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Endoscopic management for difficult common bile duct (CBD) stones still presents a challenge for several reasons, including anatomic anomalies, patients' individual conditions and stone features. In recent years, variable methods have emerged that have attributed to higher stone removal success rates, reduced cost and lower adverse events. In this review, we outline a stepwise approach in CBD stone management. As first line therapy, endoscopic sphincterotomy and large balloon dilation are recommended, due to a 30%-50% reduction of the use of mechanical lithotripsy. On the other hand, cholangioscopy-assisted lithotripsy has been increasingly reported as an effective and safe alternative technique to mechanical lithotripsy but remains to be reserved in special settings due to limited large-scale evidence. As discussed, findings suggest that management needs to be tailored to the patient's characteristics and anatomical conditions. Furthermore, we evaluate the management of CBD stones in various surgical altered anatomy (Billroth II, Roux-en-Y and Roux-en-Y gastric bypass). Moreover, we could conclude that cholangioscopy-assisted lithotripsy needs to be evaluated for primary use, rather than following a failed management option. In addition, we discuss the importance of dissecting other techniques, such as the primary use of interventional endoscopic ultrasound for the management of CBD stones when other techniques have failed. In conclusion, we recognize that endoscopic sphincterotomy and large balloon dilation, mechanical lithotripsy and intraductal lithotripsy substantiate an indication to the management of difficult CBD stones, but emerging techniques are in rapid evolution with encouraging results.

Background Assistive technologies have the potential to facilitate everyday life of people with dementia and their families. Close collaboration with affected people and interdisciplinary research are essential to understand and address the needs of prospective users. In this study, we present the results of the evaluation of such an assistive system prototype. Aims Challenges from the patient and caregiver side, technical and design problems and acceptance and usability with regard to our special target group were evaluated. Methods MEMENTO, a system of two e-ink tablets and a smartwatch, was tested in the domestic environment of dementia patients. Thirty participants from Italy, Spain and Austria took part in a 3-month field trial and compared the MEMENTO system to traditional strategies in everyday life. Quantitative and qualitative data were collected and frequency of use of the system was monitored. Results There were no significant changes in quantitative measurements, such as activities of daily living and caregiver burden over the duration of the 3-month field trial. More frequent usage was significantly correlated with positive attitude towards technology (r = 0.723, p Conclusion We show that a positive attitude towards technology is the essential variable for successful implementation of such systems, regardless of age. Participants showed great interest in digital solutions and agreed that technological systems will help in maintaining independency of persons with cognitive dysfunction in the future.

Lumen-apposing metal stents (LAMS) are recently introduced devices that allow to create anastomoses. The indications for LAMS placement are increasing and currently these stents can be used in multiple clinical situations such as endoscopic drainage of pancreatic fluid collections (PFCs), endoscopic ultrasound-guided choledocho-duodenostomy (EUS-CDS), endoscopic ultrasound gallbladder drainage (EUS-GBD), endoscopic ultrasound gastrojejunostomy (EUS-GJ). Since their introduction, they have revealed to allow a higher rate of technical and clinical success, and potentially lower risk of adverse events (AEs) compared with previously available devices. Despite ongoing innovation, any advanced intervention carries risks of AEs. These AEs may occur during the deployment or can be delayed because of the consequent effects of the procedure and/or stent itself. This review represents an overview of current indications, technical and clinical results, with an extensive focus on safety issues related to placement and on long-term indwelling related ones.

What is the relationship between the concepts of the predictive processing theory of brain functioning and the everyday concepts with which people conduct and explain their mental lives? To answer this question, we focus on predictive processing explanations of mental disorder that appeal to false inference. After distinguishing two concepts of false inference, we survey four ways of understanding the relationship between explanations of mental phenomena at the personal and sub-personal level. We then argue that if predictive processing accurately accounts for psychological and socio-cultural dynamics, then personal and sub-personal concepts must display a looping relationship that can impact the nature of at least some mental phenomena. In particular, explaining the phenomenon of delusion in terms of the sub-personal concept of false inference should change the nature of delusional experiences themselves.

