Safety Evaluation Research Articles

Safety of Empagliflozin: An Individual Participant-Level Data Meta-Analysis from Four Large Trials.

Empagliflozin is a sodium-glucose co-transporter-2 inhibitor used to treat type 2 diabetes (T2D) to improve glycemic control, reduce risk of cardiovascular death in patients with T2D, and treat patients with symptomatic chronic heart failure (HF) and chronic kidney disease (CKD). The safety profile of empagliflozin is well documented, although adverse events (AEs) remain of interest to clinicians. This study provides an up-to-date safety evaluation of empagliflozin. Data were pooled from four long-term trials which included: patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME), patients with HF, with/without diabetes (EMPEROR-Reduced and EMPEROR-Preserved), and patients with CKD, with/without diabetes (EMPA-KIDNEY). Since three of the four trials evaluated empagliflozin 10mg, the meta-analysis was restricted to this dose. Total trial medication exposure was 19,727 patient-years for patients who received empagliflozin (n = 10,472) and 19,447 patient-years for placebo (n = 10,461). The percentages of patients with serious AEs, fatal AEs, and AEs leading to discontinuation were similar for both groups. The incidences of serious urinary tract infection and serious pyelonephritis or urosepsis were similar for both groups but higher for women taking empagliflozin versus placebo. Serious genital infections were not increased with empagliflozin versus placebo. There was a slight increase in ketoacidosis and serious volume depletion in patients who received empagliflozin versus placebo. The occurrence of serious acute kidney injury was lower with empagliflozin versus placebo. Empagliflozin was not associated with an increased incidence of severe hypoglycemia, bone fractures, or lower limb amputations. Empagliflozin is therefore considered safe in people without diabetes, the elderly, patients with very low estimated glomerular filtration rate, low body mass index, and HF. Safety is unaltered by blood pressure, concomitant medication for hypertension, HF, and immunosuppression. This meta-analysis of long-term safety data extends current knowledge and confirms the safety and tolerability of empagliflozin.

Digital Twin-Enabled Response Function Analysis: A Synthetic Approach to Ship's Propulsion System Assessment

Analyzing the behavior of vessels in actual sea conditions is crucial for conceptual system design, safety and energy efficiency considerations. However, the essential seakeeping problem is reduced to the analysis of wave-hull interactions often neglecting consideration of the propulsion. But in the meantime, the synthetic consideration of wave–propulsion interactions is a key for safety and energy efficiency. Furthermore, safety evaluation of a ship's design with reduced propulsion power in adverse seas is vital for risk management. Response functions are commonly used to estimate propulsion system responses in incoming seaways. This paper proposes a synthetic approach using digital twin technology for rapid response function estimation. It introduces a companion linearized state-space model linked with the digital twin, enabling immediate retrieval of coefficients for response function analysis at the desired operating point. This integrated methodology provides a comprehensive representation of ship propulsion behavior in wave environments, offering a comprehensive framework for system performance assessment.

Investigating advection–dispersion behavior for simulation of HTO and 238Pu transport in argillaceous shale with different varying degrees of weathering

Abstract Exploring the migration behavior of radioactive nuclides in the surrounding rock media of the disposal site is the basis for the safety evaluation of radioactive waste disposal sites. In this study, the column experiment was employed to evaluate the nuclide migration behavior in the surrounding rock medium of a near-surface disposal site in China and to investigate the advection–dispersion behavior of tritium (HTO) and plutonium-238 (238Pu) in highly weathered argillaceous shale with different degree of weathering. A reasonable numerical model was selected to fit the experimental breakthrough curves (BTCs) and obtain relevant migration parameters. The results showed that: (1) the breakthrough curves of HTO and 238Pu in fractured media with varying degrees of weathering exhibited clear “peak forward” and “tail dragging” phenomena; (2) the stream tube model can better fit the BTCs of the nuclides in the highly weathered fractures and obtain the average dispersion coefficient <D>, average distribution coefficient <K d>, and other parameters; (3) the two-region non-equilibrium model can better fit the BTCs of the nuclides in the penetrating fractures and weak weathering fractures and obtain the volumetric water content of the mobile liquid region (θ m), distribution coefficient (K d), and other parameters.

