Gravitational Shock Waves for Schwarzschild and Kerr Black Holes

The metrics of gravitational shock waves for a Schwarzschild black hole in ordinary coordinates and for a Kerr black hole in Boyer-Lindquist coordinates are derived. The Kerr metric is discussed for two cases: the case of a Kerr black hole moving parallel to the rotational axis, and moving perpendicular to the rotational axis. Then, two properties from the derived metrics are investigated: the shift of a null coordinate and the refraction angle crossing the gravitational shock wave. Astrophysical applications for these metrics are discussed in short.Comment: 24 Pages, KOBE--FHD--93--03, {\LaTeX

Dual coding with STDP in a spiking recurrent neural network model of the hippocampus.

The firing rate of single neurons in the mammalian hippocampus has been demonstrated to encode for a range of spatial and non-spatial stimuli. It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animal's spatial location. These findings have led to the hypothesis that the hippocampus operates using a dual (rate and temporal) coding system. To investigate the phenomenon of dual coding in the hippocampus, we examine a spiking recurrent network model with theta coded neural dynamics and an STDP rule that mediates rate-coded Hebbian learning when pre- and post-synaptic firing is stochastic. We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues. This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology. Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain

Noninvasive Prenatal Diagnosis of Fetal Trisomy 18 and Trisomy 13 by Maternal Plasma DNA Sequencing

Massively parallel sequencing of DNA molecules in the plasma of pregnant women has been shown to allow accurate and noninvasive prenatal detection of fetal trisomy 21. However, whether the sequencing approach is as accurate for the noninvasive prenatal diagnosis of trisomy 13 and 18 is unclear due to the lack of data from a large sample set. We studied 392 pregnancies, among which 25 involved a trisomy 13 fetus and 37 involved a trisomy 18 fetus, by massively parallel sequencing. By using our previously reported standard z-score approach, we demonstrated that this approach could identify 36.0% and 73.0% of trisomy 13 and 18 at specificities of 92.4% and 97.2%, respectively. We aimed to improve the detection of trisomy 13 and 18 by using a non-repeat-masked reference human genome instead of a repeat-masked one to increase the number of aligned sequence reads for each sample. We then applied a bioinformatics approach to correct GC content bias in the sequencing data. With these measures, we detected all (25 out of 25) trisomy 13 fetuses at a specificity of 98.9% (261 out of 264 non-trisomy 13 cases), and 91.9% (34 out of 37) of the trisomy 18 fetuses at 98.0% specificity (247 out of 252 non-trisomy 18 cases). These data indicate that with appropriate bioinformatics analysis, noninvasive prenatal diagnosis of trisomy 13 and trisomy 18 by maternal plasma DNA sequencing is achievable

Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in children in Sierra Leone: a randomised, double-blind, controlled trial

