Risk Factors for the Mortality of Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation in a Non-Centralized Setting: A Nationwide Study.

BACKGROUND: Limited data are available on the mortality rates of patients receiving extracorporeal membrane oxygenation (ECMO) support for coronavirus disease 2019 (COVID-19). We aimed to analyze the relationship between COVID-19 and clinical outcomes for patients receiving ECMO. METHODS: We retrospectively investigated patients with COVID-19 pneumonia requiring ECMO in 19 hospitals across Korea from January 1, 2020 to August 31, 2021. The primary outcome was the 90-day mortality after ECMO initiation. We performed multivariate analysis using a logistic regression model to estimate the odds ratio (OR) of 90-day mortality. Survival differences were analyzed using the Kaplan-Meier (KM) method. RESULTS: Of 127 patients with COVID-19 pneumonia who received ECMO, 70 patients (55.1%) died within 90 days of ECMO initiation. The median age was 64 years, and 63% of patients were male. The incidence of ECMO was increased with age but was decreased after 70 years of age. However, the survival rate was decreased linearly with age. In multivariate analysis, age (OR, 1.048; 95% confidence interval [CI], 1.010-1.089; P = 0.014) and receipt of continuous renal replacement therapy (CRRT) (OR, 3.069; 95% CI, 1.312-7.180; P = 0.010) were significantly associated with an increased risk of 90-day mortality. KM curves showed significant differences in survival between groups according to age (65 years) (log-rank P = 0.021) and receipt of CRRT (log-rank P = 0.004). CONCLUSION: Older age and receipt of CRRT were associated with higher mortality rates among patients with COVID-19 who received ECMO.

Development of a Novel Biomarker for the Progression of Idiopathic Pulmonary Fibrosis.

The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified and validated a new biomarker for IPF progression. To identify a candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced IPF compared with early IPF and controls in three lung sample cohorts. Candidate gene expression was confirmed using immunohistochemistry and Western blotting of lung tissue samples from an independent IPF clinical cohort. Biomarker potential was assessed using an enzyme-linked immunosorbent assay of serum samples from the retrospective validation cohort. We verified that the final candidate gene reflected the progression of IPF in a prospective validation cohort. In the RNA-seq comparative analysis of lung tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, and NUPR1 were up-regulated, and ADAMTS8 was down-regulated in the samples of advanced IPF. Only CTSB showed significant differences in expression based on Western blotting (n = 12; p < 0.001) and immunohistochemistry between the three groups of the independent IPF cohort. In the retrospective validation cohort (n = 78), serum CTSB levels were higher in the progressive group (n = 25) than in the control (n = 29, mean 7.37 ng/mL vs. 2.70 ng/mL, p < 0.001) and nonprogressive groups (n = 24, mean 7.37 ng/mL vs. 2.56 ng/mL, p < 0.001). In the prospective validation cohort (n = 129), serum CTSB levels were higher in the progressive group than in the nonprogressive group (mean 8.30 ng/mL vs. 3.00 ng/mL, p < 0.001). After adjusting for baseline FVC, we found that CTSB was independently associated with IPF progression (adjusted OR = 2.61, p < 0.001). Serum CTSB levels significantly predicted IPF progression (AUC = 0.944, p < 0.001). Serum CTSB level significantly distinguished the progression of IPF from the non-progression of IPF or healthy control.

Obesity Paradox and Functional Outcomes in Sepsis: A Multicenter Prospective Study.

