Gene signature for the prediction of the trajectories of sepsis-induced acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a common complication in sepsis. However, the trajectories of sepsis-induced AKI and their transcriptional profiles are not well characterized. METHODS: Sepsis patients admitted to centres participating in Chinese Multi-omics Advances In Sepsis (CMAISE) from November 2020 to December 2021 were enrolled, and gene expression in peripheral blood mononuclear cells was measured on Day 1. The renal function trajectory was measured by the renal component of the SOFA score (SOFArenal) on Days 1 and 3. Transcriptional profiles on Day 1 were compared between these renal function trajectories, and a support vector machine (SVM) was developed to distinguish transient from persistent AKI. RESULTS: A total of 172 sepsis patients were enrolled during the study period. The renal function trajectory was classified into four types: non-AKI (SOFArenal = 0 on Days 1 and 3, n = 50), persistent AKI (SOFArenal > 0 on Days 1 and 3, n = 62), transient AKI (SOFArenal > 0 on Day 1 and SOFArenal = 0 on Day 3, n = 50) and worsening AKI (SOFArenal = 0 on Days 1 and SOFArenal > 0 on Day 3, n = 10). The persistent AKI group showed severe organ dysfunction and prolonged requirements for organ support. The worsening AKI group showed the least organ dysfunction on day 1 but had higher serum lactate and prolonged use of vasopressors than the non-AKI and transient AKI groups. There were 2091 upregulated and 1,902 downregulated genes (adjusted p < 0.05) between the persistent and transient AKI groups, with enrichment in the plasma membrane complex, receptor complex, and T-cell receptor complex. A 43-gene SVM model was developed using the genetic algorithm, which showed significantly greater performance predicting persistent AKI than the model based on clinical variables in a holdout subset (AUC: 0.948 [0.912, 0.984] vs. 0.739 [0.648, 0.830]; p < 0.01 for Delong's test). CONCLUSIONS: Our study identified four subtypes of sepsis-induced AKI based on kidney injury trajectories. The landscape of host response aberrations across these subtypes was characterized. An SVM model based on a gene signature was developed to predict renal function trajectories, and showed better performance than the clinical variable-based model. Future studies are warranted to validate the gene model in distinguishing persistent from transient AKI.

Effectiveness of anisodamine for the treatment of critically ill patients with septic shock: a multicentre randomized controlled trial.

BACKGROUND: Septic shock is characterized by an uncontrolled inflammatory response and microcirculatory dysfunction. There is currently no specific agent for treating septic shock. Anisodamine is an agent extracted from traditional Chinese medicine with potent anti-inflammatory effects. However, its clinical effectiveness remains largely unknown. METHODS: In a multicentre, open-label trial, we randomly assigned adults with septic shock to receive either usual care or anisodamine (0.1-0.5 mg per kilogram of body weight per hour), with the anisodamine doses adjusted by clinicians in accordance with the patients' shock status. The primary end point was death on hospital discharge. The secondary end points were ventilator-free days at 28 days, vasopressor-free days at 28 days, serum lactate and sequential organ failure assessment (SOFA) score from days 0 to 6. The differences in the primary and secondary outcomes were compared between the treatment and usual care groups with the χ2 test, Student's t test or rank-sum test, as appropriate. The false discovery rate was controlled for multiple testing. RESULTS: Of the 469 patients screened, 355 were assigned to receive the trial drug and were included in the analyses-181 patients received anisodamine, and 174 were in the usual care group. We found no difference between the usual care and anisodamine groups in hospital mortality (36% vs. 30%; p = 0.348), or ventilator-free days (median [Q1, Q3], 24.4 [5.9, 28] vs. 26.0 [8.5, 28]; p = 0.411). The serum lactate levels were significantly lower in the treated group than in the usual care group after day 3. Patients in the treated group were less likely to receive vasopressors than those in the usual care group (OR [95% CI] 0.84 [0.50, 0.93] for day 5 and 0.66 [0.37, 0.95] for day 6). CONCLUSIONS: There is no evidence that anisodamine can reduce hospital mortality among critically ill adults with septic shock treated in the intensive care unit. Trial registration ClinicalTrials.gov ( NCT02442440 ; Registered on 13 April 2015).