Background—Children account for a substantial proportion of cases and deaths from Ebola virus disease. We aimed to assess the safety and immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vectorbased vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in a paediatric population in Sierra Leone. Methods—This randomised, double-blind, controlled trial was done at three clinics in Kambia district, Sierra Leone. Healthy children and adolescents aged 1–17 years were enrolled in three age cohorts (12–17 years, 4–11 years, and 1–3 years) and randomly assigned (3:1), via computer-generated block randomisation (block size of eight), to receive an intramuscular injection of either Ad26.ZEBOV (5 × 1010 viral particles; first dose) followed by MVA-BN-Filo (1 × 108 infectious units; second dose) on day 57 (Ebola vaccine group), or a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo (second dose) on day 57 (control group). Study team personnel (except for those with primary responsibility for study vaccine preparation), participants, and their parents or guardians were masked to study vaccine allocation. The primary outcome was safety, measured as the occurrence of solicited local and systemic adverse symptoms during 7 days after each vaccination, unsolicited systemic adverse events during 28 days after each vaccination, abnormal laboratory results during the study period, and serious adverse events or immediate reportable events throughout the study period. The secondary outcome was immunogenicity (humoral immune response), measured as the concentration of Ebola virus glycoprotein-specific binding antibodies at 21 days after the second dose. The primary outcome was assessed in all participants who had received at least one dose of study vaccine and had available reactogenicity data, and immunogenicity was assessed in all participants who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response. This study is registered at ClinicalTrials.gov, NCT02509494. Findings—From April 4, 2017, to July 5, 2018, 576 eligible children or adolescents (192 in each of the three age cohorts) were enrolled and randomly assigned. The most common solicited local adverse event during the 7 days after the first and second dose was injection-site pain in all age groups, with frequencies ranging from 0% (none of 48) of children aged 1–3 years after placebo injection to 21% (30 of 144) of children aged 4–11 years after Ad26.ZEBOV vaccination. The most frequently observed solicited systemic adverse event during the 7 days was headache in the 12–17 years and 4–11 years age cohorts after the first and second dose, and pyrexia in the 1–3 years age cohort after the first and second dose. The most frequent unsolicited adverse event after the first and second dose vaccinations was malaria in all age cohorts, irrespective of the vaccine types. Following vaccination with MenACWY, severe thrombocytopaenia was observed in one participant aged 3 years. No other clinically significant laboratory abnormalities were observed in other study participants, and no serious adverse events related to the Ebola vaccine regimen were reported. There were no treatment-related deaths. Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second dose of the Ebola virus vaccine regimen were observed in 131 (98%) of 134 children aged 12–17 years (9929 ELISA units [EU]/mL [95% CI 8172–12 064]), in 119 (99%) of 120 aged 4–11 years (10 212 EU/mL [8419–12 388]), and in 118 (98%) of 121 aged 1–3 years (22 568 EU/mL [18 426–27 642]). Interpretation—The Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen was well tolerated with no safety concerns in children aged 1–17 years, and induced robust humoral immune responses, suggesting suitability of this regimen for Ebola virus disease prophylaxis in children

Safety and long-term immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Sierra Leone: a combined open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2 trial

