Bacterial and viral infections may cause or exacerbate various human diseases and to detect microbes in tissue, one method of choice is RNA sequencing. The detection of specific microbes using RNA ...sequencing offers good sensitivity and specificity, but untargeted approaches suffer from high false positive rates and a lack of sensitivity for lowly abundant organisms.
We introduce Pathonoia, an algorithm that detects viruses and bacteria in RNA sequencing data with high precision and recall. Pathonoia first applies an established k-mer based method for species identification and then aggregates this evidence over all reads in a sample. In addition, we provide an easy-to-use analysis framework that highlights potential microbe-host interactions by correlating the microbial to the host gene expression. Pathonoia outperforms state-of-the-art methods in microbial detection specificity, both on in silico and real datasets.
Two case studies in human liver and brain show how Pathonoia can support novel hypotheses on microbial infection exacerbating disease. The Python package for Pathonoia sample analysis and a guided analysis Jupyter notebook for bulk RNAseq datasets are available on GitHub.
Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics ...discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.
The genetic architecture of primary biliary cholangitis Gerussi, Alessio; Carbone, Marco; Corpechot, Cristophe ...
European journal of medical genetics,
September 2021, 2021-09-00, 20210901, Volume:
64, Issue:
9
Journal Article
Peer reviewed
Primary biliary cholangitis (PBC) is a rare autoimmune disease of the liver affecting the small bile ducts. From a genetic point of view, PBC is a complex trait and several genetic and environmental ...factors have been called in action to explain its etiopathogenesis. Similarly to other complex traits, PBC has benefited from the introduction of genome-wide association studies (GWAS), which identified many variants predisposing or protecting toward the development of the disease.
While a progressive endeavour toward the characterization of candidate loci and downstream pathways is currently ongoing, there is still a relatively large portion of heritability of PBC to be revealed. In addition, genetic variation behind progression of the disease and therapeutic response are mostly to be investigated yet.
This review outlines the state-of-the-art regarding the genetic architecture of PBC and provides some hints for future investigations, focusing on the study of gene-gene interactions, the application of whole-genome sequencing techniques, and the investigation of X chromosome that can be helpful to cover the missing heritability gap in PBC.
Clinical management of autoimmune hepatitis Pape, Simon; Schramm, Christoph; Gevers, Tom JG
United European Gastroenterology Journal,
November 2019, Volume:
7, Issue:
9
Book Review, Journal Article
Peer reviewed
Open access
Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and presence of circulating ...autoantibodies. An autoimmune hepatitis diagnosis justifies life-long treatment in most patients in order to prevent development of cirrhosis and end-stage liver disease. The cornerstone of treatment is steroid induction therapy followed by maintenance therapy with azathioprine, which is effective in most cases. For patients who do not respond to standard treatment, second-line treatment with other immunosuppressants can be effective. Treatment should be aimed at biochemical remission of the disease, which is defined as normalization of transaminases and immunoglobulin G. Patients should be monitored intensively during the first months of treatment in order to monitor side-effects, assess symptoms and individualise treatment. Specialist consultation should be sought in difficult-to-treat patients. Future studies and networking initiatives should result in optimization of current treatment strategies in autoimmune hepatitis.
Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life‐saving. Diagnostic criteria of the International Autoimmune ...Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff ≥6) and 81% sensitivity and 99% specificity (cutoff ≥7) in the validation set. Conclusion: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher. (HEPATOLOGY 2008.)
Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for ...PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT.
We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983–2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10–15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models.
While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio aHR 0.41; 95% CI 0.28–0.61; p <0.0001), graft loss (aHR 0.33; 95% CI 0.13–0.82; p <0.05), liver-related death (aHR 0.46; 95% CI 0.22–0.98; p <0.05), and all-cause death (aHR 0.69; 95% CI 0.49–0.96; p <0.05). On RMST analysis, preventive UDCA led to a survival gain of 2.26 years (95% CI 1.28–3.25) over a period of 20 years. Exposure to cyclosporine rather than tacrolimus had a complementary protective effect alongside preventive UDCA, reducing the cumulative incidence of PBC recurrence and all-cause death.
Preventive UDCA after LT for PBC is associated with a reduced risk of disease recurrence, graft loss, and death. A regimen combining cyclosporine and preventive UDCA is associated with the lowest risk of PBC recurrence and mortality.
