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Background Acute pancreatitis (AP) is a potentially severe or even fatal inflammation of the pancreas. Early identification of patients at high risk for developing a severe course of the disease is crucial for preventing organ failure and death. Most of the former predictive scores require many parameters or at least 24 h to predict the severity; therefore, the early therapeutic window is often missed. Methods The early achievable severity index (EASY) is a multicentre, multinational, prospective and observational study (ISRCTN10525246). The predictions were made using machine learning models. We used the scikit‐learn, xgboost and catboost Python packages for modelling. We evaluated our models using fourfold cross‐validation, and the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC), and accuracy metrics were calculated on the union of the test sets of the cross‐validation. The most critical factors and their contribution to the prediction were identified using a modern tool of explainable artificial intelligence called SHapley Additive exPlanations (SHAP). Results The prediction model was based on an international cohort of 1184 patients and a validation cohort of 3543 patients. The best performing model was an XGBoost classifier with an average AUC score of 0.81 ± 0.033 and an accuracy of 89.1%, and the model improved with experience. The six most influential features were the respiratory rate, body temperature, abdominal muscular reflex, gender, age and glucose level. Using the XGBoost machine learning algorithm for prediction, the SHAP values for the explanation and the bootstrapping method to estimate confidence, we developed a free and easy‐to‐use web application in the Streamlit Python‐based framework (http://easy‐app.org/). Conclusions The EASY prediction score is a practical tool for identifying patients at high risk for severe AP within hours of hospital admission. The web application is available for clinicians and contributes to the improvement of the model. The EASY prediction score is a practical tool for identifying patients at a greater risk for severe acute pancreatitis shortly after hospital admission. The explanation of the impact of features on the prediction helps physicians understand the decision of the machine learning model. The easy‐to‐use web application is available for clinicians and contributes to the improvement of the model.

