Impact of mechanical bowel preparation on the gut microbiome of patients undergoing left-sided colorectal cancer surgery: randomized clinical trial.

BACKGROUND: Postoperative complications after colorectal cancer surgery have been linked to the gut microbiome. However, the impact of mechanical bowel preparation using oral preparation agents or rectal enema on postoperative infections remains poorly understood. This study aimed to compare the impact of oral preparation and rectal enema on the gut microbiome and postoperative complications. METHODS: This open-label pilot RCT was conducted at the National Cancer Institute, Vilnius, Lithuania. Patients with left-side colorectal cancer scheduled for elective resection with primary anastomosis were randomized 1 : 1 to preoperative mechanical bowel preparation with either oral preparation or rectal enema. Stool samples were collected before surgery, and on postoperative day 6 and 30 for 16S rRNA gene sequencing analysis. The primary outcome was difference in ß-diversity between groups on postoperative day 6. RESULTS: Forty participants were randomized to oral preparation (20) or rectal enema (20). The two groups had similar changes in microbiome composition, and there was no difference in ß-diversity on postoperative day 6. Postoperative infections occurred in 12 patients (32%), without differences between the study groups. Patients with infections had an increased abundance of bacteria from the Actinomycetaceae family, Actinomyces genus, Sutterella uncultured species, and Enterococcus faecalis species. CONCLUSION: Mechanical bowel preparation with oral preparation or rectal enema resulted in similar dysbiosis. Patients who experienced postoperative infections exhibited distinct gut microbiome compositions on postoperative day 6, characterized by an increased abundance of bacteria from the Actinomycetaceae family, Actinomyces genus, Sutterella uncultured species, and Enterococcus faecalis species. REGISTRATION NUMBER: NCT04013841 (http://www.clinicaltrials.gov).

O2 supplementation disambiguation in clinical narratives to support retrospective COVID-19 studies.

BACKGROUND: Oxygen saturation, a key indicator of COVID-19 severity, poses challenges, especially in cases of silent hypoxemia. Electronic health records (EHRs) often contain supplemental oxygen information within clinical narratives. Streamlining patient identification based on oxygen levels is crucial for COVID-19 research, underscoring the need for automated classifiers in discharge summaries to ease the manual review burden on physicians. METHOD: We analysed text lines extracted from anonymised COVID-19 patient discharge summaries in German to perform a binary classification task, differentiating patients who received oxygen supplementation and those who did not. Various machine learning (ML) algorithms, including classical ML to deep learning (DL) models, were compared. Classifier decisions were explained using Local Interpretable Model-agnostic Explanations (LIME), which visualize the model decisions. RESULT: Classical ML to DL models achieved comparable performance in classification, with an F-measure varying between 0.942 and 0.955, whereas the classical ML approaches were faster. Visualisation of embedding representation of input data reveals notable variations in the encoding patterns between classic and DL encoders. Furthermore, LIME explanations provide insights into the most relevant features at token level that contribute to these observed differences. CONCLUSION: Despite a general tendency towards deep learning, these use cases show that classical approaches yield comparable results at lower computational cost. Model prediction explanations using LIME in textual and visual layouts provided a qualitative explanation for the model performance.

Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.

Transplantation of hepatitis D virus patients: Lifelong hepatitis B immunoglobulins?

