Upregulated microRNA-125b-5p in patients with asthma-COPD overlap mediates oxidative stress and late apoptosis via targeting IL6R/TRIAP1 signaling.

BACKGROUND: Among patients with chronic obstructive pulmonary disease (COPD), some have features of both asthma and COPD-a condition categorized as asthma-COPD overlap (ACO). Our aim was to determine whether asthma- or COPD-related microRNAs (miRNAs) play a role in the pathogenesis of ACO. METHODS: A total of 22 healthy subjects and 27 patients with ACO were enrolled. We selected 6 miRNAs that were found to correlate with COPD and asthma. The expression of miRNAs and target genes was analyzed using quantitative reverse-transcriptase polymerase chain reaction. Cell apoptosis and intracellular reactive oxygen species production were evaluated using flow cytometry. In vitro human monocytic THP-1 cells and primary normal human bronchial epithelial (NHBE) cells under stimuli with cigarette smoke extract (CSE) or ovalbumin (OVA) allergen or both were used to verify the clinical findings. RESULTS: We identified the upregulation of miR-125b-5p in patients with ACO and in THP-1 cells stimulated with CSE plus OVA allergen. We selected 16 genes related to the miR-125b-5p pathway and found that IL6R and TRIAP1 were both downregulated in patients with ACO and in THP-1 cells stimulated with CSE plus OVA. The percentage of late apoptotic cells increased in the THP-1 cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p small interfering RNA (siRNA). The percentage of reactive oxygen species-producing cells increased in the NHBE cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p siRNA. In NHBE cells, siRNA transfection reversed the upregulation of STAT3 under CSE+OVA stimulation. CONCLUSIONS: Our study revealed that upregulation of miR-125b-5p in patients with ACO mediated late apoptosis in THP-1 cells and oxidative stress in NHBE cells via targeting IL6R and TRIAP1. STAT3 expression was also regulated by miR-125b-5p.

Risk factors for prolonged mechanical ventilation in critically ill patients with influenza-related acute respiratory distress syndrome.

BACKGROUND: Patients with influenza-related acute respiratory distress syndrome (ARDS) are critically ill and require mechanical ventilation (MV) support. Prolonged mechanical ventilation (PMV) is often seen in these cases and the optimal management strategy is not established. This study aimed to investigate risk factors for PMV and factors related to weaning failure in these patients. METHODS: This retrospective cohort study was conducted by eight medical centers in Taiwan. All patients in the intensive care unit with virology-proven influenza-related ARDS requiring invasive MV from January 1 to March 31, 2016, were included. Demographic data, critical illness data and clinical outcomes were collected and analyzed. PMV is defined as mechanical ventilation use for more than 21 days. RESULTS: There were 263 patients with influenza-related ARDS requiring invasive MV enrolled during the study period. Seventy-eight patients had PMV. The final weaning rate was 68.8% during 60 days of observation. The mortality rate in PMV group was 39.7%. Risk factors for PMV were body mass index (BMI) > 25 (kg/m2) [odds ratio (OR) 2.087; 95% confidence interval (CI) 1.006-4.329], extracorporeal membrane oxygenation (ECMO) use (OR 6.181; 95% CI 2.338-16.336), combined bacterial pneumonia (OR 4.115; 95% CI 2.002-8.456) and neuromuscular blockade use over 48 h (OR 2.8; 95% CI 1.334-5.879). In addition, risk factors for weaning failure in PMV patients were ECMO (OR 5.05; 95% CI 1.75-14.58) use and bacteremia (OR 3.91; 95% CI 1.20-12.69). CONCLUSIONS: Patients with influenza-related ARDS and PMV have a high mortality rate. Risk factors for PMV include BMI > 25, ECMO use, combined bacterial pneumonia and neuromuscular blockade use over 48 h. In addition, ECMO use and bacteremia predict unsuccessful weaning in PMV patients.

E-cadherin expression in the tumor microenvironment of advanced epidermal growth factor receptor-mutant lung adenocarcinoma and the association with prognosis.

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors. METHODS: The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8+ T lymphocytes and FOXP3+ regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining. RESULTS: Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS. CONCLUSIONS: In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.

