Risk of false conformity decisions due to measurement uncertainty of Active Pharmaceutical Ingredient: A multiparametric evaluation

Abstract Medicines must be subject to physical, chemical, and biological analysis to guarantee their quality, safety, and effectiveness. Despite the efforts to ensure the reliability of analytical results, some uncertainty will always be associated with the measured value, which can lead to false decisions regarding conformity/non-conformity assessment. This work aims to calculate the specific risk of false decisions regarding conformity/non-conformity of acetaminophen oral solution dosage form. The acetaminophen samples from five different manufacturers (A, B, C, D, and E) were subject to an active pharmaceutical ingredient assay, density test, and dose per drop test according to the official compendia. Based on measured values and their respective uncertainties, the risk values were calculated using the Monte Carlo method implemented in an MS Excel spreadsheet. The results for two acetaminophen oral solution samples (C and D) provided an increased total risk value of false acceptance (33.1% and 9.6% for C and D, respectively). On the other hand, the results for the other three acetaminophen samples (A, B, and E) provided a negligible risk of false acceptance (0.004%, 0.025%, and 0.045% for A, B, and E, respectively). This indicates that measurement uncertainty is very relevant when a conformity assessment is carried out, and information on the risks of false decisions is essential to ensure proper decisions.

Nonparametric item response models: a comparison on recovering true scores / Modelos de resposta ao item não-paramétricos: comparando a recuperação de escores verdadeiros / Modelos de respuesta al item no-paramétricos: comparando la recuperación de puntuaciones verdaderas

Nonparametric procedures are used to add flexibility to models. Three nonparametric item response models have been proposed, but not directly compared: the Kernel smoothing (KS-IRT); the Davidian-Curve (DC-IRT); and the Bayesian semiparametric Rasch model (SP-Rasch). The main aim of the present study is to compare the performance of these procedures in recovering simulated true scores, using sum scores as benchmarks. The secondary aim is to compare their performances in terms of practical equivalence with real data. Overall, the results show that, apart from the DC-IRT, which is the model that performs the worse, all the other models give results quite similar to those when sum scores are used. These results are followed by a discussion with practical implications and recommendations for future studies.(AU)

Procedimentos não paramétricos são usados para adicionar flexibilidade aos modelos. Três modelos não paramétricos de resposta ao item foram propostos, mas não comparados diretamente: o Kernel smoothing (KS-IRT); a Curva Davidiana (DC-IRT); e o modelo semiparamétrico Rasch Bayesiano (SP-Rasch). O objetivo principal do presente estudo é comparar o desempenho desses procedimentos na recuperação de escores verdadeiros simulados, utilizando escores de soma como benchmarks. O objetivo secundário é comparar seus desempenhos em termos de equivalência prática com dados reais. De forma geral, os resultados mostram que, além do DC-IRT, que é o modelo que apresenta o pior desempenho, todos os outros modelos apresentam resultados bastante semelhantes aos de quando se usam somatórios. Esses resultados são seguidos de uma discussão com implicações práticas e recomendações para estudos futuros.(AU)

Se utilizan procedimientos no paramétricos para agregar flexibilidad a los modelos. Se propusieron tres modelos de respuesta al ítem no paramétricos, pero no se compararon directamente: Kernel smoothing (KS-IRT); la curva davidiana (DC-IRT); y el modelo bayesiano de Rasch semiparamétrico (SP-Rasch). El objetivo principal del presente estudio es comparar el desempeño de estos procedimientos en la recuperación de puntajes verdaderos simulados, utilizando puntajes de suma como puntos de referencia. El objetivo secundario es comparar su desempeño en términos de equivalencia práctica con datos reales. En general, los resultados muestran que, a excepción de DC-IRT, que es el modelo con peor desempeño, todos los otros modelos presentan resultados bastante similares a los obtenidos cuando se utilizan sumatorios. Estos resultados son seguidos por una discusión con implicaciones prácticas y recomendaciones para estudios futuros.(AU)

Evaluation of the dosing regimen of meropenem in elderly patients with renal insufficiency with Monte Carlo simulation / 中国药房

