Geometric Mean Values Research Articles

Semaglutide for the treatment of obesity: Results of two open randomized pharmacokinetic studies

Introduction. Obesity is a growing public health issue in Russia, increasing the risk of cardiovascular diseases, type 2 diabetes, and hypertension. Controlling obesity involves lifestyle changes and pharmacotherapy. Semaglutide, an effective obesity treatment, stimulates insulin production and reduces appetite. Developing a generic semaglutide preparation will improve its availability in Russia.Aim. To study the comparative pharmacokinetics, bioequivalence, safety and tolerability of semaglutide products GP40331 and Wegovy using concentrations of 0.68 and 3.2 mg/ml in healthy volunteers under fasting conditions.Materials and methods. Bioequivalence studies, conducted per Good Clinical Practice, were open-label, randomized, and involved healthy male volunteers. Subjects received semaglutide at single doses of 0.25 mg (0.68 mg/ml) and 0.5 mg (3.2 mg/ml) under fasting. Bioequivalence was determined by the 90% CI of the ratios of geometric mean values of the primary pharmacokinetic parameters (AUC0-t, Cmax). Semaglutide concentrations were measured using high-performance liquid chromatography with tandem mass spectrometry.Results. The 90% CI values for the ratios of geometric means of the primary PK parameters of semaglutide were 90.22–110.29 and 86.48–108.98% (0.68 mg/ml) and 90.62–115.71 and 92.86–113.51% (3.2 mg/ml). Comparable safety was proven for both concentrations.Conclusion. GP40331 and Wegovy at 0.68 and 3.2 mg/mL are bioequivalent and equally safe.

Direct measurement of indoor thoron and radon progeny and estimation of inhalation dose in three cities in Gabon: Comparison of the use of thoron typical and measured equilibrium factor values

This study focuses on public exposure to natural radioactivity caused by the inhalation of radon and thoron progeny in homes in Franceville, Moanda and Mounana in Gabon. The equilibrium factor (FTn) between thoron and its progeny was determined experimentally for a proper estimate of the effective dose. In order to assess internal exposure due to radon and thoron progeny, 150 passive radon-thoron discriminative detectors (RADUET) and thoron progeny monitors were deployed for about 3 months in the above-mentioned towns. The results of the measurements obtained showed that the average concentrations of thoron progeny (EETC) were 1.54 ± 0.08 Bq m−3, 3.05 ± 0.09 Bq m−3 and 1.84 ± 0.11 Bq m−3 in Franceville, Moanda and Mounana, respectively. The ranges of the measured thoron equilibrium factors were 0.004–0.710, 0.005–0.750, and 0.006–0.794 in Franceville, Moanda and Mounana, respectively. The arithmetic and geometric mean values were, respectively, 0.183 and 0.117 in Franceville, 0.184 and 0.122 in Moanda, and 0.221 and 0.140 in Mounana. The experimentally determined equilibrium factor (FTnexp) allowed us to compare the value of the experimentally determined effective dose with the theoretically determined one calculated using the equilibrium factor proposed by United Nation Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 2000 report. FTnexp values were around 6–11 times greater than the UNSCEAR typical value. The ranges, arithmetic and geometric mean EERC values determined were 30.40–55.60 Bq m−3, 24.00 ± 0.90 Bq m−3 and 41.68 (1.00) in Franceville, 36.40–62.50 Bq m−3, 45.30 ± 0.70 Bq m−3 and 44.72 (1.00) in Moanda, and 35.00–90.00 Bq m−3, 50.00 ± 2.00 Bq m−3 and 48.50 (1.00) in Mounana. The mean values of the annual effective inhalation dose due to thoron progeny determined using FTnexp were 0.32 mSv (compared to 0.049 mSv), 0.63 mSv (compared to 0.103 mSv), and 0.39 mSv (compared to 0.055 mSv) in Franceville, Moanda and Mounana, respectively. The main conclusion of this study is that indirect estimations of thoron progeny concentrations considerably underestimate the estimation of the annual effective inhalation dose.

