["Probiotic medicine" and certainty of the evidence.] / "Probiotic medicine" e certezza delle evidenze.

These are excellent times for probiotic medicine. We have discovered more than 150,000 genomes of the microbiome, which can be aggregated into 4,930 species. However, the dream of microbiome-based medicine requires a new approach - an ecological and evolutionary understanding of host-microbe interactions, rather than a qualitative analysis of species. Yet researchers still disagree on what constitutes a healthy microbiome or how to define an altered one. There is still uncertainty as to which properties of the microbiome will represent the most informative biomarkers in clinical and epidemiological studies. And little is known about how the microbiomes of different regions of the body, such as the mouth, intestines or skin, interact. It is time to re-establish the foundations for the certainty of evidence in myocrobiome-based medicine. We believe robust new pillars are needed: starting clinical trials whenever possible; extending the role of N-of-1 trials; ending the "one probiotic for every disease" principle; reduce the number of outcomes of each research; search for the replicability of the results (the best test for the validity of an intervention with probiotics is not statistical significance but the replication of the result). Again, we would like to urge probiotic medicine researchers not to publish in "pirate" journals.

[Side effects of antibiotic: diarrhea and Clostridium difficile infection.] / Effetti collaterali degli antibiotici. Diarrea da antibotici e colite da Clostridium difficile.

Antibiotics are some of the most frequently prescribed medications worldwide, but antibiotic therapy may disturb the colonization resistance of gut microbiota to pathogenic bacteria, resulting in a range of symptoms that include, most notably, diarrhea that occurs between 7% and 33% of adults and 66 and 80% in pediatric patients (median of 22%) who take antibiotics. The diverse class of antibiotics may damage the metabolic homeostasis and can alter the level of intestinal metabolites including amino acids, bile acids, glucose, short chain fatty acids through alteration in abundance of metabolically active bacteria. Clostridium difficile is the main cause of antibiotics associated diarrhea: 3rd generation Cephalosporin, Clyndamicin, 2nd and 4th generation Cephalosporines, Sulfamethoxazole-trimethoprim, Quinolones, Penicillin combination show the strongest association with diarrhea.

[Clostridium difficile infection and chronic inflammatory bowel disease.] / Infezione da Clostridium difficile e malattie infiammatorie croniche intestinali.

Patients with IBD are at increased risk of developing Clostridium difficile (CD) infection and have worse outcomes, including higher rates of colectomy and death, and experience higher rates of recurrence. However, it is still not clear whether CD is a cause of IBD or a consequence of the inflammatory state and of intestinal dysbiosis. The association between IBD and CD may be due to different factors, such as drugs that are used for the treatment of IBD, including repeat courses of antibiotics, that might alter the intestinal flora and promote colonization, altered immune and nutritional status, frequent hospitalizations, and even genetic predisposition. It has been suggested that up to 20% of IBD flares were associated with testing positive for CD and retrospective studies demonstrated doubling of the infection incidence among patients with Crohn Disease, and a 3-fold increase among those with Ulcerative Colitis. They have also shown that the CD infection incidence among IBD patients is estimated as being 3-fold higher than that in the general population. Decreased intestinal microbial diversity along with an inadequate immune response is thought to play a causative role in the development of CD infection.

[Probiotics for the antibiotics associated diarrhea and for Clostridium difficile infection.] / Probiotici per la diarrea da antibiotici e per l'infezione da Clostridium difficile.

The term probiotic refers to live microorganisms that survive passage through the gastrointestinal tract and have beneficial effects on the host. Many strains of probiotic microorganisms have been shown to inhibit growth and metabolic activity as well as the adhesion to intestinal cells of enteropathogenic bacteria, to modulate the gut microbiota and to have immunostimulatory or regulatory properties. The use of probiotic microorganisms for the prevention and the treatment of Antibiotic Associated Diarrhea is an obvious measure and perhaps the most usual application of probiotics. This overview summarizes the most commonly used probiotic microorganisms for DAA and IBD.