Long non-coding RNA FKSG29 regulates oxidative stress and endothelial dysfunction in obstructive sleep apnea.

Altered expressions of pro-/anti-oxidant genes are known to regulate the pathophysiology of obstructive sleep apnea (OSA).We aim to explore the role of a novel long non-coding (lnc) RNA FKSG29 in the development of intermittent hypoxia with re-oxygenation (IHR)-induced endothelial dysfunction in OSA. Gene expression levels of key pro-/anti-oxidant genes, vasoactive genes, and the FKSG29 were measured in peripheral blood mononuclear cells from 12 subjects with primary snoring (PS) and 36 OSA patients. Human monocytic THP-1 cells and human umbilical vein endothelial cells (HUVEC) were used for gene knockout and double luciferase under IHR exposure. Gene expression levels of the FKSG29 lncRNA, NOX2, NOX5, and VEGFA genes were increased in OSA patients versus PS subjects, while SOD2 and VEGFB gene expressions were decreased. Subgroup analysis showed that gene expression of the miR-23a-3p, an endogenous competitive microRNA of the FKSG29, was decreased in sleep-disordered breathing patients with hypertension versus those without hypertension. In vitro IHR experiments showed that knock-down of the FKSG29 reversed IHR-induced ROS overt production, early apoptosis, up-regulations of the HIF1A/HIF2A/NOX2/NOX4/NOX5/VEGFA/VEGFB genes, and down-regulations of the VEGFB/SOD2 genes, while the protective effects of FKSG29 knock-down were abolished by miR-23a-3p knock-down. Dual-luciferase reporter assays confirmed that FKSG29 was a sponge of miR-23a-3p, which regulated IL6R directly. Immunofluorescence stain further demonstrated that FKSGH29 knock-down decreased IHR-induced uptake of oxidized low density lipoprotein and reversed IHR-induced IL6R/STAT3/GATA6/ICAM1/VCAM1 up-regulations. The findings indicate that the combined RNA interference may be a novel therapy for OSA-related endothelial dysfunction via regulating pro-/anti-oxidant imbalance or targeting miR-23a-IL6R-ICAM1/VCAM1 signaling.

Comparison of prone positioning and extracorporeal membrane oxygenation in acute respiratory distress syndrome: A multicenter cohort study and propensity-matched analysis.

BACKGROUND/PURPOSE: Both prone positioning and extracorporeal membrane oxygenation (ECMO) are used as rescue therapies for severe hypoxemia in patients with acute respiratory distress syndrome (ARDS). This study compared outcomes between patients with severe influenza pneumonia-related ARDS who received prone positioning and those who received ECMO. METHODS: This retrospective cohort study included eight tertiary referral centers in Taiwan. All patients who were diagnosed as having influenza pneumonia-related severe ARDS were enrolled between January and March 2016. We collected their demographic data and prone positioning and ECMO outcomes from medical records. RESULTS: In total, 263 patients diagnosed as having ARDS were included, and 65 and 53 of them received prone positioning and ECMO, respectively. The baseline PaO2/FiO2 ratio, Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score did not significantly differ between the two groups. The 60-day mortality rate was significantly higher in the ECMO group than in the prone positioning group (60% vs. 28%, p = 0.001). A significantly higher mortality rate was still observed in the ECMO group after propensity score matching (59% vs. 36%, p = 0.033). In the multivariate Cox regression analysis, usage of prone positioning or ECMO was the single independent predictor for 60-day mortality (hazard ratio: 2.177, p = 0.034). CONCLUSION: While the patients receiving prone positioning had better outcome, the causality between prone positioning and the prognosis is unknown. However, the current data suggested that patients with influenza-related ARDS may receive prone positioning before ECMO support.

First tidal volume greater than 8 mL/kg is associated with increased mortality in complicated influenza infection with acute respiratory distress syndrome.

