Temporal Trends in Low-Dose Aspirin Use (from the CoLaus|PsyCoLaus Study).

Although established in secondary prevention, the use of low-dose aspirin for primary cardiovascular prevention remains uncertain. We assessed the temporal trend of low-dose aspirin use in people at primary and secondary prevention over 14 years. We used data from the population-based CoLaus|PsyCoLaus study. A baseline survey was conducted from 2003 to 2006, involving 6,733 participants. The first and second follow-up investigations were performed from 2009 to 2012 and 2014 to 2017, respectively. Low-dose aspirin use was defined as ≤300 mg/daily oral administration or administration of an anticoagulant for similar indications. For primary prevention analysis, 6,555, 4,695, and 3,893 participants were included in the analysis at baseline, first and second follow-ups, respectively. Overall, low-dose aspirin use doubled between baseline (4.1%) and second follow-up (8.1%). Appropriate use of low-dose aspirin rose from 32% at baseline to 64% at the second follow-up for primary prevention. In secondary prevention, 71.8%, 75.9%, and 71.7% of participants were taking low-dose aspirin at baseline, first, and second follow-up, respectively. On the basis of a population-based cohort, the appropriateness of low-dose aspirin use increased over a 10-year follow-up in primary prevention, but its inappropriate use still concerned 44% of subjects. In secondary prevention, a quarter of individuals were not taking low-dose aspirin which remained stable over the analyzed period

Knots: Attractive Places with High Path Tortuosity in Mouse Open Field Exploration

When introduced into a novel environment, mammals establish in it a preferred place marked by the highest number of visits and highest cumulative time spent in it. Examination of exploratory behavior in reference to this “home base” highlights important features of its organization. It might therefore be fruitful to search for other types of marked places in mouse exploratory behavior and examine their influence on overall behavior

The crystal structure of cadmium potassium orthovanadate KCd 4

International audienceThe structure of KCd4(VO4)3 has been determined from Patterson and Fourier syntheses and refined by full-matrix least squares with 1130 diffractometer data to R = 0.061..

Behavioral Sequence Analysis Reveals a Novel Role for ß2* Nicotinic Receptors in Exploration

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and modulate neuronal function in most mammalian brain structures. The contribution of defined nAChR subunits to a specific behavior is thus difficult to assess. Mice deleted for ß2-containing nAChRs (ß2−/−) have been shown to be hyperactive in an open-field paradigm, without determining the origin of this hyperactivity. We here develop a quantitative description of mouse behavior in the open field based upon first order Markov and variable length Markov chain analysis focusing on the time-organized sequence that behaviors are composed of. This description reveals that this hyperactivity is the consequence of the absence of specific inactive states or “stops”. These stops are associated with a scanning of the environment in wild-type mice (WT), and they affect the way that animals organize their sequence of behaviors when compared with stops without scanning. They characterize a specific “decision moment” that is reduced in ß2−/− mutant mice, suggesting an important role of ß2-nAChRs in the strategy used by animals to explore an environment and collect information in order to organize their behavior. This integrated analysis of the displacement of an animal in a simple environment offers new insights, specifically into the contribution of nAChRs to higher brain functions and more generally into the principles that organize sequences of behaviors in animals

Assessment the equivalence of the bioanalogue insulin lizpro biphasic 25 (Geropharm-bio, Russia) and Humalog® Mix 25 (Lilly France, France) using the euglycemic hyperinsulinum clamp method on healthy volonters

Background: Modern medicine requires use of effective antidiabetic drugs that can imitate the natural profile of insulin in the body of patients with diabetes mellitus. Examples of such preparations include biphasic insulin lispro, which is a mixture of insulin lispro ultra-short action and insulin lispro protamine suspension with prolonged effect. The clinical trials (CT) program for biosimilar insulins contains pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety studies. Aims: To demonstrate Biphasic Insulin Lispro 25, suspension for subcutaneous administration, 100 U/ml (GEROPHARM-Bio, Russia) and Humalog® Mix 25, suspension for subcutaneous administration, 100 U/ml (Lilly France, France) have comparable pharmacokinetic profiles under conditions of hyperinsulinemic euglycemic clamp (HEC) in healthy volunteers. Materials and methods: The study was conducted on 48 healthy men aged between 18 to 50 years. This was a double-blind, randomized, crossover study of comparative pharmacokinetics of drugs. The investigational products (IP) were administered before the clamp in a single dose of 0.4 U/kg subcutaneously in the abdominal wall. Regular blood sampling was performed during the study. The insulin concentrations in the samples were determined using an ELISA method. The results of the determination were used to calculate the PK parameters and construct the concentration-time curves. Adjust glucose infusion rates were based on blood glucose measurements. These data were used to calculate the PD parameters. Results: Our results demonstrated that Biphasic Insulin Lispro 25 and Humalog® Mix 25 have comparable PK and PD profiles under conditions of HEC in healthy volunteers. The confidence intervals for the ratio of the geometric mean for Cins.max and AUCins.0–12 were 87.75–99.90% and 83.76–96.98% respectively, which were well within 80–125% limits for establishing comparability. Conclusions: Biphasic Insulin Lispro 25 and Humalog® Mix 25 are equivalent based on this CT applying the HEC technique in healthy volunteers

