Safety and effectiveness of butorphanol in epidural labor analgesia:A protocol for a systematic review and meta-analysis

BACKGROUND Epidural analgesia is the most effective analgesic method during labor.Butorphanol administered epidurally has been shown to be a successful analgesic method during labor.However,no comprehensive study has examined the safety and efficacy of using butorphanol as an epidural analgesic during labor.AIM To assess butorphanol's safety and efficacy for epidural labor analgesia.METHODS The PubMed,Cochrane Library,EMBASE,Web of Science,China National Knowledge Infrastructure,and Google Scholar databases will be searched from inception.Other types of literature,such as conference abstracts and references to pertinent reviews,will also be reviewed.We will include randomized controlled trials comparing butorphanol with other opioids combined with local anesthetics for epidural analgesia during labor.There will be no language restrictions.The primary outcomes will include the visual analog scale score for the first stage of labor,fetal effects,and Apgar score.Two independent reviewers will evaluate the full texts,extract data,and assess the risk of bias.Publication bias will be evaluated using Egger's or Begg's tests as well as visual analysis of a funnel plot,and heterogeneity will be evaluated using the Cochran Q test,P values,and I2 values.Meta-analysis,subgroup analysis,and sensitivity analysis will be performed using RevMan software version 5.4.This protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)Protocols statement,and the PRISMA statement will be used for the systematic review.RESULTS This study provides reliable information regarding the safety and efficacy of using butorphanol as an epidural analgesic during labor.CONCLUSION To support clinical practice and development,this study provides evidence-based findings regarding the safety and efficacy of using butorphanol as an epidural analgesic during labor.

Effect of safety valve types on the gas venting behavior and thermal runaway hazard severity of large-format prismatic lithium iron phosphate batteries

The safety valve is an important component to ensure the safe operation of lithium-ion batteries(LIBs).However,the effect of safety valve type on the thermal runaway(TR)and gas venting behavior of LIBs,as well as the TR hazard severity of LIBs,are not known.In this paper,the TR and gas venting behavior of three 100 A h lithium iron phosphate(LFP)batteries with different safety valves are investigated under overheating.Compared to previous studies,the main contribution of this work is in studying and evaluating the effect of gas venting behavior and TR hazard severity of LFP batteries with three safety valve types.Two significant results are obtained:(Ⅰ)the safety valve type dominates over gas venting pressure of battery during safety venting,the maximum gas venting pressure of LFP batteries with a round safety valve is 3320 Pa,which is one order of magnitude higher than other batteries with oval or cavity safety valve;(Ⅱ)the LFP battery with oval safety valve has the lowest TR hazard as shown by the TR hazard assessment model based on gray-fuzzy analytic hierarchy process.This study reveals the effect of safety valve type on TR and gas venting,providing a clear direction for the safety valve design.

Safety and effectiveness of neuromuscular electrical stimulation in cardiac surgery:A systematic review

BACKGROUND Lack of mobilization and prolonged stay in the intensive care unit(ICU)are major factors resulting in the development of ICU-acquired muscle weakness(ICUAW).ICUAW is a type of skeletal muscle dysfunction and a common complication of patients after cardiac surgery,and may be a risk factor for prolonged duration of mechanical ventilation,associated with a higher risk of readmission and higher mortality.Early mobilization in the ICU after cardiac surgery has been found to be low with a significant trend to increase over ICU stay and is also associated with a reduced duration of mechanical ventilation and ICU length of stay.Neuromuscular electrical stimulation(NMES)is an alternative modality of exercise in patients with muscle weakness.A major advantage of NMES is that it can be applied even in sedated patients in the ICU,a fact that might enhance early mobilization in these patients.AIM To evaluate safety,feasibility and effectiveness of NMES on functional capacity and muscle strength in patients before and after cardiac surgery.METHODS We performed a search on Pubmed,Physiotherapy Evidence Database(PEDro),Embase and CINAHL databases,selecting papers published between December 2012 and April 2023 and identified published randomized controlled trials(RCTs)that included implementation of NMES in patients before after cardiac surgery.RCTs were assessed for methodological rigor and risk of bias via the PEDro.The primary outcomes were safety and functional capacity and the secondary outcomes were muscle strength and function.RESULTS Ten studies were included in our systematic review,resulting in 703 participants.Almost half of them performed NMES and the other half were included in the control group,treated with usual care.Nine studies investigated patients after cardiac surgery and 1 study before cardiac surgery.Functional capacity was assessed in 8 studies via 6MWT or other indices,and improved only in 1 study before and in 1 after cardiac surgery.Nine studies explored the effects of NMES on muscle strength and function and,most of them,found increase of muscle strength and improvement in muscle function after NMES.NMES was safe in all studies without any significant complication.CONCLUSION NMES is safe,feasible and has beneficial effects on muscle strength and function in patients after cardiac surgery,but has no significant effect on functional capacity.