A real-world pharmacovigilance study using disproportionality analysis of United States Food and Drug Administration Adverse Event Reporting System events for vinca alkaloids: comparing vinorelbine and Vincristine

ABSTRACT Background Vinca alkaloids are widely used in cancer treatment for their ability to target microtubule dynamics. While their efficacy in treating certain cancers is well-established, the full spectrum of their adverse event profiles remains an area of ongoing research. Methods We analyzed AEs related to vinorelbine and vincristine using a retrospective case/non-case approach with data from the FDA Adverse Event Reporting System (FAERS). We applied various algorithms to detect AE signals: the reporting odds ratio (ROR) and proportional reporting ratio (PRR) measured disproportionality and association strength; the Bayesian confidence propagation neural network (BCPNN) calculated the Information Component (IC) for associations against background rates; and the multi-item gamma Poisson shrinker (MGPS) yielded empirical Bayes geometric mean (EBGM) values, accounting for reporting variability. Results Both medications significantly involve the blood and lymphatic systems, with vinorelbine reporting 401 cases in this System Organ Class (SOC), exhibiting a ROR of 17.4, PRR of 12.4, IC of 3.63, and EBGM of 12.38. An intersection analysis of Preferred Terms (PTs) has uncovered previously unreported AEs shared by both drugs, including posterior reversible encephalopathy syndrome and inappropriate antidiuretic hormone secretion. Conclusions This analysis highlights the need for ongoing research of the risks associated with vinorelbine and vincristine.

Fault traceability of power grid dispatching system based on DPHS-MDS and LambdaMART algorithm

Under the background of increasing system service data, it is difficult to trace the faults of power dispatching system. The current fault tracing method has some problems, such as low precision, low efficiency and difficult troubleshooting. To solve this problem, a fault tracing method based on data partition hybrid sampling method and multiple incremental regression tree algorithm is proposed. In this paper, it first uses the hybrid sampling method of data partition and dynamic selection technology to detect the business anomaly, and then applies the clustering algorithm and the information difference graph model to realize the fault tracing of system components. The experimental results showed that the F-metric value and geometric mean value of the study design method were 0.964 and 0.685, respectively. In addition, normalized discounted cumulative gains were observed in the top 10, and the mean average precision of the top 10 was 0.752 and 0.186, respectively. The proposed method can effectively improve the fault tracing efficiency of power grid operation and maintenance personnel, and provide strong data support for the safety maintenance of power grid dispatching system.

In vitro antifungal activity of eucalyptol and its interaction with antifungal drugs against clinical dermatophyte isolates including Trichophyton indotineae

BackgroundDermatophytosis, a prevalent fungal infection, often exhibits treatment failure. It poses ongoing public health concerns, urging exploration of alternative treatment strategies. This study examines eucalyptol’s in vitro activity and its interaction with antifungal agents against dermatophyte isolates.MethodsOverall, 489 patients clinically suspected of dermatophytosis were investigated, and the causative agents were molecularly identified. The antifungal activity of eucalyptol, itraconazole, terbinafine, and griseofulvin was assessed according to the guideline of the Clinical and Laboratory Standards Institute (CLSI M38 ed3). The interaction between eucalyptol and the aforementioned antifungals was determined using a checkerboard method.ResultsDermatophytosis was confirmed in 30 out of 489 (6.13%) patients, with a female-to-male ratio of 3:2 and an age range of 8–67 years. The most commonly observed clinical manifestation was tinea corporis (34.21%), and Trichophyton indotineae (n = 14, 46%) was the most common causative agent. Antifungal susceptibility testing revealed that eucalyptol exhibited antidermatophyte properties with minimum inhibitory concentrations (MIC) ranging from 0.78 to 25 mg/mL. Itraconazole demonstrated the lowest geometric mean (GM) value (MIC range: 0.0019–0.25 µg/mL, GM: 0.015 µg/mL), while griseofulvin exhibited the highest GM value (MIC range: 0.125–8 µg/mL, GM: 2.37 µg/mL). The in vitro interaction of eucalyptol with antifungal drugs, except for its combination with terbinafine against two Trichophyton tonsurans isolates resulting in synergistic effects, showed indifference (n = 70, 77.77%) and antagonistic types (n = 18, 20%).ConclusionAmong the evaluated antifungals, itraconazole demonstrated the highest effectiveness against clinical isolates, while eucalyptol alone exhibited a more pronounced effect than when combined with antifungal agents.

