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Airway epithelial cells play a crucial role in investigating the physiological and pathological mechanisms of the respiratory tract in yaks, a species whose unique respiratory system has garnered extensive interest. Despite this growing interest, there currently are no available airway epithelial cell lines from yaks, underscoring the crucial need to establish a yak respiratory epithelial cell line. Therefore, our objective was to isolate a population of primary yak nasopharyngeal epithelial cells (pYNE) and transform them into immortalized yak nasopharyngeal epithelial cells (iYNE), assessing their suitability as an in vitro model. Employing a combined method of physical elimination and differential adhesion, we successfully isolated a population of high-purity pYNE, and developed an iYNE line through pCI-neo-hTERT plasmid transfection. Karyotype and transmission electron microscopy analyses confirmed that pYNE and iYNE share identical morphologies and structures. Gel electrophoresis and real-time PCR analyses demonstrated that pYNE and iYNE expressed similar levels of KRT18 and CDH1 genes (p ≥ 0.541). Notably, iYNE expressed a significantly high level of TERT gene expression (p

Abstract Background Long-distance transportation, a frequent practice in the cattle industry, stresses calves and results in morbidity, mortality, and growth suppression, leading to welfare concerns and economic losses. Alkaline mineral water (AMW) is an electrolyte additive containing multiple mineral elements and shows stress-mitigating effects on humans and bovines. Results Here, we monitored the respiratory health status and growth performance of 60 Simmental calves subjected to 30 hours of road transportation using a clinical scoring system. Within the three days of commingling before the transportation and 30 days after the transportation, calves in the AMW group (n = 30) were supplied with AMW, while calves in the Control group (n = 29) were not. On three specific days, namely the day before transportation (day -3), the 30th day (day 30), and the 60th day (day 60) after transportation, sets of venous blood, serum, and nasopharyngeal swab samples were collected from 20 calves (10 from each group) for routine blood testing, whole blood transcriptomic sequencing, serology detection, serum untargeted metabolic sequencing, and 16S rRNA gene sequencing. The field data showed that calves in the AMW group displayed lower rectal temperatures (38.967 ℃ vs. 39.022 ℃; p = 0.004), respiratory scores (0.079 vs. 0.144; p < 0.001), appetite scores (0.024 vs. 0.055; p < 0.001), ocular and ear scores (0.185 vs. 0.338; p < 0.001), nasal discharge scores (0.143 vs. 0.241; p < 0.001), and higher body weight gains (30.870 kg vs. 7.552 kg; p < 0.001). The outcomes of laboratory and high throughput sequencing data revealed that the calves in the AMW group demonstrated higher cellular and humoral immunities, antioxidant capacities, lower inflammatory levels, and intestinal absorption and lipogenesis on days -3 and 60. The nasopharynx 16S rRNA gene microbiome analysis revealed the different composition and structure of the nasopharyngeal microflora in the two groups of calves on day 30. Joint analysis of multi-omics revealed that on days -3 and 30, bile secretion was a shared pathway enriched by differentially expressed genes and metabolites, and there were strong correlations between the differentially expressed metabolites and the main genera in the nasopharynx. Conclusions These results suggest that AMW supplementation enhances peripheral immunity, nutrition absorption, and metabolic processes, subsequently affecting the nasopharyngeal microbiota and improving the respiratory health and growth performance of transported calves. This investigation provided a practical approach to mitigate transportation stress and explored its underlying mechanisms, which are beneficial for the development of the livestock industry. Video Abstract

