Risk factors for invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome: A multicenter retrospective study.

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in patients with severe fever with thrombocytopenia syndrome (SFTS), yet SFTS-associated IPA (SAPA)'s risk factors remain undefined. A multicenter retrospective cohort study across Hubei and Anhui provinces (May 2013-September 2022) utilized least absolute shrinkage and selection operator (LASSO) regression for variable selection. Multivariable logistic regression identified independent predictors of SAPA, Cox regression highlighted mortality-related risk factors. Of the 1775 screened SFTS patients, 1650 were included, with 169 developing IPA, leading to a 42-day mortality rate of 26.6% among SAPA patients. Multivariable logistic regression revealed SAPA risk factors including advanced age, petechia, hemoptysis, tremor, low albumin levels, elongated activated partial thromboplastin time (APTT), intensive care unit (ICU) admission, glucocorticoid usage, intravenous immunoglobulin (IVIG) and prolonged hospital stays. Cox regression identified predictors of 42-day mortality, including ecchymosis at venipuncture sites, absence of ICU admission, elongated prothrombin time (PT), vasopressor and glucocorticoid use, non-antifungals. Nomograms constructed on these predictors registered concordance indexes of 0.855 (95% CI: 0.826-0.884) and 0.778 (95% CI: 0.702-0.854) for SAPA onset and 42-day mortality, respectively. Lower survival rates for SAPA patients treated with glucocorticoids (p < 0.001) and improved 14-day survival with antifungal therapy (p = 0.036). Improving IPA management in SFTS-endemic areas is crucial, with effective predictive tool.

Identification of immune characteristic biomarkers and therapeutic targets in cuproptosis for sepsis by integrated bioinformatics analysis and single-cell RNA sequencing analysis.

Background: Cuproptosis is a copper-dependent cell death that is connected to the development and immune response of multiple diseases. However, the function of cuproptosis in the immune characteristics of sepsis remains unclear. Method: We obtained two sepsis datasets (GSE9960 and GSE134347) from the GEO database and classified the raw data with R packages. Cuproptosis-related genes were manually curated, and differentially expressed cuproptosis-related genes (DECuGs) were identified. Afterwards, we applied enrichment analysis and identified key DECuGs by performing machine learning techniques. Then, the immune cell infiltrations and correlation between DECuGs and immunocyte features were created by the CIBERSORT algorithm. Subsequently, unsupervised hierarchical clustering analysis was performed based on key DECuGs. We then constructed a ceRNA network based on key DECuGs by using multi-step computational strategies and predicted potential drugs in the DrugBank database. Finally, the role of these key genes in immune cells was validated at the single-cell RNA level between septic patients and healthy controls. Results: Overall, 16 DECuGs were obtained, and most of them had lower expression levels in sepsis samples. Afterwards, we obtained six key DECuGs by performing machine learning. Then, the LIPT1-T-cell CD4 memory resting was the most positively correlated DECuG-immunocyte pair. Subsequently, two different subclusters were identified by six DECuGs. Bioinformatics analysis revealed that there were different immune characteristics between the two subclusters. Moreover, we identified the key lncRNA OIP5-AS1 within the ceRNA network and obtained 4 drugs that may represent novel drugs for sepsis. Finally, these key DECuGs were statistically significantly dysregulated in another validation set and showed a major distribution in monocytes, T cells, B cells, NK cells and platelets at the single-cell RNA level. Conclusion: These findings suggest that cuproptosis might promote the progression of sepsis by affecting the immune system and metabolic dysfunction, which provides a new direction for understanding potential pathogenic processes and therapeutic targets in sepsis.

Use of pus metagenomic next-generation sequencing for efficient identification of pathogens in patients with sepsis.

