Sepsis is a life‐threatening syndrome with a high risk of mortality, which is caused by the dysregulated host response to infection. We examined significant roles of circDMNT3B and miR‐20b‐5p in the ...intestinal mucosal permeability dysfunction of rats with sepsis. SD rats were randomly divided into 6 groups (n = 10/group): sham group, sepsis group, si‐negative control group, circDNMT3B‐si1 group, circDNMT3B‐si2 group and circDNMT3B‐si1 + anti‐miR‐20b‐5p group. The level of malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, interleukin (IL)‐6 and IL‐10 levels were measured through ELISA assay kits. Cell survival rate and cell apoptosis were evaluated by Cell‐Counting Kit‐8 Assay and flow cytometry, respectively. Luciferase reporter assays were used to investigate interactions between miR‐20b‐5p circDMNT3B in HEK‐293T cells. Silencing circDNMT3B can significantly increase the level of d‐lactic acid, FD‐40, MDA, diamine oxidase, IL‐10 and IL‐6, compared with sepsis group, while the SOD activity was lower. Silencing circDNMT3B leads to oxidative damage and influence inflammatory factors level in intestinal tissue. CircDNMT3B was identified as a target gene of miR‐20b‐5p. Silencing circDNMT3B decreased cell survival and induced apoptosis in Caco2 cells treated with LPS, which was reversed by anti‐miR‐20b‐5p. MiR‐20b‐5p inhibitor remarkably down‐regulated mentioned‐above levels, in addition to up‐regulate SOD activity, which may relieve the damage of intestinal mucosal permeability caused by silencing circDNMT3B in sepsis rats. Down‐regulation of circDMNT3B was conducive to the dysfunction of intestinal mucosal permeability via sponging miR‐20b‐5p in sepsis rats, which may provide the novel strategy for sepsis treatment in the future.
► MiR-145 targets a putative binding site in the 3′UTR of PAK4. ► MiR-145 played an important role in inhibiting cell growth by directly targeting PAK4. ► MiR-145 may function as tumor suppressors.
...MicroRNAs (miRNAs) are regulators of numerous cellular events; accumulating evidence indicates that miRNAs play a key role in a wide range of biological functions, such as cellular proliferation, differentiation, and apoptosis in cancer. Down-regulated expression of miR-145 has been reported in colon cancer tissues and cell lines. The molecular mechanisms underlying miR-145 and the regulation of colon carcinogenesis remain unclear. In this study, we investigated the levels of miR-145 in human colon cancer cells using qRT-PCR and found markedly decreased levels compared to normal epithelial cells. We identified PAK4 as a novel target of miR-145 using informatics screening. Additionally, we demonstrated that miR-145 targets a putative binding site in the 3′UTR of PAK4 and that its abundance is inversely associated with miR-145 expression in colon cancer cells; we confirmed this relationship using the luciferase reporter assay. Furthermore, restoration of miR-145 by mimics in SW620 cells significantly attenuated cell growth in vitro, in accordance with the inhibitory effects induced by siRNA mediated knockdown of PAK4. Taken together, these findings demonstrate that miR-145 downregulates P-ERK expression by targeting PAK4 and leads to inhibition of tumor growth.
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event and a fatal complication of viral infections. Whether sHLH may also be observed in patients with a ...cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still uncertain. We aimed to determine the incidence of sHLH in severe COVID-19 patients and evaluate the underlying risk factors.
Four hundred fifteen severe COVID-19 adult patients were retrospectively assessed for hemophagocytosis score (HScore). A subset of 7 patients were unable to be conclusively scored due to insufficient patient data.
In 408 patients, 41 (10.04%) had an HScore ≥169 and were characterized as "suspected sHLH positive". Compared with patients below a HScore threshold of 98, the suspected sHLH positive group had higher D-dimer, total bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, triglycerides, ferritin, interleukin-6, C-reactive protein, procalcitonin, lactate dehydrogenase, creatine kinase isoenzyme, troponin, Sequential Organ Failure Assessment (SOFA) score, while leukocyte, hemoglobin, platelets, lymphocyte, fibrinogen, pre-albumin, albumin levels were significantly lower (all P < 0.05). Multivariable logistic regression revealed that high ferritin (>1922.58 ng/mL), low platelets (<101 × 10
/L) and high triglycerides (>2.28 mmol/L) were independent risk factors for suspected sHLH in COVID-19 patients. Importantly, COVID-19 patients that were suspected sHLH positive had significantly more multi-organ failure. Additionally, a high HScore (>98) was an independent predictor for mortality in COVID-19.
