Management of Epileptic Seizures in Disorders of Consciousness: An International Survey

Epileptic seizures/post-traumatic epilepsy (ES/PTE) are frequent in persons with brain injuries, particularly for patients with more severe injuries including ones that result in disorders of consciousness (DoC). Surprisingly, there are currently no best practice guidelines for assessment or management of ES in persons with DoC. This study aimed to identify clinician attitudes toward epilepsy prophylaxis, diagnosis and treatment in patients with DoC as well as current practice in regards to the use of amantadine in these individuals. A cross-sectional online survey was sent to members of the International Brain Injury Association (IBIA). Fifty physician responses were included in the final analysis. Withdrawal of antiepileptic drug/anti-seizure medications (AED/ASM) therapy was guided by the absence of evidence of clinical seizure whether or not the AED/ASM was given prophylactically or for actual seizure/epilepsy treatment. Standard EEG was the most frequent diagnostic method utilized. The majority of respondents ordered an EEG if there were concerns regarding lack of neurological progress. AED/ASM prescription was reported to be triggered by the first clinically evident seizure with levetiracetam being the AED/ASM of choice. Amantadine was frequently prescribed although less so in patients with epilepsy and/or EEG based epileptic abnormalities. A minority of respondents reported an association between amantadine and seizure. Longitudinal studies on epilepsy management, epilepsy impact on neurologic prognosis, as well as potential drug effects on seizure risk in persons with DoC appear warranted with the goal of pushing guideline development forward and improving clinical assessment and management of seizures in this unique, albeit challenging, population.

Treatment tactics of new NET G3 subgroup in first line of therapy

Considering the fact that the group of neuroendocrine carcinomas (NECs) grade 3 is heterogenous, in the year of 2017 a new subgroup of welldifferentiated neuroendocrine tumors grade 3 (NETs G3) was described. NETs G3 are tumors with more favorable prognosis and less sensitive to platinum-based chemotherapy regimens than NECs, they also have peculiar morphogenetical qualities: lower ki‑67 index (mean 35.0 %), higher somatostatin receptors expression, absence of DAXX/ATRX/MEN 1 genes mutation, p53 expression in the absence of TP53 mutation. Nowadays treatment standard for NETs G3 subgroup is still remain unclear due to lack of prospective clinical trials. At the same time taking in note historical retrospective data, NETs G3 should be treated in line with NETs G1/G2 and only patients with higher ki‑67 index can be treated as NECs with platinum-based chemotherapy. In our non-randomised phase II prospective trial, we accessed the efficacy of different chemotherapy regimens in combination with somatostatin analogues in new NETs G3 subgroup. 153 patients with IHC-confirmed neuroendocrine neoplasm diagnose were included: NETs G3 n = 53 mean ki‑67 36.4 % [21.0–60.0 %], NETs G2 n = 50 mean ki‑67 15.7 % [2.1–20.0 %], NECs n = 50 mean ki‑67 69.0 % [38.0–96.0 %]). Patients from NETs G3 subgroup received 4 chemotherapy regimens: Aranose (n = 19), Aranose (arabinopiranosilmethyl nitrosocarbamide, ALK, – cytostatic drug with a chemical structure similar to Streptozotocin and Nitrosomethylurea, approved in Russian Federation for melanoma and welldifferentiated neuroendocrine tumors treatment), XELOX (n = 8), TemCAP (n = 11), EP/EC (n = 10). mPFS in Aranose-subgroup was 19.3 ± 5.9 months (95 % CI: 7.7–30.8), in XELOX – 10.8 ± 3.6 months (3.7–17.8), in TemCAP – 14.8 ± 4.2 months (6.6–23.1) and in platinum-based regimens – 4.4 ± 1.9 months (0.6–8.2) (p = 0.01). DCR in Aranose subgroup was 73.6 % and ORR – 36.8 %, PDR – 21.1 %, in XELOX subgroup ORR was 62.5 %, SDR was 50.0 % and PDR – 25.0 %, in TemCAP subgroup DCR was 63.6 %, ORR – 9.1 %, PDR – 18.2 % and in platinum-based regimens SDR was 40.0 %, PDR – 50.0 % (p = 0.05).

