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Background: Development of pancreatic necroses or pseudocysts are typical complications of pancreatitis and may require endoscopic drainage therapy using metal or plastic stents. Microbial infection of these lesions poses a major challenge. So far, the composition and significance of the microbial colonization on drainage stents are largely unknown although it may impact outcomes during endoscopic drainage therapy., Methods: A total of 26 stents used for drainage of pancreatic lesions were retrieved and the stent microbiome was determined by 16S rRNA gene sequencing. Additional analysis included comparison of the stent microbiome to the intracavitary necrosis microbiome as well as scanning electron microscopy (SEM) and micro-computed tomography (μCT) imaging of selected metal or plastic stents., Results: The stent microbiome comprises a large proportion of opportunistic enteric pathogens such as Enterococcus (14.4%) or Escherichia (6.1%) as well as oral bacteria like Streptococcus (13.1%). Increased levels of opportunistic enteric pathogens were associated with a prolonged hospital stay ( r  = 0.77, p  = 3e-06) and the occurrence of adverse events during drainage therapy ( p  = 0.011). Higher levels of oral bacteria were associated ( r  = -0.62, p  = 8e-04) with shorter durations of inpatient treatment. SEM and μCT investigations revealed complex biofilm networks on the stent surface., Conclusion: The composition of the stent microbiome is associated with prolonged hospital stays and adverse events during endoscopic drainage therapy, highlighting the need for effective infection control to improve patient outcomes. In addition to systemic antibiotic therapy, antimicrobial stent coatings could be a conceivable option to influence the stent microbiome and possibly enhance control of the necrotic microflora., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Frost, Khaimov, Senz, Weiss, Klußmann-Fricke, Rühlemann, Bang, Franke, Pickartz, Budde, Aghdassi, Siewert, Weiss, Grabow, Lerch and Sendler.)

Acetaminophen (APAP) overdosing is a major cause of acute liver failure worldwide and an established model for drug-induced acute liver injury (ALI). While studying gene expression during murine APAP-induced ALI by 3'mRNA sequencing (massive analysis of cDNA ends, MACE), we observed splenic mRNA accumulation encoding for the neutrophil serine proteases cathepsin G, neutrophil elastase, and proteinase-3 - all are hierarchically activated by cathepsin C (CtsC). This, along with increased serum levels of these proteases in diseased mice, concurs with the established phenomenon of myeloid cell mobilization during APAP intoxication. Objective: In order to functionally characterize CtsC in murine APAP-induced ALI, effects of its genetic or pharmacological inhibition were investigated. Methods and Results: We report on substantially reduced APAP toxicity in CtsC deficient mice. Alleviation of disease was likewise observed by treating mice with the CtsC inhibitor AZD7986, both in short-term prophylactic and therapeutic protocols. This latter observation indicates a mode of action beyond inhibition of granule-associated serine proteases. Protection in CtsC knockout or AZD7986-treated wildtype mice was unrelated to APAP metabolization but, as revealed by MACE, realtime PCR, or ELISA, associated with impaired expression of inflammatory genes with proven pathogenic roles in ALI. Genes consistently downregulated in protocols tested herein included cxcl2 , mmp9 , and angpt2 . Moreover, ptpn22 , a positive regulator of the toll-like receptor/interferon-axis, was reduced by targeting CtsC. Conclusions: This work suggests CtsC as promising therapeutic target for the treatment of ALI, among others paradigmatic APAP-induced ALI. Being also currently evaluated in phase III clinical trials for bronchiectasis, successful application of AZD7986 in experimental APAP intoxication emphasizes the translational potential of this latter therapeutic approach., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The co-localization of the lysosomal protease cathepsin B (CTSB) and the digestive zymogen trypsinogen is a prerequisite for the initiation of acute pancreatitis. However, the exact molecular mechanisms of co-localization are not fully understood. In this study, we investigated the role of lysosomes in the onset of acute pancreatitis by using two different experimental approaches. Using an acinar cell-specific genetic deletion of the ras-related protein Rab7, important for intracellular vesicle trafficking and fusion, we analyzed the subcellular distribution of lysosomal enzymes and the severity of pancreatitis in vivo and ex vivo. Lysosomal permeabilization was performed by the lysosomotropic agent Glycyl-L-phenylalanine 2-naphthylamide (GPN). Acinar cell-specific deletion of Rab7 increased endogenous CTSB activity and despite the lack of re-distribution of CTSB from lysosomes to the secretory vesicles, the activation of CTSB localized in the zymogen compartment still took place leading to trypsinogen activation and pancreatic injury. Disease severity was comparable to controls during the early phase but more severe at later time points. Similarly, GPN did not prevent CTSB activation inside the secretory compartment upon caerulein stimulation, while lysosomal CTSB shifted to the cytosol. Intracellular trypsinogen activation was maintained leading to acute pancreatitis similar to controls. Our results indicate that initiation of acute pancreatitis seems to be independent of the presence of lysosomes and that fusion of lysosomes and zymogen granules is dispensable for the disease onset. Intact lysosomes rather appear to have protective effects at later disease stages., (© 2024. The Author(s).)

