Serum chemokine IL-8 acts as a biomarker for identifying COVID-19-associated persistent severe acute kidney injury.

OBJECTIVES: Persistent severe acute kidney injury (PS-AKI) is associated with poor clinical outcomes. Our study attempted to evaluate the diagnostic value of chemokines for early-stage PS-AKI prediction. METHODS: According to the KDIGO criteria, 115 COVID-19 patients diagnosed with stage 2/3 AKI were recruited from the intensive care unit between December 2022 and February 2023. Primary clinical outcomes included detecting PS-AKI in the first week (≥ KDIGO stage 2 ≥ 72 h). Cytometric Bead Array was used to detect patient plasma levels (interleukin-8 (IL-8), C-C chemokine ligand 5 (CCL5), chemokine (C-X-C Motif) ligand 9 (CXCL9), and interferon-inducible protein 10 (IP-10)) of chemokines within 24 h of enrollment. RESULTS: Of the 115 COVID-19 patients with stage 2/3 AKI, 27 were diagnosed with PS-AKI. Among the four measured chemokines, only the IL-8 level was significantly elevated in the PS-AKI group than in the Non-PS-AKI group. IL-8 was more effective as a biomarker while predicting PS-AKI with an area under the curve of 0.769 (0.675-0.863). This was superior to other biomarkers related to AKI, including serum creatinine. Moreover, plasma IL-8 levels of >32.2 pg/ml on admission could predict PS-AKI risk (sensitivity = 92.6%, specificity = 51.1%). Additionally, the IL-8 level was associated with total protein and IL-6 levels. CONCLUSION: Plasma IL-8 is a promising marker for the early identification of PS-AKI among COVID-19 patients. These findings should be validated in further studies with a larger sample size.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Vaccination for Negative Conversion Time of Nucleic Acid in Nonsevere COVID-19 Patients Infected by SARS-CoV-2 Omicron Variant.

SARS-CoV-2 Omicron variant is significantly different from all the previous variants and has rapidly replaced other variants as the dominant variant across the globe. An easily obtained, inexpensive, and rapid marker is needed to predict the negative conversion time (NCT) of nucleic acid in nonsevere COVID-19 patients infected by the Omicron variant. This retrospective study enrolled 226 patients infected by the Omicron variant between April 23, 2022, and May 16, 2022. The median age of the patients was 61 (interquartile range (IQR), 48-70) years, and 56.2% were male. 84 patients (37.2%) had at least one comorbidity, and 49 patients (21.7%) were classified into the moderate illness group. 145 patients (64.2%) received at least one dose of vaccine, in which 67 patients (29.6%) received a booster dose of vaccine. The median duration of NCT was 8 (IQR, 7-11) days. Univariate Cox analyses found that high NLR (>2.22), aged ≥65 years, vaccination, and moderate illness were significantly related to the NCT of nucleic acid. Multivariate Cox regression analysis showed that high NLR (NLR > 2.22, hazard ratio (HR):0.718, 95% CI: 0.534-0.964, p = 0.028) and vaccination (vaccinated ≥1 dose, HR: 1.536, 95% CI: 1.147-2.058, p = 0.004) were independently associated with NCT of nucleic acid. NLR is a rapid, simple, and useful prognostic factor for predicting NCT of nucleic acid in nonsevere COVID-19 patients with the Omicron variant. In addition, vaccination may also play a valuable role in predicting the NCT of nucleic acid.

Impact of Different Traditional Chinese Medicine Constitutions on the Clinical Outcomes of COVID-19 Patients Infected with SARS-CoV-2 Omicron Variant: A Retrospective Observational Study.

Purpose: Traditional Chinese Medicine (TCM) constitution and disease occurrence, development, and prognosis are interrelated. This study aimed to investigate the association between TCM constitution and the time to negative nucleic acid test results in patients with coronavirus disease 2019 (COVID-19) infected with the SARS-CoV-2 Omicron variant. Patients and Methods: We identified COVID-19 patients (≥18 years) infected with the SARS-CoV-2 Omicron variant and collected clinical data, including clinical symptoms, time to negative nucleic acid test results, and TCM constitution. Linear and logistic regression analyses explored the relationship between TCM constitution and the time to negative nucleic acid test results in patients with the COVID-19 Omicron variant. Results: We included 486 patients with COVID-19, with a mean age of 40.2 years; 321 (66.0%) men and 165 (34.0%) women. Balanced constitution accounted for 43.8%, and unbalanced constitution accounted for 56.2%. Chi-square test showed that different TCM constitutions had significant differences in the influence of clinical symptoms of COVID-19 patients (P < 0.01). After controlling for various factors, multiple linear regression analysis revealed that an unbalanced constitution was significantly positively correlated with time to negative nucleic acid test results (P < 0.05). After controlling for various factors, logistic regression analysis revealed that an unbalanced constitution was closely related to the 7-day nucleic acid test conversion rate (odds ratio (OR): 0.53, 95% confidence interval (CI): 0.36-0.80, P < 0.05). After dividing the unbalanced constitution into deficiency constitution and non-deficiency constitution, the non-deficiency constitution was closely associated with the 7-day nucleic acid test conversion rate (OR = 0.45, 95% CI: 0.28-0.74, P < 0.05). Further analysis revealed that damp-heat constitution in the non-deficiency constitution was associated with the 7-day nucleic acid test conversion rate (OR = 0.33, 95% CI: 0.18-0.60, P < 0.05). Conclusion: In patients with COVID-19, an unbalanced constitution is associated with a longer time to negative nucleic acid test results and lower 7-day nucleic acid test conversion rates.

