Liver replacement therapy with extracorporeal blood purification techniques current knowledge and future directions

Clinically,it is highly challenging to promote recovery in patients with acute liver failure(ALF)and acute-on-chronic liver failure(ACLF).Despite recent advances in understanding the underlying mechanisms of ALF and ACLF,standard medical therapy remains the primary therapeutic approach.Liver transplantation(LT)is considered the last option,and in several cases,it is the only intervention that can be lifesaving.Unfortunately,this intervention is limited by organ donation shortage or exclusion criteria such that not all patients in need can receive a transplant.Another option is to restore impaired liver function with artificial extracorporeal blood purification systems.The first such systems were developed at the end of the 20th century,providing solutions as bridging therapy,either for liver recovery or LT.They enhance the elimination of metabolites and substances that accumulate due to compromised liver function.In addition,they aid in clearance of molecules released during acute liver decompensation,which can initiate an excessive inflammatory response in these patients causing hepatic encephalopathy,multiple-organ failure,and other complications of liver failure.As compared to renal replacement therapies,we have been unsuccessful in using artificial extracorporeal blood purification systems to completely replace liver function despite the outstanding technological evolution of these systems.Extracting middle to high-molecular-weight and hydrophobic/protein-bound molecules remains extremely challenging.The majority of the currently available systems include a combination of methods that cleanse different ranges and types of molecules and toxins.Furthermore,conventional methods such as plasma exchange are being re-evaluated,and novel adsorption filters are increasingly being used for liver indications.These strategies are very promising for the treatment of liver failure.Nevertheless,the best method,system,or device has not been developed yet,and its probability of getting developed in the near future is also low.Furthermore,little is known about the effects of liver support systems on the overall and transplant-free survival of these patients,and further investigation using randomized controlled trials and meta-analyses is needed.This review presents the most popular extracorporeal blood purification techniques for liver replacement therapy.It focuses on general principles of their function,and on evidence regarding their effectiveness in detoxification and in supporting patients with ALF and ACLF.In addition,we have outlined the basic advantages and disadvantages of each system.

Research on Nursing Effect of Individualized Nursing Intervention on Critically Ill Patients with Continuous Blood Purification

Objective:This paper aims to investigate the value of individualized care for critically ill patients receiving continuous blood purification therapy.Methods:89 cases of critically ill patients who were treated from June 2021 to June 2023 were randomly divided into groups,with individualized care in group A and routine care in group B.The differences in clinical indicators,purification effect,quality of life,and complications of blood purification were compared between the groups.Results:Heart rate,respiration,body temperature,and other indicators in group A were better than those in group B,P<0.05.C-reactive protein(CRP),β2-microglobulin(β2-MG),blood urea nitrogen(BUN),and phosphorus(P)in group A were lower than those in group B,P<0.05.Group A had higher quality of life than Group B,P<0.05.The complication rate of blood purification in Group A was lower than that in Group B,P<0.05.Conclusion:During continuous blood purification in critically ill patients,individualized nursing intervention can enhance the effect of blood purification,improve the physiological indicators of patients,and reduce the complications of blood purification,which is highly effective and feasible.

Immobilized-metal affinity chromatography adsorbent with paramagnetism and its application in purification of the proteins in the natural products

Aim To investigate a new method for synthesis of an Immobilized-Metal Affinity Chromatography(IMAC) adsorbent with superparamagnetism(Fe3O4/SiO2-GPTMS-Asp-Co).Method The magnetic microspheres were synthesized in situ modification and the transmission electron microscope,field emission scanning electron microscopy,X-ray diffractometer,energy spectrometer and vibrating sample magnetometer were used to characterize the appearance,particle size distribution,phase composition,chemical constituents and magnetic properties of silica magnetic microspheres(MMS).Results The silica MMS prepared by reverse microemulsions exhibit a superior core-shell structure.The size distribution of the microspheres varies from between 100 nm to 200 nm and the main phase of microspheres is amorphous SiO2 and spinel Fe3O4.The microspheres retain superparamagnetism and can be used as biomaterials.Conclusion The result indicates that the IMAC adsorbent we prepared has outstanding advantages in the separation of the natural products proteins from the crude bacterial lysate,such as simple operation,high selectivity and capacity.