OBJECTIVES: In Asian populations, the correlation between sepsis outcomes and body mass is unclear. A multicenter, prospective, observational study conducted between September 2019 and December 2020 evaluated obesity's effects on sepsis outcomes in a national cohort. SETTING: Nineteen tertiary referral hospitals or university-affiliated hospitals in South Korea. PATIENTS: Adult patients with sepsis ( n = 6,424) were classified into obese ( n = 1,335) and nonobese groups ( n = 5,089). MEASUREMENTS AND RESULTS: Obese and nonobese patients were propensity score-matched in a ratio of 1:1. Inhospital mortality was the primary outcome. After propensity score matching, the nonobese group had higher hospital mortality than the obese group (25.3% vs 36.7%; p < 0.001). The obese group had a higher home discharge rate (70.3% vs 65.2%; p < 0.001) and lower median Clinical Frailty Scale (CFS) (4 vs 5; p = 0.007) at discharge than the nonobese group, whereas the proportion of frail patients at discharge (CFS ≥ 5) was significantly higher in the nonobese group (48.7% vs 54.7%; p = 0.011). Patients were divided into four groups according to the World Health Organization body mass index (BMI) classification and performed additional analyses. The adjusted odds ratio of hospital mortality and frailty at discharge for underweight, overweight, and obese patients relative to normal BMI was 1.25 ( p = 0.004), 0.58 ( p < 0.001), and 0.70 ( p = 0.047) and 1.53 ( p < 0.001), 0.80 ( p = 0.095), and 0.60 ( p = 0.022), respectively. CONCLUSIONS: Obesity is associated with higher hospital survival and functional outcomes at discharge in Asian patients with sepsis.

Geographical Differences of Risk of Asthma and Allergic Rhinitis according to Urban/Rural Area: a Systematic Review and Meta-analysis of Cohort Studies.

Several studies have demonstrated an association between the risk asthma/allergic rhinitis and the environment. However, to date, no systematic review or meta-analysis has investigated these factors. We conducted a systematic review and meta-analysis to assess the association between urban/rural living and the risk of asthma and allergic rhinitis. We searched the Embase and Medline databases for relevant articles and included only cohort studies to observe the effects of time-lapse geographical differences. Papers containing information on rural/urban residence and respiratory allergic diseases were eligible for inclusion. We calculated the relative risk (RR) and 95% confidence interval (CI) using a 2 × 2 contingency table and used random effects to pool data. Our database search yielded 8388 records, of which 14 studies involving 50,100,913 participants were finally included. The risk of asthma was higher in urban areas compared to rural areas (RR, 1.27; 95% CI, 1.12-1.44, p < 0.001), but not for the risk of allergic rhinitis (RR, 1.17; 95% CI, 0.87-1.59, p = 0.30). The risk of asthma in urban areas compared to rural areas was higher in the 0-6 years and 0-18 years age groups, with RRs of 1.21 (95% CI, 1.01-1.46, p = 0.04) and 1.35 (95% CI, 1.12-1.63, p = 0.002), respectively. However, there was no significant difference in the risk of asthma between urban and rural areas for children aged 0-2 years, with a RR of 3.10 (95% CI, 0.44-21.56, p = 0.25). Our study provides epidemiological evidence for an association between allergic respiratory diseases, especially asthma, and urban/rural living. Future research should focus on identifying the factors associated with asthma in children living in urban areas. The review was registered in PROSPERO (CRD42021249578).

Early prediction of need for invasive mechanical ventilation in the neonatal intensive care unit using artificial intelligence and electronic health records: a clinical study.