BACKGROUNDS: Severe influenza infection causes substantial morbidity and mortality worldwide and remains an important threat to global health. This study addressed factors related to treatment outcomes in subjects of complicated influenza infection with acute respiratory distress syndrome (ARDS) during the Taiwan epidemic in the Spring of 2016. METHODS: This is a retrospective study conducted by Taiwan Severe Influenza Research Consortium (TSIRC), including eight tertiary referral medical centers. Patients with virology-proven influenza infection admitted to intensive care unit (ICU) between January and March 2016 were included for analysis. RESULTS: We identified 263 patients with complicated influenza infection who fulfilled ARDS criteria; the mean age was 59.8 ± 14.6 (years), and 66.1% (166/263) were male. Type A influenza (77.9%, 205/263) virus was the main pathogen during this epidemic. The 30-day mortality rate was 23.2% (61/263). The mean tidal volume (VT) in the first three days after intubation was greater than 8 mL/kg of predicted body weight (PBW). Patients whose first measured VT was >8 mL/kg PBW had an increased 30-day mortality (p = 0.04, log-rank test). In a multivariate Cox proportional hazard regression model, an increase of 1 mL/kg PBW of first VT was associated with 26.1% increase in 30-day mortality (adjusted hazard ratio 1.261, 95% confidence interval [CI] 1.072-1.484, p < 0.01). CONCLUSION: First tidal volume, shortly after intubation, greater than 8 mL/kg PBW is an independent risk factor for mortality in complicated influenza infection with ARDS. Timely recognition of ARDS with strict adherence to protective ventilation strategy of lowering VT may be important in reducing mortality.

Impact of epidermal growth factor receptor gene expression level on clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients taking first-line epidermal growth factor receptor-tyrosine kinase inhibitors.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are first-choice treatments for advanced non-small-cell lung cancer patients harboring EGFR mutations. Although EGFR mutations are strongly predictive of patients' outcomes and their response to treatment with EGFR-TKIs, early failure of first-line therapy with EGFR-TKIs in patients with EGFR mutations is not rare. Besides several clinical factors influencing EGFR-TKI efficacies studied earlier such as the Eastern Cooperative Oncology Group performance status or uncommon mutation, we would like to see whether semi-quantify EGFR mutation gene expression calculated by 2-ΔΔct was a prognostic factor in EGFR-mutant non-small cell lung cancer patients receiving first-line EGFR-TKIs. This retrospective study reviews 926 lung cancer patients diagnosed from January 2011 to October 2013 at the Kaohsiung Chang Gung Memorial Hospital in Taiwan. Of 224 EGFR-mutant adenocarcinoma patients, 148 patients who had 2-ΔΔct data were included. The best cutoff values of 2-ΔΔct for in-frame deletions in exon 19 (19 deletion) and a position 858 substituted from leucine (L) to an arginine (R) in exon 21 (L858R) were determined using receiver operating characteristic curves. Patients were divided into high and low 2-ΔΔct expression based on the above cutoff level. The best cutoff point of 2-ΔΔct value of 19 deletion and L858R was 31.1 and 104.7, respectively. In all, 92 (62.1%) patients showed high 2-ΔΔct expression and 56 patients (37.9%) low 2-ΔΔct expression. The mean age was 65.6 years. Progression-free survival of 19 deletion mutant patients with low versus high expression level was 17.07 versus 12.04 months (P = 0.004), respectively. Progression-free survival of L858 mutant patients was 13.75 and 7.96 months (P = 0.008), respectively. EGFR-mutant lung adenocarcinoma patients with lower EGFR gene expression had longer progression-free survival duration without interfering overall survival.

Time courses and value of circulating microparticles in patients with operable stage non-small cell lung cancer undergoing surgical intervention.

Microparticles (MPs) are substantially increased in patients with operable stage non-small cell lung cancer (NSCLC) prior to lung resection surgery. This study tested the hypothesis that there is a decrease in MPs after surgical intervention. Between March 2012 and January 2015, 33 patients who had operable stage NSCLC were consecutively and prospectively enrolled into the study. Additionally, 31 healthy subjects who were consecutively enrolled in the study period served as age- and gender-matched controls. Circulating MPs (EDAc-MPs, EDAp-MPs, PDAc-MPs, PDAp-MPs) were measured by flow cytometry once in control subjects and twice (i.e., prior to and three months later after surgical intervention) in NSCLC patients. Compared with control subjects, these four types of circulating MPs were significantly higher in NSCLC patients prior to operation (all P < 0.005), but did not differ among the controls and NSCLC patients at 3 months after surgery (all P > 0.2). Additionally, a receiver operating characteristic curve (ROC) showed that these four types of MPs were significantly valuable predictors for detecting early stage NSCLC (all P < 0.004). Circulating MPs which were remarkably increased in the operable stage of NSCLC prior to surgery were substantially decreased 3 months later after surgery. These findings show that circulating MPs might be an accessory biomarker for monitoring those of NSCLC after receiving lung resection surgery.