A protocol to determine the acceptability and feasibility of a pilot intervention emergency department virtual observation unit fall prevention program

BackgroundAs a third of all community dwellers aged 65+ fall each year, falls are common reasons for older adults to present to an Emergency Department (ED). Although EDs should assess patients’ multifactorial fall risks to prevent future fall-related injuries, this frequently does not occur. We describe our protocol to determine the feasibility, acceptability, and safety of a pilot ED Virtual Observation Unit (VOU) Falls program.MethodsTo ensure standardized conduct and reporting, the Standard Protocol Items for Intervention Trials (SPIRIT) guidelines will be used. The VOU is a program where patients are sent home from the ED but are part of a virtual observation unit in that they can call on-call ED physicians while they are being treated for conditions such as cellulitis, congestive heart failure, or pneumonia. A paramedic conducts daily visits with the patient and facilitates a telemedicine consult with an ED physician. VOU nursing staff conduct daily assessments of patients via telemedicine. The ED VOU Falls program is one of the VOU pathways and is a multi-component fall prevention program for fall patients who present after an ED visit. The paramedic conducts a home safety evaluation, a Timed Up and Go Test (TUG). During the VOU visit, the ED physician conducts a telemedicine visit, while the paramedic is visiting the home, to review patients' fall-risk-increasing drugs and their TUG test. We will determine feasibility by calculating rates of patient enrollment refusal, and adherence to fall-risk prevention recommendations using information from 3-month follow-up telephone calls, as well as qualitative interviews with the paramedics. We will determine the acceptability of the ED VOU Falls program based on patient and provider surveys using a Likert scale. We will ask VOU nursing staff to report any safety issues encountered while the patient is in the ED VOU Falls program (e.g., tripping hazards). We will use the chi-square test or Fisher’s exact test for categorical variables, Student’s t-test for continuous variables, and Mann-Whitney for nonparametric data. We will review interview transcripts and generate codes. Codes will then be extracted and organized into concepts to generate an overall theme following grounded theory methods. This is a pilot study; hence, results cannot be extrapolated. However, a definite trial would be the next step in the future to determine if such a program could be implemented as part of fall prevention interventions.DiscussionThis study will provide insights into the feasibility and acceptability of a novel ED VOU Falls program with the aim of ultimately decreasing falls. In the future, such a program could be implemented as part of fall prevention interventions.

Advancing Drug Safety in Drug Development: Bridging Computational Predictions for Enhanced Toxicity Prediction.

The attrition rate of drugs in clinical trials is generally quite high, with estimates suggesting that approximately 90% of drugs fail to make it through the process. The identification of unexpected toxicity issues during preclinical stages is a significant factor contributing to this high rate of failure. These issues can have a major impact on the success of a drug and must be carefully considered throughout the development process. These late-stage rejections or withdrawals of drug candidates significantly increase the costs associated with drug development, particularly when toxicity is detected during clinical trials or after market release. Understanding drug-biological target interactions is essential for evaluating compound toxicity and safety, as well as predicting therapeutic effects and potential off-target effects that could lead to toxicity. This will enable scientists to predict and assess the safety profiles of drug candidates more accurately. Evaluation of toxicity and safety is a critical aspect of drug development, and biomolecules, particularly proteins, play vital roles in complex biological networks and often serve as targets for various chemicals. Therefore, a better understanding of these interactions is crucial for the advancement of drug development. The development of computational methods for evaluating protein-ligand interactions and predicting toxicity is emerging as a promising approach that adheres to the 3Rs principles (replace, reduce, and refine) and has garnered significant attention in recent years. In this review, we present a thorough examination of the latest breakthroughs in drug toxicity prediction, highlighting the significance of drug-target binding affinity in anticipating and mitigating possible adverse effects. In doing so, we aim to contribute to the development of more effective and secure drugs.