BACKGROUND: Respiratory support is crucial for newborns with underdeveloped lung. The clinical outcomes of patients depend on the clinician's ability to recognize the status underlying the presented symptoms and signs. With the increasing number of high-risk infants, artificial intelligence (AI) should be considered as a tool for personalized neonatal care. Continuous monitoring of vital signs is essential in cardiorespiratory care. In this study, we developed deep learning (DL) prediction models for rapid and accurate detection of mechanical ventilation requirements in neonates using electronic health records (EHR). METHODS: We utilized data from the neonatal intensive care unit in a single center, collected between March 3, 2012, and March 4, 2022, including 1,394 patient records used for model development, consisting of 505 and 889 patients with and without invasive mechanical ventilation (IMV) support, respectively. The proposed model architecture includes feature embedding using feature-wise fully connected (FC) layers, followed by three bidirectional long short-term memory (LSTM) layers. RESULTS: A mean gestational age (GA) was 36.61 ± 3.25 weeks, and the mean birth weight was 2,734.01 ± 784.98 g. The IMV group had lower GA, birth weight, and longer hospitalization duration than the non-IMV group (P < 0.05). Our proposed model, tested on a dataset from March 4, 2019, to March 4, 2022. The mean AUROC of our proposed model for IMV support prediction performance demonstrated 0.861 (95%CI, 0.853-0.869). It is superior to conventional approaches, such as newborn early warning score systems (NEWS), Random Forest, and eXtreme gradient boosting (XGBoost) with 0.611 (95%CI, 0.600-0.622), 0.837 (95%CI, 0.828-0.845), and 0.0.831 (95%CI, 0.821-0.845), respectively. The highest AUPRC value is shown in the proposed model at 0.327 (95%CI, 0.308-0.347). The proposed model performed more accurate predictions as gestational age decreased. Additionally, the model exhibited the lowest alarm rate while maintaining the same sensitivity level. CONCLUSION: Deep learning approaches can help accurately standardize the prediction of invasive mechanical ventilation for neonatal patients and facilitate advanced neonatal care. The results of predictive, recall, and alarm performances of the proposed model outperformed the other models.

Comparison of the end-of-life decisions of patients with hospital-acquired pneumonia after the enforcement of the life-sustaining treatment decision act in Korea.

BACKGROUND: Although the Life-Sustaining Treatment (LST) Decision Act was enforced in 2018 in Korea, data on whether it is well established in actual clinical settings are limited. Hospital-acquired pneumonia (HAP) is a common nosocomial infection with high mortality. However, there are limited data on the end-of-life (EOL) decision of patients with HAP. Therefore, we aimed to examine clinical characteristics and outcomes according to the EOL decision for patients with HAP. METHODS: This multicenter study enrolled patients with HAP at 16 referral hospitals retrospectively from January to December 2019. EOL decisions included do-not-resuscitate (DNR), withholding of LST, and withdrawal of LST. Descriptive and Kaplan-Meier curve analyses for survival were performed. RESULTS: Of 1,131 patients with HAP, 283 deceased patients with EOL decisions (105 cases of DNR, 108 cases of withholding of LST, and 70 cases of withdrawal of LST) were analyzed. The median age was 74 (IQR 63-81) years. The prevalence of solid malignant tumors was high (32.4% vs. 46.3% vs. 54.3%, P = 0.011), and the ICU admission rate was lower (42.9% vs. 35.2% vs. 24.3%, P = 0.042) in the withdrawal group. The prevalence of multidrug-resistant pathogens, impaired consciousness, and cough was significantly lower in the withdrawal group. Kaplan-Meier curve analysis revealed that 30-day and 60-day survival rates were higher in the withdrawal group than in the DNR and withholding groups (log-rank P = 0.021 and 0.018). The survival of the withdrawal group was markedly decreased after 40 days; thus, the withdrawal decision was made around this time. Among patients aged below 80 years, the rates of EOL decisions were not different (P = 0.430); however, mong patients aged over 80 years, the rate of withdrawal was significantly lower than that of DNR and withholding (P = 0.001). CONCLUSIONS: After the LST Decision Act was enforced in Korea, a DNR order was still common in EOL decisions. Baseline characteristics and outcomes were similar between the DNR and withholding groups; however, differences were observed in the withdrawal group. Withdrawal decisions seemed to be made at the late stage of dying. Therefore, advance care planning for patients with HAP is needed.

Erratum: Correction of Affiliations in the Article "Outcomes of Patients on the Lung Transplantation Waitlist in Korea: A Korean Network for Organ Sharing Data Analysis".

This corrects the article on p. e294 in vol. 37, PMID: 36281485.

Erratum: Correction of Affiliations in the Article "Validity of Outcome Prediction Scoring Systems in Korean Patients with Severe Adult Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation Therapy".

This corrects the article on p. 932 in vol. 31, PMID: 27247503.

Empiric Anti-Pseudomonal ß-Lactam Monotherapy Versus Fluoroquinolone Combination Therapy in Patients With Hospital-Acquired Pneumonia: A Multicenter Cohort Study With Propensity Score Matching.

