Gut microbiota alterations are associated with phenotype and genotype in familial Mediterranean fever.

OBJECTIVE: FMF is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another, despite similar genotype, suggesting the role of environmental factors. The objective of this study was to analyse the gut microbiota of a large cohort of FMF patients in relation to disease characteristics. METHODS: The gut microbiotas of 119 FMF patients and 61 healthy controls were analysed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics, and genotypes were evaluated using multivariable association with linear models (MaAslin2), adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily faeces. Bacterial network structures were also analysed. RESULTS: The gut microbiotas of FMF patients differ from those of controls in having increased pro-inflammatory bacteria, such as the Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with expansion of the Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure, with decreased intertaxa connectivity. CONCLUSION: The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment.

Deciphering the clinical spectrum of gastric disease in patients with Juvenile Polyposis Syndrome.

BACKGROUND AND AIMS: Juvenile Polyposis Syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PV) located in SMAD4 or BMPR1A genes. Precise clinical and endoscopic presentation as the evolution of gastric lesions remain ill-known. METHODS: Clinical, endoscopic, genetic, pathological data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL) database were prospectively collected to address uncertainties regarding gastric involvement. RESULTS: Thirty-six patients were included: 25 (69.5%) had SMAD4 PVs, 11 had BMPR1A PVs. For SMAD4 PV carriers, median age at inclusion was 43.0 years [range 10-78]. At baseline esophagogastroduodenoscopy (EGD), 22/25 (88%) exhibited at least one gastric juvenile polyp, 5/25 (20%) had macroscopic signs of inflammatory gastritis. Early gastric disease was mostly located under the cardia, then progressed to gastric antrum and body. During a mean follow-up period of 55.0 months, 12/25 had gastric disease progression (i.e. new juvenile polyps (91.6%), diffuse gastric involvement (41.6%), inflammatory flat progression (25%)). Among 62 biopsies, low-grade dysplasia was observed in 5 (7.5%) samples from 2 patients. Nine carriers (36%) underwent gastrectomy (mean age of 47.2 years) due to diffuse gastric involvement or worsening clinical symptoms. Gastric adenocarcinoma (T1) was found in one gastrectomy specimen. Among the 11 patients with BMPR1A PVs, 2 had gastric hamartomatomas at baseline EGD, none with dysplasia or symptoms. CONCLUSION: Gastric involvement in JPS appears to be progressive during life, initiating in the cardia area, and mostly concerns SMAD4 PV carriers.

Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases.

OBJECTIVE: The extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway. DESIGN: Targeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition. RESULTS: In mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models. CONCLUSION: Our study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4+ T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT.

Gut microbiota and stroke: New avenues to improve prevention and outcome.

Despite major recent therapeutic advances, stroke remains a leading cause of disability and death. Consequently, new therapeutic targets need to be found to improve stroke outcome. The deleterious role of gut microbiota alteration (often mentioned as "dysbiosis") on cardiovascular diseases, including stroke and its risk factors, has been increasingly recognized. Gut microbiota metabolites, such as trimethylamine-N-oxide, short chain fatty acids and tryptophan, play a key role. Evidence of a link between alteration of the gut microbiota and cardiovascular risk factors exists, with a possible causality link supported by several preclinical studies. Gut microbiota alteration also seems to be implicated at the acute phase of stroke, with observational studies showing more non-neurological complications, higher infarct size and worse clinical outcome in stroke patients with altered microbiota. Microbiota targeted strategies have been developed, including prebiotics/probiotics, fecal microbiota transplantation, short chain fatty acid and trimethylamine-N-oxide inhibitors. Research teams have been using different time windows and end-points for their studies, with various results. Considering the available evidence, it is believed that studies focusing on microbiota-targeted strategies in association with conventional stroke care should be conducted. Such strategies should be considered according to three therapeutic time windows: first, at the pre-stroke (primary prevention) or post-stroke (secondary prevention) phases, to enhance the control of cardiovascular risk factors; secondly, at the acute phase of stroke, to limit the infarct size and the systemic complications and enhance the overall clinical outcome; thirdly, at the subacute phase of stroke, to prevent stroke recurrence and promote neurological recovery.

Significant Differences in IBD Care and Education across Europe: Results of the Pan-European VIPER Survey.

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.

Time reversal of long coda waves: Experiments in the nonlinear regime.