Malnutrition is a common complication of chronic pancreatitis (CP) and liver cirrhosis (LC). Inadequate food intake is considered a relevant driver of malnutrition in both entities. However, the contribution of habitual diet to impaired nutritional status is unclear. In a prospective, multicenter cross-sectional study, we recruited patients with confirmed CP or LC and healthy volunteers as a control group. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition criteria. We comprehensively investigated habitual dietary intake on nutrient, food group, and dietary pattern level applying two validated food frequency questionnaires. We included 144 patients (CP: n = 66; LC: n = 78) and 94 control subjects. Malnutrition was prevalent in 64% and 62% of patients with CP or LC, respectively. In both CP and LC, despite slightly altered food group consumption in malnourished and non-malnourished patients there were no differences in energy or nutrient intake as well as dietary quality. Compared to controls patients showed distinct dietary food group habits. Patients consumed less alcohol but also lower quantities of fruits and vegetables as well as whole grain products (p < 0.001, respectively). Nevertheless, overall dietary quality was comparable between patients and healthy controls. Nutritional status in CP and LC patients is rather related to disease than habitual dietary intake supporting the relevance of other etiologic factors for malnutrition such as malassimilation or chronic inflammation. Despite distinct disease-related differences, overall dietary quality in patients with CP or LC was comparable to healthy subjects, which suggests susceptibility to dietary counselling and the benefits of nutrition therapy in these entities., (© 2024. The Author(s).)

Cathepsin C (CatC, syn. Dipeptidyl peptidase I) is a lysosomal cysteine proteinase expressed in several tissues including inflammatory cells. This enzyme is important for maintaining multiple cellular functions and for processing immune cell-derived proteases. While mutations in the CatC gene were reported in Papillon-Lefèvre syndrome, a rare autosomal recessive disorder featuring hyperkeratosis and periodontitis, evidence from clinical and preclinical studies points toward pro-inflammatory effects of CatC in various disease processes that are mainly mediated by the activation of neutrophil serine proteinases. Moreover, tumor-promoting effects were ascribed to CatC. The aim of this review is to highlight current knowledge of the CatC as a potential therapeutic target in inflammatory disorders., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aim: In short bowel syndrome, insufficient absorptive capacity of the remnant bowel may lead to metabolic and nutritional consequences including electrolyte disturbances, severe diarrhea and malnutrition. While intestinal failure requires parenteral nutrition, short bowel patients with intestinal insufficiency (SB/II) have achieved oral autonomy. The aim of this exploratory study was to assess the nutritional, muscular and functional status of orally compensated SB/II patients., Methods: 28 orally compensated SB/II patients with a mean of 46 months after termination of parenteral nutrition and 56 age- and sex-matched healthy controls (HC) were compared regarding anthropometric parameters, body composition using bioelectrical impedance analysis, handgrip strength and gait speed, blood parameters as well as nutritional intake and physical activity using validated questionnaires. Malnutrition and sarcopenia were diagnosed according to the criteria of the GLIM or EWGSOP2., Results: SB/II patients had lower body mass index (BMI) and anthropometric parameters than HC but were within the normal weight range. The GLIM algorithm operationally diagnosed malnutrition in 39% (n = 11) of SB/II patients. Reduced skeletal muscle mass index and phase angle were rarely accompanied by a reduction of handgrip strength below cut-off values and the subsequent diagnosis of sarcopenia in SB/II patients (15%, n = 4). Compared to 11% of HC, 37% of SB/II patients had low physical activity level. Female SB/II patients had higher caloric and macronutrient intake. Caloric intake negatively correlated with body weight indicating compensatory hyperphagia in patients with lower body weight. Some of the SB/II patients showed signs of dehydration., Conclusions: Orally compensated SB/II patients are thinner than HC but have mostly normal BMI. Malnutrition is frequently diagnosed but may be overestimated due to the underlying malabsorption and its interplay with hyperphagia. Muscle mass is often reduced but is rarely accompanied by functional impairment leading to sarcopenia diagnosis. Thus, SB/II patients long term after termination of parenteral support may be malnourished but usually do not develop sarcopenia., Competing Interests: Conflict of interest The authors have declared any potential conflicts of interest according to the rules of the International Committee of Medical Journal Editors (ICMJE). There are no conflicts of interest competing with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the T reg /Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP., Design: AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (T reg ) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed T reg activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing., Results: The prophylactic T reg- depletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8 + /γδTCR + IELs. T reg depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa Escherichia/Shigella which associates with severe disease and infected necrosis was diminished in T reg depleted animals., Conclusion: T regs play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, T reg -activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting T regs in AP may help to ameliorate the disease course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Disease-related malnutrition (MN) is common in patients with liver cirrhosis (LC), short bowel syndrome (SBS), and chronic pancreatitis (CP). Different MN risk screening tools and diagnostic criteria of the European Society for Clinical Nutrition and Metabolism (ESPEN) and Global Leadership Initiative on Malnutrition (GLIM) algorithms were analyzed for their diagnostic accuracy and role as specific drivers to diagnose MN in patients with LC, SBS, and CP., Methods: A total of 187 patients with LC, SBS, and CP, as well as control patients were prospectively recruited in a multicenter cross-sectional study. MN risk was screened using Nutritional Risk Screening 2002 (NRS-2002), the Malnutrition Universal Screening Tool (MUST), and the Royal Free Hospital Nutritional Prioritizing Tool (RFH-NPT), and diagnosed using the ESPEN, GLIM, and GLIM CRP+ (GLIM incorporating C-reactive protein [CRP] >5 mg/L) algorithms. For each of the individual diagnostic criteria, relative frequency, sensitivity, specificity, as well as positive and negative predictive values were calculated., Results: NRS-2002 was only sensitive in conjunction with ESPEN, while MUST was sensitive additionally with the GLIM algorithm. RFH-NPT worked the best for LC. GLIM and GLIM CRP+ diagnosed MN more frequently than the ESPEN algorithm. Diagnostic criteria were detected at remarkably different relative frequencies starting with reduced food intake/malabsorption and chronic disease/inflammation, followed by weight loss, reduced fat-free mass index, low body mass index, and body mass index <18.5 kg/m². Relative frequencies differed between LC, SBS, and CP. Weight loss in LC and CP and reduced fat-free mass index and food intake in SBS had good diagnostic accuracy, suggesting that these criteria act as specific drivers for MN., Conclusions: RFH-NPT and MUST performed better in conjunction with the GLIM algorithm than NRS-2002. MN was diagnosed more frequently by GLIM than the ESPEN algorithm in LC, SBS, and CP. Individual criteria acted as specific drivers in MN in chronic gastrointestinal diseases., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Hereditary chronic pancreatitis is a rare condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of pancreatic functions. However, the subjective perspective of individuals affected by hereditary chronic pancreatitis has been little studied. This qualitative study investigates the experience of hereditary chronic pancreatitis patients and their relatives because the awareness of the needs of those affected is an essential component of a patient-centered management of chronic conditions., Methods: Semi-structured qualitative interviews were conducted with hereditary chronic pancreatitis patients and their relatives. Data were analysed using qualitative content analysis. The concepts of 'biographical contingency,' 'biographical disruption' and the 'shifting perspectives model' served as theoretical frameworks., Results: A total of 24 participants (17 patients, 7 relatives) were interviewed individually. Four main themes were identified: (1) The unpredictable clinical course of hereditary chronic pancreatitis; (2) hereditary chronic pancreatitis as a devastating experience; (3) hereditary chronic pancreatitis as part of a normal life; and (4) being reduced to hereditary chronic pancreatitis., Discussion: The 'shifting perspectives model' of chronic illness covers the four dimensions adequately and can serve as a theoretical model to explain hereditary chronic pancreatitis patients' experience. A better understanding of the patients and their families' experience and the shifting character of hereditary chronic pancreatitis can help healthcare professionals to tailor the care to meet the needs of those affected.

