Multimodal assessment improves neuroprognosis performance in clinically unresponsive critical-care patients with brain injury.

Accurately predicting functional outcomes for unresponsive patients with acute brain injury is a medical, scientific and ethical challenge. This prospective study assesses how a multimodal approach combining various numbers of behavioral, neuroimaging and electrophysiological markers affects the performance of outcome predictions. We analyzed data from 349 patients admitted to a tertiary neurointensive care unit between 2009 and 2021, categorizing prognoses as good, uncertain or poor, and compared these predictions with observed outcomes using the Glasgow Outcome Scale-Extended (GOS-E, levels ranging from 1 to 8, with higher levels indicating better outcomes). After excluding cases with life-sustaining therapy withdrawal to mitigate the self-fulfilling prophecy bias, our findings reveal that a good prognosis, compared with a poor or uncertain one, is associated with better one-year functional outcomes (common odds ratio (95% CI) for higher GOS-E: OR = 14.57 (5.70-40.32), P < 0.001; and 2.9 (1.56-5.45), P < 0.001, respectively). Moreover, increasing the number of assessment modalities decreased uncertainty (OR = 0.35 (0.21-0.59), P < 0.001) and improved prognostic accuracy (OR = 2.72 (1.18-6.47), P = 0.011). Our results underscore the value of multimodal assessment in refining neuroprognostic precision, thereby offering a robust foundation for clinical decision-making processes for acutely brain-injured patients. ClinicalTrials.gov registration: NCT04534777 .

Computer-aided Evaluation of Polyvalent Medications' Pharmacological Potential. Multiphytoadaptogen as a Case Study.

Many human diseases including cancer, degenerative and autoimmune disorders, diabetes and others are multifactorial. Pharmaceutical agents acting on a single target do not provide their efficient curation. Multitargeted drugs exhibiting pleiotropic pharmacological effects have certain advantages due to the normalization of the complex pathological processes of different etiology. Extracts of medicinal plants (EMP) containing multiple phytocomponents are widely used in traditional medicines for multifactorial disorders' treatment. Experimental studies of pharmacological potential for multicomponent compositions are quite expensive and time-consuming. In silico evaluation of EMP the pharmacological potential may provide the basis for selecting the most promising directions of testing and for identifying potential additive/synergistic effects. Multiphytoadaptogen (MPhA) containing 70 major phytocomponents of different chemical classes from 40 medicinal plant extracts has been studied in vitro, in vivo and in clinical researches. Antiproliferative and anti-tumor activities have been shown against some tumors as well as evidence-based therapeutic effects against age-related pathologies. In addition, the neuroprotective, antioxidant, antimutagenic, radioprotective, and immunomodulatory effects of MPhA were confirmed. Analysis of the PASS profiles of the biological activity of MPhA phytocomponents showed that most of the predicted anti-tumor and anti-metastatic effects were consistent with the results of laboratory and clinical studies. Antimutagenic, immunomodulatory, radioprotective, neuroprotective and anti-Parkinsonian effects were also predicted for most of the phytocomponents. Effects associated with positive effects on the male and female reproductive systems have been identified too. Thus, PASS and PharmaExpert can be used to evaluate the pharmacological potential of complex pharmaceutical compositions containing natural products.

SCIENCE-BASED APPROACH TO THE EXPERIMENTAL DEVELOPMENT OF A BIODEGRADABLE CHITOSAN BASED CARRIER.

The aim of the study was to develop a science-based approach to the development of a carrier of a pharmaceutical substance using the modification of chitosan. Studies were carried out to determine the upper limit of acidity - ascorbic and acetic to obtain salt forms of chitosan, the choice of modification of chitosan and the experimental development of a method for obtaining its solid salt form. A scientifically based approach to research has made it possible to develop a technology for obtaining a water-soluble biodegradable carrier based on salt forms of chitosan. The experimental approach to research made it possible to establish the upper limit of the acidity of the medium, at which transparent solutions of chitosan were obtained, for acetic and ascorbic acids, which are necessary for modifying the native form of chitosan and obtaining its salt forms. Taking into account the better organoleptic properties compared to chitosan acetate, as well as higher pH values, which are close to the pH of wound exudate, and higher viscosities of the obtained solutions of salt forms of chitosan, it was possible to select a water-soluble form - chitosan ascorbate for further development of the composition of the dosage form. The optimal mode of freeze-drying in laboratory conditions was established to obtain a solid form of chitosan ascorbate with the following parameters: freezing for 2-3 hours at a temperature of minus 80 °C; drying mode for 40 hours, pressure - 0.34 mbar; post-drying mode for 8 hours, pressure - 0.12 mbar; condenser temperature minus 80°C.