Impact of clinical parameters and systemic inflammatory status on epidermal growth factor receptor-mutant non-small cell lung cancer patients readministration with epidermal growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) readministration to lung cancer patients is common owing to the few options available. Impact of clinical factors on prognosis of EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKI readministration after first-line EGFR-TKI failure and a period of TKI holiday remains unclear. Through this retrospective study, we aimed to understand the impact of clinical factors in such patients. METHODS: Of 1386 cases diagnosed between December 2010 and December 2013, 80 EGFR-mutant NSCLC patients who were readministered TKIs after failure of first-line TKIs and intercalated with at least one cycle of cytotoxic agent were included. We evaluated clinical factors that may influence prognosis of TKI readministration as well as systemic inflammatory status in terms of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR). Baseline NLR and LMR were estimated at the beginning of TKI readministration and trends of NLR and LMR were change amount from patients receiving first-Line TKIs to TKIs readministration. RESULTS: Median survival time since TKI readministration was 7.0 months. In the univariable analysis, progression free survival (PFS) of first-line TKIs, baseline NLR and LMR, and trend of LMR were prognostic factors in patients receiving TKIs readministration. In the multivariate analysis, only PFS of first-line TKIs (p < 0.001), baseline NLR (p = 0.037), and trend of LMR (p = 0.004) were prognostic factors. CONCLUSION: Longer PFS of first-line TKIs, low baseline NLR, and high trend of LMR were good prognostic factors in EGFR-mutant NSCLC patients receiving TKI readministration.

Sequential oxygenation index and organ dysfunction assessment within the first 3 days of mechanical ventilation predict the outcome of adult patients with severe acute respiratory failure.

OBJECTIVE: To determine early predictors of outcomes of adult patients with severe acute respiratory failure. METHOD: 100 consecutive adult patients with severe acute respiratory failure were evaluated in this retrospective study. Data including comorbidities, Sequential Organ Failure Assessment (SOFA) score, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) score, PaO2, FiO2, PaO2/FiO2, PEEP, mean airway pressure (mPaw), and oxygenation index (OI) on the 1st and the 3rd day of mechanical ventilation, and change in OI within 3 days were recorded. Primary outcome was hospital mortality; secondary outcome measure was ventilator weaning failure. RESULTS: 38 out of 100 (38%) patients died within the study period. 48 patients (48%) failed to wean from ventilator. Multivariate analysis showed day 3 OI (P=0.004) and SOFA (P=0.02) score were independent predictors of hospital mortality. Preexisting cerebrovascular accident (CVA) (P=0.002) was the predictor of weaning failure. Results from Kaplan-Meier method demonstrated that higher day 3 OI was associated with shorter survival time (log-Rank test, P<0.001). CONCLUSION: Early OI (within 3 days) and SOFA score were predictors of mortality in severe acute respiratory failure. In the future, prospective studies measuring serial OIs in a larger scale of study cohort is required to further consolidate our findings.

Survival outcomes of east Asian patients with advanced non-small cell lung cancer treated with first-line EGFR tyrosine kinase inhibitors: A network meta-analysis of real-world evidence.