Gene correlation network analysis to identify regulatory factors in sepsis.

BACKGROUND AND OBJECTIVES: Sepsis is a leading cause of mortality and morbidity in the intensive care unit. Regulatory mechanisms underlying the disease progression and prognosis are largely unknown. The study aimed to identify master regulators of mortality-related modules, providing potential therapeutic target for further translational experiments. METHODS: The dataset GSE65682 from the Gene Expression Omnibus (GEO) database was utilized for bioinformatic analysis. Consensus weighted gene co-expression netwoek analysis (WGCNA) was performed to identify modules of sepsis. The module most significantly associated with mortality were further analyzed for the identification of master regulators of transcription factors and miRNA. RESULTS: A total number of 682 subjects with various causes of sepsis were included for consensus WGCNA analysis, which identified 27 modules. The network was well preserved among different causes of sepsis. Two modules designated as black and light yellow module were found to be associated with mortality outcome. Key regulators of the black and light yellow modules were the transcription factor CEBPB (normalized enrichment score = 5.53) and ETV6 (NES = 6), respectively. The top 5 miRNA regulated the most number of genes were hsa-miR-335-5p (n = 59), hsa-miR-26b-5p (n = 57), hsa-miR-16-5p (n = 44), hsa-miR-17-5p (n = 42), and hsa-miR-124-3p (n = 38). Clustering analysis in 2-dimension space derived from manifold learning identified two subclasses of sepsis, which showed significant association with survival in Cox proportional hazard model (p = 0.018). CONCLUSIONS: The present study showed that the black and light-yellow modules were significantly associated with mortality outcome. Master regulators of the module included transcription factor CEBPB and ETV6. miRNA-target interactions identified significantly enriched miRNA.

Defining persistent critical illness based on growth trajectories in patients with sepsis.

BACKGROUND: Persistent critical illness is common in critically ill patients and is associated with vast medical resource use and poor clinical outcomes. This study aimed to define when patients with sepsis would be stabilized and transitioned to persistent critical illness, and whether such transition time varies between latent classes of patients. METHODS: This was a retrospective cohort study involving sepsis patients in the eICU Collaborative Research Database. Persistent critical illness was defined at the time when acute physiological characteristics were no longer more predictive of in-hospital mortality (i.e., vital status at hospital discharge) than antecedent characteristics. Latent growth mixture modeling was used to identify distinct trajectory classes by using Sequential Organ Failure Assessment score measured during intensive care unit stay as the outcome, and persistent critical illness transition time was explored in each latent class. RESULTS: The mortality was 16.7% (3828/22,868) in the study cohort. Acute physiological model was no longer more predictive of in-hospital mortality than antecedent characteristics at 15 days after intensive care unit admission in the overall population. Only a minority of the study subjects (n = 643, 2.8%) developed persistent critical illness, but they accounted for 19% (15,834/83,125) and 10% (19,975/198,833) of the total intensive care unit and hospital bed-days, respectively. Five latent classes were identified. Classes 1 and 2 showed increasing Sequential Organ Failure Assessment score over time and transition to persistent critical illness occurred at 16 and 27 days, respectively. The remaining classes showed a steady decline in Sequential Organ Failure Assessment scores and the transition to persistent critical illness occurred between 6 and 8 days. Elevated urea-to-creatinine ratio was a good biochemical signature of persistent critical illness. CONCLUSIONS: While persistent critical illness occurred in a minority of patients with sepsis, it consumed vast medical resources. The transition time differs substantially across latent classes, indicating that the allocation of medical resources should be tailored to different classes of patients.

Performance of the MEDS score in predicting mortality among emergency department patients with a suspected infection: a meta-analysis.