Early diagnosis of Cladosporium fulvum in greenhouse tomato plants based on visible/near-infrared (VIS/NIR) and near-infrared (NIR) data fusion

Plant diseases can inflict varying degrees of damage on agricultural production. Therefore, identifying a rapid, non-destructive early diagnostic method is crucial for safeguarding plants. Cladosporium fulvum (C. fulvum) is one of the major diseases in tomato growth. This work presents a method of data fusion using two hyperspectral imaging systems of visible/near-infrared (VIS/NIR) and near-infrared (NIR) spectroscopy for the early diagnosis of C. fulvum in greenhouse tomatoes. First, hyperspectral images of samples at health and different times of infection were collected. The average spectral data of the image regions of interest were extracted and preprocessed for subsequent spectral datasets. Then different classification models were established for VIS/NIR and NIR data, optimized through various variable selection and data fusion methods. The principal component analysis-radial basis function neural network (PCA-RBF) model established using low-level data fusion achieved optimal results, achieving accuracies of 100% and 99.3% for calibration and prediction, respectively. Moreover, both the macro-averaged F1 (Macro-F1) values reached 1, and the geometric mean (G-mean) values reached 1 and 1, respectively. The results indicated that it was feasible to establish a PCA-RBF model by using the hyperspectral technique with low-level data fusion for the early detection of C. fulvum in greenhouse tomatoes.

Early Detection of Pulmonary Embolism in a General Patient Population Immediately Upon Hospital Admission Using Machine Learning to Identify New, Unidentified Risk Factors: Model Development Study.

Under- or late identification of pulmonary embolism (PE)-a thrombosis of 1 or more pulmonary arteries that seriously threatens patients' lives-is a major challenge confronting modern medicine. We aimed to establish accurate and informative machine learning (ML) models to identify patients at high risk for PE as they are admitted to the hospital, before their initial clinical checkup, by using only the information in their medical records. We collected demographics, comorbidities, and medications data for 2568 patients with PE and 52,598 control patients. We focused on data available prior to emergency department admission, as these are the most universally accessible data. We trained an ML random forest algorithm to detect PE at the earliest possible time during a patient's hospitalization-at the time of his or her admission. We developed and applied 2 ML-based methods specifically to address the data imbalance between PE and non-PE patients, which causes misdiagnosis of PE. The resulting models predicted PE based on age, sex, BMI, past clinical PE events, chronic lung disease, past thrombotic events, and usage of anticoagulants, obtaining an 80% geometric mean value for the PE and non-PE classification accuracies. Although on hospital admission only 4% (1942/46,639) of the patients had a diagnosis of PE, we identified 2 clustering schemes comprising subgroups with more than 61% (705/1120 in clustering scheme 1; 427/701 and 340/549 in clustering scheme 2) positive patients for PE. One subgroup in the first clustering scheme included 36% (705/1942) of all patients with PE who were characterized by a definite past PE diagnosis, a 6-fold higher prevalence of deep vein thrombosis, and a 3-fold higher prevalence of pneumonia, compared with patients of the other subgroups in this scheme. In the second clustering scheme, 2 subgroups (1 of only men and 1 of only women) included patients who all had a past PE diagnosis and a relatively high prevalence of pneumonia, and a third subgroup included only those patients with a past diagnosis of pneumonia. This study established an ML tool for early diagnosis of PE almost immediately upon hospital admission. Despite the highly imbalanced scenario undermining accurate PE prediction and using information available only from the patient's medical history, our models were both accurate and informative, enabling the identification of patients already at high risk for PE upon hospital admission, even before the initial clinical checkup was performed. The fact that we did not restrict our patients to those at high risk for PE according to previously published scales (eg, Wells or revised Genova scores) enabled us to accurately assess the application of ML on raw medical data and identify new, previously unidentified risk factors for PE, such as previous pulmonary disease, in general populations.

Assessment of radon levels in indoor workplaces in Tunisia and associated radiological risks

ABSTRACT This study aimed to assess indoor radon levels within different workplaces in Tunisia, including universities, schools, spa centres, and phosphate fertiliser factories. A total of 110 locations within these workplaces were monitored using solid-state nuclear track detectors (LR 115). The obtained results indicated that the geometric mean (GM) values of indoor radon concentrations measured at these locations were 24.6 Bq m−3 for universities, 31.3 Bq m−3 for schools, 72.2 Bq m−3 for spa centres, and 70.0 Bq m−3 for phosphate fertiliser factories. Overall, the GM of indoor radon concentrations measured in the four studied workplaces remained below standard values. Statistical analysis using the two-sample Student t-test revealed significant differences between the workplaces. The calculated annual effective doses due to radon inhalation were found to have GM values of 0.2 mSv y−1 for universities, 0.2 mSv y−1 for schools, 0.5 mSv y−1 for spa centres, and 0.4 mSv y−1 for phosphate fertiliser factories. These values are comparable to worldwide average values. Other risk parameters, such as lung cancer risk and lung cancer cases were also determined and reported in this study. While this study did not investigate the factors influencing radon concentrations, its primary advantage lies in being the first comparative study monitoring various workplaces in Tunisia, covering both underground and above-ground settings.