Acute pancreatitis (AP) is a major, globally increasing gastrointestinal disease and a biliary origin is the most common cause. However, the effects of bile acids (BAs), given systemically, on the pancreas and on disease severity remains elusive. In this study, we have investigated the roles of different circulating BAs in animal models for AP to elucidate their impact on disease severity and the underlying pathomechanisms. BAs were incubated on isolated acini and AP was induced through repetitive injections of caerulein or L-arginine; pancreatic duct ligation (PDL); or combined biliopancreatic duct ligation (BPDL). Disease severity was assessed using biochemical and histological parameters. Serum cholecystokinin (CCK) concentrations were determined via enzyme immunoassay. The binding of the CCK1 receptor was measured using fluorescence-labeled CCK. In isolated acini, hydrophobic BAs mitigated the damaging effects of CCK. The same BAs further enhanced pancreatitis in L-arginine- and PDL-based pancreatitis, whereas they ameliorated pancreatic damage in the caerulein and BPDL models. Mechanistically, the binding affinity of the CCK1 receptor was significantly reduced by hydrophobic BAs. The hydrophobicity of BAs and the involvement of CCK seem to be relevant in the course of AP. Systemic BAs may affect the severity of AP by interfering with the CCK1 receptor.

Objective: Acute pancreatitis (AP) is an inflammatory disorder, the severe form of which is burdened with multi-organ dysfunction and high mortality. The pathogenesis of life -threatening organ complications, such as respiratory and renal failure, is unknown., Design: Organ dysfunction was investigated in a mouse model of AP. The influence of monocytes and neutrophils on multi organ dysfunction syndrome (MODS) was investigated in vivo by antibody depletion. Using real-time-fluorescence and deformability-cytometry (RT-DC) analysis we determined the mechanical properties of neutrophils and monocytes during AP. Furthermore, blood samples of pancreatitis patients were used to characterize severity-dependent chemokine profiles according to the revised Atlanta classification., Results: Similar to AP in humans, severe disease in the mouse model associates with organ dysfunction mainly of lung and kidney, which is triggered by a mobilisation of Ly6g - /CD11b + /Ly6c hi monocytes, but not of Ly6g + /CD11b + neutrophils. Monocyte depletion by anti-CCR2 antibody treatment ameliorated lung function (oxygen consumption) without interfering with the systemic immune response. RT-DC analysis of circulation monocytes showed a significant increase in cell size during SAP, but without a compensatory increase in elasticity. Patient chemokine profiles show a correlation of AP severity with monocyte attracting chemokines like MCP-1 or MIG and with leukocyte mobilisation., Conclusion: In AP, the physical properties of mobilized monocytes, especially their large size, result in an obstruction of the fine capillary systems of the lung and of the kidney glomeruli. A selective depletion of monocytes may represent a treatment strategy for pancreatitis as well as for other inflammation-related disorders., Competing Interests: OO is co-founder of Zellmechanik Dresden GmbH distributing the technology of real-time deformability cytometry. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wilden, Glaubitz, Otto, Biedenweg, Nauck, Mack, Ribback, Bröker, Rheinbaben, Lerch, Aghdassi, Weiss and Sendler.)

Pancreatic necroses are a major challenge in the treatment of patients with pancreatitis, causing high morbidity. When indicated, these lesions are usually drained endoscopically using plastic or metal stents. However, data on factors associated with the occurrence of failure or adverse events during stent therapy are scarce. We retrospectively analyzed all adverse events and their associated features which occurred in patients who underwent a first-time endoscopic drainage of pancreatic necrosis from 2009 to 2019. During the observation period, a total of 89 eligible cases were identified. Adverse events occurred in 58.4% of the cases, of which 76.9% were minor (e.g., stent dislocation, residual lesions, or stent obstruction). However, these events triggered repeated interventions (63.5% vs. 0%, p < 0.001) and prolonged hospital stays (21.0 [11.8−63.0] vs. 14.0 [7.0−31.0], p = 0.003) compared to controls without any adverse event. Important factors associated with the occurrence of adverse events during endoscopic drainage therapy were positive necrosis cultures (6.1 [2.3−16.1], OR [95% CI], p < 0.001) and a larger diameter of the treated lesion (1.3 [1.1−1.5], p < 0.001). Superinfection of pancreatic necrosis is the most significant factor increasing the likelihood of adverse events during endoscopic drainage. Therefore, control of infection is crucial for successful drainage therapy, and future studies need to consider superinfection of pancreatic necrosis as a possible confounding factor when comparing different therapeutic modalities.

