Abstract:Objective To establish an evaluation system for hand hygiene (HH) surveillance data of heath care workers (HCWs) during diagnosis and treatment. Methods In September 1-30, 2019, information about the implementation of HH of doctors and nurses in general intensive care unit (ICU), departments of respiratory diseases, orthopedics, infectious diseases, pediatric outpatient and emergency, and hemodialysis room was obtained through on-site investigation by HH observers. The workload of surveyed departments, consumption of HH products and actual number of opened beds of medical institutions were investigated, compliance rates of HH and daily consumption of HH products were calculated. Results The examination and verification of HH survey data in 1 480 medical institutions were qualified, HH should be implemented 1 353 531 times, HH were actually implemented 1 076 639 times, implementation of correct HH was 891 185 times, compliance rate of HH was 79.54%, correct HH implementation rate was 82.77%. Compliance rates of HH in different scales of medical institutions were 76.26%-82.84%, which was lowest in those with 600-899 actual opened beds, correct rates of HH were 81.87%-84.01%, which was lowest in those with ≥900 actual opened beds. Compliance rates of HH in surveyed department were 76.80%-84.44%, which was lowest in departments of pediatric outpatient and emergency, correct rates of HH were 81.19%-84.98%, which was lowest in department of orthopedics. HH compliance rates at five HH moments were 67.59%-89.84%, which was lowest after touching patient surroundings, correct rates of HH implementation were 81.51%-86.76%, which was lowest after touching patient surroundings. Consumption of HH products in general ICU, departments of respiratory diseases, orthopedics, and infectious diseases were 56.62, 10.76, 9.50, and 14.54 mL/bed-days respectively, consumption of HH products in department of pediatric outpatient and emergency as well as hemodialysis room was 2.02 and 9.06 mL/person-time respectively. Among different scales of medical institutions, consumption of HH products in general ICU was highest in those with 600-899 opened beds (61.15 mL/bed-days), consumption of HH products in departments of respiratory diseases, orthopedics, and infectious diseases was the highest in those with >900 opened beds(13.61, 10.96, and 16.55 mL/bed-days respectively), consumption of HH products in department of pediatric outpatient as well as emergency and hemodialysis room was highest in those with 300-599 opened beds (2.53, 10.76 mL/bed-days respectively). Conclusion HH compliance rates and daily consumption of HH products in medical institutions of different scales obtained in this survey can be used as a benchmark, which provide a control system for the implementation of HH in medical institutions, so as to promote the continuous improvement of HH in medical institutions in China.

Abstract:Objective To understand the occurrence, pathogen distribution, and influencing factors for fungal infection in hospitalized patients with acquired immunodeficiency syndrome (AIDS) in an infectious diseases hospital. Methods AIDS patients who were hospitalized in a hospital for the first time from January 2018 to September 2019 were selected as the research objects, fungal infection was determined through culture. Logistic regression analysis was used to determine the influencing factors for fungal infection in hospitalized AIDS patients. Results There were 667 hospitalized AIDS patients from January 2018 to September 2019, 195 (29.24%) of whom had fungal infection. The main infection strains were Candida albicans (163 strains), Cryptococcus neoformans (36 strains) and Talaromyces marneffei (22 strains). The main sources of specimens were oral swabs (leukoplakia, 133 strains), sputum (41 strains) and blood (31 strains), oral swabs and sputum mainly isolated Candida albicans (119, 18 strains respectively); blood specimens mainly isolated Talaromyces marneffei (15 strains). Combined use of antimicrobial agents (OR=2.237, 95% CI: 1.190-4.204), combined with other infectious diseases (OR=1.614, 95% CI: 1.013-2.574) and high HIV-1 RNA load (OR=1.817, 95% CI: 1.039-3.176) were independent risk factors for fungal infection in hospitalized AIDS patients (all P < 0.05); systemic antiviral therapy (OR=0.736, 95% CI: 0.576-0.940), high CD4⁺ T cell level (OR=0.583, 95% CI: 0.351-0.968) and high lymphocyte count (OR=0.798, 95% CI: 0.644-0.988) were independent protective factors for fungal infection in hospitalized AIDS xpatients (all P < 0.05). Conclusion Incidence of fungal infection in hospitalized AIDS patients is high, which can be reduced through conducting systematic examination and standardizing antiviral treatment early, improving blood protein level and nutritional status, reducing invasive diagnosis and treatment procedure, rationally selecting antimicrobial agents and standardizing types and dosage of antimicrobial agents.

