Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose

BACKGROUND: Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. OBJECTIVES: To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. METHODS: The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. RESULTS: A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. CONCLUSIONS: The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily

Application of BIM technology for surveying heritage buildings

The preservation of heritage buildings is beyond doubt an important problem of today. The examination of a heritage building involves a number of problems, viz. missing design documentation, the need to find extant reports about technical condition of the building structures and building reconstruction projects prepared by different organizations, and nonconformance of data contained in drawings and documents of different organizations. In this paper the abovementioned problems are reviewed exemplified by the case of the federal heritage-listed building "Ekaterinburg State Academic Opera and Ballet Theatre", Yekaterinburg. The paper proposes the use of solutions based on information modeling methods for the examination of structures of the abovementioned building and reviews the possibility of employing these methods for upkeeping the building. The article demonstrates the practical value of the proposed application of a BIM model method comprising the building reconstruction stages for the structure survey on a specific example. The method proposed in the paper has a great practical value and can be employed for the improvement of normative and technical documentation, heritage building survey works, and for creating design documentation for restoration of buildings

The role of the universally conserved A2450–C2063 base pair in the ribosomal peptidyl transferase center

Despite the fact that all 23S rRNA nucleotides that build the ribosomal peptidyl transferase ribozyme are universally conserved, standard and atomic mutagenesis studies revealed the nucleobase identities being non-critical for catalysis. This indicates that these active site residues are highly conserved for functions distinct from catalysis. To gain insight into potential contributions, we have manipulated the nucleobases via an atomic mutagenesis approach and have utilized these chemically engineered ribosomes for in vitro translation reactions. We show that most of the active site nucleobases could be removed without significant effects on polypeptide production. Our data however highlight the functional importance of the universally conserved non-Watson-Crick base pair at position A2450–C2063. Modifications that disrupt this base pair markedly impair translation activities, while having little effects on peptide bond formation, tRNA drop-off and ribosome-dependent EF-G GTPase activity. Thus it seems that disruption of the A2450–C2063 pair inhibits a reaction following transpeptidation and EF-G action during the elongation cycle. Cumulatively our data are compatible with the hypothesis that the integrity of this A-C wobble base pair is essential for effective tRNA translocation through the peptidyl transferase center during protein synthesis

Ladoga Ringed Seal (Pusa hispida ladogensis) Can Breed on Land: A Case Study of the Nursing Period

The ringed seal gives birth and nurses offspring in a subnivean lair in fast ice. Its breeding habitat is transforming under the impact of climate change. Here we report the outcome of an observation of a female freshwater Ladoga ringed seal (Pusa hispida ladogensis) and her pup during the 2020 breeding season, when less than 1% of Lake Ladoga was covered with ice. We located a newborn pup in a coastal zone of an island and tracked its survival on land using the camera trap method during daylight. Altogether, we captured 2978 photos, in which the seals were present in 637. The female nursed the pup at the birth site for 34 – 37 days, which is similar to the lactation period in lairs of the Arctic subspecies (36 – 41 days, 39 days on average). The female either stayed with the pup or spent time in prolonged aquatic bouts during the day. Percentage of suckling was in the range of 2.4% – 4.7% (mean 3.3%, SD = 1.1) on different days. Based on an additional video recording, we found that the pup’s behaviour was characterized by a high level of vigilance in comparison with openly breeding phocid seals. This case study indicates that the ringed seal in Lake Ladoga is able to nurse pups on land from soon after birth to pre-weaning. However, breeding success in warm springs can be constrained by predator pressure.Le phoque annelé donne naissance à ses petits et les nourrit dans un abri subnival de la glace rapide. Son habitat de reproduction se transforme sous l’effet du changement climatique. Ici, nous présentons le résultat de l’observation d’un phoque annelé de Ladoga (Pusa hispida ladogensis) en eau douce et de son nouveau-né durant la saison de reproduction de 2020, lorsque moins de 1 % du lac Ladoga était couvert de glace. Nous avons repéré un nouveau-né dans la zone côtière d’une île et avons suivi son évolution sur la terre ferme à l’aide de la méthode du piège photographique à la lumière du jour. En tout, nous avons pris 2 978 photos, et les phoques étaient présents dans 637 d’entre elles. La femelle a nourri son nouveau-né au lieu de naissance pendant 34 à 37 jours, ce qui s’apparente à la période de lactation dans les abris des sous-espèces de l’Arctique (de 36 à 41 jours, pour une moyenne de 39 jours). Pendant la journée, la femelle restait avec son petit ou passait de longues périodes dans l’eau. Le pourcentage de temps consacré à l’allaitement variait de 2,4 % à 4,7 % (moyenne de 3,3 %, écart-type = 1,1) à des jours différents. Un enregistrement vidéo nous a permis de constater que le comportement du nouveau-né était caractérisé par un grand degré de vigilance comparativement à d’autres phocidés se reproduisant dans des lieux exposés. Cette étude de cas indique que le phoque annelé du lac Ladoga est capable de nourrir ses petits sur la terre ferme en commençant peu après leur naissance jusqu’à la période de présevrage. Cependant, le succès de reproduction lors de printemps doux peut être contraint par la pression de prédation.Кольчатая нерпа рожает и выкармливает потомство в подснежной норе на припайном льду. Места её обитания трансформируются под воздействием изменения климата. В сообщении мы приводим результат наблюдения над пресноводным ладожским подвидом кольчатой нерпы (Pusa hispida ladogensis), имевшего место в сезон размножения 2020 года, когда лёд покрывал менее 1% площади Ладожского озера. Новорожденный детёныш был найден в прибрежной зоне острова. Мы проследили возможность его выживания на суше при помощи метода фотоловушки. Всего получено 2987 фотографий в светлое время суток, тюлени присутствовали на 637 из них. Детёныш выкармливался самкой в месте рождения 34 – 37 дней, что по продолжительности близко к периоду лактации у арктического подвида в норе (36 – 41 день, в среднем 39 дней). В течение светового дня самка либо длительное время держалась в акватории озера, либо находилась с детёнышем. Молочное кормление заняло от 2.2 до 4.7% времени (в среднем 3.3%, SD = 1.1) в разные дни. Поведение детёныша отличалось повышенным уровнем беспокойства по сравнению с открыто размножающимися видами настоящих тюленей, по данным дополнительных видеозаписей. Исследование подтверждает способность успешно выкармливать детёнышей на суше у кольчатой нерпы в Ладожском озере с возраста, близкого к рождению, до времени, близкого к прекращению лактации. Однако успешность размножения может быть ограничена в тёплую весну из-за влияния хищников