Objectives: To investigate the co-occurrence of 4 behavioral health risk factors (BHRFs), namely tobacco smoking, alcohol at-risk drinking, physical inactivity and unhealthy diet and their association with sick days prior to hospitalization in general hospital patients. Methods: Over 10 weeks (11/2020-04/2021), all 18-64-year-old patients admitted to internal medicine, general and trauma surgery, and otorhinolaryngology wards of a tertiary care hospital were systematically approached. Among 355 eligible patients, 278 (78.3%) participated, and 256 (72.1%) were analyzed. Three BHRF sum scores were determined, including current tobacco smoking, alcohol use, physical inactivity and 1 of 3 indicators of unhealthy diet. Associations between BHRF sum scores and sick days in the past 6 months were analyzed using multivariate zero-inflated negative binomial regressions. Results: Sixty-two percent reported multiple BHRFs (≥2). The BHRF sum score was related to the number of sick days if any ( p = 0.009) with insufficient vegetable and fruit intake as diet indicator. Conclusion: The majority of patients disclosed multiple BHRFs. These were associated with sick days prior to admission. The findings support the need to implement interventions targeting multiple BHRFs in general hospitals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Spielmann, Tiede, Krolo, Sadewasser, Aghdassi, Busch, Hinz, van der Linde, John and Freyer-Adam.)

Background: In acute pancreatitis, secondary infection of pancreatic necrosis is a complication that mostly necessitates interventional therapy. A reliable prediction of infected necrotizing pancreatitis would enable an early identification of patients at risk, which however, is not possible yet., Methods: This study aims to identify parameters that are useful for the prediction of infected necrosis and to develop a prediction model for early detection. We conducted a retrospective analysis from the hospital information and reimbursement data system and screened 705 patients hospitalized with diagnosis of acute pancreatitis who underwent contrast-enhanced computed tomography and additional diagnostic puncture or drainage of necrotic collections. Both clinical and laboratory parameters were analyzed for an association with a microbiologically confirmed infected pancreatic necrosis. A prediction model was developed using a logistic regression analysis with stepwise inclusion of significant variables. The model quality was tested by receiver operating characteristics analysis and compared to single parameters and APACHE II score., Results: We identified a total of 89 patients with necrotizing pancreatitis, diagnosed by computed tomography, who additionally received biopsy or drainage. Out of these, 59 individuals had an infected necrosis. Eleven parameters showed a significant association with an infection including C-reactive protein, albumin, creatinine, and alcoholic etiology, which were independent variables in a predictive model. This model showed an area under the curve of 0.819, a sensitivity of 0.692 (95%-CI [0.547-0.809]), and a specificity of 0.840 (95%-CI [0.631-0.947]), outperforming single laboratory markers and APACHE II score. Even in cases of missing values predictability was reliable., Conclusion: A model consisting of a few single blood parameters and etiology of pancreatitis might help for differentiation between infected and non-infected pancreatic necrosis and assist medical therapy in acute necrotizing pancreatitis., (© 2022. The Author(s).)

Background and study aims  Gastric cancer (GC) is one of the leading causes of malignancy-related death in Vietnam, with increasing incidence of non-cardia early gastric cancer (N-EGC). Data on accurate diagnosis of EGC and treatment by endoscopic submucosal dissection (ESD) in Vietnam are very sparse. The aim of this study was to describe the characteristics of N-EGC and evaluate the effectiveness and the safety of ESD in Central Vietnam. Patients and methods  We prospectively enrolled patients with N-EGC detected by magnified chromoendoscopy from December 2013 to August, 2018 in Central Vietnam. Selected cases of N-EGC received standardized ESD technique and have been following up carefully as in protocol. Results  Among 606 GC patients, 46 had N-GEC and underwent ESD. The depth of invasion was pT1a in 33 (71.7 %), pT1b1 in 10 (21.7 %), and pT1b2 in three cases (6.6 %). Mild chronic atrophic gastritis, most being C2 (63 %), and gastritis-like EGC that did not appear malignant was the predominant type. ESD achieved a 97.8 % en bloc resection rate; the mean procedure time was 76 ± 22 minutes (range 24-155), and mean endoscopic tumor size was 23 ± 5 mm (range 13-52) and ESD sample size was 28 ± 7 mm (range 16.5-60). Complications consisted of two patients with bleeding and one with a minor perforation, all of which were successfully managed by endoscopy. The longest and the mean follow-up times were 84 and 64 months, respectively, with no recurrence. Conclusions  A significant proportion patients with N-EGC have a background mucosa of mild chronic atrophic gastritis. Our results 7 years after starting ESD demonstrate early promising outcomes with the procedure., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3 + CD25 + Treg cells suppress the type-2 immune response by a repression of GATA3 + T helper cells (Th2), GATA3 + innate lymphoid cells type 2 (ILC2) and CD206 + M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue., (© 2022. The Author(s).)