Abstract:Objective To analyze the clinical characteristics, genotypes and major virulence factors of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolated from lower respiratory specimens of patients with ventilator-associated pneumonia (VAP). Methods Non-repetitive Klebsiella pneumoniae (KP) isolated from lower respiratory tract specimens of VAP patients in a hospital from January to December 2019 were collected, clinical characteristics, antimicrobial resistance, multilocus sequence typing and capsular wzi typing of patients were compared between CRKP group and non-CRKP (nCRKP) group, carrying status and homology of virulence factors of CRKP were analyzed. Results A total of 56 strains of KP were collected, 60.7% (n=34) of which were CRKP. The proportion of patients with intensive care unit (ICU) stay≥20 days, death and discharged voluntarily in CRKP group were all higher than those in nCRKP group (all P < 0.05). Resistance rate of CRKP group to commonly used antimicrobial agents was higher than that of nCRKP group (all P < 0.05). Most CRKP (97.1%) carried bla_KPC-2 gene, resistance rates to antimicrobial agents other than tigecycline were high. 82.4% of CRKP were ST11 type and K64 was the main capsule type (50.0%); 45.4% of nCRKP were ST11 type and K47 was the main capsule type (40.9%); proportion of K64 type in CRKP was higher than that of nCRKP strain (P < 0.01). CRKP carried a variety of virulence factors, virulence factors rmpA2, iucA and iroN mediated by pLVPK-like plasmid were mainly carried by K64-ST11 CRKP, PFGE analysis showed that there was clonal transmission of K64-ST11 CRKP. Conclusion CRKP isolated from VAP lower respiratory tract specimens shows multiple resistance, and its main molecular type is K64-ST11, this type carries a variety of plasmid-mediated virulence factors and has clonal transmission, clinical epidemic trend should be closely monitored.

Abstract:Objective To investigate characteristics and risk factors of healthcare-associated infection (HAI) in patients receiving extracorporeal membrane oxygenation (ECMO) support therapy. Methods Clinical data of patients receiving ECMO support therapy from January 2013 to December 2019 were collected retrospectively, characteristics and risk factors of HAI after ECMO were analyzed statistically. Results Among 163 patients receiving ECMO support therapy, 39 (23.93%) developed HAI after ECMO, lower respiratory tract infection (n=38, 59.38%) was predominant, followed by bloodstream infection (n=9, 14.06%) and digestive system infection (n=6, 9.37%). A total of 95 strains of pathogens were isolated, including 74 strains (77.89%) of Gram-negative bacilli, 20 strains (21.06%) of fungi, and 1 strain (1.05%) of Gram-positive coccus; pathogens were mainly isolated from sputum specimens (n=73 strains, 76.84%), followed by blood specimens (n=11 strains, 11.58%) and urine specimens (n=4 strains, 4.21%). There were significant differences in hospitalization days, antimicrobial use days, ventilator use days, urinary catheterization days and central venous catheterization days between patients with and without HAI after ECMO support therapy (all P < 0.001). Conclusion Patients receiving ECMO had high incidence of HAI, health care workers should take effective preventive measures against risk factors, so as to reduce the incidence of HAI.

