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OBJECTIVE: For safe implementation and broader application of fecal microbiota transplantation (FMT), quality controlled stool banking is a must. Establishing a stool bank is a complex, time-consuming, and expensive process, making it a real challenge in an Eastern European country. We aimed to establish the first stool bank in Eastern Europe - in Bulgaria. SUBJECTS AND METHODS: A multidisciplinary team of gastroenterologists, microbiologists, infectionists, and geneticists was set up. We used a questionnaire based on the First European FMT Consensus in order to recruit possible stool donors. Laboratory blood and stool tests were performed on all potential donors. RESULTS: Between October 2018 and April 2019, 112 donor volunteers completed a questionnaire; 70 (62.5%) were excluded, mainly because of age above 50, an unhealthy BMI, and risk behavior. Fourty-two (37.5%) donor candidates were invited for laboratory testing of blood and feces, of which 12 (28.6%) passed this screening. Of 12 donors, 4 (33%) failed at the following screening test, which is performed every 3-6 months. Finally, 8 (7.14%) active donors were enrolled. Ten successful FMTs were performed on patients with recurrent Clostridium difficile infection. CONCLUSIONS: Even though we found many healthy volunteers, only a low percentage (7.14%) of them were suitable to become feces donors. Establishing a stool bank in an Eastern European country is essential for making FMT safe and more popular as a treatment method, finding further implementation and regulation of FMT and supporting physicians offering this treatment to their patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To study gut barrier function in patients with liver cirrhosis (LC) by evaluating the intestinal permeability (IP) and its relationship with the severity and etiology of the disease. PATIENTS AND METHODS: The study included 31 patients with LC and 25 healthy controls. Child-Pugh score was used for evaluation of the LC severity. IP was assessed by the rise in levels of iohexol, which was administered orally (25 mL, 350 mg/mL) 2 h after breakfast. Three and six hours later serum (SIC mg/L) and urine (UIC g/mol) iohexol concentrations were determined by a validated HPLC-UV technique. RESULTS: Patients with LC had significantly higher mean SIC value compared with control group at 3 h (2.05 ± 1.67 vs. 1.25 ± 1.41 mg/L, p=0.021, as well as at 6 h (2.20 ± 2.65 vs. 1.11 ± 1.06 mg/L, p=0.001) after ingestion. No significant difference was found in mean SIC value of patients at 3 and 6 h. 23% of the patients had an increased IP. The mean iohexol urine recovery of patients was similar to that of the controls both at 3 h and at 6 h. Mean SIC values were significantly higher in patients with advanced Child C class than in healthy controls or the subgroup with Child B class, both at 3 h (2.54 ± 1.95 mg/L vs. 1.11 ± 1.06 mg/L, p=0.007) or (2.57 ± 1.85 mg/L vs. 1.35±1.32 mg/L, p=0.005) and at 6 h (2.57 ± 1.85 mg/L vs. 1.25 ± 1.40 mg/L, p=0.002) or 2.54 ± 1.95 mg/L vs. 1.07 ± 0.35 mg/L, p=0.02). Cirrhotic patients with ascites had significantly higher SIC in comparison with the controls, both at 3 h (2.31 ± 1.74 vs. 1.25 ± 1.41 mg/, p=0.009) and at 6 h (2.20 ± 1.87 vs. 1.11 ± 1.06 mg/l, p=0.007). In the subgroup of patients with alcoholic LC, the mean SIC values at 3 and 6 h (2.29 ± 1.80, 2.33 ± 1.85 mg/L, respectively) were significantly higher (p= 0.016, p=0.003) compared to the control group (1.25 ± 1.41, 1.11 ± 1.06 mg/L, respectively). CONCLUSIONS: Increased IP is found in 23% of cirrhotic patients. Permeability alterations are significantly more pronounced in patients with advanced LC with the presence of ascites and in those with alcoholic etiology. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We aimed to assess the preoperative rectal cancer angiogenesis with Endorectal Power Doppler Ultrasonography by using the Power Doppler Vascularity Index (PDVI) calculated by imaging analysis software, and to compare it with the microvessel density (MVD) in surgical specimens PATIENTS AND METHODS: This study included 110 patients (39 females; mean age 61.5 years) with rectal cancer. Immunohistochemical staining of surgical specimens with anti-CD-31 antibody was used for MVD evaluation. The PDVI of each tumor was calculated using Endorectal Power Doppler with computer-assisted quantification of colour pixels. RESULTS: Mean MVD - 163 ± 69 microvessels/ mm2 (50-328) was used as a cutoff point, differentiating two groups of tumors with high (> 160 mm2) and low (≤ 160 mm²) angiogenic activity. Mean PDVI of 8.9 ± 6.0% (0-27.3) was used as a cutoff point, dividing two groups of tumors with high (> 8%) and low (≤ 8%) PDVI. The MVD and the PDVI showed a good positive correlation (r = 0.438, p = 0.002). Patients with low PDVI had 25 months longer overall survival (p < 0.05) than patients with high PDVI. Patients with low MVD had 36 months longer survival (p < 0.05). CONCLUSIONS: Endorectal Power Doppler Ultrasonography is a reliable and noninvasive method for assessment of the extent of rectal cancer angiogenesis. Tumor angiogenesis assessed by the PDVI correlated with histological MVD determination and could predict survival rates. Endorectal Power Doppler examination is a useful and reproducible method for in vivo preoperative quantitative assessment of tumor vascularization. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In this study, we aimed to evaluate the role of serum trefoil factor 3 (TFF3) as a biomarker of disease activity in patients with inflammatory bowel disease (IBD) and to compare TFF3 values with those of fecal calprotectin (FC). PATIENTS AND METHODS: 128 patients with IBD were divided into four groups: 1) active ulcerative colitis (UC); 2) quiescent UC; 3) active Crohn's disease (CD); 4) quiescent CD. The serum levels of TFF3 and FC levels were assessed in all patients and 16 controls. RESULTS: Patients with active UC had higher TFF3 levels than those with quiescent UC (p<0.001), those with active (p<0.001) or quiescent CD (p<0.001) and controls (p <0.001). We found a correlation between TFF3 and FC values in patients with active (r = 0.478, p = 0.006) and quiescent UC (r=0.528, p=0.002). TFF3 levels correlated with endoscopic activity in UC (evaluated by UC Endoscopic Index of Severity - UCEIS) (r=0.662, p<0.001). CONCLUSIONS: Serum TFF3 is able to identify patients with active UC. It could be used as a marker to predict disease activity in patients with UC. [ABSTRACT FROM AUTHOR]