OBJECTIVES: To carry out a meta-analysis to examine the prognostic performance of the Mortality in Emergency Department Sepsis (MEDS) score in predicting mortality among emergency department patients with a suspected infection. METHODS: Electronic databases-PubMed, Embase, Scopus, EBSCO and the Cochrane Library-were searched for eligible articles from their respective inception through February 2019. Sensitivity, specificity, likelihood ratios and receiver operator characteristic area under the curve were calculated. Subgroup analyses were performed to explore the prognostic performance of MEDS in selected populations. RESULTS: We identified 24 studies involving 21 246 participants. The pooled sensitivity of MEDS to predict mortality was 79% (95% CI 72% to 84%); specificity was 74% (95% CI 68% to 80%); positive likelihood ratio 3.07 (95% CI 2.47 to 3.82); negative likelihood ratio 0.29 (95% CI 0.22 to 0.37) and area under the curve 0.83 (95% CI 0.80 to 0.86). Significant heterogeneity was seen among included studies. Meta-regression analyses showed that the time at which the MEDS score was measured and the cut-off value used were important sources of heterogeneity. CONCLUSION: The MEDS score has moderate accuracy in predicting mortality among emergency department patients with a suspected infection. A study comparison MEDS and qSOFA in the same population is needed.

Association Between the Use of Sodium Bicarbonate and Mortality in Acute Kidney Injury Using Marginal Structural Cox Model.

OBJECTIVE: Acute kidney injury with metabolic acidosis is common in critically ill patients. This study assessed the associations between the use of IV sodium bicarbonate and mortality of patients with acute kidney injury and acidosis. DESIGN: The study was conducted by using data from Beth Israel Deaconess Medical Center, which included several ICUs such as coronary care unit, cardiac surgery recovery unit, medical ICU, surgical ICU, and trauma-neuro ICU. Marginal structural Cox model was used to assess the relationship between receipt of sodium bicarbonate and hospital mortality, allowing pH, PaCO2, creatinine, and bicarbonate concentration as time-varying predictors of sodium bicarbonate exposure while adjusting for baseline characteristics of age, gender, Sequential Organ Failure Assessment score, acute kidney injury stage, Elixhauser score, quick Sequential Organ Failure Assessment, and Simplified Acute Physiology Score II. SETTING: A large U.S.-based critical care database named Medical Information Mart for Intensive Care. PATIENTS: Patients with Kidney Disease: Improving Global Outcomes acute kidney injury stage greater than or equal to 1 (> 1.5 (Equation is included in full-text article.)baseline creatinine) and one measurement of acidosis (pH ≤ 7.2). Baseline creatinine was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 3,406 eligible patients, 836 (24.5%) had received sodium bicarbonate treatment. Patients who received sodium bicarbonate treatment had a higher Sequential Organ Failure Assessment (9 vs 7; p < 0.001), lower pH (7.16 vs 7.18; p < 0.001), and bicarbonate concentration (16.51 ± 7.04 vs 20.57 ± 6.29 mmol/L; p < 0.001) compared with those who did not receive sodium bicarbonate. In the marginal structural Cox model by weighing observations with inverse probability of receiving sodium bicarbonate, sodium bicarbonate treatment was not associated with mortality in the overall population (hazard ratio, 1.16; 95% CI, 0.98-1.42; p = 0.132), but it appeared to be beneficial in subgroups of pancreatitis (hazard ratio, 0.53; 95% CI, 0.28-0.98; p = 0.044) and severe acidosis (pH < 7.15; hazard ratio, 0.75; 95% CI, 0.58-0.96; p = 0.024). Furthermore, sodium bicarbonate appeared to be beneficial in patients with severe bicarbonate deficit (< -50 kg·mmol/L). CONCLUSIONS: In the analysis by adjusting for potential confounders, there is no evidence that IV sodium bicarbonate is beneficial for patients with acute kidney injury and acidosis. Although the study suggested potential beneficial effects in some highly selected subgroups, the results need to be validated in experimental trials.

Declining Mortality in Patients With Acute Respiratory Distress Syndrome: An Analysis of the Acute Respiratory Distress Syndrome Network Trials.