Safety evaluation of lenvatinib treatment after atezolizumab plus bevacizumab therapy for patients with unresectable liver cancer: A comparison of lenvatinib as 1st‑ or 2nd‑line treatment

Safety evaluation of lenvatinib treatment after atezolizumab plus bevacizumab therapy for patients with unresectable liver cancer: A comparison of lenvatinib as 1st‑ or 2nd‑line treatment

Research on Deformation Safety Risk Warning of Super-Large and Ultra-Deep Foundation Pits Based on Long Short-Term Memory

This paper proposes transforming actual monitoring data into risk quantities and establishing a Long Short-Term Memory (LSTM) safety risk warning model for predicting the deformation of super-large and ultra-deep foundation pits in river–round gravel strata based on safety evaluation methods. Using this model, short-term deformation predictions at various monitoring points of the foundation pits are made and compared with monitoring data. The results from the LSTM safety risk warning model indicate an absolute error range between the predicted deformation values and on-site monitoring values of −0.24 to 0.16 mm, demonstrating the model’s accuracy in predicting pit deformation. Additionally, calculations reveal that both the overall risk level based on on-site monitoring data and the overall safety risk level based on predicted data are classified as level four. The acceptance criteria for the overall risk level of the foundation pit are defined as “unacceptable and requiring decision-making”, with the risk warning control scheme being “requiring decision-making, formulation of control, and warning measures”. These research findings offer valuable insights for predicting and warning about safety risks in similar foundation pit engineering projects.

Exploring adverse events of Vilazodone: evidence from the FAERS database

ObjectiveThis study aims to conduct an exhaustive evaluation of Vilazodone's safety in clinical application and to unearth the potential adverse event (AE) risks associated with its utilization based on FDA Adverse Event Reporting System (FAERS) database.MethodsThis research employed data spanning from the first quarter of 2011 to the third quarter of 2023 from the FAERS database. Various signal detection methodologies, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM), were utilized to ascertain the correlation between Vilazodone and specific AEs.ResultsThe study compiled a total of 17,439,268 reports of drug AEs, out of which 5,375 were related to Vilazodone. Through signal mining, 125 Preferred Terms (PTs) encompassing 27 System Organ Classes (SOCs) were identified. The findings indicated a higher prevalence among females and patients within the 45 to 65 age bracket. The principal categories of AEs included Psychiatric disorders, Nervous system disorders, and Gastrointestinal disorders, with prevalent incidents of Diarrhoea, Nausea, and Insomnia. Moreover, the study identified robust signals of novel potential AEs, notably in areas such as sleep disturbances (Sleep paralysis, Hypnagogic hallucination, Rapid eye movements sleep abnormal, Sleep terror, Terminal insomnia, Tachyphrenia), sexual dysfunctions (Female orgasmic disorder, Orgasm abnormal, Disturbance in sexual arousal, Spontaneous penile erection, Anorgasmia, Sexual dysfunction, Ejaculation delayed), and other symptoms and injuries (Electric shock sensation, Violence-related symptom, Gun shot wound).ConclusionAlthough Vilazodone presents a positive prospect in the management of MDD, the discovery of AEs linked to its use, particularly the newly identified potential risks such as sleep and sexual dysfunctions, necessitates heightened vigilance among clinicians.