BEVEZETÉSA veleszületett immunrendszert alkotó celluláris és humorális alkotóelemek működésének megváltozása jelentős szerepet tölt be a különféle, nagy betegpopulációt érintő krónikus gyulladással járó gasztroenterológiai kórképek patogenezisében, mint például a gyulladásos bélbetegségek (IBD) vagy a coeliakia. Elégtelen működésük számos betegcsoportban, így májcirrhosisban is gyakoribb, súlyosabb infekciók kialakulásához vezethet.A coeliakiához vezető korai pathológiás történések magukba foglalják a veleszületett immunrendszer aktivációját is, mely elsősorban az epitheliumban zajlik. Emellett a coeliakia tipikus jellegzetessége a különböző antitestek jelenléte, habár ezek termelődésének hátterében álló mehanizmusok és a betegség pathogenezisében betöltött tényleges szerepük egyelőre nem teljesen tisztázott. A szöveti transzglutamináz 2 (TG2) a fő autoantigénje az anti-endomysialis antitesteknek (EMA) és az anti-TG2/EMA vizsgálata gyakran használt módszer a CD szűrésében és diagnosztikájában. A különféle baktériumok sejtfalának szénhidrát epitópjai ellen termelődő antitestek a szövődményes Crohn-betegség markerei. Az anti-Saccharomyces cerevisiaeantitest (ASCA) gyakoribb megjelenését coeliakiában is leírták. Ugyanakkor az IBD-ben észlelt egyéb antimikrobiális antitestek (ALCA, AMCA, ACCA, anti-OMP) előfordulásának gyakorisága illetve klinikai jelentősége coeliakiában nem tisztázott.A májcirrhosisos betegek különösen fogékonyak a bakteriális fertőzések kialakulására, a cirrhosis asszociált immundeficiencia (CAID) szindróma jelenléte miatt, ennek azonban még nem minden komponense ismert. A komplement rendszer lektin útvonalának molekulái a veleszületett immunrendszerhez tartoznak, a májban képződnek és központi szerepet töltenek be a mikrobákkal szembeni védekezésben. A fikolinok (FCN) szolubilis mintázatfelismerő receptorként működnek, míg a mannóz-kötő lektin szerin proteázok (MASP) effektor molekulák. A funkcionális fehérjék alacsony szintje növeli a különféle fertőzés kialakulásának kockázatát, elsősorban immunszupresszióval járó kórképek esetén. A májcirrhosishoz kapcsolódó bakteriális fertőzésekben betöltött szerepük kevéssé ismert.CÉLKITŰZÉSEKVizsgálataink során célul tűztük ki, hogy felnőtt coeliakias betegekben meghatározzuk a különféle glikán típusú antimikrobiális antitestek előfordulási gyakoriságát, a betegség klinikai fenotípusával való kapcsolatát, valamint azok jelenlétének lehetséges összefüggését a glutén expozícióval. Prospektíven követett, nagy esetszámú májcirrhosisos betegcsoportban célul tűztük ki továbbá annak vizsgálatát, hogy a lektin útvonal egyes molekuláinak (FCN-2, FCN-3 és MASP-2) szérumszintje hogyan változik az egészséges populációhoz képest és mutat-e összefüggést a betegségspecifikus szövődmények jelenlétével. Ötéves utánkövetéses klinikai vizsgálatban elemeztük a fikolinok és a MASP-2 molekulák szérumszintjének összefüggését a klinikailag jelentős bakterális infekciók kialakulásával és a halálozással.MÓDSZEREKA coeliakiás betegcsoportban az antimikrobiális antitestek illetve a májcirrhosisos betegekben a lektin útvonal molekuláinak (FCN-2, FCN-3, MASP-2) meghatározása ELISA módszerrel történt, szérum mintákból.EREDMÉNYEKCoeliakiás betegcsoportban elvégzett vizsgálataink eredményeit az alábbiakban foglalhatjuk össze: (I) A különféle glikán típusú antitestek közül a gASCA, AMCA, és ACCA az antitest előfordulási gyakorisága szignifikánsan magasabb volt a coeliakia diagnózisának felállításakor az egészséges és a gastrointestinalis kontrollokéhoz képest. Az ALCA IgG és anti-OMP esetén különbséget a vizsgált csoportok között nem találtunk. (II) Összefüggés volt kimutatható a glikán ellenes antitestek szintjei, illetve az EMA és TGA szintek között. (III) Szigorú gluténmentes diétát tartó betegekben kellő hosszúságú idő elteltével a glikán ellenes antitestek a szérumból teljesen eltűntek. (IV)Súlyos malabsorptios betegeknél jóval gyakrabban észleltünk többszörös antitest pozitivitást, míg a nem specifikus gastrointestinális tünetek vagy vashiányos anaemia esetén gyakoribb volt a szeroreaktivitás hiánya, vagy a csupán egy glikán komponens ellen kimutatható reaktivitás.Májcirrhosisos betegcsoportban elvégzett vizsgálataink eredményeit az alábbiakban foglalhatjuk össze:(I)A FCN-2, FCN-3 és MASP-2 szintek szignifikánsan alacsonyabbak voltak cirrhosisos betegekben az egészséges kontrollokhoz képest, és a betegség súlyosságával összefüggően csökkentek.