[2020: Evidence-Based Medicine odyssey. The fall and rise of evidence-based medicine in the year of coronavirus.] / Odissea per la evidence-based medicine. Caduta e rinascita nell'anno del coronavirus.

It was a very dark year for EBM. One of the side effects of the Covid-19 pandemic is a severe compression of the evidences. Here are some worrying events. May 2020: the saga of hydroxychloroquine. October 2020: the nitazoxanide case. November 2020: Trump Administration Interferes on Expert Opinion. December 2020: the results of the trials on the first two vaccines were announced in press releases, leaving many scientific uncertainties. Peter Piot, head of the London School of Hygiene & Tropical Medicine noted that none of the CoViD-19 vaccines have offered much data to date. «It is frustrating that all of these announcements are delivered via press release, and not give us a chance to review the actual data. We desperately need total transparency on evidence and data¼, says Piot. Better now to relaunch the spread of EBM. In the issue, we have included the best EBM-based readings from the Club for Evidence-Based in Gastroenterology & Hepatology (ebgh.it).

Probiotics and Evidence-based Medicine: To All Involved: We have a Problem.

The methods used to discern the structure (anatomy) and function (physiology) of the indigenous microbiota can be divided according to which aspect of the microbiota they can interrogate and are positioned accordingly. At the most basic level, methods can simply describe the community structure of the microbiota, that is, which taxa are present and in what relative amounts. Methods that investigate functional potential generally catalog the coding potential of individual members of the microbiota or the entire community (the metagenome). To measure function directly a catalog of the expressed microbial genes (the metatranscriptome) or the proteins or metabolites present in the microbiome environment must be generated. So, complexity in understanding the role of microbiota is quite rejecting the interested clinician. Evidence-based medicine can offer an answer suggesting strict definition of populations, measurement techniques, and external validity.

[Promoting evidence-based gastroenterology: back to the future.] / Per una gastroenterologia basata sulle evidenze: ritorno al futuro.

Evidence-based medicine continues to thrive thanks to the publication of a considerable amount of papers focusing on data collection and sharing. Assessment of the accuracy of diagnostic tests still remains highly deficient, often leading to inappropriate clinical decision-making. Like most other doctors, gastroenterologists as well have to face the ever-growing availability of complex and expensive exams, being charged with the task of choosing the best diagnostic option and interpreting test results. It is therefore advisable to provide specialists with the tools they need to evaluate the available literature data. Among these, it deserves mentioning the residential courses organized by the Evidence-based Gastroenterology & Hepatology Club, which have been attended by hundreds of participants over the last years.

[Burden of diverticular disease: an observational analysis based on Italian real-world data.] / Valutazione dell'impatto economico delle complicanze della malattia diverticolare con i dati "real life" della Regione Marche.

INTRODUCTION: Diverticular disease (DD) represent a wide variety of conditions associated with the presence of diverticula in the colon. The most serious form is an acute episode of diverticulitis which can lead to hospitalization and surgery with various types of consequences. The main aim of this study was to evaluate, from both cross-sectional and longitudinal perspective, the economic burden of diverticulitis in the real practice. METHOD: A deterministic linkage was performed at individual user level between the different administrative sources of the Marche Region through anonymised ID number for a period of analysis between 1 January 2008 and 31 December 2014. We enrolled all patients with at least one hospitalization for "diverticulitis of the colon without mention of haemorrhage" (ICD-9-CM code 562.11) or "diverticulitis of the colon with haemorrhage" (ICD-9-CM code 562.13) as primary or secondary diagnosis. Cost and outcome were analysed considering transversally (for contemporaneous) and longitudinal (for cohort) perspective. Hospital mortality at one year after discharge was evaluated by mortality rates and Kaplan-Meier curve considering the surgery performed (or not performed) during the index hospitalization. RESULTS: Considering the cross-sectional perspective, 427 patients per year were estimated (about 35 patients per 100,000 adult residents) with an average number of hospitalization equal to 1.14. The direct healthcare costs incurred by the Marche region for episodes of diverticulitis in 2008-2014 amounted to approximately € 11.4 million (€ 1.6 million a year), of which € 10.9 million (95.5%) for the hospitalizations, € 246,000 (2.1%) for pharmaceutical treatment and € 270,000 (2.4%) for specialist outpatient services. The cohort analysis estimates an intra-hospital mortality rate equal to 5.9 per 100 patients' year (5.5 for non-surgery patients and 8.9 for surgery patients - P<0.05). Kaplan-Meier curve demonstrate that there were no differences between intra-hospital mortality due to surgery during index hospitalization. CONCLUSIONS: Our study is the first analysis in Italy to use real-world data to measure the burden of DD with a cross-sectional and longitudinal perspective. This study could be useful for decision maker that could quantify the economic and epidemiological burden of DD in hospital.

