Integrating Clopidogrel's First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite.

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85-90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants' data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study's generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA.

A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Cow's Milk Protein Allergy.

Cow's milk allergy refers to an immunological reaction to milk protein. It is one of the commonest food protein allergies with an estimated prevalence of 0.5% to 3% at 1 y of life. The disease may be IgE or non-IgE mediated or mixed with a wide range of symptoms often involving multiple organ systems. Gastrointestinal manifestations are common in non-IgE disease and may consist of enteropathy, proctocolitis, colic, reflux-like symptoms, constipation, enterocolitis syndrome and eosinophilic esophagitis. The gold standard for diagnosis remains a double-blind placebo-controlled oral challenge. Specific IgE and skin prick tests may predict severe and persistent disease, and aid in deciding on reintroduction or oral immunotherapy; however, they do not contribute to a definitive diagnosis as they indicate only sensitization. In practice, an elimination diet followed by open challenge under medical supervision is often used for diagnosis except when symptoms are severe such as anaphylaxis. Management consists of the elimination of the allergen with resolution of symptoms between 1-4 wk later depending on the type of allergy. Extensively hydrolyzed and Amino acid formulas are used to substitute milk in infants. Soy-based formulas are often utilized in resource-limited settings. Tolerance to the protein develops over time and periodic reintroduction should be attempted every six months after the initial one year of elimination diet. Oral immunotherapy is a newer treatment technique for IgE-mediated disease. There is no firm evidence on prevention apart from recommending breast feeding in early life along with initiating complementary feeding between 4-6 mo age.

Exploring feminist political economy and feminist critical discourse analysis as methodologies in critical nursing research.

AIMS: This paper explores two critical feminist methodologies for nursing research: feminist political economy and feminist critical discourse analysis. The aim was to appreciate varied methodological approaches available for nurses to understand complexities in healthcare environments, above and beyond socially normative ways of knowing. DESIGN: Discursive paper. DATA SOURCES: Published articles from nursing databases (CINAHL and ProQuest; no date restrictions) and interdisciplinary databases (Women's Studies International, Sociological Abstracts and Ovid MEDLINE; publication dates between 2017 and 2022). METHODS: A discursive paper exploring and critically synthesizing the literature on feminist political economy and feminist critical discourse analysis to demonstrate how each methodological approach can be used in nursing. RESULTS: The findings of this discursive paper suggest there is an opportunity to draw on interdisciplinary studies for creative insights into how these methodologies may be helpful for nurses' scholarship and programmes of research. Although few nursing studies explicitly name a feminist political economy or feminist critical discourse analysis approach, several studies apply principles of these methodological approaches. CONCLUSION: There is an opportunity for these methodologies to be applied within the same project when there is a fit between the research questions and aims of both methodologies (studies where notions of gender and power are considered central and there are potential insights from exploring social progress, structures and the material, along with the social relations of discourses). IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Feminist political economy and feminist critical discourse analysis offer novel options for methodological analyses. IMPACT: Application of these methodologies may benefit critical nursing scholars looking for diverse critical methodological avenues to explore and to broaden nursing's methodological toolbox towards meeting social justice aims. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Evaluation of Occupational Health and Safety Management of Listed Companies in China's Energy Industry Based on the Combined Weight-Cloud Model: From the Perspective of FPE Information Disclosure.

