What is the actual role of diagnosis and how to assess it?

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Severe steatohepatitis in a patient with a rare neutral lipid storage disorder due to ABDH5 mutation

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Clinical and genetic characterization of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene

<p>Abstract</p> <p>Background</p> <p>Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive disorder characterized by nonbullous congenital ichthyosiform erythroderma (NCIE) and an intracellular accumulation of triacylglycerol (TG) droplets in most tissues. The clinical phenotype involves multiple organs and systems, including liver, eyes, ears, skeletal muscle and central nervous system (CNS). Mutations in ABHD5/CGI58 gene are associated with CDS.</p> <p>Methods</p> <p>Eight CDS patients belonging to six different families from Mediterranean countries were enrolled for genetic study. Molecular analysis of the ABHD5 gene included the sequencing of the 7 coding exons and of the putative 5' regulatory regions, as well as reverse transcript-polymerase chain reaction analysis and sequencing of normal and aberrant ABHD5 cDNAs.</p> <p>Results</p> <p>Five different mutations were identified, four of which were novel, including two splice-site mutations (c.47+1G>A and c.960+5G>A) and two large deletions (c.898_*320del and c.662-1330_773+46del). All the reported mutations are predicted to be pathogenic because they lead to an early stop codon or a frameshift producing a premature termination of translation. While nonsense, missense, frameshift and splice-site mutations have been identified in CDS patients, large genomic deletions have not previously been described.</p> <p>Conclusions</p> <p>These results emphasize the need for an efficient approach for genomic deletion screening to ensure an accurate molecular diagnosis of CDS. Moreover, in spite of intensive molecular screening, no mutations were identified in one patient with a confirmed clinical diagnosis of CDS, appointing to genetic heterogeneity of the syndrome.</p

Correction:Clinical and genetic characterization of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene

AbstractFollowing the publication of this article [Redaelli C et al, Clinical and genetic characterization of Chanarin-Dorfman Syndrome patients: first report of large deletions in the ABHD5 gene. Orphanet J Rare Dis 2010; 5: 33.], it was clarified that the clinical follow-up of one of CDS family described in the manuscript was performed by Dr. Amalia Sertedaki and Talia Kakourou. The authorship of the article has been changed accordingly. The submitting authors would like to apologise to Amalia Sertedaki and Talia Kakourou for this error and they would like to thank Catherine Dacou-Voutetakis for underlining the problem

Pragmatic Trial Design to Compare Real-world Effectiveness of Different Treatments for Inflammatory Bowel Diseases: The PRACTICE-IBD European Consensus

Background and Aims Pragmatic studies designed to test interventions in everyday clinical settings can successfully complement the evidence from registration and explanatory clinical trials. The European consensus project PRACTICE-IBD was developed to identify essential criteria and address key methodological issues needed to design valid, comparative, pragmatic studies in inflammatory bowel diseases [BDs].Methods Statements were issued by a panel of 11 European experts in IBD management and trial methodology, on four main topics: [I] study design; [II] eligibility, recruitment and organisation, flexibility; [III] outcomes; [IV] analysis. The consensus process followed a modified Delphi approach, involving two rounds of assessment and rating of the level of agreement [1 to 9; cut-off &gt;= 7 for approval] with the statements by 18 additional European experts in IBD.Results At the first voting round, 25 out of the 26 statements reached a mean score &gt;= 7. Following the discussion that preceded the second round of voting, it was decided to eliminate two statements and to split one into two. At the second voting round, 25 final statements were approved: seven for study design; six for eligibility, recruitment and organisation, flexibility; eight for outcomes; and four for analysis.Conclusions Pragmatic, randomised, clinical trials can address important questions in IBD clinical practice, and may provide complementary, high-level evidence, as long as they follow a methodologically rigorous approach. These 25 statements intend to offer practical guidance in the design of high-quality, pragmatic, clinical trials that can aid decision making in choosing a management strategy for IBDs

European Society for Organ Transplantation (ESOT) Consensus Statement on Outcome Measures in Liver Transplantation According to Value-Based Health Care

Liver transplantation is a highly complex, life-saving, treatment for many patients with advanced liver disease. Liver transplantation requires multidisciplinary teams, system-wide adaptations and significant investment, as well as being an expensive treatment. Several metrics have been proposed to monitor processes and outcomes, however these lack patient focus and do not capture all aspects of the process. Most of the reported outcomes do not capture those outcomes that matter to the patients. Adopting the principles of Value-Based Health Care (VBHC), may provide an opportunity to develop those metrics that matter to patients. In this article, we present a Consensus Statement on Outcome Measures in Liver Transplantation following the principles of VBHC, developed by a dedicated panel of experts under the auspices of the European Society of Organ Transplantation (ESOT) Guidelines' Taskforce. The overarching goal is to provide a framework to facilitate the development of outcome measures as an initial step to apply the VMC paradigm to liver transplantation

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology

Bakground &amp; aims Although discrimination of the model for end stage liver disease (MELD) is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discrimination and calibration performance of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intra-hepatic portosystemic shunt (TIPS); classic MELD-Mayo; MELD-UNOS, used by United Network for Organ Sharing (UNOS). Recalibration and model updating were also explored. Methods 776 patients submitted to elective TIPS (TIPS cohort), and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results Major patient characteristics in TIPS/non-TIPS cohorts were: viral etiology 402/188, alcoholic 185/130, NASH 65/33; mean follow-up± SD 25±9/19±21months; 3-6-12 month mortality were respectively, 57-102-142/31-47-99. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post-hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used for a MELD updating. Conclusions In this validation study the MELD performance was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for a MELD updating are proposed. Lay summary While discrimination performance of the Model for End Stage Liver Disease (MELD) is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in two independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis and propose a validated model recalibration. Candidate variables for a MELD updating are proposed

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.The Lombardia GENS project has received funding from the Regione Lombardia Government as a Research Independent Project (DGR n°VIII/006128-12/12/2007). Lombardia GENS is an investigator-driven, academic, non-profit consortium and is publicly funded. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospitals NIHR Biomedical Research Centr