Abstract Introduction Endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy (SAA) is technically challenging and associated with a significant number of failures. We examined the feasibility and efficacy of a novel technique for the management of bile duct stones (BDSs), called underwater cap-assisted ERCP (u-ERCP). Methods Between June 2019 and February 2020 all patients with SAA with jaundice or cholangitis secondary to BDSs who underwent u-ERCP were enrolled. The u-ERCP technique combines the underwater advancement of a pediatric colonoscope with a transparent cap fitted on the tip of the endoscope. We evaluated the technical success, clinical success, and adverse events associated with u-ERCP. Results We describe the technique itself and our initial experience in six patients. A complete and successful procedure was carried out in all patients, with the occurrence of no adverse events. None of the patients needed additional treatments for recurrence of symptoms during the follow-up period. Conclusions u-ERCP can be considered as a promising alternative for successful endoscopic management of biliary disease in patients with SAA.

Italy recorded its first case of confirmed acute respiratory illness because of coronavirus on February 18, 2020, soon after the initial reports in China. Since that time, Italy and nations throughout the world have adopted very stringent and severe measures to protect populations from spread of infection. Despite these measures, the number of infected people is growing exponentially, with a significant number of patients developing acute respiratory insufficiency. Endoscopy departments face significant risk for diffusion of respiratory diseases that can be spread via an airborne route, including aspiration of oral and fecal material via endoscopes. The purpose of this article is to discuss the measures, with specific focus on personal protection equipment and dress code modalities, implemented in our hospital to prevent further dissemination of COVID-19 infection.

According to the recently updated Tokyo Guidelines, laparoscopic cholecystectomy still represents the gold standard for the treatment of acute cholecystitis. However, fragile patients, due to comorbidities or poor clinical conditions, have a high surgical risk. In such cases, percutaneous or endoscopic gallbladder drainage is considered the treatment of choice. In particular, endoscopic ultrasound-guided gallbladder drainage with the placement of specifically designed stents is now considered an alternative option. In addition, the opening of an access door to the lumen of the gallbladder could offer new opportunities for the endoscopic treatment of gallbladder diseases. The purpose of this review is to provide an update on the latest available evidence in the literature regarding the endoscopic ultrasound-guided gallbladder drainage.

We compare three theoretical frameworks for pursuing explanatory integration in psychiatry: a new dimensional framework grounded in the notion of computational phenotype, a mechanistic framework, and a network of symptoms framework. Considering the phenomenon of alcoholism, we argue that the dimensional framework is the best for effectively integrating computational and mechanistic explanations with phenomenological analyses.

Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard procedure for malignant jaundice palliation; however, it can be challenging when a duodenal self-expandable metal stent (SEMS) is already in place. Patients and methods The primary aim of our study was to evaluate the technical feasibility of the placement of a lumen apposing metal stent (LAMS) through the mesh (TTM) of duodenal stents. The secondary aims were to evaluate clinical outcomes and adverse events (AEs) related to the procedures. Results Data from 23 patients (11 F and 12 M; mean age: 69.5 ± 11 years old) were collected. In 17 patients (73.9 %) TTM LAMS placement was performed as first intention, while in six patients (26.1 %) it was performed after a failed ERCP. Thirteen patients (56.5 %) underwent the procedure due to advanced pancreatic head neoplasia. One technical failure was experienced (4.3 %). The TTM LAMS placement led to a significant decrease in the serum levels of bilirubin, ALP, GGT, WBC and CRP. No cases of duodenal SEMS occlusion occurred and no other AEs were observed during the follow-up. Conclusions Concomitant malignant duodenal and biliary obstruction is a challenging condition. Palliation of jaundice using TTM LAMS in patients already treated with duodenal stent is associated to promising technical and clinical outcomes.

