A cross-disorder dosage sensitivity map of the human genome.

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization.

Liquid-liquid phase separation (LLPS) mediates formation of membraneless condensates such as those associated with RNA processing, but the rules that dictate their assembly, substructure, and coexistence with other liquid-like compartments remain elusive. Here, we address the biophysical mechanism of this multiphase organization using quantitative reconstitution of cytoplasmic stress granules (SGs) with attached P-bodies in human cells. Protein-interaction networks can be viewed as interconnected complexes (nodes) of RNA-binding domains (RBDs), whose integrated RNA-binding capacity determines whether LLPS occurs upon RNA influx. Surprisingly, both RBD-RNA specificity and disordered segments of key proteins are non-essential, but modulate multiphase condensation. Instead, stoichiometry-dependent competition between protein networks for connecting nodes determines SG and P-body composition and miscibility, while competitive binding of unconnected proteins disengages networks and prevents LLPS. Inspired by patchy colloid theory, we propose a general framework by which competing networks give rise to compositionally specific and tunable condensates, while relative linkage between nodes underlies multiphase organization.

Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome.

Phase transitions involving biomolecular liquids are a fundamental mechanism underlying intracellular organization. In the cell nucleus, liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is implicated in assembly of the nucleolus, as well as transcriptional clusters, and other nuclear bodies. However, it remains unclear whether and how physical forces associated with nucleation, growth, and wetting of liquid condensates can directly restructure chromatin. Here, we use CasDrop, a novel CRISPR-Cas9-based optogenetic technology, to show that various IDPs phase separate into liquid condensates that mechanically exclude chromatin as they grow and preferentially form in low-density, largely euchromatic regions. A minimal physical model explains how this stiffness sensitivity arises from lower mechanical energy associated with deforming softer genomic regions. Targeted genomic loci can nonetheless be mechanically pulled together through surface tension-driven coalescence. Nuclear condensates may thus function as mechano-active chromatin filters, physically pulling in targeted genomic loci while pushing out non-targeted regions of the neighboring genome. VIDEO ABSTRACT.

Nucleation landscape of biomolecular condensates.

All structures within living cells must form at the right time and place. This includes condensates such as the nucleolus, Cajal bodies and stress granules, which form via liquid-liquid phase separation of biomolecules, particularly proteins enriched in intrinsically disordered regions (IDRs)1,2. In non-living systems, the initial stages of nucleated phase separation arise when thermal fluctuations overcome an energy barrier due to surface tension. This phenomenon can be modelled by classical nucleation theory (CNT), which describes how the rate of droplet nucleation depends on the degree of supersaturation, whereas the location at which droplets appear is controlled by interfacial heterogeneities3,4. However, it remains unknown whether this framework applies in living cells, owing to the multicomponent and highly complex nature of the intracellular environment, including the presence of diverse IDRs, whose specificity of biomolecular interactions is unclear5-8. Here we show that despite this complexity, nucleation in living cells occurs through a physical process similar to that in inanimate materials, but the efficacy of nucleation sites can be tuned by their biomolecular features. By quantitatively characterizing the nucleation kinetics of endogenous and biomimetic condensates in living cells, we find that key features of condensate nucleation can be quantitatively understood through a CNT-like theoretical framework. Nucleation rates can be substantially enhanced by compatible biomolecular (IDR) seeds, and the kinetics of cellular processes can impact condensate nucleation rates and specificity of location. This quantitative framework sheds light on the intracellular nucleation landscape, and paves the way for engineering synthetic condensates precisely positioned in space and time.

Composition-dependent thermodynamics of intracellular phase separation.