Background: It is essential in clinical management to determine the disease activity in ulcerative colitis (UC) patients. At present, the most accurate way of evaluating the UC severity is endoscopy with biopsy. Fecal calprotectin (FCP) is a non-invasive biomarker that is frequently used for monitoring of intestinal inflammation.

The South Balkan extensional system consists of normal faults and associated sedimentary basins within southern Bulgaria, Macedonia, eastern Albania, northern Greece, and northwestern Turkey. Extensional tectonism began during the final convergence across the Vardar, Intra-Pontide, and Izmir-Ankara suture zones, where oceanic regions closed between continental Europe and continental fragments that make up the Pelagonian, Sakar, and western Anatolian tectonic units. Earliest extension of latest Cretaceous– middle Eocene age appears to have occurred within a regional convergent tectonic setting and may be related to an increase in gravitation potential energy within a thickening continental lithosphere. Following diachronous closure across the suture zone, from the middle Eocene to late Oligocene, the transition from a regionally convergent to a regionally extensional tectonic setting occurred and was associated with abundant magmatism and formation of sedimentary basins. Extension was associated with lithospheric thinning probably related to changes in geometry of the subducted slab, dynamics of the mantle wedge, and beginning of slab rollback along the Hellenic subduction zone. A short period of local and diachronous (?) shortening (during latest Oligocene–early Miocene time) occurred in the Thrace basin of northwestern Turkey and in some basins in western Bulgaria and eastern Macedonia. Regional extension began in middle Miocene time and was related to the regional extensional tectonic setting that has dominated the Aegean extensional region to the present. Trench rollback was the dominant dynamic process, but during late Miocene time it was modified by the formation of the western part of the North Anatolian fault zone that partially decoupled the South Balkan extensional system from the Aegean extensional region. During late Cenozoic time, east-west–striking normal faults and associated sedimentary basins in the eastern part of the South Balkan extensional system propagated westward in tandem with westward migration of north-south–striking normal faults and sedimentary basins from western Bulgaria into eastern Albania. This migration was caused by evolution of the Hellenic subduction zone as it increased its curvature during trench rollback and clockwise and counterclockwise rotation of crustal fragments in the west and east, respectively. After formation of the western part of the North Anatolian fault zone, extension within the eastern part of the South Balkan extensional system was related to southward movement of its lithosphere at a slower rate than the extension within the Aegean extensional region. Active extension and basin formation show two provinces of extension that are nearly at right angles to one another and their overlap in the central South Balkan extensional system: east-west extension in central Albania to eastern Macedonia and north-south extension from northwestern Greece and eastern Macedonia to eastern Bulgaria and northwestern Turkey. [ABSTRACT FROM AUTHOR]

