Objective To analysis the relationship between the lactate-to-albumin ratio(LAR)and the 28-day prognosis in patients with sepsis.Methods Based on the Medical Information Mart for Intensive Care-Ⅳ(MIMIC-Ⅳ)database,patients with sepsis aged≥18 years were selected.Patients were divided into survival and death groups according to their 28-day prognosis.The LAR was divided into quartiles:Q1(LAR<0.45),Q2(0.45≤LAR<0.70),Q3(0.70≤LAR<1.18),and Q4(LAR≥1.18);and into two groups based on the median LAR:low LAR group(LAR≤0.70)and high LAR group(LAR>0.70).Demographic characteristics,comorbidities,laboratory indicators,clinical treatments,and disease severity scores of patients were extracted.LAR was included as a continuous variable and a four-category variable in multiple Logistic regression models,with trend tests performed.Subgroup analyses were conducted based on gender,age,comorbidities,and sequential organ failure assessment(SOFA)score.Receiver operator characteristic curve(ROC curves)were plotted to analyze the predictive efficacy of lactate,albumin(Alb),LAR and SOFA score for the prognosis of sepsis patients.Kaplan-Meier survival curves were plotted to compare the difference of 28-day cumulative survival rates of sepsis patients in the high and low LAR groups.Results A total of 9 169 patients with sepsis were included,with 6 799 in the survival group and 2 370 in the death group.Compared with the survival group,the death group had older age[years:70.80(58.64,82.25)vs.65.07(53.56,76.92)],higher levels of potassium,creatinine,blood urea nitrogen(BUN),white blood cell count(WBC),lactate,LAR,SOFA score,simplified acute physiology scoreⅡ(SAPSⅡ),and higher proportions of chronic obstructive pulmonary disease(COPD),heart failure,use of vasopressors within 48 hours,and continuous renal replacement therapy(CRRT)[potassium(mmol/L):5.0(4.5,5.7)vs.4.8(4.4,5.4),creatinine(μmol/L):132.60(88.40,212.16)vs.97.24(70.72,159.12),BUN(mmol/L):11.42(7.14,18.56)vs.7.85(5.25,13.57),WBC(×109/L):13.1(8.7,19.1)vs.11.4(7.6,16.4),lactate(mmol/L):2.9(1.8,5.1)vs.2.0(1.4,3.1),LAR:1.03(0.63,1.88)vs.0.62(0.42,0.98),SOFA score:9(6,12)vs.6(4,8),SAPSⅡscore:52(42,64)vs.38(30,47),COPD:8.19%(194/2 370)vs.6.57%(447/6 799),heart failure:29.96%(710/2 370)vs.26.31%(1 789/6 799),use of vasopressors within 48 hours:62.19%(1 474/2 370)vs.37.56%(2 554/6 799),CRRT:19.45%(461/2 370)vs.9.56%(650/6 799),all P<0.05],while lower levels of body weight,chloride,calcium,hemoglobin(Hb),platelet count(PLT),Alb and lower proportions of hypertension were observed in the death group[body weight(kg):75.8(63.6,92.3)vs.78.7(66.5,95.0),chloride(mmol/L):104(98,109)vs.104(100,108),calcium(mmol/L):1.07(1.00,1.15)vs.1.09(1.03,1.15),Hb(g/L):103(87,120)vs.105(90,121),PLT(×109/L):173(104,246)vs.174(118,243),Alb(g/L):29(24,34)vs.33(28,37),hypertension:35.36%(838/2 370)vs.38.34%(2 607/6 799),all P<0.05].In the Logistic regression model adjusted for all confounding factors,the odds ratio(OR)and 95%confidence interval(95%CI)of LAR were 1.74(1.64-1.85),P<0.001;when LAR was treated as a four-category variable,the OR values of Q2,Q3,and Q4 increased progressively compared with Q1,being 1.49(1.22-1.82),2.27(1.88-2.75),and 5.05(4.20-6.08),respectively,P<0.001.Subgroup analyses showed that LAR was an independent risk factor for the 28-day prognosis of sepsis in different subgroups based on gender,age,comorbidities,and SOFA score(all P<0.001),with no interaction effects with the subgroup variables(all P>0.05).ROC curve analysis showed that the AUC of LAR predicted the 28-day prognosis of patients with sepsis was 0.688(0.675-0.700),higher than that of lactate[0.655(0.642-0.668)]and Alb[0.636(0.623-0.649)],both P<0.001,and not significantly lower than that of SOFA score[0.699(0.687-0.712),P=0.108].Kaplan-Meier survival analysis showed that the 28-day cumulative survival rate was significantly higher in the low LAR group than in the high LAR group(Log-Rank test:χ2=533.24,P<0.001).Conclusion LAR is an independent risk factor for the 28-day prognosis of sepsis patients.Higher LAR is associated with adverse outcomes,and its predictive efficacy is superior to that of lactate and albumin.