BACKGROUND: The comparative efficacies of different generation tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) remain largely unknown. Moreover, whether one EGFR-TKI confers superior survival remains unclear, especially in East Asians. We conducted a network meta-analysis (NMA) comparing the survival outcomes of East Asian patients with advanced NSCLC treated with first-line EGFR-TKIs. METHODS: The NMA included observational real-world evidence studies on adult patients with EGFR-mutated advanced NSCLC who received first (gefitinib and erlotinib), second (afatinib), or third (osimertinib) generation EGFR-TKIs as frontline therapy. Studies were identified through an online bibliographic search of Medline articles in the PubMed, SCOPUS, Web of Science, and Cochrane Library databases. RESULTS: For overall survival (OS), afatinib had significantly better hazard ratios (HRs) than osimertinib (HR: 0.46, 95% confidence interval [CI]: 0.23-0.91), gefitinib (HR: 0.56, 95% CI: 0.43-0.72), and erlotinib (HR: 0.71, 95% CI: 0.54-0.92). For progression-free survival (PFS), afatinib had significantly better HRs than gefitinib (HR: 0.45, 95% CI: 0.36-0.56) and erlotinib (HR: 0.63, 95% CI: 0.49-0.81). Moreover, afatinib was most likely to achieve the longest OS (81.3%), followed by erlotinib (13%), osimertinib, and gefitinib. Furthermore, afatinib was most likely to achieve the longest PFS (48.3%), followed by osimertinib (34.9%) and erlotinib. CONCLUSIONS: This real-world evidence shows that afatinib confers better survival than other first-line EGFR-TKIs in East Asian patients with advanced NSCLC.

Do patient characteristics affect EGFR tyrosine kinase inhibitor treatment outcomes? A network meta-analysis of real-world survival outcomes of East Asian patients with advanced non-small cell lung cancer treated with first-line EGFR-TKIs.

BACKGROUND: Despite the well-established efficacies of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), there is limited real-world evidence comparing their effectiveness according to patients' clinical characteristics. This network meta-analysis (NMA) compared survival outcomes among first-line EGFR-TKIs in different subgroups of East Asian patients with advanced NSCLC. METHODS: This NMA included real-world observational studies reporting outcomes with TKIs in patients aged >65 years, with baseline brain metastasis, with different Eastern Cooperative Oncology Group (ECOG) statuses, or with different common EGFR mutation types. RESULTS: In patients with the EGFR L858R mutation, afatinib resulted in significantly longer progression-free survival (PFS) than erlotinib (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.46-0.75) and gefitinib (HR: 0.41, 95% CI: 0.32-0.53). Similarly, in patients with the EGFR Del19 mutation, afatinib and erlotinib resulted in significantly longer PFS than gefitinib (HR: 0.48 with 95% CI: 0.33-0.71 and HR: 0.54 with 95% CI: 0.36-0.80, respectively). Moreover, afatinib resulted in significantly longer PFS than gefitinib in patients with brain metastasis (HR: 0.53, 95% CI: 0.33-0.87) or ECOG status 0-1 (HR: 0.37, 95% CI: 0.23-0.59). CONCLUSION: This NMA suggests that afatinib results in similar PFS to erlotinib and superior PFS than gefitinib in patients with Del19 mutant NSCLC, aged ≥65 years, with ECOG scores of 0-1, and with baseline brain metastasis.

Autophagy impairment in patients with obstructive sleep apnea modulates intermittent hypoxia-induced oxidative stress and cell apoptosis via hypermethylation of the ATG5 gene promoter region.

BACKGROUND: Autophagy is a catabolic process that recycles damaged organelles and acts as a pro-survival mechanism, but little is known about autophagy dysfunction and epigenetic regulation in patients with obstructive sleep apnea (OSA). METHODS: Protein/gene expressions and DNA methylation levels of the autophagy-related genes (ATG) were examined in blood leukocytes from 64 patients with treatment-naïve OSA and 24 subjects with primary snoring (PS). RESULTS: LC3B protein expression of blood monocytes, and ATG5 protein expression of blood neutrophils were decreased in OSA patients versus PS subjects, while p62 protein expression of cytotoxic T cell was increased, particularly in those with nocturia. ATG5, ULK1, and BECN1 gene expressions of peripheral blood mononuclear cells were decreased in OSA patients versus PS subjects. LC3B gene promoter regions were hypermethylated in OSA patients, particularly in those with excessive daytime sleepiness, while ATG5 gene promoter regions were hypermethylated in those with morning headache or memory impairment. LC3B protein expression of blood monocytes and DNA methylation levels of the LC3B gene promoter region were negatively and positively correlated with apnea hyponea index, respectively. In vitro intermittent hypoxia with re-oxygenation exposure to human THP-1/HUVEC cell lines resulted in LC3B/ATG5/ULK1/BECN1 down-regulations and p62 up-regulation along with increased apoptosis and oxidative stress, while rapamycin and umbilical cord-mesenchymal stem cell treatment reversed these abnormalities through de-methylation of the ATG5 gene promoter. CONCLUSIONS: Impaired autophagy activity in OSA patients was regulated by aberrant DNA methylation, correlated with clinical phenotypes, and contributed to increased cell apoptosis and oxidative stress. Autophagy enhancers may be novel therapeutics for OSA-related neurocognitive dysfunction.