Protecting labor safety and health and actively carrying out occupational safety and health management (OSHM) is a common need worldwide, and it is also one of the important efforts of Chinese enterprises under the background of promoting the implementation of the Healthy China strategy. Based on in-depth thinking on the current stage of OHSM, this study incorporated "management framework, management process, management effectiveness" (FPE) into an integrated framework and constructed an FPE evaluation system for enterprise OHSM. This study innovatively collected and refined FPE information from the perspective of information disclosure and used the combined weight cloud model to evaluate the occupational health and safety management level (OHSML) of 69 listed companies in China's energy industry from 2009-2019. The results showed the following. (1) The OHSML of most listed companies in China's energy industry was still at a low-end level. Among the companies that have issued relevant information reports, only 5.58% (S = 30) of the sample companies' OHSML were at an acceptable level (Level IV) or declarable level (Level V). The OHSML comprehensive evaluation level of 92.56% (S = 498) of the sample companies was between the transitional level (Level III) and the improved level (Level II). (2) During 2009-2019, although the annual OHSML of listed companies in China's energy industry showed an upward trend, the growth rate was low, and even the OHSML of some listed companies in the energy industry showed the characteristics of reduced fluctuations. (3) From the perspective of the PFT three-dimensional subsystem level of OHSM, the evaluation level of the governance framework subsystem was the highest, whereas the evaluation level of the management process subsystem and the management effectiveness subsystem were relatively low. Finally, according to the relevant results, some suggestions were proposed to improve the OHSML of listed companies in China's energy industry. These findings can provide guidance for companies to improve their OSHM performance.

Protection and guidance of downstream moving fish with horizontal bar rack bypass systems.

During their life cycle, fish carry out distinct movements within rivers and migrate upstream and downstream to reproduce, to feed, and to shelter in refuge habitats. During downstream movements, they can incur severe injuries that may be lethal directly or indirectly over time when passing through hydropower plants or when being entrained at other water intakes. Horizontal bar rack bypass systems are a state-of-the-art technology to protect and guide downstream moving fish towards a reasonably safe corridor around water intakes. They have been in operation at multiple hydropower plants for more than a decade, but only little is known about the potential fish protection and guidance efficiencies and the fine scale reactions of different fish species when encountering such racks. To resolve this, systematic live fish laboratory tests were conducted under various hydraulic conditions involving a diverse assemblage of riverine fish species differing in their swimming behavior and morphology. Six riverine species, namely spirlin (Alburnoides bipunctatus), barbel (Barbus barbus), nase (Chondrostoma nasus), brown trout (Salmo trutta fario), Atlantic salmon (Salmo salar), and European eel (Anguilla anguilla) were tested with a rack consisting of foil-shaped bars, clear bar spacings of 15 and 20 mm, a horizontal rack angle of 30° to the flow direction, and a full depth open channel bypass. Variations in fish behavior were observed between different species and hydraulic conditions, but the results suggest that the guidance and protection efficiencies primarily depend on the ratio of the fish width to the clear bar spacing. Larger fish were well protected by the horizontal bar rack, while smaller fish frequently passed through the rack. New equations are proposed to estimate the protection and guidance efficiencies as a function of the clear bar spacing and the fish species' biometry, which is highly relevant to assess the effect of horizontal bar racks as fish protection measures prior to installation.

First Pass Effect and Location of Occlusion in Recanalized MCA M1 Occlusions.

Background: The first pass effect has been shown to improve clinical outcomes in patients with middle cerebral artery (MCA) M1 occlusions. Objective: To determine the rates of first pass effect in MCA M1 occlusions and determine if proximal or distal location of occlusion modified clinical outcomes. Methods: Patients with recanalized MCA M1 occlusions who underwent endovascular thrombectomy (EVT) were reviewed to determine the effect of first pass effect (FPE) and location of occlusion on clinical outcomes. MCA occlusions were classified as proximal if they included the first two thirds of the MCA and involved the lenticulostriate vessels, or distal if they did not. Results: We included 261 patients of which 27% achieved FPE. Of the cohort, there were 91 (35%) proximal MCA occlusions and 170 (65%) distal MCA occlusions. Baseline demographics and treatment time metrics were comparable across both groups. There was a trend toward good clinical outcome in patients with or without a FPE (60 vs. 46%; p = 0.06), however a higher rate of excellent clinical outcome was noted in patients with FPE (46 vs. 30%; p = 0.02). When compared by location, patients with distal MCA occlusions had a higher rate of excellent clinical outcome (40 vs. 25%; p = 0.02). Multivariable analysis showed that distal MCA occlusion was the strongest predictor of an excellent clinical outcome and first pass effect. Conclusion: Patients with MCA M1 occlusions with FPE have a higher rate of excellent clinical outcomes compared to those who did not. Location of MCA occlusion appears to modify rates of first pass effect and excellent clinical outcomes.