Abstract:Objective To analyze the clinical characteristics and risk factors of extracorporeal membrane oxygenation (ECMO)-related healthcare-associated infection (HAI), provide theoretical basis for the prevention and control of ECMO-related HAI. Methods Patients who received ECMO treatment in a tertiary hospital from June 2014 to September 2018 were retrospectively analyzed, according to the 1∶2 matching method, patients who didn't receive ECMO treatment were selected as the control group (non-ECMO group), basic information and hospitalization expense of two groups of patients were compared. According to whether ECMO-related HAI occurred, patients who received ECMO treatment were divided into ECMO infection group and ECMO control group, clinical characteristics of two groups of patients were compared, risk factors, mortality and medical expenses of ECMO-related HAI were evaluated. Results A total of 30 patients who received ECMO treatment were included in the study, with an average age of (41.9±16.2) years, 76.7% of the patients were male, and 22 patients underwent venovenous ECMO (VV ECMO). 15 patients had 24 cases of ECMO-related HAI, including 12 cases of bloodstream infection, 9 cases of pulmonary infection, 1 case of urinary tract infection, 1 case of surgical site infection and 1 case of gastrointestinal infection. Patients in ECMO infection group had longer ECMO support time, higher proportion of tracheotomy and lower hemoglobin level. Multivariate logistic regression analysis showed that ECMO support time ≥ 10 days was an independent risk factor for ECMO-related HAI. Compared with ECMO control group, patients with ECMO-related HAI had longer hospital stay ([44.5±39.6] d vs [18.4±11.7] d, P=0.021) and higher medical expense ([413 359.9±204 887.0] Yuan vs [264 925.3±76 079.7] Yuan, P=0.004). Conclusion HAI is a common complication of ECMO treatment, which significantly increases medical expense and length of hospital stay. Defining indications of ECMO treatment as well as stopping respiratory circulatory support as early as possible can reduce the incidence of ECMO-related infection.

Abstract:Objective To evaluate the efficacy and safety of ceftazidime-avibactam (CAZ/AVI) in the treatment of Gram-negative bacterial infection. Methods Randomized controlled trial(RCT) on efficacy and safety of CAZ-AVI were retrieved from domestic and foreign databases, clinical cure rate was assessed as the main outcome, microbial clearance rate and incidence of adverse reaction were as secondary outcome, Meta-analysis was performed with Review Manage 5.3. Results Seven RCTs (3 792 patients) were included in Meta-analysis, clinical cure rate of patients at the end of treatment (EOT, RR=0.99, 95% CI=0.96-1.01), at the time of test of cure (TOC, RR=0.99, 95% CI=0.96-1.02), at the time of last follow-up visit (LFU, RR=1.00, 95% CI=0.96-1.03) were not significantly different between CAZ/AVI group and control group (all P>0.05); clinical cure rate at time of TOC of microbiologically modified intention-to-treat (mMITT) of patients was no significantly different between CAZ/AVI group and control group (RR=0.95, 95%CI= 0.89-1.00, P=0.06), control group was better than CAZ/AVI group at EOT (RR=0.95, 95%CI= 0.92-0.98, P=0.005). There was no significant difference in the microbial clearance between CAZ/AVI group and control group at EOT of mMITT of patients (RR=1.00, 95%CI=0.97-1.03) and at time of TOC (RR=1.07, 95%CI=0.92-1.25) (both P>0.05), CAZ/AVI group was better than control group at time of LFU (RR=1.12, 95%CI=1.01-1.23, P=0.03), incidence of adverse reaction and drug withdrawal due to adverse reaction in CAZ/AVI group was basically similar to that in control group, but incidence of serious adverse reaction in CAZ/AVI group was higher than that in control group (RR=1.26, 95%CI=1.01-1.57, P=0.04). Conclusion The efficacy of CAZ/AVI is similar to other antimicrobial agents, which can be used as a alternative medicine for severe infection, considering that incidence of serious adverse reaction is higher than that of other drugs, more high-quality and large-scale studies are needed to demonstrate the safety of CAZ/AVI.

Abstract:Objective To study the prognosis of patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infection in intensive care unit (ICU), evaluate the economic burden and death risk of CRKP infection, and provide reference for formulating targeted prevention and control strategies. Methods Patients who were isolated Klebsiella pneumoniae from specimens in ICU of a hospital between January 2017 and June 2019 were selected as the research objects, they were divided into CRKP infection group and carbapenem-sensitive Klebsiella pneumoniae (CSKP) infection group by retrospective cohort study, direct hospitalization expense and mortality were analyzed, Kaplan-Meier was adopted to analyze the risk of death, Cox proportional hazards model was used to analyze the influencing factors for risk of death. Results A total of 236 ICU patients were included in analysis, including 175 in CRKP infection group and 61 in CSKP infection group. Lower respiratory tract infection was the major infection in both CRKP infection group and CSKP infection group. Mortality of patients in CRKP infection group was higher than that of CSKP group (28.00% vs 13.11%, P < 0.05). The total hospitalization expense of patients in CRKP infection group was 63 648.34 Yuan higher than that of patients in CSKP infection group (Z=-3.923, P < 0.001), with an increase of 48.76%; the most significant increase was the expense of antimicrobial agents, which increased by 107.78%. There was significant difference in 30-day death risk between ICU patients in CRKP infection group and CSKP infection group(χ²=5.554, P=0.018), but there was no significant difference in 90-day death risk between two groups of patients (χ²=2.603, P=0.107). Compared with CSKP infection group, risk factors for the increase of 30-day death risk in CRKP infection group were circulatory diseases, mechanical ventilation and age of patients. Conclusion CRKP infection increases hospitalization expense and risk of death in ICU patients. More use of antimicrobial agents is the main cause for the increase of hospitalization expense burden, mechanical ventilation is the main cause for the increase of death risk in ICU patients. Clinical application of antimicrobial agents should be rational, the necessity of mechanical ventilation should be evaluated in time, so as to reduce the emergence of antimicrobial-resistant organisms and improve prognosis of patients.