Status, Challenges, and Trends of International Research on Roadside Safety

Roadside safety refers to the assessment and improvement of safety measures related to roadside environment, design, management, and objects. It encompasses factors such as road design, signage, markings, traffic control devices, and roadside features, and its goal is to reduce accident risk, minimize injuries, and enhance overall safety and comfort for road users. To comprehensively summarize roadside safety research progress, this review retrieved 1637 English papers published between 2000 and 2022, using the Web of Science Core Collection database. VOSviewer software was utilized to visualize and analyze the literature, conduct a situational analysis of publication, create knowledge maps of the main research hotspots and trends, and summarize research status, methods, systems, challenges, and trends in this field. Results showed an overall increasing trend in relevant research. The countries, institutions, and journals contributing most are the United States, the University of Nebraska, and the Transportation Research Record, respectively. Current research hotspots include evaluation of roadside safety and risk levels, factors influencing roadside safety and driving risks, drunk and drug-impaired driving in relation to roadside traffic accidents, frequency and severity of roadside accidents, and roadside safety assurance techniques and improvement strategies. Current modeling methods mainly consist of mathematical statistical analyses and data-driven modeling based on machine learning. Future research should focus on comprehensive quantitative mapping of influencing factors and evaluation criteria, establishing an active-guidance-based evaluation system and optimization strategy, improving the accuracy of computational problems and model construction, and exploring theories and technologies of intelligent transportation for roadside safety management and improvement.

Ninerafaxstat in the Treatment of Cardiometabolic Disease: Shifting Metabolic Paradigms.

Cardiovascular disease (CVD) refers to a wide array of conditions that damage the heart muscle and impede its ability to effectively circulate blood throughout the body. In damaged or pathological states, the heart muscle might not function as effectively as it would have had there been no insult to it. Understanding this, certain CVDs can put the heart in a "metabolic disadvantage"-a state in which it cannot synthesize energy stores, in the form of adenosine triphosphate (ATP), as efficiently as it was once able to do. While the heart typically uses fatty acids for its ATP synthesis, the metabolic processes required to do so consume more oxygen per mole than the processes required to convert glucose (or carbohydrates) to ATP. In conditions when oxygen demand outweighs supply-such as angina, heart failure, and certain inherited CVDs-the myocardium can more efficiently run via glucose oxidation. Despite this knowledge, there are no currently approved therapeutics or interventions that encourage this "metabolic shift" in the myocardial cells. Currently in phase II clinical trials, however, is a novel medication called ninerafaxstat. This novel drug is a partial inhibitor of fatty acid oxidation and thus pushes the heart to convert glucose (instead of fatty acids) to ATP-ultimately cutting down on oxygen supply. While still completing clinical trials, ninerafaxstat must undergo further safety and efficacy evaluation before it can be used as a standard of care. If, however, the drug makes it to market, it might offer a unique way to improve both the symptoms and quality of life of the millions of Americans who suffer from CVDs.

A template wizard for the cocreation of machine-readable data-reporting to harmonize the evaluation of (nano)materials.

Making research data findable, accessible, interoperable and reusable (FAIR) is typically hampered by a lack of skills in technical aspects of data management by data generators and a lack of resources. We developed a Template Wizard for researchers to easily create templates suitable for consistently capturing data and metadata from their experiments. The templates are easy to use and enable the compilation of machine-readable metadata to accompany data generation and align them to existing community standards and databases, such as eNanoMapper, streamlining the adoption of the FAIR principles. These templates are citable objects and are available as online tools. The Template Wizard is designed to be user friendly and facilitates using and reusing existing templates for new projects or project extensions. The wizard is accompanied by an online template validator, which allows self-evaluation of the template (to ensure mapping to the data schema and machine readability of the captured data) and transformation by an open-source parser into machine-readable formats, compliant with the FAIR principles. The templates are based on extensive collective experience in nanosafety data collection and include over 60 harmonized data entry templates for physicochemical characterization and hazard assessment (cell viability, genotoxicity, environmental organism dose-response tests, omics), as well as exposure and release studies. The templates are generalizable across fields and have already been extended and adapted for microplastics and advanced materials research. The harmonized templates improve the reliability of interlaboratory comparisons, data reuse and meta-analyses and can facilitate the safety evaluation and regulation process for (nano) materials.