Analysis of mitochondrial function in lymphocytes obtained from COVID-19 patients.

OBJECTIVES: There is a significant decline in the lymphocyte subset counts in the peripheral blood of COVID-19 patients. However, the mitochondrial function of lymphocytes obtained from COVID-19 patients has rarely been studied. METHODS: A case-control study was conducted in 115 COVID-19 patients and 50 healthy controls from December 2022 to February 2023. The extent of lymphocytic mitochondrial damage in these patients using mitochondrial fluorescence staining and flow cytometry. Clinical symptoms were evaluated using the SOFA and APACHE II scores. RESULTS: The mitochondrial function of lymphocytes was severely impaired in the peripheral blood of COVID-19 patients, compared to healthy controls, and was characterized by an increased single-cell mitochondrial mass (SCMM) and increased percentage of low mitochondrial membrane potential. The increase in the SCMM of T cells was more notable in patients with severe COVID-19 and was positively correlated with the SOFA and APACHE II scores. When the SCMM-CD8 cutoff value was 38.775, the AUC for distinguishing between severe and mild COVID-19 was 0.740, and the sensitivity, specificity, and Youden index were 65.8%, 82.1%, and 0.478, respectively. CONCLUSION: SCMM-CD8 could act as a diagnostic biomarker of COVID-19 progression. However, this needs to be verified in other multi-center studies with a larger sample size.

Factors associated with COVID-19 vaccination coverage in hypertensive patients with Omicron infection in Shanghai, China.

The potential future burden of COVID-19 is determined by the level of susceptibility of the population to infection. The protective effect provided by those previously infected diminishes over several months, while individuals with mixed immunity have the highest degree and persistence of protection. This study aimed to clarify the vaccination status of COVID-19 patients with hypertension and to analyze the characteristics and risk factors of non-vaccinated patients to protect this vulnerable population in the future. The study ultimately enrolled 4576 hypertensive patients with Omicron infection from April 6, 2022, to May 15, 2022. Among them, 3556 patients (77.7%) had received at least one dose of vaccine, and 2058 patients (45.0%) received a booster dose. In the multivariate logistic analysis, male (OR 1.328, 95% CI 1.138-1.550, p < .001), age (60-69 years vs.18-49 years) (OR 0.348, 95% CI 0.270-0.448, p < .001), age (≥70 years vs.18-49 years) (OR 0.130, 95% CI 0.100-0.169, p < .001), diabetes mellitus (OR 0.553, 95% CI 0.463-0.661, p < .001), chronic pulmonary diseases (OR 0.474, 95% CI 0.260-0.863, p = .015), chronic kidney disease (OR 0.177, 95% CI 0.076-0.410, p < .001), and cancer (OR 0.225, 95% CI 0.094-0.535, p = .001) were associated with vaccinated status. The vaccine coverage rate, especially the booster vaccine, was low for hypertensive patients with Omicron infection. Females, increasing age, and coexisting chronic diseases were associated with more inadequate vaccine coverage in hypertensive COVID-19 patients. Targeted interventions are required to address the under-vaccination of diverse hypertensive populations.

Effects of intravenous sivelestat sodium on prevention of acute respiratory distress syndrome in patients with sepsis: study protocol for a double-blind multicentre randomised controlled trial.

INTRODUCTION: Sepsis is one of the most common risk factors for acute respiratory distress syndrome (ARDS). Neutrophil elastase (NE) is believed to be an important mediator of ARDS. When sepsis occurs, a large number of inflammatory factors are activated and released, which makes neutrophils migrate into the lung, eventually leading to the occurrence of ARDS. Sivelestat sodium is an NE inhibitor that can inhibit the inflammatory reaction during systemic inflammatory response syndrome and alleviate lung injury. Therefore, we hypothesise that intravenous sivelestat sodium may prevent the occurrence of ARDS in patients with sepsis. METHODS AND ANALYSIS: This is a prospective, investigator-initiated, double-blind, adaptive, multicentre, randomised, controlled clinical trial with an adaptive 'sample size re-estimation' design. Patients meeting the inclusion criteria who were transferred into the intensive care unit will be randomly assigned to receive sivelestat sodium or placebo for up to 7 days. The primary outcome is the development of ARDS within 7 days after randomisation. A total of 238 patients will be recruited based on a 15% decrease in the incidence of ARDS in the intervention group in this study. A predefined interim analysis will be performed to ensure that the calculation is reasonable after reaching 50% (120) of the planned sample size. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of ZhongDa Hospital affiliated to Southeast University (identifier: Clinical Ethical Approval No. 2021ZDSYLL153-P03). Results will be submitted for publication in peer-reviewed journals and presented at relevant conferences and meetings. TRIAL REGISTRATION NUMBER: NCT04973670.