The positive detection rate of blood metagenomic next-generation sequencing (mNGS) was still too low to meet clinical needs, while pus from the site of primary infection may be advantageous for identification of pathogens. To assess the value of mNGS using pus in patients with sepsis, thirty-five samples were collected. Pathogen identification and mixed infection diagnosis obtained by use of mNGS or cultivation methods were compared. Fifty-three aerobic or facultative anaerobes, 59 obligate anaerobes and 7 fungi were identified by the two methods. mNGS increased the accuracy rate of diagnosing aerobic or facultative anaerobic infections from 44.4% to 94.4%; mNGS also increased the sensitivity of diagnosing obligate anaerobic infections from 52.9% to 100.0%; however, mNGS did not show any advantage in terms of fungal infections. Culture and mNGS identified 1 and 24 patients with mixed infection, respectively. For obligate anaerobes, source of microorganisms was analyzed. The odontogenic bacteria all caused empyema (n = 7) or skin and soft tissue infections (n = 5), whereas the gut-derived microbes all caused intra-abdominal infections (n = 7). We also compared the clinical characteristics of non-obligate anaerobic and obligate anaerobic infection groups. The SOFA score [9.0 (7.5, 14.3) vs. 5.0 (3.0, 8.0), P = 0.005], procalcitonin value [4.7 (1.8, 39.9) vs. 2.50 (0.7, 8.0), P = 0.035], the proportion of septic shock (66.7% vs. 35.3%, P = 0.044) and acute liver injury (66.7% vs. 23.5%, P = 0.018) in the non-obligate anaerobic infection group were significantly higher than those in the obligate anaerobic infection group. In patients with sepsis caused by purulent infection, mNGS using pus from the primary lesion may yield more valuable microbiological information.

Prevention of urinary tract infection using a silver alloy hydrogel-coated catheter in critically ill patients: A single-center prospective randomized controlled study.

Background: A new type of silver alloy hydrogel-coated (SAH) catheter has been shown to prevent bacterial adhesion and colonization by generating a microcurrent, and to block the retrograde infection pathway. However, these have only been confirmed in ordinary patients. This study aims to evaluate the effectiveness of a SAH catheter for preventing urinary tract infections in critically ill patients. Methods: This was a prospective single-center, single-blind, randomized, controlled study. A total of 132 patients requiring indwelling catheterization in the intensive care unit (ICU) of the First Affiliated Hospital of the University of Science and Technology of China between October 2022 and February 2023 and who met the study inclusion/exclusion criteria were randomly divided into two groups. Patients in the SAH catheter group received a SAH catheter, while patients in the conventional catheter group received a conventional siliconized latex Foley catheter. The main outcome measure was the incidence of catheter-associated urinary tract infections (CAUTIs). Secondary outcome indicators included urine positivity for white blood cells and positive urine cultures on 3 days, 7 days, 10 days, and 14 days after catheterization, number of viable bacteria in the catheter biofilm on day 14, pathogenic characteristics of positive urine cultures, length of ICU stay, overall hospital stay, ICU mortality, and 28-day mortality. All the data were compared between the two groups. Results: A total of 68 patients in the conventional catheter group and 64 patients in the SAH catheter group were included in the study. On day 7 after catheter placement, the positivity rate for urinary white blood cells was significantly higher in the conventional catheter group than in the SAH catheter group (33.8% vs. 15.6%, P=0.016). On day 10, the rates of positive urine cultures (27.9% vs. 10.9%, P=0.014) and CAUTIs (22.1% vs. 7.8%, P=0.023) were significantly higher in the conventional catheter group than in the SAH catheter group. On day 14, the numbers of viable bacteria isolated from the catheter tip ([3.21±1.91]×106 colony-forming units [cfu]/mL vs. [7.44±2.22]×104 cfu/mL, P <0.001), balloon segment ([7.30±1.99]×107 cfu/mL vs. [3.48±2.38]×105 cfu/mL, P <0.001), and tail section ([6.41±2.07]×105 cfu/mL vs. [8.50±1.46]×103 cfu/mL, P <0.001) were significantly higher in the conventional catheter group than in the SAH catheter group. The most common bacteria in the urine of patients in both groups were Escherichia coli (n=13) and Pseudomonas aeruginosa (n=6), with only one case of Candida in each group. There were no significant differences between the two groups in terms of ICU hospitalization time, total hospitalization time, ICU mortality, and 28-day mortality. Conclusion: SAH catheters can effectively inhibit the formation of catheter-related bacterial biofilms in critically ill patients and reduce the incidence of CAUTIs, compared with conventional siliconized latex Foley catheters; however, regular replacement of the catheter is still necessary.

Diagnostic Value and Clinical Application of Metagenomic Next-Generation Sequencing for Infections in Critically Ill Patients.