OBJECTIVE To explore the appropriate dosing regimen of meropenem in the elderly with renal insufficiency. METHODS The meropenem population pharmacokinetics of the two-compartment model of elderly patients were applied for Monte Carlo simulation. The model included the effect of renal function on the parameters. The designed dosages were 0.5， 1， 2 g； the administration modes included intravenous injection （lasting for 6 min） and intravenous drip （0.5， 3 h）； the administration frequencies were q12 h， q8 h. A total of 18 dosing regimens were designed. The probability of target attainment of %fT＞4MIC≥40% and Cmin≤27.5 mg/L were calculated respectively to optimize the dosing regimen. RESULTS For elderly patients with creatinine clearance （CLcr） ≤40 mL/min， when the minimum inhibitory concentration （MIC） was equaled to 1 mg/L， the suggested dosing regimens were “0.5 g， intravenous drip 0.5 h， q12 h”“ 1 g， intravenous injection， q12 h”. When the MIC was equaled to 2 mg/L， the suggested dosing regimens were “0.5 g， intravenous injection， q8 h”“ 1 g， intravenous drip 0.5 h， q12 h”. When the MIC was equaled to 4， 8 mg/L， the suggested dosing regimens were “1 g （or 2 g）， intravenous injection， q8 h”. For elderly patients with CLcr equal to 50 mL/min， when the MIC was equaled to 1 mg/L， the suggested dosing regimens were “0.5 g， intravenous injection， q8 h“”1 g， intravenous injection， q12 h”. When the MIC was equal to 2， 4， 8 mg/L，the suggested dosing regimens were“0.5 g （or 1 g， or 2 g）， intravenous drip for 0.5 h， q8 h”. The appropriate dosing regimens of all the above protocols were above 96.6%. In the dosing regimen of “2 g，intravenous injection or intravenous drip 0.5 h， q8 h”， Cmin＞27.5 mg/L occurred in 40 times among the 1 000 times of simulation， indicating adverse reactions of the nervous system may occur. CONCLUSIONS For the elderly patients with renal insufficiency， the dosing regimen of meropenem should be adjusted accordingly with CLcr＝40 mL/min as the boundary， and the toxicity of nervous system should be considered at the same time.

Contamination status and exposure risk of mycotoxins in Coicis Semen / 中国中药杂志

By investigating the contamination status and predicting the exposure risk of mycotoxin in Coicis Semen, we aim to provide guidance for the safety supervision of Chinese medicinal materials and the formulation(revision) of mycotoxin limit standards. The content of 14 mycotoxins in the 100 Coicis Semen samples collected from five major markets of Chinese medicinal materials in China was determined by UPLC-MS/MS. The probability evaluation model based on Monte Carlo simulation method was established after Chi-square test and One-way ANOVA of the sample contamination data. Health risk assessment was performed on the basis of margin of exposure(MOE) and margin of safety(MOS). The results showed that zearalenone(ZEN), aflatoxin B_1(AFB_1), deoxynivalenol(DON), sterigmatocystin(ST), and aflatoxin B_2(AFB_2) in the Coicis Semen samples had the detection rates of 84%, 75%, 36%, 19%, and 18%, and the mean contamination levels of 117.42, 4.78, 61.16, 6.61, and 2.13 μg·kg~(-1), respectively. According to the limit standards in the Chinese Pharmacopoeia(2020 edition), AFB_1, AFs and ZEN exceeded the standards to certain extents, with the over-standard rates of 12.0%, 9.0%, and 6.0%, respectively. The exposure risks of Coicis Semen to AFB_1, AFB2, ST, DON, and ZEN were low, while 86% of the samples were contaminated with two or more toxins, which needs more attention. It is suggested that the research on the combined toxicity of different mycotoxins should be strengthened to accelerate the cumulative exposure assessment of mixed contaminations and the formulation(revision) of toxin limit standards.

Health risk assessment of chemical substances in drinking water in Shijiazhuang from 2014 to 2021 / 环境与职业医学

Background A variety of substances in drinking water are hazardous to human health and there are health risks associated with ingestion of these substances via drinking water. Objective To assess the carcinogenic and non-carcinogenic health risks of drinking water in Shijiazhuang from 2014 to 2021. Methods The collection, preservation, and testing of 10529 drinking water samples (including finished water and tap water) in Shijiazhuang were conducted from 2014 to 2021 and followed the Standard examination methods for drinking water (GB/T 5750—2006). The health risks of 15 chemicals in drinking water by oral exposure were assessed using the US Environmental Protection Agency's four-step method combined with Monte Carlo simulation. Results Among the 15 chemicals in drinking water assessed for their health risks at general exposure levels and high exposure levels via oral route in Shijiazhuang from 2014 to 2021, the leading three chemicals and related values of carcinogenic risks for adults were cadmium (1.11×10−4, 2.98×10−4), arsenic (5.88×10−5, 1.56×10−4), and chromium (5.48×10−5, 2.41×10−4), and the leading three chemicals and related values of non-carcinogenic risks were fluoride (3.57×10−1, 6.57×10−1), arsenic (1.31×10−1, 3.47×10−1), and nitrate (1.14×10−1, 5.98×10−1). The health risk values of trichloromethane and aluminum were elevated but still in acceptable ranges. Drinking water-associated health risk values were higher in males than in females, such as the cancer risk for general exposure levels of arsenic in men was 5.76×10−5, compared to 5.72×10−5 in women. The health risk values of cadmium, chromium, fluoride, nitrate, and other chemicals in ground water were higher than those of surface water, and the health risk values of trichloromethane and carbon tetrachloride were lower than those in surface water, such as the non-carcinogenic risk value for general exposure levels of fluoride in groundwater was 3.61×10−1, compared to 2.27×10−1 in surface water. Factors such as water transmission and distribution links, water period, and season affected the health risks of drinking water. The general exposure levels of trichloromethane in tap water had a higher carcinogenic risk of 1.75×10−7 compared with 8.17×10−8 in finished water. The general levels of arsenic exposure was higher in the dry season at 1.36×10−1, compared with 1.26×10−1 in the wet season. Conclusion Except that the carcinogenic risk of cadmium at general exposure levels in Shijiazhuang exceeds the maximum acceptable range recommended by US Environmental Protection Agency, the health risk values of the remaining 14 chemicals are below the maximum acceptable risk. The carcinogenic risk values of arsenic and chromium and the non-carcinogenic risk values of fluoride, arsenic, and nitrate are relatively high, but do not exceed the maximum acceptable ranges. The emphasis should be on the management of drinking water in highly exposed areas and populations.