OBJECTIVES: There has been multiple advances in the management of acute respiratory distress syndrome, but the temporal trends in acute respiratory distress syndrome-related mortality are not well known. This study aimed to investigate the trends in mortality in acute respiratory distress syndrome patients over time and to explore the roles of daily fluid balance and ventilation variables in those patients. DESIGN: Secondary analysis of randomized controlled trials conducted by the Acute Respiratory Distress Syndrome Network from 1996 to 2013. SETTING: Multicenter study involving Acute Respiratory Distress Syndrome Network trials. PATIENTS: Patients with acute respiratory distress syndrome. INTERVENTIONS: None. MEASURES AND MAIN RESULTS: Individual patient data from 5,159 acute respiratory distress syndrome patients (excluding the Late Steroid Rescue Study trial) were enrolled in this study. The crude mortality rate decreased from 35.4% (95% CI, 29.9-40.8%) in 1996 to 28.3% (95% CI, 22.0-34.7%) in 2013. By adjusting for the baseline Acute Physiology and Chronic Health Evaluation III, age, ICU type, and admission resource, patients enrolled from 2005 to 2010 (odds ratio, 0.61; 95% CI, 0.50-0.74) and those enrolled after 2010 (odds ratio, 0.73; 95% CI, 0.58-0.92) were associated with lower risk of death as compared to those enrolled before 2000. The effect of year on mortality decline disappeared after adjustment for daily fluid balance, positive end-expiratory pressure, tidal volume, and plateau pressure. There were significant trends of declines in daily fluid balance, tidal volume, and plateau pressure and an increase in positive end-expiratory pressure over the 17 years. CONCLUSIONS: Our study shows an improvement in the acute respiratory distress syndrome-related mortality rate in the critically ill patients enrolled in the Acute Respiratory Distress Syndrome Network trials. The effect was probably mediated via decreased tidal volume, plateau pressure, and daily fluid balance and increased positive end-expiratory pressure.

Machine learning for the prediction of volume responsiveness in patients with oliguric acute kidney injury in critical care.

BACKGROUND AND OBJECTIVES: Excess fluid balance in acute kidney injury (AKI) may be harmful, and conversely, some patients may respond to fluid challenges. This study aimed to develop a prediction model that can be used to differentiate between volume-responsive (VR) and volume-unresponsive (VU) AKI. METHODS: AKI patients with urine output < 0.5 ml/kg/h for the first 6 h after ICU admission and fluid intake > 5 l in the following 6 h in the US-based critical care database (Medical Information Mart for Intensive Care (MIMIC-III)) were considered. Patients who received diuretics and renal replacement on day 1 were excluded. Two predictive models, using either machine learning extreme gradient boosting (XGBoost) or logistic regression, were developed to predict urine output > 0.65 ml/kg/h during 18 h succeeding the initial 6 h for assessing oliguria. Established models were assessed by using out-of-sample validation. The whole sample was split into training and testing samples by the ratio of 3:1. MAIN RESULTS: Of the 6682 patients included in the analysis, 2456 (36.8%) patients were volume responsive with an increase in urine output after receiving > 5 l fluid. Urinary creatinine, blood urea nitrogen (BUN), age, and albumin were the important predictors of VR. The machine learning XGBoost model outperformed the traditional logistic regression model in differentiating between the VR and VU groups (AU-ROC, 0.860; 95% CI, 0.842 to 0.878 vs. 0.728; 95% CI 0.703 to 0.753, respectively). CONCLUSIONS: The XGBoost model was able to differentiate between patients who would and would not respond to fluid intake in urine output better than a traditional logistic regression model. This result suggests that machine learning techniques have the potential to improve the development and validation of predictive modeling in critical care research.

Identification of PRDX6 as a regulator of ferroptosis.

Ferroptosis is a newly characterized iron-dependent form of nonapoptotic regulated cell death triggered by lipid reactive oxygen species (LOOH). The dysregulation of ferroptosis is highly related to cancer, and the induction of ferroptosis is also proposed as a potential strategy for cancer therapy. Although several key regulators have been identified that are involved in ferroptosis, the molecular mechanism underlying this process remains largely unknown. Here, we report that Peroxiredoxin-6 (PRDX6) is a bona fide negative regulator of ferroptotic cell death. The knockdown of intracellular PRDX6 significantly enhances LOOH and ferroptotic cell death triggered by ferroptosis inducers (Erastin and RSL-3), which is correlated with the transcriptional activation of heme oxygenase-1. Moreover, overexpression of heme oxygenase-1 enhances both Erastin- and RSL-3-triggered LOOH, suggesting that heme oxygenase-1 mediates PRDX6 silencing-enhanced ferroptosis. More importantly, the application of a specific PRDX6 phospholipase A2 (iPLA2) inhibitor, MJ-33, synergistically enhances the ferroptosis induced by Erastin, suggesting that PRDX6 removes LOOH through its iPLA2 activity. Thus, our findings reveal an essential role of PRDX6 in protecting cells against ferroptosis and provide a potential target to improve the antitumor activity of ferroptosis-based chemotherapy.