Abstract: Global Positioning System (GPS) data acquired between 1996 and 2004 and fault plane solutions for four seismic zones are analyzed to obtain the velocity and strain rate fields for western Bulgaria. The GPS derived velocities suggest that southwestern Bulgaria moves to the S to SSE at a rate of ∼1 mm/year with respect to northern Bulgaria and southern Romania, defining an approximately ESE-trending extensional boundary that marks the northernmost extent of the Aegean extensional domain. The boundary includes the E–W trending Sub-Balkan graben system of central Bulgaria and its westward continuation into the Sofia graben. Active faults within the boundary region trend ENE to WNW, and they have normal or oblique normal and strike–slip displacements consistent with the velocity field. Within the western part of the boundary region, extension is transferred to the north of the Sofia graben across the westernmost part of the Stara Planina Mountains and the ridges of the western Sredna Gora. The geodetically derived N–S extension is in agreement with the seismic data that show a variable pattern, but with projections of the T axes mostly lying within the N–S quadrant. The predominant type of faulting is caused by sub-horizontal extensional stresses in an approximate N–S direction. This is consistent with extension and oblique strike–slip interpreted from geological studies that show numerous WNW, ENE to E–W-trending active normal faults in western Bulgaria. [Copyright &y& Elsevier]

The ENE-tilted Mesta half-graben contains a ∼3-km-thick section of Priabonian (Late Eocene) to Oligocene sedimentary and volcanic rocks that rest unconformably on basement metamorphic rocks along its west side. Basal strata dip 50–60° E and dip at progressively lower angles upward, indicating synrotational deposition. The southern part of the half-graben contains nested volcanic caldera complexes, formed during the deposition of the middle part of the sedimentary sequence, which have been rotated by about half the total rotation of the sedimentary succession. The half-graben is bounded on the east by a fault that steepens from more deeply exposed structural levels in the south (8–18° W) to shallower exposed structural levels in the north (∼70° W) and together with the rotation of Paleogene strata during deposition indicate the Mesta half-graben is underlain by a listric detachment fault, the Mesta detachment. Subhorizontal Middle Miocene strata that unconformably overlie tilted Paleogene strata yield an upper age limit to the extension. West and northwest of the Mesta half-graben are many other NNW-trending NE-tilted Paleogene half-grabens which we suggest are part of an important extended area in SW Bulgaria and eastern Macedonia that lies above one or more west-dipping detachment faults and date the beginning of Aegean extension in the southern Balkan region as at least as old as Priabonian. The Mesta detachment is oblique to the trend of a contemporaneous Paleogene magmatic arc in the southern Balkans and the origin of the detachment is probably related to gravitationally induced spreading of thickened hot arc crust and Hellenic trench roll back. [Copyright &y& Elsevier]

Conclusion: This case illustrates the importance of taking into account the possibility for coexistence of Peutz-Jeghers syndrome (PJS) and platelet storage pool deficiency (PSPD) because this combination can lead to serious risks for the patient following invasive procedures. Introduction: PJS is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with a distinct pattern of skin and mucosal macular melanin deposition. PSPD is a rare platelet abnormality that causes a mild to moderate bleeding disorder. The Aim: We observed a patient with both PJS and PSPD. The Case: A 30-year old female was presented with complaints of colicky pain in the abdomen, easy bruising and abnormally heavy and prolonged menstruation. The endoscopic examinations found multiple polyps in the stomach, small intestine and colon. The combination of histopathologically verified hamartomatous polyps and patient's mucocutaneous melanotic pigmentation suggested the diagnosis of Peutz-Jeghers syndrome. During the polypectomy we noticed an excessive bleeding. The laboratory tests showed that platelet aggregation after stimulation with ADP and epinephrine was reduced. Moreover, only partial agglutination after stimulation with ristocetin was observed. These results suggested a deficiency of platelet granules and allowed us to diagnose PSPD in our patient.