A problem that arises when the time-reversal process is applied in a nonlinear regime is related to the generation of harmonics: conventional piezoelectric transducers cannot work properly at the frequency of the second harmonic. Then, the time-reversed wave cannot be completely emitted. Few works provide a solution to this issue. Thus, we study the alternative of performing a cross correlation of the wavefield. In a linear regime, this procedure is an accurate method for estimating real time-reversal properties. To study both procedures in the nonlinear regime in detail, we measure the wavefield of a wave that (1) traverses a multiple scattering medium, composed by a random set of parallel copper rods and (2) propagates inside a reverberant cavity, consisting of an aluminum case immersed in water. Cross correlation yields a virtually focused wavefield, where the focal width at the frequency of the first, second, and third harmonics can be measured. We compare these values with those obtained in a real time-reversal experiment. Results suggest that both time-reversal procedures are equivalent. In addition, we discuss the possibility of amplitude estimation at the focal spot and the limits of this work based on a theoretical model.

Nonlinear wave propagation through multiple scattering media and virtual time reversal focusing.

In this work, the propagation of an ultrasonic nonlinear wave through a multiple scattering medium is experimentally studied. The interaction between multiple scattering and nonlinear phenomena is analyzed by the cross correlation of the scattered field. This approach corresponds to a virtual time reversal. The cross correlated field is focused in both time and space. In linear regime, it is known that the focal width decreases as the thickness of the multiple scattering medium is increased. In this work, it is shown that this behavior is followed by a nonlinear wave and its harmonics. Moreover, due to the spectral richness of the nonlinear wave, the focal width is reduced in the nonlinear regime. This fact allows for the conclusion that the harmonics propagate following a linear scattering equation, although a nonlinear regime is required to generate them. Beside the experimental work, an estimation on the order of magnitude of the parameters that quantify nonlinearity and scattering phenomena is performed. The estimation shows that the Lighthill-Westervelt equation is as an accurate theoretical model for describing the multiple scattering of a nonlinear wave in the experiments.

Back-to-Back Comparison of Colonoscopy With Virtual Chromoendoscopy Using a Third-Generation Narrow-Band Imaging System to Chromoendoscopy With Indigo Carmine in Patients With Lynch Syndrome.

INTRODUCTION: Colonoscopic screening with indigo carmine chromoendoscopy (ICC) in patients with Lynch syndrome (LS) improves the adenoma detection rate but is time consuming and poorly used in clinical practice. Narrow-band imaging (NBI), a virtual chromoendoscopy technique, highlights superficial mucosal vessels and improves adenoma characterization. We conducted a prospective multicenter trial in a back-to-back fashion to compare the third-generation NBI with ICC for detecting colonic adenomas in patients with LS. METHODS: In a multicenter, prospective, noninferiority trial, 138 patients underwent a double colonoscopy, first with NBI, followed by ICC, in a back-to-back design. The primary noninferiority outcome measure was the number of patients with at least one adenoma after NBI compared with the number of patients with at least one adenoma after NBI and ICC. RESULTS: The 138 analyzable patients were all proven mismatch repair mutation carriers for LS (MLH1 = 33%, MSH2 = 47%, MSH6 = 15%, PMS2 = 4%, and EPCAM = 1%). The mean age (SD) was 40.5 (14.7) years, and 64 (46.4%) were men. The median withdrawal time for an NBI procedure was 8 minutes (interquartile range 6-11) compared with 13 minutes (interquartile range 8-17) for ICC. At least one adenoma was detected during the initial NBI pass in 28 patients (20.3%), and 42 patients (30.4%) had at least one adenoma detected after both NBI and ICC (difference, 10.1%; 95% confidence interval, -0.1%-20.3%); this represents an increase of 50.0% of the adenoma detection rate. ICC detected additional adenomas in 25 patients (18.1%). DISCUSSION: Colonoscopy combining NBI and ICC detects more adenomas than third-generation NBI alone in patients with LS, respectively, 30.4% vs 20.3% (difference, 10.1%; 95% confidence interval, -0.1 to 20.3), thus failing the noninferiority assumption of NBI compared with combined NBI and ICC. Although less time consuming, colonoscopy using the third-generation NBI cannot be recommended to replace ICC in patients with LS.

Parameters influencing the pharmacokinetics/pharmacodynamics of piperacillin/tazobactam in patients with febrile neutropenia and haematological malignancy: a prospective study.