Imaging the Infant Chest without Sedation: Feasibility of Using Single Axial Rotation with 16-cm Wide-Detector CT.

Purpose To compare image quality, patient preparation time, and radiation dose using a single axial rotation with 16-cm wide-detector computed tomography (CT) in imaging the infant chest without sedation with those in infants examined by using a 64-row CT and sedation. Materials and Methods Thirty-two infants (group 1) were prospectively enrolled to undergo nonenhanced chest CT without sedation using a single axial rotation on a 16-cm wide-detector CT scanner. Patients were imaged with automatic tube current modulation and tube voltages of 80 kVp for patients weighing 5 kg or less and 100 kVp for patients weighing more than 5 kg. Patient preparation time, CT dose index (CTDI), dose-length product (DLP), and image quality were compared with those in a historical control group consisting of 30 infants (group 2) who underwent conventional helical scanning with sedation performed by using a 64-row volume CT scanner. The Student t test for independent samples was used to assess continuous variables. The Mann-Whitney rank test and the κ test were used to evaluate image quality. Results There was no statistically significant difference in body weight, age, mean CT attenuation value, image noise, and subjective image quality score between the two groups. However, compared with the group scanned by using a 64-row volume CT scanner (group 2), group 1 experienced significantly reduced scan time by 83% (0.35 second vs 2.01 seconds ± 0.21 [standard deviation]), preparation time by 57% (41.25 minutes ± 103.78 vs 96.5 minutes ± 151.77), CTDI by 42% (2.03 mGy ± 0.4 vs 3.52 mGy ± 0.03), and DLP by 52% (27.07 mGy·cm ± 6.97 vs 55.84 mGy·cm ± 6.46) (P < .05 for all). Conclusion Compared with conventional 64-row helical CT with sedation, use of a single axial rotation with 16-cm wide-detector CT in imaging the infant chest without sedation can reduce radiation dose, preparation time, and total scan time, while providing comparable image quality. © RSNA, 2017.

Identification of subclasses of sepsis that showed different clinical outcomes and responses to amount of fluid resuscitation: a latent profile analysis.

BACKGROUND AND OBJECTIVE: Sepsis is a heterogeneous disease and identification of its subclasses may facilitate and optimize clinical management. This study aimed to identify subclasses of sepsis and its responses to different amounts of fluid resuscitation. METHODS: This was a retrospective study conducted in an intensive care unit at a large tertiary care hospital. The patients fulfilling the diagnostic criteria of sepsis from June 1, 2001 to October 31, 2012 were included. Clinical and laboratory variables were used to perform the latent profile analysis (LPA). A multivariable logistic regression model was used to explore the independent association of fluid input and mortality outcome. RESULTS: In total, 14,993 patients were included in the study. The LPA identified four subclasses of sepsis: profile 1 was characterized by the lowest mortality rate and having the largest proportion and was considered the baseline type; profile 2 was characterized by respiratory dysfunction; profile 3 was characterized by multiple organ dysfunction (kidney, coagulation, liver, and shock), and profile 4 was characterized by neurological dysfunction. Profile 3 showed the highest mortality rate (45.4%), followed by profile 4 (27.4%), 2 (18.2%), and 1 (16.9%). Overall, the amount of fluid needed for resuscitation was the largest on day 1 (median 5115 mL, interquartile range (IQR) 2662 to 8800 mL) and decreased rapidly on day 2 (median 2140 mL, IQR 900 to 3872 mL). Higher cumulative fluid input in the first 48 h was associated with reduced risk of hospital mortality for profile 3 (odds ratio (OR) 0.89, 95% CI 0.83 to 0.95 for each 1000 mL increase in fluid input) and with increased risk of death for profile 4 (OR 1.20, 95% CI 1.11 to 1.30). CONCLUSION: The study identified four subphenotypes of sepsis, which showed different mortality outcomes and responses to fluid resuscitation. Prospective trials are needed to validate our findings.