Legitimate Expectations and Fair-and-Equitable-Treatment under the Energy Charter Treaty

A recent tide of ISDS cases in the renewable energy sector has generated a large number of arbitral awards that turn of the notion of legitimate expectations. The Fair and Equitable Treatment Standard (FET) and the notion of legitimate expectations has been highly undetermined in the past. This work contains a comprehensive analysis of the renewable energy awards and the interpretation of the notion of legitimate expectations therein. In particular, it is examined whether arbitral jurisprudence formed a cohesive body of caw-law. The author analyses which aspects with regard to commitment by the states, due diligence of the investors, and level of impact were considered a violation of the FET Standard by recent arbitral tribunals.

DO PROBIOTICS HAVE A FUTURE IN NEONATOLOGY? (ANALYSIS OF THE LATEST DATA. PART 3)

The issue of feasibility and effectiveness of probiotics use in newborns is still discussable. A position letter of the Committee on nutrition of the European Society for Pediatric NutritionGastroenterology, Hepatology, and(ESPGHAN) and the Working group of the ESPGHAN on probiotics and prebiotics issues was published in May 2020 in “Pediatric Gastroenterology and Nutrition” magazine as for the use of probiotics in premature newborns. The third part of the literature continues with the position paper and the results of many randomized controlled clinical trials of probiotics. The article considers the answers to 6 clinical questions posed by the working group of the Committee to assess the feasibility of use, routes of administration, dosage and duration of use, as well as the effectiveness and quality of probiotic drugs. It was proved that probiotics, in general, could decrease the level of necrotising enterocolitis, sepsis, and mortality. On the other hand, an increasing number of commercial products containing probiotics of non optimal quality are available. In addition, a large number of departments in the world regularly suggest probiotic supplements as a treatment standard despite the absence of any solid evidence. Moreover, the emphasis was placed on issues of safety of probiotic supplements for premature newborns. Guarantee of quality of probiotic product is deliverance of probiotic strains by transfer genes of resistance to antibiotics, the ability to regularly detect sepsis while using probiotics.

Immunotherapy of Ovarian Cancer with Particular Emphasis on the PD-1/PDL-1 as Target Points

Ovarian cancer is one of the most fatal cancers in women worldwide. Cytoreductive surgery combined with platinum-based chemotherapy has been the current first-line treatment standard. Nevertheless, ovarian cancer appears to have a high recurrence rate and mortality. Immunological processes play a significant role in tumorigenesis. The production of ligands for checkpoint receptors can be a very effective, and undesirable, immunosuppressive mechanism for cancers. The CTLA-4 protein, as well as the PD-1 receptor and its PD-L1 ligand, are among the better-known components of the control points. The aim of this paper was to review current research on immunotherapy in the treatment of ovarian cancer. The authors specifically considered immune checkpoints molecules such as PD-1/PDL-1 as targets for immunotherapy. We found that immune checkpoint-inhibitor therapy does not have an improved prognosis in ovarian cancer; although early trials showed that a combination of anti-PD-1/PD-L1 therapy with targeted therapy might have the potential to improve responses and outcomes in selected patients. However, we must wait for the final results of the trials. It seems important to identify a group of patients who could benefit significantly from treatment with immune checkpoints inhibitors. However, despite numerous trials, ICIs have not become part of routine clinical practice for the treatment of ovarian cancer.

Comparative Analysis of Bilateral Investment Treaties of the Russian Federation

The paper analyzes bilateral investment treaties, one of the parties to which is Russia. The article compares the provisions contained in the 1992 and 2001 model agreements of Russia, as well as the provisions of the 2016 Regulations. The concepts of “foreign investor” and “investment” are considered, discrepancies in the concepts and wording used in treaties with different states are revealed. In a comparative aspect, the authors explore the operation of treaties over time, the use of the standard of fair and equal treatment, and the application of provisions on expropriation. The features of the formulation of the national treatment standard and the most favored nation treatment standard, as well as the umbrella clause are revealed.