IN SILICO PROFILING OF THE NEW ALLOSTERIC MODULATOR OF AMPA RECEPTORS.

The aim of this study is to investigate the computer-aided prediction of pharmacological activity and mechanisms of action of 6-[4-methoxy-3-(1H-pyrazol-1-ylmethyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trione (TCT-9). The compound was designed for modulation of ionotropic glutamate AMPA receptors, and its affinity for the receptor has been earlier proven experimentally. A cognitive stimulating effect of TCT-9 has been shown using a model of freezing behavior in mice. The drug candidate TCT-9 is now under the development process: it is intended for the treatment of cognitive impairments in case of brain injury. Following the existing requirements, the present study was carried out in the framework of secondary pharmacodynamic studies to determine possible off-target effects and interaction of the compound with regulatory signaling and metabolic networks/pathways. In silico study of the TCT-9 binding to pharmacologically significant targets and the new AMPA receptor modulator's effects on signaling pathways was carried out by the analysis of structure-activity relationships. Prediction of biological activity spectra was performed using PASS (Prediction of Activity Spectra for Substances), which estimates the probabilities for more than five thousand biological activities. The PharmaExpert program assessed information on the belonging of the targets predicted by the PASS program to the signaling and metabolic pathways. The prediction results are the basis for the experimental verification of the binding of the TCT-9 to the steroid hormone receptor ERR1 and further studies of the drug activity in animal models of diseases.

ANALYSIS OF THE PROPERTIES OF NEW PAM AMPA RECEPTORS BASED ON 3,7-DIAZABICYCLO[3.3.1]NONANE FRAME.

The development study was a continuation research of the action mechanism of the developed innovative pharmaceutical substance based on the 3,7-diazabicyclo[3.3.1]nonane derivative, which belongs to the class of AMPA receptor modulators. A significant amount of data has been accumulated on the pharmacology and mechanism of action of glutamate receptors, which are widely represented in the central nervous system of animals and humans. AMPA receptors are ionotropic and, along with receptors of other subtypes, are involved in glutamate-mediated excitatory signaling. Several subunits (GluRAl-GluRA4) are distinguished in the structure of the AMPA receptor, which exhibit different sensitivity to receptor ligands. Modulators of AMPA receptors exhibiting pharmacological activity were studied: derivatives of pyrrolidinones, benzothiadiazine dioxides, benzylpiperidines and biarylpropylsulfonamides. The aim of this study was to analyze the therapeutic potential of the mechanism of action of new positive allosteric modulators of AMPA receptors based on the derivative of 3,7-diazabicyclo[3.3.1]nonane framework. Based on the analysis of the spatial structure of the AMPA receptor, its complexes with the known PAM AMPA, and the results of their molecular docking, it was shown that compounds based on the tricyclic derivative 3,7-diazabicyclo[3.3.1]nonans bind to AMPA receptors at a fundamentally different location than ampakins from other known PAM AMPA groups. These compounds have the ability to facilitate AMPA-mediated glutamatergic neurotransmission to the central nervous system. According to the analyzed studies, AMPA receptor modulators are able to accelerate the period of convalescence after neurodegenerative states, exhibit an antidepressant effect, and have neuroprotective properties. The discovery of the ability of positive allosteric modulators of the AMPA receptor to induce the expression of neurotrophic factors BDNF and NGF, triggering the mechanisms responsible for the survival of existing functioning neurons, as well as growth and differentiation, the formation of new synapses makes the development of new drugs based on tricyclic derivatives of 3,7-diazabicyclo[3.3.1]nonane is especially promising for use in the later stages of post-stroke rehabilitation.

Can FDG-PET/MR help to overcome limitations of sequential MRI and PET-FDG for differential diagnosis between recurrence/progression and radionecrosis of high-grade gliomas?