In Vitro/In Vivo Correlation of Two Extended-Release Cilostazol Formulations.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets.

Lossless and Near-Lossless Compression Algorithms for Remotely Sensed Hyperspectral Images.

Rapid and continuous advancements in remote sensing technology have resulted in finer resolutions and higher acquisition rates of hyperspectral images (HSIs). These developments have triggered a need for new processing techniques brought about by the confined power and constrained hardware resources aboard satellites. This article proposes two novel lossless and near-lossless compression methods, employing our recent seed generation and quadrature-based square rooting algorithms, respectively. The main advantage of the former method lies in its acceptable complexity utilizing simple arithmetic operations, making it suitable for real-time onboard compression. In addition, this near-lossless compressor could be incorporated for hard-to-compress images offering a stabilized reduction at nearly 40% with a maximum relative error of 0.33 and a maximum absolute error of 30. Our results also show that a lossless compression performance, in terms of compression ratio, of up to 2.6 is achieved when testing with hyperspectral images from the Corpus dataset. Further, an improvement in the compression rate over the state-of-the-art k2-raster technique is realized for most of these HSIs by all four variations of our proposed lossless compression method. In particular, a data reduction enhancement of up to 29.89% is realized when comparing their respective geometric mean values.

Nuclear magnetic resonance experiments on the time-varying law of oil viscosity and wettability in high-multiple waterflooding sandstone cores

A simulated oil viscosity prediction model is established according to the relationship between simulated oil viscosity and geometric mean value of T2 spectrum, and the time-varying law of simulated oil viscosity in porous media is quantitatively characterized by nuclear magnetic resonance (NMR) experiments of high multiple waterflooding. A new NMR wettability index formula is derived based on NMR relaxation theory to quantitatively characterize the time-varying law of rock wettability during waterflooding combined with high-multiple waterflooding experiment in sandstone cores. The remaining oil viscosity in the core is positively correlated with the displacing water multiple. The remaining oil viscosity increases rapidly when the displacing water multiple is low, and increases slowly when the displacing water multiple is high. The variation of remaining oil viscosity is related to the reservoir heterogeneity. The stronger the reservoir homogeneity, the higher the content of heavy components in the remaining oil and the higher the viscosity. The reservoir wettability changes after water injection: the oil-wet reservoir changes into water-wet reservoir, while the water-wet reservoir becomes more hydrophilic; the degree of change enhances with the increase of displacing water multiple. There is a high correlation between the time-varying oil viscosity and the time-varying wettability, and the change of oil viscosity cannot be ignored. The NMR wettability index calculated by considering the change of oil viscosity is more consistent with the tested Amott (spontaneous imbibition) wettability index, which agrees more with the time-varying law of reservoir wettability.

Epstein - Barr Virus Salivary Shedding in Patients with Acute Infectious Diseases: A Pilot Study.

Epstein-Barr virus (EBV) is a widely disseminated herpesvirus for which antibodies have been demonstrated in over 90% of adults worldwide. After subclinical primary EBV infections, as well as after infectious mononucleosis, the virus can be shed in saliva for a prolonged period of time. Diseases and disorders that can induce EBV salivary shedding include mental disorders and sex, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, malaria and HIV infection. Since the occurrence of EBV in saliva during acute infectious diseases has not yet been systematically researched, we aimed to investigate the possible relationship between acute infectious diseases and salivary shedding of EBV. This pilot cross-sectional study included consenting adults hospitalized for acute infectious conditions and their peers free of acute infectious diseases. A total of 40 patients with acute infectious diseases were enrolled, along with 41 adults free of acute infections. Peripheral venous blood samples for serodiagnosis and saliva samples for EBV PCR testing were collected from both groups. We fitted logit and general linear models to proportions and to ln (viral copy counts) to generate adjusted proportions and geometric mean values in the two groups of subjects. We used SAS for Windows 9.4. The most common acute infectious disease was COVID-19 pneumonia, followed by hemorrhagic fever with renal syndrome. Crude proportions of people with positive serological test results and those with saliva viral shedding were similar in the two groups. The presented preliminary data do not indicate acute infectious conditions as a marked "contributor" in increasing salivary EBV shedding.