Intracellular bodies such as nucleoli, Cajal bodies and various signalling assemblies represent membraneless organelles, or condensates, that form via liquid-liquid phase separation (LLPS)1,2. Biomolecular interactions-particularly homotypic interactions mediated by self-associating intrinsically disordered protein regions-are thought to underlie the thermodynamic driving forces for LLPS, forming condensates that can facilitate the assembly and processing of biochemically active complexes, such as ribosomal subunits within the nucleolus. Simplified model systems3-6 have led to the concept that a single fixed saturation concentration is a defining feature of endogenous LLPS7-9, and has been suggested as a mechanism for intracellular concentration buffering2,7,8,10. However, the assumption of a fixed saturation concentration remains largely untested within living cells, in which the richly multicomponent nature of condensates could complicate this simple picture. Here we show that heterotypic multicomponent interactions dominate endogenous LLPS, and give rise to nucleoli and other condensates that do not exhibit a fixed saturation concentration. As the concentration of individual components is varied, their partition coefficients change in a manner that can be used to determine the thermodynamic free energies that underlie LLPS. We find that heterotypic interactions among protein and RNA components stabilize various archetypal intracellular condensates-including the nucleolus, Cajal bodies, stress granules and P-bodies-implying that the composition of condensates is finely tuned by the thermodynamics of the underlying biomolecular interaction network. In the context of RNA-processing condensates such as the nucleolus, this manifests in the selective exclusion of fully assembled ribonucleoprotein complexes, providing a thermodynamic basis for vectorial ribosomal RNA flux out of the nucleolus. This methodology is conceptually straightforward and readily implemented, and can be broadly used to extract thermodynamic parameters from microscopy images. These approaches pave the way for a deeper understanding of the thermodynamics of multicomponent intracellular phase behaviour and its interplay with the nonequilibrium activity that is characteristic of endogenous condensates.

Accuracy of the No-Biopsy Approach for the Diagnosis of Celiac Disease in Adults: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Current international guidelines recommend duodenal biopsies to confirm the diagnosis of celiac disease in adult patients. However, growing evidence suggests that immunoglobulin A (IgA) anti-tissue transglutaminase (tTg) antibody levels ≥10 times the upper limit of normal (ULN) can accurately predict celiac disease, eliminating the need for biopsy. We performed a systematic review and meta-analysis to evaluate the accuracy of the no-biopsy approach to confirm the diagnosis of celiac disease in adults. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, and Web of Science from January 1998 to October 2023 for studies reporting the sensitivity and specificity of IgA-tTG ≥10×ULN against duodenal biopsies (Marsh grade ≥2) in adults with suspected celiac disease. We used a bivariate random effects model to calculate the summary estimates of sensitivity, specificity, and positive and negative likelihood ratios. The positive and negative likelihood ratios were used to calculate the positive predictive value of the no-biopsy approach across different pretest probabilities of celiac disease. The methodological quality of the included studies was evaluated using the QUADAS-2 tool. This study was registered with PROSPERO, number CRD42023398812. RESULTS: A total of 18 studies comprising 12,103 participants from 15 countries were included. The pooled prevalence of biopsy-proven celiac disease in the included studies was 62% (95% confidence interval [CI], 40%-83%). The proportion of patients with IgA-tTG ≥10×ULN was 32% (95% CI, 24%-40%). The summary sensitivity of IgA-tTG ≥10×ULN was 51% (95% CI, 42%-60%), and the summary specificity was 100% (95% CI, 98%-100%). The area under the summary receiver operating characteristic curve was 0.83 (95% CI, 0.77 - 0.89). The positive predictive value of the no-biopsy approach to identify patients with celiac disease was 65%, 88%, 95%, and 99% if celiac disease prevalence was 1%, 4%, 10%, and 40%, respectively. Between-study heterogeneity was moderate (I2 =30.3%), and additional sensitivity analyses did not significantly alter our findings. Only 1 study had a low risk of bias across all domains. CONCLUSION: The results of this meta-analysis suggest that selected adult patients with IgA-tTG ≥10×ULN and a moderate to high pretest probability of celiac disease could be diagnosed without undergoing invasive endoscopy and duodenal biopsy.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Author Correction: A population of luminous accreting black holes with hidden mergers.

In this Letter, the spelling of author Benny Trakhtenbrot was corrected; the affiliation for author Sylvain Veilleux was amended; and a new ref. 9 was added to the Abstract with subsequent references renumbered; these errors have been corrected online.

New entity of adult ultra-short coeliac disease: the first international cohort and case-control study.

BACKGROUND: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. METHODS: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. FINDINGS: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. INTERPRETATION: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

Biophysical and biochemical characterization of the thioredoxin system from Colwellia psychrerythraea.