The aim of our study was assessing the potential of FDG-PET-MRI to overcome limitations of separately performed MRI and PET-FDG and improving the performance of high-grade gliomas evaluation. Combined PET-MRI analysis allowed differentiating between recurrence/progression and radionecrosis with improved diagnostic accuracy (95% vs 63% for PET and 82% for MRI). FDG being a reliable, cost-saving tracer in this indication, combined FDG PET-MRI analysis could play a significant role in the follow-up of high-grade brain tumors.

Are Gadolinium-Enhanced MR Sequences Needed in Simultaneous 18F-FDG-PET/MRI for Tumor Delineation in Head and Neck Cancer?

BACKGROUND AND PURPOSE: PET/MRI with 18F-FDG has demonstrated the advantages of simultaneous PET and MR imaging in head and neck cancer imaging, MRI allowing excellent soft-tissue contrast, while PET provides metabolic information. The aim of this study was to evaluate the added value of gadolinium contrast-enhanced sequences in the tumor delineation of head and neck cancers on 18F-FDG-PET/MR imaging. MATERIALS AND METHODS: Consecutive patients who underwent simultaneous head and neck 18F-FDG-PET/MR imaging staging or restaging followed by surgery were retrospectively included. Local tumor invasion and lymph node extension were assessed in 45 head and neck anatomic regions using 18F-FDG-PET/MR imaging by 2 rater groups (each one including a radiologist and a nuclear medicine physician). Two reading sessions were performed, one without contrast-enhanced sequences (using only T1WI, T2WI, and PET images) and a second with additional T1WI postcontrast sequences. The results were compared with the detailed histopathologic analysis, used as reference standard. The κ concordance coefficient between the reading sessions and sensitivity and specificity for each region were calculated. RESULTS: Thirty patients were included. There was excellent agreement between the contrast-free and postgadolinium reading sessions in delineating precise tumor extension in the 45 anatomic regions studied (Cohen κ = 0.96, 95% CI = [0.94-0.97], P < .001). The diagnostic accuracy did not differ between contrast-free and postgadolinium reading sessions, being 0.97 for both groups and both reading sessions. For the 2 rater groups, there was good sensitivity for both contrast-free (0.83 and 0.85) and postgadolinium reading sessions (0.88 and 0.90, respectively). Moreover, there was excellent specificity (0.98) for both groups and reading sessions. CONCLUSIONS: Gadolinium chelate contrast administration showed no added value for accurate characterization of head and neck primary tumor extension and could possibly be avoided in the PET/MR imaging head and neck workflow.

[The development of the physicochemical characteristics of the new original nootropic substance TST-9]. / Izuchenie fiziko-khimicheskikh svoistv novogo original'nogo nootropnogo sredstva TST-9.

Physicochemical properties of the original pharmaceutical substance TST-9 based on the 3,7-diazabicyclo[3.3.1]nonane derivative with the chemical name IUPAC 6-[4methoxy-3-(1H-pyrazol-1-ylmethyl) benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trion, were studied. TST-9 is used as an active substance for the development of the composition and technology for the preparation of an innovative oral drug. The pharmaceutical substance TST-9 is an amorphous white powder, odorless, soluble in chloroform, acetonitrile, methylene chloride, acetone, dimethyl sulfoxide, dimethylformamide and alcohol, sparingly soluble in diethyl ether, dioxane and is very slightly soluble in water, hexane, and heptane. The melting point ranged from 94°C to 96°C without visible decomposition of the substance. The microbiological purity corresponds to category 2.2. Residual organic solvents in the form of chloroform did not exceed 0.006%. The amount of impurities was not more than 0.15%. The loss in mass upon drying was not more than 0.5%. The "identity" was confirmed using nuclear magnetic resonance spectroscopy and HPLC with UV detection. The data obtained in the study will contribute to the further development of the dosage form, the choice of the route of administration and the dosage regimen, as well as the selection of analytical methods for analyzing the quality of the finished dosage form and the effective, high-precision determination of the content of the active substance and its likely decay products.

[Pharmacokinetic properties of an innovative nootropic agent based on a derivative of 3,7-diazabicyclo[3.3.1]nonane]. / Farmakokineticheskie svoistva veshchestva na osnove proizvodnogo 3,7-diazabitsiklo[3.3.1]nonana.