Objective To analysis the relationship between the lactate-to-albumin ratio(LAR)and the 28-day prognosis in patients with sepsis.Methods Based on the Medical Information Mart for Intensive Care-Ⅳ(MIMIC-Ⅳ)database,patients with sepsis aged≥18 years were selected.Patients were divided into survival and death groups according to their 28-day prognosis.The LAR was divided into quartiles:Q1(LAR<0.45),Q2(0.45≤LAR<0.70),Q3(0.70≤LAR<1.18),and Q4(LAR≥1.18);and into two groups based on the median LAR:low LAR group(LAR≤0.70)and high LAR group(LAR>0.70).Demographic characteristics,comorbidities,laboratory indicators,clinical treatments,and disease severity scores of patients were extracted.LAR was included as a continuous variable and a four-category variable in multiple Logistic regression models,with trend tests performed.Subgroup analyses were conducted based on gender,age,comorbidities,and sequential organ failure assessment(SOFA)score.Receiver operator characteristic curve(ROC curves)were plotted to analyze the predictive efficacy of lactate,albumin(Alb),LAR and SOFA score for the prognosis of sepsis patients.Kaplan-Meier survival curves were plotted to compare the difference of 28-day cumulative survival rates of sepsis patients in the high and low LAR groups.Results A total of 9 169 patients with sepsis were included,with 6 799 in the survival group and 2 370 in the death group.Compared with the survival group,the death group had older age[years:70.80(58.64,82.25)vs.65.07(53.56,76.92)],higher levels of potassium,creatinine,blood urea nitrogen(BUN),white blood cell count(WBC),lactate,LAR,SOFA score,simplified acute physiology scoreⅡ(SAPSⅡ),and higher proportions of chronic obstructive pulmonary disease(COPD),heart failure,use of vasopressors within 48 hours,and continuous renal replacement therapy(CRRT)[potassium(mmol/L):5.0(4.5,5.7)vs.4.8(4.4,5.4),creatinine(μmol/L):132.60(88.40,212.16)vs.97.24(70.72,159.12),BUN(mmol/L):11.42(7.14,18.56)vs.7.85(5.25,13.57),WBC(×109/L):13.1(8.7,19.1)vs.11.4(7.6,16.4),lactate(mmol/L):2.9(1.8,5.1)vs.2.0(1.4,3.1),LAR:1.03(0.63,1.88)vs.0.62(0.42,0.98),SOFA score:9(6,12)vs.6(4,8),SAPSⅡscore:52(42,64)vs.38(30,47),COPD:8.19%(194/2 370)vs.6.57%(447/6 799),heart failure:29.96%(710/2 370)vs.26.31%(1 789/6 799),use of vasopressors within 48 hours:62.19%(1 474/2 370)vs.37.56%(2 554/6 799),CRRT:19.45%(461/2 370)vs.9.56%(650/6 799),all P<0.05],while lower levels of body weight,chloride,calcium,hemoglobin(Hb),platelet count(PLT),Alb and lower proportions of hypertension were observed in the death group[body weight(kg):75.8(63.6,92.3)vs.78.7(66.5,95.0),chloride(mmol/L):104(98,109)vs.104(100,108),calcium(mmol/L):1.07(1.00,1.15)vs.1.09(1.03,1.15),Hb(g/L):103(87,120)vs.105(90,121),PLT(×109/L):173(104,246)vs.174(118,243),Alb(g/L):29(24,34)vs.33(28,37),hypertension:35.36%(838/2 370)vs.38.34%(2 607/6 799),all P<0.05].In the Logistic regression model adjusted for all confounding factors,the odds ratio(OR)and 95%confidence interval(95%CI)of LAR were 1.74(1.64-1.85),P<0.001;when LAR was treated as a four-category variable,the OR values of Q2,Q3,and Q4 increased progressively compared with Q1,being 1.49(1.22-1.82),2.27(1.88-2.75),and 5.05(4.20-6.08),respectively,P<0.001.Subgroup analyses showed that LAR was an independent risk factor for the 28-day prognosis of sepsis in different subgroups based on gender,age,comorbidities,and SOFA score(all P<0.001),with no interaction effects with the subgroup variables(all P>0.05).ROC curve analysis showed that the AUC of LAR predicted the 28-day prognosis of patients with sepsis was 0.688(0.675-0.700),higher than that of lactate[0.655(0.642-0.668)]and Alb[0.636(0.623-0.649)],both P<0.001,and not significantly lower than that of SOFA score[0.699(0.687-0.712),P=0.108].Kaplan-Meier survival analysis showed that the 28-day cumulative survival rate was significantly higher in the low LAR group than in the high LAR group(Log-Rank test:χ2=533.24,P<0.001).Conclusion LAR is an independent risk factor for the 28-day prognosis of sepsis patients.Higher LAR is associated with adverse outcomes,and its predictive efficacy is superior to that of lactate and albumin.