Monte Carlo simulation and analysis of eye lens dose of the first operator in interventional therapy / 中国辐射卫生

Objective To establish a model for estimating the eye lens dose of the first operator in interventional therapy based on the Monte Carlo simulation, and to provide a scientific basis for the rapid and accurate evaluation of the eye lens dose for radiation workers in interventional therapy. Methods Based on the MIRD phantom and eye model for adult Chinese males, the MCNPX program was used to establish the physical model to calculate the spatial distribution of radiation field and eye lens dose for the first operator. A GR200 Type A LiF (Mg, Cu, P) thermoluminescence dosimeter was used for experimental measurement to verify the simulation results. Results Monte Carlo simulation and experimental measurements showed that the spatial distribution of radiation field was symmetrical. Compared with the measured doses, the errors of the simulated eye lens dose of the first operator were between −8.3% and 7.3%. The dose of the left eye lens was higher than that of the right eye. Conclusion The Monte Carlo model constructed in this study initially realizes the simulation of eye lens dose of the first operator in interventional therapy. In the future, the model will be further optimized based on irradiation parameters such as exposure time, tube voltage, tube current, and projection direction used in clinic practice, so as to more accurately evaluate the eye lens dose of interventional therapy staff.

Analysis of factors influencing the medical insurance balance of hospitalization expenses for gastric cancer surgery patients under DRG payment / 中华医院管理杂志

Objective:To analyze the influencing factors of the medical insurance balance of hospitalization expenses for gastric cancer surgery patients under DRG payment, for reference for promoting the reform of DRG payment in public hospitals and controlling hospitalization expenses reasonably.Methods:The gastric cancer patients enrolled in the gastroenterology department of a tertiary comprehensive hospital from January to July 2022 were selected as the research subjects. The indicators such as patient age, medical insurance balance, hospitalization expenses and their composition were extracted from the hospital information management system and the medical insurance settlement system a certain city. Descriptive analysis was conducted for all data, and stepwise multiple linear regression was used to analyze the influencing factors of patients′ medical insurance balance. Monte Carlo simulation method was used to simulate different combination scenarios of various influencing factors to analyze the probability of medical insurance balance.Results:A total of 205 patients were contained, including 117 in the medical insurance balance group and 88 in the loss group. The difference in hospitalization expenses and medical insurance balance between the two groups of patients were statistically significant ( P<0.05). The intervention of medical insurance specialists, correct DRG enrollment, parenteral nutrition preparation costs, anti infective drug costs, examination costs, and consumables costs were the influencing factors of patient medical insurance balance ( P<0.05). Through Monte Carlo simulation verification, patients with different cost parenteral nutrition preparations, or different anti infective drug schemes had the higher probability of medical insurance balance in the scenario where the medical insurance commissioner intervenes and the DRG enrollment was correct. Conclusions:The hospital adopted interventions from medical insurance specialists to ensure the correct DRG enrollment of patients, accurate use of parenteral nutrition and anti infective drugs, and reasonable control the cost of examinations and consumables, which could increase the probability of medical insurance balance for gastric cancer surgery patients. In the future, hospitals should further promote the procurement of drug consumables in bulk, reduce unnecessary examinations, develop standardized perioperative nutritional interventions and anti infection treatment pathways, ensure the accuracy of DRG enrollment, optimize clinical diagnosis and treatment pathways to improve the efficiency of medical insurance fund utilization and provide high-quality medical services for patients.

Eficácia in sílico do florfenicol no tratamento de pododermatite infecciosa por Fusobacterium necrophorum em ovelhas / In sílico efficacy of florfenicol in the treatment of Fusobacterium necrophorum infectious pododermatitis in sheep

Objetivou-se comparar o efeito in silico do florfenicol nas doses de 20 e 30 mg/Kg em ovinos pelas vias intravenosa (IV) e intramuscular (IM), usando a modelagem PK/PD. Realizou-se uma simulação de Monte Carlo com base nos dados de concentração plasmática de um estudo publicado anteriormente. Calculou-se a área sob a curva (ASC) e as taxas de eficácia do florfenicol para os efeitos bacteriostático, bactericida e de erradicação bacteriológica. A dose de 20 mg/Kg IV demonstrou efeitos de erradicação de 100, 93 e 0% para CIM de 0,5, 1 e acima, respectivamente. O efeito bacteriostático foi de 99 e 90% para CIM de 4 e 2 µg/ml, enquanto o bactericida foi de 14% para CIM de 2 µg/ml. A dose de 30 mg/Kg IV apresentou 100% de erradicação para CIM de 1 µg/mL e 100% de efeito bactericida para CIM de 2 µg/mL. Há 100% de efeito bacteriostático em CIM de 4 µg/ml. As doses de 20 e 30 mg/Kg IM mostraram 100% de erradicação para CIM até 1 µg/mL e 0% para CIM maiores. O efeito bacteriostático foi mantido em 100% para uma CIM de 4 µg/mL em ambas as doses. Este estudo mostra o efeito de erradicação bacteriológica do florfenicol nas doses de 20 e 30 mg/Kg, IV e IM. Recomenda-se que seja feito um estudo de eficácia in vivo com a dose de 30mg/Kg IM em ovinos infectados por F. necrophorum com MIC superior a 2 µg/mL.