Advancement in separation materials for blood purification therapy

Blood purification refers to the extra corporeal therapies of removing potentially toxic substances, in which blood is circulated through an adsorption system loading separation materials. High-efficient inexpensive separation materials are critical to success. In this review, separation materials such as polymers and nanomaterials are summarized and compared. Combining the advantages of the adsorptive membranes and nanomaterials, organic–inorganic hybrid/blend membranes have been developed explosively. These hybrid/blend membranes have both the characteristics of high permeability, easy fabrication, good biocompatibility of adsorptive membranes, and characteristics of fast adsorption rate and high adsorption capacity of nanomaterials. The preparation and modification methodology of the separation materials is reviewed. For affinity separation materials, the relationship of ligand chemistry, ligand density and pores of the matrix is discussed. This paper also summarizes some interesting applications in separation materials for removal of bilirubin, endotoxin, toxic metal ions, cytokine, etc.

Application of bedside continuous blood purification in patients with multiple organ dysfunction syndromes

BACKGROUND:The complications of systemic inflammatory response syndrome(SIRS)include acute lung injury,acute kidney injury,shock,and multiple organ dysfunction syndrome(MODS).In recent years,how to clear inflammatory mediators has become a hot topic in critical care medicine.Researchers hypothesize that continuous blood purification(CBP) can effectively eliminate a variety of inflammatory mediators which participate in the occurrence of MODS and adjust the immune imbalance.This study aimed to observe the effects of CBP in MODS patients.METHODS:In this retrospective clinical study,a total of 38 MODS patients,18 males and 20 females,were enrolled.After conventional therapy,all the patients received CBP.Biochemistry,blood gas analysis,oxygenation index,mean arterial blood pressure(MAP),acute physiology and chronic health evaluation(APACHE) II scores were monitored.RESULTS:After CBP,the vital signs of patients were rapidly stable,and electrolyte disorders and acid-base imbalance were corrected.Renal function,blood gas,oxygenation index were all improved.MAP was increased,and APACHE II score was significantly decreased.All patients had good tolerance,stable hemodynamics,and no obvious adverse reaction on CBP compared with pre-CBP.CONCLUSION:CBP can effectively clean toxins,correct electrolyte acid-base balance,and improve systemic inflammatory response syndrome and the organ function of MODS patients.

Production, Purification and Characterization of Inulinase from a Newly Isolated <i>Streptomyces</i>sp. CP01

Inulinase is an enzyme catalyzing the hydrolysis of inulin, a plant reserve polysaccharide, into fructoses and fructooligosaccharides which are widely used as food additives. Here we report inulinase from a newly isolated Streptomyces as in the past decade there have been very few reports on inulinases from Streptomyces, especially purification and characterization of these enzymes. Out of 371 Streptomyces isolates, Streptomyces sp. CP01 produced highest inulinase activity of 0.50 U/ml. The enzyme activity was increased to 1.60 U/ml when CP01 was cultivated under the optimal conditions which consisted of using basal medium (Czapek’s Dox) containing 1% (w/v) inulin extract from Jerusalem artichoke’s root tubers and 0.7% (w/v) tryptone at pH8, shaking at 200 rpm and 28℃ for 24 h. The enzyme was purified from culture filtrate to about 67-fold purity by (NH4)2SO4 precipitation followed by four consecutive column chromatography steps. The purified enzyme is a single peptide with approximate molecular mass of 73 kDa as analyzed by gel filtration and 70.8 kDa as assessed by SDS-PAGE. The enzyme is optimally active at 55℃ and pH 6.0, however it still possesses more than 80% of the maximal activity at pH ranging from 5.5 to 9.0. It is stable at temperature up to 50℃ and at broad range of pH from 5.0 to 9.0 for 30 min. Its Km and Vmax values for inulin were 2.34 mM and 440 μmolmin–1mg–1, respectively. This enzyme has potential for industrial application as it is active at moderately high temperature and wide range of pH.