Association between diastolic blood pressure during the first 24 h and 28-day mortality in patients with septic shock: a retrospective observational study.

BACKGROUND: Although the mean arterial pressure (MAP) target of 65 mmHg was achieved, diastolic blood pressure (DBP) was still low in some septic shock patients. The effects of DBP on the prognosis and optimal target for patients with septic shock are unclear. We sought to investigate the relationship between DBP and 28-day mortality in septic shock patients. METHODS: In this retrospective observational study, we obtained data from the Chinese Database in Intensive Care (CDIC). We included patients with an admission diagnosis of septic shock and shock was controlled. DBP was measured every 1 h, and the mean DBP during the first 24 h (mDBP24h) was recorded. The primary outcome was 28-day mortality. Multivariable logistic regression determined the relationship between mDBP24h and 28-day mortality. RESULTS: In total, 1251 patients were finally included. The 28-day mortality of included septic shock patients was 28.3%. The mDBP24h, not mSBP24h, was higher among 28-day survivors compared with non-survivors. 28-day mortality was inversely associated with mDBP24h (unadjusted OR 0.814 per 10 mmHg higher mDBP24h, P = 0.003), with a stepwise increase in 28-day mortality at lower mDBP24h. The 28-day mortality of patients with mDBP24h < 59 mmHg had an absolute risk reduction of 9.4% (P = 0.001). And mDBP24h < 59 mmHg was the remaining high risk factor inversely associated with 28-day mortality after multivariable adjustment (adjusted OR 1.915, 95% CI 1.037-3.536, P = 0.038), while mMAP24h and mSBP24h were not. CONCLUSION: In patients with septic shock after initial resuscitation, we observed an inverse association between mDBP24h and 28-day mortality. The poor outcomes in patients with mDBP24h < 59 mmHg provide indirect evidence supporting a further DBP goal of 59 mmHg for patients with septic shock after MAP of 65 mmHg was achieved.

Remifentanil versus Fentanyl for Analgesia in Mechanically Ventilated Patients: A Multicenter, Prospective, Randomized, Double-Blind, Parallel-Group Clinical Trial.

Purpose: Fentanyl is approved for use in many countries as an analgesic for patients requiring mechanical ventilation. However, it redistributes and accumulates easily in the plasma because of its long half-life. Remifentanil is a short context-sensitive half-life analgesic with a lower risk of redistribution and accumulation. Materials and methods: We conducted a multicenter, randomized, double-blind, non-inferiority trial. Critically ill patients requiring mechanical ventilation were randomly allocated to receive an infusion of either remifentanil or fentanyl for up to 72 h. The primary outcome was the analgesic success rate. A 95% confidence interval lower boundary greater than -8% for the difference between the groups was considered to indicate non-inferiority between the drugs. Results: A total of 137 patients received remifentanil (69) or fentanyl (68). Remifentanil's non-inferiority to fentanyl concerning its analgesic success rate was established (difference, 5.97%; 95% confidence interval: -3.99% to 16.35%). Mechanical ventilation duration, extubation duration, successful extubation, intensive care unit discharge, intensive care unit length of stay, and adverse events did not differ significantly between the two groups. Conclusions: Remifentanil was non-inferior to fentanyl regarding the analgesic success rate in critically ill patients requiring mechanical ventilation.

Efficacy of Immature Platelet Fraction in Predicting Septic Acute Kidney Injury.

BACKGROUND: Immature platelet fraction (IPF) is a new hematological parameter. Although its value in predicting the severity and mortality of sepsis patients has been shown, no study has assessed whether IPF can predict sepsis-associated acute kidney injury (S-AKI). Thus, this study aimed to analyze the predictive value of IPF in the occurrence and mortality of S-AKI. METHODS: Sepsis patients from the intensive care unit were screened and divided into S-AKI (n = 53) and non-S-AKI (n = 71) groups. IPF values were calculated by using the CDR mode of the BC-6800Plus hematology analyzer (Mindary, Shenzhen, China). Relevant data, such as serum creatinine (Scr) and uric acid (UA) levels, of the patients were obtained through the hospital information-management system. RESULTS: The sepsis patients with S-AKI had lower high-density lipoprotein (HDL) levels, higher IPF values, higher Scr, UA, C-reactive protein (CRP), and procalcitonin (PCT) levels, and higher SOFA and APACHE Ⅱ scores than the non-S-AKI patients (p < 0.05). IPF value was found correlated with Scr, HDL, CRP, and PCT levels and APACHE Ⅱ score but not with age, UA level, urine output in 24 hours, or SOFA score. Multivariate logistic regression analysis suggested that IPF, UA, and HDL are independent risk factors for S-AKI. The area under the curve (AUC) of IPF in the identification of S-AKI incidence was found superior to the AUC of UA and 1/HDL with a cutoff value of 12.15. However, IPF was not found associated with mortality in S-AKI. CONCLUSIONS: IPF can serve as a biomarker to predict S-AKI in sepsis patients.