HScore should be measured as a prognostic biomarker in COVID-19 patients. In particular, it is important that HScore is assessed in patients with high ferritin, triglycerides and low platelets to improve the detection of suspected sHLH.
Background
Currently, there are no reliable predictors of risk of development and severity of acute kidney injury (AKI) in septic patients. The surfactant protein D (SP-D) polymorphism rs721917C/T is ...associated with a greater susceptibility to AKI in the Chinese population. Our aim was to evaluate the value of SP-D polymorphisms rs721917C/T and of plasma SP-D levels to predict the risk of development of AKI (defined with KDIGO criterion) in septic patients.
Methods
The study enrolled septic patients admitted to the Critical Care Department of two tertiary care hospitals.
SP
-
D
rs721917C/T polymorphisms were determined using the PCR-SSP method. Plasma SP-D and urine NGAL contents were measured using commercially available ELISA kits.
Results
330 septic patients were included. Their SOFA scores were 12 ± 3. Patients with AKI (
n
= 156) had higher plasma SP-D levels (median: 153 ng/mL, range 111–198 ng/mL) and urinary NGAL levels (median: 575 ng/mL, range 423–727 ng/mL) than those without AKI (SP-D median: 124 ng/mL, range 81–159 ng/mL,
P
= 0.001; NGAL median: 484 ng/mL, range 429–573 ng/mL). Plasma SP-D levels of AKI patients were correlated with urinary NGAL contents (
r
= 0.853). In 32 patients receiving continuous renal replacement therapy (CRRT), plasma SP-D levels correlated with duration of CRRT (
r
= 0.448). The area under the receiver operating characteristic curve for plasma SP-D levels to predict AKI was 0.84. Patients with AKI had a higher rate of rs721917 CC genotype (AKI: 35% vs. non-AKI: 20%;
P
= 0.012), but a significantly lower rate of TT genotype (AKI: 19% vs. non-AKI: 26%; P = 0.005). SP-D rs721917 CC genotype was an independent predictor of AKI (
P
= 0.044) and mortality (
P
= 0.014).
Conclusion
Our study showed that increased plasma SP-D level is associated with a higher risk of AKI in patients with sepsis. The SP-D rs721917CC genotype is an independent and significant predictor of AKI development and mortality of septic patients. The SP-D rs721917C/T polymorphisms should be further studied as diagnostic and prognostic biomarkers to facilitate early recognition of AKI.
Thymosin alpha 1 (Tα1) is widely used to treat patients with COVID-19 in China; however, its efficacy remains unclear. This study aimed to explore the efficacy of Tα1 as a COVID-19 therapy.
We ...performed a multicenter cohort study in five tertiary hospitals in the Hubei province of China between December 2019 and March 2020. The patient non-recovery rate was used as the primary outcome.
All crude outcomes, including non-recovery rate (65/306
290/1,976,
= 0.003), in-hospital mortality rate (62/306
271/1,976,
= 0.003), intubation rate (31/306
106/1,976,
= 0.001), acute respiratory distress syndrome (ARDS) incidence (104/306
499/1,976,
= 0.001), acute kidney injury (AKI) incidence (26/306
66/1,976,
< 0.001), and length of intensive care unit (ICU) stay (14.9 ± 12.7
8.7 ± 8.2 days,
< 0.001), were significantly higher in the Tα1 treatment group. After adjusting for confounding factors, Tα1 use was found to be significantly associated with a higher non-recovery rate than non-Tα1 use (OR 1.5, 95% CI 1.1-2.1,
= 0.028). An increased risk of non-recovery rate associated with Tα1 use was observed in the patient subgroups with maximum sequential organ failure assessment (SOFA) scores ≥2 (OR 2.0, 95%CI 1.4-2.9,
= 0.024), a record of ICU admission (OR 5.4, 95%CI 2.1-14.0,
< 0.001), and lower PaO2/FiO2 values (OR 1.9, 95%CI 1.1-3.4,
= 0.046). Furthermore, later initiation of Tα1 use was associated with a higher non-recovery rate.
Tα1 use in COVID-19 patients was associated with an increased non-recovery rate, especially in those with greater disease severity.
Background
The mortality of extensively drug-resistant Gram-negative (XDR GN) bacilli-induced ventilator-associated pneumonia (VAP) is extremely high. The purpose of this study was to compare the ...efficacy and safety of inhaled (IH) plus intravenous (IV) polymyxin B versus IV polymyxin B in XDR GN bacilli VAP patients.