Association of baseline parameters with year 0 and year 1 acute exacerbations in male patients with chronic obstructive pulmonary disease.

OBJECTIVES: Acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) can affect health status, hospitalization and readmission rates, and disease progression. This study aimed to identify independent markers associated with COPD AEs. METHODS: This study included male patients with COPD and collected data regarding their AEs and baseline clinical parameters. RESULTS: We included 149 male patients. Among them, 58 were included in the year 0 high-AE group and 91 in the low-AE group. Multivariate analysis revealed that the high-AE group had higher white blood cell count, lower serum albumin level, and post-bronchodilator (BD) forced expiratory volume in one second (FEV1) (%) with a combined receiver operating characteristic curve (ROC) of 0.721 (p < 0.001). Additionally, 34 patients were included in the year 1 high-AE group and 70 in the low-AE group (p < 0.001). Multivariate analysis revealed that the high-AE group had higher platelet count, positive asthma history, and lower pre-BD FEV1 (%) with a combined ROC of 0.782 (p < 0.001). CONCLUSION: In male patients with COPD, baseline white blood cell count, albumin level, and post-BD FEV1 (%) were correlated with year 0 AE; on the other hand, baseline platelet count, positive asthma history, and pre-BD FEV1 (%) were associated with year 1 AE.

The Survival of Septic Patients with Compensated Liver Cirrhosis Is Not Inferior to That of Septic Patients without Liver Cirrhosis: A Propensity Score Matching Analysis.

Background: We aimed to determine whether septic patients with liver cirrhosis (LC) had worse survival than septic patients without liver cirrhosis (WLC). We also investigated the survival of septic patients with compensated liver cirrhosis (CLC) and decompensated liver cirrhosis (DLC). Methods: This study enrolled 776 consecutive adult patients with sepsis admitted to the medical intensive care units of a tertiary referral hospital. Clinical factors and laboratory data were collected for analysis. Propensity scoring was also used for the control of selection bias. The variables included in the propensity model were age, sex, presence of diabetes mellitus, hypertension, cardiovascular accident, chronic kidney disease, malignancy, APCHE II (Acute Physiology and Chronic Health Evaluation) score, hemoglobin, and platelet data on the day when sepsis was confirmed. Seven-day, ICU, and hospital mortality were analyzed after correcting for these confounding factors. Results: Of the 776 septic patients, 64 (8.2%) septic patients presented with LC. Patients were divided into two groups­LC (n = 64) and WLC (n = 712)­which presented different rates of hospital mortality (LC: 62.5% vs. WLC: 41.0%, p = 0.001). We further separated septic patients with LC into two groups: patients with CLC (n = 24) and those with DLC (n = 40). After propensity score matching, the survival of septic patients with CLC (63.6%) was not inferior to patients WLC (54.5%) (p = 0.411). Patients with DLC had more hospital mortality, even after matching (p < 0.05). The Quick SOFA (qSOFA) score, SOFA score, and sub-SOFA score were also comparable between groups. SOFA scores were not significantly different between the CLC and WLC groups after matching. Poor SOFA scores were observed in the DLC group on days 3 and 7 after matching (p < 0.05). Conclusions: Septic patients with LC had higher mortality compared to patients WLC before matching. However, after propensity score matching, the survival of septic patients with CLC was non-inferior to patients WLC.

Association of Hypernatremia with Immune Profiles and Clinical Outcomes in Adult Intensive Care Unit Patients with Sepsis.