An Optical Acoustic Detection System Based on Fabry Pérot Etalon Stability Structure.

The optical acoustic detection system based on the Fabry Pérot Etalon (FPE) with high quality-factor (High Q) and stability structure is described and tested. The FPE contains two high-reflectivity Plano-Concave lenses, achieving high fineness and stability. The protective structure of the confocal stabilized FPE is composed of an invar tube, copper sheath, Bakelite sheath and aluminum housing to protect the sensor from the effects of ambient temperature and vibration. The audio signal is injected into the cavity through the sound hole located in the center of the cavity. Acoustic waves induce the vibration of the medium in the cavity, which leads to a simultaneous change in the FPE optical path and a shift of the interference spectrum. The acoustic detection system is built, and the frequency of the laser is locked on the resonant frequency points of the FPE by using phase modulation technology, so as to detect acoustic signals of different frequencies and amplitudes. In addition, the sensitivity of the proposed sensor exceeds 34.49 mV/Pa in the range of 20 Hz-20 kHz. A Signal-to-Noise Ratio (SNR) of 37 dB can be achieved at 20 Hz. Acoustic signal detection technology based on the FPE stability model is used to test the theoretical feasibility of the future high sensitivity Fabry Pérot Interferometric (FPI) acoustic sensors.

Pathophysiology of Non-IgE-Mediated Food Allergy.

Non-IgE-mediated food allergies are a group of disorders characterized by subacute or chronic inflammatory processes in the gut. Unlike IgE mediated food allergies that may result in multi-organ system anaphylaxis, the non-IgE mediated food allergies primarily affect the gastrointestinal tract. This review outlines the clinical manifestations, epidemiology, pathophysiology, and management of non-IgE-mediated food allergies. An updated literature search of selected non-IgE-mediated food allergies was conducted for this review using PubMed database to the current year (2021). Reviewed disorders include food protein-induced enterocolitis syndrome (FPIES), food-protein enteropathy (FPE), food protein-induced allergic proctocolitis (FPIAP), and eosinophilic gastrointestinal disorders (EGIDs) such as eosinophilic esophagitis (EoE). While extensive gains have been made in understanding FPIES, FPIAP, FPE, and EoE, more information is needed on the pathophysiology of these food allergies. Similarities among them include involvement of innate immunity, T-lymphocyte processes, alteration of the intestinal lumen at the cellular level with the appearance of inflammatory cells and associated histologic changes, and specific cytokine profiles suggesting food-specific, T-cell, and immune-mediated responses. While FPIES and FPIAP typically resolve in early childhood, EGIDs typically do not. Emerging new therapies for EoE offer promise of additional treatment options. Further studies identifying the immunopathogenesis, associated biomarkers, and mechanisms of tolerance are needed to inform prevention, diagnosis and management.

Nutritional Management With a Casein-Based Extensively Hydrolysed Formula in Infants With Clinical Manifestations of Non-IgE-Mediated CMPA Enteropathies and Constipation.

Background: The majority of mixed-fed infants with non-IgE-mediated cow's milk protein allergy (CMPA) enteropathies are managed with an extensively hydrolysed cow's milk based infant formula (eHF). Given the high variability in peptide distribution of available eHFs, it is important to understand the suitability of a specific product in the management of distinct phenotypes. Objective: To assess the symptom resolution of various phenotypes of clinical manifestations of CMPA enteropathies and constipation managed by a casein-based eHF. Methods: The data of 20 full-term infants (n = 15 with non-IgE-mediated CMPA and n = 5 with constipation) attending a paediatric allergy clinic in Cyprus and managed with a casein-based eHF were retrospectively analysed. Results: Based on the clinical symptoms and history, infants were classified into the following phenotypes: (a) 11/15 (73.3%) FPIAP, (b) 3/15 (20%) FPIES, and (c) 1/15 (6.7%) severe diarrhoea. Overall, 14 (93.3%) patients were successfully managed with the casein-based eHF and 1 (6.7%) required an AAF. This formula was effective in 91% of patients with FPIAP, in 100% with FPIES and with diarrhoea. Three (60%) patients with constipation responded to the eHF. Conclusion: This case-series report supports the efficacy of a particular casein-based eHF for the nutritional management of non-IgE mediated CMPA enteropathies.