Background The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis. Materials and methods A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated. Results Of 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90–0.95; ARD=−3.3%; 95% CI −4.2–−2.4; P  <   0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80–0.92; P  <   0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19–2.88; ARD=0.47; 95% CI 0.21–0.73; P  <   0.01). Conclusions Our findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) care and education might differ around Europe. Therefore, we conducted this European Variation In IBD PracticE suRvey (VIPER) to investigate potential differences between countries., Methods: This trainee-initiated survey, run through SurveyMonkey®, consisted of 47 questions inquiring basic demographics, IBD training, and clinical care. Results were compared according to gross domestic product (GDP) per capita, for which countries were divided into 2 groups (low/high income, according to the World Bank)., Results: The online survey was completed by 1,285 participants from 40 European countries, with a majority of specialists (65.3%) working in academic institutions (50.4%). Significant differences in IBD-specific training (55.9% vs. 38.4%), as well as availability of IBD units (58.4% vs. 39.7%) and multidisciplinary meetings (73.2% vs. 40.1%), were observed between respondees from high and low GDP countries (p < 0.0001). In high GDP countries, IBD nurses are more common (85.9% vs. 36.0%), also mirrored by more nurse-led IBD clinics (40.6% vs. 13.7%; p < 0.0001). IBD dieticians (33.4% vs. 16.5%) and psychologists (16.8% vs. 7.5%) are mainly present in high GDP countries (p < 0.0001). In the current COVID era, telemedicine is available in 73.2% versus 54.1% of the high/low GDP countries, respectively (p < 0.0001). Treat-to-target approaches are implemented everywhere (85.0%), though access to biologicals and small molecules differs significantly., Conclusion: Much variability in IBD practice exists across Europe, with marked differences between high and low GDP countries. Further work is required to help address some of these inequalities, aiming to improve and standardize IBD care and training across Europe., (© 2022 S. Karger AG, Basel.)

Background: The global pooled prevalence of gastroesophageal reflux disease (GORD) is approximately 14% and varies significantly according to the country. More population-based studies are needed in regions lacking epidemiological data on the prevalence of GORD, such as Eastern Europe, particularly Bulgaria. This current study aimed to evaluate the prevalence of GORD in Bulgaria and assess the risk factors associated with this disorder., Methods: An internet-based health survey was sent to Bulgarian adults. Individuals were invited to complete an online questionnaire on general and gastrointestinal health. The aim of the study was not explicitly stated. The survey collected data on sociodemographic and behavioral characteristics, validated questions to assess GORD, diagnostic questions based on Rome IV criteria to assess irritable bowel syndrome (IBS) and functional dyspepsia (FD), and questions about antisecretory drugs usage., Results: Data were collected from 1,896 individuals (mean age = 35.5 years, SD = 11.7, 73.1% females). The prevalence of GORD in the study population was 27.5%, while 57.29% of all GORD patients taking PPIs had PPI-refractory GORD. Age (p = 0.02), body mass index (BMI) (p < 0.001), marital status (p = 0.03), occupation (p < 0.001), sexual problems (p < 0.001), FD (p < 0.001), and IBS (p < 0.001) were significantly associated with GORD prevalence. Patients with FD (p < 0.001; OR 5.38), IBS (p = 0.03; OR 1.07), and with higher BMI (p < 0.001, OR 1.05) were at an increased risk of having GORD., Conclusions: The first data on GORD prevalence in the adult population in Bulgaria have been reported. Disorders of gut-brain interaction have a significant impact on the prevalence of GORD., (© 2022 S. Karger AG, Basel.)

Both ulcerative colitis (UC) and irritable bowel syndrome (IBS) are chronic gastrointestinal (GI) conditions that show some typical features. Persistent GI symptoms typical for IBS are observed in patients with diagnosed UC. Both IBS and UC are characterised by dysregulation of the enteric nervous system, alterations in the gut flora, low-grade mucosal inflammation, and activation of the brain-gut axis. Therefore, it appears that there may be some overlap between the two conditions. It is rather difficult to tell if the lower gastrointestinal symptoms are secondary to coexisting IBS or a hidden UC condition., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: Validated questionnaires help to minimize diagnostic bias, to standardize symptom assessment and to achieve comparability between studies and centers. In a recent European guideline the adult and the pediatric carbohydrate perception questionnaires (aCPQ and pCPQ), were recommended to be used for the diagnosis of carbohydrate intolerances in adult and pediatric patients. The implementation of this guideline into clinical practice makes availability of validated translations a necessity., Methods: Clinical experts who recognized the need for these questionnaires to be available in their own language participated in the translation process. The tasks were assigned and a workflow following a predefined procedure based on recommendations of the Rome foundation was developed. The procedure had 5 phases: foundation, nomination, translation, revision, cognitive debriefing., Results: Within eight months the aCPQ was translated into Bulgarian, French, Hungarian, Italian, Polish, Romanian, Russian and Slovenian language and the pCPQ into Dutch, French and Romanian. This expands the population which can be served with the aCPQ from 160 million to over 500 million Europeans. The reach of pCPQ expanded from 92 million to 193 million Europeans., Conclusions: We report the development and implementation of a centrally organized process of translation of validated questionnaires, following a predefined procedure based on recommendations of the Rome foundation. This structured procedure may aid future efforts to standardize and harmonize the translation of validated questionnaires.