Comparative observation of the effectiveness and safety of remimazolam besylate versus dexmedetomidine in gastrointestinal surgery in obese patients

BACKGROUND Surgery for obese patients carries a higher risk of anesthesia complications compared with surgery for nonobese patients.Thus,a safe and effective anesthesia strategy is necessary to improve the medical experience of such patients and ensure their safety.AIM To compared the effectiveness and safety of remimazolam besylate versus dexmedetomidine(DEX)in gastrointestinal surgery in obese patients.METHODS The study cohort included 60 obese patients undergoing gastrointestinal surgery between July 2021 and April 2023,comprising 30 patients who received DEX intervention(control group)and 30 patients who received remimazolam besylate intervention(research group).Heart rate(HR),respiratory rate(RR),mean arterial pressure(MAP),blood oxygen saturation(SpO_(2)),safety(nausea and vomiting,bradycardia,hypotension,and apnea),anesthesia and examination indices[induction time,anesthesia recovery time,and postanesthesia care unit(PACU)discharge time],sedation effect(Ramsay Sedation Scale),and postoperative pain visual analog scale were comparatively analyzed before anesthesia(T0),during anesthesia(T1),and after anesthesia(T2).RESULTS At T1,the research group showed significantly smaller changes in HR,RR,MAP,and SpO_(2) than the control group,with a significantly lower adverse reaction rate and shorter induction,anesthesia recovery,and PACU discharge times.Additionally,the intra-and postoperative Ramsay Sedation Scale scores were statistically higher in the research group than in the control group.CONCLUSION Remimazolam besylate was significantly more effective than DEX in gastrointestinal surgery in obese patients and had a higher safety profile and value in clinical promotion.

Evaluation of Anti-Wrinkle, Relieving Effect and Safety of A Group of Hexapeptide Compounds

The anti-wrinkle,relieving effect and safety of a group of hexapeptide compounds(HCs)were evaluated by in vitro antioxidant test,hyaluronidase inhibition test and human clinical test.The results showed that HCs possess+high overall antioxidant activity,and the scavenging activity of ABTS•radical and DPPH radical by 4 mg/mL HCs solution were(92.23±1.15)%and(90.24±1.25)%.The scavenging activity of PTIO radical by 80 mg/mL HCs solution was(80.29±2.41)%.The inhibition rate of 80 mg/mL HCs on hyaluronidase was(75.00±6.13)%.The test of clinical results showed that the HCs have good anti-wrinkle and relieving effect,and no case of grade 1 or above skin adverse reactions occurred,indicating that HCs have good safety.

Review on Hydroxyurea Usage in Young Children with Sickle Cell Disease: Examining Hemoglobin Induction, Potential Benefits, Responses, Safety, and Effectiveness