Objective To compare withdrawal of antiseizure medications (ASM) to continued treatment in newly diagnosed individuals achieving seizure freedom, and assess the risk of relapse and factors associated with relapse. Methods This is a multicenter retrospective cohort study with long-term follow-up. Patients with newly diagnosed epilepsy were identified from the medical records of 13 Italian epilepsy centers and followed up until the most recent visit or death. Seizure-free patients discontinuing treatment were compared to patients who maintained treatment for baseline characteristics. Treatment was stopped upon clinical judgment. The probability of relapse was calculated with the Kaplan–Meier method. Demographic, clinical, and instrumental variables associated with relapse were assessed with Cox proportional hazards models. Results One thousand and six patients aged 1 month to 72 years at diagnosis were enrolled and followed up for 17,892 person-years (median follow-up, 9.9 years). Three hundred and twenty patients (31.8%) underwent one or more treatment discontinuations. Factors associated with ASM withdrawal were younger age at remission and normal psychiatric examination. The probability of relapse after the first withdrawal was 16% at six months, 24% at 12 months, and 36%, 45%, and 53% at three, five, and ten years, respectively. The probability of remission after the first relapse was 59% at one month, 67%, 72, and 76% at three, six, and 12 months, respectively. Variables associated with relapse were age 14+ years, structural etiology, abnormal neuroimaging, ASM initiation after a single seizure, and symptomatic/cryptogenic epilepsy. Conclusions About one half of seizure-free patients stopping ASM relapse in 10 years. However, the possibility of remission after relapse is high, particularly in children and patients with idiopathic/cryptogenic epilepsy. Treatment deprescription might be encouraged at least in these patients.

An adequate explication of miscomputation should do justice to relevant practices in the computational sciences. While philosophers of computation have neglected scientific practices outside computer science, here I focus on computational psychiatry. I argue that computational psychiatrists use a concept of miscomputation in their explanations, and that this concept should be explicated as interest-relative and perspectival, although non-arbitrary, relatively clear-cut, experimentally evaluable, and instrumentally useful. To the extent my argument is convincing, we should reconsider the general adequacy of the mechanistic view of computation for illuminating relevant methodological and explanatory practices in the computational sciences.

Climate change, nutrition, poverty and medical drugs are widely discussed and pressing issues in science, policy and society. Despite these issues being of great importance for the quality of our lives it remains unclear how well people understand them. Specifically, do particular demographic and socioeconomic factors explain variation in public understanding of these four concepts? To what extent are people's changes in understanding associated with changes in their behaviour? Do people judge scientific practices relying on the more descriptive concepts of climate change and effective medical drugs to be more objective (less controversial) than practices relying on the more value-laden concepts of poverty and healthy nutrition? To address these questions, an experimental survey and regression analyses are conducted using data collected from about one thousand participants across different continents. The study finds that public understanding of science is generally low. A smaller proportion of people were able to correctly identify the common explanation accepted internationally among the scientific community for climate change and effectiveness of medical drugs (42% and 43% of participants in the study, respectively) than for poverty and healthy nutrition (61% and 65% of participants, respectively). Older age and political non-conservativeness were the strongest predictors of correctly understanding these four concepts. Greater levels of education and political non-conservativeness were in turn the strongest predictors of people's reported changes in their behaviour based on their improved understanding of these concepts. Because climate change is among the least understood scientific concepts but is arguably the greatest challenge of our time, better efforts are needed to improve how media, awareness campaigns and education systems mediate information on the topic in order to tackle the large knowledge deficits that constrain behavioural change.

Background and aims Restarting activity in Endoscopic Departments (ED) after COVID-19 lockdown raises critical issues. This survey investigates strategies and uncertainties on resumption of elective activity. Methods Directors of 55 EDs in Northern Italy received a questionnaire focusing on the impact of pandemic on activity and organization and on the resources available at re-opening. A section was devoted to gather forecasts and proposals on the return path to normality. Results All centres had reduced their activities of at least 50% of the pre-COVID-19 period. A rate of endoscopists (13.6%), nurses (25.2%), and health assistants (14%) were not available since infected, or relocated to other departments. One third of endoscopic rooms were converted to COVID-19 care. Two third had the waiting or the recovery areas too small for distancing. A dedicated pathway for infected patients could not be guaranteed in 20% of EDs. Only one third of EDs judged realistic to completely restore a pre-crisis workload by the next months. Optimizing appropriateness of procedures, closer interaction with GPs and triaging patients with telemedicine were the proposals to re-open EDs. Conclusions The critical issues while re-opening EDs calls for reducing the workload in the endoscopy units through appropriate rescheduling of procedures. Funding None