Yaks are often subject to long-term starvation and a high prevalence of respiratory diseases and mortality in the withered season, yet the mechanisms that cause this remain unclear. Research has demonstrated that β-hydroxybutyrate (BHB) plays a significant role in regulating the immune system. Hence, we hypothesize that the low glucose and high BHB condition induced by severe starvation might have an effect on the pro-inflammatory response of the alveolar macrophages (AMs) in yaks. To validate our hypothesis, we isolated and identified primary AMs from freshly slaughtered yaks and cultured them in a medium with 5.5 mM of glucose or 2.8 mM of glucose plus 1–4 mM of BHB. Utilizing a real-time quantitative polymerase chain reaction (RT-qPCR), immunoblot assay, and enzyme-linked immunosorbent assay (ELISA), we evaluated the gene and protein expression levels of GPR109A (G-protein-coupled receptor 109A), NF-κB p65, p38, and PPARγ and the concentrations of pro-inflammatory cytokines interleukin (IL)-1β and IL-6 and tumor necrosis factor (TNF)-α in the supernatant. The results demonstrated that AMs exposed to low glucose plus BHB had significantly higher levels of IL-1β, IL-6, and TNF-α (p < 0.05) and higher activity of the GPR109A/NF-κB signaling pathway. A pretreatment of either pertussis toxin (PTX, inhibitor of GPR109A) or pyrrolidinedithiocarbamic (PDTC, inhibitor of NF-κB p65) was effective in preventing the elevated secretion of pro-inflammatory cytokines induced by low glucose plus BHB (p < 0.05). These results indicated that the low glucose plus BHB condition would induce an enhanced pro-inflammatory response through the activation of the GPR109A/NF-κB signaling pathway in primary yak AMs, which is probably the reason why yaks experience a higher rate of respiratory diseases and mortality. This study will offer new insight into the prevention and treatment of bovine respiratory diseases.

The receptor of advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) are important receptors for inflammatory responses induced by high glucose (HG) and lipopolysaccharide (LPS) and show crosstalk phenomena in inflammatory responses. However, it is unknown whether RAGE and TLR4 can influence each other’s expression through a crosstalk mechanism and whether the RAGE–TLR4 crosstalk related to the molecular mechanism of HG enhances the LPS-induced inflammatory response. In this study, the implications of LPS with multiple concentrations (0, 1, 5, and 10 μg/mL) at various treatment times (0, 3, 6, 12, and 24 h) in primary bovine alveolar macrophages (BAMs) were explored. The results showed that a 5 μg/mL LPS treatment at 12 h had the most significant increment on the pro-inflammatory cytokine interleukin 1β (IL-1β), IL-6, and tumor necrosis factor (TNF)-α levels in BAMs (p < 0.05) and that the levels of TLR4, RAGE, MyD88, and NF-κB p65 mRNA and protein expression were upregulated (p < 0.05). Then, the effect of LPS (5 μg/mL) and HG (25.5 mM) co-treatment in BAMs was explored. The results further showed that HG significantly enhanced the release of IL-1β, IL-6, and TNF-α caused by LPS in the supernatant (p < 0.01) and significantly increased the levels of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression (p < 0.01). Pretreatment with FPS-ZM1 and TAK-242, the inhibitors of RAGE and TLR4, significantly alleviated the HG + LPS-induced increment of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression in the presence of HG and LPS (p < 0.01). This study showed that RAGE and TLR4 affect each other’s expression through crosstalk during the combined usage of HG and LPS and synergistically activate the MyD88/NF-κB signaling pathway to promote the release of pro-inflammatory cytokines in BAMs.

Ketone bodies are crucial intermediate metabolites widely associated with treating metabolic diseases. Accumulating evidence suggests that ketone bodies may act as immunoregulators in humans and animals to attenuate pathological inflammation through multiple strategies. Although the clues are scattered and untrimmed, the elevation of these ketone bodies in the circulation system and tissues induced by ketogenic diets was reported to affect the immunological barriers, an important part of innate immunity. Therefore, beta-hydroxybutyrate, a key ketone body, might also play a vital role in regulating the barrier immune systems. In this review, we retrospected the endogenous ketogenesis in animals and the dual roles of ketone bodies as energy carriers and signal molecules focusing on beta-hydroxybutyrate. In addition, the research regarding the effects of beta-hydroxybutyrate on the function of the immunological barrier, mainly on the microbiota, chemical, and physical barriers of the mucosa, were outlined and discussed. As an inducible endogenous metabolic small molecule, beta-hydroxybutyrate deserves delicate investigations focusing on its immunometabolic efficacy. Comprehending the connection between ketone bodies and the barrier immunological function and its underlining mechanisms may help exploit individualised approaches to treat various mucosa or skin-related diseases.