Risk Factors and Disease Profile Associated with the Nucleic Acid Conversion Time of COVID-19 Patients Infected with the SARS-CoV-2 Omicron Variant in Fangcang Shelter Hospitals.

Purpose: This study aimed to determine the clinical profile connected to the nucleic acid conversion time of COVID-19 patients harboring the SARS-CoV-2 Omicron variant at the hospitals at the Fangcang shelter. Methods: We reported 39,584 COVID-19 patients who were hospitalized in Shanghai, China, between April 5 and May 5, 2022, and who had contracted the Omicron strain of SARS-CoV-2. Demographic data, medical and vaccination history, clinical symptoms, and NCT were reported for the patient. Results: The median age of the patients with COVID-19 included in this study was 45 (interquartile range [IQR]: 33-54), and 64.2% of them were male. The two most prevalent comorbidities among the patients were hypertension and diabetes. Additionally, we discovered that the percentage of unimmunized patients was negligible (13.2%). We found that male sex, age under 60, and other comorbidities including hypertension and diabetes are significant risk factors for extending NCT when we analyzed the risk variables for NCT. We discovered that vaccination with two or more doses can significantly reduce NCT. The analysis of the young (18-59 years) and older (60 years) populations produced the same outcomes. Conclusion: Our findings confirm that a full COVID-19 vaccine series or booster doses are highly recommended to significantly reduce NCT. In order to reduce NCT, it is also advised that elderly people who have no clear contraindications take vaccination shots.

Value of Laboratory Indicators in Predicting Pneumonia in Symptomatic COVID-19 Patients Infected with the SARS-CoV-2 Omicron Variant.

Background: The pathogenicity of Omicron is different from that of the previous strains. The value of hematological indicators in patients at high risk of Omicron infection remains unclear. We need rapid, inexpensive and widely available biomarkers to guide the early detection of people at risk of pneumonia and to provide early intervention. We aimed to assess the value of hematological indicators as risk factors for pneumonia in symptomatic COVID-19 patients infected with the SARS-CoV-2 Omicron variant. Patients and Methods: The study enrolled 144 symptomatic COVID-19 patients with Omicron infection. We collected available clinical details, including laboratory tests and CT examinations. Univariate and multivariate logistic analyses and receiver operating characteristic (ROC) curve analyses were used to assess the value of laboratory markers in predicting the development of pneumonia. Results: Among the 144 patients, 50 (34.7%) had pneumonia. The ROC analysis revealed that the areas under the ROC curve (AUC) for leukocytes, lymphocytes, neutrophils, and fibrinogen were 0.603 (95% confidence interval (CI): 0.501-0.704, P=0.043), 0.615 (95% CI: 0.517-0.712, P=0.024), 0.632 (95% CI: 0.534-0.730, P=0.009) and 0.635 (95% CI: 0.539-0.730, P=0.008), respectively. The AUC for neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), fibrinogen to lymphocyte ratio (FLR), and fibrinogen to D-dimer ratio (FDR) were 0.670 (95% CI: 0.580-0.760, P=0.001), 0.632 (95% CI: 0.535-0.728, P=0.009), 0.669 (95% CI: 0.575-0.763, P=0.001) and 0.615 (95% CI: 0.510-0.721, P=0.023), respectively. Univariate analysis showed that elevated levels of NLR (odds ratio (OR): 1.219, 95% CI: 1.046-1.421, P=0.011), FLR (OR: 1.170, 95% CI: 1.014-1.349, P=0.031) and FDR (OR: 1.131, 95% CI: 1.039-1.231, P=0.005) were significantly correlated with the presence of pneumonia. Multivariate analysis indicated elevated NLR (OR: 1.248, 95% CI: 1.068-1.459, P=0.005) and FDR (OR: 1.160, 95% CI: 1.054-1.276, P=0.002) levels were associated with the existence of pneumonia. The AUC for the combination of NLR and FDR was 0.701 (95% CI: 0.606-0.796, P<0.001, sensitivity 56.0%, specificity 83.0%). Conclusion: NLR and FDR can predict the presence of pneumonia in symptomatic COVID-19 patients infected with the SARS-CoV-2 Omicron variant.

Mental health symptoms and sleep quality of asymptomatic/mild SARS-CoV-2 infected individuals during the Omicron wave of the COVID-19 pandemic in Shanghai China.