The pharmacokinetics and bioavailability of a derivative of 3,7-diazabicyclo[3.3.1]nonane exhibiting a nootropic effect, were studied after a single dose to rats. The pharmacokinetics of the compound was studied after oral and intravenous administration to 270 male rats Sprague Dawley at doses of 2.5 mg/kg, 13 mg/kg and 25 mg/kg. Its distribution in organs and tissues (brain, thymus, heart, lungs, liver, kidneys, and spleen) was also investigated. It was found that after a single intravenous administration, the investigated substance was determined in the blood of animals for 24 h; the half-life was 4.69 h. The relative bioavailability of the 3,7-diazabicyclo[3.3.1]nonane derivative after oral administration was 42.3%, thus suggesting the prospect of creating dosage forms for oral administration. After a single oral administration, the dose dependence of AUC0-t was exponential. The substance is characterized by heterogeneous distribution in the body with preferential accumulation mainly in well-vascularized tissues.

Exploring new landmarks: analysis of Twitter usage during the 41st ESNR Annual Meeting.

We analyzed the use of Twitter during the 41st Annual Meeting of the European Society of Neuroradiology (ESNR) held in Rotterdam from 19 to 23 September 2018. The aim was to check the status of the European neuroradiology Twitter community and to discover which topics were discussed most often. The data were compared with a similar analysis performed during the Annual Meeting of the American Society of Neuroradiology (ASNR) in 2014. Even though the analysis demonstrated a low use of Twitter during the ESNR meeting, the platform still generated an important volume of impressions and engagement. This use was noted by the global community because topics of the meeting, such as the value of radiological reporting and advanced imaging, were discussed worldwide. These data, also compared to the American meeting, suggests a need for more prolific use and engagement with ESNR social media accounts in order to draw our members into discussions during meetings and to reinforce the place of European neuroradiology in the debate on key imaging topics as well as promoting society events.

Characterization of Skull Base Lesions Using Pseudo-Continuous Arterial Spin Labeling.

PURPOSE: Pseudo-continuous arterial spin labeling (pCASL) is a non-invasive magnetic resonance (MR) perfusion technique. Our study aimed at estimating the diagnostic performance of the pCASL sequence in assessing the perfusion of skull base lesions both qualitatively and quantitatively and at providing cut-off values for differentiation of specific skull base lesions. METHODS: In this study 99 patients with histopathologically confirmed skull base lesions were retrospectively enrolled. Based on a pathological analysis, the lesions were classified as hypervascular and non-hypervascular. Patients were divided into two subgroups according to the anatomical origin of each lesion. The MRI study included pCASL and 3D T1-weighted fat-saturated post-contrast sequences. Of the patients seven were excluded due to technical difficulties or patient movement. The lesions were classified by two raters, blinded to the diagnosis as either hyperperfused or non-hyperperfused, based on the pCASL sequence. The normalized tumor blood flow (nTBF) of each lesion was determined. Qualitative and quantitative characteristics of hypervascular and non-hypervascular lesions were compared. RESULTS: Visual assessment enabled correct classification of 98% of the lesions to be performed. Quantitatively, we found significant differences between the nTBF values for hypervascular and non-hypervascular lesions (p < 0.001) and provided cut-off values, allowing meningioma and schwannoma to be distinguished from meningioma and adenoma. Significant differences were also found within the hypervascular group, namely, paraganglioma was more hyperperfused than meningioma (p = 0.003) or metastases (p = 0.009). CONCLUSION: The present study demonstrates the high diagnostic performance of pCASL in characterizing skull base lesions by either visual assessment or nTBF quantification. Adding the pCASL sequence to the conventional protocol of skull base assessment can be recommended.

Comparative Study of MRI Biomarkers in the Substantia Nigra to Discriminate Idiopathic Parkinson Disease.