We aimed to compare the in silico effect of florfenicol at doses of 20 and 30 mg/Kg in sheep by intravenous (IV) and intramuscular (IM) routes, using PK/PD modeling. We performed a Monte Carlo simulation based on plasma concentration data from a previously published study. We calculated the area under the curve (AUC) and the efficacy rates of florfenicol to bacteriostatic, bactericidal, and bacteriological eradication effects. The dose of 20 mg/Kg IV demonstrated 100, 93, and 0% eradication effects for MICs of 0.5, 1, and above, respectively. The bacteriostatic effect was 99 and 90% for MIC of 4 and 2 µg/ml, while the bactericide was 14% for MIC of 2 µg/ml. The 30 mg/Kg IV dose showed 100% eradication for MIC of 1 µg/mL and 100% bactericidal effect for MIC of 2 µg/mL. There is a 100% of bacteriostatic effect at MIC of 4 µg/ml. Doses of 20 and 30 mg/Kg IM showed 100% eradication for MIC up to 1 µg/mL and 0% for MIC above. The bacteriostatic effect was maintained at 100% for a MIC of 4 µg/mL at both doses. This study shows the bacteriological eradication effect of florfenicol at doses of 20 and 30 mg/Kg, IV, and IM. Therefore, we recommend an in vivo efficacy study with a dose of 30mg/Kg IM in sheep infected with F. necrophorum with MIC greater than two µg/mL.

Simulation of detection efficiency of a portable NaI(Tl) γ spectrometer for monitoring 131I in the thyroid / 中华放射医学与防护杂志

Objective:To simulate the effects of different thyroid-neck phantoms and monitoring positions on the detection efficiency of portable γ spectrometer, and to provide guidance for more accurate on-site measurement of 131I activity in the human thyroid. Methods:Based on the models of 4 typical thyroid-neck phantoms and a 3-inch NaI (TI) γ spectrometer used for the measurement of 131I in the thyroid and combined with the possible field monitoring scenarios, the Monte Carlo method was used to simulate and calculate the detection efficiency of the spectrometer under different conditions of monitoring distance, thyroid depth and thyroid volume. Results:The detection efficiency decreased significantly with the increase in the distance between the detector and the neck surface. The efficiency close to the neck surface was about 15 times that at 15 cm away from the neck surface. The detection efficiency decreased significantly with the increase in thyroid depth. When it was measured at the surface of the neck, the detection efficiency of thyroid at depth of 2 mm was about 3.6 times that of 30 mm. The detection efficiency decreases with the increase in thyroid volume. When it was measured at the neck surface, the detection efficiency of thyroid with 1 ml volume was 1.71 times that with 30 ml. The detection efficiency decreased with the center-point offset of the detector, especially at the neck surface, an offset of 2 cm would reduce the detection efficiency by about 15%.Conclusions:Not only the measurement distance used in calibration, but also the information of the depth and volume of thyroid in the neck-thyroid phantom, is important to know in advance for an accurate measurement of 131I activity in thyroid by using a portable gamma spectrometer.

Preliminary study on Monte Carlo-based simulation and verification of spot scanning carbon ion beam model / 中华放射医学与防护杂志

Objective:To develop a spot scanning carbon ion beam model based on Monte Carlo code FLUKA and verify the accuracy of physical dose.Methods:A geometric model of the treatment nozzle was established in FLUKA. Various parameters such as monoenergy nominal energy, Gaussian energy spectrum distribution, initial spot size, and beam angular distribution in the model were adjusted to match the reference data of integral depth dose (IDD) and in-air spot size measuremed experimentally. Carbon ion beam plans were generated by using the treatment planning system (TPS). The difference in output dose distribution between FLUKA and TPS was compared by the gamma analysis.Results:The differences in Bragg peak width, beam range, and distal falloff width extracted from the IDD curve between the FLUKA model and measured vaues were less than 0.1 mm, with the maximum difference in spot sizes of 0.17 mm. Under the criterion of 2 mm/2% in all the simulations, 2D- and 3D-γ pass rates were all above 95%.Conclusions:An accurate spot scanning carbon beam model was developed based on the Monte Carlo code FLUKA. It has the potential to be used for not only the verification of clinical treatment plans, but also the development of new ion beam therapy equipment and the calculation of biologically effective dose.

