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The presence of extracorporeal membrane oxygenation (ECMO) is suggested to further exacerbate the pharmacokinetics (PK) alterations that occur during critical illness. The objectives of this study were to determine the population PK model of polymyxin B in critically ill patients with or without ECMO support investigated the influence of ECMO on PK variability and to identify an optimal dosing strategy.Forty-four critically ill patients were enrolled, including eight patients with ECMO support. Eight serial serum samples were collected from each patient at steady state. The population PK was determined using NONMEM and Monte Carlo simulation was performed to evaluate the exposures of different dosing regimens.The PK analyses included 342 steady-state concentrations and a two-compartment model was optimal for polymyxin B PK data modelling. In the final model, creatinine clearance (CLThe impact of ECMO on the polymyxin B PK is likely to be minimal. Our study showed a potential relationship between CL

The demand-responsive public transport system with multi-vehicles has the potential to efficiently meet real-time and high-volume transportation needs through effective scheduling. This paper focuses on studying the real-time vehicle scheduling problem, which involves dispatching and controlling different model vehicles uniformly based on generated vehicle number tasks at a given point in time. By considering the immediacy of real-time itinerary tasks, this paper optimizes the vehicle scheduling problem at a single time point. The objective function is to minimize the total operating cost of the system while satisfying constraints such as passenger capacity and vehicle transfer time. To achieve this, a vehicle scheduling optimization model is constructed, and a solution approach is proposed by integrating bipartite graph optimal matching theory and the Kuhn–Munkres algorithm. The effectiveness of the proposed approach is demonstrated by comparing it with a traditional greedy algorithm using the same calculation example. The results show that the optimization method has higher solution efficiency and can generate a scheduling scheme that effectively reduces operating costs, improves transportation efficiency, and optimizes the operation organization process for demand-responsive buses.

What is known and objective The influence of venovenous extracorporeal membrane oxygenation (VV-ECMO) on the population pharmacokinetics (PPK) of vancomycin in recipients after lung transplantation (LTx) is unknown. We investigated whether VV-ECMO influences vancomycin PPK and determined optimal recommended dosage for patients after LTx. Methods We tested vancomycin serum concentration and calculated PPK parameters using NONMEM. To check for any potential influence of ECMO on vancomycin PK, we compared ECMO patients with a non-ECMO patient control group, and patients before and after ECMO weaning as self-control to analysed changes in vancomycin PK. Monte Carlo dosing simulation was conducted to explore vancomycin dosing regimens. Results Nineteen ECMO and 6 non-ECMO lung transplant recipients were enrolled. Vancomycin serum concentrations did not significantly differ between patients with and without ECMO support. Comparison of separate vancomycin population pharmacokinetic models showed that ECMO patients had smaller peripheral compartment volume of distribution (V2 ) [Estimate (relative standard error, RSE, %) 19.7 (12) vs. 22 (17) L, P = .003] than non-ECMO patients. For treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections with MIC ≤ 0.5 µg/mL, venous infusion of 400 mg vancomycin every 8 hours was recommended. For MRSA infection with MIC ≤ 1 µg/mL, the proposed dosage was 600 mg every 8 hours. What is new and conclusion Venovenous extracorporeal membrane oxygenation slightly alters vancomycin PK but does not significantly impact vancomycin serum concentration in patients after LTx. Dose adjustment is not necessary for VV-ECMO support. Specific vancomycin dosing regimens with lower nephrotoxicity may benefit LTx recipients with VV-ECMO.

Introduction: The most common physiological and psychological disorders associated with critical care patients are pain and anxiety. Sedatives and analgesics are commonly used to relieve these symptoms. However, the adverse effects of sedatives and analgesics are common and inevitable. As a new type of sedative drug, limited number of trials are available to evaluate Remimazolam Besylate's availability and safety compared with propofol.Methods: This study is a single center, randomized, open-label, controlled trial. A total of 84 patients who meet ERAS criteria and receive mechanical ventilation in ICU, aged ≥18 years old will be included. Patients will be randomized (1:1) into two groups: Remimazolam Besylate group and Propofol group. The Primary outcomes includes satisfaction rate of sedation and incidence rate of major clinical events. Secondary outcomes including incidence of delirium, time to weaning and extubation, Difficulty of nursing RASS, BIS and PI, 28-days survival, side-effect and vital signs during medications, total dose and dose per kilogram body weight of analgesic and sedatives and incidence of rescue therapy in experimental group.Ethics and Dissemination: This trial has been approved by the ethics boards of Peking Union Medical College Hospital. Recruitment began in January 2022 and will continue until June 2022. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04947345