Sickle cell disease (SCD) is a prevalent condition, particularly in the countries of sub-Saharan Africa, where the presence of specific genes associated with Malaria contributes to its high prevalence. Patients with sickle cell disease frequently experience painful episodes necessitating hospitalization, and their hemoglobin levels are typically lower than those of the general population. There are different treatment options available to manage complications, such as transfusing blood, hydroxyurea, and strong anti-pains. However, with all these treatments, patients still commonly experience pain crises and suffer from organ damage. Hydroxyurea, the sole approved medication for sickle cell anemia in developed and developing countries, is widely used in children despite being primarily indicated for adults. Multiple studies have demonstrated the efficacy of hydroxyurea in inducing HbF production in young children with SCD. Elevated HbF levels have been associated with improved clinical outcomes, including a reduction in vaso-occlusive crises, acute chest syndrome, and the need for blood transfusions. Furthermore, increased HbF levels have been shown to ameliorate disease-related organ damage, such as pulmonary hypertension and sickle cell retinopathy. The response to hydroxyurea treatment in young children with SCD is variable. Some patients achieve substantial increases in HbF levels and experience significant clinical benefits, while others may have a more modest response. Factors influencing the response include baseline HbF levels, genetic modifiers, treatment adherence, and dose optimization. Safety is a crucial consideration when using hydroxyurea in young children. Studies have shown that hydroxyurea is generally well-tolerated, with the most common adverse effects being myelosuppression, gastrointestinal symptoms, and dermatological manifestations. However,long-term effects and potential risks, such as renal dysfunction and reproductive impacts, require further investigation. The effectiveness of hydroxyurea in young children with SCD has been demonstrated in various clinical trials and observational studies. These studies have shown a significant reduction in disease-related complications and improved quality of life. However, optimal dosing, treatment duration, and long-term outcomes are still areas of ongoing research. This review focuses on recent studies investigating the benefits, effectiveness, responses, and safety of hydroxyurea in pediatric individuals diagnosed with sickle cell disease.

Demonstration of safety characteristics and effects on gut microbiota of Lactobacillus gasseri HMV18

Human normal flora is a source of probiotics.The safety characteristics of a specific isolate determine its application in foods or drugs.The food-borne-pathogen antagonist strain Lactobacillus gasseri HMV18 is one of the isolates from normal human flora.In this work,we assessed the in vitro pH tolerance,bile tolerance,biogenic amine production,mucin utilization,and safety of in vivo administration to mice to evaluate general health,organ-body weight index,organ histopathological change,whether L.gasseri HMV18 can colonize in the gut or modulate the gut microbiota after oral administration.The results suggest that L.gasseri HMV18 can tolerate pH 3 for 2 h,3%bile for 3 h,biogenic amine negative,mucin usage negative,does not encode verified toxins,and cause no visible change in mice's organs.L.gasseri HMV18 might not colonize in mice's gut,but can significantly affect the structure of gut microbiota.A bibliographical survey suggested that there were as few as 8 opportunistic infection cases from 1984 to 2022 and that the possibility for L.gasseri to cause infection is relatively low.Therefore,this work provides a basis for the foods or drugs application of L.gasseri HMV18 and gives a map of experiments for the safety assessment of probiotics.

Effect of a Nutrition Education Intervention on Food Safety Knowledge, Attitudes and Practices of Mothers of Children under 5 Years in the Peri-Urban Areas of Bobo-Dioulasso: Before and after Study

Background: This study assessed the effect of a nutrition education intervention. This intervention aimed to improve the knowledge, attitudes, and practices of mothers on food safety in the peri-urban areas of Bobo-Dioulasso in Burkina Faso. Methods: A total of 243 mothers of children under 5 years in the peri-urban of Bobo-Dioulasso were administered the FAO questionnaire for food safety knowledge, attitudes, and practices assessment during two cross-sectional surveys, before and after the intervention, in January and October 2017. The intervention included two components consisting of a theoretical phase (counselling and discussion) and cooking demonstrations implemented for ten months. To account for the before-and-after design of the study, the McNemar’s test was used to assess the effect of the intervention on food safety KAP of mothers of children under 5 years. Results: The mean age of mothers was 29 ± 6.2 years and 50.6% of them were between 20 and 29 years old. One for knowledge (cooking thoroughly with, p-value = 0.0001) and another for attitudes (perceived benefits of reheating leftovers before eating them, p-value = 0.0001), significantly increased after the intervention. In terms of food safety practices, all the indicators (cleaning of dirty surfaces, plates and utensils and storage of perishable foods) significantly increased (all p = 0.0001 Conclusion: This study provided some evidence of an effective nutrition education intervention for improving maternal KAP on food safety for their child’s feeding.

Application effect of case management nursing based on patient safety in patients with prostate cancer

BACKGROUND Globally,prostate cancer has become a major threat to men's health,with an increasing incidence and causes serious effects on the quality and length of life of patients.Despite the rapid development of medical technology,which provides treatments,including surgery,radiotherapy,and endocrine therapy,the treatment of patients with prostate cancer,especially with endocrine therapy,has become a major challenge in clinical treatment owing to the lengthy course of treatment,side effects of drugs,and impact of the disease on the psychological and physiological functioning of the patient,producing poor treatment adherence and a decline in quality of life.After the nursing intervention,the anxiety and depression scores of the observation group were significantly lower than those of the control group(P<0.05).The quality of life score,sexual function,and hormone function were significantly higher than those in the control group(P<0.05).CONCLUSION Case management guidance based on patient safety effectively reduced anxiety and depression in patients undergoing endocrine therapy for prostate cancer and improved their quality of life,treatment compliance,and satisfaction.