The thioredoxin system is a ubiquitous oxidoreductase system consisting of the enzyme thioredoxin reductase, the protein thioredoxin, and the cofactor nicotinamide adenine dinucleotide phosphate. The system has been comprehensively studied from many organisms, such as Escherichia coli; however, structural and functional analysis of this system from psychrophilic bacteria has not been as extensive. In this study, the thioredoxin system proteins of a psychrophilic bacterium, Colwellia psychrerythraea, were characterized using biophysical and biochemical techniques. Analysis of the complete genome sequence of the C. psychrerythraea thioredoxin system suggested the presence of a putative thioredoxin reductase and at least three thioredoxin. In this study, these identified putative thioredoxin system components were cloned, overexpressed, purified, and characterized. Our studies have indicated that the thioredoxin system proteins from E. coli were more stable than those from C. psychrerythraea. Consistent with these results, kinetic assays indicated that the thioredoxin reductase from E. coli had a higher optimal temperature than that from C. psychrerythraea.

Surpoint algorithm for improved guidance of ablation for ventricular tachycardia (SURFIRE-VT): A pilot study.

INTRODUCTION: The utility of ablation index (AI) to guide ventricular tachycardia (VT) ablation in patients with structural heart disease is unknown. The aim of this study was to assess procedural characteristics and clinical outcomes achieved using AI-guided strategy (target value 550) or conventional non-AI-guided parameters in patients undergoing scar-related VT ablation. METHODS: Consecutive patients (n = 103) undergoing initial VT ablation at a single center from 2017 to 2022 were evaluated. Patient groups were 1:1 propensity-matched for baseline characteristics. Single lesion characteristics for all 4707 lesions in the matched cohort (n = 74) were analyzed. The impact of ablation characteristics was assessed by linear regression and clinical outcomes were evaluated by Cox proportional hazard model. RESULTS: After propensity-matching, baseline characteristics were well-balanced between AI (n = 37) and non-AI (n = 37) groups. Lesion sets were similar (scar homogenization [41% vs. 27%; p = .34], scar dechanneling [19% vs. 8%; p = .18], core isolation [5% vs. 11%; p = .4], linear and elimination late potentials/local abnormal ventricular activities [35% vs. 44%; p = .48], epicardial mapping/ablation [11% vs. 14%; p = .73]). AI-guided strategy had 21% lower procedure duration (-47.27 min, 95% confidence interval [CI] [-81.613, -12.928]; p = .008), 49% lower radiofrequency time per lesion (-13.707 s, 95% CI [-17.86, -9.555]; p < .001), 21% lower volume of fluid administered (1664 cc [1127, 2209] vs. 2126 cc [1750, 2593]; p = .005). Total radiofrequency duration (-339 s [-24%], 95%CI [-776, 62]; p = .09) and steam pops (-155.6%, 95% CI [19.8%, -330.9%]; p = .08) were nonsignificantly lower in the AI group. Acute procedural success (95% vs. 89%; p = .7) and VT recurrence (0.97, 95% CI [0.42-2.2]; p = .93) were similar for both groups. Lesion analysis (n = 4707) demonstrated a plateau in the magnitude of impedance drops once reaching an AI of 550-600. CONCLUSION: In this pilot study, an AI-guided ablation strategy for scar-related VT resulted in shorter procedure time and average radiofrequency time per lesion with similar acute procedural and intermediate-term clinical outcomes to a non-AI-guided approach utilizing traditional ablation parameters.

Road map to small bowel endoscopy quality indicators.

PURPOSE OF REVIEW: Quality indicators for upper and lower gastrointestinal endoscopy are well established and linked to patient outcomes. However, there is a perceived gap in the development and implementation of quality indicators for small bowel endoscopy. In this review, we aimed to discuss the development of quality indicators in small bowel endoscopy and their implementation in clinical practice. RECENT FINDINGS: The proposed quality indicators for small bowel endoscopy focus on process measures, which mainly evaluate the procedural aspects, rather than the outcomes or the overall patient experience. These quality indicators have rarely been studied in clinical practice, leading to a limited understanding of their applicability and impact on patient outcomes and experience. SUMMARY: Real-world studies evaluating the quality indicators of small bowel endoscopy are warranted to establish an evidence-based framework for their practical application and effectiveness. Linking these indicators to relevant patient outcomes is crucial for their broader acceptance and implementation.