The study aimed to evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for 28-day mortality in patients treated with extracorporeal membrane oxygenation (ECMO). Patients receiving ECMO treatment were selected from the Department of Intensive Care Medicine of Zhejiang Hospital from January 2019 to February 2022. The moment when patients started receiving ECMO treatment was set as the starting point, and death at 28 days was set as the endpoint. The patients were divided into survivors and deaths. Laboratory tests, such as neutrophil, lymphocyte, and platelet counts, using the peripheral blood of all patients were collected within 24 h after ECMO treatment. NLR and PLR were calculated. The risk factors influencing prognosis were analyzed by logistic regression. The correlation between NLR, PLR, acute physiology, and chronic health score Ⅱ (APACHE Ⅱ) was investigated. Receiver operating characteristic (ROC) curve analysis was used to analyze the value of NLR and PLR in predicting the 28-day mortality of patients treated with ECMO. Kaplan-Meier method was used to analyze the cumulative survival of patients at 28 days. The results showed that of 53 patients, 20 survived, and 33 died. The NLR and PLR of the deceased were higher than those of the survivors (NLR: 30.67±14.48 vs. 17.41±7.06;PLR: 303.34±159.23 vs. 191.54±106.03; P<0.001). NLR and PLR were positively correlated with APACHE Ⅱ ( r=0.296, r=0.284, P<0.05). ROC curve analysis showed that the area under the curve (AUC) of NLR and PLR to predict the 28 d death of ECMO-treated patients was 0.805 and 0.714, respectively, and the optimal cutoff values of NLR and PLR were 18.93 and 253.0, respectively. The 28-day fatality rate in patients with NLR≥18.93 was higher than that in patients with NLR<18.93 [86.20%(25/29) vs. 33.33%(8/24), χ2=15.625, P<0.01],that in patients with a PLR≥253.0 was higher than that in patients with PLR<253.0 [82.61%(19/23) vs. 46.67%(14/30), χ2=7.158, P<0.01]. Kaplan-Meier survival curve showed that the 28-day cumulative survival rate of NLR≥18.93 was lower than that of NLR<18.93 [9.00 (2.00, 19.50) d vs. 28.00 (10.75, 28.00) d, Z=-3.124, P<0.01], and that of PLR≥253.0 was lower than that of PLR<253.0 [6.00 (2.00, 19.00) d vs. 28.00 (6.25, 28.00) d, Z=-2.673, P<0.01]. Thus, NLR and PLR have good predictive value for 28-day mortality in patients treated with ECMO.