BACKGROUND: There is insufficient data on the benefits of empiric antibiotic combinations for hospital-acquired pneumonia (HAP). We aimed to investigate whether empiric anti-pseudomonal combination therapy with fluoroquinolones decreases mortality in patients with HAP. METHODS: This multicenter, retrospective cohort study included adult patients admitted to 16 tertiary and general hospitals in Korea between January 1 and December 31, 2019. Patients with risk factors for combination therapy were divided into anti-pseudomonal non-carbapenem ß-lactam monotherapy and fluoroquinolone combination therapy groups. Primary outcome was 30-day mortality. Propensity score matching (PSM) was used to reduce selection bias. RESULTS: In total, 631 patients with HAP were enrolled. Monotherapy was prescribed in 54.7% (n = 345) of the patients, and combination therapy was prescribed in 45.3% (n = 286). There was no significant difference in 30-day mortality between the two groups (16.8% vs. 18.2%, P = 0.729) or even after the PSM (17.5% vs. 18.2%, P = 0.913). After the PSM, adjusted hazard ratio for 30-day mortality from the combination therapy was 1.646 (95% confidence interval, 0.782-3.461; P = 0.189) in the Cox proportional hazards model. Moreover, there was no significant difference in the appropriateness of initial empiric antibiotics between the two groups (55.0% vs. 56.8%, P = 0.898). The proportion of multidrug-resistant (MDR) pathogens was high in both groups. CONCLUSION: Empiric anti-pseudomonal fluoroquinolone combination therapy showed no survival benefit compared to ß-lactam monotherapy in patients with HAP. Caution is needed regarding the routine combination of fluoroquinolones in the empiric treatment of HAP patients with a high risk of MDR.

Vasopressor Initiation Within 1 Hour of Fluid Loading Is Associated With Increased Mortality in Septic Shock Patients: Analysis of National Registry Data.

OBJECTIVES: To investigate whether administration of a vasopressor within 1 hour of first fluid loading affected mortality and organ dysfunction in septic shock patients. DESIGN: Prospective, multicenter, observational study. SETTING: Sixteen tertiary or university hospitals in the Republic of Korea. PATIENTS: Patients with septic shock (n = 415) were classified into early and late groups according to whether the vasopressor was initiated within 1 hour of the first resuscitative fluid load. Early (n = 149) patients were 1:1 propensity matched to late (n = 149) patients. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: The median time from the initial fluid bolus to vasopressor was shorter in the early group (0.3 vs 2.3 hr). There was no significant difference in the fluid bolus volume within 6 hours (33.2 vs 35.9 mL/kg) between the groups. The Sequential Organ Failure Assessment score and lactate level on day 3 in the ICU were significantly higher in the early group than that in the late group (Sequential Organ Failure Assessment, 9.2 vs 7.7; lactate level, 2.8 vs 1.7 mmol/L). In multivariate Cox regression analyses, early vasopressor use was associated with a significant increase in the risk of 28-day mortality (hazard ratio, 1.83; 95% CI, 1.26-2.65). CONCLUSIONS: Vasopressor initiation within 1 hour of fluid loading was associated with higher 28-day mortality in patients with septic shock.

Outcomes of Patients on the Lung Transplantation Waitlist in Korea: A Korean Network for Organ Sharing Data Analysis.