Device-assisted enteroscopy performance measures in the United Kingdom: DEEP-UK quality improvement project.

BACKGROUND: Device-assisted enteroscopy (DAE) has become a well-established diagnostic and therapeutic tool for the management of small-bowel pathology. We aimed to evaluate the performance measures for DAE across the UK against the quality benchmarks proposed by the European Society of Gastrointestinal Endoscopy (ESGE). METHODS: We retrospectively collected data on patient demographics and DAE performance measures from electronic endoscopy records of consecutive patients who underwent DAE for diagnostic and therapeutic purposes across 12 enteroscopy centers in the UK between January 2017 and December 2022. RESULTS: A total of 2005 DAE procedures were performed in 1663 patients (median age 60 years; 53% men). Almost all procedures (98.1%) were performed for appropriate indications. Double-balloon enteroscopy was used for most procedures (82.0%), followed by single-balloon enteroscopy (17.2%) and spiral enteroscopy (0.7%). The estimated depth of insertion was documented in 73.4% of procedures. The overall diagnostic yield was 70.0%. Therapeutic interventions were performed in 42.6% of procedures, with a success rate of 96.6%. Overall, 78.0% of detected lesions were marked with a tattoo. Patient comfort was significantly better with the use of deep sedation compared with conscious sedation (99.7% vs. 68.5%; P<0.001). Major adverse events occurred in only 0.6% of procedures. CONCLUSIONS: Performance measures for DAE in the UK meet the ESGE quality benchmarks, with high diagnostic and therapeutic yields, and a low incidence of major adverse events. However, there is room for improvement in optimizing sedation practices, standardizing the depth of insertion documentation, and adopting marking techniques to aid in the follow-up of detected lesions.

Factors influencing gastrostomy tube removal.

BACKGROUND: When commencing enteral feeding, patients and families will want to know the likelihood of returning to an oral diet. There is a paucity of data on the prognosis of patients with gastrostomies. We describe a large dataset of patients, which identifies factors influencing gastrostomy removal and assesses the likelihood of the patient having at home enteral nutrition. METHODS: Retrospective data was collected on patients from Sheffield Teaching Hospitals who had received a gastrostomy and had outpatient enteral feeding between January 2016 and December 2019. Demographic data, indication and outcomes were analysed. RESULTS: A total of 451 patients were assessed, median age: 67.7. 183/451(40.6%) gastrostomies were for head and neck cancer, 88/451 (19.5%) for stroke, 28/451 (6.2%) for Motor Neuron Disease, 32/451 (7.1%) for other neurodegenerative causes, 120/451 (26.6%) other. Of the 31.2% who had their gastrostomy removed within 3 years, head and neck cancer was the most common indication (58.3%) followed by stroke (10.2%), Motor Neuron Disease (7.1%) and other neurodegenerative diseases (3.1%). Gastrostomy removal was significantly influenced by age, place of residence, and having head and neck cancer (p < 0.05). There was the greatest likelihood of removal within the first year (24%). 70.5% had enteral feeding at home. CONCLUSION: This large cohort study demonstrates 31.2% of patients had their gastrostomy removed within 3 years. Head and neck cancer patients, younger age and residing at home can help positively predict removal. Most patients manage their feeding at home rather than a nursing home. This study provides new information on gastrostomy outcomes when counselling patients to provide realistic expectations.

A population of luminous accreting black holes with hidden mergers.