Background/aims: Patients with chronic pancreatitis (CP) have an increased risk of malnutrition, a condition linked to reduced muscle mass and physical performance. We have investigated the risk factors, phenotypic presentation, and health implications associated with malnutrition in CP., Materials and Methods: In a multicenter cross-sectional study we recruited patients with confirmed CP and healthy volunteers as a control group. Malnutrition was diagnosed according to the criteria proposed by the Global Leadership Initiative on Malnutrition. We performed detailed examinations of body composition and physical function as well as testing of routine blood parameters and markers of inflammation., Results: We included 66 patients [mean (±SD) age: 56.0 (±14.5) years; 51 males] and an equal number of age- and sex-matched controls. Moderate malnutrition was diagnosed in 21% ( n = 14) and severe malnutrition in 42% ( n = 28) of patients. Besides weight loss malnourished patients showed lower fat and skeletal muscle mass compared to both non-malnourished subjects and healthy controls. Only in severe malnutrition, blood parameters reflected elevated inflammation and reduced muscle reserves. Handgrip strength in patients did not differ by nutritional status but there was a significant correlation (rho = 0.705, p < 0.001) with skeletal muscle mass. Although 20 patients (30%) had pathologically reduced skeletal muscle mass, only two individuals (3%) had sarcopenia with concomitantly reduced handgrip strength., Conclusion: Malnutrition is a frequent complication of CP characterized by loss of skeletal muscle mass. As this condition becomes evident only at an advanced stage, regular testing for altered body composition is recommended. Suitable biomarkers and the link between loss of muscle mass and physical function require further investigation., Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT04474743], identifier [NCT04474743]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wiese, Gärtner, von Essen, Doller, Frost, Tran, Weiss, Meyer, Valentini, Garbe, Metges, Bannert, Sautter, Ehlers, Jaster, Lamprecht, Steveling, Lerch and Aghdassi.)

Genetic testing is associated with many ethical challenges on the individual, organizational and macro level of health care systems. The provision of genetic testing for rare diseases in particular requires a full understanding of the complexity and multiplicity of related ethical aspects. This systematic review presents a detailed overview of ethical aspects relevant to genetic testing for rare diseases as discussed in the literature. The electronic databases Pubmed, Science Direct and Web of Science were searched, resulting in 55 relevant publications. From the latter, a total of 93 different ethical aspects were identified. These ethical aspects were structured into three main categories (process of testing, consequences of the test outcome and contextual challenges) and 20 subcategories highlighting the diversity and complexity of ethical aspects relevant to genetic testing for rare diseases. This review can serve as a starting point for the further in-depth investigation of particular ethical issues, the education of healthcare professionals regarding this matter and for informing international policy development on genetic testing for rare diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kruse, Mueller, Aghdassi, Lerch and Salloch.)

Abdominal imaging is an important component of the diagnostics of acute pancreatitis. In addition to the clinical features and the laboratory constellation, it serves to establish the diagnosis or the exclusion of other diseases and also the identification and assessment of the course of local complications and vascular changes that can arise during the course of acute pancreatitis. Due to the numerous imaging examination methods that are available, their combination options and the different examination times, there are diverse application options that have to be taken into account, such as the severity and duration of the disease, concomitant diseases and complications of acute pancreatitis. A rational use of imaging is an important prerequisite for high quality and at the same time cost-effective patient care. This review summarizes the current importance of imaging in acute pancreatitis, with particular reference to the updated S3 guidelines on acute pancreatitis., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: It is still controversial if increased hepatic fat independently contributes to cardiovascular risk. We aimed to assess the association between hepatic fat quantified by MRI and various subclinical vascular disease parameters., Design: We included two cross-sectional investigations embedded in two independent population-based studies (Study of Health in Pomerania (SHIP): n=1341; Cooperative Health Research in the Region of Augsburg (KORA): n=386). The participants underwent a whole-body MRI examination. Hepatic fat content was quantified by proton-density fat fraction (PDFF). Aortic diameters in both studies and carotid plaque-related parameters in KORA were measured with MRI. In SHIP, carotid intima-media thickness (cIMT) and plaque were assessed by ultrasound. We used (ordered) logistic or linear regression to assess associations between hepatic fat and subclinical vascular disease., Results: The prevalence of fatty liver disease (FLD) (PDFF >5.6%) was 35% in SHIP and 43% in KORA. In SHIP, hepatic fat was positively associated with ascending (β, 95% CI 0.06 (0.04 to 0.08)), descending (0.05 (0.04 to 0.07)) and infrarenal (0.02 (0.01 to 0.03)) aortic diameters, as well as with higher odds of plaque presence (OR, 95% CI 1.22 (1.05 to 1.42)) and greater cIMT (β, 95% CI 0.01 (0.004 to 0.02)) in the age-adjusted and sex-adjusted model. However, further adjustment for additional cardiometabolic risk factors, particularly body mass index, attenuated these associations. In KORA, no significant associations were found., Conclusions: The relation between hepatic fat and subclinical vascular disease was not independent of overall adiposity. Given the close relation of FLD with cardiometabolic risk factors, people with FLD should still be prioritised for cardiovascular disease screening., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Excess body weight (EBW) is a risk factor for various acute and chronic conditions. Conversely, the "obesity paradox" suggests a protective effect of higher body weight on some disease outcomes. This article discusses the role of EBW along the disease continuum of pancreatitis and pancreatic cancer (PC) in terms of incidence and outcome., Summary: Comparison of findings is hampered by the use of different methods to assess EBW. Nevertheless, in acute pancreatitis (AP) and PC, EBW, especially visceral obesity, presents a distinct risk factor and predictor of a negative outcome. Findings of a protective effect likely result from nonconsideration of fat distribution or other confounders. Regarding chronic pancreatitis (CP), few studies indicate lower incidence and a better outcome with higher body mass. However, there is insufficient evidence to confirm the existence of an obesity paradox. The precise mechanisms of how EBW affects the disease continuum require further elucidation but both common and disease-specific effects seem involved., Key Messages: EBW is associated with higher incidence and a negative outcome in AP and PC. The association with CP is less conclusive. Thus, maintaining normal weight is advisable at any stage of the disease continuum., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTR tm1HGU ) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTR tm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild-type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK-induced trypsin activation and necrosis in acini from CFTR tm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTR tm1HGU resulted in increased INF-γ and IL-6, but decreased IL-10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis-mostly via impairing duct cell function and a shift towards a pro-inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Gallstone disease affects up to twenty percent of the population in western countries and is a significant contributor to morbidity and health care expenditure. Intestinal microbiota have variously been implicated as either contributing to gallstone formation or to be affected by cholecystectomy. We conducted a large-scale investigation on 404 gallstone carriers, 580 individuals post-cholecystectomy and 984 healthy controls with similar distributions of age, sex, body mass index, smoking habits, and food-frequency-score. All 1968 subjects were recruited from the population-based Study-of-Health-in-Pomerania (SHIP), which includes transabdominal gallbladder ultrasound. Fecal microbiota profiles were determined by 16S rRNA gene sequencing. No significant differences in microbiota composition were detected between gallstone carriers and controls. Individuals post-cholecystectomy exhibited reduced microbiota diversity, a decrease in the potentially beneficial genus Faecalibacterium and an increase in the opportunistic pathogen Escherichia/Shigella. The absence of an association between the gut microbiota and the presence of gallbladder stones suggests that there is no intestinal microbial risk profile increasing the likelihood of gallstone formation. Cholecystectomy, on the other hand, is associated with distinct microbiota changes that have previously been implicated in unfavorable health effects and may not only contribute to gastrointestinal infection but also to the increased colon cancer risk of cholecystectomized patients.