Non-IgE-Mediated Gastrointestinal Food Allergies in Children: An Update.

Non-immunoglobulin E-mediated gastrointestinal food allergic disorders (non-IgE-GI-FA) include food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE) and food protein-induced allergic proctocolitis (FPIAP), which present with symptoms of variable severity, affecting the gastrointestinal tract in response to specific dietary antigens. The diagnosis of non-IgE-GI-FA is made clinically, and relies on a constellation of typical symptoms that improve upon removal of the culprit food. When possible, food reintroduction should be attempted, with the documentation of symptoms relapse to establish a conclusive diagnosis. Management includes dietary avoidance, nutritional counselling, and supportive measures in the case of accidental exposure. The prognosis is generally favorable, with the majority of cases resolved before school age. Serial follow-up to establish whether the acquisition of tolerance has occurred is therefore essential in order to avoid unnecessary food restriction and potential consequent nutritional deficiencies. The purpose of this review is to delineate the distinctive clinical features of non-IgE-mediated food allergies presenting with gastrointestinal symptomatology, to summarize our current understanding of the pathogenesis driving these diseases, to discuss recent findings, and to address currents gaps in the knowledge, to guide future management opportunities.

Recent advances in devices for mechanical thrombectomy.

INTRODUCTION: Acute ischemic stroke (AIS) secondary to the occlusion of a large intracranial vessel (LVO) is a recognized public health problem. Mechanical thrombectomy (MT) has gained full acceptance: Class A, Level 1 in 2015 after the publication of numerous trials. Further meta-analyses have scrutinized extensively those results and international recommendations and guidelines have been given. Nevertheless, multiple-specific points remain to be clarified and are or will be under investigations. AREAS COVERED: This review of the most recent literature (mostly publications after 2015) will cover the actual common practice for MT, especially focusing on the devices available (and their validation), how they are commonly used, relate the most relevant results, and detail some emerging technologies. EXPERT OPINION: The authors will express their own view on the current practice and emphasize on the areas where questions remain and hypothesize what specific improvements are necessary and prone to occur.

The Family Psychoeducation Fidelity Scale: Psychometric Properties.

This study examined psychometric properties and feasibility of the Family Psychoeducation (FPE) Fidelity Scale. Fidelity assessors conducted reviews using the FPE fidelity scale four times over 18 months at five sites in Norway. After completing fidelity reviews, assessors rated feasibility of the fidelity review process. The FPE fidelity scale showed excellent interrater reliability (.99), interrater item agreement (88%), and internal consistency (mean = .84 across four time points). By the 18-month follow-up, all five sites increased fidelity and three reached adequate fidelity. Fidelity assessors rated feasibility as excellent. The FPE fidelity scale has good psychometric properties and is feasible for evaluating the implementation of FPE programs. Trial registration ClinicalTrials.gov Identifier: NCT03271242.

A Novel Message-Preserving Scheme with Format-Preserving Encryption for Connected Cars in Multi-Access Edge Computing.

