NLRC4-mediated pyroptosis was involved in coagulation disorders of acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a potentially lethal acute disease highly involved in coagulation disorders. Pyroptosis has been reported to exacerbate coagulation disorders, yet this implication has not been illustrated completely in AP. METHODS: RNA sequencing data of peripheral blood of AP patients were downloaded from the Gene Expression Omnibus database. Gene set variation analysis and single sample gene set enrichment analysis were used to calculate the enrichment score of coagulation-related signatures and pyroptosis. Spearman and Pearson correlation analysis was used for correlation analysis. Peripheral blood samples and related clinical parameters were collected from patients with AP and healthy individuals. A severe AP (SAP) model of mice was established using caerulein and lipopolysaccharide. Enzyme-linked immunosorbent assay, chemiluminescence immunoassay and immunohistochemical analysis were employed to detect the level of coagulation indicators and pyroptosis markers in serum and pancreas tissues. Additionally, we evaluated the effect of pyroptosis inhibition and NLRC4 silence on the function of human umbilical vein endothelial cells (HUVECs). RESULTS: Coagulation disorders were significantly positively correlated to the severity of AP, and they could be a predictor for AP severity. Further analyses indicated that six genes-DOCK9, GATA3, FCER1G, NLRC4, C1QB and C1QC-may be involved in coagulation disorders of AP. Among them, NLRC4 was positively related to pyroptosis that had a positive association with most coagulation-related signatures. Data from patients showed that NLRC4 and other pyroptosis markers, including IL-1ß, IL-18, caspase1 and GSDMD, were significant correlation to AP severity. In addition, NLRC4 was positively associated with coagulation indicators in AP patients. Data from mice showed that NLRC4 was increased in the pancreas tissues of SAP mice. Treatment with a pyroptosis inhibitor effectively alleviated SAP and coagulation disorders in mice. Finally, inhibiting pyroptosis or silencing NLRC4 could relieve endothelial dysfunction in HUVECs. CONCLUSIONS: NLRC4-mediated pyroptosis damages the function of endothelial cells and thereby exacerbates coagulation disorders of AP. Inhibiting pyroptosis could improve coagulation function and alleviate AP.

Smart Enzyme-Like Polyphenol-Copper Spray for Enhanced Bacteria-Infected Diabetic Wound Healing.

Developing functional medical materials is urgent to treat diabetic wounds with a high risk of bacterial infections, high glucose levels and oxidative stress. Here, a smart copper-based nanocomposite acidic spray has been specifically designed to address this challenge. This copper-based nanocomposite is pH-responsive and has multienzyme-like properties. It enables the spray to effectively eliminate bacteria and alleviate tissue oxidative pressure, thereby accelerating the healing of infected diabetic wounds. The spray works by generating hydroxyl radicals through catalysing H2O2, which has a high sterilization efficiency of 97.1%. As alkaline micro-vessel leakage neutralizes the acidic spray, this copper-based nanocomposite modifies its enzyme-like activity to eliminate radicals. This reduces the level of reactive oxygen species in diabetic wounds by 45.3%, leading to a similar wound-healing effect between M1 diabetic mice and non-diabetic ones by day 8. This smart nanocomposite spray provides a responsive and regulated microenvironment for treating infected diabetic wounds. It also offers a convenient and novel approach to address the challenges associated with diabetic wound healing.

Machine learning improves early prediction of organ failure in hyperlipidemia acute pancreatitis using clinical and abdominal CT features.