Associations of soybean products intake with blood pressure changes and hypertension incidence: the China-PAR project

Background The relationships between dietary intake of soybean products and incident hypertension were still uncertain.This study aimed to illustrate the associations between intake of soybean products with risks of incident hypertension and longitudinal changes of blood pressure in a prospective cohort study.Methods We included 67,499 general Chinese adults from the Project of Prediction for Atherosclerosis Cardiovascular Disease Risk in China(China-PAR).Information about soybean products consumption was collected by standardized questionnaires,and study participants were categorized into the ideal(≥125 g/day)or non-ideal(<125 g/day)group.Hazard ratios(HRs)and corresponding 95%confidence intervals(95%CIs)for incident hypertension were calculated using Cox proportional hazard models.Among participants with repeated measures of blood pressure,generalized linear models were used to examine the relationships between soybean products consumption and blood pressure changes.Results During a median follow-up of 7.4 years,compared with participants who consumed<125 g of soybean products per day,multivariable adjusted HR for those in the ideal group was 0.73(0.67-0.80).This inverse association remained robust across most subgroups while significant interactions were tested between soybean products intake and age,sex,urbanization and geographic region(P values for interaction<0.05).The mean systolic and diastolic blood pressure levels were 1.05(0.71-1.39)mmHg and 0.44(0.22-0.66)mmHg lower among participants in the ideal group than those in the non-ideal group.Conclusions Our study showed that intake of soybean products might reduce the long-term blood pressure levels and hypertension incidence among Chinese population,which has important public health implications for primary prevention of hypertension.

MOF-Like 3D Graphene-Based Catalytic Membrane Fabricated by One-Step Laser Scribing for Robust Water Purification and Green Energy Production

Increasing both clean water and green energy demands for survival and development are the grand challenges of our age.Here,we successfully fabricate a novel multifunctional 3D graphene-based catalytic membrane(3D-GCM)with active metal nanoparticles(AMNs)loading for simultaneously obtaining the water purification and clean energy generation,via a“green”one-step laser scribing technology.The as-prepared 3D-GCM shows high porosity and uniform distribution with AMNs,which exhibits high permeated fluxes(over 100 L m^(−2) h^(−1))and versatile super-adsorption capacities for the removal of tricky organic pollutants from wastewater under ultra-low pressure-driving(0.1 bar).After adsorption saturating,the AMNs in 3D-GCM actuates the advanced oxidization process to self-clean the fouled membrane via the catalysis,and restores the adsorption capacity well for the next time membrane separation.Most importantly,the 3D-GCM with the welding of laser scribing overcomes the lateral shear force damaging during the long-term separation.Moreover,the 3D-GCM could emit plentiful of hot electrons from AMNs under light irradiation,realizing the membrane catalytic hydrolysis reactions for hydrogen energy generation.This“green”precision manufacturing with laser scribing technology provides a feasible technology to fabricate high-efficient and robust 3D-GCM microreactor in the tricky wastewater purification and sustainable clean energy production as well.

Treatment of hyperbilirubinemia with blood purification in China

The incidence of hyperbilirubinemia is high clinically, which is difficult to cure by medication, surgery or interventional therapies. Non-bioartificial liver is the main alternative in the blood purification for hyperbilirubinemia, which includes plasma exchange, hemoperfusion, hemodialysis, molecular adsorbent recycling system and so on. The research results and clinical experiences in China show that these methods are effective in lowering high levels of bilirubin with fewer side effects. The hyperbilirubinemias of different causes, with different complications or accompanying different diseases can be treated by different methods. Bioartificial liver, hybrid artificial liver support system and adsorbent membrane material have also been studied and their development in reducing hyperbilirubinemias has been achieved. This article gives a brief overview on the actuality and research improvement in blood purification for hyperbilirubinemia in China.

Effects of Antimicrobial Peptides on Production,Slaughter Performance and Blood Routine of Tan Sheep