In connected cars with various electronic control unit (ECU) modules, Ethernet is used to communicate data received by the sensor in real time, but it is partially used alongside a controller area network (CAN) due to the cost. There are security threats in the CAN, such as replay attacks and denial-of-service attacks, which can disrupt the driver or cause serious damage, such as a car accident through malicious manipulation. Although several secure protocols for protecting CAN messages have been proposed, they carry limitations, such as combining additional elements for security or modifying CAN messages with a limited length. Therefore, in this paper, we propose a method for encrypting the data frame, including real data in the CAN message structure, using format-preserving encryption (FPE), which ensures that the plaintext and ciphertext have the same format and length. In this way, block ciphers such as AES-128 must be divided into two or three blocks, but FPE can be processed simultaneously by encrypting them according to the CAN message format, thus providing better security against denial-of-service attacks. Based on the 150 ms CAN message, a normal message was received from a malicious message injection of 180 ms or more for AES-128 and a malicious message injection of 100 ms or more for FPE. Finally, based on the proposed scheme, a CAN transmission environment is constructed for analyzing the encryption/decryption rate and the process of transmitting and processing the encrypted message for connected cars in multi-access edge computing (MEC). This scheme is compared with other algorithms to verify that it can be used in a real environment.

Study on the Main Influencing Factors in the Removal Process of Non-Stick Fluoropolymer Coatings Using Nd:YAG Laser.

The coatings with fluoropolymer resins rich in fluorinated ethylene propylene (FEP) and polytetrafluoroethylene (PTFE) are applied as anti-adherent coatings on aluminum⁻magnesium substrates for use in food containers. In many cases, due to wear, they must be stripped for the application of a new coating on the same substrate. There are several processes for this: blasting, plasma, pyrolysis, chemical processes, laser, high pressure water, and combinations of these. This work focuses on the characterization of the main factors that condition the FEP coating removal process by a continuous wave (CW) Nd:YAG laser, and on the determination of the efficiency of this type of technology used for this purpose. Stripping surface per unit of time and energy consumption per unit area has been determined among other efficiency indicators. Regarding the characterization of the coating object of study, its thickness, surface roughness, contact angle, microhardness and absorbance-reflectance responses have been determined, and the results have been compared with those obtained in the case of PTFE. In addition, to evaluate the mechanical damage caused in the substrate after coating removal by (CW) Nd:YAG laser, the tensile strength, Vickers hardness, Ra and Rz roughness, and the substrate thickness have been measured and analyzed.

Cow milk protein allergy and other common food allergies and intolerances.

The prevalence of food allergy and food intolerance is increasing and it is an important public health problem affecting children. Food allergy results from an immunological reaction to certain food(s) and affects numerous organs in the body. Food intolerances are non-immunological reactions including metabolic, toxic, pharmacological and undefined mechanisms. Cow milk is the most common cause of food allergy and food intolerance, especially in young children. Food intolerance can present with similar symptoms to those of food allergy. Health-care personnel, patients and their caregivers often confuse food intolerance with food allergy. This review focuses on the clinical manifestations, diagnostic evaluation, treatment and prevention of food allergy and food intolerance.

Fluoride-Promoted Esterification (FPE) Chemistry: A Robust Route to Bis-MPA Dendrons and Their Postfunctionalization.

Bifunctional dendrons based on 2,2-bis(methylol)propionic acid (bis-MPA) are highly desirable scaffolds for biomedical applications. This is due to their flawless nature and large and exact number of functional groups as well as being biodegradable and biocompatible. Herein, we describe a facile divergent growth approach to their synthesis from monobenzylated tetraethylene glycol and post functionalization utilizing fluoride-promoted esterification (FPE) chemistry protocols. The scaffolds, presenting selectively deprotectable hydroxyls in the periphery and at the focal point, were isolated on a multigram scale with excellent purity up to the fourth generation dendron with a molecular weight of 2346 Da in seven reactions with a total yield of 50%. The third generation dendron was used as a model compound to demonstrate its functionalizability. Selective deprotection of the dendron's focal point was achieved with an outstanding yield of 94%, and biotin as well as azido functionalities were introduced to its focal point and periphery, respectively, through FPE chemistry. Bulky disperse red dyes were clicked through CuAAC to the dendron's azido groups, giving a biotinylated dendron with multivalent dyes with a molecular weight of 6252 Da in a total yield of 37% in five reactions with an average yield of 82% starting from the third generation focally and peripherally protected dendron. FPE chemistry proved to be a superb improvement over previous protocols towards bis-MPA dendrons as high purity and yields were obtained with less toxic solvents and greatly improved monomer utilization.