The introduction of direct-acting antiviral agents (DAA) has revolutionized management and care of patients with chronic hepatitis C virus (HCV) infection, leading to cure rates higher than 90% in patients with advanced liver disease as well. Viral eradication has been associated with longer survival, reduced mortality from both hepatic and extrahepatic causes, improvement in liver function, and reduced incidence of HCV-related extrahepatic diseases. While patients with mild fibrosis can safely be discharged after achievement of a sustained virological response, patients with advanced fibrosis and cirrhosis remain at risk of developing complications of liver disease, thus requiring regular and life-long surveillance. Major complications of cirrhosis that need to be monitored are hepatocellular carcinoma onset and development or progression of clinically significant portal hypertension.

Background and Aims Hot snare polypectomy and EMR are the standard of care in resecting colorectal polyps ≥10 mm. To avoid the risk of electrocautery-induced damage, there is recent evidence about using cold snare polypectomy and cold EMR for such lesions. The aim of this pooled analysis is to report outcomes of cold snare resection for polyps ≥10 mm. Methods PubMed/Medline, Embase, Google Scholar, and Cochrane databases were searched up to July 2018 to identify studies that performed cold snare resection for colorectal polyps ≥10 mm. Primary outcomes were adverse events (bleeding, perforation, and postpolypectomy abdominal pain), and secondary outcomes were the rates of complete resection, overall residual polyp rates, and rates for adenomas versus sessile serrated polyps (SSPs). Subgroup analysis was performed focusing on lesion size, location, and resection technique. Results Eight studies were included in the final analysis that included 522 colorectal polyps with a mean polyp size of 17.5 mm (range, 10-60). The overall adverse event rate was 1.1% (95% confidence interval, CI, 0.2%-2.0%; I2 = 0%). Intra- and postprocedural bleeding rates were .7% (95% CI, 0%-1.4%) and .5% (95% CI, .1%-1.2%), respectively, with abdominal pain rate being .6% (95% CI, .1%-1.3%). Polyps ≥20 mm had a higher intraprocedural bleeding rate of 1.3% (95% CI, .7%-3.3%) and abdominal pain rate of 1.2% (95% CI, .7%-3.0%) but no delayed bleedings. No perforations were reported. The complete resection rate was 99.3% (95% CI, 98.6%-100%). Overall pooled residual rates of polyps of any histology, adenomas, and SSPs were 4.1% (95% CI, .2%-8.4%), 11.1% (95% CI, 4.1%-18.1%), and 1.0% (95% CI, .4%-2.4%), respectively, during a follow-up period ranging from 154 to 258 days. Conclusions The results of this systematic review and pooled analysis were excellent with cold snare resection of colorectal polyps >10 mm in terms of postpolypectomy bleeding, complete resection, and residual polyp rates. Randomized controlled trials comparing cold snare resection with hot snare resections of polyps ≥10 mm are required for further investigation.

There continues to be significant confusion about the goals, scope, and nature of modellingpracticeinneuroeconomics.Thisarticleaimstodispelsomesuchconfusionbyusing one of the most recent critiques of neuroeconomic modelling as a foil. The article argues fortwoclaims.First,currently,foratleastsomeeconomicmodelofchoicebehaviour,the benefits derivable from neurally informing an economic model do not involve special tractabilitycosts.Second,modellinginneuroeconomicsisbestunderstoodwithinMarr’s three-levelofanalysisframeworkandinlightofaco-evolutionaryresearchideology.The first claim is established by elucidating the relationship between the tractability of a model, its descriptive accuracy, and its number of variables. The second claim relies on an explanation of what it can take to neurally inform an economic model of choice behaviour.