Both hypernatremia and an abnormal immune response may increase hospital mortality in patients with sepsis. This study examined the association of hypernatremia with abnormal immune response and mortality in 520 adult patients with sepsis in an intensive care unit (ICU). We compared the mortality and ex vivo lipopolysaccharide (LPS)-induced inflammatory response differences among patients with hyponatremia, eunatremia, and hypernatremia, as well as between patients with acquired hypernatremia on ICU day 3 and those with sustained eunatremia over first three ICU days. Compared with eunatremia or hyponatremia, hypernatremia led to higher 7 day, 14 day, 28 day, and hospital mortality rates (p = 0.030, 0.009, 0.010, and 0.033, respectively). Compared with sustained eunatremia, acquired hypernatremia led to higher 7, 14, and 28 day mortality rates (p = 0.019, 0.042, and 0.028, respectively). The acquired hypernatremia group nonsignificantly trended toward increased hospital mortality (p = 0.056). Day 1 granulocyte colony-stimulating factor (G-CSF) and tumor necrosis factor (TNF) α levels were relatively low in patients with hypernatremia (p = 0.020 and 0.010, respectively) but relatively high in patients with acquired hypernatremia (p = 0.049 and 0.009, respectively). Thus, in ICU-admitted septic patients, hypernatremia on admission and in ICU-acquired hypernatremia were both associated with higher mortality. The higher mortality in patients with hypernatremia on admission was possibly related to the downregulation of G-CSF and TNF-α secretion after endotoxin stimulation. Compared to sustained eunatremia, acquired hypernatremia showed immunoparalysis at first and then hyperinflammation on day 3.

Dynamic monitoring of kidney injury status over 3 days in the intensive care unit as a sepsis phenotype associated with hospital mortality and hyperinflammation.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) often worsens with the deterioration of a patient's condition. Therefore, we hypothesized that monitoring AKI dynamically from day 1 to day 3 was potential to predict hospital mortality. Specifically, we explored whether monitoring AKI dynamically in the intensive care unit (ICU) could be a sepsis phenotype predictive of mortality. A new classification was established based on the change in the AKI stage from admission day 1 and day 3. We compared the hospital mortality, cytokines, and immune response pattern between each group. METHODS: We retrospectively enrolled 523 patients with sepsis, and we calculated the AKI stages on day 1 and day 3 admission to ICUs. Among these 523 people, 388 of them were assigned to normal, improved, and deteriorated groups according to the changes in the AKI stages. 263 of which did not develop AKI on day 1 and day 3 (normal group). The AKI stage improved in 68 patients (improved group) and worsened in 57 (deteriorated group). We compared the mortality rates between the groups, and identified the relationship between the dynamic AKI status, immune response patterns, and cytokine levels. RESULTS: The hospital mortality rate in the deteriorated group was higher than that in the non-deteriorated group (combination of normal and improved group) (p = 0.004). Additionally, according to the Kaplan-Meier analysis, the non-deteriorated group had a distinct hospital survival curve (p = 0.004). Furthermore, both the overexpression of tumor necrosis factor-α and decreased monocyte expression of human leukocyte antigen-DR were present in the deteriorated group. CONCLUSIONS: The deteriorated group was associated with a higher hospital mortality rate, potentially resulting from an abnormal inflammatory response. Worsening AKI in the first 3 days of ICU admission may be a sepsis phenotype predictive of hospital mortality.

Disrupted Expression of Circadian Clock Genes in Patients with Bronchial Asthma.