Abstract:Objective To analyze antimicrobial susceptibility and carrying status of antimicrobial resistance genes of carbapenem-resistant Klebsiella pneumoniae (CRKP) in China. Methods Antimicrobial susceptibility testing was performed on CRKP collected from the China Antimicrobial Resistance Surveillance Trial from 2017 to 2018 by Institute of Clinical Pharmacology of Peking University, carrying status of carbapenemase genes and other extended-spectrum beta-lactamases (ESBLs) genes in CRKP were detected by polymerase chain reaction (PCR) and sequencing detection. Results A total of 129 strains of CRKP were screened out, polymyxin E, tigecycline, fosfomycin trometamol and minocycline were the effective antimicrobial agents, susceptibility rates were 80.62%, 79.07%, 51.16% and 51.16% respectively, susceptibility rates of other antimicrobial agents were all lower than 46%. PCR and sequencing results showed that 112 strains carried carbapenemase gene, mainly bla_KPC-2 (77.52%) and bla_NDM (8.53%) genes, and 3 strains (2.33%) carried both bla_KPC-2 and bla_NDM genes. Detection rate of bla_TEM gene was 51.94% (67/129), all of which were bla_TEM-1; detection rate of bla_SHV gene was 64.34% (83/129), mainly bla_SHV-12 gene (27.91%, 36/129); detection rate of bla_CTX-M gene was 53.49% (69/129), which were bla_CTX-M-9 (43.41%) and bla_CTX-M-15 (10.08%) respectively, 4 strains (3.10%) contained both bla_CTX-M-9 and bla_CTX-M-15 genes. Among carbapenemase gene positive strains, 80.36% (90/112) carried ESBLs genes simultaneously, and 32.14% (36/112) carried two or more ESBLs genes simultaneously. Conclusion Antimicrobial resistance of CRKP isolated in China is serious, and there are multiple antimicrobial resistance genes at the same time, the most common carbapenemase gene is bla_KPC-2 gene, and the most common ESBLs genes are bla_SHV-12 and bla_CTX-M-9 genes.

Abstract:Objective To perform active screening on carbapenem-resistant Gram-negative bacilli (CR-GNB), carry out centralized resettlement for patients according to the screening results, evaluate the efficacy of intervention measures, and provide scientific basis for the prevention and control of healthcare-associated infection(HAI) due to CR-GNB. Methods From January 2017 to December 2018, patients who were admitted to key departments of a pediatric hospital (neonatal room, neonatal intensive care unit [NICU], pediatric intensive care unit [PICU], department of hematology) were selected as the research objects, all patients were performed HAI real-time monitoring. In 2017, active screening on CR-GNB (throat swab and anal swab) was performed for hospitalized patients 48 hours after admission and once a week during hospitalization. From January 2018, centralized resettlement measures were carried out for patients with positive CR-GNB in active screening and clinically delivered specimen detection, changes of active screening rate and colonization rate of CR-GNB as well as centralized resettlement rate and HAI rate were compared. Results Active screening rates of throat swab and anal swab in 2018 was higher than those in 2017 (P < 0.05). The highest centralized resettlement rate was in neonatal room (97.8%), followed by NICU (88.9%), PICU was the lowest (47.7%). In 2018, colonization rate of CR-GNB in key departments showed a downward trend after 3 and 7 days of hospitalization (P < 0.05). HAI rate of CR-GNB in 2018 decreased compared with that in 2017 (P < 0.05), carbapenem-resistant Enterobacterales HAI rate in neonatal room and NICU decreased significantly, HAI rates of carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aegurinosa (CRPA) in patients in PICU decreased significantly. Carbapenem-resistant Klebsiella pneumoniae (CRKP) was the main pathogen in active screening of colonized bacteria and pathogens of CR-GNB HAI (44.0% vs 51.7%). Conclusion Active screening of CR-GNB combined with centralized resettlement intervention for patients can reduce the colonization rate of CR-GNB and effectively reduce HAI rate.

