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Patients with gastrointestinal bleeding (GIB) exhibit varying tolerances to acute blood loss. We aimed to investigate the effect of relative Hb decrease (ΔHb%) on GIB outcomes. Participants enrolled in the Hungarian GIB Registry between 2019 and 2022 were analyzed. The primary outcome, defined as a composite endpoint, included in-hospital bleeding-related mortality and the need for urgent intervention. Four groups were created based on the lowest Hb measured during hospitalization (nadirHb), along with four subgroups categorized by ΔHb%. Regardless of the nadirHb, participants with higher ΔHb% had a higher probability of reaching the composite endpoint. A 30–40% ΔHb% decrease to a nadirHb of 80–90 g/L resulted in a similar likelihood of reaching the primary endpoint as a 0–10% ΔHb% to 70–80 g/L or 60–70 g/L, respectively (10% vs. 12%, p  = 1.00; 10% vs. 10%, p  = 1.00). Our results showed that a higher Hb decrease in GIB is associated with an increased untoward outcome rate even when the lowest hemoglobin exceeds the recommended transfusion thresholds. New randomized controlled trials investigating transfusion thresholds should consider ΔHb% as a potential key variable and risk factor.

IntroductionOnly a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate.Materials and methodsWe scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case–Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase.ResultsThe C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10−8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1.ConclusionWe identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Chronic pancreatitis (CP) is characterised by irreversible damage to the pancreas causing endocrine and exocrine dysfunction which results in decreased quality of life and reduced life expectancy.1

Introduction Non‐alcoholic fatty liver disease (NAFLD) is a proven risk factor for acute pancreatitis (AP). However, NAFLD has recently been redefined as metabolic‐associated fatty liver disease (MAFLD). In this post hoc analysis, we quantified the effect of MAFLD on the outcomes of AP. Methods We identified our patients from the multicentric, prospective International Acute Pancreatitis Registry of the Hungarian Pancreatic Study Group. Next, we compared AP patients with and without MAFLD and the individual components of MAFLD regarding in‐hospital mortality and AP severity based on the revised Atlanta classification. Lastly, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) using multivariate logistic regression analysis. Results MAFLD had a high prevalence in AP, 39% (801/2053). MAFLD increased the odds of moderate‐to‐severe AP (OR = 1.43, CI: 1.09–1.89). However, the odds of in‐hospital mortality (OR = 0.89, CI: 0.42–1.89) and severe AP (OR = 1.70, CI: 0.97–3.01) were not higher in the MAFLD group. Out of the three diagnostic criteria of MAFLD, the highest odds of severe AP was in the group based on metabolic risk abnormalities (OR = 2.68, CI: 1.39–5.09). In addition, the presence of one, two, and three diagnostic criteria dose‐dependently increased the odds of moderate‐to‐severe AP (OR = 1.23, CI: 0.88–1.70, OR = 1.38, CI: 0.93–2.04, and OR = 3.04, CI: 1.63–5.70, respectively) and severe AP (OR = 1.13, CI: 0.54–2.27, OR = 2.08, CI: 0.97–4.35, and OR = 4.76, CI: 1.50–15.4, respectively). Furthermore, in patients with alcohol abuse and aged ≥60 years, the effect of MAFLD became insignificant. Conclusions MAFLD is associated with AP severity, which varies based on the components of its diagnostic criteria. Furthermore, MAFLD shows a dose‐dependent effect on the outcomes of AP.

There is a noteworthy overlap between the clinical picture of biliary acute pancreatitis (AP) and the 2018 Tokyo guidelines currently used for the diagnosis of cholangitis (AC) and cholecystitis (CC). This can lead to significant antibiotic and endoscopic retrograde cholangiopancreatography (ERCP) overuse. We aimed to assess the on-admission prevalence of AC/CC according to the 2018 Tokyo guidelines (TG18) in a cohort of biliary AP patients, and its association with antibiotic use, ERCP and clinically relevant endpoints. We conducted a secondary analysis of the Hungarian Pancreatic Study Group's prospective multicenter registry of 2195 AP cases. We grouped and compared biliary cases (n = 944) based on the on-admission fulfillment of definite AC/CC according to TG18. Aside from antibiotic use, we evaluated mortality, AC/CC/AP severity, ERCP performance and length of hospitalization. We also conducted a literature review discussing each criteria of the TG18 in the context of AP. 27.8% of biliary AP cases fulfilled TG18 for both AC and CC, 22.5% for CC only and 20.8% for AC only. Antibiotic use was high (77.4%). About 2/3 of the AC/CC cases were mild, around 10% severe. Mortality was below 1% in mild and moderate AC/CC patients, but considerably higher in severe cases (12.8% and 21.2% in AC and CC). ERCP was performed in 89.3% of AC cases, common bile duct stones were found in 41.1%. Around 70% of biliary AP patients fulfilled the TG18 for AC/CC, associated with a high rate of antibiotic use. Mortality in presumed mild or moderate AC/CC is low. Each of the laboratory and clinical criteria are commonly fulfilled in biliary AP, single imaging findings are also unspecific-AP specific diagnostic criteria are needed, as the prevalence of AC/CC are likely greatly overestimated. Randomized trials testing antibiotic use are also warranted.