In drilling industries, hydraulic fracturing of unconventional shale-gas wells is a highly industrialized process involving multiple equipment, substances, and operational stages. However, fracturing operations also involve extremely hazardous work relating to high-pressure chemicals, heavy equipment, and flammable gases. During the fracturing process, human error frequently causes sand blockages, equipment damage, and fracturing fluid leakage. An assessment of human error likelihood is essential for the prevention of resulting incidents, and thereby improving the safety and stability of the entire shale-gas fracturing operations. However, due to the latency, unpredictability, and variety of human errors in fracturing operations, previous studies have not sufficiently considered uncertainties. Hence, an integrated method that applies the UAHP-SPA model is proposed to assess human error likelihood in the fracturing process. The indexes of human error likelihood assessment in fracturing operations are first established based on 4M theory. Then, the Set Pair Analysis (SPA) technique is used to consider epistemic uncertainties from assessed objects, assessment procedures, assessor subjectivities, and incomplete data. Furthermore, the SPA-based Uncertainty Analytic Hierarchy Process (UAHP) is applied for reducing aleatory uncertainties in the index weight optimization. The proposed method is able to effectively provide static likelihood states and dynamic likelihood trends of various human errors. To illustrate its validity, an on-site fracturing operator is selected as a test case. Results show that this UAHP-SPA model is more accurate and practical compared to conventional approaches.

Little is known about the influence of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of caspofungin. The aim of this study was to describe population PK of caspofungin in patients with and without ECMO during the postoperative period of lung transplantation (LTx) and to investigate covariates influencing caspofungin PK. We compared ECMO patients with non-ECMO patients, and patients before and after ECMO weaning as self-controls, to analyzed changes in caspofungin PK. Eight serial blood samples were collected from each patient for PK analysis., Little is known about the influence of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of caspofungin. The aim of this study was to describe population PK of caspofungin in patients with and without ECMO during the postoperative period of lung transplantation (LTx) and to investigate covariates influencing caspofungin PK. We compared ECMO patients with non-ECMO patients, and patients before and after ECMO weaning as self-controls, to analyzed changes in caspofungin PK. Eight serial blood samples were collected from each patient for PK analysis. The population PK of caspofungin was described using nonlinear mixed-effects modeling. Twelve ECMO and 7 non-ECMO lung transplant recipients were enrolled in this study. None of the patients received renal replacement therapy during any part of the study period. The PK of caspofungin was best described by a two-compartment model. There were no significant differences in the PK parameters and concentrations of caspofungin among the ECMO, non-ECMO, and self-control group. In the final covariate model, we found that there was a significant association between the male gender and increased distribution volume, that a higher sequential organ failure assessment score was related to an increase in intercompartmental clearance, and that a longer operative time was related to an increase in clearance and the volume of distribution. ECMO did not have a significant impact on the PK of caspofungin in patients after LTx. Some factors were identified as statistically significant covariates related to the PK of caspofungin; however, their impact on clinical practice of caspofungin needs to be investigated further in more studies. (This study has been registered at ClinicalTrials.gov under identifier NCT03766282.)

Background: The presentation of psittacosis can vary from subclinical infection to fatal pneumonia with a high mortality rate. Chlamydia psittaci infection during pregnancy is rare and might result in placental involvement, premature delivery or miscarriage. Herein, we report a case of severe pneumonia in a pregnant woman caused by C. psittaci.Case presentation: A 27-year-old female with a pregnancy at 22 weeks was admitted with hyperpyrexia, dry cough and dyspnea. Laboratory tests showed increased white blood cell count and slightly-elevated procalcitonin. Chest computed tomography scan revealed consolidation in the lingual and inferior lobe of the left lung. She suffered rapidly progressing respiratory failure and required mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Her sample of bronchoalveolar lavage fluid (BALF) was collected, from which C. psittaci was detected using next-generation sequencing (NGS). The pathogen was further confirmed by polymerase chain reaction (PCR) with the primers specific for the microorganism. Moreover, paired serum tests showed elevated C. psittaci group titer in both IgG and IgM. She was treated with azithromycin and tigecycline. After 24-day hospitalization, the patient was clinically well and discharged home.Conclusion: We report a case of severe pneumonia in a pregnant woman caused by C. psittaci, which diagnosed by NGS, and was cured without adverse effects on infant with tigecycline. The introduction of NGS and other effective assays might increase the detection rate. C. psittaci infection in pregnant women is very rare, but critical. Early diagnosis and correct treatment may save the mother and fetus. New tetracycline agent, tigecycline, may also be an effective alternative and should be further evaluated in psittacosis.

The efficacy and toxicity of polymyxin B (PB) are closely related to its pharmacokinetic/pharmacodynamic (PK/PD) index area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio. The purpose of this study was to obtain PK data for PB in Chinese severe pneumonia patients and establish appropriate blood sampling time points for the PB therapeutic drug monitoring (TDM). After treatment with at least four doses of PB (50 IU, q12h), the blood samples were collected immediately after the end of infusion (C0) and 1.5, 2, 4, 6, 8, and 12 h (C1.5, C2, C4, C6, C8, C12) after PB administration. The PB blood plasma concentrations were determined using an ultra-performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS). All 42 patients were randomly divided into modeling (n = 24) and validation (n = 18) groups. The relationship between AUCss,24h and PB plasma concentration at each time point in modeling group was analyzed using limited sampling strategy and a PK method based on one-compartment with correction model. C6 scheme was found to provide the most accurate prediction of AUCss,24h values (r2 = 0.984) with the target value of 1.9–4.2 μg/ml at steady state to reach the 50–100 μg h/ml criteria of AUCss,24h. C0 with target value of 1.0–2.8 μg/ml can be considered an alternative sampling scheme (r2 = 0.900) but prediction deviation may exist. C0 and Cmax sampling scheme also demonstrated good predicting ability of AUC values using PK model. This study provides a clear plan for the implementation of TDM of PB, which is useful for optimizing the dosing regimen and individualizing treatment in severe pneumonia patients.