Humans ; COVID-19 ; Consensus ; SARS-CoV-2 ; China

Objective: To investigate the endothelial protective effects of simvastatin on the coagulation system in septic rats. Methods: A total of 54 SD male rats were divided into 3 groups. Six healthy rats were intraperitoneally injected with normal salineas control group. Twenty-four rats in septic group were intraperitoneally injected with normal saline followed by lipopolysaccharide 2.5 mg. Study group had 24 rats intraperitoneally injected with simvastatin followed by lipopolysaccharide. Plasma von Willebrand factor (vWF), thrombomodulin (TM), platelet activating factor (PAF) and antithrombin-Ⅲ (AT-Ⅲ) were tested at 1 h, 3 h, 6 h and 12 h after treatment. Scanning electron microscopy and transmission electron microscopy were used to observe the morphology and apoptosis of rat aorta endothelial cells. Results: Compared with healthy control group, vWF [(68.3±4.8) ng/ml, (59.2±5.1) ng/ml, (74.2±20.1) ng/ml, (53.5±4.0)ng/ml, respectively], TM [(1.4±0.3) ng/ml, (1.6±0.4) ng/ml, (2.8±0.9) ng/ml, (1.4±0.5) ng/ml, respectively], PAF [(29.1±6.5) pg/ml, (28.6±1.5) pg/ml, (28.7±2.7) pg/ml, (18.2±4.1) pg/ml, respectively] and AT-Ⅲ [(262.2±38.1)μg/ml, (233.0±70.4) μg/ml, (218.7±54.7) μg/ml, (162.2±37.2) μg/ml, respectively] were significantly increased in the sepsis group at 1 h, 3 h, 6 h and 12 h (P<0.05). Compared with the sepsis group, the plasma levels of PAF in simvastatin intervention group at 1 h [(15.6±2.5) pg/ml, 3 h(10.4±5.3) pg/ml, 6 h (9.3±1.4) pg/ml, 12 h(11.0±2.7) pg/ml] were significantly decreased, so were the TM level at 6 h (1.6±0.9) ng/ml, and the AT-Ⅲ levels at 1 h[(190.3±29.2) μg/ml],6 h [(104.4±33.6) μg/ml] and 12 h [(73.6±39.0) μg/ml, P<0.05]. Conclusion In the condition of sepsis, toxins and over-activated inflammatory factors damage the vascular endothelium. A large amount of circulating vWF, TM, PAF, and AT-Ⅲ cause early hypercoagulability. Simvastatin significantly reduces plasma amount of these procoagulants, suggesting it smodification of coagulopathy and vascular protective effectsin a septic rat model.

To establish the experts consensus on the management of delirium in critically ill patients.A special committee was set up by 15 experts from the Chinese Critical Hypothermia-Sedation Therapy Study Group.Each statement was assessed based on the GRADE (Grading of Recommendations Assessment,Development,and Evaluation) principle.Then the Delphi method was adopted by 36 experts to reassess all the statements.(1) Delirium is not only a mental change,but also a clinical syndrome with multiple pathophysiological changes.(2) Delirium is a form of disturbance of consciousness and a manifestation of abnormal brain function.(3) Pain is a common cause of delirium in critically ill patients.Analgesia can reduce the occurrence and development of delirium.(4) Anxiety or depression are important factors for delirium in critically ill patients.(5) The correlation between sedative and analgesic drugs and delirium is uncertain.(6) Pay attention to the relationship between delirium and withdrawal reactions.(7) Pay attention to the relationship between delirium and drug dependence/ withdrawal reactions.(8) Sleep disruption can induce delirium.(9) We should be vigilant against potential risk factors for persistent or recurrent delirium.(10) Critically illness related delirium can affect the diagnosis and treatment of primary diseases,and can also be alleviated with the improvement of primary diseases.(11) Acute change of consciousness and attention deficit are necessary for delirium diagnosis.(12) The combined assessment of confusion assessment method for the intensive care unit and intensive care delirium screening checklist can improve the sensitivity of delirium,especially subclinical delirium.(13) Early identification and intervention of subclinical delirium can reduce its risk of clinical delirium.(14) Daily assessment is helpful for early detection of delirium.(15) Hopoactive delirium and mixed delirium are common and should be emphasized.(16) Delirium may be accompanied by changes in electroencephalogram.Bedside electroencephalogram monitoring should be used in the ICU if conditions warrant.(17) Pay attention to differential diagnosis of delirium and dementia/depression.(18) Pay attention to the role of rapid delirium screening method in delirium management.(19) Assessment of the severity of delirium is an essential part of the diagnosis of delirium.(20) The key to the management of delirium is etiological treatment.(21) Improving environmental factors and making patient comfort can help reduce delirium.(22) Early exercise can reduce the incidence of delirium and shorten the duration of delirium.(23) Communication with patients should be emphasized and strengthened.Family members participation can help reduce the incidence of delirium and promote the recovery of delirium.(24) Pay attention to the role of sleep management in the prevention and treatment of delirium.(25) Dexmedetomidine can shorten the duration of hyperactive delirium or prevent delirium.(26) When using antipsychotics to treat delirium,we should be alert to its effect on the heart rhythm.(27) Delirium management should pay attention to brain functional exercise.(28) Compared with non-critically illness related delirium,the relief of critically illness related delirium will not accomplished at one stroke.(29) Multiple management strategies such as ABCDEF,eCASH and ESCAPE are helpful to prevent and treat delirium and improve the prognosis of critically ill patients.(30) Shortening the duration of delirium can reduce the occurrence of long-term cognitive impairment.(31) Multidisciplinary cooperation and continuous quality improvement can improve delirium management.Consensus can promote delirium management in critically ill patients,optimize analgesia and sedation therapy,and even affect prognosis.