Irritable bowel syndrome with diarrhoea (IBS-D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS-D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work-up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS-D and FDr. In terms of diagnosis, the consensus supports a symptom-based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C-reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo-, di-, monosaccharides and polyols, gut-directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5-hydroxytryptamine-3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS-D and FDr., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction: Measurement of breath hydrogen (H 2 ) and methane (CH 4 ) excretion after ingestion of test-carbohydrates is used for different diagnostic purposes. There is a lack of standardization among centers performing these tests and this, together with recent technical developments and evidence from clinical studies, highlight the need for a European guideline., Methods: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of H 2 -CH 4 -breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 44 experts from 18 European countries. Eighty eight statements and recommendations were drafted based on a review of the literature. Consensus (≥80% agreement) was reached for 82. Quality of evidence was evaluated using validated criteria., Results: The guideline incorporates new insights into the role of symptom assessment to diagnose carbohydrate (e.g., lactose) intolerances and recommends that breath tests for carbohydrate malabsorption require additional validated concurrent symptom evaluation to establish carbohydrate intolerance. Regarding the use of breath tests for the evaluation of oro-cecal transit time and suspected small bowel bacterial overgrowth, this guideline highlights confounding factors associated with the interpretation of H 2 -CH 4 -breath tests in these indications and recommends approaches to mitigate these issues., Conclusion: This clinical practice guideline should facilitate pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, it identifies areas of future research needs to clarify diagnostic and therapeutic approaches., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background: Quarantine with social distancing has reduced transmission of COVID-19; however, fear of the disease and these remedial measures cause anxiety and stress. It is not known whether these events have impacted the prevalence of gastrointestinal (GI) symptoms and disorders of brain-gut interaction (DGBI)., Methods: An online platform evaluated the prevalence of GI symptoms during the COVID-19 pandemic. Data collection utilized validated questionnaires and was fully anonymized. Findings were compared with identical data acquired in 2019. The association of results with stress and anxiety was analyzed., Results: Data were collected from 1896 subjects May - August 2019 to 980 non-identical subjects May - June 2020. GI symptoms were reported by 68.9% during the COVID-19 lockdown compared with 56.0% the previous year (p < 0.001). The prevalence of irritable bowel syndrome (26.3% vs. 20.0%; p < 0.001), functional dyspepsia (18.3% vs. 12.7%; p < 0.001), heartburn (31.7% vs. 26.2%, p = 0.002), and self-reported milk intolerance (43.5% vs. 37.8% p = 0.004) was higher during the pandemic. Many individuals reported multiple symptoms. Anxiety was associated with presence of all GI symptoms. High levels of stress impacted functional dyspepsia (p = 0.045) and abdominal pain (p = 0.013). The presence of DGBI (p < 0.001; OR 22.99), self-reported milk intolerance (p < 0.001; OR 2.50), and anxiety (p < 0.001; OR 2.18) was independently associated with increased GI symptoms during COVID-19 pandemic., Conclusions: The prevalence of GI symptoms was significantly higher during the COVID-19 lockdown than under normal circumstances the previous year. This increase was attributable to increased numbers of patients with DGBI, an effect that was associated with anxiety., (© 2021 John Wiley & Sons Ltd.)

Background: Patients with irritable bowel syndrome (IBS) usually suffer from nonspecific and overlapping signs that hamper the diagnostic process. In line with this, biomarkers specific for IBS could be of great benefit for diagnosing and managing patients. In IBS, the need is for apparent distinguishing features linked to the disease that improve diagnosis, differentiate from other organic diseases, and discriminate between IBS subtypes., Summary: Some biomarkers are associated with a possible pathophysiologic mechanism of IBS; others are used for differentiating IBS from non-IBS patients. Implementation of IBS biomarkers in everyday clinical practice is critical for early diagnosis and treatment. However, our knowledge about their efficient use is still scarce. Key Messages: This review discusses the biomarkers implemented for IBS diagnosis and management, such as blood (serum), fecal, immunological, related to the microbiome, microRNAs, and some promising novel biomarkers associated with imaging and psychological features of the disease. We focus on the most commonly studied and validated biomarkers and their biological rationale, diagnostic, and clinical value., (© 2021 S. Karger AG, Basel.)