Methods
A retrospective multi-center observational cohort study was performed at eight ICUs between January 1
st
2018, and January 1
st
2020 in China. Data from all patients treated with polymyxin B for a microbiologically confirmed VAP were analyzed. The primary endpoint was the clinical cure of VAP. The favorable clinical outcome, microbiological outcome, VAP-related mortality and all-cause mortality during hospitalization, and side effects related with polymyxin B were secondary endpoints. Favorable clinical outcome included clinical cure or clinical improvement.
Results
151 patients and 46 patients were treated with IV polymyxin B and IH plus IV polymyxin B, respectively. XDR
Klebsiella pneumoniae
was the main isolated pathogen (
n
= 83, 42.1%). After matching on age (± 5 years), gender, septic shock, and Apache II score (± 4 points) when polymyxin B was started, 132 patients were included. 44 patients received simultaneous IH plus IV polymyxin B and 88 patients received IV polymyxin B. The rates of clinical cure (43.2% vs 27.3%,
p
= 0.066), bacterial eradication (36.4% vs 23.9%,
p
= 0.132) as well as VAP-related mortality (27.3% vs 34.1%,
p
= 0.428), all-cause mortality (34.1% vs 42.0%,
p
= 0.378) did not show any significant difference between the two groups. However, IH plus IV polymyxin B therapy was associated with improved favorable clinical outcome (77.3% vs 58.0%,
p
= 0.029). Patients in the different subgroups (admitted with medical etiology, infected with XDR
K. pneumoniae
, without bacteremia, with immunosuppressive status) were with odd ratios (ORs) in favor of the combined therapy. No patient required polymyxin B discontinuation due to adverse events. Additional use of IH polymyxin B (aOR 2.63, 95% CI 1.06, 6.66,
p
= 0.037) was an independent factor associated with favorable clinical outcome.
Conclusions
The addition of low-dose IH polymyxin B to low-dose IV polymyxin B did not provide efficient clinical cure and bacterial eradication in VAP caused by XDR GN bacilli.
Keypoints
Additional use of IH polymyxin B was the sole independent risk factor of favorable clinical outcome. Patients in the different subgroups were with HRs substantially favoring additional use of IH polymyxin B. No patients required polymyxin B discontinuation due to adverse events.
Novel coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with high mortality. Although several studies have reported different risk factors for mortality in patients based on ...traditional analytics, few studies have used artificial intelligence (AI) algorithms. This study investigated prognostic factors for COVID-19 patients using AI methods.
COVID-19 patients who were admitted in Wuhan Infectious Diseases Hospital from December 29, 2019 to March 2, 2020 were included. The whole cohort was randomly divided into training and testing sets at a 6:4 ratio. Demographic and clinical data were analyzed to identify predictors of mortality using least absolute shrinkage and selection operator (LASSO) regression and LASSO-based artificial neural network (ANN) models. The predictive performance of the models was evaluated using receiver operating characteristic (ROC) curve analysis.
A total of 1145 patients (610 male, 53.3%) were included in the study. Of the 1145 patients, 704 were assigned to the training set and 441 were assigned to the testing set. The median age of the patients was 57 years (range: 47–66 years). Severity of illness, age, platelet count, leukocyte count, prealbumin, C-reactive protein (CRP), total bilirubin, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and Sequential Organ Failure Assessment (SOFA) score were identified as independent prognostic factors for mortality. Incorporating these nine factors into the LASSO regression model yielded a correct classification rate of 0.98, with area under the ROC curve (AUC) values of 0.980 and 0.990 in the training and testing cohorts, respectively. Incorporating the same factors into the LASSO-based ANN model yielded a correct classification rate of 0.990, with an AUC of 0.980 in both the training and testing cohorts.
Both the LASSO regression and LASSO-based ANN model accurately predicted the clinical outcome of patients with COVID-19. Severity of illness, age, platelet count, leukocyte count, prealbumin, CRP, total bilirubin, APACHE II score, and SOFA score were identified as prognostic factors for mortality in patients with COVID-19.
Extended/continuous infusion and therapeutic drug monitoring (TDM) of time-dependent antimicrobials are recommended for optimizing drug exposure for patients in intensive care units (ICUs), although ...practical application of these measures remains uncertain. We surveyed current practices in infusion and monitoring of commonly prescribed time-dependent antimicrobials in ICUs across China.