Hepatotoxicity of newer antiseizure medications in children: an overview and disproportionality analysis of VigiBase

ABSTRACT Background We aimed to characterize newer antiseizure medications (ASMs)-induced hepatotoxicity in children and identify signals of disproportionate reporting of hepatotoxicity-related adverse drug events (ADEs). Research Design and Methods Case reports reported to VigiBase were accessed using Empirica™ Signal software. To summarize characteristics of the retrieved cases, descriptive statistics were used. A disproportionality analysis was conducted using the Multi-item Gamma Poisson Shrinker algorithm, which calculates Empirical Bayesian Geometric Mean value and its lower and upper 95% confidence limits (EB05 and EB95, respectively). EB05 > 2, N > 0 was considered a signal. Results Based on 870 analyzed cases, a higher proportion of cases was reported in girls than in boys and in patients aged 2–11 years than in other age groups. Most cases were serious. In 25 cases, hepatotoxicity resulted in death. A high proportion of patients (n = 275, 31.61%) experienced hypersensitivity reactions, mostly due to lamotrigine. The disproportionality analysis yielded 17 signals concerning felbamate, lamotrigine, levetiracetam, oxcarbazepine, stiripentol, and topiramate. Four signals were for severe liver injury and concerned felbamate, lamotrigine, levetiracetam, and topiramate. Gender-biased reporting frequency was detected for four ASM-ADE combinations. Conclusion Our results should serve to raise clinicians’ awareness about the potential association between several newer ASMs and drug-induced liver injury in children.

Results of biosimilar assessing of insulin aspart preparations of Russian and foreign production using the hyperinsulinemic euglycemic clamp method and studying the use of a new ultra-fast-acting Russian biosimilar in pumps

Introduction. Ultra-fast-acting insulin aspart has great potential for improving postprandial glycemia in patients with type 1 and type 2 diabetes mellitus due to its pharmacological characteristics. The development and production of biosimilars are increasing the availability of modern insulins for patients.Aim. To evaluate the comparability of the pharmacokinetics and pharmacodynamics profiles of insulin aspart GP40311 (tested biosimilar of domestic production) and the reference drug (produced in Denmark) under conditions of a hyperinsulinemic euglycemic clamp in healthy volunteers. To evaluate the stability of a new ultrafast-acting biosimilar when used for continuous subcutaneous infusion in insulin pumps.Materials and methods. Double-blind, randomized, crossover study assessing the pharmacokinetics, pharmacodynamics and safety of the tested biosimilar GP40311 of domestic production and the reference drug produced in Denmark, in the form of a solution for intravenous and subcutaneous administration of 100 IU/ml, the study was conducted under conditions of a hyperinsulinemic euglycemic clamp with the participation of 36 healthy volunteers. A study of the stability, dosing accuracy and tendency to catheter occlusion of a domestic drug for continuous subcutaneous infusion was carried out using several types of insulin pumps using the gravimetric method for 72 hours. Dosing accuracy was determined at the minimum and maximum bolus dose, stability was assessed by pH and quantitative insulin content aspart. The quantitative content of insulin and impurities was assessed by high-performance liquid chromatography.Results and discission. The 90% confidence interval for the ratio of geometric mean values of the main parameters of pharmacokinetics (AUCins.0-t and Cins.max) of insulin aspart test and reference drugs corresponded to the acceptable values of 80.00– 125.00%, which indicated their biosimilarity. When assessing PD, the comparability of action parameters is shown. The safety of the study drugs is comparable. Domestic insulin aspart met the specification standards when used for continuous subcutaneous infusion according to physicochemical parameters: pH, quantitative determination of insulin aspart, impurity content. The accuracy of dosing and the absence of occlusions in systems for 72 hours when using the drug in pumps have been established.Conclusion. The study drugs were found to be biosimilar and equally safe. Domestic insulin aspart meets specification standards and can be used in various types of pumps.

Bordetella pertussis isolates in Finland after acellular vaccination: serotype change and biofilm formation