Critical ultrasonography(CUS) is different from the traditional diagnostic ultrasound,the examiner and interpreter of the image are critical care medicine physicians.The core content of CUS is to evaluate the pathophysiological changes of organs and systems and etiology changes.With the idea of critical care medicine as the soul,it can integrate the above information and clinical information,bedside real-time diagnosis and titration treatment,and evaluate the therapeutic effect so as to improve the outcome.CUS is a traditional technique which is applied as a new application method.The consensus of experts on critical ultrasonography in China released in 2016 put forward consensus suggestions on the concept,implementation and application of CUS.It should be further emphasized that the accurate and objective assessment and implementation of CUS requires the standardization of ultrasound image acquisition and the need to establish a CUS procedure.At the same time,the standardized training for CUS accepted by critical care medicine physicians requires the application of technical specifications,and the establishment of technical specifications is the basis for the quality control and continuous improvement of CUS.Chinese Critical Ultrasound Study Group and Critical Hemodynamic Therapy Collabration Group,based on the rich experience of clinical practice in critical care and research,combined with the essence of CUS,to learn the traditional ultrasonic essence,established the clinical application technical specifications of CUS,including in five parts:basic view and relevant indicators to obtain in CUS;basic norms for viscera organ assessment and special assessment;standardized processes and systematic inspection programs;examples of CUS applications;CUS training and the application of qualification certification.The establishment of applied technology standard is helpful for standardized training and clinical correct implementation.It is helpful for clinical evaluation and correct guidance treatment,and is also helpful for quality control and continuous improvement of CUS application.

Objective:To assess the influence of glimepiride on the plasma concentrations and antihypertensive effects of losartan and its active metabolite losartan carboxylic acid(E-3174) in the patients with type 2 diabetes mellitus and hypertension. Methods:Pragmatic randomized controlled trial was used in the clinical study. Forty-five patients were enrolled and randomized into glimepiride group and the control group. Losartan was used as the antihypertensive drug in the two groups. After two-week interference,the plasma concentrations of losartan and its active metabolite E-3174 were determined using an LC-MS/MS method and the reduction of hyperten-sion was measured. Results:The plasma trough concentrations of losartan in glimepiride group was not higher than those in the control group,and those of E-3174 in glimepiride group was not lower than those in the control group. Additionally,the reduction of hyperten-sion was similar in the two groups. Conclusion: Glimepiride does not influence the plasma concentrations and the antihypertensive effects of losartan and its active metabolite E-3174 in the patients with type 2 diabetes mellitus and hypertension, suggesting no drug-drug interactions between them. Owing to the small sample,large clinical trial should be performed to confirm the above conclusion.

BACKGROUNDFew studies have reported the effect of different volume responsiveness evaluation methods on volume therapy results and prognosis. This study was carried out to investigate the effect of two volume responsiveness evaluation methods, stroke volume variation (SVV) and stroke volume changes before and after passive leg raising (PLR-ΔSV), on fluid resuscitation and prognosis in septic shock patients.