Major galaxy mergers are thought to play an important part in fuelling the growth of supermassive black holes1. However, observational support for this hypothesis is mixed, with some studies showing a correlation between merging galaxies and luminous quasars2,3 and others showing no such association4,5. Recent observations have shown that a black hole is likely to become heavily obscured behind merger-driven gas and dust, even in the early stages of the merger, when the galaxies are well separated6-8 (5 to 40 kiloparsecs). Merger simulations further suggest that such obscuration and black-hole accretion peaks in the final merger stage, when the two galactic nuclei are closely separated9 (less than 3 kiloparsecs). Resolving this final stage requires a combination of high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray observations to detect highly obscured sources. However, large numbers of obscured luminous accreting supermassive black holes have been recently detected nearby (distances below 250 megaparsecs) in X-ray observations10. Here we report high-resolution infrared observations of hard-X-ray-selected black holes and the discovery of obscured nuclear mergers, the parent populations of supermassive-black-hole mergers. We find that obscured luminous black holes (bolometric luminosity higher than 2 × 1044 ergs per second) show a significant (P < 0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a sample of inactive galaxies with matching stellar masses and star formation rates (1.1 per cent), in agreement with theoretical predictions. Using hydrodynamic simulations, we confirm that the excess of nuclear mergers is indeed strongest for gas-rich major-merger hosts of obscured luminous black holes in this final stage.

Management of intraoperatively identified small bile duct stones in patients undergoing cholecystectomy.

INTRODUCTION: The management of CBDS (common bile duct stones) in patients with co-existing gallbladder stones has been debated. Guidelines recommend patients with CBDS identified on imaging should be offered duct clearance; however, this is based on low-quality evidence. This study aimed to investigate the natural history of small CBDS identified using IOUS (intraoperative ultrasound) in patients undergoing cholecystectomy. This may provide evidence to support a short-term expectant management approach in such patients. METHODS: Patients with CBDS diagnosed on IOUS during cholecystectomy were identified from a database of consecutive patients undergoing surgery. Patients with CBDS identified were divided into small stone (SS, ≤5 mm) and large stone (LS, >5 mm) groups. Intraoperative CBDS management, postoperative investigations, postoperative bile duct clearance, re-admissions, complications, length of stay (LOS) and follow-up are described. RESULTS: Fifty-nine of 427 patients had CBDS identified on IOUS. In the SS group (n=51), 46 patients underwent short-term expectant management rather than immediate/planned bile duct clearance. Following short-term expectant management, 41/46 patients (89.1%) did not require postoperative endoscopic retrograde cholangiopancreatography and at >3 year follow-up, none has since presented with residual CBDS. Median LOS was 0 days in the short-term expectant management group and 2 days in the immediate/planned bile duct clearance group, P=0.039. CONCLUSIONS: This study reports the natural history of small CBDS identified on IOUS in patients undergoing cholecystectomy. Such patients were safely treated with short-term expectant management associated with a reduced hospital LOS. This provides rationale for undertaking further research to establish this as a preferred management strategy.

Persistent villous atrophy predicts development of complications and mortality in adult patients with coeliac disease: a multicentre longitudinal cohort study and development of a score to identify high-risk patients.

OBJECTIVE: Persistent villous atrophy (pVA) in coeliac disease (CD) despite a gluten-free diet (GFD) has unclear meaning. We aimed to (i) study the relationship between pVA and long-term outcomes and (ii) develop a score to identify patients at risk of pVA. DESIGN: This is a multicentre retrospective-prospective study consisting of a study cohort (cohort 1) and an external validation cohort (cohort 2) of patients with biopsy-proven CD diagnosed between 2000 and 2021. Cohort 1 was used to (i) compare long-term outcomes between patients with and without pVA (Marsh ≥3a) at follow-up biopsy and (ii) to develop a score to evaluate the risk of pVA, which was validated in cohort 2. RESULTS: Of 2211 patients, 694 (31%) underwent follow-up duodenal biopsy and were included in the study cohort (491F, 44±16 years). 157/694 (23%) had pVA. Risk of complications (HR 9.53, 95% CI 4.77 to 19.04, p<0.001) and mortality (HR 2.93, 95% CI 1.43 to 6.02, p<0.01) were increased in patients with pVA. A 5-point score was developed and externally validated (receiver operating characteristic area under the curve 0.78, 95% CI 0.68 to 0.89) to stratify patients by risk of pVA: low (0-1 points, 5% pVA), intermediate (2 points, 16% pVA) and high (3-5 points, 73% pVA). Predictors for pVA used in the score were age at diagnosis ≥45 years (OR 2.01, 95% CI 1.21 to 3.34, p<0.01), classical pattern of CD (OR 2.14, 95% CI 1.28 to 3.58, p<0.01), lack of clinical response to GFD (OR 2.40, 95% CI 1.43 to 4.01, p<0.001) and poor GFD adherence (OR 48.9, 95% CI 26.1 to 91.8, p<0.001). CONCLUSIONS: Risk of complications and mortality were increased in patients with pVA. We developed a score to identify patients at risk of pVA and in need of histological reassessment and closer follow-up.