A meta-analysis using data from 3 phase 1 studies evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of Sandoz biosimilar versus US- and EU-reference pegfilgrastim. The studies included a single-dose, double-blind, 3-arm, parallel-group study (study 1); a single-dose, double-blind, 2-way crossover study (study 2); and a single-dose, double-blind, 3-way, 6-sequence crossover study (study 3). Healthy male and female subjects were randomized to receive the proposed biosimilar (all studies), US-reference biologic (studies 1 and 3), or EU-reference biologic (studies 1, 2, and 3). For PK parameters (area under the serum concentration-time curve from time of dosing and extrapolated to infinity, area under the serum concentration-time curve from the time of dosing to the last measurable concentration, and maximum observed serum concentration) and PD parameters (absolute neutrophil count area under the effect curve from the time of dosing to the last measurable concentration and maximum measured absolute neutrophil count) geometric mean ratios and 90% confidence intervals (CIs) for treatment comparisons were calculated using the meta-analysis approach with a fixed-effects model. PK/PD biosimilarity was concluded if the 90%CIs were within the equivalence margins of 0.80 to 1.25. The 90%CIs for the geometric mean ratios for the PK/PD parameters were all within the equivalence margins. Safety and tolerability were similar between the proposed biosimilar and the US- and EU-reference pegfilgrastim in healthy subjects. This meta-analysis of 3 phase 1 studies supports PK/PD similarity of Sandoz biosimilar pegfilgrastim to US- and EU-reference pegfilgrastim. No clinically meaningful differences in safety or tolerability were observed., (© 2021 Sandoz Biopharmaceuticals. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Introduction: Medical professionals use social media to interact with other healthcare professionals, discuss medical issues and promote healthcare information. These platforms have tremendous power to promote healthcare messages but also have potential to damage the profession if used inappropriately. It is currently unknown how others perceive medical doctors' Twitter activity and, therefore, we conducted an online survey exploring these views., Methods: We used a Google Forms questionnaire consisting of 21 questions, which we distributed on Twitter, exploring doctors', patients', the public's and other healthcare professionals' views of doctors' Twitter activities. We investigated factors that were associated with mistrust by univariate and multivariate analysis., Results: Seven-hundred and twenty-six respondents completed the survey. By univariate analysis, a higher proportion of non-doctors reported witnessing unprofessional behaviour and potential breaches of patient confidentiality compared with doctors (p<0.01). In addition, a significantly higher proportion of non-doctors felt that doctors' Twitter accounts should be monitored by both their employer and regulator when compared with doctors. By multivariate analysis, the main predictor of mistrust in the profession were those that had previously witnessed unprofessional behaviour (odds ratio 2.70; 95% confidence interval 2.08-3.33; p<0.01)., Conclusion: There are discrepancies in how doctors and non-doctors view Twitter activity and significant mistrust in the profession was brought about by doctors' Twitter activity. To help limit this, adherence to current guidelines set out by the General Medical Council and British Medical Association is vital and doctors should be cautious about how their Twitter activity is professionally perceived by others before posting., (© Royal College of Physicians 2021. All rights reserved.)

As the gastrointestinal tract may also be a crucial entry or interaction site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the role of the gut mucosal immune system as a first-line physical and immunological defense is critical. Furthermore, gastrointestinal involvement and symptoms in coronavirus disease 2019 (COVID-19) patients have been linked to worse clinical outcomes. This review discusses recent data on the interactions between the virus and the immune cells and molecules in the mucosa during the infection. By carrying out appropriate investigations, the mucosal immune system role in SARS-CoV-2 infection in therapy and prevention can be established. In line with this, COVID-19 vaccines that stimulate mucosal immunity against the virus may have more advantages than the others., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Transthyretin amyloid (ATTR) amyloidosis is a rare disorder with an adult-onset defined by the accumulation of misfolded fibrils predominantly in peripheral nerves, the heart, and the digestive tract. The disease is characterized by two forms - hereditary (ATTRv) or acquired (ATTRwt). Various point mutations in the transthyretin gene induce the hereditary form of the disease. For finding new cases of ATTR amyloidosis and proper screening, the establishment of a multidisciplinary team and a Centre of Excellence (CoE) is essential. CoE provides regular education and training for better diagnosis and treatment. In the current review, we focus on the importance of having a multidisciplinary team and CoE, the screening strategy for ATTR amyloidosis in Bulgaria, and assessments performed when a patient is first suspected of having this rare disease.