BACKGROUND: The demand for lung transplants continues to increase in Korea, and donor shortages and waitlist mortality are critical issues. This study aimed to evaluate the factors that affect waitlist outcomes from the time of registration for lung transplantation in Korea. METHODS: Data were obtained from the Korean Network for Organ Sharing for lung-only registrations between September 7, 2009, and December 31, 2020. Post-registration outcomes were evaluated according to the lung disease category, blood group, and age. RESULTS: Among the 1,671 registered patients, 49.1% had idiopathic pulmonary fibrosis (group C), 37.0% had acute respiratory distress syndrome and other interstitial lung diseases (group D), 7.2% had chronic obstructive pulmonary disease (group A), and 6.6% had primary pulmonary hypertension (group B). Approximately half of the patients (46.1%) were transplanted within 1 year of registration, while 31.8% died without receiving a lung transplant within 1 year of registration. Data from 1,611 patients were used to analyze 1-year post-registration outcomes, which were classified as transplanted (46.1%, n = 743), still awaiting (21.1%, n = 340), removed (0.9%, n = 15), and death on waitlist (31.8%, n = 513). No significant difference was found in the transplantation rate according to the year of registration. However, significant differences occurred between the waitlist mortality rates (P = 0.008) and the still awaiting rates (P = 0.009). The chance of transplantation after listing varies depending on the disease category, blood type, age, and urgency status. Waitlist mortality within 1 year was significantly associated with non-group A disease (hazard ratio [HR], 2.76, P < 0.001), age ≥ 65 years (HR, 1.48, P < 0.001), and status 0 at registration (HR, 2.10, P < 0.001). CONCLUSION: Waitlist mortality is still higher in Korea than in other countries. Future revisions to the lung allocation system should take into consideration the high waitlist mortality and donor shortages.

Performance Changes Following the Revision of Organ Allocation System of Lung Transplant: Analysis of Korean Network for Organ Sharing Data.

BACKGROUND: There is currently a lack of data on the impact of the recent revision of the domestic lung allocation system on transplant performance. METHODS: We conducted a retrospective analysis of transplant candidates and transplant patients registered in Korean Network for Organ Sharing between July 2015 and July 2019. Study periods were classified according to the introduction of the revised lung allocation system as follows: period 1 from July 2015 to June 2017 and period 2 from August 2017 to July 2019. RESULTS: During the study period, a total of 627 patients were on the waiting list, of which 398 lung transplantations were performed. Total waiting list size increased by 98.6%, from 210 in period 1 to 417 in period 2. The number of transplant patients also increased by 32.7%, from 171 in period 1 to 227 in period 2. The number of donors decreased from 1,042 to 878, whereas the usage rate, i.e., the number of lung donors used for transplantation among the total number of reported lung donors, increased from 16.4% to 25.9%. The proportion of patients with high urgent status at transplantation increased from 45% to 60.4%, whereas those with urgent status decreased from 46.8% to 35.7% (P = 0.006). The use of marginal donor lungs increased from 29.8% to 53.7% (P < 0.001). To adjust urgency status and marginal donor usage between two groups, we conducted a propensity score matching analysis. No significant differences were detected in 1-year survival rates between the two periods after propensity score matching. As well, no significant difference was observed in mortality on the waiting list between the two periods. CONCLUSION: The recent revision of the lung allocation system in Korea did not change the performance of lung transplant in terms of waiting list mortality and 1-year survival. The rapid increase in the volume of waiting list between the two periods increased the waiting time, transplantation of high-urgency patients, and use of marginal lung donors.

Extracorporeal membrane oxygenation as a bridge to lung transplantation: analysis of Korean organ transplantation registry (KOTRY) data.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation has greatly increased. However, data regarding the clinical outcomes of this approach are lacking. The objective of this multicenter prospective observational cohort study was to evaluate lung transplantation outcomes in Korean Organ Transplantation Registry (KOTRY) patients for whom ECMO was used as a bridge to transplantation. METHODS: Between March 2015 and December 2017, a total of 112 patients received lung transplantation and were registered in the KOTRY, which is a prospective, multicenter cohort registry. The entire cohort was divided into two groups: the control group (n = 85, 75.9%) and bridge-ECMO group (n = 27, 24.1%). RESULTS: There were no significant differences in pre-transplant and intraoperative characteristics except for poorer oxygenation, more ventilator use, and longer operation time in the bridge-ECMO group. The prevalence of primary graft dysfunction at 0, 24, 48, and 72 h after transplantation did not differ between the two groups. Although postoperative hospital stays were longer in the bridge-ECMO group than in the control group, hospital mortality did not differ between the two groups (25.9% vs. 13.3%, P = 0.212). The majority of patients (70.4% of the bridge-ECMO group and 77.6% of the control group) were discharged directly to their homes. Finally, the use of ECMO as a bridge to lung transplantation did not significantly affect overall survival and graft function. CONCLUSIONS: Short- and long-term post-transplant outcomes of bridge-ECMO patients were comparable to recipients who did not receive ECMO.