The introduction of Hepatitis B Immunoglobulins (HBIg) prophylaxis at and after liver transplantation (LT) facilitated excellent long-term survival of transplant patients with chronic hepatitis B virus (HBV) infection. Several studies suggested that only short-term (i.e. 4-8 weeks) HBIg prophylaxis after LT followed by the long-term administration of HBV polymerase inhibitors prevents HBV recurrence. In hepatitis D virus (HDV)/HBV co-infected patients, the need for long-term HBIg prophylaxis on top of HBV polymerase inhibitors is unknown. HDV requires HBV surface antigen (HBsAg) for uptake into hepatocytes to subsequently establish HDV replication. Data on HDV recurrence and its impact on outcomes after LT are limited. In this review, we evaluated the available data on post-LT recurrence of HBV and/or HDV. Overall, HBIg prophylaxis was effective, but 10-13% of patients became HBsAg positive after LT. Only a single study from Turkey reported HDV recurrence, which was not observed in other LT centres. Since all studies administered continuous HBIg prophylaxis, the post-LT recurrence rates without HBIg prophylaxis remain unknown. In a German study, the clinical course and histopathological aspects of liver injury (inflammation, fibrosis and steatosis) were similar in post-LT patients on continuous HBIg and those who stopped HBIg after a median of 72 months. Discontinuation of HBIg in stable patients after LT for HBV/HDV co-infection did not lead to impaired overall survival or a higher recurrence rate in this long-term follow-up. In summary, discontinuation of HBIg after liver transplantation for HBV/HDV liver disease seems safe, but randomized controlled studies are needed before it can be generally recommended.

Fungal translocation measured by serum 1,3-ß-D-glucan correlates with severity and outcome of liver cirrhosis-A pilot study.

BACKGROUND & AIMS: On a global scale, liver cirrhosis is attributable to ~1 million deaths per year. This systemic disease comes along with diverse sequelae, including microbiota alterations, increased gut permeability and translocation of microbial components into the systemic circulation. Alongside the extensively studied influence of bacterial translocation and its host-pathogen interactions, far less is known about the role and impact of fungal components once having crossed the intestinal barrier. METHODS: Including 70 patients with different aetiologies of liver cirrhosis, we investigated the relationship between fungal translocation, measured by 1,3-ß-D-glucan (BDG), and biomarkers of gut integrity, inflammation and severity/outcome of liver disease. RESULTS: Patients with cirrhosis Child-Pugh class (CPC)-B were more likely to have positive serum BDG (aOR 5.4, 95% CI 1.2-25.2) compared to patients with cirrhosis CPC-A. BDG showed a moderate positive correlation with several markers of inflammation (sCD206, sCD163, Interleukin 8, interferon-gamma-induced protein). Mortality differed significantly between patients with positive versus negative BDG (log-rank test, p = 0.015). The multivariable Cox regression model yielded an aHR of 6.8 (95% CI 1.8-26.3). DISCUSSION: We observed trends for increased fungal translocation depending on the severity of liver cirrhosis, an association of BDG with an inflammatory environment and the adverse effects of BDG on disease outcome. In order to gain more in-depth knowledge about (fungal-)dysbiosis and its detrimental consequences in the setting of liver cirrhosis, these trends need to be studied in more detail including prospective sequential testing in larger cohorts together with mycobiome analyses. This will further elucidate complex host-pathogen interactions and potentially introduce points of application for therapeutic interventions.

INTERmittent FASTing in people with insulin-treated type 2 diabetes mellitus - the INTERFAST-2 study protocol.

AIM: Intermittent fasting, a dietary intervention of alternate eating and fasting, has gained popularity in people trying to lose weight. Intermittent fasting could provide an alternative to classic caloric restriction in people with type 2 diabetes mellitus. The aim of the study is to determine the impact of a 12-week intermittent fasting regimen compared with usual care in people with type 2 diabetes mellitus receiving insulin therapy. METHODS: This open, single-centre, randomized controlled trial investigates participants with type 2 diabetes mellitus on insulin therapy and a glycated haemoglobin A1c (HbA1c) of ≥53 mmol/mol (≥7.0%) and a minimum insulin dose of 0.3 IU/kg body weight per day. Participants are randomized in a 1:1 ratio to either 12 weeks of intermittent fasting or the standard care group. All participants receive dietary counselling, continuous glucose monitoring, measurement of the resting metabolic rate, an oral glucose tolerance test, body composition measurement via dual-energy X-ray absorptiometry and stool samples for microbiome analyses at the beginning and at the end of the intervention. Two co-primary outcomes (analysed in hierarchical order) were chosen for the study: (i) the difference in the change of HbA1c from baseline to 12 weeks and (ii) the difference in the number of participants achieving a combined end point encompassing a body weight reduction of at least 2%, an insulin dose reduction of at least 10% and an absolute HbA1c reduction of at least 3 mmol/mol (0.3%) between the two groups.