[Objectives]This study was conducted to analyze effects of antimicrobial peptides added to the diet of Tan sheep on their production, slaughter performance and blood composition. [Methods] Ninety two four-month-old Tan sheep were randomly divided into two treatment groups according to their body weight, 46 in each group. The control check group(CK) was feed with conventional diet, and the experimental group was fed with the addition of antimicrobial peptide on the basis of the conventional diet, with the added amount of 2.5 g/sheep per day. The experimental period was 60 d. [Results] The incidence rate was 75.06% lower in the experimental group than in the CK. The average daily weight gain per sheep was 11.27% higher in the experimental group than in the CK(P<0.05). The feed conversion ratio was 8.45% lower in the experimental group than in the CK(P<0.05). The average daily gross profit per sheep was 12.12% higher in the experimental group than in the CK. For slaughter performance, the data difference of each item was not significant. The PH at 45 min and 24 h after slaughter was within the normal range of fresh mutton. The cooked meat percentage and water loss rate showed no significant differences(P>0.05). The marbling ranged from 2.45 to 2.50, indicating that the fat content was moderate, and the difference between groups was not significant(P>0.05). The flesh color ranged from 3.00 to 3.15, between light red and bright red, belonging to the normal color of mutton, and the difference between groups was not significant(P>0.05). The shear force was between 2.50 and 2.65, without a significant difference between groups(P>0.05). The white blood cells, lymphocytes and platelets in the experimental group were lower than those in the CK(P<0.01). The erythrocytes and hemoglobin in the erythrocyte group were higher than those in the CK(P<0.05). The neutrophils and monocytes in the experimental group were lower than those in the CK(P<0.05). [Conclusions] This study provides a technical basis for the rational use of antimicrobial peptides and their application in ruminants.

Isolation and Purification of Anthocyanins from Blood Oranges by Column Chromatography

In this study, isolation and purification of anthocyanins from blood oranges by column chromatography were investigated, and then the anthocyanins of blood orange were identified. The behaviors of static adsorption and desorption, dynamic adsorption and desorption of 12 kinds of resins were compared. The results indicated that NKA-9 macroporous resin was optimum for isolation of blood orange anthocyanins, and the optimal elution reagent was 50% ethanol with citric acid (pH 2.5). Toyopearl TSK HW-40S column was employed to separate and purify the anthocyanin extracts from blood orange. The best separation of Toyopearl TSK HW-40S column was obtained using a mobile phase of 35% methanol with 2% formic acid at a flow-rate of 0.6 mL min-1. Three kinds of anthocyanins were purified from blood orange. Then, the anthocyanins of blood orange were identified by HPLC-ESI/MS analysis. The results showed that cyanidin-3-glucoside (35.2%) and cyaniding-3-(6′′-malonyl) glucoside (42.9%) were the major anthocyanins of blood orange. Furthermore, cyanidin-3-(3′′-malonyl) glucoside, cyanidin 3-(6′′-dioxalyl) glucoside and cyanidin-3-glucoside adduct:4-vinylcatechol were identified in blood orange. The combination of NKA-9 macroporous resin and Toyopearl TSK HW-40S column chromatography for isolation and purification of blood orange anthocyanins was an effective method, and HPLC-ESI/MS analysis was a convenient, rapid and effective method for identification of anthocyanins from blood orange.

Sequential blood purification therapy for critical patients with hyperlipidemic severe acute pancreatitis

AIM: To evaluate the efficacy of sequential blood purification therapy in the treatment of critical patients with hyperlipidemic severe acute pancreatitis.METHODS: Thirty-one intensive care unit(ICU) patients with hyperlipidemic severe acute pancreatitis treated at the Second Affiliated Hospital of Harbin Medical University were divided into either a study group(n = 15; July 1, 2012 to June 30, 2014) or a control group(n = 16; July 1, 2010 to June 30, 2012) based on the implementation of sequential blood purification therapy. The control group received continuous venous-venous hemofiltration(CVVH) on the basis of conventional treatments, and the therapeutic dose of CVVH was 30 m L/kg per hour. The study group received sequential plasma exchange and CVVH on the basis of conventional treatments. The anticoagulation regimen of CVVH is the regional citrate anticoagulation. Mortality rate on day 28, rates of systemic and local complications, duration of ICU, and time to target serum lipid level, as well as physiologic and laboratory indices were compared between the two groups.RESULTS: The mortality rate on day 28 was significantly lower in the study group than in the control group(13.33% vs 37.50%; P < 0.05). The duration of ICU stay was significantly shorter in the study group than in the control group(7.4 ± 1.35 d vs 9.19 ± 2.99 d, P < 0.05). The time to target serum lipid level was significantly shorter in the study group than in the control group(3.47 ± 0.52 d vs 7.90 ± 1.14 d, P < 0.01). There were no significant differences in the rates of systemic complications and local complications between the two groups(60% vs 50% and 80% vs 81%, respectively). In the comparisons of physiologic and laboratory indices, serum albumin and C-reactive protein were significantly better in the study group than in the control group after treatment(37.8 ± 4.6 g/L vs 38.9 ± 5.7 g/L, and 20.5 ± 6.4 mg/L vs 28.5 ± 7.1 mg/L, respectively, both P < 0.05). With the exception of plateletcrit, no other indices showed significant differences between the two groups.CONCLUSION: Sequential blood purification therapy is effective in the treatment of ICU patients with hyperlipidemic severe acute pancreatitis and can improve patient prognosis.