Chlorhexidine bathing of the exposed circuits in extracorporeal membrane oxygenation: an uncontrolled before-and-after study.

BACKGROUND: Although the prevention of extracorporeal membrane oxygenation (ECMO) catheter-related infection is crucial, scientific evidence regarding best practices are still lacking. METHODS: We conducted an uncontrolled before-and-after study to test whether the introduction of disinfection with 2% chlorhexidine gluconate (CHG) and 70% isopropyl alcohol (IPA) of the exposed circuits and hub in patients treated with ECMO would affect the rate of blood stream infection (BSI) and microbial colonization of the ECMO catheter. We compared the microbiological and clinical data before and after the intervention. RESULTS: A total of 1740 ECMO catheter days in 192 patients were studied. These were divided into 855 ECMO catheter days in 96 patients before and 885 ECMO catheter days in 96 patients during the intervention. The rates of BSI were significantly decreased during the intervention period at 11.7/1000 ECMO catheter days before vs. 2.3/1000 ECMO catheter days during (difference 9.4, 95% confidence interval (CI) 1.5-17.3, p = 0.019). Furthermore, the colonization of the ECMO catheter was similarly significantly reduced during the intervention period at 10.5/1000 ECMO catheter days before vs. 2.3/1000 ECMO catheter days during intervention (difference 8.3, 95% CI 0.7-15.8, p = 0.032). Hospital mortality (41.7% vs. 24%, p = 0.009) and sepsis-related death (17.7% vs. 6.3%, p = 0.014) were also significantly decreased during intervention. CONCLUSION: Extensive disinfection of exposed ECMO circuits and hub with 2% CHG/IPA was associated with a reduction in both BSI and microbial colonization of ECMO catheters. A further randomized controlled study is required to verify these results. TRIAL REGISTRATION: KCT 0004431.

Improvement in the survival rates of extracorporeal membrane oxygenation-supported respiratory failure patients: a multicenter retrospective study in Korean patients.

BACKGROUND: Although the utilization of extracorporeal membrane oxygenation (ECMO) is increasing and its technology is evolving, only a few epidemiologic reports have described the uses and outcomes of ECMO. The aim of this study was to investigate the changes in utilization and survival rate in patients supported with ECMO for severe respiratory failure in Korea. METHODS: This was a multicenter study on consecutive patients who underwent ECMO across 16 hospitals in Korea. The records of all patients who required ECMO for acute respiratory failure between 2012 and 2015 were retrospectively reviewed, and the utilization of ECMO was analyzed over time. RESULTS: During the study period, 5552 patients received ECMO in Korea as a whole, and a total of 2472 patients received ECMO at the participating 16 hospitals. We analyzed 487 (19.7%) patients who received ECMO for respiratory failure. The number of ECMO procedures provided for respiratory failure increased from 104 to 153 during the study period. The in-hospital survival rate increased from 30.8% to 35.9%. The use of prone positioning increased from 6.8% to 49.0% (p < 0.001), and the use of neuromuscular blockers also increased from 28.2% to 58.2% (p < 0.001). Multiple regression analysis showed that old age (OR 1.038 (95% CI 1.022, 1.054)), use of corticosteroid (OR 2.251 (95% CI 1.153, 4.397)), continuous renal replacement therapy (OR 2.196 (95% CI 1.135, 4.247)), driving pressure (OR 1.072 (95% CI 1.031, 1.114)), and prolonged ECMO duration (OR 1.020 (95% CI 1.003, 1.038)) were associated with increased odds of mortality. CONCLUSIONS: Utilization of ECMO and survival rates of patients who received ECMO for respiratory failure increased over time in Korea. The use of pre-ECMO prone positioning and neuromuscular blockers also increased during the same period.