Evaluation of biosimilarity of RinGlar® (GEROPHARM LLC, Russia) and Lantus® (Sanofi-Aventis Deutschland GmbH, Germany) using the euglycemic hyperinsulinemic clamp technique in patients with type 1 diabetes: double-blind randomized clinical trial

Background: Prevention of the development of micro-and macrovascular complications in patients with diabetes melli-tus (DM) encouraged the search for insulin analogues that allow imitating, as close as possible, a normal physiological insulin secretion in healthy people. Biosimilars (bioanalogues of reference products) play an important role in the full provision with high-quality insulin medications throughout patients. The program of clinical trials of insulin bioanalogues includes pharmacology studies: pharmacokinetics (PK), pharmacodynamics (PD) and clinical safety research.Aims: To test whether RinGlar® (GEROPHARM LLC, Russia) and Lantus® (Sanofi-Aventis Deutschland GmbH, Germany) have similar PK and PD profiles in a hyperinsulinemic euglycaemic clamp (HEC) setting in patients with type 1 diabetes mellitus. Permission of the Ministry of Health of the Russian Federation No. 150 of 03/03/2016.Materials and methods: The study was conducted in 42 patients with type 1 diabetes aged 18 to 65 years. A doubleblind, randomized, crossover study of comparative PK and PD of drugs was chosen as a study design. The investigational products were injected after achieving a state of euglycemia before the HEC in a single dose of 0.6 U/kg subcutaneously into the subcutaneous fat of the anterior abdominal wall. During the study, regular blood sampling was performed, the amount of insulin glargine in the samples was determined by ELISA. The results are used to calculate the PK parameters and generate the concentration-time curves. The glucose infusion rate was corrected based on the measurement of glycemia. These data are used to calculate the PD parameters.Results: RinGlar® and Lantus® interventions have comparable PK and PD profiles in HEC setting in patients with type 1 diabetes. This is confirmed by the similarity of the main PK/PD parameters, PK/PD curves, and comparable safety. The confidence intervals of the geometric mean ratio were 81.02% - 120.62% for the PK parameter AUCins0-T, and 85.43% - 115.64% for the PD-parameter AUCGIR0_T, which fall within the specified limits of 80% - 125% to establish comparability between drugs.Conclusions: Results of the clinical trial demonstrate the biosimilarity of the products RinGlar® and Lantus®

Mouse Cognition-Related Behavior in the Open-Field: Emergence of Places of Attraction

Spatial memory is often studied in the Morris Water Maze, where the animal's spatial orientation has been shown to be mainly shaped by distal visual cues. Cognition-related behavior has also been described along “well-trodden paths”—spatial habits established by animals in the wild and in captivity reflecting a form of spatial memory. In the present study we combine the study of Open Field behavior with the study of behavior on well-trodden paths, revealing a form of locational memory that appears to correlate with spatial memory. The tracked path of the mouse is used to examine the dynamics of visiting behavior to locations. A visit is defined as either progressing through a location or stopping there, where progressing and stopping are computationally defined. We then estimate the probability of stopping at a location as a function of the number of previous visits to that location, i.e., we measure the effect of visiting history to a location on stopping in it. This can be regarded as an estimate of the familiarity of the mouse with locations. The recently wild-derived inbred strain CZECHII shows the highest effect of visiting history on stopping, C57 inbred mice show a lower effect, and DBA mice show no effect. We employ a rarely used, bottom-to-top computational approach, starting from simple kinematics of movement and gradually building our way up until we end with (emergent) locational memory. The effect of visiting history to a location on stopping in it can be regarded as an estimate of the familiarity of the mouse with locations, implying memory of these locations. We show that the magnitude of this estimate is strain-specific, implying a genetic influence. The dynamics of this process reveal that locations along the mouse's trodden path gradually become places of attraction, where the mouse stops habitually