Objective: To evaluate the diagnostic value and clinical application of metagenomic next-generation sequencing (mNGS) for infections in critically ill patients. Methods: Comparison of diagnostic performance of mNGS and conventional microbiological testing for pathogens was analyzed in 234 patients. The differences between immunocompetent and immunocompromised individuals in mNGS-guided anti-infective treatment adjustment were also analyzed. Results: The sensitivity and specificity of mNGS for bacterial and fungal detection were 96.6% (95% confidence interval [CI], 93.5%-99.6%) and 83.1% (95% CI, 75.2%-91.1%), and 85.7% (95% CI, 71.9%-99.5%) and 93.2% (95% CI, 89.7%-96.7%), respectively. Overall, 152 viruses were detected by mNGS, but in which 28 viruses were considered causative agents. The proportion of mNGS-guided beneficial anti-infective therapy adjustments in the immunocompromised group was greater than in the immunocompetent group (48.5% vs 30.1%; P=0.008). In addition, mNGS-guided anti-infective regimens with peripheral blood and BALF specimens had the highest proportion (39.0%; 40.0%), but the proportion of patients not helpful due to peripheral blood mNGS was also as high as 22.0%. Conclusion: mNGS might be a promising technology to provide precision medicine for critically ill patients with infection.

Identification of immune-related lncRNA in sepsis by construction of ceRNA network and integrating bioinformatic analysis.

BACKGROUND: Sepsis is a high mortality disease which seriously threatens human life and health, for which the pathogenetic mechanism still unclear. There is increasing evidence showed that immune and inflammation responses are key players in the development of sepsis pathology. LncRNAs, which act as ceRNAs, have critical roles in various diseases. However, the regulatory roles of ceRNA in the immunopathogenesis of sepsis have not yet been elucidated. RESULTS: In this study, we aimed to identify immune biomarkers associated with sepsis. We first generated a global immune-associated ceRNA (IMCE) network based on data describing interactions pairs of gene-miRNA and miRNA-lncRNA. Afterward, we excavated a dysregulated sepsis immune-associated ceRNA (SPIMC) network from the global IMCE network by means of a multi-step computational approach. Functional enrichment indicated that lncRNAs in SPIMC network have pivotal roles in the immune mechanism underlying sepsis. Subsequently, we identified module and hub genes (CD4 and STAT4) via construction of a sepsis immune-related PPI network. Then, we identified hub genes based on the modular structure of PPI network and generated a ceRNA subnetwork to analyze key lncRNAs associated with sepsis. Finally, 6 lncRNAs (LINC00265, LINC00893, NDUFA6-AS1, NOP14-AS1, PRKCQ-AS1 and ZNF674-AS1) that identified as immune biomarkers of sepsis. Moreover, the CIBERSORT algorithm and the infiltration of circulating immune cells types were performed to identify the inflammatory state of sepsis. Correlation analyses between immune cells and sepsis immune biomarkers showed that the LINC00265 was strongly positive correlated with the macrophages M2 (r = 0.77). CONCLUSION: Collectively, these results may suggest that these lncRNAs (LINC00265, LINC00893, NDUFA6-AS1, NOP14-AS1, PRKCQ-AS1 and ZNF674-AS1) played important roles in the immune pathogenesis of sepsis and provide potential therapeutic targets for further researches on immune therapy treatment in patients with sepsis.

Efficacy and Safety of Ciprofol Sedation in ICU Patients Undergoing Mechanical Ventilation: A Multicenter, Single-Blind, Randomized, Noninferiority Trial.