[Revival of evidence-based medicine in gastroenterology.] / Per la rinascita della evidence-based medicine in gastroenterologia.

The evidence-based medicine (EBM) in gastroenterology is born with the XIII International Congress of Gastroenterology, the world congress of Gastroenterology, held in Rome in 1988. A clinical epidemiology manual was placed in the congress bag for each participant. The book contained an approach to biostatistics, interpretation of epidemiological data, clinical trials, meta-analysis and decision analysis. In the pocket appeared for the first time a floppy disk that offered softwares for the analysis of Student's and χ2, for randomization and for meta-analysis. In the following years the clinical epidemiology courses of Torgiano were born, now arriving at the 18th edition. The dedicated EBGH.it portal was also born. The reflections of recent years have suggested 8 theses for the renaissance of EBM in gastroenterology. 1. The patient must return to the center of the EBM. 2. There is an urgent need for more efficient production and implementation of evidences. 3. Researchers in gastroenterology should start studies only in relevant clinical fields where are not yet sufficient answers. 4. The EBM must move towards the evidence on the different effects of an intervention. 5. The relevance of the P-value should be reconsidered. 6. Precision medicine is growing. But EBM can not wait. 7. The best validity test is not the significance but the reproducibility of the data. 8. Data from the real world (real world evidence) can help increase the validity of clinical results.

[Clinical outcomes and hospital costs of hepatic encephalopathy: an analysis of "real life" data from Marche Region.] / Valutazione degli outcome clinici e dei costi ospedalieri dell'encefalopatia epatica conclamata: un'analisi sui dati "real life" della Regione Marche.

Hepatic encephalopathy (HE) describes a spectrum of potentially reversible neuropsychiatric changes observed in patients with hepatic dysfunction and/or portosystemic shunt. The aim of this study is to compare data from clinical trials and observational studies with Italian real-world (RW) data as for clinical outcomes; other aim is to evaluate economic burden of hepatic encephalopathy related to hospitalization for overt HE. The work is based on data from the Health Information Systems (SIS) of Marche Region, Italy (about 1.5 million patients) available for the period 2008-2014. 450 subjects were identified (62% men, mean age 68 years) with a first episode of overt HE (OHE) in the three-year period 2010-2012. The mortality in the index hospitalization was equal to 32.2%; the 2-year mortality rate for a specific cause was 24.3% while that for all cases was 33.1%. The proportion of patients discharged alive from the hospitalization index that in the following two years incurs in rehospitalization, correlated with OHE is on average 66.6%. These figures largely exceed those identified in clinical trials or observational studies. Assuming that the incidence of OHE cases observed in the Marche region is representative of the national one we could estimate a charge to the NHS equal to about € 200 million for hospital assistance in the first year from the OHE event.

Gut Microbiota and the Liver: A Tale of 2 Cities: A Narrative View in 2 Acts.

