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Growing evidence suggests that cholestatic and fatty liver disease share common pathophysiological mechanisms. Rare loss-of-function variants in the ATP binding cassette subfamily B member 4 (ABCB4) gene have been associated with gallstone disease and with a spectrum of cholestatic liver diseases, ranging from progressive familial intrahepatic cholestasis to less severe conditions, like low phospholipid-associated cholelithiasis or intrahepatic cholestasis during pregnancy. Whole-genome sequencing of Icelanders revealed the common variant rs2109505 T>A in ABCB4 , conferring protection against gallstone disease and being associated with lower transaminases. To identify common variants in ABCB4 associated with severe liver disease. We examined the association of missense and nonsense common variants (minor allele frequency >1%) at the ABCB4 locus with ALT in 412,912 Europeans from the UK Biobank using a whole-genome regression model. Next, we tested the association of the lead variant in the region with liver-related traits and incident severe liver disease in a subset of 365,449 unrelated Europeans by multiple linear/logistic regression models and Cox proportional hazards models, respectively. Analyses were adjusted for age, gender, BMI, type 2 diabetes, alcohol intake, and first 10 PCs of ancestry. We identified the ABCB4 rs1468615 T>C as the lead variant independently associated with ALT (P = 2.26 × 10−34). The rs1468615 is an intronic variant in high linkage disequilibrium with the rs2109505 (r2 = 0.94). The rs1468615 was associated with lower risk of gallstone disease (P = 8.56 × 10−12) and with lower liver enzymes (P = 2.28 × 10−30, P = 8.31 × 10−09, and P = 8.08 × 10−04 for ALT, AST, and GGT respectively). No association was found with liver cirrhosis, liver cancer, and gallbladder/biliary tract cancer. No association was found with incident severe liver disease. The rs1468615 T>C in ABCB4 confers protection against gallstone disease but not against the development of severe liver disease. [ABSTRACT FROM AUTHOR]

Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation associates with NAFLD severity in individuals with liver biopsy. We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2,889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNASeq in a subset of NAFLD individuals (n=121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele. The rs13023138 C>G showed the most robust association with HCC in UK Biobank (P = 5.28E-4, OR=1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95%C.I. 1.02-1.34; p=0.01), NASH (OR 1.22, 95%C.I. 1.09-1.37; p<0.001) and advanced fibrosis (OR 1.26, 95%C.I. 1.06-1.50; p=0.07). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6. The PDCD1 rs13023138 G allele was associated with HCC development in general population and with liver disease severity in patients at high risk of NASH. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of our study is to assess the incidence of prosthetic joint infection (PJI) after total Knee arthroplasty (TKA), total Hip arthroplasty (THA) and total Shoulder arthroplasty (TSA), to identify risk factors, determine the microbial spectrum and management’s outcome. PATIENTS AND METHODS: A case-control, retrospective observational study was performed analyzing patients who developed a PJI after TKA, THA, and TSA from 2000 to 2017 at our hospital. The patient’s risk profile was defined extracting from clinical records the following data: sex, age, BMI, type of implant, comorbidity, year of surgery, year of infection, previous intra-articular injection, microbial isolation, medical and surgical management outcome. We include in the “control group” for each “case” at least 3 patients who didn’t have a PJI after TJA. RESULTS: 28 patients met all inclusion and exclusion criteria. Comparing the “cases” with “controls” demographics parameters, medical comorbidities and previous intra-articular injection were not associated with an increased risk of PJI. Comparing the “early/delayed group” with “late group”, BMI was associated with an increased risk of early/delayed PJI, while demographics parameters, medical comorbidities, and previous intra-articular injection did not significantly increase the risk of PJI. Logistic regression showed that for each BMI unit there was a 20-fold increased risk of early prosthetic infection (OR 1.19, IC 1.03-1.38, p=0.01). Staphylococci were isolated most frequently from pre-operative and intra-operative cultures. Twostage arthroplasty exchange and surgical debridement resulted in the most performed surgical treatment with a success rate of 88 and 87%. CONCLUSIONS: Obesity is a risk factor for “early/delayed infection” of TJA. Two-stage arthroplasty exchange, debridement, antibiotics, and implant retention in patients are treatments with a high rate of success in terms of reinfection. [ABSTRACT FROM AUTHOR]