An exploration of shielding optimization for self-shielded accelerators / 中国辐射卫生

Objective To analyze the room layout and shielding of three types of self-shielded accelerators, and to provide a basis for optimizing the shielding design of rooms for self-shielded accelerators. Methods We compared the radiation shielding levels (transmitted radiation dose rate outside the primary barrier and scattered radiation dose rate outside the secondary barrier) of three self-shielded accelerator rooms by Monte Carlo simulation and empirical formula calculation. Results According to Monte Carlo simulation and empirical formula calculation, for the Unity MR Linac accelerator, the scatter radiation dose rate outside the secondary barrier was significantly higher (up to five times) than the transmitted primary radiation dose rate outside the primary barrier. The scatter radiation dose rate of the cross section was significantly higher than that of the sagittal section for both Unity MR Linac and TOMO accelerators. Conclusion The differences in the shape, material, and thickness of self-shielding structures complicate the shielding calculation and design for accelerator rooms. The shielding calculation method should be improved to optimize the radiation shielding of novel accelerator rooms.

Discussion on shielding calculation method for proton therapy room / 中国辐射卫生

@#<b>Objective</b> To discuss the shielding calculation method for proton therapy room, and to provide a scientific basis for shielding design of proton therapy room and improvement of existing national standards. <b>Methods</b> Using the calculation formula and key characteristic parameters from national standards and Chinese and foreign literature, combining with the FLUKA Monte Carlo method, empirical formula calculation and Monte Carlo simulation were conducted for the neutron ambient dose equivalent rates of the focuses outside the shielding of proton therapy room. The estimation results of the two methods were analyzed. <b>Results</b> Relative to the calculation results of the single exponential formula in the two directions of 0° and 50° in the beam loss point of divergence slit (0.13 and 12.4), the calculation results of the double exponential formula (0.40 and 17.9) were more consistent with the Monte Carlo simulation results (0.32 ± 0.19 and 18.2 ± 4.98). The Monte Carlo simulation results of copper target and nickel target were similar, suggesting that the key characteristic parameters of concrete shielding for copper target could be well applied to the calculation of nickel target, but the neutron ambient dose equivalent rates were underestimated when applied to tantalum target, with a difference of 5.7 times and 1.3 times in the two directions of 0° and 40°, respectively. <b>Conclusion</b> The dose rate estimates based on the calculation formula and key characteristic parameters from Chinese and foreign literature are consistent with FLUKA simulation results, and this method can be used in the shielding design of proton therapy room as a supplement and improvement to the existing national standards.

Health risk assessment of N-nitrosodimethylamine in drinking water in Nanjing, Jiangsu Province / 环境与职业医学

Background N-nitrosodimethylamine (NDMA), a new disinfection by-product in drinking water, has attracted extensive attention due to its high detection rate and concentration. Objective To investigate the concentration of NDMA in drinking water in Nanjing situated in the lower Yangtze River Basin of China, and to evaluate associated human health risk. Methods In dry period (January–March) and wet period (July–September) of 2021, raw water, finished water, and tap water from 16 centralized water treatment plants in Nanjing were collected to detect the concentration of NDMA in water samples by solid phase extraction and gas chromatography-triple quadrupole mass spectrometry with programmable temperature vaporizer-based large volume injection. The concentrations of NDMA in water samples of different water types, water periods, and disinfection methods were analyzed, and the daily exposure levels and carcinogenic risk values of NDMA in drinking water of different exposure routes and different exposed populations were calculated. Monte Carlo simulation was implemented with Crystal Ball 11 software to establish a health risk assessment model and conduct sensitivity analysis. Results A total of 61 drinking water samples were collected in Nanjing, and NDMA was positive in all the water samples, with concentrations ranging from 1.36 to 25.65 ng·L−1 and an overall average concentration of (8.00±4.06) ng·L−1. There were no statistically significant differences in the average concentrations of NDMA among raw water, finished water, and tap water samples (F=2.875, P=0.064), between wet season and dry season (t=−0.855, P=0.397), or among different disinfection methods by liquid chlorine, sodium hypochlorite, and chlorine dioxide (F=0.977, P=0.385). The results of health risk assessment showed that the average carcinogenic risk of NDMA and its P95 were 5.95×10−6 and 1.12×10−5 respectively for oral intake of drinking water, and the values for dermal contact were both lower than 1.00×10−6. The mean carcinogenic risks of exposure to drinking water NDMA in children, adolescents, and adults were 1.84×10−6, 8.27×10−7, and 3.28×10−6, respectively. The results of sensitivity analysis showed that the contributions of daily drinking water volume and NDMA concentration in drinking water to the calculated health risk were high, and the contribution of body weight was negative. Conclusion There is a potential carcinogenic risk of NDMA in the drinking water of Nanjing section of the lower Yangtze River Basin，but it is within the acceptable range.