Background and Aim: Malnutrition is a frequent complication of chronic pancreatitis. Adequate nutritional support is imperative, but there is still uncertainty about the optimal nutritional treatment. This work systematically compiles evidence from randomized controlled trials investigating dietary interventions in chronic pancreatitis and, in a further step, contrasts those findings with existing dietary recommendations., Methods: The literature search (PubMed and Cochrane Central Register of Controlled Trials) included English and German full-text articles, which had been published in peer-reviewed journals. Two independent reviewers identified and selected studies. For meta-analysis, forest plots with 95% confidence intervals were generated using a random-effects model., Results: Eleven randomized controlled trials fulfilled all selection criteria. In these trials, the following dietary interventions were tested: antioxidant treatment (n = 6), vitamin D supplementation (n = 3), supplementation with oral nutritional supplements (n = 1), and symbiotics supplementation (n = 1). Studies were of good methodological quality (mean Jadad score of 3.6) but heterogeneous in terms of interventions and study populations. Only for vitamin D, there was convincing evidence for efficacy of supplementation. We found no effect for antioxidant treatment on pain relief (standardized mean difference = -0.12; 95% confidence interval -0.73 to 0.48) and limited generalizability for interventions with oral nutritional supplements and symbiotics., Conclusions: Nutritional management in chronic pancreatitis remains challenging. As well-designed randomized controlled trials are scarce, in large part, recommendations can only be based on low-level evidence studies or expert opinion. For now, consumption of a balanced diet remains the cornerstone recommendation for prevention, whereas more goal-directed interventions are indicated for specific nutrient deficiencies., (© 2020 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: Patients who are overweight or obese have an increased risk of developing type 2 diabetes mellitus (T2DM). Weight loss can have a positive effect on glycemic control., Objective: We aimed to investigate glycemic control in patients with T2DM and overweight or obesity during a structured weight-loss program., Methods: This was a prospective, interventional study. We recruited 36 patients (14 men and 22 women) with a median age of 58.5 years and median body mass index (BMI) of 34.1, to a 15-week structured weight-loss program with a low-calorie (800 kcal) formula diet for 6 weeks. The primary end point, HbA1c level, and secondary end points, anthropometric data, medication, and safety, were assessed weekly. Laboratory values and quality of life were assessed at baseline and after 15 weeks., Results: HbA1c decreased from 7.3% at baseline to 6.5% at 15 weeks (p < 0.001), median body weight by 11.9 kg (p < 0.001), median BMI by 4.3 (p < 0.001) and median waist circumference by 11.0 cm (p < 0.001). Two participants discontinued insulin therapy, 4 could reduce their dosage of oral antidiabetic agents, and 6 completely discontinued their antidiabetic medication. Insulin dose decreased from 0.63 (0.38-0.89) to 0.39 (0.15-0.70) units/kg body weight (p < 0.001). No patient experienced hypoglycemic episodes or hospital emergency visits. Triglycerides and total cholesterol decreased as well as surrogate markers of liver function. However, the levels of high-density and low-density lipoprotein cholesterol (HDL-C and LDL-C) as well as uric acid remain unchanged. Regarding quality of life, the median physical health score increased from 44.5 (39.7-51.4) at baseline to 48.0 (43.1-55.3; p = 0.007), and the median mental health score decreased from 42.1 (36.1-46.7) to 37.4 (30.3-43.7; p = 0.004)., Conclusions: A structured weight-loss program is effective in the short term in reducing HbA1c, weight, and antidiabetic medication in patients with T2DM who are overweight or obese. Levels of HDL-C and LDL-C were not affected by short-term weight loss. The decline in mental health and the long-term effects of improved glycemic control require further trials., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Hereditary chronic pancreatitis (HCP) is a genetically determined condition characterized by intermittent acute episodes of pancreatitis and long-term impairment of the exocrine and endocrine pancreatic functions. Genetic test results can have substantial psychological and social consequences for the individuals tested and their families. Nevertheless, little is known so far about the subjective experience of individuals genetically tested for HCP. This qualitative study examines the viewpoints of HCP patients and their relatives in order to identify the psychosocial and ethical implications related to genetic testing within families. Semi-structured qualitative individual interviews and a focus group with HCP patients and their family members were conducted. Data were audio-recorded, transcribed verbatim and analysed using qualitative content analysis. A total of 28 individuals were enrolled in the study: 24 individuals (17 patients, 7 relatives) were interviewed in semi-structured one-on-one interviews and 4 individuals (2 patients, 2 life partners) participated in the focus group. Emerging topics covered (1) genetic testing in childhood, (2) genetic testing within the family and (3) family planning. The study reveals that genetic testing for HCP has a wide influence in familial contexts and is accompanied by normative issues, such as autonomy, reproductive decisions and sharing of information within the family. The results raise the awareness of the complexity of family contexts: familial relationships and dynamics can have great influence on the individual decisions related to genetic testing. Increased understanding of these relational contexts can help health professionals, for example, in counselling, to discuss genetic testing better with patients and families.