Vaporized hydrogen peroxide (VHP) is a highly active disinfectant, and VHP decontamination systems have been widely applied in hospitals, microbiological laboratories, and pharmaceutical industries. However, the decomposition of VHP into non-toxic by-products is essential. Evaluation of the disinfection efficacy of VHP is crucial to ensuring the reliability of VHP disinfection and controlling microbial contamination. In this study, a rapid and sensitive strategy is proposed to evaluate the efficacy of VHP in surface disinfection by detecting the survived and killed bacteria from VHP-exposed biological indicators (BIs). A dual-channel solid-phase cytometer is designed, and fluorescent dyes are used as indicators to automatically and accurately distinguish live cells from dead cells in the mixtures of bacteria. To verify the availability and effectiveness of the laser scanning cytometry, experiments on its application in estimating the efficacy of VHP disinfection practice have been carried out in this study, and its estimation effect compared with that of the traditional plate counting method. Results show that the proposed assay might distinctly identify live or killed cells labeled by green and red fluorescent dyes and examined the disinfection efficacy in 30 min by calculating the bactericidal rate. Compared with the plate counting method, the proposed approach is accurate and practical, with an average detection efficiency of 98.47% ± 1.55%. Moreover, an excellent correlation between the concentrations of B. subtilis var niger (ATCC 9372) measured by the proposed detection system and by the plate counting method is noticed (R2 = 0.9971), indicating that this approach had advantages in the detection of trace microorganisms. To summarize, the proposed strategy appears practical and significant in many fields in which microbial counting and identification are required.

Biosafety equipment is the key barrier enabling high containment laboratories to handle high risk agents that may cause serious and potentially lethal infections. This perspective thoroughly analyzes the development of many kinds of key biosafety technologies, and equipment for protection of laboratory workers and for high containment laboratory facilities in China. Over more than ten years of rapid development, China has had remarkable achievements in key biosafety technologies and equipment in high containment laboratories. These technologies basically meet the needs of high containment laboratories construction in China. Furthermore, according to the current global situation regarding the prevention and control of infectious diseases and the technical development level of biosafety equipment, this paper proposes targeted suggestions and notes that China still needs to increase investment in scientific research to provide further technical and equipment support enabling us to build a community with a bright future in terms of human biosafety.

The frequent and sudden occurrence of both known and unknown infectious diseases can cause global social panic. If the source of infection can be effectively controlled in the early stages of an outbreak, the spread of infectious diseases can be prevented. In view of this situation, this study developed for infectious or suspected infectious patients a negative pressure isolation hood which effectively achieves direct individual isolation during the early stages of disease outbreak, and facilitates long-distance transport. The hood body is made of flexible transparent polyvinyl chloride (PVC) material, and the combination of the hood material is airtight. The unique inflatable column support structure and the design of the inflatable neck sleeve effectively ensure both stiffness and air tightness of the hood body. The electrical exhaust system maintains a stable negative pressure environment inside the hood, and polluted air inside the hood can be purified by a high efficiency filter. Test results showed that the internal noise of the hood was 68 ± 1 dB (A), the air exhaust volume of the electric exhaust system was not 99.99%, indicating that the hood achieved effective isolation protection for patients with respiration infectious diseases.

Abnormal glycemia is frequently along with nephritis, whose pathogenesis is unexplicit. Here, we investigated the effects of abnormal glucose on the renal glomerulus epithelial cells by stimulating immortalized bovine renal glomerulus epithelial (MDBK) cells with five different levels of glucose, including low glucose (2.5 mM for 48 h, LG), normal glucose (5 mM for 48 h, NG), high glucose (25 mM for 48 h, HG), increasing glucose (24 h of 2.5 mM glucose followed by 24 h of 25 mM, IG), and reducing glucose (24 h of 25 mM glucose followed by 24 h of 2.5 mM, RG). The results showed that LG and RG treatments had nonsignificant effects (p > 0.05) on the viability of MDBK cells. HG treatment decreased the viabilities of cells (p < 0.01) without triggering an apparent inflammatory response by activating the nox4/ROS/p53/caspase-3-mediated apoptosis pathway. IG treatment decreased the viabilities of cells significantly (p < 0.01) with high levels of pro-inflammatory cytokines IL-1β and IL-18 in the supernatant (p < 0.05) by triggering the txnip/nlrp3/gsdmd-mediated pyroptosis pathway. These results indicated that the process of glucose increase rather than the constant high glucose was the main cause of abnormal glucose-induced MDBK cell inflammatory death, prompting that the process of glycemia increases might be mainly responsible for the nephritis in diabetic nephropathy, underlining the importance of glycemic control in diabetes patients.