ObjectivesIn Finland, whole cell pertussis vaccine (wP) was introduced in 1952 and was replaced by acellular pertussis vaccine (aP) without fimbrial (FIM) antigen in 2005. We aimed to analyse the changes in serotypes of circulating Bordetella pertussis before and after acellular vaccination and to explore the relationship between biofilm formation and serotype diversity after the introduction of aP vaccine. MethodsSerotyping of 1399 B. pertussis isolates collected at the Finnish National Reference Laboratory for Pertussis and Diphtheria in Turku, Finland, from 1974 to 2023 was performed by slide agglutination or indirect ELISA. Of 278 isolates collected after 2005, 53 were selected, genotyped for fim3 and fim2 alleles, and tested for biofilm formation. The selection criteria included maintaining a relatively equal distribution of isolates per time interval, ensuring approximately a 50:50 ratio of FIM2 (N = 26) and FIM3 (N = 27) serotypes. The reference strain Tohama I was used as a control. ResultsDuring the wP era, the majority of circulating B. pertussis exhibited the FIM2 serotype. However, FIM3 strains have appeared since 1999 and become prevalent. After the implementation of aP vaccines, the distribution of serotypes has exhibited substantial variability. FIM3 isolates displayed an enhanced biofilm formation compared to FIM2 isolates (Geometric mean value (95% CI): 0.90 (0.79–1.03) vs. 0.75 (0.65–0.85); p < 0.05). Of the 27 FIM3 isolates, 8 harboured fim3-1 and 19 fim3-2 alleles. FIM3 isolates with fim3-2 allele were significantly associated with increased biofilm formation when compared to those with fim3-1 (1.07 (0.96–1.19) vs. 0.61 (0.52–0.72); p < 0.0001). ConclusionFollowing the implementation of aP vaccines, the distribution of serotypes in Finland has exhibited substantial variability. FIM3 isolates with the fim3-2 allele displayed an enhanced biofilm formation capability compared to FIM2 isolates.

Comparative analysis of physicochemical properties, bioequivalence, safety and tolerability of the first domestic semaglutide

Semaglutide is a representative of analogues of the incretin hormone human glucagon-like peptide-1 (GLP-1) and is currently used in Russia for the treatment of type 2 diabetes mellitus (T2DM; in monotherapy and in combination therapy), including patients with obesity and overweight.The aim of the work was to conduct a comparative assessment of the physicochemical properties, a biological activity, bioequivalence and safety, including tolerability and immunogenicity, of the drug Quincent® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) and the drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark) when administered to healthy volunteers.Materials and methods. To assess the degree of similarity of the study drug Quincenta® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Promomed Rus LLC, Russia) with a chemically synthesized active substance to the original (reference) drug Ozempic® (semaglutide, 1.34 mg/ml, a solution for a subcutaneous administration, Novo Nordisk A/S, Denmark), a comparative study of physicochemical properties and a biological activity was carried out. To assess the bioequivalence of the study drug and the reference drug, an open randomized parallel comparative study with the participation of healthy volunteers (n=54), 54 participants of which had been included in the population, was conducted. The volunteers were randomized into 2 groups in a 1:1 ratio, and received a single dose subcutaneously either of the study drug (domestic semaglutide at a dose of 0.5 mg) or the reference drug (foreign semaglutide at a dose of 0.5 mg). The mode of administration was in the morning on an empty stomach. A semaglutide concentration was determined in serum samples using a previously validated enzyme-linked immunosorbent assay (ELISA) method. A quantitative determination of antibodies to semaglutide in the human serum by ELISA was carried out with a microplate photometer using ready-made kits pre-validated by the manufacturer. The conclusion about the bioequivalence of the compared drugs was made using an approach based on the assessment of 90% confidence intervals for the ratios of the geometric mean values of the parameters Cmax, AUC(0–t) of semaglutide in the measurement original units.Results. The results of the comparative analysis of the study drug and the reference drug demonstrate the comparability of their physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the test drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the Cmax value for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® it was 42.2556±7.84. Herewith, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the Cmax and AUC0–t values of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. The tolerability of the drugs in the volunteers was notified as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of Results. The results of a comparative analysis of the study drug and the reference drug demonstrate the comparability of physicochemical properties and biological activity. The results of the clinical study demonstrated the bioequivalence of the study drug and the reference drug. Thus, the pharmacokinetic parameters of the drugs were comparable to each other: the Cmax value for the study drug was 42.088±8.827 ng/ml, for the reference drug Ozempic® this figure was 42.2556±7.84. At the same time, the half-life for the study drug and the reference drug was 168.39±39.47 and 157.99±28.57 hours, respectively. The resulting 90% confidence intervals for the ratio of the Cmax and AUC0–t values of the study drug and the reference drug were 90.89–109.15 and 91.66–111.27%, respectively. Tolerability of the drugs in volunteers was noted as good. No adverse events were recorded during the study. No serious adverse events were reported throughout the study. According to the results of the immunogenicity analysis, no antibodies to Russian-made semaglutide were detected in the blood serum of the volunteers, which indicated the lack of the drug immunogenicity.Conclusion. In the course of the study, the comparability of the physicochemical properties and biological activity of the studied Russian drug with the chemically synthesized active substance Quincenta® to the reference drug Ozempic® was confirmed: the activity range of the studied drugs was within 80–120% in relation to the standard sample of semaglutide. The bioequivalence and a similar safety profile, including the immunogenicity and tolerability of the Russian drug Quincenta® (semaglutide 1.34 mg/ml, Promomed Rus LLC, Russia) were shown in comparison with the foreign drug Ozempic® (semaglutide 1.34 mg/ml, Novo Nordisk A/C, Denmark).