PURPOSE: Circadian clock is synchronized to the 24-hour day by the daily light-dark cycle and proper function of circadian rhythm is essential for many physiological processes. Disruption of circadian rhythm can affect disease processes and influence disease severity, treatment responses, and even survivorship. In this retrospective case-controlled study, we tried to explore whether expression of circadian clock genes was disturbed in patients with bronchial asthma. PATIENTS AND METHODS: We performed real-time quantitative reverse transcriptase-polymerase chain reactions to examine the expression of the nine core circadian clock genes (BMAL1, CK1ε, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIM) in total leukocytes of peripheral blood collected at chest clinics from 120 patients with asthma and 60 health individuals. RESULTS: Expression levels of the nine circadian clock genes were significantly different between patients and healthy individuals, but not associated with the asthma control status. We also noted the difference of PER3 expression in asthmatic patients with and without nocturnal symptoms. In well-controlled asthmatics, expression of BMAL1, CK1ε, CLOCK, CRY1, CRY2, and PER1 was significantly lower in patients with nocturnal symptoms than those without nocturnal symptoms. However, in not well-controlled asthmatics, expression of only BMAL1, CK1ε, PER1, and PER2 was significantly different between patients with and without nocturnal symptoms. Binary logistic regression analysis selected BMAL1, CKIε, PER3, and TIM as independent factors for bronchial asthma and ROC curves showed the combined expression of these four genes enhanced the capability of predicting asthma (AUC=0.924; 95% CI=0.875-0.958; P<0.001). CONCLUSION: Our results showed altered expression of circadian clock genes in patients with bronchial asthma and down-regulated PER3 in patients with nocturnal symptoms. Altered expression of circadian clock genes was also observed in asthmatics with or without nocturnal symptoms in well- or not well-controlled subgroups. Combined expression of BMAL1, CKIε, PER3, and TIM could be a potential predictor for bronchial asthma.

Impact of Body Mass Index on the Survival of Patients with Sepsis with Different Modified NUTRIC Scores.

Nutritional status affects the survival of patients with sepsis. This retrospective study analyzed the impact of body mass index (BMI) and modified nutrition risk in critically ill (mNUTRIC) scores on survival of these patients. Data of 1291 patients with sepsis admitted to the intensive care unit (ICU) were extracted. The outcomes were mortality, duration of stay, ICU stay, and survival curve for 90-day mortality. Logistic regression analysis was performed to examine the risk factors for mortality. Cytokine and biomarker levels were analyzed in 165 patients. The 90-day survival of underweight patients with low mNUTRIC scores was significantly better than that of normal-weight patients with low mNUTRIC scores (70.8% vs. 58.3%, respectively; p = 0.048). Regression model analysis revealed that underweight patients with low mNUTRIC scores had a lower risk of mortality (odds ratio = 0.557; p = 0.082). Moreover, normal-weight patients with low mNUTRIC scores had the lowest human leukocyte antigen DR (HLA-DR) level on days 1 (underweight vs. normal weight vs. overweight: 94.3 vs. 82.1 vs. 94.3, respectively; p = 0.007) and 3 (91.8 vs. 91.0 vs. 93.2, respectively; p = 0.047). Thus, being underweight may not always be harmful if patients have optimal clinical nutritional status. Additionally, HLA-DR levels were the lowest in patients with low survival.

Application of a 72 h National Early Warning Score and Incorporation with Sequential Organ Failure Assessment for Predicting Sepsis Outcomes and Risk Stratification in an Intensive Care Unit: A Derivation and Validation Cohort Study.

We investigated the best timing for using the National Early Warning Score 2 (NEWS2) for predicting sepsis outcomes and whether combining the NEWS2 and the Sequential Organ Failure Assessment (SOFA) was applicable for mortality risk stratification in intensive care unit (ICU) patients with severe sepsis. All adult patients who met the Third International Consensus Definitions for Sepsis and Septic Shock criteria between August 2013 and January 2017 with complete clinical parameters and laboratory data were enrolled as a derivation cohort. The primary outcomes were the 7-, 14-, 21-, and 28-day mortalities. Furthermore, another group of patients under the same setting between January 2020 and March 2020 were also enrolled as a validation cohort. In the derivation cohort, we included 699 consecutive adult patients. The 72 h NEWS2 had good discrimination for predicting 7-, 14-, 21-, and 28-day mortalities (AUC: 0.780, 0.724, 0.700, and 0.667, respectively) and was not inferior to the SOFA (AUC: 0.740, 0.680, 0.684, and 0.677, respectively). With the new combined NESO tool, the hazard ratio was 1.854 (1.203-2.950) for the intermediate-risk group and 6.810 (3.927-11.811) for the high-risk group relative to the low-risk group. This finding was confirmed in the validation cohort using a separated survival curve for 28-day mortality. The 72 h NEWS2 alone was non-inferior to the admission SOFA or day 3 SOFA for predicting sepsis outcomes. The NESO tool was found to be useful for 7-, 14-, 21-, and 28-day mortality risk stratification in patients with severe sepsis.