A novel score predicts mortality after transjugular intrahepatic portosystemic shunt: MOTS - Modified TIPS Score.

BACKGROUND AND AIMS: The high risk for severe shunting-related post-interventional complications demands a stringent selection of candidates for transjugular intrahepatic portosystemic shunt (TIPS). We aimed to develop a simple and reliable tool to accurately predict early post-TIPS mortality. METHODS: 144 cases of TIPS implantation were retrospectively analysed. Using univariate and multivariate Cox regression analysis of factors predicting mortality within 90 days after TIPS, a score integrating urea, international normalized ratio (INR) and bilirubin was developed. The Modified TIPS-Score (MOTS) ranges from 0 to 3 points: INR >1.6, urea >71 mg/dl and bilirubin >2.2 mg/dl account for one point each. Additionally, MOTS was tested in an external validation cohort (n = 187) and its performance was compared to existing models. RESULTS: Modified TIPS-Score achieved a significant prognostic discrimination reflected by 90-day mortality of 8% in patients with MOTS 0-1 and 60% in patients with MOTS 2-3 (p < .001). Predictive performance (area under the curve) of MOTS was accurate (c = 0.845 [0.73-0.96], p < .001), also in patients with renal insufficiency (c = 0.830 [0.64-1.00], p = .02) and in patients with refractory ascites (c = 0.949 [0.88-1.00], p < .001), which are subgroups with particular room for improvement of post-TIPS mortality prediction. The results were reproducible in the validation cohort. CONCLUSIONS: Modified TIPS-Score is a novel, practicable tool to predict post-TIPS mortality, that can significantly simplify clinical decision making. Its practical applicability should be further investigated.

Changing paradigms in the treatment of gastrointestinal complications of cystic fibrosis in the era of cystic fibrosis transmembrane conductance regulator modulators.

Cystic fibrosis (CF) - although primarily a lung disease - also causes a variety of gastrointestinal manifestations which are important for diagnosis, prognosis and quality of life. All parts of the gastrointestinal tract can be affected by CF. Besides the well-known pancreatic insufficiency, gastroesophageal reflux disease, liver disease and diseases of the large intestine are important pathologies that impact on prognosis and also impair quality of life. Diagnosis and management of gastrointestinal manifestations will be discussed in this review. Since optimisation of CF therapy is associated with a significantly longer life-span of CF patients nowadays, also gastrointestinal malignancies, which are more common in CF than in the non-CF population need to be considered. Furthermore, novel evidence on the role of the gut microbiome in CF is emerging. The introduction of cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators gives hope for symptom alleviation and even cure of gastrointestinal manifestations of CF.

Red urine and a red herring - diagnosing rare diseases in the light of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has occupied the time and resources of health care professionals for more than 1 year. The risk of missed diagnoses has been discussed in the medical literature, mainly for common diseases such as cancer and cardiovascular events. However, rare diseases also need appropriate attention in times of a pandemic. CASE REPORT: We report a 34-year-old woman with fever, pinprick sensation in her chest and thoracic spine, and dizziness after receiving the first dose of ChAdOx1 nCoV-19 vaccination. The patient's condition worsened with abdominal pain, red urine, and hyponatremia, needing intensive care admission. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) was diagnosed. Vaccine-induced thrombocytopenia and thrombosis were ruled out. Acute hepatic porphyria was finally diagnosed, and the patient recovered completely after treatment with hemin. CONCLUSION: Currently, the focus of physicians is on COVID-19 and associated medical problems, such as vaccine side effects. However, it is important to be vigilant for other uncommon medical emergencies in medically exceptional situations that may shift our perception.

Criminal and Civil Responsibility of the Donor in a Case of Transmission of Malaria by a Blood Transfusion in a Nonendemic Country.