Abstract:Objective To investigate the effect of hemodialysis supervision form on incidence of vascular access-related infection(VAI) in hemodialysis outpatients. Methods A prospective monitoring study was conducted, 2 059 patients in the outpatient hemodialysis center of a large teaching hospital from the third quarter of 2018 to the second quarter of 2019 were selected as control group, and 2 074 patients from the third quarter of 2019 to the second quarter of 2020 were selected as intervention group (patients were monitored by hemodialysis supervision form), incidence of VAI before and after intervention was compared. Results The total incidence of infection at puncture sites before and after intervention were 1.51%(n=31) and 0.82% (n=17) respectively, difference between two groups was statistically significant (P < 0.05). For patients with non-tunnelled internal jugular vein catheterization, 1 patient had vascular access-related bloodstream infection, incidence of infection at puncture sites decreased from 7.69% before intervention to 0 after intervention; incidence of infection at puncture sites decreased obviously in patients with non-tunnelled internal jugular vein catheterization, which decreased from 10.53% in the third quarter of 2018 to 0. Conclusion Incidence of VAI can be reduced by the intervention in hemodialysis outpatients with hemodialysis supervision form.

Abstract:Objective To understand the level of post-traumatic stress response and group differences of health care workers (HCWs) during the treatment of coronavirus disease 2019 (COVID-19), and propose suggestions and opinions to effectively restore the psychological state of HCWs after the epidemic. Methods From June to July in 2020, the information of public hospitals in 19 provinces and autonomous regions of China was collected by conve-nient sampling, HCWs on duty during COVID-19 epidemic period were investigated, the questionnaire included demographic data, social capital, sense of control and post-traumatic stress disorder (PTSD). Descriptive statistics, independent sample t-test, correlation analysis and hierarchical regression were adopted for data analysis. Results A total of 760 available questionnaires were collected, 315 HCWs participated in the treatment of confirmed or suspected COVID-19 patients. There was a certain degree of PTSD in HCWs, which was at a medium level (2.2155-2.9385). After experiencing COVID-19 epidemic, doctors showed higher tendency of avoidance, intrusion and arousal than nurse group, differences were all statistically significant (all P < 0.05). HCWs in designated hospitals for COVID-19 treatment had higher avoidance response than HCWs in non-designated hospitals, difference was statistically significant (P < 0.05). HCWs who directly participated in treatment of COVID-19 had high level of avoi-dance, intrusion and arousal than HCWs who didn't directly participate in treatment of COVID-19, difference were all statistically significant (all P < 0.05). Structural capital (r=0.566), interpersonal capital (r=0.577) and cognitive capital (r=0.596) had significant positive effect on the sense of control of HCWs. Structural capital (r=-0.166), interpersonal capital (r=-0.177) and cognitive capital (r=-0.168) had significant negative effect on PTSD of HCWs. Sense of control (r=-0.179) had significant negative effect on PTSD of HCWs. Conclusion Structural capital, interpersonal capital and cognitive capital perceived by HCWs can effectively suppress the formation and development of PTSD through enhancing their sense of control, hospitals should take measures to reduce the impact of PTSD by improving HCWs' sense of social capital and sense of control.