Use of a tourniquet in total knee arthroplasty: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: A tourniquet is commonly used in total knee arthroplasty (TKA). However, the effectiveness and safety of tourniquets are debated. We performed this study to investigate whether patients benefit from the use of tourniquets in TKA. METHODS: The literature search was conducted using PubMed, Cochrane Library, MEDLINE, Embase, and other medical databases. After a literature search, 26 randomized controlled trials involving 1,450 knees were analyzed. RESULTS: Tourniquet use significantly decreased intraoperative blood loss, transfusion rate, and operation time but not postoperative blood loss, measurable total blood loss, calculated total blood loss, transfusion volume, incidence of pulmonary embolism, or duration of hospital stay. It also slowed down joint functional recovery in the short term and increased the incidence of deep vein thrombosis and other minor wound complications. CONCLUSIONS: Data from this meta-analysis indicate that patients may benefit from the use of a tourniquet in TKA; however, it use is accompanied by disadvantages and complications. Because of the very low-evidence quality and lower grading of recommendations, assessment, development, and evaluation recommendation strength, no guidelines can be developed based on current evidence.

Application of Artificial Intelligence to Advance Individualized Diagnosis and Treatment in Emergency and Critical Care Medicine.

Emergency and critical illnesses refer to severe diseases or conditions characterized by rapid changes in health that may endanger life within a short period [...].

Genetic correlations and causal relationships between cardio-metabolic traits and sepsis.

Cardio-metabolic traits have been reported to be associated with the development of sepsis. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability, or are confounded by environmental factors. We performed three analyses to explore the relationships between cardio-metabolic traits and sepsis. Mendelian randomization (MR) study to evaluate the causal effects of multiple cardio-metabolic traits on sepsis. Global genetic correlation analysis to explore the correlations between cardio-metabolic traits and sepsis. Local genetic correlation (GC) analysis to explore shared genetic heritability between cardio-metabolic traits and sepsis. Some loci were further examined for related genes responsible for the causal relationships. Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies with sample sizes between 200,000 to 750,000. In MR, we found causality between BMI and sepsis (OR: 1.53 [1.4-1.67]; p < 0.001). Body mass index (BMI), which is confirmed by sensitivity analyses and multivariable MR adjusting for confounding factors. Global GC analysis showed a significant correlation between BMI and sepsis (rg = 0.55, p < 0.001). More cardio-metabolic traits were identified to be correlated to the sepsis onset such as CRP (rg = 0.37, p = 0.035), type 2 diabetes (rg = 0.33, p < 0.001), HDL (rg = - 0.41, p < 0.001), and coronary artery disease (rg = 0.43, p < 0.001). Local GC revealed some shared genetic loci responsible for the causality. The top locus 1126 was located at chromosome 7 and comprised genes HIBADH, JAZF1, and CREB5. The present study provides evidence for an independent causal effect of BMI on sepsis. Further detailed analysis of the shared genetic heritability between cardio-metabolic traits and sepsis provides the opportunity to improve the preventive strategies for sepsis.

Genomic surveillance indicates clonal replacement of hypervirulent Klebsiella pneumoniae ST881 and ST29 lineage strains in vivo.