An Overview of Tools and Challenges for Safety Evaluation and Exposure Assessment in Industry 4.0

Airborne pollutants pose a significant threat in the occupational workplace resulting in adverse health effects. Within the Industry 4.0 environment, new systems and technologies have been investigated for risk management and as health and safety smart tools. The use of predictive algorithms via artificial intelligence (AI) and machine learning (ML) tools, real-time data exchange via the Internet of Things (IoT), cloud computing, and digital twin (DT) simulation provide innovative solutions for accident prevention and risk mitigation. Additionally, the use of smart sensors, wearable devices and virtual (VR) and augmented reality (AR) platforms can support the training of employees in safety practices and signal the alarming concentrations of airborne hazards, providing support in designing safety strategies and hazard control options. Current reviews outline the drawbacks and challenges of these technologies, including the elevated stress levels of employees, cyber-security, data handling, and privacy concerns, while highlighting limitations. Future research should focus on the ethics, policies, and regulatory aspects of these technologies. This perspective puts together the advances and challenges of Industry 4.0 innovations in terms of occupational safety and exposure assessment, aiding in understanding the full potential of these technologies and supporting their application in industrial manufacturing environments.

Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease

BackgroundAlzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved amyloid beta (Aβ)-directed antibody indicated for the treatment of early AD, binds with high affinity to soluble Aβ protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. Lecanemab has been shown to be well tolerated in multiple clinical trials, although risks include an increased rate of amyloid-related imaging abnormalities (ARIA) and infusion reactions relative to placebo.MethodsClarity AD was an 18-month treatment (Core study), multicenter, double-blind, placebo-controlled, parallel-group study with open-label extension (OLE) in participants with early AD. Eligible participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly). Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by magnetic resonance imaging, read both locally and centrally.ResultsOverall, 1795 participants from Core and 1612 participants with at least one dose of lecanemab (Core + OLE) were included. Lecanemab was generally well-tolerated in Clarity AD, with no deaths related to lecanemab in the Core study. There were 9 deaths during the OLE, with 4 deemed possibly related to study treatment. Of the 24 deaths in Core + OLE, 3 were due to intracerebral hemorrhage (ICH): 1 placebo in the Core due to ICH, and 2 lecanemab in OLE with concurrent ICH (1 on tissue plasminogen activator and 1 on anticoagulant therapy). In the Core + OLE, the most common adverse events in the lecanemab group (> 10%) were infusion-related reactions (24.5%), ARIA with hemosiderin deposits (ARIA-H) microhemorrhages (16.0%), COVID-19 (14.7%), ARIA with edema (ARIA-E; 13.6%), and headache (10.3%). ARIA-E and ARIA-H were largely radiographically mild-to-moderate. ARIA-E generally occurred within 3–6 months of treatment, was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%).ConclusionsLecanemab was generally well-tolerated, with the most common adverse events being infusion-related reactions, ARIA-H, ARIA-E. Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care.Trial registrationClinicalTrials.gov numbers: Clarity AD NCT03887455)

Safety evaluation of synthesized magnesium carbonate hydrate particles following inhalation exposure

Numerous fine particles or mist from environmental substances significantly contribute to human beings, affecting health issues for both humans and the environment by irritating the respiratory system. To achieve scarcity of information regarding exposure routes and the relationship between substance and health effects needs to be investigated more. Here, we investigated flame retardants (FRs): magnesium carbonate was synthesized, and its inhalation toxicity was examined for the first time by applying it to Sprague-Dawley rats using a mist aerosol-supplying chamber condition. The synthesized magnesium carbonate was fully physiochemically characterized, exhibiting a mesoporous sheet-like morphology, size distribution of 4.971 ± 2.363 μm, the dypingite phase, a surface area of 10.718 m² g−1, and a pore volume of 0.051 cm³ g−1. As a result of the inhalation toxicity study, the 50% lethal concentration (LC50) of magnesium carbonate was determined to be equal to or greater than 1.91 mg m−3. Microscopic examination for assessing pulmonary residue levels of magnesium carbonate reveals the presence of residues in the lungs up to 3 days post-administration. However, over time, there is a gradual decrease of pulmonary residues, and by the 14th day of administration, it is regarded that no residual presence is observable within the pulmonary system.