BACKGROUND AND PURPOSE: Several new MR imaging techniques have shown promising results in patients with Parkinson disease; however, the comparative diagnostic values of these measures at the individual level remain unclear. Our aim was to compare the diagnostic value of MR imaging biomarkers of substantia nigra damage for distinguishing patients with Parkinson disease from healthy volunteers. MATERIALS AND METHODS: Thirty-six patients and 20 healthy volunteers were prospectively included. The MR imaging protocol at 3T included 3D T2-weighted and T1-weighted neuromelanin-sensitive images, diffusion tensor images, and R2* mapping. T2* high-resolution images were also acquired at 7T to evaluate the dorsal nigral hyperintensity sign. Quantitative analysis was performed using ROIs in the substantia nigra drawn manually around the area of high signal intensity on neuromelanin-sensitive images and T2-weighted images. Visual analysis of the substantia nigra neuromelanin-sensitive signal intensity and the dorsolateral nigral hyperintensity on T2* images was performed. RESULTS: There was a significant decrease in the neuromelanin-sensitive volume and signal intensity in patients with Parkinson disease. There was also a significant decrease in fractional anisotropy and an increase in mean, axial, and radial diffusivity in the neuromelanin-sensitive substantia nigra at 3T and a decrease in substantia nigra volume on T2* images. The combination of substantia nigra volume, signal intensity, and fractional anisotropy in the neuromelanin-sensitive substantia nigra allowed excellent diagnostic accuracy (0.93). Visual assessment of both substantia nigra dorsolateral hyperintensity and neuromelanin-sensitive images had good diagnostic accuracy (0.91 and 0.86, respectively). CONCLUSIONS: The combination of neuromelanin signal and volume changes with fractional anisotropy measurements in the substantia nigra showed excellent diagnostic accuracy. Moreover, the high diagnostic accuracy of visual assessment of substantia nigra changes using dorsolateral hyperintensity analysis or neuromelanin-sensitive signal changes indicates that these techniques are promising for clinical practice.

Specificity of Good Manufacturing Practice (GMP) for Biomedical Cell Products.

The article describes special aspects of Good Manufacturing Practice (GMP) for biomedical cell products (BMCP) that imply high standards of aseptics throughout the entire productio process, strict requirements to donors and to the procedure of biomaterial isolation, guaranty of tracing BMCP products, defining processing procedures which allow to identify BMCP as minimally manipulated; continuous quality control and automation of the control process at all stages of manufacturing, which will ensure product release simultaneously with completion of technological operations.

Women's career choices in radiology in France.

PURPOSE: The purpose of this study was to determine the possible effects of gender on residents' and fellows' motivations in choosing radiology as a career in France, and on choosing a practice setting later on. MATERIAL AND METHODS: An online survey was sent to French residents and fellows in order to access their radiology practice and career aspirations, as well as the potential influence of their gender. Influence of being a woman on initial professional expectations, professional choices, and the evolution of career paths was investigated using the chi-square test. RESULTS: Responses were collected from 206 French residents and fellows. The reasons for choosing radiology residency were, at first, mostly the same for men and women such as interest in the specialty (100% of women and men), work conditions (74% of women and men), technical aspects of the specialty (63% of men and 52% of women, P=0.11) or "reasonable" workload (29% women and 21% men, P=0.19); however, 74% of women stated that maternity might influence their career choices, and were less interested in unstable positions exclusively in private practice (45% men and 33% women, P=0.05). CONCLUSION: Male and female radiologists primarily considered the same factors in choosing their specialties. However, maternity is still a source of inequality in France, including fewer opportunities for fellowship positions or academic careers. Furthermore, more women were willing to work in salaried positions to acquire a secure job, even though compensation might be lower.

Women authorship in radiology research in France: An analysis of the last three decades.

PURPOSE: The aim of this study was to evaluate the evolution of women authorship in France and to analyze the recent trends of the evolution of gender differences in French academic radiology. MATERIALS AND METHODS: A retrospective bibliometric analysis was performed by searching for articles published in Diagnostic and Interventional Imaging (Diagn Interv Imaging) and in Journal de Radiologie (J Radiol) in Pubmed over the last three decades. For each of these articles, we determined the gender of the first and last author. The specific radiological field of each article was also determined. RESULTS: The proportion of women authors has significantly increased from 12% in 1984 to 34% in 2014 (P<0.0001) for the first authors and from 11% (11/96) in 1984 to 20% (38/193) in 2014 for last authors (P =0.03). CONCLUSION: Women authorship in Diagnostic and Interventional Imaging has increased over the last years together with the proportion of women first authors. However, the fraction of women last authors is still underrepresented. More women need to become leaders in radiological research to contribute to stimulate women authorship.