OBJECTIVES: To determine the effectiveness and safety of ciprofol for sedating patients in ICUs who required mechanical ventilation (MV). DESIGN: A multicenter, single-blind, randomized, noninferiority trial. SETTING: Twenty-one centers across China from December 2020 to June 2021. PATIENTS: A total of 135 ICU patients 18 to 80 years old with endotracheal intubation and undergoing MV, who were expected to require sedation for 6-24 hours. INTERVENTIONS: One hundred thirty-five ICU patients were randomly allocated into ciprofol ( n = 90) and propofol ( n = 45) groups in a 2:1 ratio. Ciprofol or propofol were IV infused at loading doses of 0.1 mg/kg or 0.5 mg/kg, respectively, over 4 minutes ± 30 seconds depending on the physical condition of each patient. Ciprofol or propofol were then immediately administered at an initial maintenance dose of 0.3 mg/kg/hr or 1.5 mg/kg/hr, to achieve the target sedation range of Richmond Agitation-Sedation Scale (+1 to -2). Besides, continuous IV remifentanil analgesia was administered (loading dose: 0.5-1 µg/kg, maintenance dose: 0.02-0.15 µg/kg/min). MEASUREMENTS AND MAIN RESULTS: Of the 135 patients enrolled, 129 completed the study. The primary endpoint-sedation success rates of ciprofol and propofol groups were 97.7% versus 97.8% in the full analysis set (FAS) and were both 100% in per-protocol set (PPS). The noninferiority margin was set as 8% and confirmed with a lower limit of two-sided 95% CI for the inter-group difference of -5.98% and -4.32% in the FAS and PPS groups. Patients who received ciprofol had a longer recovery time ( p = 0.003), but there were no differences in the remaining secondary endpoints (all p > 0.05). The occurrence rates of treatment-emergent adverse events (TEAEs) or drug-related TEAEs were not significantly different between the groups (all p > 0.05). CONCLUSIONS: Ciprofol was well tolerated, with a noninferior sedation profile to propofol in Chinese ICU patients undergoing MV for a period of 6-24 hours.

Comparison of endotracheal aspirate and bronchoalveolar lavage fluid metagenomic next-generation sequencing in severe pneumonia: a nested, matched case-control study.

OBJECTIVES: To compare clinical outcomes in patients with severe pneumonia according to the diagnostic strategy used. METHODS: In this retrospective, nested, case-control study, patients with severe pneumonia who had undergone endotracheal aspirate (ETA) metagenomic next-generation sequencing of (mNGS) testing (n = 53) were matched at a ratio of 1 to 2 (n = 106) by sex, age, underlying diseases, immune status, disease severity scores, and type of pneumonia with patients who had undergone bronchoalveolar lavage fluid (BALF) mNGS. The microbiological characteristics and patient's prognosis of the two groups were compared. RESULTS: An overall comparison between the two groups showed no significant differences in bacterial, fungal, viral, or mixed infections. However, subgroup analysis of 18 patients who received paired ETA and BALF mNGS showed a complete agreement rate for the two specimens of 33.3%. There were more cases for whom targeted treatment was initiated (36.79% vs. 22.64%; P = 0.043) and fewer cases who received no clinical benefit after mNGS (5.66% vs. 15.09%; P = 0.048) in the BALF group. The pneumonia improvement rate in the BALF group was significantly higher than in the ETA group (73.58% vs. 87.74%, P = 0.024). However, there were no significant differences in ICU mortality or 28-day mortality. CONCLUSIONS: We do not recommend using ETA mNGS as the first-choice method for analyzing airway pathogenic specimens from severe pneumonia patients.

[Dynamic changes of platelet count in first week and their predictive value for prognosis in septic shock patients].