OBJECTIVE: To investigate mental health symptoms (anxiety, depression, and sleep status) and their associated factors among people infected with the SARS-CoV-2 omicron variant during the quarantine period in Shanghai. METHODS: To investigate the mental health symptoms among participants with SARS-CoV-2 omicron infection, an anonymous online survey questionnaire was used. The survey panel included the 9-item Patient Health Questionnaire-9 (PHQ-9), 7-item Generalized Anxiety Disorder Scale (GAD-7), Pittsburgh Sleep Quality Index (PSQI), and 22-item Ruminative Responses Scale (RRS). Group comparisons and correlation analyses were employed to explore the epidemiological characteristics of patients and factors related to depression and anxiety symptoms. RESULTS: A total of 960 participants completed the survey. Of the total respondents, 583 participants (60.7%) were male, and the mean (SD) age was 34.33 (9.21) years (95% CI: 33.74-34.91). The prevalence of depressive and anxiety symptoms among the participants was 13.7% (n = 151, 95% CI: 11.6%-15.7%) and 8.6% (n = 90, 95% CI: 6.9%-10.3%), respectively. Age-stratified analysis showed that the prevalence of anxiety among the 36- to 45-year-old group (12.9%; n = 35, 8.9%-16.9%) was significantly higher than that of the 18- to 15-year-old group (7.4%; n = 42, 5.3%-9.6%, p = .011). Spearman's correlation analyses showed that rumination (assessed by the RRS) was significantly and positively correlated with depression (rho = .706, p < .001) and anxiety symptoms (rho = .758, p < .001). CONCLUSION: The results suggest that female and middle-aged populations manifest higher susceptibility to mental health distress during the current Omicron wave of the COVID-19 pandemic. Population-specific psychological crisis intervention is warranted to improve the quality of epidemic prevention methods and to promote the mental well-being of the public.

Diagnostic Utility of CD64 and CD38 Biomarkers for the Differential Diagnosis of Infections.

Purpose: Identification of infection type in patients with fever is particularly important in the emergency departments (EDs) of hospitals. This study was designed to evaluate the performance of two biomarkers, the modified neutrophil CD64 (nCD64) index and CD38 presence on T cells, using flow cytometry. Methods: A total of 305 potentially infected patients with fever were admitted to the ED of Zhongda Hospital (Nanjing, China) between March 2021 and August 2021. This study included three groups of patients: bacterial (N = 180), viral (N = 30) , and uninfected (N = 65) based on their final diagnostic outcomes and clinical records. Results: The expression level of traditional/modified nCD64 was significantly increased in the bacterial infection group, especially in case of patients infected with Gram-negative bacteria. The most prevalent species were Staphylococcus spp. and Escherichia coli. In contrast, CD3+CD38+ cell percentages were elevated in patients with viral infections, which were mostly caused by Epstein-Barr virus and cytomegalovirus. CD38 expression is age dependent, and higher percentages of CD3+CD38+ cells were observed in children with viral infections. For the prediction of bacterial infections, the area under the curve (AUC) of modified nCD64 (AUC: 0.800) was significantly higher than that of C-reactive protein and heparin-binding protein but slightly lower than that of traditional nCD64 (AUC: 0.831). The AUC, specificity, and sensitivity values for the prediction of viral infections using CD3+CD38+ cells percentages in children were 0.899 (0.785-1.000), 96.2%, and 85.9%, respectively. Conclusion: nCD64 levels and CD3+CD38+ cell percentage are potential biomarkers that facilitate identification of patients with bacterial and viral infections.

Synbiotic Therapy Prevents Nosocomial Infection in Critically Ill Adult Patients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials Based on a Bayesian Framework.

Background: The efficacy of synbiotics, probiotics, prebiotics, enteral nutrition or adjuvant peripheral parenteral nutrition (EPN) and total parenteral nutrition (TPN) in preventing nosocomial infection (NI) in critically ill adults has been questioned. We conducted a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) to evaluate and rank the effectiveness of these therapies on NI amongst critically ill adults. Methods: Four electronic databases were systematically searched up to June 30, 2019 for RCTs comparing the administration of probiotics, prebiotics, synbiotics, EPN and TPN in critically ill adults. The primary outcome was NI. The relative efficacy of all outcomes was determined by a Bayesian framework with random effects NMA. We estimated the odds ratio (OR) and mean difference (MD) and ranked the comparative effects of all regimens with the surface under the cumulative ranking probabilities. The study has been registered on PROSPERO (CRD42019147032). Results: Fifty-five RCTs (7,119 patients) were identified. Primary outcome showed that synbiotics had the best effect in preventing NI than EPN (OR 0.37; 95% CrI 0.22-0.61), probiotics followed (OR 0.52; 95% CrI 0.34-0.77), whereas TPN significantly increased NI (OR 2.29; 95% CrI 1.48-3.67). Subgroup analysis showed that TPN significantly increased NI in intensive care unit (ICU) patients (OR 1.57; 95% CrI 1.01-2.56) and severe acute pancreatitis (SAP) patients (OR 3.93; 95% CrI 1.74-9.15). Secondary outcomes showed that synbiotics were more effective in preventing hospital-acquired pneumonia (HAP) (OR 0.34; 95% CrI 0.11-0.85), catheter-related bloodstream infection (OR 0.08; 95% CrI 0.01-0.80), urinary tract infection (OR 0.27; 95% CrI 0.08-0.71) and sepsis (OR 0.34; 95% CrI 0.16-0.70) than EPN. Amongst the treatments, probiotics were most effective for shortening the mechanical ventilation duration (MD -3.93; 95% CrI -7.98 to -0.02), prebiotics were most effective for preventing diarrhea (OR 0.24; 95% CrI 0.05-0.94) and TPN was the least effective in shortening hospital length of stay (MD 4.23; 95% CrI 0.97-7.33). Conclusions: Amongst the five therapies, synbiotics not only prevented NI in critically ill adults but also demonstrated the best treatment results. By contrast, TPN did not prevent NI and ranked last, especially in ICU and SAP patients. Take-Home Message: Nosocomial infection is a leading cause of mortality in critically ill patients in the ICU. However, the efficacy of synbiotics, probiotics, prebiotics, enteral nutrition or adjuvant peripheral parenteral nutrition and total parenteral nutrition in preventing nosocomial infection in critically ill adults has been questioned. The network meta-analysis provides evidence that amongst the five therapies, synbiotics not only prevented NI in critically ill adults but also demonstrated the best treatment results. By contrast, TPN did not prevent NI and ranked last, especially in ICU and SAP patients. The results of this study will provide a new scientific basis and a new idea for the debate on the efficacy of synbiotics and other treatments in the improvement of prognosis in critically ill adult patients. Tweet: Synbiotic prevents nosocomial infection in critically ill adults, while total parenteral nutrition has the adverse curative.

Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials.

The benefits and harms of corticosteroids for patients with severe coronavirus disease 2019 (COVID-19) remain unclear. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from December 31, 2019 to October 1, 2020 to identify randomized controlled trials (RCTs) that evaluated corticosteroids in severe COVID-19 patients. The primary outcome was all-cause mortality at the longest follow-up. Secondary outcomes included a composite disease progression (progression to intubation, ventilation, extracorporeal membrane oxygenation, ICU transfer, or death among those not ventilated at enrollment) and incidence of serious adverse events. A random-effects model was applied to calculate risk ratio (RR) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation approach to evaluate the certainty of the evidence. Seven RCTs involving 6250 patients were included, of which the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial comprised nearly 78% of all included subjects. Results showed that corticosteroids were associated with a decreased all-cause mortality (27.3 vs. 31.1%; RR: 0.85; 95% CI: 0.73-0.99; P = 0.04; low-certainty evidence). Trial sequential analysis suggested that more trials were still required to confirm the results. However, such survival benefit was absent if RECOVERY trial was excluded (RR: 0.83; 95% CI: 0.65-1.06; P = 0.13). Furthermore, corticosteroids decreased the occurrence of composite disease progression (30.6 vs. 33.3%; RR: 0.77; 95% CI: 0.64-0.92; P = 0.005), but not increased the incidence of serious adverse events (3.5 vs. 3.4%; RR: 1.16; 95% CI: 0.39-3.43; P = 0.79).

The etiological role of endoplasmic reticulum stress in acute lung injury-related right ventricular dysfunction in a rat model.

This study aimed to ascertain whether endoplasmic reticulum (ER) stress participates in acute lung injury (ALI) and related right ventricular dysfunction (RVD) as well as to explore the underlying mechanisms of these conditions. A single intratracheal instillation of lipopolysaccharide (LPS) (10 mg/kg) was used to establish the RVD model. The ER stress inhibitor, 4-PBA (500 mg/kg), was administered using a gavage 2 hours before and after the LPS treatment for prevention and treatment, respectively. At 12 hours post-LPS exposure, mRNA and protein expressions of ER stress-specific biomarkers, glucose regulating protein 78 (GRP78) and CCAAT/enhancer binding protein homology (CHOP), were significantly upregulated. This effect was inhibited by both 4-PBA prevention and treatment. In addition, echocardiography showed that 4-PBA improved the LPS-induced abnormality in the tricuspid annular plane systolic excursion (TAPSE) and the right ventricular end-diastolic diameter (RVEDD), however not in the pulmonary artery acceleration time (PAAT). Furthermore, hematoxylin and eosin staining (HE) and terminal transferase dUTP nick end labeling (TUNEL) assays revealed that the proportion of proapoptotic cells was higher in RVD rats. This was prominently ameliorated by 4-PBA treatment. Moreover, 4-PBA had a similar reverse effect on the LPS-induced increase in the Bax/Bcl-2 ratio, caspase-12, and caspase-3 expressions as revealed by western blotting. Furthermore, 4-PBA improved LPS-induced right ventricle (RV) myeloperoxidase (MPO)-positive neutrophil infiltration percentage, inhibited nuclear factor kappa B (NF-κB) activity, and reduced the expressions of inflammatory cytokines, TNF-α, IL-1ß, and IL-6, in serum and RV. Taken together, our results indicated that ER stress-mediated apoptosis and inflammation might contribute to the development of ALI-related RVD induced by intratracheal LPS instillation. Gavage-administered 4-PBA could improve right ventricle (RV) systolic dysfunction and dilation, plausibly by blocking ER stress.

[Protective effect of sodium 4-phenylbutyrate on rats with acute respiratory distress syndrome related right ventricular dysfunction by alleviating endoplasmic reticulum stress].