Importance Coronavirus disease 2019 (COVID-19) is a global pandemic and can involve the gastrointestinal (GI) tract, including symptoms like diarrhea and shedding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in feces. Objective To provide a pooled estimate of GI symptoms, liver enzyme levels outside reference ranges, and fecal tests positive for SARS-CoV-2 among patients with COVID-19. Data Sources An electronic literature search was performed for published (using MEDLINE/PubMed and Embase) and preprint (using bioRxiv and medRxiv) studies of interest conducted from November 1, 2019, to March 30, 2020. Search terms included “COVID-19,” “SARS-Cov-2,” and/or “novel coronavirus.” Study Selection Eligible studies were those including patients with SARS-CoV-2 infection who reported GI symptoms. Data Extraction and Synthesis Data on patients with GI symptoms (ie, diarrhea, nausea, or vomiting), liver enzyme level changes, and fecal shedding of virus were extracted. Quality of studies was examined using methodological index for nonrandomized studies. Pooled estimates (%) were reported with 95% CIs with level of heterogeneity (I2). Main Outcomes and Measures Study and patient characteristics with pooled detection rates for diarrhea, nausea or vomiting, liver enzyme levels outside reference ranges, and SARS-CoV-2 positivity in feces tests were analyzed. Results Of 1484 records reviewed, 23 published and 6 preprint studies were included in the analysis, with a total of 4805 patients (mean [SD] age, 52.2 [14.8] years; 1598 [33.2%] women) with COVID-19. The pooled rates were 7.4% (95% CI, 4.3%-12.2%) of patients reporting diarrhea and 4.6% (95% CI, 2.6%-8.0%) of patients reporting nausea or vomiting. The pooled rate for aspartate aminotransferase levels outside reference ranges was 20% (95% CI, 15.3%-25.6%) of patients, and the pooled rate for alanine aminotransferase levels outside reference ranges was 14.6% (95% CI, 12.8%-16.6%) of patients. Fecal tests that were positive for SARS-CoV-2 were reported in 8 studies, and viral RNA shedding was detected in feces in 40.5% (95% CI, 27.4%-55.1%) of patients. There was high level of heterogeneity (I2 = 94%), but no statistically significant publication bias noted. Conclusions and Relevance These findings suggest that that 12% of patients with COVID-19 will manifest GI symptoms; however, SAR-CoV-2 shedding was observed in 40.5% of patients with confirmed SARS-CoV-2 infection. This highlights the need to better understand what measures are needed to prevent further spread of this highly contagious pathogen.

According to the reward-prediction error hypothesis (RPEH) of dopamine, the phasic activity of dopaminergic neurons in the midbrain signals a discrepancy between the predicted and currently experienced reward of a particular event. It can be claimed that this hypothesis is deep, elegant and beautiful, representing one of the largest successes of computational neuroscience. This paper examines this claim, making two contributions to existing literature. First, it draws a comprehensive historical account of the main steps that led to the formulation and subsequent success of the RPEH. Second, in light of this historical account, it explains in which sense the RPEH is explanatory and under which conditions it can be justifiably deemed deeper than the incentive salience hypothesis of dopamine, which is arguably the most prominent contemporary alternative to the RPEH.

β-2 microglobulin (β2m) is an amyloidogenic protein responsible for dialysis-related amyloidosis in man. In the early stages of amyloid fibril formation, β2m associates into dimers and higher oligomers, although the structural details of such aggregates are poorly understood. To characterize the protein-protein interactions supporting the formation of oligomers, three individual β2m cysteine mutants and their disulfide-linked homodimers (DIMC20, DIMC50 and DIMC60) were prepared. Amyloid propensity, oligomerization state in solution and crystallogenesis were tested for each β2m homodimer: DIMC20 and DIMC50 display a mixture of tetrameric and dimeric species in solution and also yield protein crystals and amyloid fibrils, whereas DIMC60 is dimeric in solution but does not form protein crystals nor amyloid fibrils. The X-ray structures of DIMC20 and DIMC50 show that the two engineered dimers form a tetrameric assembly; for both tetrameric species, the noncovalent association interface is based on the interaction of facing β2m D-strands and is conserved. Notably, DIMC20 and DIMC50 trigger amyloid formation in wild-type β2m in unseeded reactions. Thus, when the D-D-strand interface is impaired by an intermolecular disulfide bond (as in DIMC60), the formation of tetramers is hindered, and the protein is not amyloidogenic and does not promote amyloid aggregation of wild-type β2m. Implications for β2m oligomerization are discussed.