Microbes are mostly important for the digestion of food, the absorption of some micronutrients, and the production of vitamins. The microbiota stimulates lymphoid structures in the gastrointestinal mucosa and decrease pathogens by competing for nutrients and space. Bacterial translocation is defined as the escape of gut bacteria and their products through the intestinal mucosa to the outside of the intestine as portovenous or systemic circulation. This is induced by a leaky gut barrier. There is evidence for a role of intestinal permeability in the pathogenesis of nonalcoholic fatty liver disease. In the liver, bacterial products can bind to their specific pathogen recognition receptors on parenchymal and nonparenchymal cells, producing an inflammatory response and enhancing disease progression. When binding, bacterial products bind to their receptors, initiating intracellular signalling and inducing an inflammatory cascade, thus accelerating liver cell damage and fibrosis. However, the liver can also increase gut permeability, producing proinflammatory cytokines, and reversing them into the blood stream. Modification of the gut microbiota could lead to benefit in patients with liver disease. Nonabsorbable antibiotics (rifaximin) prevent and relieve overt encephalopathy. Probiotics alone are not capable of turning back overt encephalopathy, but could prevent its development. There is some evidence that probiotics could relent the progression of nonalcoholic liver disease, and possibly reverse steatosis. Antibiotics, such as fluoroquinolones, reduce the risk of development of the first episode of spontaneous bacterial peritonitis and mortality in cirrhotic patients.

[Epatology towards 2020]. / L'epatologia verso il 2020.

Research in hepatology is booming. The spectrum of liver disease is very extensive. The recent advances in antiviral therapy have dramatically changed the clinical course of the diseases. This Editorial introduces the issue of Recenti Progressi in Medicina entirely focused on the near future of hepatology. Italian experts illustrate the forthcoming research and clinical innovation we should expect by 2020.

[Gastroenterology towards 2020]. / La gastroenterologia verso il 2020.

Research in gastroenterology and hepatology is booming. The spectrum of digestive diseases is very extensive, and growing. This issue of the journal focuses on the near future of gastreonterology, and announces what changes should we expect between now and 2020. The next number will be devoted to changes in hepatology.

[Diverticular disease: towards 2020. An evidence-based approach]. / La malattia diverticolare verso il 2020. Un approccio evidence-based.

Diverticular disease (DD) of the colon has an increasing burden on health service resources, in terms of hospital admissions, mortality and surgery rate. We present an overview of the clinical history of DD, and of the ways that gastroenterologists have to modify it. Prevalence of the disease increases with aging. Most of diverticulosis are occasionally identified on colonscopy, and most of them remain asymptomatic for all life. Only 4% of these subjects develop diverticulitis. However, 4-25% of these patients are expected to present a second episode of diverticulitis, and 15% of them develop complications. Hospitalizations for diverticulitis and relapses of diverticulitis show strong growth (+21% 2013 vs 2003 in USA). The total annual costs for hospitalization for DD in USA are over 2,2 billion of dollars, and in Italy exceed 63 million of euros. In-hospital mortality can reach 0,5%. Diagnosis of diverticulitis is based on clinical history, lab tests and imaging (ultrasonography, CAT). Clinical diagnosis has a sensitivity of 68% and specificity around 98%. According to a meta-analysis, the performance of ultrasonograhy and CAT results very high ("pooled" sensitivity 92-94%, and specificity 90-99%; "pooled" Likelihood Ratio positive 9.6 for ultrasonography and 78.4 for CAT. Likelihood Rato negative 0.09 and 0.06 respectively). Evidences for preventing relapse are poor. Anyway, a very recent meta-analysis on 6 RCTs suggests no role for mesalazine (GRADE SCALE for evidence 3). Non absorbable antibiotics (rifaximin) have been used in two studies (one RCT, one retrospective observational). Data from the two studies suggest some evidence in favour of its use (GRADE SCALE 1). The number of admitted patients is 291. Considering a base-line risk of 19 relapses every 100 patients (5-year observation period), the absolute risk difference is minus 9 patients with relapse (CI 95% -14 a + 3) in the RCT and minus 14 patients (CI 95% -17 a -5) in the observational study. A 2020 preview suggests an exploding interest in assessing the risk factors for relapse (including aspirin and NSAIDs) and identifying the better strategy to reduce it. Further trials are requested, including the use of probiotics alone.