Monte Carlo simulation study to optimize administration regimens of linezolid, teicoplanin and daptomycin for Staphylococcal bloodstream infections / 中华传染病杂志

Objective:To predict and evaluate the antibacterial efficacy of linezolid, teicoplanin and daptomycin against Staphylococci bloodstream infections with Monte Carlo simulation, and to optimize the clinical administration program. Methods:A total of 1 847 Staphylococci strains isolated from blood samples between January 2018 to December 2019 were collected with the help of the Blood Bacterial Resistant Investigation Collaborative System (BRICS). Minimum inhibitory concentrations (MIC) of linezolid and daptomycin were detected by broth dilution method, while MIC of teicoplanin were detected by agar dilution method. The dosage regimens of linezolid were 800 mg once daily, 500 mg once every 12 hours, 600 mg once every 12 hours and 600 mg once every eight hours. The dosage regimens of teicoplanin were 400 mg once every 12 hours, 600 mg once every 12 hours, 800 mg once every 12 hours, and 1 000 mg once every 12 hours. The dosage regimens of daptomycin were 4 mg·kg -1·d -1, 6 mg·kg -1·d -1, 8 mg·kg -1·d -1, 10 mg·kg -1·d -1and 12 mg·kg -1·d -1. The probability of target attainment (PTA) and cumulative fraction of response (CFR) of three different dosage regimens were calculated by Monte Carlo simulation. A dosage regimen with CFR≥90.0% was a reasonable choice for empirical antimicrobial therapy. Results:PTA of linezolid against Staphylococci when MIC≤0.500 mg/L at four dosage regimens (800 mg once daily, 500 mg once every 12 hours, 600 mg once every 12 hours and 600 mg once every eight hours) were all over 90.0%. When MIC was 1.000 mg/L, the PTA of linezolid against Staphylococci under the dosages of 500 mg once every 12 hours, 600 mg once every 12 hours and 600 mg once every eight hours were 92.2%, 96.6% and 97.6%, respectively. The CFR of the four dosage regimens of linezolid were 73.9%, 83.7%, 90.8% and 95.3%, respectively. When MIC≤1.000 mg/L, PTA of teicoplanin against Staphylococci were all 100.0% at four dosage regimens (400 mg once every 12 hours, 600 mg once every 12 hours, 800 mg once every 12 hours and 1 000 mg once every 12 hours). When MIC was 2.000 mg/L, the PTA of teicoplanin (800 mg once every 12 hours and 1 000 mg once every 12 hours) against Staphylococci were both 100.0%. The CFR of the four dosage regimens of teicoplanin were 90.8%, 92.8%, 93.5% and 94.6%, respectively. When MIC≤0.500 mg/L, PTA of daptomycin against Staphylococci under the five dosages of 4 mg·kg -1·d -1, 6 mg·kg -1·d -1, 8 mg·kg -1·d -1, 10 mg·kg -1·d -1 and 12 mg·kg -1·d -1 were all over 90.0%. When MIC was 1.000 mg/L, the PTA of daptomycin against Staphylococci under the three dosages of 8 mg·kg -1·d -1, 10 mg·kg -1·d -1 and 12 mg·kg -1·d -1were 96.9%, 100.0% and 100.0%, respectively. The CFR of the five dosage regimens of daptomycin against Staphylococci were 97.4%, 99.2%, 99.9%, 100.0% and 100.0%, respectively. Conclusions:Linezolid (600 mg once every 12 hours), teicoplanin (400 mg once every 12 hours) and daptomycin (4 mg·kg -1·d -1) can achieve satisfactory antibacterial activity for Staphylococci bloodstream infections.

Distribution and health risk assessment of formaldehyde in non-newly decorated houses in Ningbo, China / 环境与职业医学

Background Formaldehyde is a common air pollutant in residential buildings, and the health risks caused by formaldehyde in residential buildings can not be ignored. Objective This study aims to evaluate the air concentration of formaldehyde in non-newly decorated houses in Ningbo and its possible health risks. Methods A total of 72 houses without any decoration in the past one year in Ningbo were selected by multi-stage random sampling method. From July 2018 to January 2019, the air samples of living rooms and bedrooms were collected and their temperature and humidity were also measured. The concentrations of formaldehyde were detected by AHMT method according to Standred method for hygienic examination of formaldehyde in air of residential areas — Spectrophotometric method (GB/T 16129—1995) , the health risk assessment model of U.S. Environmental Protection Agency was used to evaluate the non-carcinogenic risk and carcinogenic risk of formaldehyde, and Monte Carlo simulation was used for sensitivity analysis. Results The median (P25, P75) of formaldehyde concentration in the 72 houses was 0.019 (0.012,0.026) mg·m−3. Only one house showed a formaldehyde concentration that exceeded the national standard in the living room, and the total qualified rate of formaldehyde concentration was 98.61%. The median (P25, P75) of formaldehyde concentration in the bedroom was 0.019 (0.011, 0.031) mg·m−3, which was higher than that in the living room, 0.015 (0.010, 0.024) mg·m−3, and the difference was statistically significant. The median and 90th percentile of non-cancer risk (hazard quotient, HQ) of the 72 houses were 1.35 and 2.80, respectively, and the proportion of the houses with HQ>1 was 62.50%. The median and 90th percentile of cancer risk (CR) of the 72 houses were 1.12×10−4 and 2.32×10−4, respectively, and the proportions of the houses with CR>1×10−6, CR>1×10−5, and CR>1×10−4 were 100.00%, 100.00%, and 54.20%, respectively. After using Monte Carlo simulation, the median (90th percentile) of non-carcinogenic risk was reduced to 0.91 (1.94), where the median was lower than the national limit, and the proportion of samples with HQ>1 was 44.73%; the carcinogenic risk was reduced to 7.52×10−5 (1.79×10−4), and the proportions of samples with CR>1×10−6, CR>1×10−5, and CR>1×10−4 were 100.00%, 98.96%, and 34.37%, respectively. Conclusion The concentration of formaldehyde in non-newly decorated houses in Ningbo basically meets the national requirements, but it is still necessary to pay attention to the non-carcinogenic risk and carcinogenic risk caused by indoor formaldehyde, among which the carcinogenic risk is more important. Residents should prevent the harm of formaldehyde from its source by considering clean decoration materials and environmentally friendly furniture.