The emergence of hypervirulent Klebsiella pneumoniae (hvKp) poses a significant public health threat, particularly regarding its carriage in the healthy population. However, the genomic epidemiological characteristics and population dynamics of hvKp within a single patient across distinct infection episodes remain largely unknown. This study aimed to investigate the clonal replacement of hvKp K2-ST881 and K54-ST29 lineage strains in a single patient experiencing multiple-site infections during two independent episodes. Two strains, designated EDhvKp-1 and EDhvKp-2, were obtained from blood and cerebrospinal fluid during the first admission, and the strain isolated from blood on the second admission was named EDhvKp-3. Whole-genome sequencing, utilizing both short-read Illumina and long-read Oxford Nanopore platforms, was conducted. In silico multilocus sequence typing (MLST), identification of antimicrobial resistance and virulence genes, and the phylogenetic relationship between our strains and other K. pneumoniae ST881 and ST29 genomes retrieved from the public database were performed. Virulence potentials were assessed through a mouse lethality assay. Our study indicated that the strains were highly susceptible to multiple antimicrobial agents. Plasmid sequence analysis confirmed that both virulence plasmids, pEDhvKp-1 (166,008 bp) and pEDhvKp-3 (210,948 bp), belonged to IncFIB type. Multiple virulence genes, including rmpA, rmpA2, rmpC, rmpD, iroBCDN, iucABCD, and iutA, were identified. EDhvKp-1 and EDhvKp-2 showed the closest relationship to strain 502 (differing by 51 SNPs), while EDhvKp-3 exhibited 69 SNPs differences compared to strain TAKPN-1, which all recovered from Chinese patients in 2020. In the mouse infection experiment, both ST881 EDhvKp-1 and ST29 EDhvKp-3 displayed similar virulence traits, causing 90 and 100% of the mice to die within 72 h after intraperitoneal infection, respectively. Our study expands the spectrum of hvKp lineages and highlights genomic alterations associated with clonal switching between two distinct lineages of hvKP that successively replaced each other in vivo. The development of novel strategies for the surveillance, diagnosis, and treatment of high-risk hvKp is urgently needed.

Corrigendum: Adiponectin modified BMSCs alleviate heart fibrosis via inhibition TGF-beta1/smad in diabetic rats.

[This corrects the article DOI: 10.3389/fcell.2021.644160.].

Exploring disease axes as an alternative to distinct clusters for characterizing sepsis heterogeneity.

PURPOSE: Various studies have analyzed sepsis subtypes, yet the reproducibility of such results remains unclear. This study aimed to determine the reproducibility of sepsis subtypes across multiple cohorts. METHODS: The study examined 63,547 sepsis patients from six distinct cohorts who had similar sepsis-related characteristics (vital signs, lactate, sequential organ failure assessment score, bilirubin, serum, urine output, and Glasgow coma scale). Identical cluster analysis techniques were used, employing 27 clustering schemes, and normalized mutual information (NMI), a metric ranging from 0 to 1 with higher values indicating better concordance, was employed to quantify the clustering solutions' reproducibility. Principal component analysis (PCA) was utilized to obtain the disease axis, and its uniformity across cohorts was evaluated through patterns of feature loading and correlation. RESULTS: The reproducibility of sepsis clustering subtypes across the various studies was modest (median NMI ranging from 0.08 to 0.54). The top-down transfer learning method (model trained on cohorts with greater severity was transferred to cohorts with lower severity score) had a higher NMI value than the bottom-up approach (median [Q1, Q3]: 0.64 [0.49, 0.78] vs. 0.23 [0.2, 0.31], p < 0.001). The reproducibility was greater when the transfer solution was performed within United States (US) cohorts. The PCA analysis revealed that the correlation pattern between variables was consistent across all cohorts, and the first two disease axes were the "shock axis" and "systemic inflammatory response syndrome (SIRS) axis." CONCLUSIONS: Cluster analysis of sepsis patients across various cohorts showed modest reproducibility. Sepsis heterogeneity is better characterized through continuous disease axes that coexist to varying degrees within the same individual instead of mutually exclusive subtypes.

Insight into the history and trends of surgical simulation training in education: a bibliometric analysis.

BACKGROUND: Surgical simulation training enables surgeons to acquire clinical experience or skills from the operating room to the simulation environment. Historically, it has changed with advances in science and technology. Moreover, no previous study has analyzed this field from the bibliometric analysis dimension. The study aimed to review changes in surgical simulation training worldwide using bibliometric software. MATERIALS AND METHODS: Two searches were performed on the core collection database, Web of Science, regarding data from 1991 to the end of 2020 using three topic words (surgery, training, and simulation). From 1 January 2000, to 15 May 2022, the keyword 'robotic' was added for the hotspot exploration. The data were chiefly analyzed by publication date, country, author(s), and keywords using bibliometric software. RESULTS: A total of 5285 articles were initially analyzed, from which it was clear that laparoscopic skill, three-dimensional printing, and virtual reality were the main focuses during those study periods. Subsequently, 348 publications on robotic surgery training were identified. CONCLUSION: This study systematically summarizes the current status in the field of surgical simulation training and provides insights into the research focuses and future hotspot in a global context.