[Environmental factors and clinical course of inflammatory bowel disease: which evidences?]. / Impatto dei fattori ambientali sul decorso delle malattie infiammatorie croniche dell'intestino: quali evidenze?

Identify environmental factors that can influence the course of inflammatory bowel disease (IBD) is of great interest since managing on these factors might improve the prognosis of patients. No environmental factor has been shown to have a linear cause-and-effect link with the relapse of the disease, but many environmental factors (smoking, diet, medications, stress, etc.) seem to play a plausible role in influencing the clinical course of IBD. The aim of this review is to describe the current evidence of the impact of different environmental factors on the long-term course of IBD and to give practical indications that can help doctors and patients in the management of IBD.

Pegylated interferon α plus ribavirin for the treatment of chronic hepatitis C: a multicentre independent study supported by the Italian Drug Agency.

BACKGROUND: Data on the efficacy of Peg-interferon/ribavirin therapy for chronic hepatitis C are mostly derived from treatment of selected patients enrolled in clinical trials. This study aimed to assess the effectiveness of Peg-interferon/ribavirin therapy in "real world" chronic hepatitis C patients in Italy. METHODS: Independent observational multicentre study including consecutive patients receiving Peg-interferon/ribavirin in the 18 months before (retrospective phase) and after (prospective phase) the start of the study. RESULTS: 4176 patients were eligible. The final study population consisted of 2051 patients in the retrospective and 2073 in the prospective phase. Sustained virological response was achieved by 1036 patients (50.5%) during the retrospective phase: 325 were genotypes 1/4 (34.1%) and 684 were genotypes 2/3 (67.2%) and by 800 patients (38.6%) during the prospective phase: 300 were genotypes 1/4 (28.4%) and 473 were genotypes 2/3 (51.5%). During multivariate analysis genotypes 2/3 were significantly associated with higher sustained virological response rates; cirrhosis and γ-glutamil-transpeptidase >2 times the normal limit were associated with poorer response. CONCLUSIONS: The response to Peg-interferon/ribavirin therapy in "real world" clinical practice is distinctly lower than in registration trials. The difference in response rates was more pronounced among easy-to-treat than among difficult-to-treat hepatitis C virus genotypes.

Predictors of favourable outcome in non-variceal upper gastrointestinal bleeding: implications for early discharge?

BACKGROUND: There is a lack of validated predictors on which to decide the timing of discharge in patients already hospitalized for upper nonvariceal bleeding. AIMS: Identify factors that appear to protect nonvariceal bleeders from the development of negative outcome (rebleeding, surgery, death). METHODS: Secondary analysis of two prospective multicenter studies. Multivariate analyses for each investigated outcome were performed; a single model was developed including all factors that were statistically significant in each sub-model. A final score was developed to predict favourable outcomes. Prognostic accuracy was tested with ROC curve analysis. RESULTS: Out of 2398 patients, 211 (8.8%) developed one or more adverse outcomes: 87 (3.63%) had rebleeding, 46 (1.92%) needed surgery and 107 (4.46%) died. Predictors of favourable prognosis were: ASA score 1 or 2, absence of neoplasia, outpatient bleeding, use of low-dose aspirin, no need for transfusions, clean-based ulcer, age <70 years, no haemodynamic instability successful endoscopic diagnosis/therapy, no Dieulafoy's lesion at endoscopy, no hematemesis on presentation and no need for endoscopic treatment. Overall prognostic accuracy of the model was 83%. The final score accurately identified 20-30% of patients that eventually do not develop any negative outcome. CONCLUSIONS: The "good luck score" may be a useful tool in deciding when to discharge a patient already hospitalized for acute non-variceal bleeding.