Transportation is an inevitable phase for the cattle industry, and its effect on the respiratory system of transported cattle remains controversial. To reveal cattle’s nasopharyngeal microbiota dynamics, we tracked a batch of beef calves purchased from an auction market, transported to a farm by vehicle within 3 days, and adaptively fed for 7 days. Before and after the transport and after the placement, a total of 18 nasopharyngeal mucosal samples were collected, and microbial profiles were obtained using a metagenomic shotgun sequencing approach. The diversity, composition, structure, and function of the microbiota were collected at each time point, and their difference was analyzed. The results showed that, before the transportation, there were a great abundance of potential bovine respiratory disease (BRD)-related pathogens, and the transportation did not significantly change their abundance. After the transportation, 7 days of placement significantly decreased the risk of BRD by decreasing the abundance of potential BRD-related pathogens even if the diversity was decreased. We also discussed the controversial results of transportation’s effect in previous works and the decrease in diversity induced by placement. Our work provided more accurate information about the effect of transportation and the followed placement on the calf nasopharyngeal microbial community, indicated the importance of adaptive placement after long-distance transport, and is helpful to prevent BRD induced by transportation stress.

Objective: The analysis of standards related to positive pressure biological protective clothing in China and other countries. Method: We examined the protection standard systems established by the major standards organizations in China and other developed countries. We also analyzed the technical indicators closely related to positive pressure biological protective clothing. We aimed to identify the status of China’s standards in the area of personnel protection and put forward feasible suggestions for the production of positive pressure biological protective clothing in China. Results: Developed countries in Europe and North America have a complete system of standard protective clothing. China should also strengthen the construction of standard protective clothing, especially positive pressure biological protective clothing. Conclusion: With the improvements in infectious disease prevention and control on a global scale, the demand for positive pressure biological protective clothing continues to increase and consideration should be given to the establishment of standards for this. Keywords: Biosafety, Protective clothing, Positive pressure, Standard

The positive pressure biological protective suit is the highest degree of personal protective equipment, and its performance directly impacts the health and safety of the wearer. Protection factor is the most critical measure of the performance of a positive pressure bio-protective suit. This study establishes a dynamic detection system for the positive pressure bio-protective suit, to evaluate its safety risks, and explores methods to reduce these risks. A manikin was used to perform human actions, such as raising the arms, sitting, and walking, that were simulated at different levels. Integrity breaches of different shapes and sizes were made to different parts of the suit for evaluation. The aerosol concentration and the pressure of the suit were detected. Positive-pressure suits provide exceptionally good protection even in accident scenarios and provide a greater flexibility and more ergonomic benefits. However, sufficiently large (>3 cm) breaches caused a negative-pressure and an inward airflow during vigorous activities. The location of the breach site on the suit also had a significant effect on bio-aerosol leakage. Studies have shown that effective methods to avoid the risk of damage include increasing the air supply flow and performing gentle movements while wearing the suit. The dynamic detection method and the results obtained in this study are a significant advance to predict and avoid the risks associated with powered air-purifying suits.

Concerns have been raised about both the disinfection and the reusability of respiratory protective equipment following a disinfection process. Currently, there is little data available on the effects of disinfection and decontamination on positive pressure respiratory protective hoods (PPRPH). In this study, we evaluated the effect of vaporized hydrogen peroxide (VHP) on the disinfection of PPRPH to determine applicability of this method for disinfection of protective equipment, especially protective equipment with an electric supply system.A hydrogen peroxide-based fumigation sterilization cabinet was developed particularly for disinfection of protective equipment, and the disinfection experiments were conducted using four PPRPHs hung in the fumigation chamber. The pathogenic microorganism Geobacillus stearothermophilus ATCC 7953 was used as a biological indicator in this study and the relationship between air flow (the amount of VHP) and disinfection was investigated. Both function and the material physical properties of the PPRPH were assessed following the disinfection procedure. No surviving Geobacillus stearothermophilus ATCC 7953, both inside and outside of these disinfected PPRPHs, could be observed after a 60 min treatment with an air flow of 10.5–12.3 m3/h. Both function and material physical properties of these PPRPHs met the working requirements after disinfection.This study indicates that air flow in the fumigation chamber directly influences the concentration of VHP. The protective equipment fumigation sterilization cabinet developed in this paper achieves the complete sterilization of the PPRPHs when the air flow is at 10.5–12.3 m3/h, and provides a potential solution for the disinfection of various kind of protective equipment.