Background The Ebola epidemics in west Africa and the Democratic Republic of the Congo highlight an urgent need for safe and effective vaccines to prevent Ebola virus disease. We aimed to assess the safety and long-term immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in Sierra Leone, a country previously affected by Ebola. Methods The trial comprised two stages: an open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2. The study was done at three clinics in Kambia district, Sierra Leone. In stage 1, healthy adults (aged ≥18 years) residing in or near Kambia district, received an intramuscular injection of Ad26.ZEBOV (5×1010 viral particles) on day 1 (first dose) followed by an intramuscular injection of MVA-BN-Filo (1×108 infectious units) on day 57 (second dose). An Ad26.ZEBOV booster vaccination was offered at 2 years after the first dose to stage 1 participants. The eligibility criteria for adult participants in stage 2 were consistent with stage 1 eligibility criteria. Stage 2 participants were randomly assigned (3:1), by computer-generated block randomisation (block size of eight) via an interactive web-response system, to receive either the Ebola vaccine regimen (Ad26.ZEBOV followed by MVA-BN-Filo) or an intramuscular injection of a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo on day 57 (second dose; control group). Study team personnel, except those with primary responsibility for study vaccine preparation, and participants were masked to study vaccine allocation. The primary outcome was the safety of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen, which was assessed in all participants who had received at least one dose of study vaccine. Safety was assessed as solicited local and systemic adverse events occurring in the first 7 days after each vaccination, unsolicited adverse events occurring in the first 28 days after each vaccination, and serious adverse events or immediate reportable events occurring up to each participant’s last study visit. Secondary outcomes were to assess Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second vaccine in a per-protocol set of participants (ie, those who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response) and to assess the safety and tolerability of the Ad26.ZEBOV booster vaccination in stage 1 participants who had received the booster dose. This study is registered at ClinicalTrials.gov, NCT02509494. Findings Between Sept 30, 2015, and Oct 19, 2016, 443 participants (43 in stage 1 and 400 in stage 2) were enrolled; 341 participants assigned to receive the Ad26.ZEBOV and MVA-BN-Filo regimen and 102 participants assigned to receive the MenACWY and placebo regimen received at least one dose of study vaccine. Both regimens were well tolerated with no safety concerns. In stage 1, solicited local adverse events (mostly mild or moderate injection-site pain) were reported in 12 (28%) of 43 participants after Ad26.ZEBOV vaccination and in six (14%) participants after MVA-BN-Filo vaccination. In stage 2, solicited local adverse events were reported in 51 (17%) of 298 participants after Ad26.ZEBOV vaccination, in 58 (24%) of 246 after MVA-BN-Filo vaccination, in 17 (17%) of 102 after MenACWY vaccination, and in eight (9%) of 86 after placebo injection. In stage 1, solicited systemic adverse events were reported in 18 (42%) of 43 participants after Ad26.ZEBOV vaccination and in 17 (40%) after MVA-BN-Filo vaccination. In stage 2, solicited systemic adverse events were reported in 161 (54%) of 298 participants after Ad26.ZEBOV vaccination, in 107 (43%) of 246 after MVA-BN-Filo vaccination, in 51 (50%) of 102 after MenACWY vaccination, and in 39 (45%) of 86 after placebo injection. Solicited systemic adverse events in both stage 1 and 2 participants included mostly mild or moderate headache, myalgia, fatigue, and arthralgia. The most frequent unsolicited adverse event after the first dose was headache in stage 1 and malaria in stage 2. Malaria was the most frequent unsolicited adverse event after the second dose in both stage 1 and 2. No serious adverse event was considered related to the study vaccine, and no immediate reportable events were observed. In stage 1, the safety profile after the booster vaccination was not notably different to that observed after the first dose. Vaccine-induced humoral immune responses were observed in 41 (98%) of 42 stage 1 participants (geometric mean binding antibody concentration 4784 ELISA units [EU]/mL [95% CI 3736–6125]) and in 176 (98%) of 179 stage 2 participants (3810 EU/mL [3312–4383]) at 21 days after the second vaccination. Interpretation The Ad26.ZEBOV and MVA-BN-Filo vaccine regimen was well tolerated and immunogenic, with persistent humoral immune responses. These data support the use of this vaccine regimen for Ebola virus disease prophylaxis in adults

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Фармацевтична опіка як кінцева мета формування сучасного провізора