Evaluation of the Effectiveness and Safety of One-Time Endodontics in the Treatment of Chronic Apical Periodontitis with Sinus Tract in Pediatric Deciduous Teeth

Objective:To observe the effectiveness and safety of one-time endodontics in the treatment of chronic apical periodontitis with sinus tract in pediatric deciduous teeth.Methods:109 cases of children with chronic apical periodontitis with sinus tract in the deciduous teeth treated in our hospital from January 2022 to December 2023 were selected and grouped by the randomized numerical table method,with 54 cases in the experimental group and 55 cases in the control group.The experimental group was treated with one-time endodontics and the control group was treated with conventional endodontics.Results:After the treatment,the total effective rate of treatment was higher in the experimental group than in the control group(P<0.05);the incidence of adverse events was lower in the experimental group than in the control group(P<0.05);the satisfaction of the children's family members was higher in the experimental group than in the control group(P<0.05);the pain duration was lower in the experimental group than in the control group(P<0.05).Conclusion:In the experimental group,children with chronic apical periodontitis with sinus tract of the deciduous teeth were given one-time endodontic treatment,and the results of its implementation were relatively good.

Research on the effect estimation of seismic safety evaluation

Seismic safety evaluation is a basic work for determining the seismic resistance requirements of major construc-tion projects. The effect, especially the economic effect of the seismic safety evaluation has been generally con-cerned. The paper gives a model for estimating the effect of seismic safety evaluation and calculates roughly the economic effect of seismic safety evaluation with some examples.

基于DNV SAFETI Route模型的危险货物道路运输风险模拟

DNV SAFETI Route运输路线模型是专业的运输活动风险评估模型,根据所有可能发生事故的地点分布潜在事故的总频率,计算出沿线的总体风险水平。选择事故场景为大孔泄漏,对发生泄漏情景引发的火灾、爆炸和毒性物质扩散事故后果进行预测。根据后果预测结果,进而可以得到周边防护目标所承受的个人风险和社会风险曲线。

In Vitro and In Vivo Effects and Safety Assessment of Corn Peptides on Alcohol Dehydrogenase Activities

The in vitro and in vivo effects of corn peptides（CPs） prepared from corn gluten meal by proteolysis with an alkaline protease and fractions of CPs from Sephadex G-15 and G-10 columns on activities of alcohol dehydroge-nase（ADH） were studied. The results show that CPs and fraction 3 of CPs from Sephadex G-10 column enhance in vitro ADH activity. Furthermore, the in vitro accelerating effect of the fraction 3 of CPs on ADH activity was superior to that of glutathione, which was also found even in the presence of ADH inhibitor, such as pyrazole. In the in vivo experiments, the animals were fed with different dosages of CPs and with a dose of Chinese distilled spirit orally, and sacrificed for the measurement of ADH activity. In vivo experimental results indicate that CPS enhanced hepatic ADH activities. To test the safety of CPs as health food, 30 d feeding test was performed. No obvious toxic effects were detected in treated Wistar rats.

Food safety regulatory systems in Europe and China:A study of how co-regulation can improve regulatory effectiveness

Food safety has received a great deal of attention in both developed and developing countries in recent years. In China, the numerous food scandals and scares that have struck over the past decade have spurred significant food safety regulatory reform, which has been increasingly oriented towards the public-private partnership model adopted by the Europe Union＇s （EU） food safety regulatory system. This paper analyzes the development of both the EU＇s and China＇s food safety regu- latory systems, identifies the current challenges for China and additionally considers the role of public-private partnership. The success of co-regulation in the food regulatory system would bring significant benefits and opportunities for China. Finally, this paper recommends additional measures like training and grants to improve the private＇s sector effectiveness in co-regulating China＇s food safety issues.