Bacterial translocation plays important role in the complications of liver cirrhosis. Antibody formation against various microbial antigens is common in Crohn's disease and considered to be caused by sustained exposure to gut microflora constituents. We hypothesized that anti-microbial antibodies are present in patients with liver cirrhosis and may be associated with the development of bacterial infections. Sera of 676 patients with various chronic liver diseases (autoimmune diseases: 266, viral hepatitis C: 124, and liver cirrhosis of different etiology: 286) and 100 controls were assayed for antibodies to Saccharomyces cerevisiae (ASCA) and to antigens derived from two intestinal bacterial isolates (one gram positive, one gram negative, neither is Escherichia coli). In patients with liver cirrhosis, we also prospectively recorded the development of severe episodes of bacterial infection. ASCA and anti-OMP Plus™ antibodies were present in 38.5% and 62.6% of patients with cirrhosis and in 16% and 20% of controls, respectively (p<0.001). Occurrence of these antibodies was more frequent in cases of advanced cirrhosis (according to Child-Pugh and MELD score; p<0.001) or in the presence of ascites (p<0.001). During the median follow-up of 425 days, 81 patients (28.3%) presented with severe bacterial infections. Anti-microbial antibody titers (p = 0.003), as well as multiple seroreactivity (p = 0.036), was associated with infectious events. In logistic regression analysis, the presence of ascites (OR: 1.62, 95%CI: 1.16-2.25), co-morbidities (OR: 2.22, 95%CI: 1.27-3.86), and ASCA positivity (OR: 1.59, 95%CI: 1.07-2.36) were independent risk factors for severe infections. A shorter time period until the first infection was associated with the presence of ASCA (p = 0.03) and multiple seropositivity (p = 0.037) by Kaplan-Meier analysis, and with Child-Pugh stage (p = 0.018, OR: 1.85) and co-morbidities (p<0.001, OR: 2.02) by Cox-regression analysis. The present study suggests that systemic reactivity to microbial components reflects compromised mucosal immunity in patients with liver cirrhosis, further supporting the possible role of bacterial translocation in the formation of anti-microbial antibodies.

Functional differences and association with inflammatory disorders were found relating to three major haptoglobin (Hp) phenotypes. Our aim was to investigate Hp polymorphisms in Hungarian patients with Crohn's disease (CD). Four hundred sixty-eight CD patients and 384 healthy controls were examined. Hp phenotypes were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting of the sera. The frequency of the Hp(1) allele was significantly higher in CD (0.395; OR, 1.24; 95% CI, 1.02-1.52; P=0.03) compared to controls (0.345). In CD, Hp phenotype was associated with disease behavior (OR [Hp(2-1) vs other], 2.06; 95% CI, 1.29-3.28 for inflammatory behavior). Furthermore, an increased frequency of primary sclerosing cholangitis was observed in the Hp 2-2 compared to the Hp 1-1 phenotype (6.5% vs. 0.0%; P=0.039). We conclude that the Hp polymorphism is associated with CD, inflammatory disease behavior, and primary sclerosing cholangitis in Hungarian patients. Further studies are required to evaluate the significance of Hp polymorphisms in other populations from geographically diverse regions.

Antibodies to Saccharomyces cerevisiae (S. cerevisiae) (ASCA) and porin protein-C of Escherichia coli (anti-OmpC) are associated with disease phenotype and may be of diagnostic importance in inflammatory bowel diseases (IBD). Our aim was to determine whether a panel of new antibodies against bacterial proteins and carbohydrates could help differentiate among the various forms of IBD, and whether they were associated with particular clinical manifestations in a Hungarian cohort of IBD patients. Six hundred fifty-two well-characterized, unrelated, consecutive IBD patients (CD [Crohn's disease] 557, men/women 262/295, duration 8.1 +/- 11.3 yr; ulcerative colitis [UC] 95, men/women 44/51, duration 8.9 +/- 9.8 yr) and 100 healthy and 48 non-IBD gastrointestinal (GI) controls were investigated. Sera were assayed for anti-OmpC and antibodies against a mannan epitope of S. cerevisiae (gASCA), laminaribioside (ALCA), chitobioside (ACCA), and mannobioside (AMCA). TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined by reviewing the patients' medical charts. Sixty-six percent of the CD patients had at least one of the investigated antibodies. Among glycan antibodies, gASCA or the combination of gASCA and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA) was most accurate for differentiating between CD and UC. ASCA and gASCA assays performed similarly. Increasing amount and level of antibody responses toward gASCA, ALCA, ACCA, AMCA, and OmpC were associated with more complicated disease behavior (P < 0.0001) and need for surgery in CD (P= 0.023). A serological dosage effect was also observed. gASCA and AMCA antibodies were associated with NOD2/CARD15, in addition to a gene-dosage effect. No serotype-phenotype associations were found in UC. Antibody response to this new panel of serological markers was associated with complicated disease phenotype, NOD2/CARD15 genotype, and a need for surgery in this eastern European IBD cohort.