Objective: Airtightness of containment structures of a high-level biosafety laboratory is a critical parameter for preventing leakage of harmful bioaerosols. The aim of this study is to investigate the sealing technology of stainless steel structural airtight biosafety containment facilities. Methods: An experimental study was conducted on a domestic high-level pathogenic microorganism model laboratory, considering the sealing process of the containment structure, including airtight doors, pass boxes, dunk tanks, through-wall pipeline sealing devices, and sealed floor drains. Results: The results indicate that the airtightness of the model laboratory containment structure meets the tightness requirements of a biosafety level-4 (BSL-4) laboratory. They also indicate that the construction technology of stainless steel enclosure structures used by the laboratory and the tightness performance and installation process of the developed airtight protective equipment meet the technical requirements of a BSL-4 laboratory. Conclusions: This successful model laboratory indicates that China has the research and development capacity for stainless steel airtight containment structure manufacturing processes, airtight protective equipment, and technical capacity for independent construction of the highest-level pathogenic microorganism laboratories. Keywords: Biosafety level-4 laboratory, Airtightness, Containment structure, Sealing process

It is widely accepted that maintenance of microbial diversity is essential for the health of the respiratory tract; however, there are limited reports on the correlation between starvation and respiratory tract microbial diversity. In the present study, saline/β-hydroxybutyric acid (BHBA) intravenous injection after dietary restriction was used to imitate different degrees of starvation. A total of 13 healthy male yaks were imposed to different dietary restrictions and intravenous injections, and their nasopharyngeal microbiota profiles were obtained by metagenomic shotgun sequencing. In healthy yaks, the main dominant phyla were Proteobacteria (33.0%), Firmicutes (22.6%), Bacteroidetes (17.2%), and Actinobacteria (13.2%); the most dominated species was Clostridium botulinum (10.8%). It was found that 9 days of dietary restriction and 2 days of BHBA injection (imitating severe starvation) significantly decreased the microbial diversity and disturbed its structure and functional composition, which increased the risk of respiratory diseases. This study also implied that oral bacteria played an important role in maintaining nasopharynx microbial homeostasis. In this study, the correlation between starvation and nasopharynx microbial diversity and its potential mechanism was investigated for the first time, providing new ideas for the prevention of respiratory diseases.

Abstract Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

Caustic paste disbudding (CPD) is widely utilized for calves, which has been known to result in adverse effects on the calves and ethical concerns related to animal welfare, despite the use of local anesthetics. The administration of meloxicam has been demonstrated to provide benefits in alleviating pain and inflammation in juvenile calves under 9 d old and subjected to CPD. Nonetheless, there is a scarcity of literature documenting the beneficial impact of meloxicam in alleviating pain in calves aged over 9 d that have undergone CPD. Therefore, the objective of this clinical trial was to evaluate the efficacy of administering meloxicam and lidocaine for cornual nerve block together in mitigating the deleterious effects of CPD, as opposed to using lidocaine alone in calves older than 9 d. Thirty Holstein calves, aged between 10 and 21 d, were enrolled and randomly assigned to 1 of 2 treatments: lidocaine alone (Placebo), lidocaine and normal saline treatment before CPD, and lidocaine plus meloxicam, lidocaine and 0.5 mg/kg of meloxicam treatment prior to CPD. The researchers were blind to the treatment of calves to control the subjective error. The occurrences of actions associated with pain, which included head shaking, head rubbing, ear flicking, tail flicking, kicking, and head passing through the fence, were recorded. Physiological performance, including the respiration rate, heart rate, rectal temperature, mechanical nociceptive threshold (MNT), food intake, and daily activity level, was monitored. Hematological conditions were ascertained through the use of routine blood tests and enzyme-linked immunosorbent assay. The generalized linear mixed model was employed to analyze the data. The research findings revealed that applying the CPD procedure significantly elevated the frequencies of tail flicking, head shaking, and kicking, resulted in increases in respiratory rate, heart rate, daily active steps, and food intake and a decrease in MNT, and led to alterations in hematological markers, including platelet counts, mean platelet volume, prostaglandin E2, constitutive nitric oxide synthase, and hydroxyl radical. Considerable benefits, such as lower heart rates, higher food intake, and MNTs, as well as lower levels of white blood cell counts, lymphocyte counts, hemoglobin, mean platelet volume, prostaglandin E2, tumor necrosis factor-α, constitutive nitric oxide synthase, malondialdehyde, and hydroxyl radical, were observed in the calves that received meloxicam treatment in response to CPD. The findings of the study indicate that the co-administration of lidocaine and meloxicam provides obvious benefits in mitigating pain, inflammation, and oxidative stress in calves aged over 9 d and undergoing CPD. This endorses the use of meloxicam during the disbudding and dehorning procedures of calves. [ABSTRACT FROM AUTHOR]