BACKGROUND: This study aimed to investigate and validate machine-learning predictive models combining computed tomography and clinical data to early predict organ failure (OF) in Hyperlipidemic acute pancreatitis (HLAP). METHODS: Demographics, laboratory parameters and computed tomography imaging data of 314 patients with HLAP from the First Affiliated Hospital of Wenzhou Medical University between 2017 and 2021, were retrospectively analyzed. Sixty-five percent of patients (n = 204) were assigned to the training group and categorized as patients with and without OF. Parameters were compared by univariate analysis. Machine-learning methods including random forest (RF) were used to establish model to predict OF of HLAP. Areas under the curves (AUCs) of receiver operating characteristic were calculated. The remaining 35% patients (n = 110) were assigned to the validation group to evaluate the performance of models to predict OF. RESULTS: Ninety-three (45.59%) and fifty (45.45%) patients from the training and the validation cohort, respectively, developed OF. The RF model showed the best performance to predict OF, with the highest AUC value of 0.915. The sensitivity (0.828) and accuracy (0.814) of RF model were both the highest among the five models in the study cohort. In the validation cohort, RF model continued to show the highest AUC (0.820), accuracy (0.773) and sensitivity (0.800) to predict OF in HLAP, while the positive and negative likelihood ratios and post-test probability were 3.22, 0.267 and 72.85%, respectively. CONCLUSIONS: Machine-learning models can be used to predict OF occurrence in HLAP in our pilot study. RF model showed the best predictive performance, which may be a promising candidate for further clinical validation.

Analysis of PROS1 mutations and clinical characteristics in three Chinese families with hereditary protein S deficiency.

We report three heterozygous PROS1 mutations that caused type I protein S deficiency in three unrelated Chinese families. We measured protein S activity and antigen levels for all participants, screened them for mutations in the PROS1 gene. And we employed the calibrated automated thrombin generation (CAT) method to investigate thrombin generation. Numerous bioinformatics tools were utilized to analyze the conservation, pathogenicity of mutation, and spatial structure of the protein S. Phenotyping analysis indicated that all three probands exhibited simultaneous reduced levels of PS:A, TPS:Ag, and FPS:Ag. Genetic testing revealed that proband A harbored a heterozygous c.458_458delA (p.Lys153Serfs*6) mutation in exon 5, proband B carried a heterozygous c.1687C>T (p.Gln563stop) mutation in exon 14, and proband C exhibited a heterozygous c.200A>C (p.Glu67Ala) mutation in exon 2. Bioinformatic analysis predicted that the p.Lys153Serfs*6 frameshift mutation and the p.Gln563stop nonsense mutation in the protein S were classified as "disease-causing." The identification of the novel mutation p.Lys153Serfs*6 in PROS1 enriches the Human Genome Database. Our research suggests that these three mutations (p.Lys153Serfs*6, p.Gln563stop, and p.Glu67Ala) are possibly responsible for the decreased level of protein S in the three families. Furthermore, the evidence also supports the notion that individuals who are asymptomatic but have a family history of PSD can benefit from genetic analysis of the PROS1 gene.

Beta vulgaris-derived exosome-like nanovesicles alleviate chronic doxorubicin-induced cardiotoxicity by inhibiting ferroptosis.

Dose-dependent heart failure is a major complication of the clinical use of doxorubicin (Dox), one of the most potent chemotherapeutic agents. Effective adjuvant therapy is required to prevent Dox-induced cardiotoxicity. Currently, plant-derived exosome-like nanovesicle (PELNV) has revealed their salubrious antioxidant and immunological regulating actions in various disease models. In this study, we isolated, purified and characterized Beta vulgaris-derived exosome-like nanovesicle (BELNV). Dox or normal saline was given to HL-1 cells (3 µM) and 8-week C57BL/6N mice (5 mg/kg bodyweight per week for 4 weeks) to establish the in vitro and in vivo model of Dox-induced cardiotoxicity. Administration of BELNV significantly alleviated chronic Dox-induced cardiotoxicity in terms of echocardiographic and histological results. A reduced malondialdehyde (MDA), increased ratio of glutathione (GSH) to oxidized glutathione (GSSG) and levels of system xc- and glutathione peroxidase 4 were observed, indicating that DOX-stimulated ferroptosis was reversed by BELNV. Besides, the safety of BELNV was also validated since no liver, spleen, and kidney toxicity induced by BELNV was observed. These findings provide evidence that BELNV may act as a novel therapeutic biomaterial for patients undergoing adverse effects of Dox, at least partly mediated by inhibiting Dox-induced ferroptosis.

FIB-4 index is associated with mortality in critically ill patients with alcohol use disorder: Analysis from the MIMIC-IV database.

BACKGROUND: The relationship between fibrosis-4 (FIB-4) index and all-cause mortality in critically ill patients with alcohol use disorder (AUD) is unclear. The present study aimed to investigate the predictive ability of FIB-4 for all-cause mortality in critically ill AUD patients and the association between them. METHODS: A total of 2528 AUD patients were included using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. FIB-4 was calculated for each patient using the existing formula. The patients were equally divided into four groups based on the quartiles of FIB-4. Multivariate logistic regression and Cox proportional hazard model were used to evaluate the association of FIB-4 with in-hospital mortality, 28-day mortality and 1-year mortality. Kaplan-Meier curves were used to analyse the incidence of 28-day mortality among four groups. RESULTS: FIB-4 was positively associated with 28-day mortality of AUD patients with hazard ratio (HR) of 1.354 [95% confidence interval (CI) 1.192-1.538]. There were similar trends in the in-hospital mortality [odds ratio (OR): 1.440, 95% CI (1.239-1.674)] and 1-year mortality [HR: 1.325, 95% CI (1.178-1.490)]. CONCLUSION: Increased FIB-4 is associated with greater in-hospital mortality, 28-day mortality and 1-year mortality in critically ill AUD patients.

Identification of the RNase-binding site of SARS-CoV-2 RNA for anchor primer-PCR detection of viral loading in 306 COVID-19 patients.

The pandemic of coronavirus disease 2019 (COVID-19) urgently calls for more sensitive molecular diagnosis to improve sensitivity of current viral nuclear acid detection. We have developed an anchor primer (AP)-based assay to improve viral RNA stability by bioinformatics identification of RNase-binding site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and implementing AP dually targeting the N gene of SARS-CoV-2 RNA and RNase 1, 3, 6. The arbitrarily primed polymerase chain reaction (AP-PCR) improvement of viral RNA integrity was supported by (a) the AP increased resistance of the targeted gene (N gene) of SARS-CoV-2 RNA to RNase treatment; (b) the detection of SARS-CoV-2 RNA by AP-PCR with lower cycle threshold values (-2.7 cycles) compared to two commercially available assays; (c) improvement of the viral RNA stability of the ORF gene upon targeting of the N gene and RNase. Furthermore, the improved sensitivity by AP-PCR was demonstrated by detection of SARS-CoV-2 RNA in 70-80% of sputum, nasal, pharyngeal swabs and feces and 36% (4/11) of urine of the confirmed cases (n = 252), 7% convalescent cases (n = 54) and none of 300 negative cases. Lastly, AP-PCR analysis of 306 confirmed and convalescent cases revealed prolonged presence of viral loading for >20 days after the first positive diagnosis. Thus, the AP dually targeting SARS-CoV-2 RNA and RNase improves molecular detection by preserving SARS-CoV-2 RNA integrity and reveals the prolonged viral loading associated with older age and male gender in COVID-19 patients.

Association between triglyceride-glucose index and in-hospital mortality in critically ill patients with sepsis: analysis of the MIMIC-IV database.

BACKGROUND: This study aimed to explore the association between the triglyceride-glucose (TyG) index and the risk of in-hospital mortality in critically ill patients with sepsis. METHODS: This was a retrospective observational cohort study and data were obtained from the Medical Information Mart for Intensive Care-IV (MIMIC IV2.2) database. The participants were grouped into three groups according to the TyG index tertiles. The primary outcome was in-hospital all-cause mortality. Multivariable logistics proportional regression analysis and restricted cubic spline regression was used to evaluate the association between the TyG index and in-hospital mortality in patients with sepsis. In sensitivity analysis, the feature importance of the TyG index was initially determined using machine learning algorithms and subgroup analysis based on different subgroups was also performed. RESULTS: 1,257 patients (56.88% men) were included in the study. The in-hospital, 28-day and intensive care unit (ICU) mortality were 21.40%, 26.17%, and 15.43% respectively. Multivariate logistics regression analysis showed that the TyG index was independently associated with an elevated risk of in-hospital mortality (OR 1.440 [95% CI 1.106-1.875]; P = 0.00673), 28-day mortality (OR 1.391; [95% CI 1.52-1.678]; P = 0.01414) and ICU mortality (OR 1.597; [95% CI 1.188-2.147]; P = 0.00266). The restricted cubic spline regression model revealed that the risks of in-hospital, 28-day, and ICU mortality increased linearly with increasing TyG index. Sensitivity analysis indicate that the effect size and direction in different subgroups are consistent, the results is stability. Additionally, the machine learning results suggest that TyG index is an important feature for the outcomes of sepsis. CONCLUSION: Our study indicates that a high TyG index is associated with an increased in-hospital mortality in critically ill sepsis patients. Larger prospective studies are required to confirm these findings.

Fibroblast growth factor 2 (FGF2) ameliorates the coagulation abnormalities in sepsis.

BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by dysregulation of the host response to infection. There is still a lack of specific treatment for sepsis. Here, we report that Fibroblast growth factor-2 (FGF2) can reduce the mortality of sepsis by ameliorating the coagulation abnormalities. METHODS: FGF2 was intraperitoneally injected into septic mice induced by lipopolysaccharide (LPS) and then assessed for coagulation response, organ damage and survival. RAW264.7 cells with or without FGF2 pretreating were exposed to LPS, and then changes in coagulation related factors expression and signaling were tested. RESULTS: The findings showed that intraperitoneal injection of FGF2 inhibited coagulation activity, reduced lung and liver damage, and increased survival in septic mice. In RAW264.7 cells, LPS upregulated the expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); however, pretreatment with FGF2 prevented this upregulation, while FGF2 knockdown exacerbated TF upregulation. Moreover, FGF2 suppressing the AKT/mTOR/S6K1 signaling pathway in septic mice and RAW264.7 cells stimulated by LPS. CONCLUSIONS: This study revealed a therapeutic role of FGF2 in ameliorating the coagulation abnormalities during sepsis.

ChK1 activation induces reactive astrogliosis through CIP2A/PP2A/STAT3 pathway in Alzheimer's disease.

Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is upregulated and causes reactive astrogliosis, synaptic degeneration, and cognitive deficits in Alzheimer's disease (AD). However, the mechanism underlying the increased CIP2A expression in AD brains remains unclear. We here demonstrated that the DNA damage-related Checkpoint kinase 1 (ChK1) is activated in AD human brains and 3xTg-AD mice. ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induces reactive astrogliosis, degeneration of neurons, and exacerbation of AD through the CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 may be a potential therapeutic approach for AD treatment.

Causal effects of genetically vitamins and sepsis risk: a two-sample Mendelian randomization study.

BACKGROUND: In recent years, observational studies have been conducted to investigate the potential impact of vitamins on sepsis. However, many of these studies have produced inconsistent results. Our Mendelian randomization (MR) study aims to evaluate the causality between vitamins and sepsis from a genetic perspective. METHODS: Our MR study was designed following the STROBE-MR guidelines. Genetic instrumental variables for vitamins including folate, vitamin B12, B6, A (Retinol), C, D, and K were obtained from previous genome-wide association studies (GWAS) and MR studies. Five different sepsis severity levels were included in the analysis. The genetic instrumental variables were screened for potential confounders using PhenoScanner V2. MR analysis was performed using MR-egger, inverse-variance weighted multiplicative random effects (IVW-RE), inverse-variance weighted multiplicative fixed-effects (IVW-FE), and wald ratio methods to assess the relationship between vitamins and sepsis. Sensitivity analysis was performed using the MR-egger_intercept method, and the MR-PRESSO package and Cochran's Q test were used to evaluate the heterogeneity of the instrumental variables. RESULTS: Our MR study found no statistically significant association between vitamins and sepsis risk, regardless of the type of vitamin (P-value > 0.05). The odds ratios (ORs) for folate, vitamin B6, vitamin B12, vitamin A, vitamin D, vitamin K, and vitamin C were 1.164 (95% CI: 0.895-1.514), 0.987 (95% CI: 0.969-1.005), 0.975 (95% CI: 0.914-1.041), 0.993 (95% CI: 0.797-1.238), 0.861 (95% CI: 0.522-1.42), 0.955 (95% CI: 0.86-1.059), and 1.049 (95% CI: 0.911-1.208), respectively. Similar results were observed in subgroups of different sepsis severity levels. CONCLUSIONS: Our MR study found no evidence of a causal association between vitamins and sepsis risk from a genetic perspective. Further randomized controlled trials are necessary to confirm these results.

Platelet transfusion and mortality in patients with sepsis-induced thrombocytopenia: A propensity score matching analysis.

BACKGROUND AND OBJECTIVES: Thrombocytopenia is common among sepsis patients. Platelet transfusions are frequently administered to increase platelet counts, but their clinical impacts remain unclear in sepsis-induced thrombocytopenia. The goal of this study was to explore the association between platelet transfusion and mortality in patients with sepsis-induced thrombocytopenia. MATERIALS AND METHODS: The study was based on the Medical Information Mart for Intensive Care (MIMIC) III database. Septic patients with severe thrombocytopenia (a platelet count ≤ 50/nl) were included in the study and were divided into two groups: a platelet transfusion group (PT group) and a no platelet transfusion group (NPT group). The primary outcome was in-hospital mortality, and the secondary outcomes were the length of intensive care unit (ICU) stay (LOS-ICU) and 90-day mortality. Propensity score matching multivariable logistic regression was used to reduce the imbalance. RESULTS: A total of 1733 patients were included: 296 patients were included in the PT group and 1437 patients were included in the NPT group. After propensity score matching, 296 paired patients constituted each group. Crude hospital mortality was significantly higher in the PT group than in the NPT group (145 [48.99%] vs. 567 [39.46%], p = 0.002). In the extended multivariable logistic models for hospital mortality, the odds ratio (OR) of receiving a platelet transfusion was consistently significant in all six models (OR range, 1.340-1.525, p < 0.05 for all). In the following subgroups, platelet transfusion was associated with increased in-hospital mortality: age > 60 years; sex: female; sequential organ failure assessment score ≤8; simplified acute physiology score ≤ 47; platelet count >29/nl and the complication of congestive heart failure. However, there were no significant differences in the 90-day mortality rate (170 [57.43%] vs. 741 [51.57%], p = 0.066) or the LOS-ICU (5.84 [2.68-11.78] vs. 4.94 [2.18-12.72], p = 0.442) between the two groups. All these results remained stable after adjustment for confounders and in the comparisons after propensity score matching. CONCLUSIONS: The propensity score-matched analysis showed that platelet transfusion was associated with increased in-hospital mortality in septic patients with severe thrombocytopenia (a platelet count ≤ 50/nl). However, it was not associated with 90-day mortality or the length of ICU stay.

Evaluation of droplet digital PCR rapid detection method and precise diagnosis and treatment for suspected sepsis (PROGRESS): a study protocol for a multi-center pragmatic randomized controlled trial.

BACKGROUND: Sepsis is still a major public health concern and a medical emergency due to its high morbidity and mortality. Accurate and timely etiology diagnosis is crucial for sepsis management. As an emerging rapid and sensitive pathogen detection tool, digital droplet PCR (ddPCR) has shown promising potential in rapid identification of pathogens and antimicrobial resistance genes. However, the diagnostic value and clinical impact of ddPCR tests remains to be studied in patients with suspected sepsis. PROGRESS trial is aimed to evaluate the clinical effectiveness of a novel ddPCR assay compared with standard practice. METHODS: PROGRESS is a multicenter, open-label, pragmatic randomized controlled trial (pRCT) set in ten hospitals, including departments of infectious disease and intensive care units. In this study, a total of 2292 patients with suspected sepsis will be randomly assigned to two arms: the ddPCR group and the control group with a ratio of 3:1. The primary outcome is the diagnostic efficacy, that is, the sensitivity and specificity of the ddPCR assay compared with the synchronous blood culture. Secondary outcomes include the mortality rates and the mean Sequential Organ Failure Assessment (SOFA) score at follow-up time points, the length of stay in the hospital, the time to directed antimicrobial therapy, duration of broad-spectrum antibiotic use, and the EQ-5D-5L score on day 90. DISCUSSION: It is the first multicenter pragmatic RCT to explore the diagnostic efficacy and clinical impact of the ddPCR assay in patients with suspected sepsis, taking advantage of both RCT's ability to establish causality and the feasibility of pragmatic approaches in real-world studies (RWS). This trial will help us to get a comprehensive view of the assay's capacity for precise diagnosis and treatment of sepsis. It has the potential to monitor the pathogen load change and to guide the antimicrobial therapy, making a beneficial impact on the prognosis of sepsis patients. TRIAL REGISTRATION: ClinicalTrial.gov, NCT05190861. Registered January 13, 2022-'Retrospectively registered', https://clinicaltrials.gov/ct2/show/NCT05190861 .

Prediction model of renal function recovery for primary membranous nephropathy with acute kidney injury.

BACKGROUND AND OBJECTIVES: The clinical and pathological impact factors for renal function recovery in acute kidney injury (AKI) on the progression of renal function in primary membranous nephropathy (PMN) with AKI patients have not yet been reported, we sought to investigate the factors that may influence renal function recovery and develop a nomogram model for predicting renal function recovery in PMN with AKI patients. METHODS: Two PMN with AKI cohorts from the Nephrology Department, the First Affiliated Hospital of Wenzhou Medical University during 2012-2018 and 2019-2020 were included, i.e., a derivation cohort during 2012-2018 and a validation cohort during 2019-2020. Clinical characteristics and renal pathological features were obtained. The outcome measurement was the recovery of renal function within 12 months. Lasso regression was used for clinical and pathological features selection. Prediction model was built and nomogram was plotted. Model evaluations including calibration curves were performed. RESULT: Renal function recovery was found in 72 of 124 (58.1%) patients and 41 of 72 (56.9%) patients in the derivation and validation cohorts, respectively. The prognostic nomogram model included determinants of sex, age, the comorbidity of hypertensive nephropathy, the stage of glomerular basement membrane and diuretic treatment with a reasonable concordance index of 0.773 (95%CI,0.716-0.830) in the derivation cohort and 0.773 (95%CI, 0.693-0.853) in the validation cohort. Diuretic use was a significant impact factor with decrease of renal function recovery in PMN with AKI patients. CONCLUSION: The predictive nomogram model provides useful prognostic tool for renal function recovery in PMN patients with AKI.

Can a multitiered copayment system affect people's healthcare-seeking behavior? A case study of Wenzhou, China.

BACKGROUND: Facilitating the primary health care (PHC) system and maintaining people's reasonable healthcare-seeking behavior are key to establishing a sustainable healthcare system. China has employed a multitiered copayment system/medical insurance differentiated payment policies to incentivize the public to utilize PHC services through its hierarchical medical care system; however, most people still prefer visiting tertiary care hospitals. We question whether the quality gap in healthcare services reduces the effect of the multitiered copayment system, which is considered an important factor in the lack of reform in the Chinese healthcare system. Thus, we explore the effect and influencing factors of the multitiered copayment system that drives primary healthcare-seeking behavior under the current situation with a large quality gap. We also consider the hypothetical situation of a reduced gap in the future. METHODS: This study used the hypothetical quality improvement scenario to elicit people's hypothetical behaviors, and a multistage stratified cluster random sampling method. This preliminary study was conducted in 2016 using 1829 individuals from four regions of Wenzhou in Zhejiang Province: Ouhai, Ruian, Yongjia, and Taishun. A descriptive statistical analysis, chi-square analysis, Fisher's exact test, and multinomial logistic regression model were performed to introduce the effect of the multitiered copayment system, and to explore the factors affecting the selection of PHC institutions at pre- and post-change phases. RESULT: The results show that compared with the large quality gap phase, the number of respondents who believed the multitiered copayment system had an effect on their selection of PHC institutions after the equalization of healthcare services quality increased threefold (from 14.0% to 50.8%). Moreover, the main determinants in people's selection of PHC institutions changed from age and needs variables (self-rated health status) to age, needs variables (self-rated health status) and enabling variables (distance to a medical care facility). CONCLUSION: The results indicate limited initial effects of the multitiered copayment system. However, they become more pronounced after the equalization of healthcare services quality. This study confirms that changes in the quality gap in healthcare services influence the effect of the multitiered copayment system. Hence, reducing this gap can help achieve the intended outcome of the tiered healthcare insurance schedule.

Reference equations for the six-minute walking distance in obese Chinese subjects more than 40 years old.

BACKGROUND: Studies have shown that the reference equations for the six-minute walking distance (6MWD), which were mainly derived from healthy, normal-weight people, are not suitable for individuals with obesity. The main purpose of this study was to establish reference equations for the 6MWD in obese Chinese subjects. METHODS: In our study, a total of 214 individuals with obesity performed the six-minute walking tests (6MWTs) according to the American thoracic society (ATS) guidelines, and the longer 6MWD was used for further analysis. The reference equations for the 6MWD were developed using stepwise multiple regression analysis. The newly established equations for the 6MWD were compared to the existing prediction equations. RESULTS: The mean 6MWD for the cohort was 523 ± 56 m. We found that the reliability of two 6MWTs was good. Age and BMI were identified as independent factors, and explained 31% and 27% of the variance in the 6MWD for the male and female participants, respectively. Thus, the reference equations reported in the previous studies did not accurately predict the 6MWD in our subjects. CONCLUSION: Our study was the first to describe the 6MWD in obese Chinese subjects and to propose new predictive equations. These established equations can improve the assessment of the health of obese Chinese patients whose exercise capacity is affected by the disease. LEVEL OF EVIDENCE: III, Cohort study.

Population pharmacokinetic and optimization of polymyxin B dosing in adult patients with various renal functions.

AIMS: Current FDA-approved label recommends that the dosage of polymyxin B should be adjusted according to renal function. However, the correlation between polymyxin B pharmacokinetics (PK) and creatinine clearance (CrCL) is poor. This study aimed to develop a population PK model of polymyxin B in adult patients with various renal functions and to identify a dosing strategy. METHODS: A retrospective PK study was performed in 32 adult patients with various renal function. Nonlinear mixed effects modelling was applied to build a population PK model of polymyxin B followed by Monte Carlo simulations which designed polymyxin B dosing regimens across various renal function. RESULTS: Polymyxin B PK analyses included 112 polymyxin B concentrations at steady state from 32 adult patients, in which 71.9% of them were critically ill. In the final PK model, CrCL was the significant covariate on CL (typical value 1.59 L/h; between-subject variability 13%). The mean (SD) individual empirical Bayesian estimate of CL was 1.75 (0.43) L/h. In addition, a new dosing strategy combining the PK/pharmacodynamic (PD) targets and Monte Carlo simulation indicated that the reduction of polymyxin B dose in patients with renal insufficiency improved the probability of achieving optimal exposure. For severe infections caused by organisms with minimum inhibitory concentration (MIC) ≥ 2 mg/L, a high daily dose of polymyxin B might be possible for bacterial eradication, but the risk of nephrotoxicity is increased. CONCLUSIONS: Renal function plays a significant role in polymyxin B PK, and the dose of polymyxin B should be adjusted according to CrCL in patients with renal insufficiency.

TDM-guided medication of polymyxin B in a patient with CRKP-induced bloodstream infection: a case report.

The narrow therapeutic window of polymyxin B constrains its clinical use against the multidrug-resistant organisms (MDRO). A 45-year-old patient was suffering with bloodstream infection with high fever and received a combined treatment with polymyxin B and tigecycline. Therapeutic drug monitoring (TDM) was applied to polymyxin B to develop a personalized medication against MDRO. The dose adjustment of polymyxin B with TDM successfully alleviated the infection and reduced the incident of acute kidney injury as caused in case of the original doses of polymyxin B. TDM of polymyxin B represents a valid treatment to ensure the efficiency and safety.

Association of FIB-4 index and clinical outcomes in critically ill patients with acute kidney injury: a cohort study.

BACKGROUND: The relationship between fibrosis-4 (FIB-4) index and clinical outcomes in patients with acute kidney injury (AKI) is unclear. We aimed to investigate the association between FIB-4 index and all-cause mortality in critically ill patients with AKI. METHODS: We used data from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database (v1.4). The FIB-4 score was calculated using the existing formulas. logistic regression model, and Cox proportional hazards model were used to assessed the relationship between the FIB-4 index and in-hospital,28-day and 90-day mortality, respectively. RESULTS: A total of 3592 patients with AKI included in the data analysis. 395 (10.99%) patients died during hospitalization and 458 (12.74%) patients died in 28-day. During the 90-day follow-up, 893 (22.54%) patients were dead. An elevated FIB-4 value was significantly associated with increased in-hospital mortality when used as a continuous variable (odds ratio [OR] 1.183, 95% confidence interval [CI] 1.072-1.305, P = 0.002) and as a quartile variable (OR of Q2 to Q4 1.216-1.744, with Q1 as reference). FIB-4 was positively associated with 28-day mortality of AKI patients with hazard ratio (HR) of 1.097 (95% CI 1.008, 1.194) and 1.098 (95% 1.032, 1.167) for 90-day mortality, respectively. CONCLUSION: This study demonstrated the FIB-4 index is associated with clinical outcomes in critically ill patients with acute kidney injury.

Reduced serum albumin as a risk factor for poor prognosis in critically ill patients receiving renal replacement therapy.

BACKGROUND: Albumin is the primary body protein, which can predict the poor prognosis of several critical diseases. However, there are a few scientific studies on the relationship between albumin and the prognosis of dialysis patients. This study aims to explore the impact of hypoalbuminemia on the prognosis of critically ill patients with acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). METHODS: This was a secondary study. Clinical, biochemical, and 28-day and 90-day mortality rates for critical patients with AKI who received CRRT between 2009 and 2016 were searched from the database to determine the effect of hypoalbuminemia on poor outcomes by univariate, multivariate, smooth curve fitting, and subgroup analysis. RESULTS: A total of 837 participants were enrolled in this study. Multivariate Cox proportional hazard regression analysis showed that hypoalbuminemia was associated with both 28-day and 90-day mortality risks after full adjustment for confounding variables, with an adjusted hazard ratio (95% confidence interval) of 0.63 (0.50-0.80) and 0.63 (0.51-0.78), respectively for each 1 g/dL increase of albumin. Stratified analysis showed that hypoalbuminemia was not associated with poor prognosis in oliguria. CONCLUSION: Hypoalbuminemia is associated with poor prognosis in critically ill AKI patients with CRRT; therefore, measuring albumin may be helpful for predicting the prognosis. However, in those with oliguria, this conclusion is not valid.