OBJECTIVES: To assess population pharmacokinetics (PK) and pharmacodynamics (PD) of both piperacillin and tazobactam in neutropenia patients and examine dosage requirements related to the MIC distribution for Gram-negative bacteria involved in bloodstream infections (BSIs). METHODS: We conducted a prospective study including adult haematological malignancy patients with febrile neutropenia receiving piperacillin/tazobactam as short (30 min) or prolonged (4 h) intravenous infusions. Concentration data were analysed using a population approach. Dosing simulations with the final model investigated factors influencing the PK/PD of piperacillin/tazobactam quantified by fT>MIC or PTA for piperacillin and tazobactam, respectively. In parallel, the local MIC distribution of ß-lactams was documented for Gram-negative bacteria involved in BSIs. RESULTS: Over 10 months, 31 patients were enrolled, with 11 (35.5%) short and 20 (64.5%) prolonged infusion regimens. A one-compartment model adequately described the data for both drugs. Prolonged infusion, increased serum alkaline phosphatase (ALP) values and renal function impairment were associated with increased piperacillin fT>MIC. For patients with normal or augmented renal CL, dosing regimens q8h or q6h with 30 min of infusion were insufficient to achieve acceptable PTA for piperacillin/tazobactam at the median MIC value of 8 mg/L. Prolonged infusion of large doses was associated with the best PTA for both piperacillin and tazobactam. CONCLUSIONS: In a population of haematological malignancy patients with neutropenia, renal function and ALP influenced the PK of piperacillin/tazobactam. Prolonged intravenous infusion would optimize the PK of piperacillin/tazobactam, especially in the case of augmented renal CL and/or low-range bacterial susceptibility.

Management of small bowel polyps: from small to big.

PURPOSE OF REVIEW: Benign small bowel polyps or mass are clinically poorly distinguishable from malignant small bowel masses, and the diagnostic conditions are almost the same. The important point for clinicians is first to take advantage of the different available diagnostic tools to optimize the diagnostic algorithm of a small bowel polyp or mass. Next, according to the clinical situation, associated disease or sporadic situation, the difficulty is to adapt the treatment decision to the patient situation. RECENT FINDINGS: The last 20 years have been marked by the development of major diagnostic tools for small bowel diseases (capsule endoscopy, cross-sectional imaging with enteroclysis and balloon-assisted enteroscopy) and by the major decrease of intra-operative enteroscopy as a diagnostic mean. SUMMARY: On the basis of considerable development of capsule endoscopy and the improvement of cross-sectional small bowel imagining, small bowel polyps represent now a frequent clinical situation for gastroenterologists.

Multicenter Evaluation of Clinical Efficacy and Safety of Per-oral Endoscopic Myotomy in Children.

OBJECTIVES: Per-oral endoscopic myotomy (POEM) is a recommended treatment modality for achalasia, but there is little published data for its use in children. The objective of the present study was to evaluate whether POEM is clinically effective and safe for children. METHODS: International multicenter retrospective study conducted in 14 tertiary centers that included consecutive children who underwent POEM between January 2012 and August 2018. Outcomes, such as clinical response were assessed whenever available. Adverse events and factors associated with clinical failure were also investigated. RESULTS: A total of 117 patients (mean ±â€ŠSD age: 14.2 ±â€Š3.7 years) underwent POEM for achalasia (type I, n = 36; type II n=66; type III, n=8). Among these, 30 (26%) were pretreated (botulinum injection and/or pneumatic dilatation). Mean ±â€ŠSD baseline Eckardt score was 7.5 ±â€Š2.0. Clinical success was achieved in 90.6% of cases (95%CI [83.8%;95.2%]) in the intention-to-treat analysis. The mean ±â€ŠSD Eckardt score post-POEM was 0.9 ±â€Š1.2 (P < 0.001). The mean duration of follow-up time 545 days (range: 100-1612). A total of 7 adverse events occurred (4 mucosotomies, 2 subcutaneous emphysema, 1 esopleural fistula). Gastroesophageal reflux symptoms were seen in 17 patients (15%); missing data for 10 patients (9%). There was a trend towards more frequent clinical failure in achalasia associated with genetic disorders (40% vs 8%, P = 0.069). CONCLUSIONS: POEM in pediatric patients appears to be effective and safe, although there was a trend towards more frequent clinical failure achalasia associated with genetic disorders. Further studies are needed to assess the long-term outcomes, especially the consequences of GERD.

The seismic wave motion camouflage of large carnivorous dinosaurs.

Living elephants produce seismic waves during vocalizations and locomotion that are potentially detectable at large distances. In the Mesozoic world, seismic waves were probably a very relevant source of information about the behavior of large dinosaurs. In this work, we study the relationship between foot shape and the directivity pattern of seismic waves generated during locomotion. For enlarged foot morphologies (based on a morphological index) of theropod dinosaurs, there is a marked effect of seismic wave directivity at 20 m. This effect is not important in the foot morphologies of other dinosaurs, including the foot shapes of herbivores and theropods such as therizinosaurids. This directivity produces a lower intensity in the forward direction that would slightly reduce the probability of detection of an ambush predator. Even more relevant is the fact that during the approach of a predator, the intensity of seismic waves detected by potential prey remains constant in the mentioned distance range. This effect hides the predator's approach, and we call this "seismic wave camouflage". We also discuss the potential relationship of this effect with enlarged fossil footprints assigned to metatarsal support.