Management strategy of prevention and control of nosocomial infection of COVID-19 in blood purification center

There are many patients in the blood purification center who need maintenance hemodialysis to maintain life. Those patients generally havelow resistance and are easily exposed to coronavirus because they go back and forth the hospital and residence three times a week andclosely contact with family, caregivers, community personnel, people in various means of transportation, medical staff, and other patientsvisiting hospital. Therefore, the blood purification center has become a high‑risk environment for the spread of COVID-19 infection. In viewof this, our center quickly responded to the formulation and implementation of infection prevention and control measures suitable for thecharacteristics of the blood purification center and continuous renal replacement therapy (CRRT) emergency plan for fever and suspectedpatients. According to these measures, we have a positive effect on preventing and controlling nosocomial infection in the blood purificationcenter.

Prokaryotic Expression,Purification,Antibody Production of a NH_2-Terminal Fragment of mCLCA3 Protein and Analysis of mClCA3 Protein Expression in Asthmatic Mouse Lung

mCLCA3 is a member of calcium activated chloride channel(CACC)family that may play an important role in mucin packaging and secretion in asthmatic and cystic fibrosis lung.To study the protein structure and expression of mCLCA3 in asthmatic mouse lung,an N-terminal 269 amino acid peptide of mCLCA3 was expressed in E.coli,purified to homogeneity and rabbit polyclonal antibodies against this peptide were generated.Immunohistochemistry of asthmatic mouse lung using the antibody indicated exclusive mCLCA3 expression in mucin granules of goblet cells in airway surface and lumen.Immunoblot analysis of lavage fluid from asthmatic mouse lung revealed a single 90 kDa protein form of mClCA3.The results demonstrate that the 90 kDa N-terminal peptide,neither the full-length protein nor the reported N-terminal 35 kDa cleaved form of mClCA3 is the major functional form involved in the packaging and exocytosis of mucin granules in asthmatic goblet cells.

A simple method for purification of genomic DNA from whole blood using Fe_3O_4/Au composite particles as a carrier

Objective:To establish a method of genomic DNA extraction from whole blood using Fe3O4/Au composite particles as a carrier. Methods: Two crucial conditions (sodium chloride concentration and amount of the magnetic particles) were optimized and 8 different human whole blood samples were used to purify genomic DNA under the optimal condition. Then agarose gel electrophoresis and polymerase chain reaction (PCR) were performed. Results: The optimal binding condition was 1.5 mol/L NaCl/10% PEG, and the optimal amount of Fe3O4/Au composite particles was 600 μg. The yields of the genomic DNA from 100 μl of different whole blood samples were 2-5 μg, and the ratio of A260/A280 was in the range of 1.70-1.90. The size of genomic DNA was about 23 kb and the PCR was valid. Conclusion: The purification system using Fe3O4/Au composite microparticles has advantages in high yield, high purity, ease of operating, time saving and avoiding centrifugation. The purified sample was found to function satisfactorily in PCR amplification.

Shock index of patients with sepsis after continuous blood purification treatment and its relationship with systemic inflammatory response syndrome and immune response

Objective:To study the shock index of patients with sepsis after continuous blood purification (CBP) treatment and its relationship with systemic inflammatory response syndrome and immune response.Methods:A total of 88 patients with sepsis who underwent continuous blood purification treatment in our hospital between June 2012 and May 2016 were chosen as research subjects, shock index (SI) was compared before and after the treatment, and according to the level of SI after treatment, all patients were divided into shock group (n=27) with SI>0.5 points and no shock group (n=61) with SI≤0.5 points. Serum contents of inflammatory mediators, Th1/Th2 cellular immunity indexes, immunoglobulin and complement were compared between two groups of patients after treatment.Results: The level of SI in patients with sepsis was significantly lower than that before treatment. Serum contents of inflammatory mediators PCT, CRP and HMGB1 in no shock group were lower than those in shock group, contents of Th1 cytokines IL-2 and IFN-γ were higher than those in shock group, contents of Th2 cytokines IL-10 and IL-13 were lower than those in shock group, and contents of IgG, IgM, IgA, C3 and C4 were higher than those in shock group.Conclusion: The level of SI decreases in the patients with sepsis after CBP treatment, and SI level is directly correlated with the systemic inflammatory response syndrome and immune response levels.