With the increasing development of hydraulic fracturing technologies, shale gas exploitation is becoming a highly industrial process. Casing-failure incidents which could cause serious leakage of the high-pressure and hazardous chemicals have triggered an intense public discussion in the fracturing industry. Quantitative risk analysis (QRA) is a common technique used to study the carrying capacity of a casing. However, this technique tends to only show static risk state after the casing has been run down to the formation, but is not sufficient to monitor its real-time failure risk during the whole fracturing process. Therefore, a matrix-based risk assessment method is proposed to improve the conventional QRA by using stress-strength interference theory and value function modelling to calculate the static and dynamic failure probabilities of casings, respectively, over a period of multi-stage sand fracturing. Further studies are developed to integrate these two probabilities with the application of a design matrix, particularly for the quantitative analysis and assessment of casing failures. The visual risk graphs are also provided to show the failure risk states and levels for the casings in real time. The assessment procedures can clearly delineate the operation characteristics of shale gas fracturing − high pressure, large displacement, and sand erosion. To illustrate the validity of the methodology, a production casing of a gas well at one fracturing stage is chosen as a test case. Results show that the real-time risk is more accurate and practical, as well as improving the assessment effectiveness of casing-failure incidents during a whole fracturing period.

Shale gas fracturing is a complex system of continuous operation. If human errors occur, it will cause a chain reaction, from abnormal events to fracturing accidents, and even lead to abandonment o...

In the process of shale gas fracturing, long time, high strength, and boring task could trigger psychological or physical operation fatigues, and then lead to downtime, sand blocking, or other accidents, which are the main problems in safety management. However, conventional studies either separately analyze risks without considering the interaction and relationship between humans or teams, or only form a qualitative framework for team analysis. These methods can't be directly applied for the fracturing operators due to complex operation procedures and diversified human errors. An improved methodology, therefore, is proposed to assess human holistic risk during the whole cycle of fracturing operation. Firstly, D-S evidence theory is introduced to obtain the individual risk, and team performance shaping factor is also presented to establish risk assessment model for fracturing teams. Secondly, individual and team risks are integrated to calculate the quantitative value of human holistic risk. A sca...

This paper proposes an expert-based method to analyze functional failure risk in the fracturing system of unconventional natural gas. The newly proposed Fuzzy-FFIP method integrates functional failure identification and propagation (FFIP) with fuzzy logic. Fuzzy-FFIP is sufficient for dealing with the complexity and correlation of functional failures and the lack of failure data, as well as capturing the fuzziness of functional states of a critical component and entire system. From a configuration-behavior-function aspect, FFIP is a common framework used to represent system-wide logical relationships and study functional failure propagation paths. This framework is an expert system where knowledge base and inference engine are based on behavioral rules (BRs) and functional failure logic (FFL), respectively. Using FFL as a support, fuzzy logic is specifically applied to analyze the fuzzification and defuzzification of functional states – operating, degraded, and lost. The proposed method can clearly provide functional failure modes, effectively reveal failure propagation paths, and quantitatively assess functional failure risk levels in the fracturing system. To illustrate its validity, an on-site pump lubricant subsystem of fracturing unit is selected as a test case. Results show that Fuzzy-FFIP is more detailed and accurate, and contributes to system safety during the whole fracturing period.

In the process of shale gas fracturing, high-pressure manifold is always subjected to high horsepower, large displacement and fluid-solid coupled impact, resulting in serious failures such as erosion defect, stress corrosion and fatigue crack. Some kinds of manifold failures are correlated to each other, and the relationship between these failures and real-time monitoring parameters – pressure, displacement and sand ratio is non-linear in most cases. There is a study gap on the comprehensive risk evaluation for high-pressure manifold in existing research, which leads to inadequate or inaccurate safety decision. In this paper, manifold failures, failure characteristics as well as real-time monitoring parameters are considered respectively as the first-level, second-level and third-level indexes, and a set of index system is established for the failure risk evaluation. The correlation among indexes at the same hierarchy level is expressed as index weight by a weight optimization model. And a value function model is also presented to deal with the dynamic and non-linear index relationship among different hierarchy levels. Finally this comprehensive methodology is proposed to evaluate the overall risk, failure bucket and the risk level of high-pressure manifold in a real-time and accurate way. Results from a study of the DPT-115 well in Daniudi gas field indicate that the overall risk of manifold is mostly at levelⅡ and erosion defect acts as the main failure bucket.