Introduction: The blood donation process is strictly regulated by law. The process includes the necessity of a medical history taken to determine if a donor is suitable to donate, which shall guarantee both donor and recipient safety. Supplementary screening for a limited number of infections is performed by antibody (HIV, HCV, syphilis) or antigen (HBV) tests or NAT (HIV, HCV, HBV). Case Presentation: With regard to a possible infection due to (sexual) risk behavior or foreign travel, blood donation facilities are predominantly dependent on information provided by the donor. This is especially true for malaria in nonendemic areas such as Europe. Transmission of malaria by a blood transfusion in a nonendemic country that led to fulminant septic shock and death of the patient happened. Discussion: From a legal perspective, the donor thus assumes a high level of responsibility with regard to the accuracy and completeness of the information provided on the donor questionnaire. Incorrect information may, as in this Austrian case reported, result in civil or criminal responsibility of the donor.

Transition to decompensation and acute-on-chronic liver failure: Role of predisposing factors and precipitating events.

The transition from compensated to decompensated cirrhosis results from a complex interplay of predisposing and precipitating factors and represents an inflection point in the probability of a patient surviving. With the progression of cirrhosis, patients accumulate multiple disorders (e.g. altered liver architecture, portal hypertension, local and systemic inflammation, bacterial translocation, gut dysbiosis, kidney vasoconstriction) that predispose them to decompensation. On the background of these factors, precipitating events (e.g. bacterial infection, alcoholic hepatitis, variceal haemorrhage, drug-induced liver injury, flare of liver disease) lead to acute decompensation (ascites, hepatic encephalopathy, variceal bleeding, jaundice) and/or organ failures, which characterise acute-on-chronic liver failure. In this review paper, we will discuss the current hypotheses and latest evidences regarding predisposing and precipitating factors associated with the transition to decompensated liver disease.

Distal Gastrectomy with Billroth II Reconstruction is Associated with Oralization of Gut Microbiome and Intestinal Inflammation: A Proof-of-Concept Study.

BACKGROUND: Subtotal gastrectomy with Billroth II reconstruction (SGB2) results in increased gastric pH and diminished gastric barrier. Increased gastric pH following PPI therapy has an impact on the gut microbiome, intestinal inflammation, and possibly patient health. If similar changes are present after SGB2, these can be relevant for patient health and long-term outcomes after surgery. The aim of the study is to investigate whether SGB2 is associated with specific changes in gut microbiome composition and intestinal inflammation. PATIENTS AND METHODS: This cross-sectional proof-of-concept study includes patients after SGB2 (n = 14) for early gastric cancer and their nongastrectomized in-house relatives as controls (n = 8). Fecal microbiome composition, intestinal inflammation (fecal calprotectin), gut permeability (DAO, LBP, sCD14), systemic inflammation (CRP) markers, and gastrointestinal symptoms are investigated. This study is registered at ClinicalTrials.gov (NCT03418428). RESULTS: Microbiome oralization following SGB2 was defined by an increase in Escherichia-Shigella, Enterococcus, Streptococcus, and other typical oral cavity bacteria (Veillonella, Oribacterium, and Mogibacterium) abundance. The fecal calprotectin was increased in the SGB2 group [100.9 (52.1; 292) vs. 25.8 (17; 66.5); p = 0.014], and calprotectin levels positively correlated with the abundance of Streptococcus (rs = 0.639; padj = 0.023). Gastrointestinal symptoms in SGB2 patients were associated with distinct taxonomic changes of the gut microbiome. CONCLUSIONS: SGB2 is associated with oralization of the gut microbiome; intestinal inflammation and microbiome changes were associated with gastrointestinal symptoms. These novel findings may open gut microbiome as a new target for therapy to improve quality of life and general patient health in long-term survivors after SGB2.

(S)-Reutericyclin: Susceptibility Testing and In Vivo Effect on Murine Fecal Microbiome and Volatile Organic Compounds.

