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1.
The long-term changes of liver stiffness (LS) in patients who achieve viral clearance after direct-acting anti-HCV therapy remain undefined. We conducted a multicentre prospective study to investigate this aspect. Patients with HCV infection treated with DAAs were enrolled from six Italian centres; they underwent clinical, biochemical, ultrasound and transient elastography evaluations before treatment (T0), 12 weeks (SVR12) and 24 months (T24) after the end of therapy. Among the 516 consecutive patients enrolled, 301 had cirrhosis. LS significantly decreased from T0 to SVR (14.3 vs 11.1 kPa, p = .002), with a progressive reduction until T24 (8.7 kPa, p < .001). However, only patients with steatosis and those who developed HCC did not experience a late improvement in LS. Multivariate analysis of baseline and follow-up variables identified steatosis as the only independent predictor of failure of LS improvement (OR 1.802, p = .013). ROC curve analysis of the association of LS with the risk of developing HCC showed that SVR12 ≥14.0 kPa had the highest accuracy (sensitivity 82%, specificity 99%; AUC: 0.774). Multivariate analysis revealed that LS was the only variable independently associated with an increased risk of developing HCC (OR 6.470, p = .035). Achieving an SVR was associated with a progressive, long-term decline of LS, suggesting a late improvement in liver fibrosis, besides the resolution of inflammation. Fatty liver and the development of HCC interfered with late reduction of LS. Patients with an LS ≥14 kPa at 12 weeks after the end of treatment were at higher risk for developing HCC.  相似文献   
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Introduction: Epidemiological studies indicate an association between type 2 diabetes and pancreatic cancer but the complex and multidirectional relationship between them remains unclear.

Areas covered: We summarized epidemiological evidence on diabetes and pancreatic cancer exploring the time–risk relationship. We described mechanisms linking long-standing diabetes to pancreatic cancer. We discussed pancreatic cancer-associated diabetes and its implication in the early detection of pancreatic cancer.

Expert opinion: The markedly increased risk of pancreatic cancer in patients with new-onset diabetes compared with long-standing diabetes observed in several epidemiological studies indicates a complex and bidirectional connection, with long-standing diabetes being a predisposing factor for pancreatic cancer (increasing the risk of the malignancy 1.5- to 2-fold) and new-onset diabetes an early manifestation of the tumor. Identifying clinical features and biomarkers to distinguish pancreatic cancer-associated diabetes from type 2 diabetes is an important goal to improve management and survival of this cancer. Imaging (MRI) for middle-age patients with new-onset diabetes may be considered.  相似文献   

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Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities.  相似文献   
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Methicillin-resistant Staphylococcus aureus (MRSA) is an important infectious human pathogen responsible for diseases ranging from skin and soft tissue infections to life-threatening endocarditis. β-Lactam resistance in MRSA involves acquisition of penicillin-binding protein 2a (PBP2a), a protein with low affinity for β-lactams that mediates cell wall assembly when the normal staphylococcal PBPs (PBP1 to -4) are blocked by these agents. Many MRSA strains display heterogeneous expression of resistance (HeR) against β-lactam antibiotics. The β-lactam-mediated homoresistant (HoR) phenotype is associated with both expression of the mecA gene and activation of the LexA-RecA-mediated SOS response, a regulatory network induced in response to DNA damage. Ceftaroline (CPT) is the only FDA-approved cephalosporin targeting PBP2a. We investigated the mechanistic basis of CPT activity against HeR-MRSA strains, including a set of strains displaying an intermediate level of resistance to CPT. Mechanistically, we found that 1 exposure of HeR-MRSA to subinhibitory concentrations of CPT selected for the HoR derivative activated the SOS response and increased mutagenesis. Importantly, CPT-selected HoR cells remained susceptible to CPT while still being resistant to most β-lactams, and 2-CPT activity in HeR-MRSA resided in an attenuated induction of mecA expression in comparison to other β-lactams. In addition, 3-CPT intermediate-resistant strains displayed a significant increase in CPT-induced mecA expression accompanied by mutations in PBP2, which together may interfere with the complete repression by CPT of both PBP2a and PBP2a-PBP2 interactions and thus be a determining factor in the low level of CPT resistance in the absence of mecA gene mutations. The present study provides mechanistic evidence that CPT represents an alternative therapeutic option for the treatment of heteroresistant MRSA strains.  相似文献   
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Purpose

Childhood trauma may increase vulnerability to numerous specific psychiatric disorders, or a generalised liability to experience dimensions of internalising or externalising psychopathology. We use a nationally representative sample (N?=?34,653) to examine the long-term consequences of childhood trauma and their combined effect as predictors of subsequent psychopathology.

Methods

Data from the US National Epidemiologic Survey on Alcohol and Related Conditions were used. Latent class analysis was used to identify childhood trauma profiles and multinomial logistic regression to validate and explore these profiles with a range of associated demographic and household characteristics. We used Structural Equation Modelling to substantiate initial latent class analysis findings by investigating a range of mental health diagnoses. Internalising and externalising domains of psychopathology were regressed on trauma profiles and associated demographic and household characteristics. We used Differential Item Functioning to examine associations between the trauma groups and a number of psychiatric disorders within internalising and externalising dimensions of mental health.

Results

We found a 3-class model of childhood trauma in which 85% of participants were allocated to a low trauma class; 6% to a multi-type victimization class (reporting exposures for all the child maltreatment criteria); and 9% to a situational trauma class (exposed to a range of traumas). Confirmatory Factor Analysis revealed an internalising–externalising spectrum was used to represent lifetime reporting patterns of mental health disorders. Both trauma groups showed specific gender and race/ethnicity differences, related family discord and increased psychopathology. Additionally, we found significant associations between the trauma groups and specific diagnoses within the internalising–externalising spectrum of mental health.

Conclusions

The underlying patterns in the exposure to types of interpersonal and non-interpersonal traumas and associated mental health highlight the need to screen for particular types of childhood traumas when individuals present with symptoms of psychiatric disorders.
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Aims To examine differences in alcohol‐related mortality risk between areas, while adjusting for the characteristics of the individuals living within these areas. Design A 5‐year longitudinal study of individual and area characteristics of those dying and not dying from alcohol‐related deaths. Setting The Northern Ireland Mortality study. Participants A total of 720 627 people aged 25–74, enumerated in the Northern Ireland 2001 Census, not living in communal establishments. Measurements Five hundred and seventy‐eight alcohol‐related deaths. Findings There was an increased risk of alcohol‐related mortality among disadvantaged individuals, and divorced, widowed and separated males. The risk of an alcohol‐related death was significantly higher in deprived areas for both males [hazard ratio (HR) 3.70; 95% confidence interval (CI) 2.65, 5.18] and females (HR 2.67 (95% CI 1.72, 4.15); however, once adjustment was made for the characteristics of the individuals living within areas, the excess risk for more deprived areas disappeared. Both males and females in rural areas had a reduced risk of an alcohol‐related death compared to their counterparts in urban areas; these differences remained after adjustment for the composition of the people within these areas. Conclusions Alcohol‐related mortality is higher in more deprived, compared to more affluent areas; however, this appears to be due to characteristics of individuals within deprived areas, rather than to some independent effect of area deprivation per se. Risk of alcohol‐related mortality is lower in rural than urban areas, but the cause is unknown.  相似文献   
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