Economic viability of a crop-livestock integration system / Viabilidade econômica de um sistema de integração lavoura-pecuária

ABSTRACT: Crop monoculture and single conventional cattle raising were designed for a rapid increase in productivity and food supply. However, some of these production systems have shown signs of saturation and negative environmental impacts. Crop-livestock integration systems have been developed as an alternative that delivers increased productivity and greater environmental sustainability. This article presents an evaluation of the economic viability and the financial risk associated with an investment in crop-livestock integration with a focus on the production of beef cattle in São Carlos, SP, Brazil. Results showed that the investment is economically viable and has an Internal Rate of Return higher than that of a conventional system. Monte Carlo simulations showed that the integrated system presents lower market risks when compared to the conventional system.

RESUMO: A produção agrícola em monocultivo e a pecuária convencional não integrada com culturas foram desenhadas para um aumento rápido da produtividade e da oferta de alimentos. Entretanto, alguns destes sistemas de produção têm mostrado sinais de saturação e impactos ambientais negativos. Sistemas de integração lavoura-pecuária têm sido desenvolvidos como uma alternativa que oferece aumento de produtividade e maior sustentabilidade ambiental. O presente trabalho tem por objetivo estimar a viabilidade econômica e o risco financeiro associado a um projeto de investimento em integração lavoura-pecuária com foco para a produção de animais de corte em São Carlos, SP. Os resultados mostraram que o investimento é economicamente viável e apresenta Taxa Interna de Retorno superior à de um sistema convencional. Por meio da simulação de Monte Carlo constatou-se o sistema integrado apresenta menores riscos de mercado quando comparado com o sistema convencional.

Design of a drum-shaped applicator through Monte Carlo simulation for breast intraoperative radiotherapy / 中华放射肿瘤学杂志

Objective:To design a drum-shaped applicator through Monte Carlo simulation for breast intraoperative radiotherapy.Methods:Applicator designing process is as follows: first, determined the shape of the applicator based on the geometric characteristics of the breast tumor bed closed to the chest wall; second, calculated the scattering angle and dose rate of the electron beam after passing through a series of scattering foils of different thicknesses to determine the thickness of the scattering foil; thrid, modeled the layer according to the applicator′s geometric characteristics where modulator located, and designed the modulator through the relationship between the geometric characteristics of the layer and the surface dose of the applicator. EGSnrc/BEAMnrc and EGS4/DOSXYZ were employed to model the head of the Mobetron, the layer, the applicator, and to calculate the dose distributions.Results:The applicator has two components. The upper component is a 3cm-diametre cylindrical collimator with 0.5cm wall made of 0.3cm steel and 0.2cm water equivalent material (WEM), a 0.13cm-foil made of tansgen. The lower component is a 4cm-diametre drum made of 0.2cm WEM and a 0.14cm maximum thickness hill-shaped modulator made of steel. When the energy of electron beam was 12MeV, the dose rate was about 90.44 cGy/min, and the depth of the 50% isodose curve was 1cm.Conclusion:The applicator is successfully designed, and can obtain a drum-shaped dose distribution.

Effects of tissue heterogeneity on dose evaluation of brachytherapy for cervical cancer / 中华放射医学与防护杂志