We aimed to assess the in vitro antimicrobial activity and the in vivo effect on the murine fecal microbiome and volatile organic compound (VOC) profile of (S)-reutericyclin. The antimicrobial activity of (S)-reutericyclin was tested against Clostridium difficile, Listeria monocytogenes, Escherichia coli, Enterococcus faecium, Staphylococcus aureus, Staphylococcus (S.) epidermidis, Streptococcus agalactiae, Pseudomonas aeruginosa and Propionibacterium acnes. Reutericyclin or water were gavage fed to male BALBc mice for 7 weeks. Thereafter stool samples underwent 16S based microbiome analysis and VOC analysis by gas chromatography mass spectrometry (GC-MS). (S)-reutericyclin inhibited growth of S. epidermidis only. Oral (S)-reutericyclin treatment caused a trend towards reduced alpha diversity. Beta diversity was significantly influenced by reutericyclin. Linear discriminant analysis Effect Size (LEfSe) analysis showed an increase of Streptococcus and Muribaculum as well as a decrease of butyrate producing Ruminoclostridium, Roseburia and Eubacterium in the reutericyclin group. VOC analysis revealed significant increases of pentane and heptane and decreases of 2,3-butanedione and 2-heptanone in reutericyclin animals. The antimicrobial activity of (S)-reutericyclin differs from reports of (R)-reutericyclin with inhibitory effects on a multitude of Gram-positive bacteria reported in the literature. In vivo (S)-reutericyclin treatment led to a microbiome shift towards dysbiosis and distinct alterations of the fecal VOC profile.

[Proton Pump Inhibitors and their Microbiome-Mediated Side Effects]. / Das Mikrobiom als Drehscheibe für Nebenwirkungen der Protonenpumpenhemmer-Therapie.

Proton pump inhibitors are valuable treatment options for gastric acid associated diseases, such as peptic ulcer disease or reflux diseases. Due to their irreversible inhibition of the proton pumps in the parietal cells of the stomach, gastric acid secretion can be effectively reduced. With the reduction in gastric acid, however, proton pump inhibitors also block a highly conserved, crucial part of the unspecific immune system. The gastric barrier protects the body - and here mainly the intestinal microbiome - from food-borne pathogens and oral bacteria that can reach more distal parts of the gastrointestinal tract during proton pump inhibitor therapy. Resulting changes in the intestinal microbiome, such as the reduction in microbial diversity or small intestinal bacterial overgrowth, can be linked to side effects of (long-term) proton pump inhibitor therapy, such as the increased risk of Clostridium difficile infections or gastrointestinal discomfort. In liver cirrhosis patients, the increase in oral bacteria in the intestine is associated with intestinal inflammation and permeability, and can even be used as a biomarker for 3-year liver related mortality. Therefore, microbiome-mediated side effects should be included in the risk assessment of proton pump inhibitor therapy and the evaluation of potential alternatives.

HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure.

BACKGROUND & AIMS: High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease. METHODS: HDL-related biomarkers were studied in 508 patients with compensated or decompensated cirrhosis (including acute-on-chronic liver failure [ACLF]) and 40 age- and gender-matched controls. Specifically, we studied levels of HDL-C, its subclasses HDL2-C and HDL3-C, and apolipoprotein A1 (apoA-I), as well as HDL cholesterol efflux capacity as a metric of HDL functionality. RESULTS: Baseline levels of HDL-C and apoA-I were significantly lower in patients with stable cirrhosis compared to controls and were further decreased in patients with acute decompensation (AD) and ACLF. In stable cirrhosis (n = 228), both HDL-C and apoA-I predicted the development of liver-related complications independently of model for end-stage liver disease (MELD) score. In patients with AD, with or without ACLF (n = 280), both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, both HDL-C and apoA-I had high diagnostic accuracy for 90-day mortality in patients with AD (AUROCs of 0.79 and 0.80, respectively, similar to that of MELD 0.81). On Kaplan-Meier analysis, HDL-C <17 mg/dl and apoA-I <50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to advanced chronic liver disease (AUROCs HDL-C: 0.81 vs. MELD: 0.77). CONCLUSION: HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure. LAY SUMMARY: People who suffer from cirrhosis (scarring of the liver) have low levels of cholesterol carried by high-density lipoproteins (HDL-C). These alterations are connected to inflammation, which is a problem in severe liver disease. Herein, we show that reduced levels of HDL-C and apolipoprotein A-I (apoA-I, the main protein carried by HDL) are closely linked to the severity of liver failure, its complications and survival. Both HDL-C and apoA-I can be easily measured in clinical laboratories and are as good as currently used prognostic scores calculated from several laboratory values by complex formulas.

Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis.

BACKGROUND & AIMS: Compositional changes of the faecal microbiome in cirrhosis are well described and have been associated with complications and prognosis. However, it is less well known, which disease or treatment-related factors affect microbiome composition most distinctively. METHODS: 16S rDNA sequencing data of 88 cirrhotic outpatients were investigated. Factors influencing microbiome composition were analysed by univariate and multivariate redundancy analysis. The association of the identified factors with changes in diversity and taxonomic composition was studied in depth using analysis of composition of microbiome, LDA-effect size and least absolute shrinkage and selection operator regularized regression. RESULTS: Disease severity and aetiology, proton pump inhibitor (PPI) use, nutritional status, age and C-reactive protein are significant explanatory variables for faecal microbiome composition in liver cirrhosis. Despite some taxonomic overlaps especially between disease severity and PPI use, we could show that the effects of disease severity, aetiology, PPI use and age are independent factors influencing microbiome composition also in subgroup analyses. CONCLUSION: Our cross sectional system biology study identifies disease severity, aetiology, PPI use and age as independent factors that influence microbiome composition in liver cirrhosis. In chronic diseases with high morbidity, such as liver cirrhosis, precise patient metadata documentation is of utmost importance in microbiome analysis. Further studies with a higher sample size are necessary to validate this finding. TRIAL REGISTRATION NUMBER: NCT01607528.

Effects of a multispecies synbiotic on glucose metabolism, lipid marker, gut microbiome composition, gut permeability, and quality of life in diabesity: a randomized, double-blind, placebo-controlled pilot study.

PURPOSE: Diabesity, the combination of obesity and type 2 diabetes, is an ever-growing global health burden. Diabesity-associated dysbiosis of the intestinal microbiome has gained attention as a potential driver of disease and, therefore, a possible therapeutic target by means of pro- or prebiotic supplementation. This study tested the effects of a multispecies synbiotic (i.e. a combination of probiotics and prebiotics) on glucose metabolism, gut microbiota, gut permeability, neutrophil function and quality of life in treatment-experienced diabesity patients. METHODS: A randomized, double-blind, placebo-controlled pilot study with 26 diabesity patients was conducted in which patients received a daily dose of a multispecies probiotic and a prebiotic (or a placebo) for 6 months. RESULTS: There were no changes in glucose metabolism or mixed meal tolerance test responses throughout the study. The analysis of secondary outcomes revealed beneficial effects on hip circumference [- 1 (95% CI - 4; 3) vs +3 (- 1; 8) cm, synbiotics vs. placebo, respectively, p = 0.04], serum zonulin [- 0.04 (- 0.2; 0.1) vs +0.3 (- 0.05; 0.6) ng/ml, p = 0.004)] and the physical role item of the SF36 quality of life assessment [+ 5.4 (- 1.7; 12.5) vs - 5.0 (- 10.1; 0.2) points, p = 0.02] after 3 months of intervention, and lipoprotein (a) [- 2.1 (- 5.7; 1.6) vs +3.4 (- 0.9; 7.9) mg/dl, p = 0.02] after 6 months. There were no significant differences in alpha or beta diversity of the microbiome between groups or time points. CONCLUSIONS: Glucose metabolism as the primary outcome was unchanged during the intervention with a multispecies synbiotic in patients with diabesity. Nevertheless, synbiotics improved some symptoms and biomarkers of type 2 diabetes and aspects of quality of life suggesting a potential role as adjuvant tool in the management of diabesity.

Dysbiosis, gut barrier dysfunction and inflammation in dementia: a pilot study.