IntroductionBaloxavir Marboxil is a per oral small-molecule antiviral for the treatment of influenza. While the efficacy and safety of Baloxavir Marboxil have been thoroughly characterized across an extensive clinical trial, studies on the effectiveness of Baloxavir Marboxil in a real-world setting are still scarce.MethodsWe conducted an ambispective, observational, multi-center study that enrolled uncomplicated in-fluenza outpatients treated with Baloxavir Marboxil or Oseltamivir in East China. The primary endpoint was time from treatment to alleviation of all influenza symptoms (TTAIS). The secondary endpoints included time from treatment to alleviation of fever (TTAF) and household transmission during the duration of influenza.ResultsA total of 509 patients were enrolled. The median TTAIS in the Baloxavir Marboxil group and the Oseltamivir group was 28.0 h (IQR, 20.0 to 50.0) and 48.0 h (IQR, 30.0 to 67.0), respectively. The median TTAF in the Baloxavir Marboxil group and the Oseltamivir group was 18 h (IQR, 10.0–24.0) and 30.0 h (IQR, 19.0–48.0). In the COX multivariable analysis, Baloxavir Marboxil reduced the duration of influenza symptoms (HR = 1.36 [95%CI:1.12–1.64], p = 0.002) and the duration of fever (HR = 1.93 [95%CI:1.48–2.52], p

Background: Cefuroxime has played a crucial role in the prevention and treatment of bacterial infections. However, the differences in adverse events across formulations and routes remain unclear. Objectives: This study aimed to investigate the post-marketing safety of cefuroxime, particularly concerning formulations and routes. Design: A retrospective pharmacovigilance study of cefuroxime was conducted using the data from Food and Drug Administration Adverse Event Reporting System database. Methods: The clinical characteristics and concomitant drugs reported with cefuroxime were investigated. Adverse event signals of cefuroxime were identified based on four disproportionality algorithms. The signal differences of cefuroxime across formulations and routes were further examined. Results: A total of 1810 adverse event reports associated with cefuroxime were identified, and 181 cefuroxime-associated signals were detected. Compared with tablets, injections were more likely to cause preferred terms ‘blood pressure decreased’ and ‘anaphylactic shock’. In addition, system organ class ‘eye disorders’ significantly increased when cefuroxime was administered intraocularly, underscoring the importance of exercising caution regarding ocular toxicity. Conclusion: The adverse events associated with cefuroxime were significantly different across formulations and routes, which deserve special attention in clinical use.

Language instructors worldwide use various types and strategies for providing feedback on the learners’ written production. Written corrective feedback (WCF) plays a vital role in systematically learning second or other languages. Additionally, students’ perception of feedback and its delivery has a specific value. Therefore, the current study examined perceptions and preferences of the WCF of EFL students they received in high school back in their home countries. However, the data was collected when they were studying in China as international students. To achieve these objectives, the researchers utilized a self-administered questionnaire and collected data from 91 international students at Chinese University, China. The results showed that most students supported positive statements (in the first part of the questionnaire) regarding WCF perceptions. The most preferred types were direct and unfocused WCF. Also, in order to establish a statistical basis on whether there are differences among various nationalities in terms of their perception, One-way ANOVA was performed. The findings displayed that all nationalities have difference in positive perceptions, and same tendency toward negative perceptions about WCF and focused feedback. Overall, according to their answers, WCF helps them to know what to avoid and adapt to compose an effective writing piece.