From December 2019 to January 2020, we sent online questionnaires about various aspects of infusion and monitoring of time-dependent antimicrobials to intensivists across China. Responses from clinicians were matched with their professional titles using the Sankey diagram. Univariate and multivariate logistic regression analyses were performed to find factors associated with TDM.
A total of 3,687 ICU specialists from 31 provincial administrative regions of China responded to our questionnaires. Antibiotic stewardship (ABS) teams were available in hospitals as reported by 3,243 (88.0%) intensivists, including 1,308 (35.5%) who were ABS team members. Although most intensivists (3,490, 94.7%) were acquainted with the concept of prolonged/continuous infusion, nearly half of them (1,634, 44.3%) commonly administered β-lactam antibiotics intermittently. Nearly two-thirds of the respondents reported that their hospitals could not perform TDM. Our multivariable logistic regression analysis revealed that at the hospital level, knowledge of drug sample timing and attitude toward monitoring treatment effects, and drug trough or peak concentration influenced the decision to conduct TDM.
We found great variability in prescribing practices, from drug administration to TDM, for several time-dependent antibiotics commonly used for patients with severe infections. Further studies are necessary to effectively evaluate strategies to promote consistent prescribing behavior.
Continuous renal replacement therapy (CRRT) has become an effective multiple organ support therapy instead of single renal replacement as initially expected, and it is widely used in intensive care ...unit (ICU). After the outbreak of coronavirus disease 2019 (COVID-19), a series of expert recommendation or consensus have been developed to diagnose and treat the disease, including CRRT in acute kidney injury (AKI) and hyper inflammatory response. However, CRRT in COVID-19 is extraordinarily different from regular one due to different pathophysiology and infectious clinical scenarios. Accordingly, the paper aims to elaborate the similarities and differences between CRRT in COVID-19 and routine treatment in terms of safety and accessibility, indications and timing, clinical operation, anticoagulation, fluid management, prevention and control of infectious diseases, etc.
The potential relationship among airway
Candida
spp. de-colonization, nebulized amphotericin B (NAB), and occurrence of ventilator-associated pneumonia (VAP) in patients who are critically ill has ...not been fully investigated, especially concerning effects on survival. In this observational, retrospective, cohort study in a 22-bed central intensive care unit, we included patients aged >18 years who required mechanical ventilation (MV) for >48 h, with at least two consecutive positive
Candida
spp. test results. Patients were categorized into NAB and no NAB (control) groups. Propensity matching at 1:1 was performed according to strict standards, and multiple Cox proportional hazard model and multivariate analyses were performed to evaluate the effects of NAB treatment. Throughout an 8-year study period, 526 patients had received MV and had positive respiratory tract
Candida
spp. cultures. Of these, we included 275 patients and excluded 251 patients. In total, we successfully matched 110 patients from the two groups (each group,
n
= 55; total population median age, 64 years; Acute Physiology and Chronic Health Evaluation II APACHE II score, 25.5; sequential organ failure assessment score, 9). The
Candida
spp. de-colonization rate was 69.1% in patients treated with NAB. VAP incidence did not differ significantly between the NAB (10.91%) and control (16.36%) groups (
P
= 0.405).
Pseudomonas aeruginosa-
related VAP rates differed significantly between the NAB (10.91%) and control (25.45%) groups (
P
= 0.048). Five (9.1%) patients in the NAB group died during hospitalization compared with 17 (30.9%) controls (
P
= 0.014). At 28 days, 9 (16.4%) and 16 (29.1%) deaths occurred in the NAB and control groups, respectively, (
P
= 0.088). The cumulative 90-day mortality rate differed significantly between the two groups (23.6 vs. 43.6%,
P
= 0.015). Multivariate logistic regression analyses indicated a decreased 90-day mortality in the NAB group (adjusted odds ratio 0.413; 95% confidence interval 0.210–0.812;
P
= 0.01). In subgroup analyses, the NAB-associated decreased risk of death at 90 days was consistent across subgroups of patients with a
Candida
score of 2, younger age (<64 years), a higher APACHE II score (≥25), fewer
Candida
sites (<2), or MV at admission. NAB treatment contributed to
Candida
spp. airway de-colonization, was associated with a reduced risk of
P. aeruginosa-
related VAP, and improved 90-day mortality in patients critically ill with
Candida
spp. tracheobronchial colonization who had received MV for >2 days. NAB may be an alternative treatment option for critically ill patients with VAP.
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