OBJECTIVE: To observe the dynamic changes of platelet counts in septic shock patients within first week, and to explore their predictive value for prognosis. METHODS: Retrospective analysis of clinical data of patients with septic shock admitted to the department of intensive care unit (ICU) of the First Affiliated Hospital of University of Science and Technology of China from January 2020 to December 2021 was conducted. The baseline data on gender, age and primary diseases, clinical indicators on infection site, pathogenic microbial type, acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA), laboratory indicators and the trend of platelet count (PLT) on day 1, 3, 5 and 7 admitting ICU and patients prognosis of in-hospital were collected. Binary Logistic regression was used to assess the independent risk factors of in-hospital death in septic shock patients. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive power of each index for in-hospital mortality. RESULTS: A total of 193 patients with sepsis were enrolled. Among them, 73 patients died and 120 patients survived. Univariate analysis showed that the age, proportion of hypertension and respiratory system infection, APACHE II score, SOFA score and blood lactic acid (Lac) in the death group were significantly higher than those in the survival group, while the proportion of urinary system infection, white blood cell (WBC) and neutrophil (NEU) were significantly lower in the death group. Within 7 days after admitting ICU, the platelet (PLT) firstly decreased and then rebounded in the survival group, whereas it's showed a continuous downward trend in the death group. And the PLT count in both day 5 and 7 were significantly higher in the survival group compared with the dead group [×109/L: 94.5 (54.0, 182.0) vs. 50.0 (30.5, 87.5), 135.0 (86.8, 205.8) vs. 46.0 (23.5, 71.5), all P < 0.05]. Multivariate binary Logistic regression analysis showed that age [odds ratio (OR) = 1.059, 95% confidence interval (95%CI) was 1.002-1.118], hypertension (OR = 6.108, 95%CI was 1.340-27.851), respiratory system infection (OR = 5.300, 95%CI was 1.116-25.118), APACHE II score (OR = 1.158, 95%CI was 1.054-1.273), SOFA score (OR = 1.494, 95%CI was 1.060-2.107) and PLT on day 7 after admitting ICU (OR = 0.926, 95%CI was 0.894-0.958) were independent risk factors for in-hospital prognosis in septic shock patients (all P < 0.05). ROC analysis showed that APACHE II score, SOFA score and PLT on day 7 after admitting ICU all had good predictive value for in-hospital prognosis in septic shock patients, and the area under the ROC curve (AUC) of PLT on day 7 (AUC = 0.899, 95%CI was 0.857-0.941) was significantly higher than that of APACHE II score (AUC = 0.748, 95%CI was 0.680-0.816), SOFA score (AUC = 0.767, 95%CI was 0.702-0.833). CONCLUSIONS: Clinicians should pay close attention to the dynamic changes of platelet counts in septic shock patients, especially the platelet counts on day 7 after admitting ICU. And active intervention should be provided to improve the prognosis.

Clinical Value of Metagenomics Next-Generation Sequencing in Bronchoalveolar Lavage Fluid for Patients with Severe Hospital-Acquired Pneumonia: A Nested Case-Control Study.

Background: Metagenomics next-generation sequencing (mNGS) is more efficient in identifying pathogens responsible for pneumonia. However, whether these patients ultimately benefit from this improvement remains unknown. Methods: In this retrospective, nested, case-control study, patients with severe hospital-acquired pneumonia (HAP) who had undergone mNGS of bronchoalveolar lavage fluid while in our intensive care unit from March 2017 to December 2020 (n = 33) were matched in a ratio of 1 to 2 (n = 66) by sex, age, comorbidities, immune status, Acute Physiology and Chronic Health Evaluation II score, severity of pulmonary infection, and use of extracorporeal life support with patients who had undergone conventional microbiological testing only. The primary outcome was 90-day mortality; secondary outcomes being length of intensive care unit stay, duration of mechanical ventilation support, 7-day and 28-day mortality, and efficacy of treatment of pulmonary infection. Results: In the CMT group, 17 patients (25.8%) had negative results, whereas only one (3.0%) had negative results in the mNGS group (P < 0.001). After receipt of microbiology results, antibiotics were altered in 23/33 patients (70.0%) in the mNGS group, but in only 29/66 (43.9%) in the CMT group (P = 0.016). Pulmonary infection-related findings improved in 20/33 patients (60.6%) in the mNGS group in the subsequent 7 days, but in only 25/66 (37.9%) in the CMT group (P = 0.032). However, the 28-day (33.3% vs 31.2%, P = 1.0) and 90-day (48.5% vs 45.5%, P = 0.78) mortality rates did not differ significantly between the two groups. These findings were supported by Cox-regression and Kaplan-Meier survival curve analyses. Conclusion: mNGS is helpful in the treatment of severe HAP but does not improve medium or long-term survival rates, especially in patients with severe comorbidities.

[Influence of hypomagnesemia on the prognosis of severe septic patients].

