (intrinsic and extrinsic) analyses suggest that the stability of tertiary structure of RSV proteins is maximized near neutral pH. In agreement with these results, the secondary structure of RSV polypeptides seems to be more stable at pH 7-8, as evaluated by circular dichroism spectroscopy. The integrity of the viral particles studied by turbidity and dynamic light scattering also revealed that RSV is more thermally stable near neutral pH and particularly prone to aggregation below pH 6. By combination of the spectroscopic data employing a multidimensional eigenvector phase space approach, an empirical phase diagram for RSV was constructed. The pharmaceutical utility of this approach and the optimal formulation conditions are discussed.