Condensate interfaces can accelerate protein aggregation.

Protein aggregates, formed from the assembly of aberrant, misfolded proteins, are a hallmark of neurodegenerative diseases. Disease-associated aggregates such as mutant Huntingtin polyQ inclusions, are typically enriched in p62/SQSTM1, an oligomeric protein that binds to and sequesters aberrant proteins. p62 has been suggested to sequester proteins through formation of liquid-like biomolecular condensates, but the physical mechanisms by which p62 condensates may regulate pathological protein aggregation remain unclear. Here, we use a light-inducible biomimetic condensate system to show that p62 condensates enhance coarsening of mutant polyQ aggregates through interface-mediated sequestration, which accelerates polyQ accumulation into larger aggregates. However, the resulting large aggregates accumulate polyubiquitinated proteins, which depletes free p62, ultimately suppressing further p62 condensation. This dynamic interplay between interface-mediated coarsening of solid aggregates and downstream consequences on the phase behavior of associated regulatory proteins could contribute to the onset and progression of protein aggregation diseases.

Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2022.

MR1: ESGE recommends small-bowel capsule endoscopy as the first-line examination, before consideration of other endoscopic and radiological diagnostic tests for suspected small-bowel bleeding, given the excellent safety profile of capsule endoscopy, its patient tolerability, and its potential to visualize the entire small-bowel mucosa.Strong recommendation, moderate quality evidence. MR2: ESGE recommends small-bowel capsule endoscopy in patients with overt suspected small-bowel bleeding as soon as possible after the bleeding episode, ideally within 48 hours, to maximize the diagnostic and subsequent therapeutic yield.Strong recommendation, high quality evidence. MR3: ESGE does not recommend routine second-look endoscopy prior to small-bowel capsule endoscopy in patients with suspected small-bowel bleeding or iron-deficiency anemia.Strong recommendation, low quality evidence. MR4: ESGE recommends conservative management in those patients with suspected small-bowel bleeding and high quality negative small-bowel capsule endoscopy.Strong recommendation, moderate quality evidence. MR5: ESGE recommends device-assisted enteroscopy to confirm and possibly treat lesions identified by small-bowel capsule endoscopy.Strong recommendation, high quality evidence. MR6: ESGE recommends the performance of small-bowel capsule endoscopy as a first-line examination in patients with iron-deficiency anemia when small bowel evaluation is indicated.Strong recommendation, high quality evidence. MR7: ESGE recommends small-bowel capsule endoscopy in patients with suspected Crohn's disease and negative ileocolonoscopy findings as the initial diagnostic modality for investigating the small bowel, in the absence of obstructive symptoms or known bowel stenosis.Strong recommendation, high quality evidence. MR8: ESGE recommends, in patients with unremarkable or nondiagnostic findings from dedicated small-bowel cross-sectional imaging, small-bowel capsule endoscopy as a subsequent investigation if deemed likely to influence patient management.Strong recommendation, low quality evidence. MR9: ESGE recommends, in patients with established Crohn's disease, the use of a patency capsule before small-bowel capsule endoscopy to decrease the capsule retention rate.Strong recommendation, moderate quality evidence. MR10: ESGE recommends device-assisted enteroscopy (DAE) as an alternative to surgery for foreign bodies retained in the small bowel requiring retrieval in patients without acute intestinal obstruction.Strong recommendation, moderate quality evidence. MR11: ESGE recommends DAE-endoscopic retrograde cholangiopancreatography (DAE-ERCP) as a first-line endoscopic approach to treat pancreaticobiliary diseases in patients with surgically altered anatomy (except for Billroth II patients).Strong recommendation, moderate quality evidence.