OBJECTIVE: To investigate the role of endoplasmic reticulum stress (ERS) in rats with acute respiratory distress syndrome (ARDS) related right ventricular dysfunction and the protective effect of sodium 4-phenylbutyrate (4-PBA) on right ventricle. METHODS: Sixty male Spragne-Dawley (SD) rats were randomly divided into control group (CON group), lipopolysaccharide (LPS) model group, 4-PBA prevention group and 4-PBA treatment group, with 15 rats in each group. ARDS rat model was established by intratracheal instillation of LPS 10 mg/kg after tracheotomy; CON group was given the same amount of saline. 4-PBA prevention group and 4-PBA treatment group were given 4-PBA 500 mg/kg intragastric administration 2 hours before and after LPS respectively. Echocardiography was performed 12 hours after treatment to evaluate the right ventricular function. Then, the rats were sacrificed by bloodletting, and the serum and right ventricular tissue were harvested. The histopathological changes of myocardial were observed by hematoxylin-eosin (HE) staining, the levels of tumor necrosis factor-α (TNF-α), interleukins (IL-1ß and IL-6) in serum and myocardial were detected by enzyme linked immunosorbent assay (ELISA), and Western Blot was used to detect the expression of the marker proteins of ERS in myocardial, including glucose regulatory protein 78 (GRP78), C/EBP cyclic adenosine phosphate reaction primitive binding transcription factor homologous protein (CHOP), caspase-12 and caspase-3. RESULTS: Compared with the CON group, the echocardiography showed pulmonary artery maximum pressure gradient (PAmaxPG), pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE) in LPS model group were significantly decreased, and right ventricular end-diastolic excursion (RVDd) was significantly increased, and the levels of TNF-α, IL-1ß and IL-6 in serum and myocardial, as well as the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly increased. Compared with LPS model group, TAPSE of 4-PBA preventive and treatment groups were significantly increased (mm: 3.08±0.65, 2.96±0.61 vs. 2.48±0.45), RVDd were significantly decreased (mm: 3.67±0.58, 3.60±0.61 vs. 4.18±0.71), the levels of TNF-α, IL-1ß and IL-6 in serum and myocardial were significantly decreased [TNF-α (ng/L): 187.98±18.98, 176.08±17.98 vs. 332.00±19.90 in serum, 135.06±19.00, 132.78±17.00 vs. 155.00±20.00 in myocardial; IL-1ß(ng/L): 12.07±2.98, 11.05±2.41 vs. 24.06±4.01 in serum, 19.89±2.80, 21.06±2.80 vs. 26.00±2.60 in myocardial; IL-6 (ng/L): 42.98±7.90, 34.05±6.09 vs. 89.80±10.07 in serum, 129.45±25.00, 127.08±26.06 vs. 145.77±23.00 in myocardial]; the expressions of GRP78, CHOP, caspase-12 and caspase-3 in myocardial were significantly decreased (GRP78/GAPDH: 0.090±0.070, 0.103±0.060 vs. 0.167±0.090, CHOP/GAPDH: 0.109±0.090, 0.090±0.080 vs. 0.186±0.090, caspase-12/GAPDH: 0.769±0.230, 0.799±0.210 vs. 1.040±0.350, caspase-3/GAPDH: 0.391±0.060, 0.401±0.054 vs. 0.603±0.340), with statistically significant differences (all P < 0.05). There were no significant differences in each indexes between 4-PBA prevention group and 4-PBA treatment group (all P > 0.05). CONCLUSIONS: ERS is involved in ARDS-related right ventricular dysfunction. 4-PBA can protect the right ventricular function of ARDS rats by inhibiting ERS and alleviating inflammation, and the preventive and therapeutic effects of 4-PBA are similar.

RNA-Sequencing and Bioinformatics Analysis of Long Noncoding RNAs and mRNAs in the Prefrontal Cortex of Mice Following Repeated Social Defeat Stress.

BACKGROUND: Repeated or continuous chronic psychological stress may induce diverse neuropsychiatric disorders; however, the underlying mechanisms remain unclear. In this study, we explored the expression profiles of long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, in mice after repeated social defeat (RSD) stress to explore their potential involvement in the development of anxiety-like behaviors. MAIN METHODS: RNA-sequencing was used to screen all differentially expressed (DE) lncRNAs and mRNAs between the RSD and control groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for confirmation of the RNA-sequencing results. The function of DE lncRNAs was predicted by Gene Ontology (GO) enrichment and pathway analyses of target mRNAs. In addition, the functional regulatory network of the target mRNAs was constructed to reveal potential relationships between lncRNAs and their target genes with bioinformatics approaches. KEY FINDINGS: In mice experiencing RSD, 373 and 454 lncRNAs, along with 1142 and 654, mRNAs were significantly upregulated and downregulated, respectively. The detailed regulatory network included 126 eligible lncRNA-mRNA pairs. Among them, 14 genes such as Arhgef1, Chchd2, Fam107a, Dlg1, Nova2, Dpf1, and Shank3 involved in neurite growth, neural development, and synaptic plasticity were direct targets of the DE lncRNAs. qRT-PCR of four of the DE lncRNAs and mRNAs confirmed the reliability of RNA-sequencing. GO clustering analyses showed that the top enriched biological process, cellular component, and molecular function terms were synaptic transmission, neuron spine, and glutamate receptor binding, respectively. Further, the top three significant enriched pathways were synaptic adhesion-like molecule (SALM) protein interactions at the synapses, trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as glutamate binding, activation of AMPA receptors, and synaptic plasticity. SIGNIFICANCE: Hundreds of lncRNAs and mRNAs are dysregulated after RSD, and many of these lncRNAs might participate in the development of anxiety-like behaviors via multiple complex mechanisms such as target regulation. Available informatics evidence highlighted the likely role of synapse dysfunction and abnormal synaptic neurotransmission in these behaviors. Thus, our findings provide potential candidate biomarkers or intervention targets for chronic psychological stress-induced neuropsychiatric disorders.