Wavelet Cycle Spinning Denoising of NDE Ultrasonic Signals Using a Random Selection of Shifts

Wavelets are a powerful tool for signal and image denoising. Most of the denoising applications in different fields were based on the thresholding of the discrete wavelet transform (DWT) coefficients. Nevertheless, DWT transform is not a time or shift invariant transform and results depend on the selected shift. Improvements on the denoising performance can be obtained using the stationary wavelet transform (SWT) (also called shift-invariant or undecimated wavelet transform). Denoising using SWT has previously shown a robust and usually better performance than denoising using DWT but with a higher computational cost. In this paper, wavelet shrinkage schemes are applied for reducing noise in synthetic and experimental non-destructive evaluation ultrasonic A-scans, using DWT and a cycle-spinning implementation of SWT. A new denoising procedure, which we call random partial cycle spinning (RPCS), is presented. It is based on a cycle-spinning over a limited number of shifts that are selected in a random way. Wavelet denoising based on DWT, SWT and RPCS have been applied to the same sets of ultrasonic A-scans and their performances in terms of SNR are compared. In all cases three well known threshold selection rules (Universal, Minimax and Sure), with decomposition level dependent selection, have been used. It is shown that the new procedure provides a good robust denoising performance, without the DWT fluctuating performance, and close to SWT but with a much lower computational cost.This work was partially supported by Spanish MCI Project DPI2011-22438San Emeterio Prieto, JL.; Rodríguez-Hernández, MA. (2015). Wavelet Cycle Spinning Denoising of NDE Ultrasonic Signals Using a Random Selection of Shifts. 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Control 58, 1027–1036 (2011)Shi, G.M., Chen, X.Y., Song, X.X., Qui, F., Ding, A.L.: Signal matching wavelet for ultrasonic flaw detection in high background noise. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 58, 776–787 (2011)Song, S.P., Que, P.W.: Wavelet based noise suppression technique and its application to ultrasonic flaw detection. Ultrasonics 44, 188–193 (2006)Rodriguez, M.A., San Emeterio, J.L., Lázaro, J.C., Ramos, A.: Ultrasonic flaw detection in NDE of highly scattering materials using wavelet and Wigner-Ville transform processing. Ultrasonics 42, 847–851 (2004)Zhang, G.M., Zhang, S.Y., Wang, Y.W.: Application of adaptive time-frequency decomposition in ultrasonic NDE of highly-scattering materials. Ultrasonics 38, 961–964 (2000)Drai, R., Khelil, M., Benchaala, A.: Time frequency and wavelet transform applied to selected problems in ultrasonics NDE. 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Опыт проведения валидации in vitro методики оценки инсулинозависимого захвата глюкозы