Abstract: Acute pancreatitis (AP) is one of the most common gastroenterological disorders leading to hospitalization. It has long been debated whether biliary AP, about 30% to 50% of all cases, is induced by bile acids (BAs) when they reach the pancreas via reflux or via the systemic blood circulation.Besides their classical function in digestion, BAs have become an attractive research target because of their recently discovered property as signaling molecules. The underlying mechanisms of BAs have been investigated in various studies. Bile acids are internalized into acinar cells through specific G-protein-coupled BA receptor 1 and various transporters. They can further act via different receptors: the farnesoid X, ryanodine, and inositol triphosphate receptor. Bile acids induce a sustained Ca2+ influx from the endoplasmic reticulum and release of Ca2+ from acidic stores into the cytosol of acinar cells. The overload of intracellular Ca2+ results in mitochondrial depolarization and subsequent acinar cell necrosis. In addition, BAs have a biphasic effect on pancreatic ductal cells. A more detailed characterization of the mechanisms through which BAs contribute to the disease pathogenesis and severity will greatly improve our understanding of the underlying pathophysiology and may allow for the development of therapeutic and preventive strategies for gallstone-inducedAP., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Exocrine pancreatic function is a critical host factor in determining the intestinal microbiota composition. Diseases affecting the exocrine pancreas could therefore influence the gut microbiome. We investigated the changes in gut microbiota of patients with chronic pancreatitis (CP)., Methods: Patients with clinical and imaging evidence of CP (n = 51) were prospectively recruited and compared with twice the number of nonpancreatic disease controls matched for distribution in age, sex, body mass index, smoking, diabetes mellitus, and exocrine pancreatic function (stool elastase). From stool samples of these 153 subjects, DNA was extracted, and intestinal microbiota composition was determined by bacterial 16S ribosomal RNA gene sequencing., Results: Patients with CP exhibited severely reduced microbial diversity (Shannon diversity index and Simpson diversity number, P < 0.001) with an increased abundance of facultative pathogenic organisms (P < 0.001) such as Enterococcus (q < 0.001), Streptococcus (q < 0.001), and Escherichia.Shigella (q = 0.002). The CP-associated changes were independent of exocrine pancreatic insufficiency. Short-chain fatty acid producers, considered protective for epithelia such as Faecalibacterium (q < 0.001), showed reduced abundance in patients with CP. Of 4 additional patients with CP previously treated with antibiotics (ceftriaxone and metronidazole), 3 patients were characterized by distinct Enterococcus overgrowth., Discussion: CP is associated with marked gut microbiota dysbiosis, greatly reduced diversity, and increased abundance of opportunistic pathogens, specifically those previously isolated from infected pancreatic necrosis. Taxa with a potentially beneficial role in intestinal barrier function are depleted. These changes can increase the probability of complications from pancreatitis such as infected fluid collections or small intestinal bacterial overgrowth (see Graphical Abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A383).

Muscle wasting represents a constant pathological feature of common chronic gastrointestinal diseases, including liver cirrhosis (LC), inflammatory bowel diseases (IBD), chronic pancreatitis (CP) and pancreatic cancer (PC), and is associated with increased morbidity and mortality. Recent clinical and experimental studies point to the existence of a gut-skeletal muscle axis that is constituted by specific gut-derived mediators which activate pro- and anti-sarcopenic signalling pathways in skeletal muscle cells. A pathophysiological link between both organs is also provided by low-grade systemic inflammation. Animal models of LC, IBD, CP and PC represent an important resource for mechanistic and preclinical studies on disease-associated muscle wasting. They are also required to test and validate specific anti-sarcopenic therapies prior to clinical application. In this article, we review frequently used rodent models of muscle wasting in the context of chronic gastrointestinal diseases, survey their specific advantages and limitations and discuss possibilities for further research activities in the field. We conclude that animal models of LC-, IBD- and PC-associated sarcopenia are an essential supplement to clinical studies because they may provide additional mechanistic insights and help to identify molecular targets for therapeutic interventions in humans., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Liver cirrhosis is frequently accompanied by disease-related malnutrition (DRM) and sarcopenia, defined as loss of skeletal muscle mass and function. DRM and sarcopenia often coexist in cirrhotic patients and are associated with increased morbidity and mortality. The clinical manifestation of both comorbidities are triggered by multifactorial mechanisms including reduced nutrient and energy intake caused by dietary restrictions, anorexia, neuroendocrine deregulation, olfactory and gustatory deficits. Maldigestion and malabsorption due to small intestinal bacterial overgrowth, pancreatic insufficiency or cholestasis may also contribute to DRM and sarcopenia. Decreased protein synthesis and increased protein degradation is the cornerstone mechanism to muscle loss, among others mediated by disease- and inflammation-mediated metabolic changes, hyperammonemia, increased myostatin and reduced human growth hormone. The concise pathophysiological mechanisms and interactions of DRM and sarcopenia in liver cirrhosis are not completely understood. Furthermore, most knowledge in this field are based on experimental models, but only few data in humans exist. This review summarizes known and proposed molecular mechanisms contributing to malnutrition and sarcopenia in liver cirrhosis and highlights remaining knowledge gaps. Since, in the prevention and treatment of DRM and sarcopenia in cirrhotic patients, more research is needed to identify potential biomarkers for diagnosis and development of targeted therapeutic strategies.