Proteins hosting main β-sheets adopt specific strategies to avoid intermolecular interactions leading to aggregation and amyloid deposition. Human beta-2 microglobulin (β2m) displays a typical immunoglobulin fold and is known to be amyloidogenic in vivo. Upon severe kidney deficiency, β2m accumulates in the bloodstream, triggering, over the years, pathological deposition of large amyloid aggregates in joints and bones. A β-bulge observed on the edge D β-strand of some β2m crystal structures has been suggested to be crucial in protecting the protein from amyloid aggregation. Conversely, a straight D-strand, observed in different crystal structures of monomeric β2m, could promote amyloid aggregation. More recently, the different conformations observed for the β2m D-strand have been interpreted as the result of intrinsic flexibility, rather than being assigned to a functional protective role against aggregation. To shed light on such contrasting picture, the mutation Asp53→Pro was engineered in β2m, aiming to impair the formation of a regular/straight D-strand. Such a mutant was characterized structurally and biophysically by CD, X-ray crystallography and MS, in addition to an assessment of its amyloid aggregation trends in vitro. The results reported in the present study highlight the conformational plasticity of the edge D-strand, and show that even perturbing the D-strand structure through a Pro residue has only marginal effects on protecting β2m from amyloid aggregation in vitro.

β2 microglobulin (β2m) is the light chain of class-I major histocompatibility complex (MHC-I). Its accumulation in the blood of patients affected by kidney failure leads to amyloid deposition around skeletal joints and bones, a severe condition known as Dialysis Related Amyloidosis (DRA). In an effort to dissect the structural determinants of β2m aggregation, several β2m mutants have been previously studied. Among these, three single-residue mutations in the loop connecting strands D and E (W60G, W60V, D59P) have been shown to affect β2m amyloidogenic properties, and are here considered. To investigate the biochemical and biophysical properties of wild-type (w.t.) β2m and the three mutants, we explored thermal unfolding by Trp fluorescence and circular dichroism (CD). The W60G mutant reveals a pronounced increase in conformational stability. Protein oligomerization and reduction kinetics were investigated by electrospray-ionization mass spectrometry (ESI-MS). All the mutations analyzed here reduce the protein propensity to form soluble oligomers, suggesting a role for the DE-loop in intermolecular interactions. A partially folded intermediate, which may be involved in protein aggregation induced by acids, accumulates for all the tested proteins at pH 2.5 under oxidizing conditions. Moreover, the kinetics of disulfide reduction reveals specific differences among the tested mutants. Thus, β2m DE-loop mutations display long-range effects, affecting stability and structural properties of the native protein and its low-pH intermediate. The evidence presented here hints to a crucial role played by the DE-loop in determining the overall properties of native and partially folded β2m.

Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy is likely to be a class side effect of these drugs, although its severity is largely variable, and it deserves to be further investigated, since the mechanisms of BTZ-induced peripheral neurotoxicity (BiPN) are still unknown. In our study, we investigated in vivo and in vitro possible pathogenic events relevant to BiPN using a well-established rat model, with particular reference to the extent of proteasome inhibition and the effects on α-tubulin polymerization in sciatic nerves and dorsal root ganglia specimens obtained from animals treated with chronic regimens at a dose of 0.2 mg/kg intravenously. The same assessments were also performed after a single injection. Moreover, these studies were replicated in vitro using embryonic DRG neurons exposed to 100 nM BTZ and adult DRG neurons exposed to 10-50 nM BTZ for 24 h and 48 h. A significant increase in the polymerized fraction of α-tubulin and prolonged proteasome inhibition were observed after the chronic BTZ treatment in vivo. Recovery to physiological levels was observed after a 4-week follow-up post-treatment period. Proteasome inhibition and increased α-tubulin polymerization were also observed following BTZ treatment of both embryonic and adult DRG neurons in vitro. Our in vivo results suggest that proteasome inhibition and alteration of tubulin dynamics contribute to BiPN. The in vitro systems here described reliably replicate the in vivo results, and might therefore be used for further mechanistic studies on the effects of proteasome inhibitors on neurons.