Optimization of power plants management structure based on the generalized criteria of the efficiency

In the article, the analysis of the operation of power plants in the conditions of economic restructuring to ensure successful entry into the market is carried out. The analysis of the five management structures, including current, typical structure and re-designed by the authors is presented. There are developed the partial efficiency criteria of the management structures that characterize the most important properties - the balance, integrity, controllability and stability. Local criteria of the analyzed structures do not allow to make a definite conclusion about the effectiveness of one of the structures analyzed, formulated global efficiency criterion. There is developed the global criterion of the comparative effectiveness of the management systems based on the DEA method (Data envelopment analysis), taking into account the complex of the proposed local criteria. The considered management structures are ranked based on the generalized criterion of efficiency

Optimization of power plants management structure based on the generalized criteria of the efficiency

In the article, the analysis of the operation of power plants in the conditions of economic restructuring to ensure successful entry into the market is carried out. The analysis of the five management structures, including current, typical structure and re-designed by the authors is presented. There are developed the partial efficiency criteria of the management structures that characterize the most important properties - the balance, integrity, controllability and stability. Local criteria of the analyzed structures do not allow to make a definite conclusion about the effectiveness of one of the structures analyzed, formulated global efficiency criterion. There is developed the global criterion of the comparative effectiveness of the management systems based on the DEA method (Data envelopment analysis), taking into account the complex of the proposed local criteria. The considered management structures are ranked based on the generalized criterion of efficiency

Application of BIM technology for surveying heritage buildings

The preservation of heritage buildings is beyond doubt an important problem of today. The examination of a heritage building involves a number of problems, viz. missing design documentation, the need to find extant reports about technical condition of the building structures and building reconstruction projects prepared by different organizations, and nonconformance of data contained in drawings and documents of different organizations. In this paper the abovementioned problems are reviewed exemplified by the case of the federal heritage-listed building "Ekaterinburg State Academic Opera and Ballet Theatre", Yekaterinburg. The paper proposes the use of solutions based on information modeling methods for the examination of structures of the abovementioned building and reviews the possibility of employing these methods for upkeeping the building. The article demonstrates the practical value of the proposed application of a BIM model method comprising the building reconstruction stages for the structure survey on a specific example. The method proposed in the paper has a great practical value and can be employed for the improvement of normative and technical documentation, heritage building survey works, and for creating design documentation for restoration of buildings

Streamlining the screening cascade for active Hepatitis C in Russia: A cost-effectiveness analysis.

ObjectiveScreening for hepatitis C in Russia is a complex process that involves several visits and stepwise testing, limiting adherence and substantially reducing the yield in the identification of active infections. We aimed to evaluate the cost-effectiveness of different screening algorithms from a health system perspective.MethodsA decision analytic model was applied to a hypothetical adult population eligible to participate in a general screening program for hepatitis C in Russia. The standard pathway (I: Screen for anti-HCV antibodies followed by a nucleic acid test for HCV RNA on antibody positives) was compared to three alternatives (II: Screen for antibodies, a reflexed test for HCV antigen on antibody positives, and RNA on antigen negatives; III: Screen for antibodies, a reflexed test for HCV antigen on antibody positives; IV: Screen for antigen). Each strategy considered a cascade of events (referral, adherence, testing, diagnosis) that must occur for screening to be effective. The primary measure of effectiveness was the number of diagnosed active infections. Calculations followed a health system perspective with costs derived from 2017 reimbursement rates and a willingness-to-pay of 2,000RUB ($82) per diagnosed active infection. Model was tested with deterministic and probabilistic sensitivity analyses.ResultsNon-adherence to screening stages reduced the capture rate of active infections in Strategy I from 79.0$3,681) for I to 53,072RUB ($2,180), 53,004RUB ($2,177), and 59,633RUB ($2,450) for II, III, and IV, respectively. With a probability of 97$-56; CI: -$206 to -$84). Below a willingness-to-pay of 91,000RUB ($3,738), Strategy IV was not cost-effective. Sensitivity analyses confirmed the robustness of results.ConclusionsTesting strategies for hepatitis C with HCV antigen on HCV antibody positive cases offer a streamlining opportunity for population screening programs. Those shall increase the chances for detecting active infections and are cost-effective over current practice in Russia

Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose

Background Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. Objectives To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. Methods The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. Results A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. Conclusions The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily