Machine-learning model comprising five clinical indices and liver stiffness measurement can accurately identify MASLD-related liver fibrosis.

BACKGROUND & AIMS: aMAP score, as a hepatocellular carcinoma risk score, is proven to be associated with the degree of chronic hepatitis B-related liver fibrosis. We aimed to evaluate the ability of aMAP score for metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD)-related fibrosis diagnosis and establish a machine-learning (ML) model to improve the diagnostic performance. METHODS: A total of 946 biopsy-proved MASLD patients from China and the United States were included in the analysis. The aMAP score, demographic/clinical indices and liver stiffness measurement (LSM) were included in seven ML algorithms to build fibrosis diagnostic models in the training set (N = 703). The performance of ML models was evaluated in the external validation set (N = 125). RESULTS: The AUROCs of aMAP versus fibrosis-4 index (FIB-4) and aspartate aminotransferase-platelet ratio (APRI) in cirrhosis and advanced fibrosis were (0.850 vs. 0.857 [P = 0.734], 0.735 [P = 0.001]) and (0.759 vs. 0.795 [P = 0.027], 0.709 [P = 0.049]). When using dual cut-off values, aMAP had a smaller uncertainty area and higher accuracy (26.9%, 86.6%) than FIB-4 (37.3%, 85.0%) and APRI (59.0%, 77.3%) in cirrhosis diagnosis. The seven ML models performed satisfactorily in most cases. In the validation set, the ML model comprising LSM and 5 indices (including age, sex, platelets, albumin and total bilirubin used in aMAP calculator), built by logistic regression algorithm (called LSM-plus model), exhibited excellent performance. In cirrhosis and advanced fibrosis detection, the LSM-plus model had higher accuracy (96.8%, 91.2%) than LSM alone (86.4%, 67.2%) and Agile score (76.0%, 83.2%), respectively. Additionally, the LSM-plus model also displayed high specificity (cirrhosis: 98.3%; advanced fibrosis: 92.6%) with satisfactory AUROC (0.932, 0.875, respectively) and sensitivity (88.9%, 82.4%, respectively). CONCLUSIONS: The aMAP score is capable of diagnosing MASLD-related fibrosis. The LSM-plus model could accurately identify MASLD-related cirrhosis and advanced fibrosis.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

aMAP Score and Its Combination With Liver Stiffness Measurement Accurately Assess Liver Fibrosis in Chronic Hepatitis B Patients.

BACKGROUND & AIMS: The changes in liver stiffness measurement (LSM) are unreliable to estimate regression of fibrosis during antiviral treatment for chronic hepatitis B (CHB) patients. The age-male-albumin-bilirubin-platelets score (aMAP), as an accurate hepatocellular carcinoma risk score, may reflect the liver fibrosis stage. Here, we aimed to evaluate the performance of aMAP for diagnosing liver fibrosis in CHB patients with or without treatment. METHODS: A total of 2053 patients from 2 real-world cohorts and 2 multicentric randomized controlled trials in China were enrolled, among which 2053 CHB patients were included in the cross-sectional analysis, and 889 CHB patients with paired liver biopsies before and after 72 or 104 weeks of treatment were included in the longitudinal analysis. RESULTS: In the cross-sectional analysis, the areas under the receiver operating characteristic curve of aMAP in diagnosing cirrhosis and advanced fibrosis were 0.788 and 0.757, which were comparable with or significantly higher than those of the fibrosis index based on 4 factors and the aspartate aminotransferase-platelet ratio. The stepwise approach using aMAP and LSM further improved performance in detecting cirrhosis and advanced fibrosis with the smallest uncertainty area (29.7% and 46.2%, respectively) and high accuracy (82.3% and 79.8%, respectively). In the longitudinal analysis, we established a novel model (aMAP-LSM model) by calculating aMAP and LSM results before and after treatment, which had satisfactory performance in diagnosing cirrhosis and advanced fibrosis after treatment (area under the receiver operating characteristic curve, 0.839 and 0.840, respectively), especially for those with a significant decrease in LSM after treatment (vs LSM alone, 0.828 vs 0.748; P < .001 [cirrhosis]; 0.825 vs 0.750; P < .001 [advanced fibrosis]). CONCLUSIONS: The aMAP score is a promising noninvasive tool for diagnosing fibrosis in CHB patients. The aMAP-LSM model could accurately estimate fibrosis stage for treated CHB patients.

Biosynthesis of uniform fluorescent-stable telluride quantum dots in Escherichia coli and its detection of Fe3+ in water.

Quantum dots (QDs) containing zinc (Zn) and tellurium (Te) have low toxicity and excellent optoelectronic properties, which make them ideal fluorescent probes for use in environmental monitoring. However, their size/shape distribution synthesized by existing methods is not as good as that of other nanoparticles, thus limiting their application. Exploring whether this kind of QD can be biosynthesized and whether it can act as a nanoprobe are favorable attempts to expand the synthesis method and the application of QDs. Telluride QDs were biosynthesized in Escherichia coli cells. The nanoparticles were characterized by transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), energy dispersive X-ray spectroscopy (EDX), and inductively coupled plasma-atomic emission spectrometry (ICP‒AES), indicating that they were Zn3STe2 QDs. The QDs were monodispersed, spherical and fluorescently stable, with a uniform particle size of 3.05 ± 0.48 nm. The biosynthesis conditions of the QDs, including substrate concentrations and their process time, were optimized respectively. It was verified that the cysE and cysK genes were involved in the biosynthesis of telluride QDs. The biosynthesis ability of the QDs was improved by knocking out the tehB gene and overexpressing the pckA gene. Escherichia coli BW25113 cells that synthesized Zn3STe2 QDs were used as environmentally friendly fluorescent bioprobes to specifically select and quantitatively detect Fe3+ in water with a low limit of detection (2.62 µM). The fluorescent cells were also photobleach resistant and had good fluorescence stability. This study expands on the synthesis method of telluride QDs and the application of fluorescent probes.

Novel urinary protein panels for the non-invasive diagnosis of non-alcoholic fatty liver disease and fibrosis stages.

BACKGROUND & AIMS: There is an unmet clinical need for non-invasive tests to diagnose non-alcoholic fatty liver disease (NAFLD) and individual fibrosis stages. We aimed to test whether urine protein panels could be used to identify NAFLD, NAFLD with fibrosis (stage F ≥ 1) and NAFLD with significant fibrosis (stage F ≥ 2). METHODS: We collected urine samples from 100 patients with biopsy-confirmed NAFLD and 40 healthy volunteers, and proteomics and bioinformatics analyses were performed in this derivation cohort. Diagnostic models were developed for detecting NAFLD (UPNAFLD model), NAFLD with fibrosis (UPfibrosis model), or NAFLD with significant fibrosis (UPsignificant fibrosis model). Subsequently, the derivation cohort was divided into training and testing sets to evaluate the efficacy of these diagnostic models. Finally, in a separate independent validation cohort of 100 patients with biopsy-confirmed NAFLD and 45 healthy controls, urinary enzyme-linked immunosorbent assay analyses were undertaken to validate the accuracy of these new diagnostic models. RESULTS: The UPfibrosis model and the UPsignificant fibrosis model showed an AUROC of .863 (95% CI: .725-1.000) and 0.858 (95% CI: .712-1.000) in the training set; and .837 (95% CI: .711-.963) and .916 (95% CI: .825-1.000) in the testing set respectively. The UPNAFLD model showed an excellent diagnostic performance and the area under the receiver operator characteristic curve (AUROC) exceeded .90 in the derivation cohort. In the independent validation cohort, the AUROC for all three of the above diagnostic models exceeded .80. CONCLUSIONS: Our newly developed models constructed from urine protein biomarkers have good accuracy for non-invasively diagnosing liver fibrosis in NAFLD.

Novel and portable test strip platform for rapid and sensitive on-site detection of procymidone pesticide.

A novel and portable detection platform for procymidone (PRM) was developed by combining simple sample pretreatment, lateral flow test strips based on multi-branched gold nanoparticle (LFTS-MBGNP), and a smartphone. Based on the large surface area of MBGNPs, rapid detection of PRM was realized by simple naked eye observation. By utilizing a smartphone as a portable signal analyzer, ultrasensitive quantitative detection of PRM in red wine was realized with the limits of detection (LOD) of 1.60 ng/mL, which was 3000 times lower than the US limit (5 ppm). Moreover, rapid detection of four kinds of fruits and vegetables was achieved within 10 min, with LODs of 4.34 ng/g, 6.93 ng/g, 8.99 ng/g, and 5.03 ng/g, respectively, which could meet the PRM limit of the European Union (10 ng/g). Integrating the optimized QuEChERS pretreatment method, the developed platform realized a simple and sensitive on-site detection of PRM pesticide in foods and red wine within 45 min. This platform provides a useful tool and new idea for rapid screening and detection of pesticide residues in food.

Substantia nigra integrity correlates with sequential working memory in Parkinson's disease.

Maintaining and manipulating sequences online is essential for daily activities such as scheduling a day. In Parkinson's disease (PD), sequential working memory deficits have been associated with altered regional activation and functional connectivity in the basal ganglia. This study demonstrates that the substantia nigra (SN) integrity correlated with basal ganglia function and sequencing performance in 29 patients with PD (17 women) and 29 healthy controls (HC, 18 women). In neuromelanin-sensitive structural MRI, PD patients showed smaller SN than HC. In a digit ordering task with functional MRI, participants either recalled sequential digits in the original order ('pure recall') or rearranged the digits and recalled the new sequence ('reorder & recall'). PD patients performed less accurately than HC, accompanied by the caudate and pallidal hypo-activation, subthalamic hyper-activation, and weakened functional connectivity between the bilateral SN and all three basal ganglia regions. PD patients with larger SN tended to exhibit smaller ordering-related accuracy costs ('reorder & recall' versus 'pure recall'). This effect was fully mediated by the ordering-related caudate activation. Unlike HC, the ordering-related accuracy cost correlated with the ordering-related caudate activation but not subthalamic activation in PD. Moreover, the ordering-related caudate activation correlated with the SN area but not the daily dose of D2/3 receptor agonists. In PD, the daily dose of D2/3 receptor agonists correlated with the ordering-related subthalamic activation, which was not related to the accuracy cost. The findings suggest that damage to the SN may lead to sequential working memory deficits in PD, mediated by basal ganglia dysfunction.SIGNIFICANCELiu et al. demonstrate that damage to the substantia nigra (SN) correlates with basal ganglia dysfunction and poor sequencing performance in Parkinson's disease (PD). In neuromelanin-sensitive MRI, PD showed smaller SN than healthy controls. In a digit ordering task with functional MRI, PD's lower task accuracy was accompanied by the caudate and pallidal hypo-activation, subthalamic hyper-activation, and weakened functional connectivity between the SN and basal ganglia. PD with larger SN exhibited greater ordering-related caudate activation and lower ordering-related accuracy cost when sequencing digits. PD with more daily exposure to D2/3 receptor agonists exhibited greater ordering-related subthalamic activation, which did not reduce accuracy cost. It suggests that the SN may affect sequencing performance by regulating the task-dependent caudate activation in PD.

Impact of red cell distribution width and red cell distribution width/albumin ratio on all-cause mortality in patients with type 2 diabetes and foot ulcers: a retrospective cohort study.

BACKGROUND: Red blood cell distribution width (RDW) has emerged as a prognostic factor for mortality in various diseases. Up to now, few studies have focused on the prognostic value of RDW in patients with diabetic foot ulcers (DFUs). This retrospective cohort study aimed to investigate the impact of RDW and RDW/albumin (ALB) ratio on all-cause mortality in patients with DFUs. METHODS: This study included 860 patients with DFUs in a tertiary academic hospital. The associations of RDW and RDW/ALB with all-cause mortality were assessed by multivariable cox regression analyses. The pairwise comparisons of receiver operating characteristic (ROC) curves were performed to compare the predictive performance of RDW and RDW/ALB ratio. Harrell's concordance index, integrated discrimination improvement, and net reclassification improvement were used to estimate the improvements in risk discrimination. RESULTS: Patients with high RDW and RDW/ALB had lower overall survival rates (all P < 0.001). The multivariable Cox regression revealed that high RDW [adjusted hazard ratio (HR) 2.426, 95% confidence interval (CI): 1.557-3.778, P < 0.001] and high RDW/ALB (adjusted HR 2.360, 95% CI: 1.414-3.942, P = 0.001) were independent associated with high all-cause mortality. In subgroup analyses, the comparative analysis of ROC curves revealed that the discriminating ability of the RDW/ALB ratio was significantly superior to RDW in patients with no severe DFUs or no severe peripheral artery disease, or in young and middle-aged patients (all P < 0.05). Adding RDW and RDW/ALB ratio to base models improved discrimination and risk reclassification for all-cause mortality. CONCLUSIONS: RDW and RDW/ALB ratio are robust and independent prognostic markers in patients with DFUs. The RDW/ALB ratio appears to be of more predictive value for mortality in younger and less severely ill patients with DFUs. Both RDW and RDW/ALB ratio can provide incremental predictive value for all-cause mortality over traditional risk factors. RDW and RDW/ALB ratio can be used to identify high-risk patients with DFUs.

Extrapulmonary complications of COVID-19: A multisystem disease?

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recently declared a pandemic by the World Health Organization. In addition to its acute respiratory manifestations, SARS-CoV-2 may also adversely affect other organ systems. To date, however, there is a very limited understanding of the extent and management of COVID-19-related conditions outside of the pulmonary system. This narrative review provides an overview of the current literature about the extrapulmonary manifestations of COVID-19 that may affect the urinary, cardiovascular, gastrointestinal, hematological, hematopoietic, neurological, or reproductive systems. This review also describes the current understanding of the extrapulmonary complications caused by COVID-19 to improve the management and prognosis of patients with COVID-19.

FNDC5 polymorphism influences the association between sarcopenia and liver fibrosis in adults with biopsy-proven non-alcoholic fatty liver disease.

The FNDC5 gene encodes the fibronectin type III domain-containing protein 5 that is a membrane protein mainly expressed in skeletal muscle, and the FNDC5 rs3480 polymorphism may be associated with liver disease severity in non-alcoholic fatty liver disease (NAFLD). We investigated the influence of the FNDC5 rs3480 polymorphism on the relationship between sarcopenia and the histological severity of NAFLD. A total of 370 adult individuals with biopsy-proven NAFLD were studied. The association between the key exposure sarcopenia and the outcome liver histological severity was investigated by binary logistic regression. Stratified analyses were undertaken to examine the impact of FNDC5 rs3480 polymorphism on the association between sarcopenia and the severity of NAFLD histology. Patients with sarcopenia had more severe histological grades of steatosis and a higher prevalence of significant fibrosis and definite non-alcoholic steatohepatitis than those without sarcopenia. There was a significant association between sarcopenia and significant fibrosis (adjusted OR 2·79, 95 % CI 1·31, 5·95, P = 0·008), independent of established risk factors and potential confounders. Among patients with sarcopenia, significant fibrosis occurred more frequently in the rs3480 AA genotype carriers than in those carrying the FNDC5 rs3480 G genotype (43·8 v. 17·2 %, P = 0·031). In the association between sarcopenia and liver fibrosis, there was a significant interaction between the FNDC5 genotype and sarcopenia status (P value for interaction = 0·006). Sarcopenia is independently associated with significant liver fibrosis, and the FNDC5 rs3480 G variant influences the association between sarcopenia and liver fibrosis in patients with biopsy-proven NAFLD.

Association between NAFLD and risk of prevalent chronic kidney disease: why there is a difference between east and west?

BACKGROUNDS: There is a discrepancy between west and east on the relationship between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). This study aimed to find out the possible reason for this and to clarify the association between NAFLD and CKD by analyzing two population-based datasets from the US and China. METHODS: Two health examination datasets from China and the US were used. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 or and/or abnormal albuminuria and/or overt proteinuria. Binary logistic regression was used to examine the association between NAFLD and CKD. RESULTS: A total of 60,965 participants were analyzed, including 11,844 from the US and 51,229 from China. The prevalence of NAFLD was 27.12% in the Chinese population and 36.08% in the US population (p < 0.001). The proportions of CKD and late stage CKD (stages 3-5) were higher in the US population than the Chinese one. NAFLD was independently associated with an increased risk of CKD in Chinese population, whereas in the US population, the NAFLD was not an independent risk factor of CKD. In subgroup analyses which excluded late stages CKD (stages 3-5), the risks of mild renal function decline became consistent: NAFLD was associated with early stages of CKD but not the late stages of CKD in both populations. CONCLUSION: NAFLD increased the risk of early stages of CKD in both Chinese and the US population. The conflicting results reported by previous studies might result from the different proportion of late stages of CKD.

Development and validation of a novel non-invasive test for diagnosing fibrotic non-alcoholic steatohepatitis in patients with biopsy-proven non-alcoholic fatty liver disease.

BACKGROUND AND AIM: There is an immediate need for non-invasive accurate tests for diagnosing liver fibrosis in patients with non-alcoholic steatohepatitis (NASH). Previously, it has been suggested that MACK-3 (a formula that combines homeostasis model assessment-insulin resistance with serum serum aspartate aminotransferase and cytokeratin [CK]18-M30 levels) accurately identifies patients with fibrotic NASH. Our aim was to assess the performance of MACK-3 and develop a novel, non-invasive algorithm for diagnosing fibrotic NASH. METHODS: Six hundred and thirty-six adults with biopsy-proven non-alcoholic fatty liver disease (NAFLD) from two independent Asian cohorts were enrolled in our study. Liver stiffness measurement (LSM) was assessed by vibration-controlled transient elastography (Fibroscan). Fibrotic NASH was defined as NASH with a NAFLD activity score (NAS) ≥ 4 and F ≥ 2 fibrosis. RESULTS: Metabolic syndrome (MetS), platelet count and MACK-3 were independent predictors of fibrotic NASH. On the basis of their regression coefficients, we developed a novel nomogram showing a good discriminatory ability (area under receiver operating characteristic curve [AUROC]: 0.79, 95% confidence interval [CI 0.75-0.83]) and a high negative predictive value (NPV: 94.7%) to rule out fibrotic NASH. In the validation set, this nomogram had a higher AUROC (0.81, 95%CI 0.74-0.87) than that of MACK-3 (AUROC: 0.75, 95%CI 0.68-0.82; P < 0.05) with a NPV of 93.2%. The sequential combination of this nomogram with LSM data avoided the need for liver biopsy in 56.9% of patients. CONCLUSIONS: Our novel nomogram (combining MACK-3, platelet count and MetS) shows promising utility for diagnosing fibrotic NASH. The sequential combination of this nomogram and vibration-controlled transient elastography limits indeterminate results and reduces the number of unnecessary liver biopsies.

Effect of PNPLA3 polymorphism on diagnostic performance of various noninvasive markers for diagnosing and staging nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) genotype influences clinical/biochemical characteristics in patients with nonalcoholic fatty liver disease (NAFLD), but whether PNPLA3-I148M (rs738409) genotype also influences the diagnostic performance of noninvasive diagnostic tests for NAFLD is uncertain. Our aim was to investigate the differences in diagnostic performance of noninvasive diagnostic tests for NAFLD according to PNPLA3-I148M (rs738409) genotype. METHODS: Fifty-eight healthy controls and 349 patients with biopsy-proven NAFLD were included. Areas under the receiver operating characteristic curve (AUROCs) were calculated to predict hepatic steatosis (fatty liver index and hepatic steatosis index), nonalcoholic steatohepatitis (cytokeratin-18 M30 and M65), and significant fibrosis (≥F2 fibrosis) (fibrosis-4 and BARD), stratifying by rs738409 genotypes (CC and CG + GG groups). RESULTS: Fatty liver index and hepatic steatosis index showed good diagnostic performance for diagnosing steatosis only in the CG + GG group with AUROCs ranging from 0.819 to 0.832. Cytokeratin-18 M30 (AUROC = 0.688) and M65 (AUROC = 0.678) had suboptimal performance for diagnosing nonalcoholic steatohepatitis in the CG + GG group, whereas both had good performance (AUROC = 0.814 and 0.813, respectively) in the CC group. BARD score showed good performance in the CG + GG group compared with the CC group (AUROC = 0.805 and 0.532, respectively). Fibrosis-4 had suboptimal performance in the CG + GG group and good performance in the CC group (AUROC = 0.662 and 0.801, respectively). CONCLUSIONS: Diagnostic performance of noninvasive tests for NAFLD varied markedly according to PNPLA3 genotypes. Clinicians should be aware that PNPLA3 genotype limits the clinical utility of noninvasive diagnostic tests for diagnosing NAFLD.

Improved comprehensive ecological risk assessment method and sensitivity analysis of polycyclic aromatic hydrocarbons (PAHs).

Based on the existing comprehensive ecological risk assessment methods of PAHs, this paper proposed an improved hierarchical Archimedean copula integral assessment (HACIA) model with the optimization in the model selection mechanism and accelerating the calculation speed, and according to which performed the sensitivity analysis of the integrated risk relative to the underlying grouped risk probability. Taihu Lake in China and the Bay of Santander in Spain were taken as study areas, whose samples were obtained and extracted concentrations of 16 priority polycyclic aromatic hydrocarbons (PAHs). After briefly analyzing their concentration characteristics and source, their comprehensive ecological risks were evaluated by the improve HACIA model and their sensitivity was also analyzed. The results proved that, for Taihu Lake, pyrogenic sources occupied the dominance, especially grass, coal and wood combustion, while the risk proportion of 5-rings PAHs was the lowest indeed based on the improved HAICA model. For the Bay of Santander, source apportionment indicated both petrogenic and pyrogenic sources, mainly from vehicle emissions including gasoline and diesel engines, and 4-ring PAHs were urgently needed to be managed. However, the sensitivity analysis results of two study areas showed that the most effective control target for reducing integral risk has no obvious relationship with the maximum grouped risk. And a clear linear relationship between the maximum sensitivity range and the logarithm of the initial overall risk only presented in one of study areas, which required further research to clarify. In brief, the improved HACIA model is helpful to evaluate the comprehensive ecological risk of 16 PAHs, and formulate risk management strategies based on grouped risk assessment and sensitivity analysis, with the former points out the admonitory risk and the latter helps to find the most effective mitigation measures.

Butyrate Suppresses the Proliferation of Colorectal Cancer Cells via Targeting Pyruvate Kinase M2 and Metabolic Reprogramming.

Butyrate is a short chain fatty acid present in a high concentration in the gut lumen. It has been well documented that butyrate, by serving as an energetic metabolite, promotes the proliferation of normal colonocytes while, by serving as a histone deacetylase inhibitor, epigenetically suppressing the proliferation of cancerous counterparts undergoing the Warburg effect. However, how butyrate interrupts the metabolism of colorectal cancer cells and ultimately leads to the suppression of cell proliferation remains unclear. Here, we employed a metabolomics-proteomics combined approach to explore the link between butyrate-mediated proliferation arrest and cell metabolism. A metabolomics study revealed a remodeled metabolic profile with pronounced accumulation of pyruvate, decreased glycolytic intermediates upstream of pyruvate and reduced levels of nucleotides in butyrate-treated HCT-116 cells. Supplementation of key metabolite intermediates directly affected cancer-cell metabolism and modulated the suppressive effect of butyrate in HCT-116 cells. By a Drug Affinity Responsive Target Stability (DARTS)-based quantitative proteomics approach, we revealed the M2 isoform of a pyruvate kinase, PKM2, as a direct binding target of butyrate. Butyrate activates PKM2 via promoting its dephosphorylation and tetramerization and thereby reprograms the metabolism of colorectal cancer cells, inhibiting the Warburg effect while favoring energetic metabolism. Our study thus provides a mechanistic link between PKM2-induced metabolic remodeling and the antitumorigenic function of butyrate and demonstrates a widely applicable approach to uncovering unknown protein targets for small molecules with biological functions.

Apatinib, a selective VEGFR2 inhibitor, improves the delivery of chemotherapeutic agents to tumors by normalizing tumor vessels in LoVo colon cancer xenograft mice.

Tumor vascular normalization has been proposed as a therapeutic strategy for malignant neoplasms, which can also interpret the synergistic effect of anti-angiogenesis agents combined with chemotherapy. Apatinib (Apa), a highly selective VEGFR2 inhibitor, attracts much attentions due to its encouraging anticancer activity, especially in the clinical trials of combined treatment. In this study, we investigated whether Apa could promote vascular normalization in tumor in a certain time window. Mice bearing LoVo colon cancer xenograft were orally administrated Apa (150 mg kg-1 per day) for 5, 7, 10, or 12 days. Apa significantly inhibited tumor growth and decreased the microvessel density. Using multi-photon microscopy and electron microscopy, we found that Apa improved tumor vessel morphology by pruning distorted vessel branches and decreased the gap between endothelial cells after a 7-day treatment. Furthermore, Apa decreased vessel leakage and increased pericyte coverage on vascular endothelial cells, suggesting that tumor vessels were more mature and integrated. The intratumoral distribution of adriamycin (ADR) in Apa group was improved from day 7 to 10 without change in plasma drug concentration. Tumor blood perfusion was also increased in this window, and the expression of hypoxia induced factor 1α was downregulated, suggesting the effect of Apa on alleviating tumor hypoxic micro-environment. In conclusion, Apa may improve the effective perfusion of tumor vessels and increase the intratumoral distribution of ADR in a certain time window via normalizing tumor vessels. This normalization window (7 to 10 days of treatment) may contribute to develop a regimen of combined medication in clinic use of Apa.

A Novel Use of Model for End-Stage Liver Disease (MELD) Score in Guiding Therapeutic Antibiotics Choice for Critically Ill Cirrhotic Patients.

BACKGROUND Inappropriate use of antibiotics results in antimicrobial resistance and dysbacteriosis. Among critically ill cirrhotic patients, consensus regarding the most optimal prescription strategy for antibiotics use has not been achieved. For these patients, the score for end-stage liver disease (MELD) demonstrated its value in predicting prognosis of cirrhosis. This study investigated use of the MELD score to guide antibiotics choice. MATERIAL AND METHODS We enrolled 1250 patients with cirrhosis. We collected patient information, including antibiotics administration. Linear regression analyses were performed to determine independent predictors of antibiotic administration. Survival curves were constructed based on Cox regression models. Cox proportional hazard models were used to calculate the hazard ratio, shown by forest plots. RESULTS The population was equally stratified into 4 groups based on the MELD score (Q1: MELD <10; Q2: 10≤ MELD <17; Q3: 17≤ MELD <26; Q4: 26≤ MELD). In Q1, all the HR (hazard ratio) related to the duration of antibiotics use demonstrated no statistical significance. In Q2, the HR related to the duration of antibiotics use revealed a successive decrease. In Q3, the HR showed statistical significance only with a duration of antibiotics use of 7 days or more. In Q4, all the HR were statistically significant. As for categories of antibiotics use, whatever the MELD score was, the HR continued to increase with ascending categories. CONCLUSIONS For low MELD score patients (MELD <17), changing the duration of antibiotics use was not associated with a better prognosis. For high MELD score patients (MELD ≥17), longer duration of antibiotics use was associated with a reduction in mortality. Whatever the MELD score was, an increase of number of antibiotic categories was positively associat ed with poor prognosis.

The Comparison of Scars in Breast Implantation Surgery with Inframammary Fold Incision Versus Axillary Incision: A Prospective Cohort Study in Chinese Patients.

BACKGROUND: A prospective cohort study was developed to compare the surgical scars in the axilla and the inframammary fold at short-, medium- and long-term time periods after surgery. METHODS: Patients who underwent primary breast augmentation with implants in our department were divided into two groups based on the incision location they chose and were followed up for scar assessment at 1 month, 6 months and 12 months post-surgery from June 2012 to March 2016. Each scar was evaluated by the Vancouver Scar Scale (VSS) and patient satisfaction score. The data were analyzed with Wilcoxon rank-sum tests, Cochran-Armitage trend tests and Fisher's exact probability tests based on the data type. RESULTS: One hundred and sixty-three patients were completely investigated three times. Ninety-four patients underwent breast augmentation surgeries with implants through axillary approaches and 69 patients through IMF approaches. At 1 month after surgery, the median total VSS score was 6 in the axillary incision group and 4 in the IMF group, with statistically significant differences (P < 0.05). Larger proportions of high scores in terms of vascularity and height were found in the axillary incision group (P < 0.05). At 6 months after surgery, the median total VSS score was 4 in the axillary incision group and 3 in the IMF group, with statistical significance (P < 0.05). The axillary group still had a larger proportion of high scores in terms of vascularity and height than that of the IMF group (P < 0.05). At 12 months after surgery, the median total VSS score was 2 in both groups. The median patient satisfaction score was 9 in both groups. No significant differences were noted in the total VSS and patient satisfaction scores between the two groups. However, the axillary group had a larger proportion of high scores in terms of vascularity and low scores in terms of pliability. CONCLUSIONS: The total VSS score for the axillary incision group was significantly higher than that for the IMF incision group one and 6 months after surgery, mainly on the subscales of vascularity and height. At 12 months after surgery, the total VSS scores were not different between the two groups, and patients with both kinds of incisions were highly satisfied with scar appearance. The research confirmed that the scars at two locations can achieve comparable appearance in the long term after surgery. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Locally Increased Level of Inorganic Phosphate Induced Nodules or Calcification After Bolus Fat Grafting.

BACKGROUND: Nodules or calcifications have been a common complication after breast augmentation with fat grafting, especially in cases with partial bolus fat grafting. There are some clinical preventive measures, but mechanisms related to this complication have not been elucidated yet. Inorganic phosphate (PI), being a product of fat metabolism, is a well-known stimulus of other kinds of pathological calcification such as vascular calcification. We aimed to determine whether PI had a similar effect on formation of nodules after fat grafting. METHODS: Nodules or calcification after fat grafting models using nude mice were created by bolus fat injection. Levels of PI of necrotic liquid located in the central zone and mineralization deposition of graft were examined 1 week, 2 weeks, 1 month, 2 months and 7 months after bolus fat injection. External high phosphate solution was injected 3 times a week to the fat grafts for 2 months, and mineral deposition was examined. In addition, adipose-derived stem cells (ADSCs) were treated with high phosphate osteogenic differentiation medium in various concentrations and times. ADSCs were also treated with osteogenic differentiation in addition to tetramisole which could reduce the level of PI. Mineral depositions of the cells were examined. The central necrotic liquid was extracted from patients who found palpable nodules after breast augmentation with fat grafting. The level of PI of this necrotic liquid and normal lipoaspirates from patients who received normal liposuction for body contouring was compared. RESULTS: The in vivo study indicated that the local PI concentration of the necrotic zone increased significantly 2 months after large volume bolus fat injection. Calcification was not formed after 2 months, but was formed after 7 months, indicating that the effect of PI on calcification was time-dependent. In addition, with the effect of external injection of high phosphate solution into the fat graft, calcification was formed after 2 months, indicating the effect of PI on calcification was dose-dependent. The in vitro study also indicated PI could induce calcification of ADSC in a time- and dose-dependent manner. The study in humans indicated that the level of PI in the necrotic zone of nodules after fat grafting was higher than that in normal lipoaspirates. CONCLUSIONS: This study indicated that the level of PI in the central necrotic zone was elevated after bolus fat injection, which could provide an environment to induce calcification of surrounding tissue. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Roles and expression profiles of long non-coding RNAs in triple-negative breast cancers.

Triple-negative breast cancer (TNBC) refers to the breast cancers that express little human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR) and oestrogen receptor (ER). When compared to other types of breast cancers, TNBC behaves more aggressively with relatively poorer prognosis. Moreover, except chemotherapy, no targeted treatments have been approved yet until now. Although the molecular-biological mechanisms of the initiation and development of TNBC have been explored a lot, the exact details underlying its progressions are still not clear. Long non-coding RNAs (lncRNAs), with the length greater than 200 nucleotides, are non-protein coding transcripts. Previous researches have shown that lncRNAs are significantly involved in a variety of pathophysiological processes such as cell migration, invasion, proliferation, differentiation and development. lncRNAs' dysregulated expressions have been observed in many types of tumours including TNBCs. This article will review the functional roles and dysregulations of lncRNAs in TNBCs. These lncRNAs are worthy of exploitation regarding their potential application values of TNBC's diagnosis and treatment.