DO PROBIOTICS HAVE A FUTURE IN NEONATOLOGY?

The issue of feasibility and effectiveness of probiotics use in newborns is still discussable. A position letter of the Committee on nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the Working group of the ESPGHAN on probiotics and prebiotics issues was published in May 2020 in “Pediatric Gastroenterology and Nutrition” magazine as for the use of probiotics in premature newborns. It stated that over 10,000 premature newborns from all over the world had taken part in random controlled probiotics tests. It was proved that probiotics, in general, could decrease the level of necrotizing enterocolitis, sepsis, and mortality. But the question of choice of microorganism strains, dosing, and duration of medication course remains open. On the other hand, an increasing number of commercial products containing probiotics of non optimal quality are available. In addition, a large number of departments in the world regularly suggest probiotic supplements as a treatment standard despite the absence of any solid evidence. According to the data of the latest meta-analysis, effectiveness in decreasing mortality and incidence was found in the minority of investigated strains or combinations. In the position letter authors wanted to give advice which specific strains can be potentially used and which cannot. Moreover, the emphasis was placed on issues of safety of probiotic supplements for premature newborns. Guarantee of quality of probiotic product is deliverance of probiotic strains by transfer genes of resistance to antibiotics and the possibility of regular identification of probiotic sepsis. There is a conditional recommendation (with a low credibility of evidence) to provide eitherLactobacillus rhamnosus GG ATCC53103, or combination of Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12, and Streptococcus thermophilus TH-4 for decreasing a risk of the necrotizing enterocolitis development subject to all issues of safety.

Predictors of Parental Accommodation and Response Treatment in Young Children With Obsessive-Compulsive Disorder

Background: Cognitive–behavioral family-based treatment (CBFT) is the treatment standard in very young children with obsessive–compulsive disorder (OCD), which includes the same core components of cognitive–behavioral therapy (CBT) with significant family involvement. Although the latter reports high rates of remission, some children do not improve with treatments. Therefore, it is necessary to identify possible moderating variables such as comorbidity, severity of disorder, years of onset, parental anxiety, and parental accommodation. This study has two main aims: (1) to propose a predictive model on family accommodation (father and mother), taking into account variables related to the children (severity of obsessive–compulsive responses, internalizing and externalizing symptoms, and comorbidity) and with the parents before intervention (worry, accommodation of one parental member over the other) and (2) to examine the mediating role of externalizing symptoms and mother's accommodation in the relation between initial severity and improvement of severity of obsessive–compulsive responses in children aged 5–8 years.Methods: Participants comprised 56 children with OCD [mean = 6.61 (SD = 0.76)] and their parents; 79% of the sample was men. Treatment was implemented by two clinicians specialized in OCD (>15 years of experience). Clinicians were trained to administer CBT protocol in the same way. They were doctors of clinical psychology and researchers at the OCD.Results: Mother's accommodation was associated with child variables (Child Behavior Checklist–Externalizing and Initial Severity, Children's Yale–Brown Obsessive–Compulsive Scale). Father's accommodation could be explained by parent variables (mother's accommodation and worry). Simple mediation model tested using the SPSS macro PROCESS supported the relation of the initial severity of symptoms with that following intervention, through the simple indirect effect of externalizing symptoms of the child.Conclusions: Comorbidities with externalizing symptoms, father's worry, and mother's accommodation were variables that should be controlled in treatment of pediatric OCD.