Research Progress of Continuous Blood Purification in the Treatment of Severe Sepsis in Children

Pediatric sepsis is the most common disease in pediatric critical illness,because the main reason for the disease is that children's immune level is not high or the immune system is not perfect,when children's lung,abdominal cavity and blood system are infected,it will cause systemic inflammation and immune dysfunction.Early clinical symptoms are mainly irregular and intermittent fever.When the disease develops to severe sepsis,the children will suffer from acute heart failure,oliguria,respiratory alkalosis and even multiple organ failure.The incidence of death is high.It is reported that the incidence rate of sepsis in children can reach 0.3%,and the mortality rate is 50%.High incidence rate,high mortality rate and high treatment cost are the biggest problems in the pediatric field.In the past,the clinical hope of clearing away heat and toxin,promoting blood circulation and removing stasis,strengthening inflammation and other methods in traditional Chinese medicine,but the treatment effect is not ideal.With the improvement of modem medical understanding of sepsis,continuous blood purification therapy is introduced into the treatment of children with severe sepsis.In order to further explore the effect of continuous blood purification in the treatment of children with severe sepsis,the author summarizes the clinical practice experience and relevant literature,hoping to provide reference for relevant medical staff。

Determination of Melamine in Animal Blood Products by High Performance Liquid Chromatography

[Objective] To investigate the optimal determination conditions of melamine in animal blood products by high performance liquid chromatography(HPLC).[Method] The blood samples were extracted with ultrasonic in 1% trichloroacetic acid(TDA) and acetonitrile.After purifying by solide phase extraction(SPE),the samples were analyzed by HPLC.[Result] The optimal conditions of HPLC were as follows:the chromatographic column was Zorbax SB-C8;the mobile phase was ion-pairs buffer-acetonitrile(95/5,V/V);the flow rate was 1.0 ml/min;the column temperature was 25 °C and the UV detection wavelength was 235 nm.The determined melamine concentration range was 0.001-0.050 mg/ml;the linear correlation coefficient was 0.999 4;the concentration limit of melamine was 0.1 mg/kg;the average recovery rate of the melamine were 97.60%-100.65%,and the relative standard deviation(RSD) was 1.23%-3.04%.[Conclusion] The HPLC is simple,accurate and repeatable for determination of the melamine in animal blood products.

Bacterial Contamination of Blood and Blood Products at Mbarara Regional Blood Bank in Rural South Western Uganda

Background: Screening blood donors has practically eliminated viral and bacterial pathogens in blood used for transfusion. However, transfusion-associated bacterial sepsis remains an important health-care concern and the commonest cause of transfusion-related fatality in resource limited settings. Data on bacterial contamination of blood are scarce while the demand of blood transfusion is continuously growing. Therefore we conducted a study to determine the prevalence and type of bacterial contamination in donor blood and blood products, at the Mbarara Regional Blood Bank. Methodology: A total of 510 units of screened blood and blood products consisting of refrigerated whole blood and packed cells were randomly sampled following aseptic procedures from Mbarara Regional Blood Bank. Two samples from each unit were collected in universal containers containing Brain Heart Infusion Broth and incubated at 37℃ for up to 7 days. Subcultures were carried out on Blood agar, Chocolate agar and MacConkey agar. Isolates were identified by standard microbiologic techniques and drug susceptibility testing was performed by Kirby Bauer disc diffusion method. Results: Of the 510 samples collected between June and October 2012, 18 (3.5%) samples showed growth. The contaminants were Staphylococcus aureus 17/18 (94.4%) and Streptococcus viridans 1/18 (5.6%). Isolates were sensitive to erythomycin, ampicillin, chloramphenicol and ciprofloxacin and resistant to penicillin and cloxacillin. Conclusion: Blood and blood products from Mbarara Regional Blood have unacceptable levels of bacterial contamination that can affect patient safety especially in an area with high malaria endemicity. Therefore it is critical to improve hygiene precautions in order to minimize bacterial contamination and ensure patient safety.