Effectiveness and safety of ultrasound-guided intramuscular lauromacrogol injection combined with hysteroscopy in cervical pregnancy treatment:A case report

BACKGROUND Cervical pregnancy is increasing in morbidity,and a definite diagnosis in early stages is challenging due to its specific onset site.Surgery is the mainstay of treatment for cervical pregnancy,but it may result in the loss of natural fertility.Therefore,it is a great challenge to pursue a safe and effective treatment for cervical pregnancy.CASE SUMMARY We report the case of a cervical pregnancy successfully treated by ultrasoundguided cervical-intramuscular lauromacrogol injection combined with hysteroscopy.A 23-year-old woman with minor irregular vaginal bleeding was admitted to our department with suspected ectopic pregnancy.Transvaginal ultrasound revealed a gestational sac(approximately 22 mm x 13 mm)situated in the cervical canal with a yolk sac and blood flow signals.No cardiac activity was detected.Serum beta progesterone was 17.06 ng/m L,and serum beta human chorionic gonadotropin(β-HCG)was 5077.0 IU/L.The patient was diagnosed with cervical pregnancy.She was treated by ultrasound-guided cervicalintramuscular injections of lauromacrogol(3 m L)in combination with aborting under hysteroscopic visualization.A gradual decrease inβ-HCG levels and normal ultrasound findings were observed.Postoperative pathologic examination showed the presence of villi and changes in the endometrium in the secretory phase.The patient was discharged on day 6,and herβ-HCG level was 0.67 m IU/m L after 1 wk.There was no statistical difference between baseline and 1-week postoperative data in terms of serum indices including liver function,renal function,and routine blood analysis after treatment.The patient subsequently became pregnant 2 mo later and no abnormalities were detected on routine screening during pregnancy.CONCLUSION Ultrasound-guided cervical-intramuscular lauromacrogol injection combined with hysteroscopy may be effective and safe in the treatment of cervical pregnancy.

Research on effectiveness of coal mine safety supervision system reform on three types of collieries in China

Coal mine safety supervision system plays an important role in the coal mine safety management in China.However,the current supervision system is established on the basis of learning the advanced experience from other developed countries.It needs to be further improved according to national conditions.Therefore,the effectiveness of coal mine safety supervision system reform on three types of collieries are assessed by using time series analysis method based on comparative analysis of the supervision system before and after the reform in this paper.The regression results show that the structural reform is not conductive to the improvement of coal mine safety situation in the short term,but conductive significantly in the long term.Specifically,the effects in township coal mines are more significant than stateowned key coal mines in the long run,but negative effects also exist in the short term.The negative effects in state-owned key coal mines are non-significant compared with township coal mines.Moreover,the regression results are analyzed from the aspects of the closure policy of illegal small township coal mines at the end of 1998 and shortage of the new supervision system.Finally,the suggestions on improving the new supervision system are put forward based on the above analysis.

Antiviral treatment for chronic hepatitis B: Safety, effectiveness, and prognosis

The goal of chronic hepatitis B (CHB) therapy is to improve the patient prognosis through the sustained inhibition of viral replication. However, due to the uncertainty and potentially unlimited duration of the treatment course, nucleus(t)ide analogue (NA) resistance and safety, financial costs and patient compliance, different endpoints of antiviral treatment have been proposed in CHB prevention and treatment guidelines. Different treatment endpoints are closely associated with the safety of drug withdrawal and improvements in prognosis. Antiviral treatment suppresses HBV DNA replication, drug withdrawal leads to relapse, and long-term treatment causes drug safety and resistance issues. Although hepatitis B e antigen seroconversion based on HBV DNA inhibition is considered as “a satisfactory endpoint”, drug withdrawal still leads to high relapse rates. Hepatitis B surface antigen (HBsAg) clearance is the “ideal endpoint” in terms of the safety of drug withdrawal and improvements in prognosis. However, the HBsAg clearance rate is low using the conventional single drug treatment and fixed course regimens. Recently, the application of an “optimized antiviral treatment strategy” has improved the HBsAg clearance rate, and make an “ideal endpoint” possible. This article reviews the different antiviral treatment endpoints in terms of the safety of drug withdrawal, improvements in prognosis and relevant advances.