Clinical and Immunological Characteristics of Patients with Odontogenic Maxillary Sinusitis

Inflammatory diseases of the maxillary sinus of odontogenic aetiology have a high prevalence and hold leading positions in the structure of otorhinolaryngological and dental morbidity. High-intensity lesions in all age and social groups, the lack of over the last decade a downward trend in frequency, refractory to traditional drug therapy determine the high medical and social problem significance.To date, the main treatment standard is the surgical removal of the “causal” infection focus, but this stage is not always resolved by complete recovery, in consequence of which the disease acquires a cyclical character. Many authors point out the role of the immune system in chronization of the inflammatory process in the sinuses and the development of exacerbation frequent periods. Treatment of odontogenic sinusitis is more complex and prone to relapses. The main objectives of treatment are differential diagnosis of odontogenic sinusitis and its treatment.In this regard, determination of the immunological reactivity state and search for pathogenetically significant disorders in the effector protective link in patients with odontogenic sinusitis becomes especially relevant. The article presents a detailed analysis of the immune status of 60 patients with odontogenic maxillary sinusitis caused by acute periodontitis, radicular cyst, and filling material. Clearly demonstated the results of the paranasal sinuses x-ray examination and clinical examination of patients. In the course of the research were found significant changes of immunological indicators for several considered criteria. They indicate the presence of pronounced autoimmune shifts in the subjects, which play a key role in aggravating the disease severity and its outcome. This type of research is crucial for the development of improved drug therapy strategies for individuals with odontogenic sinusitis aimed at correcting immune disorders. The aim of the article is research of the immunological molecular changes that occur in odontogenic sinusitis, and to lay the foundation for studying the molecular mechanism of odontogenic sinusitis.

719. Susceptibility Testing of Oteseconazole (VT-1161) Against Clinical Isolates from Phase 3 Clinical Studies in Subjects with Recurrent Vulvovaginal Candidiasis

Background Oteseconazole (VT-1161) is a novel, investigational oral therapy that is currently under FDA review for the treatment of recurrent vulvovaginal candidiasis (RVVC). Susceptibility testing was performed on all viable clinical isolates collected from three Phase 3 studies to determine the susceptibility of causative pathogens to oteseconazole versus the current treatment standard of care, fluconazole. Methods Vaginal cultures were obtained at screening and at all subsequent study visits throughout the duration of the studies (approx. 48 Weeks) and submitted to a central mycology laboratory for fungal species identification and storage. Susceptibility testing was conducted in accordance with the CLSI Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeast M27-Ed4. Results Candida albicans was identified as the primary causative pathogen in 87% of women with RVVC presenting with an acute infection, followed by C. glabrata (8%). Other non-albicans species including; C. parapsilosis, C. tropicalis, C. krusei, C. dubliniensis, C. kefyr and Saccharomyces cerevisiae were responsible for < 1% of infections. A total of 1910 isolates were collected. The MIC range, MIC50 and MIC90 values against all isolates for oteseconazole were ≤ 0.0005 to > 0.25, 0.002 and 0.06 µg/mL, respectively. In comparison, the MIC range, MIC50 and MIC90 values for fluconazole were, ≤ 0.06 to > 32, 0.25 and 8 µg/mL respectively. The MIC range, MIC50 and MIC90 values against all C.glabrata isolates for oteseconazole were 0.002 to > 0.25, 0.03 and 0.125 µg/mL, respectively. In comparison, the MIC range, MIC50 and MIC90 values for fluconazole were, ≤ 0.06 to 32, 2 and 8 µg/mL respectively. Conclusion Oteseconazole demonstrated very low MIC values against most Candida strains, including fluconazole resistant isolates, aligning with clinical study outcomes. Oteseconazole MICs against C. glabrata strains were approximately 6-fold lower than fluconazole. Disclosures Mahmoud Ghannoum, PhD, Mycovia Pharmaceuticals (Grant/Research Support, Research Grant or Support) Thorsten Degenhardt, Ph.D, Mycovia Pharmaceuticals (Employee, Shareholder) Karen Person, M.S., Mycovia Pharmaceuticals, Inc. (Employee)Mycovia Pharmaceuticals, Inc. (Employee) Stephen Brand, Ph.D, Mycovia Pharmaceuticals (Employee)