Background: Faecal microbiota transplantation (FMT) is an emerging treatment modality, but its current clinical use and organisation are unknown. We aimed to describe the clinical use, conduct, and potential for FMT in Europe., Methods: We invited all hospital-based FMT centres within the European Council member states to answer a web-based questionnaire covering their clinical activities, organisation, and regulation of FMT in 2019. Responders were identified from trials registered at clinicaltrials.gov and from the United European Gastroenterology (UEG) working group for stool banking and FMT., Findings: In 2019, 31 FMT centres from 17 countries reported a total of 1,874 (median 25, quartile 10-64) FMT procedures; 1,077 (57%) with Clostridioides difficile infection (CDI) as indication, 791 (42%) with experimental indications, and 6 (0•3%) unaccounted for. Adjusted to population size, 0•257 per 100,000 population received FMT for CDI and 0•189 per 100,000 population for experimental indications. With estimated 12,400 (6,100-28,500) annual cases of multiple, recurrent CDI and indication for FMT in Europe, the current European FMT activity covers approximately 10% of the patients with indication. The participating centres demonstrated high safety standards and adherence to international consensus guidelines. Formal or informal regulation from health authorities was present at 21 (68%) centres., Interpretation: FMT is a widespread routine treatment for multiple, recurrent CDI and an experimental treatment. Embedded within hospital settings, FMT centres operate with high standards across Europe to provide safe FMT. A significant gap in FMT coverage suggests the need to raise clinical awareness and increase the FMT activity in Europe by at least 10-fold to meet the true, indicated need., Funding: NordForsk under the Nordic Council and Innovation Fund Denmark (j.no. 8056-00006B)., Competing Interests: Andreas Stallmach reports consulting fees from Institut Allergosan, MSD, Norgine, lecture fees and travel support from Astellas, Ferring, Janssen, MSD. Benjamin H. Mullish reports consultancy fees from Finch Therapeutics Group. Simon D. Goldenberg reports Consultancy fees from Astellas, Enterobiotix, Menarini, MSD, Pfizer, Shionogi and research grants from Shionogi. Laurent Alric reports consultant/speaker/investigator fees from AbbVie, BMS, Gilead, Janssen, and Merck. Cyriel Ponsioen reports grant support form Takeda, consultancy fees from Takeda, Shire, and Pliant, and speaker's fees from Tillotts and Pfizer. Caroline Trang-Poisson reports lecture fees from AbbVie, Amgen, Janssen, MaaT Pharma, MSD, takeda, advisory board fees from Arena, CT scout, MSD and meeting from AbvVie, takeda, MSD, and Janssen. Maria Vehreschild reports research grants from 3 M, Astellas Pharma, Biontech, DaVolterra, Evonik, Gilead Sciences, Glycom, Immunic, MaaT Pharma, Merck/MSD, Organobalance, Seres Therapeutics, Takeda Pharmaceutical, and speaker fees and/or consulting from Alb Fils Kliniken GmbH, Arderypharm, Astellas Pharma, Basilea, Bio-Mérieux, DaVolterra, Farmak International Holding GmbH, Ferring, Gilead Sciences, Immunic AG, MaaT Pharma, Merck/MSD, Pfizer, Roche, Organobalance, and SocraTec R&D GmbH. Severine Vermeire reports consulting fees from Prodigest/MRM Health. Elisabeth Terveer and Ed Kuijper reports research grants from Vedanta Bioscience, Boston. Simon Mark Dahl Baunwall, Christian Lodberg Hvas, Jens Frederik Dahlerup, Christian Erikstrup report research grant from the Innovation Fund Denmark (j.no. 8056–00006B). All other authors declare no competing interest., (© 2021 The Authors.)

Transthyretin amyloid (ATTR) amyloidosis is an adult-onset, rare systemic disorder characterized by the accumulation of misfolded fibrils in the body, including the peripheral nerves, the heart and the gastrointestinal tract. Gastrointestinal manifestations are common in hereditary (ATTRv) amyloidosis and are present even before the onset of the polyneuropathy in some cases. Delays in diagnosis of ATTRv amyloidosis with gastrointestinal manifestations commonly occur because of fragmented knowledge among gastroenterologists and general practitioners, as well as a shortage of centers of excellence and specialists dedicated to disease management. Although the disease is becoming well-recognized in the societies of Neurology and Cardiology, it is still unknown for most gastroenterologists. This review presents the recommendations for ATTRv amyloidosis with gastrointestinal manifestations elaborated by a working group of European gastroenterologists and neurologists, and aims to provide digestive health specialists with an overview of crucial aspects of ATTRv amyloidosis diagnosis to help facilitate rapid and accurate identification of the disease by focusing on disease presentation, misdiagnosis and management of gastrointestinal symptoms., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We aimed to determine if there was a higher incidence of small intestinal bacterial overgrowth (SIBO) in non-alcoholic fatty liver disease (NAFLD) than in patients without NAFLD. Moreover, we assessed whether patients with significant fibrosis (SF) had a higher incidence of SIBO compared with patients with non-significant or no liver fibrosis., Methods: NAFLD was diagnosed in 117 patients by using Fibroscan with a controlled attenuation parameter (CAP) as well as liver biopsy (LB). SIBO was defined by esophagogastroduodenoscopy with an aspiration of the descending duodenum., Results: Patients with non-alcoholic steatohepatitis (NASH) and those with SF on LB had a significantly higher incidence of SIBO than patients without NASH and those without SF, respectively (P < .05). According to histological characteristics, there was a higher proportion of patients in the SIBO group with higher steatosis and fibrosis grade, lobular and portal inflammation, and ballooning grade (P < .001). In multivariate analysis, significant predictors associated with SF and NASH were type 2 diabetes mellitus (T2DM) and SIBO. Moreover, in multivariate analysis, significant predictors that were independently associated with SIBO were T2DM, fibrosis stage and ballooning grade (OR 8.80 (2.07-37.37), 2.50 (1.16-5.37) and 27.6 (6.41-119), respectively). The most commonly isolated were gram-negative bacteria, predominantly Escherichia coli and Klebsiella pneumoniae., Conclusion: In this relatively large population of patients, we used a gold standard for both SIBO (quantitative culture of duodenum's descending part aspirate) and NAFLD (LB), and we demonstrated that NASH patients and those with SF had a higher incidence of SIBO. Moreover, significant predictors independently associated with SIBO were T2DM, fibrosis stage and ballooning grade. Although TE is a well-investigated method for steatosis and fibrosis detection, in our study, independent predictors of SIBO were histological characteristics of NAFLD, while elastographic parameters did not reach statistical significance., (© 2021 John Wiley & Sons Ltd.)