Assessment of investment attractiveness of enterprises: theoretical, methodological and practical aspects

The article examines the essence of the investment attractiveness of the enterprise as an economic category according to normative sources, educational and methodological and scientific literature, and dissertation studies. Methodical approaches to the assessment of the investment attractiveness of the enterprise are defined according to the financial condition, the integral indicator, the matrix approach, and others. The existing methodology for assessing the investment attractiveness of the enterprise, chosen based on the criteria of a comprehensive approach and relative simplicity of calculations, has been improved by refining the indicators that will be used for calculation. The choice of indicators is justified, including, based on the same positive dynamics – growth, which ensures the same positive dynamics for the indicator of the investment attractiveness of the enterprise calculated on their basis. According to the method justified for use and specified by the author, an assessment of the level of investment attractiveness of two agricultural enterprises of the Volyn region was carried out, and the results were interpreted. The advantages of the methodology specified by the author, which is based on the calculation of the geometric mean value of four main indicators that characterize the level of turnover of assets, the level of capital profitability, the level of financial stability of the enterprise and the level of liquidity of its assets, are established: the relative simplicity of calculations and, accordingly, the high speed of obtaining results. At the same time, this method takes into account indicators that characterize the main areas of financial analysis of the company's activity. The methods of application of the proposed methodology are substantiated – the analysis of the investment attractiveness of the enterprise in dynamics and the possibility, based on the results of factor analysis, to identify negative changes in certain areas of financial analysis (business activity, profitability, financial stability or liquidity); comparing the level of investment attractiveness of two or more enterprises and establishing, on this basis, a more attractive investment object for a potential investor.

Quantification of Cervical Elasticity During Pregnancy Based on Transvaginal Ultrasound Imaging and Stress Measurement.

To overcome these limitations, we develop a quantitative cervical elastography system by adding a stress sensor to a clinically used transvaginal ultrasound imaging system. We record the cervical deformation in B-mode images and measure the probe-surface stress through the sensor. Then we quantify the strain using a customized algorithm and estimate the cervical Young's modulus through stress-strain linear regression. In phantom experiments, we demonstrate the system's high accuracy (alignment with the quasi-static compression method, p-value = 0.369 > 0.05), robustness (alignment between 60°- and 90°-contact measurements, p-value = 0.638 > 0.05), repeatability (consistency of single sonographers' measurements, coefficient of variation < 0.06), and reproducibility (alignment between two sonographers' measurements, Pearson correlation coefficient = 0.981). Applying it to pregnant participants, we observe significant cervical softening (p-value < 0.001): Young's modulus decreases 3.95% weekly and its geometric mean value during the first (11 to 13 weeks), second, and third trimesters are 13.07 kPa, 7.59 kPa, and 4.40 kPa, respectively. The proposed system is accurate, robust, and safe, and enables longitudinal and inter-examiner comparisons. The system applies to different ultrasound machines with minor software updates, which allows for studies of cervical softening patterns in pregnancy for larger populations, facilitating insights into conditions such as preterm birth.

Daily Exposure to Environmental Volatile Organic Compounds Triggers Oxidative Damage: Evidence from a Large-Scale Survey in China.

Volatile organic compounds (VOCs) are ubiquitous environmental pollutants and have been implicated in adverse health outcomes. In this study, concentrations of 11 VOC metabolites (mVOCs) and three oxidative stress biomarkers (8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxo-7,8-dihydro-guanosine, and dityrosine) were determined in 205 urine samples collected from 12 cities across mainland China. Urinary ∑11mVOC concentrations ranged from 498 to 1660 ng/mL, with a geometric mean (GM) value of 1070 ng/mL. The factorial analysis revealed that cooking, solvents, and vehicle emissions were the three primary sources of VOC exposure. A significant regional variation was clearly found in ∑11mVOC concentrations across four regions in China, with high urine VOC concentrations found in North and South China (GM: 1450 and 1340 ng/mL). The multiple linear regression model revealed that most mVOCs were significantly positively correlated with three oxidative stress markers (β range: 0.06-0.22). Mixture effect regression showed that isoprene, crotonaldehyde, acrolein, and benzene were the strongest contributors to oxidative stress. Approximately 80% of the participants have HQ values greater than 1.0 for 1,3-butadiene and benzene, suggesting that their exposure doses were close to potential adverse health effects. Our findings provide comprehensive information on human exposure and potential health risks of VOCs in China.