OBJECTIVE: To investigate the influence of hypomagnesemia on the prognosis of patients with severe sepsis. METHODS: A retrospective study was conducted. The clinical data of 207 septic patients admitted to the department of critical care medicine of the First Affiliated Hospital of University of Science and Technology of China from January 1, 2016 to December 21, 2020 were analyzed, including gender, age and laboratory indicators within 24 hours after sepsis diagnosis [procalcitonin (PCT), C-reactive protein (CRP), blood lactic acid (Lac), pH value and blood magnesium, calcium, chlorine and phosphorus levels]. The acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score and 28-day prognosis were collected. The patients were divided into survival group and non-survival group according to the prognosis, and the clinical data and laboratory indexes were compared between the two groups. Pearson correlation test was used to analyze the correlation between clinical indicators. Multivariate Logistic regression analysis was used to screen the risk factors affecting the prognosis. The receiver operator characteristic curve (ROC curve) was drawn, and the area under ROC curve (AUC) was calculated to evaluate the potential prognostic indicators. RESULTS: Among the 207 septic patients, 102 survived and 105 died on the 28th day, and the 28-day mortality was 50.72%. There were no significant differences in gender, age, CRP, pH value, blood chlorine or blood phosphorus levels between the two groups. The blood magnesium and blood calcium levels in the non-survival group were significantly lower than those in the survival group [blood magnesium (mmol/L): 0.68±0.14 vs. 0.80±0.12, blood calcium (mmol/L): 1.93±0.21 vs. 2.01±0.20, both P > 0.01], and PCT, Lac, APACHE II score and SOFA score were significantly higher than those in the survival group [PCT (mg/L): 8.32 (1.64, 55.01) vs. 3.55 (0.97, 12.31), Lac (mmol/L): 2.90 (1.70, 4.30) vs. 2.10 (1.03, 3.89), APACHE II score: 21.24±6.40 vs. 17.42±7.02, SOFA score: 9.14±3.55 vs. 6.91±3.31, all P > 0.01]. Among the 207 patients, 96 patients had normal blood magnesium level (0.75-1.25 mmol/L) and 111 patients had hypomagnesemia (> 0.75 mmol/L). The 28-day mortality of septic patients in the hypomagnesemia group was significantly higher than that in the normal magnesium group [61.26% (68/111) vs. 38.54% (37/96), P < 0.01]. Pearson correlation analysis showed that the blood magnesium level of sepsis patients was negatively correlated with PCT (r = -0.173, P < 0.05), and it was positively correlated with APACHE II score (r = 0.159, P < 0.05), but it had no correlation with CRP or SOFA score (r values were -0.029 and 0.091, both P > 0.05). Logistic regression analysis showed that serum magnesium, APACHE II score and SOFA score were independent risk factors for 28-day death in patients with sepsis [serum magnesium: odds ratio (OR) < 0.001, 95% confidence interval (95%CI) was 0.000-0.002, P < 0.001; APACHE II score: OR = 1.092, 95%CI was 1.022-1.168, P = 0.010; SOFA score: OR = 1.168, 95%CI was 1.026-1.330, P = 0.019]. ROC curve analysis showed that blood magnesium and APACHE II score had a certain predictive value for 28-day mortality in patients with severe sepsis [AUC (95%CI) was 0.723 (0.655-0.791) and 0.680 (0.607-0.754), respectively]. When the blood magnesium threshold was 0.64 mmol/L, the sensitivity was 41.0% and the specificity was 93.1%. When APACHE II score threshold was 16.50, the sensitivity was 78.1% and the specificity was 55.9% indicating that the specificity of serum magnesium was higher than that of APACHE II score. CONCLUSIONS: Severe septic patients complicated with hypomagnesemia have a poor prognosis. Serum magnesium level can be used as a prognostic indicator for severe septic patients.

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BACKGROUND: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. METHODS: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. RESULTS: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups. CONCLUSIONS: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. TRIAL REGISTRATION: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial.

Tocilizumab has been reported to attenuate the "cytokine storm" in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI-7.19%-21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI-99.17% to-17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.

[Diagnostic value of detection of pathogens in bronchoalveolar lavage fluid by metagenomics next-generation sequencing in organ transplant patients with pulmonary infection].