Herbal Innovations in Eczema Care: A Comprehensive Review of Formulation Development, Safety, and Efficacy

Eczema, also known as atopic dermatitis, presents a significant challenge in clinical management due to its multifactorial etiology and variable clinical manifestations. Conventional treatments often focus on symptom relief and inflammation control, yet concerns regarding their long-term safety and efficacy persist. In recent years, there has been growing interest in exploring herbal therapies as adjunctive or alternative treatments for eczema management. This review aims to provide a comprehensive overview of the development and evaluation of topical herbal formulations specifically targeted at managing infectious eczema. Beginning with an introduction to eczema, encompassing its prevalence, underlying pathophysiology, and conventional treatment modalities, the review sets the stage for exploring the potential of herbal therapies. It delves into the significance of herbal treatments in eczema care, emphasizing their potential advantages such as efficacy, safety, and patient acceptability. The review then outlines the systematic approach to formulation development, encompassing the selection of herbal ingredients, optimization of base formulations, and rigorous stability testing. Safety evaluation strategies, including toxicological assessments, skin irritation potential, and allergenicity testing, are discussed to ensure the safety and tolerability of the herbal formulations. Efficacy evaluation involves assessing anti-inflammatory properties, antimicrobial activity, and conducting well-controlled clinical trials to determine their clinical efficacy and impact on patient outcomes. Through a comprehensive discussion and analysis, this review aims to elucidate the potential of topical herbal formulations as promising therapeutic options for managing infectious eczema, while also identifying areas for further research and optimization

The efficacy and safety of leucine-enriched essential amino acids in knee osteoarthritis patients: A randomized controlled trial.

Supplementation with leucine-enriched essential amino acids (LEAAs) has shown efficacy in the recovery of muscle injury and activation of muscle synthesis. Muscle function in knee osteoarthritis is a crucial factor for managing pain and preserving ambulatory function. However, the efficacy and safety of LEAAs supplementation in patients with knee osteoarthritis have not been evaluated. In this prospective analysis, we evaluated the efficacy and safety of supplementation with 12 g of LEAAs daily for 8 weeks in knee-symptomatic osteoarthritis patients. For assessing the efficacy, clinical pain, calf circumference, and disability were assessed using questionnaires (visual analog scale, Knee Society Score, and 36-item short form survey [SF-36]), laboratory analyses (total protein and albumin), and radiologic study (dual-energy X-ray absorptiometry [DEXA]) for muscle and bone density. To evaluate safety, generalized or localized protein allergic reactions, complete blood count, liver and kidney function, and serum glucose were measured. Sixty-five participants, categorized into the experimental (n = 32) and control (n = 33) groups, were included in this 8-week trial from March 2022 to July 2022. A significantly higher efficacy was observed in the experimental group than in the control group, as indicated by muscle density in the DEXA scan (P = .001) and SF-36 (P < .001). The safety evaluation revealed no related generalized or local protein allergy. Hematological findings, serum glucose, and kidney and liver toxicity were not significantly different between the groups. Supplementation with leucine-enriched proteins is safe and efficacious in the improvement of muscle density and quality of life.

Pilot PET study of vaginally administered bioadhesive nanoparticles in cynomolgus monkeys: Kinetics and safety evaluation

AbstractLong‐lasting vaginal dosage forms could improve the therapeutic efficacy of vaginal microbicides, but achieving long‐term delivery to the vaginal canal has been a significant challenge. To advance understanding of vaginal dosage retention and biodistribution, we describe a method of noninvasive imaging with 89Zr‐labeled bioadhesive nanoparticles (BNPs) in non‐human primates. We additionally examined the safety of repeated BNP application. BNPs administered vaginally to cynomolgus monkeys were still detected after 24 h (1.7% retention) and 120 h (0.1% retention). BNPs did not translocate to the uterus or into systemic circulation. Analysis of inflammatory biomarkers in the vaginal fluid and plasma suggest that BNPs are safe and biocompatible, even after multiple doses. BNPs are a promising delivery vehicle for vaginally administered therapeutics. Further studies using the non‐human primate imaging materials and methods developed here could help advance clinical translation of BNPs and other long‐lasting vaginal dosage forms.