Premature intrapancreatic trypsinogen activation is widely regarded as an initiating event for acute pancreatitis. Previous studies have alternatively implicated secretory vesicles, endosomes, lysosomes, or autophagosomes/autophagolysosomes as the primary site of trypsinogen activation, from which a cell-damaging proteolytic cascade originates. To identify the subcellular compartment of initial trypsinogen activation we performed a time-resolution analysis of the first 12 h of caerulein-induced pancreatitis in transgenic light chain 3 (LC3)-GFP autophagy reporter mice. Intrapancreatic trypsin activity increased within 60 min and serum amylase within 2 h, but fluorescent autophagosome formation only by 4 h of pancreatitis in parallel with a shift from cytosolic LC3-I to membranous LC3-II on Western blots. At 60 min, activated trypsin in heavier subcellular fractions was co-distributed with cathepsin B, but not with the autophagy markers LC3 or autophagy protein 16 (ATG16). Supramaximal caerulein stimulation of primary pancreatic acini derived from LC3-GFP mice revealed that trypsinogen activation is independent of autophagolysosome formation already during the first 15 min of exposure to caerulein. Co-localization studies (with GFP-LC3 autophagosomes versus Ile-Pro-Arg-AMC trypsin activity and immunogold-labelling of lysosomal-associated membrane protein 2 [LAMP-2] versus trypsinogen activation peptide [TAP]) indicated active trypsin in autophagolysosomes only at the later timepoints. In conclusion, during the initiating phase of caerulein-induced pancreatitis, premature protease activation develops independently of autophagolysosome formation and in vesicles arising from the secretory pathway. However, autophagy is likely to regulate overall intracellular trypsin activity during the later stages of this disease.

Introduction: Transabdominal ultrasound (US) and magnetic resonance imaging (MRI) are commonly used for the examination of the pancreas in clinical routine. We therefore were interested in the concordance of these two imaging methods for the size measurement of the pancreas and how age, gender, and body mass index (BMI) affect the organ size., Methods: A total of 342 participants from the Study of Health in Pomerania underwent whole-body MRI and transabdominal US on the same day, and the diameter of the pancreatic head, body, and tail were measured. The agreement between US and MRI measurements was assessed by Bland and Altman plots. Intraclass correlation coefficients were used to compare observers. A multivariable regression model was applied using the independent variables age, gender, and body mass index., Results: Compared to MRI, abdominal US returned smaller values for each segment of the pancreas, with a high level of inconsistency between these two methods. The mean difference was 0.39, 0.18, and 0.54 cm for the head, body, and tail, respectively. A high interobserver variability was detected for US. Multivariable analysis showed that pancreatic size in all three segments increased with BMI in both genders whereas pancreatic head and tail size decreased with age, an effect more marked in women., Conclusions: Agreement of pancreatic size measurements is poor between US and MRI. These limitations should be considered when evaluating morphologic features for pathologic conditions or setting limits of normal size. Adjustments for BMI, gender, and age may also be warranted., (© 2019 The Authors. Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.)

Background: Little is known about the clustering of behavioral health risk factors (HRFs), namely the occurrence of 16 specific combinations of tobacco smoking, at-risk alcohol use, overweight and physical inactivity in general hospital patients. Furthermore, social inequalities in HRFs, health and life expectancy are a major concern in public health. In order to establish the need for screening and intervention in general hospital care, the study aimed to determine the co-occurrence of HRFs in patients in four medical departments, and to investigate differences by gender, age and socio-economic characteristics., Methods: Over 17 months, a systematic multiple HRF screening was conducted at one general hospital in northeastern Germany. In total, 6251 18-64 year old patients (92% of eligibles) participated. Proportions and confidence intervals were calculated for all 16 HRF profiles stratified by department, gender, age group, school education, and employment status., Results: In total, 92.2% of the participants (58.6% male) reported ≥1 HRF, and 65.7% ≥2 HRFs. Men (71.2%), patients aged 35-49 (67.9%) and 50-64 years (69.5%), lower educated (79.0%), and unemployed (77.8%) patients had larger proportions of ≥2 HRFs than their counterparts. In all departments, the most common HRF profiles included overweight. HRF profiles that included alcohol and/ or smoking were more common in ear-nose-throat and trauma surgery than in internal medicine and general surgery patients. Men had higher rates concerning almost all HRF profiles including ≥2 HRFs and alcohol; women concerning profiles that included ≤2 HRFs and inactivity. In older patients, profiles with ≥2 HRFs including overweight; and in younger patients, profiles with smoking and/or alcohol were more common. In lower educated patients, profiles with ≥2 HRFs including inactivity; and in higher educated patients profiles with ≤2 HRFs including alcohol were more common. Compared to others, unemployed patients had higher rates of profiles with ≥3 HRFs including smoking., Conclusions: Two in three patients require interventions targeting two or more HRFs. The findings help to develop screening and brief intervention for patients with specific health risk profiles, that can reach most patients, including those most in need and those most hard to reach, with socio-economically disadvantaged people in particular. REGISTRY: clinicaltrials.gov: NCT01291693.

Acute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG -/- mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG -/- mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.