Russian and international regulatory documents require that analytical procedures for establishing bioequivalence and comparability of quality attributes of biotechnological (biological) products, carrying out batch release of medicinal products, and conducting other equally important in vitro studies must be validated. These in vitro studies include molecule–receptor binding and product bioactivity assays. However, at present, there is no single approach to validation of in vitro bioanalytical methods not involving the determination of active ingredient concentrations in biological fluids.The aim of the work was to validate a procedure for assessing insulin-dependent glucose uptake and demonstrate the suitability of GOD-PAP GLUCOSE kits for glucose determination in culture media.Materials and methods: The study used RinFast® insulin aspart by Geropharm, Russia; a placebo for insulin aspart; the L6J1 rat myogenic cell line; and a GOD-PAP GLUCOSE kit for quantitative determination of glucose. The study was carried out on differentiated cells cultured for 7 days. To encourage L6J1 differentiation, the authors used DMEM with 4.5 g/L glucose and 2% horse serum. The statistical analysis of results was performed using Prism 9.Results: The study demonstrated the analytical procedure’s specificity, as the concentration of residual glucose in the culture medium observed with the placebo was 4 times higher than that with the maximum concentration of the medicinal product. The determination of precision showed the repeatability of 4–9% and the intralaboratory precision of 11–16%. The coefficient of variation for robustness amounted to 14% in 4 independent experiments comprising a total of 9 analytical runs. The authors compared insulin products (the insulin aspart and a genetically engineered human insulin), and the half-maximal inhibitory concentration (IC50) values differed by 1.5 times. For the GOD-PAP GLUCOSE kit, the linear regression coefficient of determination was 0.9983, the sensitivity amounted to 1 mmol/L, and the accuracy ranged between 95% and 107%.Conclusions: the procedure using L6J1 rat myoblasts as a test system may be considered specific, highly precise, and robust in assessing insulin-dependent glucose uptake and suitable for detecting biological activity of insulin preparations in vitro.Согласно требованиям нормативных документов, как российских, так и международных, методики, применяющиеся при исследовании биоэквивалентности, сопоставимости показателей качества биотехнологических (биологических) препаратов, выпускающем контроле качества лекарственных препаратов и прочих не менее важных in vitro исследованиях, должны быть валидированы. Для этих исследований in vitro используют тесты на связывание молекулы с рецептором и на биологическую активность препаратов. Однако в настоящее время не существует единого подхода к валидации биоаналитических методик in vitro, не связанных с определением концентрации действующего вещества в биологических жидкостях.Цель работы: валидировать методику оценки инсулинозависимого захвата глюкозы и доказать пригодность набора ГЛЮКОЗА GOD-PAP для определения глюкозы в культуральной среде.Материалы и методы: в исследовании использовали препараты производства ОАО «ГЕРОФАРМ» РинФаст® и плацебо к инсулину аспарт, клеточную линию миобластов крысы L6J1, набор ГЛЮКОЗА GOD-PAP для определения концентрации глюкозы. Исследование проводили на дифференцированных клетках, которые культивировали в течение 7 сут. Для дифференцировки L6J1 использовали питательную среду DMEM с содержанием глюкозы 4,5 г/л и 2% сыворотки лошадиной. Статистическую обработку полученных результатов проводили с использованием программного обеспечения Prism 9.Результаты: продемонстрированы показатели специфичности методики; в максимальной концентрации препарат отличается от плацебо в 4 раза по остаточному уровню глюкозы в культуральной среде. Определена прецизионность методики: сходимость составила 4–9%, внутрилабораторная прецизионность 11–16%. Коэффициент вариации устойчивости методики составил 14% в 4 независимых экспериментах в 9 аналитических сериях. Проведено сравнение инсулиновых продуктов (инсулин аспарт и генно-инженерный инсулин человека), для которых показатели концентрации полумаксимального ингибирования (IC50) различались в 1,5 раза. Для набора ГЛЮКОЗА GOD-PAP коэффициент детерминации линейной регрессии составил 0,9983; чувствительность — 1 ммоль/л, диапазон правильности — 95–107%.Выводы: можно утверждать, что методика является специфичной, высокопрецизионной и устойчивой для проведения оценки инсулинозависимого захвата глюкозы с использованием клеточной линии миобластов крысы L6J1 в качестве тест-системы и является пригодной для детектирования биологической активности препаратов инсулина в in vitro исследованиях

Enzyme-Linked Immunosorbent Assay Method Application in the Study of Comparative Pharmacokinetics of Insulin Glargin Preparations

Aims: adaptation and validation of the ELISA method insulin glargine determination for the pharmacokinetic study, practical approval in the biosimilars clinical trial.Materials and methods. Serum insulin glargine determination was measured using a commercial ELISA kit. All tests were run on a Personal LAB machine (Adaltis S.r.l., Rome, Italy) with test systems for measuring the concentration of insulin glargine (Invitron Ltd., United Kingdom); human insulin concentrations were measured in the samples from the study for correction of cross-reactivity. Clinical part of this study included 42 male patients aged 18–65 with diabetes mellitus type 1. This was a double-blind, randomized, crossover clamp study with wash-out period of 7–14 days. Comparisons drugs: Insulin Glargine (glargine) solution for subcutaneous administration, 100 U/ml (GEROPHARM, Russia) and Lantus® (glargine) solution for subcutaneous administration, 100 U/ml (Sanofi-Aventis Deutschland GmbH, Germany).Results. At the stage of the method adaptation the modification of original manufacturer’s method was performed; the full validation of modified analytical method for all parameters (selectivity, specificity, precision of calibration curves, intra- and inter-batch precision and accuracy, carry-over, dilution integrity, stability of solutions, stability in biologic matrix, parallelism) in accordance with regulatory authorities requirements has been done. The primary endpoint for long-acting insulins – AUCins.0-τ was calculated. Insulin Glargine and Lantus® are equivalent based on AUCins.0-τ data (point estimation for ratio of geometric means was 99 %, the confidence intervals for the ratio of the geometric mean for AUCins.0-τ was 81.02–120.62 %, that correspond to acceptance range 80.00–125.00 %)