        The World Health Organization (WHO) has identified the current strategic direction of health care throughout the world as "Focus on the patient." Therefore, the pharmacist role in the healthcare system is changing - a pharmacist has a key role in public health.         Pharmacist provides assistance to the patient and guarantees that assistance is designed correctly, effective among all the available options, is safe and right for this patient. Due to this the approaches to teaching students are changed significantly, it is necessary to create the clinical thinking in future pharmacists.         The main objective in teaching pharmacotherapy and clinical pharmacy is training the pharmacist to have an adequate theoretical knowledge and practical skills to control the conduct of the most rational drug therapy in a concrete patient. Pharmacist must choose the appropriate therapy for a patient based on pharmacokinetics, pharmacodynamics, possible side effects and age, sex, presence of comorbidities of the patient.         Practical sessions conducted directly in the clinic, include this organizational structure:The preparatory phase (organization and setting teaching purposes and motivations, control the output level of knowledge - tests, oral theoretical questions);The basic phase (formation of professional skills and knowledge to identify general principles of clinical pharmacy, work near a bed, definition of clinical syndromes, define treatment plan, analysis of the tests results, solving typical tasks and tests).The final phase – control of the the final level of knowledge and skills (solving atypical problems, writing prescriptions).We provided a special sense to the independent work of students on the preparation and wrote recommendation "The efficacy and safety protocol of medicines". Particular attention is paid to the following sections:medication and allergy history;pharmacotherapy;assessment of possible interactions of drugs;selecting assess the efficacy and safety of pharmacotherapy;daily logs of the dynamic control to the pharmacotherapy efficacy and safety.The important stage in the formation of clinical thinking in students is educational practice. During the practical training students should be familiar with the basics of deontology and the ethics of communication with pharmacies visitors; acquire skills of medicinal history collecting.Students are expected to acquire skills of choosing the optimal OTC medicine for a concrete patient and use to practice the algorithm of the distribution patients who need and do not need doctor consultation.Thus, an integrated approach to the teaching of pharmacotherapy, clinical pharmacy, practical training in clinical pharmacy, promotes the formation of clinical thinking in students. Современное стратегическое направление  развития ВОЗ в корне изменяет роль провизора в системе здравоохранения. В связи с этим существенных изменений претерпевают подходы к обучению студентов, возникает острая необходимость в формировании у будущих провизоров клинического мышления. В процессе преподавания необходимо закрепить и углубить навыки системного анализа медико-биологических ситуаций, клинического мышления, формирование социальной и профессиональной мобильности студентов. Применение комплексного подхода в процессе преподавания фармакотерапии и клинической фармации, учебной практики по клинической фармации при сочетании аудиторной части с использованием интерактивных форм способствует актуализации системного анализа медико-биологических ситуаций, клинического мышления и формированию социальной и профессиональной мобильности у студентов. Сучасний стратегічний напрям розвитку ВООЗ докорінно змінює роль провізора в системі охорони здоров’я. У зв’язку з цим істотно змінюються підходи до навчання студентів, виникає гостра потреба формувати у майбутніх провізорів клінічне мислення. У процесі викладання необхідно закріпити та поглибити навички системного аналізу медико-біологічних ситуацій, клінічного мислення, виховання соціальної та професійної мобільності студентів. Застосування комплексного підходу у процесі викладання фармакотерапії та клінічної фармації, навчальної практики із клінічної фармації при поєднанні аудиторної частини з використанням інтерактивних форм сприяє актуалізації системного аналізу медико-біологічних ситуацій, клінічного мислення та формуванню соціальної та професіональної мобільності у студентів

Pharmaceutical care as the ultimate goal of the мodern pharmacist formation

The World Health Organization (WHO) has identified the current strategic direction of health care throughout the world as "Focus on the patient." Therefore, the pharmacist role in the healthcare system is changing - a pharmacist has a key role in public health. Pharmacist provides assistance to the patient and guarantees that assistance is designed correctly, effective among all the available options, is safe and right for this patient. Due to this the approaches to teaching students are changed significantly, it is necessary to create the clinical thinking in future pharmacists. The main objective in teaching pharmacotherapy and clinical pharmacy is training the pharmacist to have an adequate theoretical knowledge and practical skills to control the conduct of the most rational drug therapy in a concrete patient. Pharmacist must choose the appropriate therapy for a patient based on pharmacokinetics, pharmacodynamics, possible side effects and age, sex, presence of comorbidities of the patient. Practical sessions conducted directly in the clinic, include this organizational structure: The preparatory phase (organization and setting teaching purposes and motivations, control the output level of knowledge - tests, oral theoretical questions); The basic phase (formation of professional skills and knowledge to identify general principles of clinical pharmacy, work near a bed, definition of clinical syndromes, define treatment plan, analysis of the tests results, solving typical tasks and tests). The final phase – control of the the final level of knowledge and skills (solving atypical problems, writing prescriptions). We provided a special sense to the independent work of students on the preparation and wrote recommendation "The efficacy and safety protocol of medicines". Particular attention is paid to the following sections: medication and allergy history; pharmacotherapy; assessment of possible interactions of drugs; selecting assess the efficacy and safety of pharmacotherapy; daily logs of the dynamic control to the pharmacotherapy efficacy and safety. The important stage in the formation of clinical thinking in students is educational practice. During the practical training students should be familiar with the basics of deontology and the ethics of communication with pharmacies visitors; acquire skills of medicinal history collecting. Students are expected to acquire skills of choosing the optimal OTC medicine for a concrete patient and use to practice the algorithm of the distribution patients who need and do not need doctor consultation. Thus, an integrated approach to the teaching of pharmacotherapy, clinical pharmacy, practical training in clinical pharmacy, promotes the formation of clinical thinking in students