Efficacy of Parallel and Crossover Analysis As Well As Pharmacokinetic Similarity Were Confirmed between ABP 959 and Eculizumab Reference Product in Patients with PNH

Introduction: ABP 959, a biosimilar to eculizumab reference product (RP), binds to the human complement component 5 protein to inhibit terminal complement activation. Eculizumab RP is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optical spectrum disorder. Regulatory approval of biosimilars is based on a totality of evidence approach which includes demonstration of similarity in analytical and non-clinical characteristics, and in comparative clinical studies. Analytical and non-clinical similarities of ABP 959 with eculizumab RP and clinical pharmacokinetics (PK)/pharmacodynamics (PD) and safety similarities in healthy adults have been previously reported. Similarity of the primary efficacy and safety results from the parallel and crossover comparisons in patients with PNH have also been previously reported. Here, we report together the primary efficacy results from both the parallel and the cross-over comparisons along with additional PK analyses in patients with PNH to further support the demonstration of similarity of ABP 959 with eculizumab RP. Methods: A multicenter, randomized, double-blind, active-controlled, 2-period crossover study evaluated the clinical similarity of ABP 959 compared with eculizumab RP in adult patients with PNH. Patients were randomized 1:1 to receive each investigational product (900 mg of ABP 959 or eculizumab RP IV q14d) in 1 of 2 treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959). Primary efficacy determined by hemolysis, measured by lactate dehydrogenase (LDH), was analyzed for both the parallel and crossover comparisons. The parallel comparison endpoint was measured at week 27 and clinical similarity was assessed by comparing the 1-sided 97.5% upper confidence interval (CI) limit for the geometric least squares (LS) mean ratio of LDH between ABP 959 treatment group and eculizumab RP treatment group with a non-inferiority (NI) margin of 2.873. The crossover comparison endpoint was measured by the time-adjusted area under the effect curve (AUEC) of LDH from weeks 13 to 27, 39 to 53, and 65 to 79. The similarity of efficacy between treatment groups was assessed by comparing the 2-sided 90% CI for the geometric mean ratio (GMR) of the time-adjusted AUEC of LDH with a similarity margin of (0.77, 1.30). The total and unbound PK area under the curve (AUC) of ABP 959 and eculizumab RP from week 13 to week 15 and trough PK were identified as secondary endpoints in this study. Results: Forty-two patients (20 in ABP 959/eculizumab RP group; 22 in eculizumab RP/ABP 959 group) were randomized across 25 centers. Similarity of efficacy was established in both the parallel and crossover comparisons. In the parallel comparison, the ratio of the geometric LS means of LDH at week 27 (ABP 959 vs eculizumab RP) was 1.0628, with a 1-sided 97.5% upper CI of 1.1576 was contained within the NI margin of 2.873. In the crossover comparison, a point estimate of the GMR of time-adjusted AUEC of LDH (ABP 959 vs eculizumab RP) of 0.9812 with a 2-sided 90% CI of (0.9403-1.0239) was contained within the prespecified margin of similarity. The GMR (90% CI) for the total and unbound PK AUC from week 13 to week 15 was 0.9122 (0.7586, 1.0968) and 0.9508 (0.7454, 1.2130), respectively. Geometric mean values for trough total and unbound concentrations of ABP 959 and eculizumab RP were similar between the treatment groups at all time points tested over the entire study. Conclusions: Similarity in clinical efficacy in both parallel and crossover comparisons as determined by hemolysis in patients with PNH was established between ABP 959 and eculizumab RP. Additionally, analyses of serum total and unbound PK concentrations for patients with PNH further demonstrated PK similarity between ABP 959 and eculizumab RP. The results of this study, along with previously demonstrated analytical, non-clinical, clinical PK/PD in healthy adults, and efficacy and safety evaluations in PNH patients, further support a demonstration of no clinically meaningful differences between ABP 959 and eculizumab RP.