BackgroundAntibodies directed against Saccharomyces cerevisiae (ASCA), perinuclear components of neutrophils (pANCA), and porin protein C of Escherichia coli (anti-OmpC) are reported to be associated with disease phenotype and may be of diagnostic importance in inflammatory bowel disease (IBD). Since limited data are available from Eastern Europe, we assessed the above antibodies in Hungarian IBD patients.MethodsIn all, 653 well-characterized, unrelated consecutive IBD patients (Crohn's disease [CD]: 558, m/f: 263/295, duration: 8.1 ± 10.7 years; ulcerative colitis [UC]: 95, m/f: 44/51, duration: 8.9 ± 9.8 years) and 100 healthy subjects were investigated. Sera were assayed for anti-Omp and ASCA by enzyme-linked immunosorbent assay (ELISA) and ANCA by indirect immunofluorescence assay (IIF). TLR4 and NOD2/CARD15 variants were tested by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). Detailed clinical phenotypes were determined by reviewing the medical charts.ResultsAnti-Omp, ASCA, and atypical pANCA antibodies were present in 31.2%, 59.3%, and 13.8% of CD, 24.2%, 13.7%, and 48.5% of UC patients, and in 20%, 16%, and 5.6% of controls, respectively. ASCA and anti-Omp positivity were associated with increased risk for CD (odds ratio [OR]ASCA = 7.65, 95% confidence interval [CI]: 4.37–13.4; OROmp = 1.81, 95% CI: 1.08–3.05). In a logistic regression analysis, anti-Omp and ASCA were independently associated with ileal and noninflammatory disease, but not with a risk for surgery or response to steroids or infliximab. A serology dosage effect was also observed. ASCA and anti-Omp antibodies were associated with NOD2/CARD15, in addition to a gene dosage effect. No associations were found in UC.ConclusionsSerological markers were useful in the differentiation between CD and UC in an Eastern European IBD cohort. Reactivity to microbial components was associated with disease phenotype and NOD2/CARD15 genotype, further supporting the role of altered microbial sensing in the pathogenesis of CD.

Background: Haptoglobin (Hp) α-chain alleles 1 and 2 account for 3 phenotypes that may influence the course of inflammatory diseases via biologically important differences in their antioxidant, scavenging, and immunomodulatory properties. Hp1-1 genotype results in the production of small dimeric, Hp2-1 linear, and Hp2-2 cyclic polymeric haptoglobin molecules. We investigated the haptoglobin polymorphism in patients with celiac disease and its possible association to the presenting symptoms. Methods: We studied 712 unrelated, biopsy-proven Hungarian celiac patients (357 children, 355 adults; severe malabsorption 32.9%, minor gastrointestinal symptoms 22.8%, iron deficiency anemia 9.4%, dermatitis herpetiformis 15.6%, silent disease 7.2%, other 12.1%) and 384 healthy subjects. We determined haptoglobin phenotypes by gel electrophoresis and assigned corresponding genotypes. Results: Hp2-1 was associated with a significant risk for celiac disease (P = 0.0006, odds ratio [OR] 1.54, 95% CI 1.20–1.98; prevalence 56.9% in patients vs 46.1% in controls). It was also overrepresented among patients with mild symptoms (69.2%) or silent disease (72.5%). Hp2-2 was less frequent in patients than in controls (P = 0.0023), but patients having this phenotype were at an increased risk for severe malabsorption (OR 2.21, 95% CI 1.60–3.07) and accounted for 45.3% of all malabsorption cases. Celiac and dermatitis herpetiformis patients showed similar haptoglobin phenotype distributions. Conclusions: The haptoglobin polymorphism is associated with susceptibility to celiac disease and its clinical presentations. The predominant genotype in the celiac population was Hp2-1, but Hp2-2 predisposed to a more severe clinical course. The phenotype-dependent effect of haptoglobin may result from the molecule’s structural and functional properties.