This study investigates the impact of task-induced involvement and time on task on incidental second language (L2) vocabulary acquisition. Utilizing a 3 (task-induced involvement) × 2 (time on task) × 2 (post-test time) research design, three task-induced involvement conditions were employed based on the Involvement Load Hypothesis (ILH): reading and gap-fill task, reading and sentence-making task, and reading and translation task, with corresponding involvement load (IL) indices of 2, 3, and 4, respectively. Two time-on-task conditions were implemented: uncontrolled time on task, where participants in different groups completed tasks with varied durations, and controlled time on task, where participants in different groups completed tasks with roughly equal durations. Five intact classes comprising 256 Chinese middle school students participated and were randomly assigned to one of five designed tasks aimed at learning 10 carefully selected target words. The results of a three-way repeated measures ANOVA indicate a significant three-way interaction effect among task-induced involvement, time on task, and post-test time, as well as a significant two-way interaction effect between task-induced involvement and time on task. These findings demonstrate that task-induced involvement and time on task interact to significantly influence both initial acquisition and retention of incidental L2 vocabulary. Specifically, under uncontrolled time conditions, tasks with higher ILs and longer durations yield better initial vocabulary gains and retention, partially supporting the ILH. Conversely, under controlled time conditions, tasks with lower ILs exhibit superior initial vocabulary gains and retention, contradicting the predictions of the ILH. Relevant implications are also discussed.

Abstract Pitolisant, a novel histamine H3‐receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real‐world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant‐associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant‐associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life‐threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.

Written corrective feedback (WCF) in enhancing writing proficiency has been the subject of numerous studies, but few studies have examined students’ perceptions about the value of feedback on their written errors. Language teachers use global tools and techniques to give students feedback on their written work. How feedback is delivered and received by students is valued differently. The current study concentrated on how students interpret written corrective feedback and which WCF tactics they favor in writing classrooms. To examine these objectives empirically, the researchers employed a self-administered questionnaire to collect data from 180 participants from a high secondary school in Multan, Pakistan. At the same time, 40 participants were interviewed for their opinions about written corrective feedback (WCF). Some participants expressed concerns about ambiguous feedback that confuses them about their errors, whereas most participants favored the feedback process as beneficial. The most preferred strategies were meta-linguistic explanation and direct written corrective feedback that facilitated writing proficiency and language knowledge. Overall, WCF guides errors to avoid and how to adapt their writing style for composing compelling manuscripts.

Background: Over the past decade, the potential advantages of employing deep learning models and leveraging auxiliary data in data-driven end-to-end (E2E) frameworks to enhance inventory decision-making have gained recognition. However, current approaches predominantly rely on feed-forward networks, which may have difficulty capturing temporal correlations in time series data and identifying relevant features, resulting in less accurate predictions. Methods: Addressing this gap, we introduce novel E2E deep learning frameworks that combine Convolutional Neural Networks (CNN) and Long Short-Term Memory (LSTM) for resolving single-period inventory ordering decisions, also termed the Newsvendor Problem (NVP). This study investigates the performance drivers of hybrid CNN-LSTM architectures, coupled with an evolving algorithm for optimizing network configuration. Results: Empirical evaluation of real-world retail data demonstrates that our proposed models proficiently extract pertinent features and interpret sequential data characteristics, leading to more accurate and informed ordering decisions. Notably, results showcase substantial benefits, yielding up to an 85% reduction in costs compared to a univariate benchmark and up to 40% savings compared to a feed-forward E2E deep learning architecture. Conclusions: This confirms that, in practical scenarios, understanding the impact of features on demand empowers decision-makers to derive tailored, cost-effective ordering decisions for each store or product category.