Background: In chronic diarrhea patients, massive over-reporting symptom-based criteria for functional bowel disorders are pitfalls. There is currently no objective biomarker that may provide a correct correlation with the severity of chronic diarrhea. To clarify the role of fibroblast growth factor-19 (FGF-19) as a biomarker of objective measurements of the severity of diarrhea in comparison with a patientreported outcome, based on the Bristol Stool Form (BSF) Scale., Methods: Consecutive 100 patients with chronic diarrhea underwent standard investigations with laboratory tests, fecal calprotectin (FC), endoscopy with biopsies, and serum FGF-19. All patients and 14 healthy controls completed a diary recording, BSF, and stool frequency., Results: We found that irritable bowel syndrome with diarrhea (IBS-D) n = 21/23 (91%) reported a high number on BSF ≥6, compared to patients with inflammatory bowel diseases (IBD) 56/77 (72%) with BSF ≥ 6 (P = .011). FGF-19 median serum levels were significantly lower in Microscopic colitis (0.010 pg/mL) and IBD patients (0.009 pg/mL) compare to IBS-D (266.9 pg/mL) and high levels in healthy subjects (463 pg/mL) (P < .001). Strong inverse correlation of FGF-19 with the stool frequency/day and stool index was found (r = -0.800, P < .001; r = -0.739, P < .001), independently from disease activity (r = -0.718, P = .001; r = -0.792, P = .001)., Conclusion: Serum FGF-19 can become a new biomarker for evaluating the severity of diarrhea with objectively and independently from intestinal inflammation. FC and FGF-19 are predictive biomarkers for the organic cause of diarrhea.

Background: Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council., Objective: Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document., Methods: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation., Results: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening., Conclusion: The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients., (© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background: Guidelines give robust recommendations on which biopsies should be taken when there is endoscopic suggestion of gastric inflammation. Adherence to these guidelines often seems arbitrary. This study aimed to give an overview on current practice in tertiary referral centres across Europe., Methods: Data were collected at 10 tertiary referral centres. Demographic data, the indication for each procedure, endoscopic findings, and the number and sampling site of biopsies were recorded. Findings were compared between centres, and factors influencing the decision to take biopsies were explored., Results: Biopsies were taken in 56.6% of 9,425 procedures, with significant variation between centres (p < 0.001). Gastric biopsies were taken in 43.8% of all procedures. Sampling location varied with the procedure indication (p < 0.001) without consistent pattern across the centres. Fewer biopsies were taken in centres which routinely applied the updated Sydney classification for gastritis assessment (46.0%), compared to centres where this was done only upon request (75.3%, p < 0.001). This was the same for centres stratifying patients according to the OLGA system (51.8 vs. 73.0%, p < 0.001). More biopsies were taken in centres following the MAPS guidelines on stomach surveillance (68.1 vs. 37.1%, p < 0.001). Biopsy sampling was more likely in younger patients in 8 centres (p < 0.05), but this was not true for the whole cohort (p = 0.537). The percentage of procedures with biopsies correlated directly with additional costs charged in case of biopsies (r = 0.709, p = 0.022)., Conclusion: Adherence to guideline recommendations for biopsy sampling at gastroscopy was inconsistent across the participating centres. Our data suggest that centre-specific policies are applied instead., (© 2020 The Author(s) Published by S. Karger AG, Basel.)