The oxytocin system has a crucial role in human sociality; several results prove that polymorphisms of the oxytocin receptor gene are related to complex social behaviors in humans. Dogs' parallel evolution with humans and their adaptation to the human environment has made them a useful species to model human social interactions. Previous research indicates that dogs are eligible models for behavioral genetic research, as well. Based on these previous findings, our research investigated associations between human directed social behaviors and two newly described (-212AG, 19131AG) and one known (rs8679684) single nucleotide polymorphisms (SNPs) in the regulatory regions (5' and 3' UTR) of the oxytocin receptor gene in German Shepherd (N = 104) and Border Collie (N = 103) dogs. Dogs' behavior traits have been estimated in a newly developed test series consisting of five episodes: Greeting by a stranger, Separation from the owner, Problem solving, Threatening approach, Hiding of the owner. Buccal samples were collected and DNA was isolated using standard protocols. SNPs in the 3' and 5' UTR regions were analyzed by polymerase chain reaction based techniques followed by subsequent electrophoresis analysis. The gene-behavior association analysis suggests that oxytocin receptor gene polymorphisms have an impact in both breeds on (i) proximity seeking towards an unfamiliar person, as well as their owner, and on (ii) how friendly dogs behave towards strangers, although the mediating molecular regulatory mechanisms are yet unknown. Based on these results, we conclude that similarly to humans, the social behavior of dogs towards humans is influenced by the oxytocin system.

Sporulation is the most widespread means of reproduction and dispersal in fungi. In the Basidiomycota, sexual spores are produced on specialised cells known as basidia, from which they are discharged forcibly by a powered process called ballistospory, the highest known acceleration in nature. However, the genetics of sporulation, in particular postmeiotic events related to spore morphogenesis and ballistospory, remain poorly known. Here, we explore the genetics of these processes, based on a new, highly conserved transcription factor, Sporulation-Related Regulator 1 (SRR1), and its putative downstream regulatory network. Reverse genetics of Srr1 in the model mushroom Coprinopsis cinerea and commercially produced oyster mushroom indicated a conserved role of Srr1 in sporulation across Agaricomycetes. RNA-Seq analysis and motif-based inference of a hypothetical SRR1 gene regulatory network allowed delimiting putative targets regulated by SRR1 in a direct and indirect manner. Using this network and comparative genomics, we identified genes associated with ballistospory, including a putative SRR1-target chitinase, which was found to be required for normal spore production and morphology. Overall, our study offers new insights into the genetic mechanisms governing postmeiotic spore morphogenesis and ballistospory in the Agaricomycetes.

The oxytocin system has a crucial role in human sociality; several results prove that polymorphisms of the oxytocin receptor gene are related to complex social behaviors in humans. Dogs' parallel evolution with humans and their adaptation to the human environment has made them a useful species to model human social interactions. Previous research indicates that dogs are eligible models for behavioral genetic research, as well. Based on these previous findings, our research investigated associations between human directed social behaviors and two newly described (-212AG, 19131AG) and one known (rs8679684) single nucleotide polymorphisms (SNPs) in the regulatory regions (5' and 3' UTR) of the oxytocin receptor gene in German Shepherd (N = 104) and Border Collie (N = 103) dogs. Dogs' behavior traits have been estimated in a newly developed test series consisting of five episodes: Greeting by a stranger, Separation from the owner, Problem solving, Threatening approach, Hiding of the owner. Buccal samples were collected and DNA was isolated using standard protocols. SNPs in the 3' and 5' UTR regions were analyzed by polymerase chain reaction based techniques followed by subsequent electrophoresis analysis. The gene-behavior association analysis suggests that oxytocin receptor gene polymorphisms have an impact in both breeds on (i) proximity seeking towards an unfamiliar person, as well as their owner, and on (ii) how friendly dogs behave towards strangers, although the mediating molecular regulatory mechanisms are yet unknown. Based on these results, we conclude that similarly to humans, the social behavior of dogs towards humans is influenced by the oxytocin system.