BACKGROUND: Dementia is an increasing public health threat worldwide. The pathogenesis of dementia has not been fully elucidated yet. Inflammatory processes are hypothesized to play an important role as a driver for cognitive decline but the origin of inflammation is not clear. We hypothesize that disturbances in gut microbiome composition, gut barrier dysfunction, bacterial translocation and resulting inflammation are associated with cognitive dysfunction in dementia. METHODS: To test this hypothesis, a cohort of 23 patients with dementia and 18 age and sex matched controls without cognitive impairments were studied. Gut microbiome composition, gut barrier dysfunction, bacterial translocation and inflammation were assessed from stool and serum samples. Malnutrition was assessed by Mini Nutritional Assessment Short Form (MNA-SF), detailed information on drug use was collected. Microbiome composition was assessed by 16S rRNA sequencing, QIIME 2 and Calypso 7.14 tools. RESULTS: Dementia was associated with dysbiosis characterized by differences in beta diversity and changes in taxonomic composition. Gut permeability was increased as evidenced by increased serum diamine oxidase (DAO) levels and systemic inflammation was confirmed by increased soluble cluster of differentiation 14 levels (sCD14). BMI and statin use had the strongest impact on microbiome composition. CONCLUSION: Dementia is associated with changes in gut microbiome composition and increased biomarkers of gut permeability and inflammation. Lachnospiraceae NK4A136 group as potential butyrate producer was reduced in dementia. Malnutrition and drug intake were factors, that impact on microbiome composition. Increasing butyrate producing bacteria and targeting malnutrition may be promising therapeutic targets in dementia. TRIAL REGISTRATION: NCT03167983 .

Family discussions and demographic factors influence adolescent's knowledge and attitude towards organ donation after brain death: a questionnaire study.

BACKGROUND: Knowledge and attitude towards organ donation are critical factors influencing organ donation rate. We aimed to assess the knowledge and attitude towards organ donation in adolescents in Austria and Switzerland. METHODS: A paper-based survey was performed in two secondary schools (age range 11-20 years) in Austria and Switzerland. 354/400 surveys were sufficiently answered and analyzed. RESULTS: Our study found that knowledge on organ donation is scarce in adolescents. Less than 60% of those surveyed thinks that a person is dead when declared brain dead. 84.6% would authorize organ donation after brain death for themselves, but only 69% would authorize organ donation after brain death for a close relative. 93.7% would accept a donor organ if they needed one. Family discussions, rather than school discussions, influenced knowledge on organ donation, the percentage of respondents who have a firm opinion on organ donation and the rate of declaration of this opinion. Age, gender, nationality and religion also influenced knowledge and attitude towards organ donation. Nearly one third of adolescents are of the opinion that selling non-vital organs should be legalized. CONCLUSION: Since having had family discussions, a potentially modifiable factor, was positively associated with knowledge and attitude towards organ donation, we postulate that educational programs stimulating family discussions on organ donation may be a promising strategy to increase knowledge.

Metabolic disease and ABHD6 alter the circulating bis(monoacylglycerol)phosphate profile in mice and humans.

Bis(monoacylglycerol)phosphate (BMP) is a phospholipid that is crucial for lipid degradation and sorting in acidic organelles. Genetic and drug-induced lysosomal storage disorders (LSDs) are associated with increased BMP concentrations in tissues and in the circulation. Data on BMP in disorders other than LSDs, however, are scarce, and key enzymes regulating BMP metabolism remain elusive. Here, we demonstrate that common metabolic disorders and the intracellular BMP hydrolase α/ß-hydrolase domain-containing 6 (ABHD6) affect BMP metabolism in mice and humans. In mice, dietary lipid overload strongly affects BMP concentration and FA composition in the liver and plasma, similar to what has been observed in LSDs. Notably, distinct changes in the BMP FA profile enable a clear distinction between lipid overload and drug-induced LSDs. Global deletion of ABHD6 increases circulating BMP concentrations but does not cause LSDs. In humans, nonalcoholic fatty liver disease and liver cirrhosis affect the serum BMP FA composition and concentration. Furthermore, we identified a patient with a loss-of-function mutation in the ABHD6 gene, leading to an altered circulating BMP profile. In conclusion, our results suggest that common metabolic diseases and ABHD6 affect BMP metabolism in mice and humans.