Abstract:Objective To construct the structure-process-outcome index of hand hygiene (HH) compliance of staff in blood purification center by Donabedian quality theory, conduct continuous quality improvement, and explore whether the three-dimensional indexes guided by the quality theory can improve the quality of HH management. Methods HH compliance of all staff in blood purification center of a medical center was continuously improved, before the intervention, the routine continuous quality improvement method focusing on outcome indexes was adop-ted, intervention measures were performed under the guidance of Donabedian quality theory, structure-process-outcome three-dimensional index of HH compliance of staff in blood purification center was paid attention to, effect of the method and routine continuous quality improvement method on HH was observed. Results Compared with before intervention, HH compliance rate of all kinds of staff in blood purification center improved after intervention (doctor group: 52.38% vs 75.22%; nursing group: 69.49% vs 88.17%; attendant group: 52.72% vs 73.93%; cleaner group: 12.54% vs 56.83%), accuracy rate also improved (doctor group: 80.91% vs 94.07%; nursing group: 87.08% vs 95.49%; attendant group: 37.74% vs 56.20%; cleaner group: 57.14% vs 59.49%), diffe-rences were all statistically significant (all P < 0.05). Before and after the intervention, scores of HH knowledge check in staff in blood purification center ([78.12±8.37] points vs [88.82±6.57] points), consumption of alcohol-based hand rub ([33.33±2.07] bottles vs [53.50±1.81] bottles), qualified rate of detection result of hand bacteria (58.82% vs 91.18%), and patients' satisfaction with HH of staff (88.92% vs 96.30%) were all significantly different (all P < 0.05). The deep venous catheter infection rate was 2.1 per 1 000 catheter-days before intervention, and no deep venous catheter infection occurred after intervention. Conclusion HH quality management of staff under the guidance of Donabedian quality theory has remarkable achievement in HH compliance rate and accuracy rate, HH knowledge examination, as well as patients' satisfaction with HH of staff, which is worthy to be promoted.

Abstract:Objective To analyze the occurrence and direct economic loss of post-operative healthcare-associated infection (HAI) in patients undergoing esophageal cancer surgery, and provide basis for the prevention and control of HAI. Methods A 1∶1 case-control study was used to retrospectively analyze patients undergoing esophageal cancer surgery in a hospital from January 2018 to December 2019, patients with post-operative HAI were in case group, those without post-operative infection were in control group, hospitalization time and medical expense of two groups of patients were compared. Results The median hospitalization time of case group and control group were 37.0 days and 16.0 days respectively, the increased hospitalization time due to HAI was 21.0 days, difference was statistically significant (P < 0.001). The median total hospitalization expense of case group and control group were 131 170.3 Yuan and 90 455.6 Yuan respectively, direct economic loss due to infection was 40 714.7 Yuan, diffe-rence was statistically significant (P < 0.001). Hospitalization days and expense in patients with multiple site infection were higher than those with single site infection, difference was statistically significant (both P < 0.05), patients with pulmonary infection and bloodstream infection had longer hospitalization days and higher hospitalization expense than control group. Conclusion Post-operative HAI in esophageal cancer patients can significantly prolong the length of hospital stay and increase the expense of hospitalization, the impact of different infection sites on the direct economic loss of patients is different, prevention and control of HAI in patients undergoing esophageal cancer surgery should be strengthened.

Abstract:Since the mid-1980s, incidence of hypervirulent Klebsiella pneumoniae (hvKp) has increased year by year, which has attracted global attention. hvKp is more pathogenic than classic Klebsiella pneumoniae (cKp), it can lead to invasive infection in healthy people, not only with high mortality (3%-31%), but also often accompanied by serious sequelae, such as blindness or neurological diseases. What is more worrying is that, in recent years, the emergence of hvKp strains resistant to the third generation cephalosporins, carbapenem antibiotics and colistin has brought great challenge to clinical treatment and management. Therefore, understanding virulence and drug resis-tance mechanism of hvKp is particularly important, this paper reviews the latest research progress of hvKp.

Abstract:In 1991, sepsis was first defined as systemic inflammatory response syndrome (SIRS) caused by infection. International consensus on sepsis was updated to Sepsis 3.0 in 2016, which is the life-threatening organ dysfunction caused by the host immune response disorder due to infection. During the immunosuppressive stage of sepsis, the combination of programmed cell death receptor-1 (PD-1) and programmed cell death receptor ligand-1 (PD-L1) can inhibit the activation and proliferation of some immune cells, resulting in negative regulation of the immune system. This review mainly focuses on the role of PD-1/PD-L1 in the immune function of T cells, dendritic cells (DCs), monocytes, macrophages and other immune cells during sepsis, as well as application prospect of anti-PD-1/PD-L1 antibody therapy in sepsis.