Background The genomes of present-day non-Africans are composed of 1–3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50–60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. Results The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19–1.54, P = 3.59 × 10 –6 ), with a P-value close to a threshold that takes into account multiple testing. Conclusions Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Metabolic inactivation of progesterone within uterine myocytes by 20α-hydroxysteroid dehydrogenase (20α-HSD) has been postulated as a mechanism contributing to functional progesterone withdrawal at term. In humans, 20α-HSD is encoded by the gene AKR1C1 . Myometrial AKR1C1 mRNA abundance has been reported to increase significantly during labor at term. In spontaneous preterm labor, however, we previously found no increase in AKR1C1 mRNA level in the myometrium except for preterm labor associated with clinical chorioamnionitis. This suggests that increased 20α-HSD activity is a mechanism through which inflammation drives progesterone withdrawal in preterm labor. In this study, we have determined the effects of various treatments of therapeutic relevance on AKR1C1 expression in pregnant human myometrium in an ex vivo culture system. AKR1C1 expression increased spontaneously during 48 h culture ( p  < 0.0001), consistent with the myometrium transitioning to a labor-like phenotype ex vivo , as reported previously. Serum supplementation, prostaglandin F 2α , phorbol myristate acetate, and mechanical stretch had no effect on the culture-induced increase, whereas progesterone ( p  = 0.0058) and cAMP ( p  = 0.0202) further upregulated AKR1C1 expression. In contrast, culture-induced upregulation of AKR1C1 expression was dose-dependently repressed by three histone/protein deacetylase inhibitors: trichostatin A at 5 ( p  = 0.0172) and 25 µM ( p  = 0.0115); suberoylanilide hydroxamic acid at 0.5 ( p  = 0.0070), 1 ( p  = 0.0045), 2.5 ( p  = 0.0181), 5 ( p  = 0.0066) and 25 µM ( p  = 0.0014); and suberoyl bis-hydroxamic acid at 5 ( p  = 0.0480) and 25 µM ( p  = 0.0238). We propose the inhibition of histone/protein deacetylation helps to maintain the anti-inflammatory, pro-quiescence signaling of progesterone in pregnant human myometrium by blocking its metabolic inactivation. Histone deacetylase inhibitors may represent a class of agents that preserve or restore the progesterone sensitivity of the pregnant uterus.

Sulfuric acid has been shown to be a key driver for new particle formation and subsequent growth in various environments, mainly due to its low volatility. However, direct measurements of gas-phase sulfuric acid are oftentimes not available, and the current sulfuric acid proxies cannot predict, for example, its nighttime concentrations or result in significant discrepancies with measured values. Here, we define the sources and sinks of sulfuric acid in different environments and derive a new physical proxy for sulfuric acid to be utilized in locations and during periods when it is not measured. We used H2SO4 measurements from four different locations: Hyytiälä, Finland; Agia Marina, Cyprus; Budapest, Hungary; and Beijing, China, representing semi-pristine boreal forest, rural environment in the Mediterranean area, urban environment and heavily polluted megacity, respectively. The new proxy takes into account the formation of sulfuric acid from SO2 via OH oxidation and other oxidation pathways, specifically via stabilized Criegee intermediates. The sulfuric acid sinks included in the proxy are its condensation sink (CS) and atmospheric clustering starting from H2SO4 dimer formation. Indeed, we found that the observed sulfuric acid concentration can be explained by the proposed sources and sinks with similar coefficients in the four contrasting environments where we have tested it. Thus, the new proxy is a more flexible and an important improvement over previous proxies. Following the recommendations in this paper, a proxy for a specific location can be derived.

The interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.

IntroductionDual endoscopic therapy has been considered the standard of care for endoscopic management of GI bleeding. We aimed to look at the outcomes of Hemospray as a monotherapy treatment for GI bleeds.MethodsData was collected on patients with GI bleeds treated with Hemospray monotherapy in 18 centres. Haemostasis was defined as cessation of bleeding within 5 minutes of hemospray application.Results62 patients with peptic ulcer bleeds were treated. There was an immediate haemostasis of 90% (56/62), re-bleed rate of 16% (7/44) (Table 1). 69% were Forrest 1a/1b ulcers.72 patients with malignancy related bleeds. There was a haemostasis rate of 100% and a re-bleed rate of 18% (11/63). There was a haemostasis rate of 100% with post endoscopic therapy bleeds. 48% were post endoscopic mucosal resection.22 patients with lower GI bleeds were treated. 36% secondary to colonic tumours. There was a haemostasis rate of 96% (21/22) and re-bleed of 26% (5/19). A 100% haemostasis was achieved in 5 patients treated for gastric angiodysplasia with one re-bleed.Abstract PTU-24 Table 1Outcomes of treatment with Hemospray monotherapy Peptic ulcer(N =62) Malignancy (n = 72) Post endoscopic therapy(N=23) Lower GI bleeds (N = 22) Angiodysplasia(N =5) Inflammation(N =22) Variceal (N =7) Haemostasis 56/62 (90%) 72/72 (100%) 23/23 (100%) 21/22 (96%) 5/5(100%) 21/22(96%) 4/7 (57%) Rockall 7(IQR, 7-8) 8(IQR, 7-9) 6(IQR, 5-6) n/a 7(IQR, 6-7) 7(IQR, 6-8) 8(IQR, 7-8) Re-bleed 7/44 (16%) 11/63(18%) 1/20 (5%) 5/19 (26%) 1/5(20%) 4/19(21%) 1/3 (33%) 7-day mortality 6/50 (12%) 5/63(8%) 1/20 (5%) 2/20 (10%) 0 5/20(25%) 3/6 (50%) 30-day mortality 15/50 (30%) 17/63 (27%) 1/20 (5%) 4/20 (20%) 0 10/20(50%) 3/6 (50%) ConclusionsResults show high haemostasis and comparable re-bleed rates with Hemospray monotherapy treatment. It may play a potential role in actively bleeding peptic ulcers in difficult anatomical positions to help bridge towards definitive therapy. These data may represent the evolution of new treatment paradigms as experience with haemostatic powders increases.