Safety and effectiveness of lurasidone in the treatment of Chinese schizophrenia patients:An interim analysis of post-marketing surveillance

BACKGROUND Schizophrenia is a psychiatric disorder characterized by chronic or recurrent symptoms.Lurasidone was licensed in China in 2019 for the treatment of adult schizophrenia in adults with a maximum dose of 80 mg/d.However,post-market surveillance(PMS)with an adequate sample size is required for further validation of the drug’s safety profile and effectiveness.AIM To conduct PMS in real-world clinical settings and evaluate the safety and effectiveness of lurasidone in the Chinese population.METHODS A prospective,multicenter,open-label,12-wk surveillance was conducted in China's Mainland.All patients with schizophrenia from 10 sites who had begun medication with lurasidone between September 2019 and August 2022 were eligible for enrollment.Safety assessments included adverse events(AEs),adverse drug reactions(ADRs),extrapyramidal symptoms(EPS),akathisia,use of EPS drugs,weight gain,and laboratory values as metabolic parameters and the QTc interval.The effectiveness was assessed using the brief psychiatric rating scale(BPRS)from baseline to the end of treatment.RESULTS A total of 965 patients were enrolled in the full analysis set and 894 in the safety set in this interim analysis.The average daily dose was 61.7±19.08 mg(mean±SD)during the treatment.AEs and ADRs were experienced by 101 patients(11.3%)and 78 patients(8.7%),respectively,which were mostly mild.EPS occurred in 25 individuals with a 2.8%incidence,including akathisia in 20 individuals(2.2%).Moreover,59 patients received drugs for treating EPS during the treatment,with an incidence of 6.6%which dropped to 5.4%at the end of the treatment.The average weight change was 0.20±2.36 kg(P=0.01687)with 0.8%of patients showing a weight gain of≥7%at week 12 compared with that at the baseline.The mean values of metabolic parameters and the QTc interval at baseline and week 12 were within normal ranges.The mean changes in total BPRS scores were-8.9±9.76(n=959),-13.5±12.29(n=959),and-16.8±13.97(n=959)after 2/4,6/8,and 12 wk,respectively(P<0.001 for each visit compared with the baseline)using the last-observation-carried-forward method.CONCLUSION The interim analysis of the PMS of adult patients with schizophrenia demonstrate the safety and effectiveness of lurasidone in the Chinese population.No new safety or efficacy concerns were identified.

Study on Communication Effect of Food Safety Risk in Social Media:the Influence of Response Effort Level on Consumption Willingness Change

By constructing influence model for communication effect of food safety risk in social media environment,the influences of different response manners taken by relevant enterprises on consumers' cognition and purchasing intention are analyzed,and influence mechanisms of response effort level,interaction and content reliability on consumers' attitudes are revealed. Based on quasi-experimental study with three kinds of response effort levels,it is found that content reliability,interaction and effort degree of enterprise response under negative information of food safety event have significant impacts on communication effect and consumers' purchasing intention.

Effectiveness and safety of over-the-scope clip in closing perforations after duodenal surgery

BACKGROUND Endoscopic resection of duodenal subepithelial lesions(SELs)is a difficult procedure with a high risk of perforation.At present,dealing with perforation after endoscopic resection of duodenal SELs is still considered a great challenge.AIM To evaluate the effectiveness and safety of an over-the-scope clip(OTSC)in the treatment of perforation post-endoscopic resection of duodenal SELs.METHODS From May 2015 to November 2019,18 patients with perforation following endoscopic resection of duodenal SELs were treated with OTSCs.Data comprising the rate of complete resection,closure of intraprocedural perforation,delayed bleeding,delayed perforation,and postoperative infection were extracted.RESULTS The rate of complete removal of duodenal SELs and successful closure of the perforation was 100%.The median perforation size was 1 cm in diameter.Seventeen patients had minor intraoperative bleeding,while the remaining 1 patient had considerable amount of bleeding during the procedure.Seven patients had postoperative abdominal infections,of which 1 patient developed an abscess in the right iliac fossa and another patient developed septic shock.All 18 patients recovered and were discharged.No delayed bleeding or perforation was reported.The mean time taken to resume normal diet after the procedure was 6.5 d.The mean postoperative hospital stay was 9.5 d.No residual or recurrent lesions were detected during the follow-up period(15-66 mo).CONCLUSION Closing a perforation after endoscopic resection of duodenal SELs with OTSCs seems to be an effective and reasonably safe therapeutic method.