Roles of apoptosis and inflammation in a rat model of acute lung injury induced right ventricular dysfunction.

AIM: The effect of intratracheal lipopolysaccharide (LPS) instillation on right ventricular dysfunction in rats was studied with the aim of exploring underlying mechanisms. MAIN METHODS: A single dose of LPS (10 mg/kg) or an equal volume of saline was instilled intratracheally and lung injury evaluated using histopathologic scoring and wet/dry (W/D) weight ratio at 6 or 12 h post-administration. Besides, serum atrial natriuretic peptide (ANP) was detected using an enzyme-linked immunosorbent assay (ELISA) and right ventricle ß-myosin heavy chain (ß-MHC) presence was examined using reverse transcription polymerase chain reaction (RT-PCR). Echocardiography examined pulmonary artery acceleration time (PAAT), right ventricular free wall thickness (RVFWT), tricuspid annular plane systolic excursion (TAPSE), and right ventricular end-diastolic diameter (RVEDD). In addition, right ventricular TUNEL staining and Western blots of Bax and Bcl-2 were performed. Right ventricle and left ventricle caspases-3, -8, and -9 activity were examined using fluorometric assay. Finally, right ventricle myeloperoxidase (MPO) neutrophil staining, and right ventricle and plasma cytokines TNF-α, IL-1ß, IL-6 detection was performed. KEY FINDINGS: Histopathologic lung injury and increased W/D weight ratio was seen at 6 h after LPS intratracheal instillation, along with increased ANP, but not ß-MHC. Pulmonary hypertension was indicated by decreased PAAT at 6 h post-exposure. Right ventricular systolic dysfunction and dilation were observed at 12 h post-exposure, as indicated by a significant decrease of TAPSE and increase of RVEDD. Of note, the procedure led to an increased right ventricle TUNEL positive cardiomyocytes, an increased Bax/Bcl-2 ratio, and increased right and left ventricle caspases-3, -8, and -9 activity as early as 6 h post-exposure, which was paralleled by increased right ventricle MPO staining and increased expression of right ventricle and serum cytokines TNF-α, IL-1ß, and IL-6. SIGNIFICANCE: As well as acute lung injury, a single dose of LPS intratracheally instilled can induce pulmonary hypertension at 6 h post-exposure, with obvious right ventricular systolic dysfunction and right ventricular dilation present at 12 h post-exposure, possibly via cardiomyocytes apoptosis and inflammation.

Sodium Tanshinone IIA Sulfonate Improves Hemodynamic Parameters, Cytokine Release, and Multi-Organ Damage in Endotoxemia Rabbits.

BACKGROUND The aim of this study was to evaluate the protective effects of sodium tanshinone IIA sulfonate (STS) on hemodynamic parameters, cytokine release, and multiple organ damage in an animal model of lipopolysaccharide (LPS)-induced endotoxemia. MATERIAL AND METHODS Twenty-four rabbits were randomly divided into 3 groups: control (n=8), LPS (n=8), and STS pretreatment + LPS (n=8) groups. With arterial invasive monitoring, hemodynamic variables were observed at 30 min before and at 0, 10, 20, 30, 60, 120, 180, 240, and 300 min after LPS injection. Circulatory inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10), and relevant biochemical markers, including arterial partial pressure of oxygen (PaO2), plasma cardiac troponin I (cTnI), alanine aminotransferase (ALT), and creatinine (Cr), were measured at each time point. At the end of the experiment, all rabbits were sacrificed; histopathological examination of the heart, lung, liver, and kidney tissue was performed and organ injury was semi-quantitatively scored for each organ. RESULTS Mean arterial pressure (MAP) and heart rate (HR) significantly decreased within 30 min and again after 120 min following LPS injection. However, STS pretreatment gradually normalized MAP and HR after 120 min following LPS injection. In addition, STS ameliorated LPS-induced decrease of PaO2, LPS-induced increase of TNF-α, cTnI, and ALT, and enhanced LPS-induced increase of IL-10. Moreover, STS reduced heart, lung, and liver histopathologic injury. CONCLUSIONS STS can significantly stabilize LPS-induced hemodynamic deterioration, regulate inflammatory cytokine secretion, and protect heart, lung, and liver in rabbits.