Objective:To evaluate the impacts of tissue heterogeneity on dose calculation of cervical brachytherapy by comparing the doses calculated by two clinically used dose calculation method and the CT image-based Monte Carlo (MC) method.Methods:This study retrospectively selected 11 patients with cervical cancer treated with 3D brachytherapy in Anhui Provincial Cancer Hospital from January 2018 to June 2020. The dose distribution of each plan was calculated via three methods, dose calculation method described in American Association of Physicist in Medicine(AAPM) Task Group No. 43 Report (TG43-BT), Acuros BV(BV-BT) used to perform accurate dose calculations in high-dose-rate (HDR) brachytherapy with phantom heterogeneity, and CT image-based EGSnrc tool kit used to perform Monte Carlosimulation (MC-BT). The dose volumes( V3 Gy, V6 Gy, V9 Gy, and V12 Gy), target volume doses( D98, D90, D50), D2 cm 3 of organs at risk (OARs) calculated by the three methods were compared. Results:The HRCTV D90obtained by TG43-BT was 6.274 Gy, which was even overestimated by around 5% compared to the result calculated by MC-BT. Meanwhile, TG43-BT overestimated the dose volumesand the target volume doses compared to MC-BT.Except for D50 and V12 Gy, the differences between the doses to tumor calculated by BV-BT and MC-BT were not statistically significant( P>0.05). There was also no significant statistical difference between the D2 cm 3 of rectum, small intestine, and sigmoid calculated by BV-BT and MC-BT ( P>0.05). In contrast, the dose to D2 cm 3 of bladder determined by MC-BT was 4.609 Gy, which was notably higher than those deter mined by TG43-BT and BV-BT. Conclusions:TG43-BT overestimated the doses to tumor targets and most OARs since the effects of tissue heterogeneity were not taken into consideration. BV-BT performed efficient calculation and most of the dose distributionin target volume and OARs obtained by BV-BT were consistent with that calculated by MC-BT. Nevertheless, low accuracy occurred for the regions near the sources and full bladder, which warrants further caution in clinical evaluation.

Physical dose estimation for an accidental exposed person in industrial γ-ray flaw detection / 中华放射医学与防护杂志

Objective:To estimate the physical dose of an over exposed person working for industrial radiography.Methods:The main exposure parameters were obtained. The exposure duration was 8 min. The exposure pattern was external exposure by isotropic point radioactive source. The radioactive activity was 2.183 TBq. In the present calculation, the Chinese reference adult voxel phantom was used, and the Monte Carlo simulation was performed using the program based on the secondary development of Geant4 to obtain the absorbed dose of each part of the victim.Results:The dose distribution in the victim′s hands was obtained. The doses to most areas of the palm were 2-10 Gy, and the doses to the fingers were 10-20 Gy. The equivalent doses to 23 tissues or organs of the exposed person were estimated to be in the range of 0.012-0.207 Gy.Conclusions:The physical dose estimation method could evaluate rapidly the local dose distribution of the victim′s key exposed body parts, and thus provide an important reference for medical treatment.

Modelo de avaliação da viabilidade econômico-financeira da implantação de usinas de reciclagem de resíduos da construção civil em municípios brasileiros / Economic and financial viability evaluation model for the implementation of waste recycling plants construction in Brazilian municipalities

RESUMO Este trabalho teve como objetivo geral desenvolver um modelo de avaliação da viabilidade econômico-financeira da implantação de usinas de reciclagem de resíduos da construção civil e demolição (URRCD) em municípios brasileiros. O modelo de avaliação proposto para cada projeto de investimento (PI) em estudo uniu o modelo de negócio Canvas, o plano de negócios, a metodologia multi-índice proposta por Souza e Clemente (2009) e ampliada por Lima et al. (2015) por meio do aplicativo web $AVEPI. Também foi realizada uma análise de sensibilidade por meio de limites de elasticidade e valores-limite, bem como uma análise estocástica utilizando a simulação de Monte Carlo (SMC). Com base na proposição desse modelo, este foi aplicado em um estudo de caso no município de Pato Branco (PR). Os resultados mostram que há viabilidade econômico-financeira na implantação desse PI, uma vez que o valor presente líquido médio é de aproximadamente R$ 583.919,87, e a recuperação do investimento se concretizará em 12 anos (payback). Por meio da SMC, visualizou-se que há alta probabilidade (99,78%) de que o investimento na URRCD de Pato Branco seja rentável. Entretanto, os índices de elasticidade mostraram que é preciso monitorar as receitas esperadas e os custos estimados com mais atenção. Assim, será preciso um trabalho, por parte dos gestores da URRCD, em prol de sempre estarem buscando aumentar a demanda pelos agregados reciclados, como maneira de aumentar a receita da usina, desde que se respeite a sua capacidade de produção.

ABSTRACT This work had as main objective to develop an evaluation model for analyzing the economic and financial feasibility of implementing Construction and Demolition Waste Recycling Plants (URRCD) in Brazilian municipalities. The evaluation model proposed for the Investment Project (IP) under study was performed using the business model Canvas, the business plan, the multi-index method proposed by Souza and Clemente (2009) and expanded by Lima et al. (2015) through the $AVEPI Web app. Also, a sensitivity analysis was performed, through the elasticity limits and limit values as well as a stochastic analysis using the Monte Carlo Simulation (MCS). From the proposition of this model, it was applied in a case study in Pato Branco, Paraná. The results showed that there is economic and financial viability in the implementation of this IP, since the average Net Present Value (NPV) is about R$ 583,919.87 and the investment recovery will materialize in 12 years (Payback). Through MCS, it was observed that there is a high probability (99.78%) that the investment in the URRCD of Pato Branco, Paraná, be profitable. However, the elasticity indices showed that it is necessary to monitor the expected revenues and the estimated costs with more attention. Thus, it will require a work by the managers of the URRCD, in favor of always seeking to increase the demand for recycled aggregates, as a way to increase the revenue of the plant, as long as it does not exceed its production capacity.