Learning curve for multidisciplinary team setup in veno-venous extracorporeal membrane oxygenation for acute respiratory failure.

BACKGROUND: Quality control is essential for a successful extracorporeal membrane oxygenation program. We investigated the learning curve for outcome improvement and focused on factors associated with failure of extracorporeal membrane oxygenation treatment. METHODS: Between August 2011 and May 2017, 150 patients were supported with veno-venous extracorporeal membrane oxygenation for acute respiratory failure. The learning curve was examined using cumulative sum analysis. We defined successful extracorporeal membrane oxygenation treatment as intensive care unit discharge, acceptable failure rate as 40%, and unacceptable failure rate as 60%. We chronologically divided patients into three periods with 50 consecutive patients each and retrospectively compared the clinical outcomes by period. RESULTS: Overall, weaning and survival to discharge rates were 72.7% and 56%, respectively. Cumulative sum analysis indicated that the extracorporeal membrane oxygenation team achieved nearly acceptable performance after 56 cases and consistently acceptable performance after 104 cases. Clinical outcomes were improved by period: weaning rate (58% vs. 80% vs. 80%, p = 0.017); intensive care unit discharge rate (42% vs. 60% vs. 78%, p = 0.001); survival to discharge rate (40% vs. 58% vs. 70%, p = 0.010); and 1 year survival rate (40% vs. 56% vs. 70%, p = 0.010). In multivariate analysis, infection (odds ratio: 4.54, 95% confidence interval: 1.83-11.27, p = 0.001), immune compromise (odds ratio: 5.78, 95% confidence interval: 1.66-20.14, p = 0.006), extracorporeal membrane oxygenation team period (odds ratio: 2.12, 95% confidence interval: 1.14-3.92, p = 0.017), and age (odds ratio: 1.09, 95% confidence interval: 1.05-1.14, p < 0.001) were associated with extracorporeal membrane oxygenation failure. CONCLUSION: More than 100 cases of extracorporeal membrane oxygenation experience were necessary for acceptable performance and stabilization of outcomes.

Association of TRPV1 and TLR4 through the TIR domain potentiates TRPV1 activity by blocking activation-induced desensitization.

BACKGROUND: We have previously reported that histamine-induced pruritus was attenuated in toll-like receptor 4 (TLR4) knockout mice due to decreased transient receptor potential V1 (TRPV1) sensitivity. Our results implied that TLR4 potentiated TRPV1 activation in sensory neurons; however, the molecular mechanism has yet to be elucidated. In this study, we investigated the molecular mechanisms of TLR4-mediated TRPV1 potentiation using TLR4-deficient sensory neurons and a heterologous expression system. METHODS: Primary sensory neurons were obtained from wild-type or TLR4 knockout mice, and HEK293T cells expressing TRPV1 and TLR4 were prepared by transient transfection. TRPV1 activity was analyzed by calcium imaging, fluorophotometry, and patch-clamp recording. Subcellular protein distribution was tested by immunocytochemistry and cell surface biotinylation assay. Protein interaction was assessed by western blot and immunoprecipitation assay. RESULTS: Direct association between TRPV1 and TLR4 was detected in HEK293T cells upon heterologous TRPV1 and TLR4 expression. In an immunoprecipitation assay using TLR4-deletion mutants and soluble toll/interleukin-1 receptor (TIR) protein, the cytoplasmic TIR domain of TLR4 was required for TLR4-TRPV1 association and TRPV1 potentiation. In TLR4-deficient sensory neurons, the activation-induced desensitization of TRPV1 increased, accompanied by enhanced TRPV1 clearance from the cell membrane upon activation compared to wild-type neurons. In addition, heterologous TLR4 expression inhibited activation-induced TRPV1 endocytosis and lysosomal degradation in HEK293T cells. CONCLUSION: Our data show that direct association between TRPV1 and TLR4 through the TIR domain enhances TRPV1 activity by blocking activation-induced TRPV1 desensitization.