Recurrence of primary biliary cholangitis after liver transplantation is frequent and can impair graft and patient survival. We performed the largest international study of transplanted patients with primary biliary cholangitis to date. Preventive administration of ursodeoxycholic acid after liver transplantation was associated with reduced risk of disease recurrence, graft loss, liver-related and all-cause mortality. A regimen combining cyclosporine and preventive ursodeoxycholic acid was associated with the best outcomes.
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•Preventive UDCA after liver transplantation for PBC is associated with a reduced risk of disease recurrence.•This parallels a reduction in the long-term risk of graft loss, liver-related death and all-cause death.•Exposure to cyclosporine rather than to tacrolimus added to the protective effect of UDCA.
Summary Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and ...frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The I nternational P rimary S clerosing C holangitis S tudy G roup (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.
Centers for rare diseases serve as contact points for patients with complex, often undiagnosed complaints and persistent somatic symptoms of heterogeneous origin. Little is known about psychological ...distress of patients consulting these centers.
To better understand psychological distress of adult patients presenting at a center for rare diseases by determining the proportion of patients screening positive for depressive, anxiety, and somatic symptom disorders (SSD) and to identify factors associated with increased psychopathology.
Cross-sectional data from the routine care registry of the Martin Zeitz Center for Rare Diseases (MZCSE) at the University Medical Center Hamburg-Eppendorf in Germany was retrieved and analyzed. We included all adult patients presenting between October 01,2020 and September 30,2021, who gave written informed consent.
Sociodemographic variables, medical history and healthcare utilization, as well as validated measures to screen for a depressive disorder (PHQ-8), an anxiety disorder (GAD-7), and SSD (PHQ-15, SSD-12).
N = 167 patients were included (age 44.5 ± 14.3 years, 64.7% female). A total of 40.7% of the patients screened positive for a depressive disorder (PHQ-8 ≥ 10), 27.5% for an anxiety disorder (GAD-7 ≥ 10) and 45.0% screened positive for SSD (PHQ-15 ≥ 9 & SSD-12 ≥ 23). Factors associated with increased psychopathology included the number of symptoms, the number of different specialties consulted before and past psychotherapy.
Patients presenting at centers for rare diseases are likely to experience high rates of psychological distress. Systematically screening patients with rare and undiagnosed diseases for mental disorders can help to detect those at risk at an early stage and initiate adequate psychological care.
Background. Existing colorectal cancer (CRC) screening models mostly focus on the adenoma pathway of CRC development, overlooking the serrated neoplasia pathway, which might result in overly ...optimistic screening predictions. In addition, Bayesian inference methods have not been widely used for model calibration. We aimed to develop a CRC screening model accounting for both pathways, calibrate it with approximate Bayesian computation (ABC) methods, and validate it with large CRC screening trials. Methods. A discrete event simulation (DES) of the CRC natural history (DECAS) was constructed using the adenoma and serrated pathways in R software. The model simulates CRC-related events in a specific birth cohort through various natural history states. Calibration took advantage of 74 prevalence data points from the German screening colonoscopy program of 5.2 million average-risk participants using an ABC method. CRC incidence outputs from DECAS were validated with the German national cancer registry data; screening effects were validated using 17-y data from the UK Flexible Sigmoidoscopy Screening sigmoidoscopy trial and a German screening colonoscopy cohort study. Results. The Bayesian calibration rendered 1,000 sets of posterior parameter samples. With the calibrated parameters, the observed age- and sex-specific CRC prevalences from the German registries were within the 95% DECAS-predicted intervals. Regarding screening effects, DECAS predicted a 41% (95% intervals 30%–51%) and 62% (95% intervals 55%–68%) reduction in 17-y cumulative CRC mortality for a single screening sigmoidoscopy and colonoscopy, respectively, falling within 95% confidence intervals reported in the 2 clinical studies used for validation. Conclusions. We presented DECAS, the first Bayesian-calibrated DES model for CRC natural history and screening, accounting for 2 CRC tumorigenesis pathways. The validated model can serve as a valid tool to evaluate the (cost-)effectiveness of CRC screening strategies.
Highlights
This article presents a new discrete event simulation model, DECAS, which models both adenoma-carcinoma and serrated neoplasia pathways for colorectal cancer (CRC) development and CRC screening effects.
DECAS is calibrated based on a Bayesian inference method using the data from German screening colonoscopy program, which consists of more than 5 million first-time average-risk participants aged 55 years and older in 2003 to 2014.
DECAS is flexible for evaluating various CRC screening strategies and can differentiate screening effects in different parts of the colon.
DECAS is validated with large screening sigmoidoscopy and colonoscopy clinical study data and can be further used to evaluate the (cost-)effectiveness of German colorectal cancer screening strategies.
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