Human T-lymphotropic virus type 1 (HTLV-1) prevalence and quantitative detection of DNA proviral load in individuals with indeterminate/positive serological results

BACKGROUND: HTLV-1 infection is currently restricted to endemic areas. To define the prevalence of HTLV-1 infection in patients living in Italy, we first carried out a retrospective serological analysis in a group of people originating from African countries referred to our hospital from January 2003 to February 2005. We subsequently applied a real time PCR on peripheral blood mononuclear cells from subjects with positive or indeterminate serological results. METHODS: All the sera were first analysed by serological methods (ELISA and/or Western Blotting) and then the peripheral blood mononuclear cells from subjects with positive or inconclusive serological results were analyzed for the presence of proviral DNA by a sensitive SYBR Green real time PCR. In addition, twenty HTLV-I ELISA negative samples were assayed by real time PCR approach as negative controls. RESULTS: Serological results disclosed serum reactivity by ELISA (absorbance values equal or greater than the cut-off value) in 9 out of 3408 individuals attending the Sexually Transmitted Diseases Clinic and/or Oncology Department, and 2 out 534 blood donors enrolled as a control population. Irrespective of positive or inconclusive serological results, all these subjects were analyzed for the presence of proviral DNA in peripheral blood mononuclear cells by SYBR real time PCR. A clear-cut positive result for the presence of HTLV-1 DNA was obtained in two subjects from endemic areas. CONCLUSION: SYBR real time PCR cut short inconclusive serological results. This rapid and inexpensive assay showed an excellent linear dynamic range, specificity and reproducibility readily revealing and quantifying the presence of virus in PBMCs. Our results highlight the need to monitor the presence of HTLV-1 in countries which have seen a large influx of immigrants in recent years. Epidemiological surveillance and correct diagnosis are recommended to verify the prevalence and incidence of a new undesirable phenomenon

Reimbursement and economic factors influencing dialysis modality choice around the world

The worldwide incidence of kidney failure is on the rise and treatment is costly; thus, the global burden of illness is growing. Kidney failure patients require either a kidney transplant or dialysis to maintain life. This review focuses on the economics of dialysis. Alternative dialysis modalities are haemodialysis (HD) and peritoneal dialysis (PD). Important economic factors influencing dialysis modality selection include financing, reimbursement and resource availability. In general, where there is little or no facility or physician reimbursement or payment for PD, the share of PD is very low. Regarding resource availability, when centre HD capacity is high, there is an incentive to use that capacity rather than place patients on home dialysis. In certain countries, there is interest in revising the reimbursement structure to favour home-based therapies, including PD and home HD. Modality selection is influenced by employment status, with an association between being employed and PD as the modality choice. Cost drivers differ for PD and HD. PD is driven mainly by variable costs such as solutions and tubing, while HD is driven mainly by fixed costs of facility space and staff. Many cost comparisons of dialysis modalities have been conducted. A key factor to consider in reviewing cost comparisons is the perspective of the analysis because different costs are relevant for different perspectives. In developed countries, HD is generally more expensive than PD to the payer. Additional research is needed in the developing world before conclusive statements may be made regarding the relative costs of HD and PD

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Renal replacement therapy in acute kidney injury: controversy and consensus

Renal replacement therapies (RRTs) represent a cornerstone in the management of severe acute kidney injury. This area of intensive care and nephrology has undergone significant improvement and evolution in recent years. Continuous RRTs have been a major focus of new technological and treatment strategies. RRT is being used increasingly in the intensive care unit, not only for renal indications but also for other organ-supportive strategies. Several aspects related to RRT are now well established, but others remain controversial. In this review, we review the available RRT modalities, covering technical and clinical aspects. We discuss several controversial issues, provide some practical recommendations, and where possible suggest a research agenda for the future

Trace elements in hemodialysis patients: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Hemodialysis patients are at risk for deficiency of essential trace elements and excess of toxic trace elements, both of which can affect health. We conducted a systematic review to summarize existing literature on trace element status in hemodialysis patients.</p> <p>Methods</p> <p>All studies which reported relevant data for chronic hemodialysis patients and a healthy control population were eligible, regardless of language or publication status. We included studies which measured at least one of the following elements in whole blood, serum, or plasma: antimony, arsenic, boron, cadmium, chromium, cobalt, copper, fluorine, iodine, lead, manganese, mercury, molybdenum, nickel, selenium, tellurium, thallium, vanadium, and zinc. We calculated differences between hemodialysis patients and controls using the differences in mean trace element level, divided by the pooled standard deviation.</p> <p>Results</p> <p>We identified 128 eligible studies. Available data suggested that levels of cadmium, chromium, copper, lead, and vanadium were higher and that levels of selenium, zinc and manganese were lower in hemodialysis patients, compared with controls. Pooled standard mean differences exceeded 0.8 standard deviation units (a large difference) higher than controls for cadmium, chromium, vanadium, and lower than controls for selenium, zinc, and manganese. No studies reported data on antimony, iodine, tellurium, and thallium concentrations.</p> <p>Conclusion</p> <p>Average blood levels of biologically important trace elements were substantially different in hemodialysis patients, compared with healthy controls. Since both deficiency and excess of trace elements are potentially harmful yet amenable to therapy, the hypothesis that trace element status influences the risk of adverse clinical outcomes is worthy of investigation.</p

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

OBJECTIVE: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING Intercept Pharmaceuticals