OBJECTIVE: To evaluate the diagnostic value of metagenomics next-generation sequencing (mNGS) in detecting pathogens in bronchoalveolar lavage fluid (BALF) for pulmonary infection in solid organ transplant patients in intensive care unit (ICU). METHODS: A retrospective study was conducted, the BALF samples from 46 patients with post organ transplant pneumonia/suspected pneumonia admitted to the Department of Critical Care Medicine of the First Affiliated Hospital of University of Science and Technology of China from August 2018 to August 2021 were collected, all tested by simultaneous mNGS and conventional comprehensive microbial test (CMT), and the results of CMT were used as the reference standard to compare the differences in the diagnostic value of mNGS and CMT for pulmonary infections in solid organ transplant patients, and to analyze the diagnostic value of mNGS for mixed infections. RESULTS: (1) Pneumonia pathogens: a total of 31 pathogens were detected in 35 patients, including bacteria (16 species), fungi (9 species) and viruses (6 species). Among them, 25 pathogens were detected by mNGS and CMT, and only 19 pathogens were detected by mNGS. Among the microorganisms isolated by mNGS method, the detection rates of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae were higher [51.4% (18/35), 42.9% (15/35), 31.4% (11/35), respectively]; Candida albicans, Aspergillus and Pneumocystis carinii were the most commonly detected fungi [31.4% (11/35), 22.9% (8/35), 22.9% (8/35), respectively]; 20 patients were positive for the virus, and the most commonly detected viruses were cytomegalovirus, herpesvirus and EB virus [28.6% (10/35), 20.0% (7/35), 17.1% (6/35), respectively]. In addition, one case of Brucella was detected by mNGS. (2) Diagnostic efficiency: as far as bacterial detection is concerned, 20 cases of negative results were obtained by CMT detection of 35 samples included in the study, and a total of 10 cases of positive results were obtained by mNGS detection of negative samples; the percentage of mNGS positive samples was significantly higher than that of CMT positive samples [odds ratio (OR) = 5.5, 95% confidence interval (95%CI) = 1.2-24.8, P = 0.02]. When compared with CMT, the sensitivity and specificity of mNGS were 93.3% and 50.0%, and the positive predictive value (PPV) and negative predictive value (NPV) were 58.3%, 91.1%. As far as fungal detection was concerned, there was no significant difference in the percentage of positive samples between the two methods (OR = 1.5, 95%CI = 0.5-4.2, P = 0.60); the sensitivity and specificity of mNGS were 72.2% and 64.7%, and the PPV and NPV were 68.4%, 68.8%; CMT test of the 35 included samples produced 17 negative results, and mNGS test of the negative samples produced 6 positive results. A total of 20 patients tested positive for the virus by mNGS. In addition, 23 patients (65.7%) were diagnosed with pulmonary mixed infection. CONCLUSIONS: The use of mNGS to detect pathogens in BALF can improve the sensitivity and specificity of bacterial identification of pulmonary infection in critically ill organ transplant patients, and mNGS has obvious advantages in detecting virus and identifying mixed infections.

Metagenomic next-generation sequencing technology for detection of pathogens in blood of critically ill patients.

OBJECTIVE: To explore the applicability of metagenomic next-generation sequencing (mNGS) technology for the detection of blood pathogens in intensive care unit patients. METHODS: The clinical data of 63 critically ill patients who could not be diagnosed with blood culture (BC) and who underwent mNGS blood sample testing were retrospectively analyzed. The diagnostic efficacy of mNGS was compared with that of traditional detection methods; the distribution of the pathogens identified by mNGS was analyzed; and the differences in laboratory tests, comorbidities, treatment, and prognosis between the mNGS-positive and mNGS-negative groups were compared. RESULTS: The positive rate of mNGS was 41.3% (26/63), and 16 patients were found to have mixed infections. However, the positive rate of BCs performed simultaneously with mNGS was only 7.9% (5/63). The results of univariate analysis showed that the average length of intensive care unit stay (ß, -8.689 [95% CI, -16.176, -1.202]; P = 0.026) and the time from onset to sequencing (ß, -5.816 [95% CI,-9.936, -1.696]; P = 0.007) of the mNGS-positive group were significantly shorter than those of the mNGS-negative group. More patients in the positive group were adjusted for anti-infective treatment after mNGS (OR, 3.789 [95% CI,1.176, 12.211]; P < 0.001). CONCLUSIONS: Detection of blood pathogens by mNGS has good applicability for critically ill patients who cannot be diagnosed by BC in the early stages of infection, and mNGS should be performed as early as possible to obtain higher pathogen detection rates.