Researchers have been striving to investigate the causes and consequences associated with writing anxiety experienced by students of foreign languages. This study aimed to investigate the level and nature of writing anxiety experienced by learners of foreign languages, considering gender as a variable. The study's second goal was to uncover the learners' perspectives on writing anxiety and the factors that contribute to it. The convenience sample method was used to choose seventy-six students to participate in the English language teacher training course. Second Language Writing Anxiety Reasons Inventory (SLWARI) and Second Language Writing Anxiety Inventory (SLWAI) (Cheng, 2004; Kara, 2013) [1,2] were used in order to determine the levels and types of anxiety that are associated with learners' foreign language writing. Both inventories were used to determine what causes learners' foreign language writing. In order to gain a comprehensive understanding of how students perceive the level of anxiety they feel when writing, a semi-structured interview was conducted with each participant. The data showed that there was no difference when taking into account learners' gender concerning their anxiety levels and kinds. The vast majority of individuals reported feeling a significant amount of anxiety. The subjects exhibited cognitive anxiety symptoms, although there were no indications of gender effect. The responses to the interview questions highlighted a deficiency in both writing practice and linguistic expertise as critical contributors to anxious sentiments.

Psychologically complicated by nature, anxiety refers to feelings of worry, fear, or apprehension. Several research studies have been devoted to exploring anxiety's effects on language skills, including writing. Since foreign language anxiety directly influences a learner's motivation and determination to learn that language, it is imperative to study the findings and reasons behind these anxious feelings. One-third of foreign language learners have been experiencing at least a moderate level of anxiety. Researchers have attempted to investigate the causes of anxiety among foreign language pre-service teachers. The present study objectifies two goals to determine the extent of writing anxiety, followed by reasons and references to the role of gender. Seventy-two pre-service teachers of the English language training department from the University of Education, Multan, Pakistan, were selected for the study using convenience sampling. Second language writing anxiety inventory (SLWAI) and second language writing anxiety reasons inventory (SLWARI) were used to collect data, and semi-structured interviews were taken with students. The findings presented no difference in anxiety levels between genders, whereas cognitive anxiety type was distinctive in results. Most of the participants experienced high and medium levels of anxiety.

In the traditional distributed control network, due to the difficulty in detection and the ambiguous defense responsibility, it is not efficient and effective to detect Distributed Denial of Service (DDoS) attacks in the network where they are launched, which is so-called source-based defense mechanism. Moreover, with the development of cloud computing, Internet of Things (IoT), and mobile Internet, the number of terminals and the communication bandwidth in a single autonomous domain have increased significantly, providing much more easy conditions for organizing large-scale botnets to launch a threatening DDoS attack. Therefore, there is an urgent need for source-based defense against DDoS attacks. The emerging Software-Defined Networking (SDN) provides some new ideas and advantages to solve this problem, such as centralized control and network programmability. In this paper, we proposed a defense method based on sFlow and improved Self-Organizing Map (SOM) model in SDN. This method consists of an sFlow-based macro-detection, which could cover the entire network to perceive DDoS attacks, a SOM-based micro-detection, which is used to recognize the attack traffic, and a response strategy based on the global view given by the controller. The experimental results under open data and simulated attack scenarios have proved the effectiveness of the proposed method, and it also has better overall detection performance than k-means and k-medoids.

Two-stage ensemble-based forecasting methods have been studied extensively in the wind power forecasting field. However, deep learning-based wind power forecasting studies have not investigated two aspects. In the first stage, different learning structures considering multiple inputs and multiple outputs have not been discussed. In the second stage, the model extrapolation issue has not been investigated. Therefore, we develop four deep neural networks for the first stage to learn data features considering the input-and-output structure. We then explore the model extrapolation issue in the second stage using different modeling methods. Considering the overfitting issue, we propose a new moving window-based algorithm using a validation set in the first stage to update the training data in both stages with two different moving window processes. Experiments were conducted at three wind farms, and the results demonstrate that the model with single-input–multiple-output structure obtains better forecasting accuracy compared to existing models. In addition, the ridge regression method results in a better ensemble model that can further improve forecasting accuracy compared to existing machine learning methods. Finally, the proposed two-stage forecasting algorithm can generate more accurate and stable results than existing algorithms.