English

Background: Bilastine is a second-generation antihistamine for the symptomatic treatment of allergic rhinoconjunctivitis (ARC) and urticaria in adults, adolescents, and children. The pharmacokinetics and safety of oral bilastine 10 mg/d in children aged 2 to 5 years were evaluated. Methods: This was a multicenter, open-label clinical trial in children aged 2 to 5 years with seasonal or perennial ARC or urticaria treated once daily with bilastine 10 mg orodispersible tablets. The safety evaluation included treatment-emergent adverse events (TEAEs), vital signs, and physical examination. Pharmacokinetic data were pooled with data from a prior pediatric study, and pharmacokinetic modeling was performed to assess consistency. Results: A total of 37 children with ARC (81.1%), urticaria (8.1%), or both (10.8%) were included in the study, with a mean (SD) age of 3.7 (1.2) years. The highest plasma concentrations of bilastine were observed 1 hour after administration (634.91 ng/mL). Eight patients (21.6%) experienced 1 TEAE each, none of which was severe. Body weight and age were not covariates of variation in either systemic clearance or the volume of distribution in children aged 2 to 5 years and did not affect the pharmacokinetic parameters of bilastine. Conclusions: The pharmacokinetics of bilastine was linear and consistent with data from a previous trial, suggesting that a 10-mg dose may be used in children (2 to &lt;12 years). No dose adjustments are deemed necessary. Oral once-daily bilastine 10 mg presented a good safety profile in children aged 2 to 5.

Study on tubing string safety during perforation detonation in ultra-deep wells

ABSTRACT To address the challenge of quantitatively predicting the wellbore pressure and the force of the tubing string below the packer during the perforation detonation, a prediction model for the wellbore pressure and the axial force of the tubing string is established. The evolution laws of the wellbore pressure and the axial force of the tubing are analyzed. The sensitivity analysis of four primary controlling factors is further studied. The obtained results indicate that the peak pressure of the wellbore at the bottom of the perforating gun is the cause of the tubing string failure. The relative error of the predicted peak pressure of the wellbore is 2.22%. The major sensitive parameters affecting the peak pressure of the wellbore at the bottom of the perforating gun and the peak axial force at the bottom of the tubing are ranked as follows: the initial wellbore pressure, the shot density, the explosive mass, and the perforating fluid density. The work presented can provide a theoretical foundation and technological basis for the quantification of the wellbore pressure and the force of the tubing string during the perforation detonation, which is critical for well completion design and wellbore safety evaluation.

Reducing false damage detections in guided ultrasonic wave monitoring systems using a denoising autoencoder

ABSTRACT Guided ultrasonic wave (GUW) monitoring systems for pipeline structures are gaining much attention in critical sectors such as the petrochemical, nuclear and energy sectors. However, the effects of environmental and operational conditions (EOCs), especially temperature, may generate substantial false damage detections. The temperature effect may interfere with different coherent noise sources and generate unwanted peaks that are falsely identified as damage. In this paper, a denoising autoencoder (DAE) is proposed to reduce the frequency of false damage detections in GUW monitoring systems. A DAE decodes high dimensional data into low-dimensional features and reconstructs the original data from these low-dimensional features. By providing signals at a reference temperature with the fewest false damage detections, this structure forces the DAE to learn the essential features hidden within complex data. A database of GUW signals is formed based on the experimental measurements using a six-metre-long stainless steel Schedule 20 pipe. Variations in temperature and damage severity are applied to develop the database to mimic a simple step change in damage growth under EOCs. The outcomes obtained from this study show that the proposed methodology can reduce false damage detections during GUW monitoring and is valuable for pipeline safety evaluations.