Beta2-microglobulin (beta2m) is the light chain component of class I major histocompatibility complex (MHC-I). beta2m is an intrinsically amyloidogenic protein that can assemble into amyloid fibrils in vitro and in vivo. Several recent reports suggested that the polypeptide loop comprised between beta-strands D and E of beta2m is important for protein stability and for the protein propensity to aggregate as amyloid fibrils. In particular, the roles of Trp60 for MHC-I assembly and beta2m stability have been highlighted by showing that the beta2m Trp60-->Gly mutant is more stable and less prone to aggregation than the wild type protein. To further analyse such properties, the Trp60-->Cys and Asp59-->Pro beta2m mutants have been expressed, purified, and their crystal structures determined. The stability to thermal denaturation and propensity to fibrillar aggregation have also been analysed. The experimental evidences gathered on the two mutants reinforce the hypothesis that conformational strain in the DE loop can affect beta2m stability and amyloid aggregation properties.

Background and Aims Gastroparesis (GP) is a chronic debilitating condition. Prior pyloric-targeted procedures are either invasive or have questionable efficacy. Gastric peroral pyloromyotomy (G-POEM) has been proposed as a minimally invasive approach. We performed a pooled analysis to evaluate the efficacy and safety of G-POEM for GP. Methods Electronic databases (Medline, Scopus, EMBASE) were searched up to January 2019. Studies including patients who underwent G-POEM for GP were eligible. Procedural, clinical, and safety outcomes were assessed by pooling data with a random- or fixed-effect model according to the degree of heterogeneity to obtain a proportion with a 95% confidence interval. Results Ten studies were eligible for inclusion (292 patients), and 2 of the 10 studies were prospective. Seven studies were performed in the United States, 2 in France, and 1 in China. Endoscopic pyloromyotomy was feasible in all patients. Significant symptomatic improvement was achieved after 83.9% of procedures (mean follow-up, 7.8 ± 5.5 months). When comparing the mean values of pre- and postprocedural scintigraphic evolution, there was a significant decrease of the residual percentage at 2 and 4 hours. The overall adverse events rate was 6.8%. Conclusions G-POEM appears to be a promising approach for GP in terms of safety and efficacy outcomes in the short term.

Background The genome of measles virus consists of a non-segmented single-stranded RNA molecule of negative polarity, which is encapsidated by the viral nucleoprotein (N) within a helical nucleocapsid. The N protein possesses an intrinsically disordered C-terminal domain (aa 401–525, NTAIL) that is exposed at the surface of the viral nucleopcapsid. Thanks to its flexible nature, NTAIL interacts with several viral and cellular partners. Among these latter, the Interferon Regulator Factor 3 (IRF-3) has been reported to interact with N, with the interaction having been mapped to the regulatory domain of IRF-3 and to NTAIL. This interaction was described to lead to the phosphorylation-dependent activation of IRF-3, and to the ensuing activation of the pro-immune cytokine RANTES gene. Results After confirming the reciprocal ability of IRF-3 and N to be co-immunoprecipitated in 293T cells, we thoroughly investigated the NTAIL-IRF-3 interaction using a recombinant, monomeric form of the regulatory domain of IRF-3. Using a large panel of spectroscopic approaches, including circular dichroism, fluorescence spectroscopy, nuclear magnetic resonance and electron paramagnetic resonance spectroscopy, we failed to detect any direct interaction between IRF-3 and either full-length N or NTAIL under conditions where these latter interact with the C-terminal X domain of the viral phosphoprotein. Furthermore, such interaction was neither detected in E. coli nor in a yeast two hybrid assay. Conclusion Altogether, these data support the requirement for a specific cellular environment, such as that provided by 293T human cells, for the NTAIL-IRF-3 interaction to occur. This dependence from a specific cellular context likely reflects the requirement for a human or mammalian cellular co-factor.