METHODSSeptic shock patients admitted to the Department of Critical Care Medicine of Zhejiang Hospital, China, from March 2011 to March 2013, who were under controlled ventilation and without arrhythmia, were studied. Patients were randomly assigned to the SVV group or the PLR-ΔSV group. The SVV group used the Pulse Indication Continuous Cardiac Output monitoring of SVV, and responsiveness was defined as SVV ≥12%. The PLR-ΔSV group used ΔSV before and after PLR as the indicator, and responsiveness was defined as ΔSV ≥15%. Six hours after fluid resuscitation, changes in tissue perfusion indicators (lactate, lactate clearance rate, central venous oxygen saturation (SCVO2), base excess (BE)), organ function indicators (white blood cell count, neutrophil percentage, platelet count, total protein, albumin, alanine aminotransferase, total and direct bilirubin, blood urea nitrogen, serum creatinine, serum creatine kinase, oxygenation index), fluid balance (6- and 24-hour fluid input) and the use of cardiotonic drugs (dobutamine), prognostic indicators (the time and rate of achieving early goal-directed therapy (EGDT) standards, duration of mechanical ventilation and intensive care unit stay, and 28- day mortality) were observed.

RESULTSSix hours after fluid resuscitation, there were no significant differences in temperature, heart rate, blood pressure, SpO2, organ function indicators, or tissue perfusion indicators between the two groups (P > 0.05). The 6- and 24-hour fluid input was slightly less in the SVV group than in the PLR-ΔSV group, but the difference was not statistically significant (P > 0.05). The SVV group used significantly more dobutamine than the PLR-ΔSV group (33.3% vs. 10.7%, P = 0.039). There were no significant differences in the time ((4.8±1.4) h vs. (4.3±1.3) h, P = 0.142) and rate of achieving EGDT standards (90.0% vs. 92.9%, P = 0.698), or in the length of mechanical ventilation and ICU stay. The 28-day mortality in the SVV group (16.7% (5/30)) was slightly higher than the PLR-?SV group (14.3% (4/28)), but the difference was not statistically significant (P = 0.788).

CONCLUSIONSIn septic shock patients under controlled ventilation and without arrhythmia, using SVV or PLR-ΔSV methods to evaluate volume responsiveness has a similar effect on volume therapy results and prognosis. The evaluation and dynamic monitoring of volume responsiveness is more important for fluid resuscitation than the evaluation methods themselves. Choosing different methods to evaluate volume responsiveness has no significant influence on the effect of volume therapy and prognosis.

Adult ; Female ; Fluid Therapy ; Humans ; Male ; Middle Aged ; Monitoring, Physiologic ; methods ; Shock, Septic ; pathology ; therapy ; Stroke Volume ; physiology

Objective To investigate the effects of ω-3 fish oil lipid emulsion via vein on the inflammatory response,immune and organ function in patients with severe acute pancreatitis.Methods A total of 53 patients with severe acute pancreatitis were randomized into conventional therapy plus fish oil group (FO group) and conventional therapy group (CON group).The patients in FO group were treat with ω-3 fish oil lipid emulsion (0.2 g · kg-1 · d-1,10％) based on conventional therapy for 14 days.The level of C-reactive protein (CRP),TG and TC were detected before treatment and at day 7 and day 14 after treatment.CD4+,CD4+/CD8+ and C3,C4 were also detected at day 1 and day 14 after treatment.At the same time,acute physiology and chronic health evaluation Ⅱ score (APACHE Ⅱ score),intra-abdominal pressure,negative fluid balance time,enteral nutrition start-time and ICU stay time were observed and recorded.Results Forty-five out of 53 patients were finally recruited into results statistics.The level of CD4+,CD4+/CD8+ and C3 at day 14 after treatment in FO groups improved significantly than that in the CON group (P ＜0.05).The levels of CRP,intra-abdominal pressure and APACHE Ⅱ score at day 7 and day 14in FO group descended more obviously than that in the CON group (P ＜ 0.05).The negative liquid balance time in FO group (3.55 ±0.86) days was obvious shorter than that in CON group (4.61 ± 1.12) days,while enteral nutrition start-time (3.86 ± 1.17) days was significantly earlier compared with CON group (5.30 ± 1.61) days (P ＜ 0.05),however ICU stay time and 28 days mortality rate had no significant difference between the two groups.Conclusions ω-3 fish oil lipid emulsion can decrease the inflammatory response and the negative liquid balance time,improve the immune function and restore bowel function in severe acute pancreatitis patients.Therefore,it maybe provide a new and effective means for severe acute pancreatitis.