Anchoring fins of fully covered self-expandable metal stents affect pull-out force and stent migration.

BACKGROUND AND AIMS: Stent migration and subsequent adverse events are frequently observed in the use of fully covered self-expandable metal stents (FCSEMSs) for distal biliary stenosis. In this study, we identified predictors for stent migration based on biomechanical stent characteristics and associated these findings with clinical outcomes. METHODS: The migration resistance of FCSEMSs was quantified by measuring the pull-out force. We analyzed a single-center retrospective cohort of 178 FCSEMSs for treatment success and adverse events occurring during 180 days of follow-up. RESULTS: Biomechanical measurements revealed a 4-fold higher migration resistance of FCSEMSs with anchoring fins (AF-FCSEMSs; Fmax = 14.2 ± .1 N) compared with FCSEMSs with flared ends (FE-FCSEMSs; Fmax = 3.8 ± 1.0 N; P < .0001). Clinically, AF-FCSEMSs showed lower rates of migration compared with FE-FCSEMSs (5% vs 34%, P < .0001). Unscheduled ERCP procedures because of stent dysfunction were less frequent in the AF group compared with the FE group (15% vs 29%, P = .046). Cholangitis because of stent dysfunction was observed in 5% of the AF group compared with 19% in the FE group (P = .02). Stent patency rates at 1, 3, and 6 months were higher in the AF group (96%, 90%, and 80%, respectively) compared with the FE group (90%, 74%, and 66%; log-rank test: P = .03). CONCLUSIONS: The pull-out force as a biomechanical stent property predicts the migration resistance of FCSEMSs in distal biliary stenosis and may thus be used to classify stents for this application. AF-FCSEMSs showed a significantly lower rate of migration and adverse events compared with FE-FCSEMSs.

Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment.

Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor-free margins were significantly more frequent when full-dose neoCTx was applied. We determined if patient-derived organoids (PDOs) can be used to personalize poly-chemotherapy regimens by pharmacotyping of treatment-naïve and post-neoCTx PDAC PDOs. Five out of ten CTx-naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx-naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly-chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial.

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.

Detectability and structural stability of a liquid fiducial marker in fresh ex vivo pancreas tumour resection specimens on CT and 3T MRI.

PURPOSE: To test the detectability of a liquid fiducial marker injected into ex vivo pancreas tumour tissue on magnetic resonance imaging (MRI) and computed tomography (CT). Furthermore, its injection performance using different needle sizes and its structural stability after fixation in formaldehyde were investigated. METHODS: Liquid fiducial markers with a volume of 20-100 µl were injected into freshly resected pancreas specimens of three patients with suspected adenocarcinoma. X­ray guided injection was performed using different needle sizes (18 G, 22 G, 25 G). The specimens were scanned on MRI and CT with clinical protocols. The markers were segmented on CT by signal thresholding. Marker detectability in MRI was assessed in the registered segmentations. Marker volume on CT was compared to the injected volume as a measure of backflow. RESULTS: Markers with a volume ≥20 µl were detected as hyperintensity on X­ray and CT. On T1- and T2-weighted 3T MRI, marker sizes ranging from 20-100 µl were visible as hypointensity. Since most markers were non-spherical, MRI detectability was poor and their differentiation from hypointensities caused by air cavities or surgical clips was only feasible with a reference CT. Marker backflow was only observed when using an 18-G needle. A volume decrease of 6.6 ± 13.0% was observed after 24 h in formaldehyde and, with the exception of one instance, no wash-out occurred. CONCLUSIONS: The liquid fiducial marker injected in ex vivo pancreatic resection specimen was visible as hyperintensity on kV X­ray and CT and as hypointensity on MRI. The marker's size was stable in formaldehyde. A marker volume of ≥50 µL is recommended in clinically used MRI sequences. In vivo injection is expected to improve the markers sphericity due to persisting metabolism and thereby enhance detectability on MRI.

EUS-guided drainage in the management of postoperative pancreatic leaks and fistulas (with video).

BACKGROUND AND AIMS: Postoperative pancreatic leakage and fistulae (POPF) are a leading adverse event after partial pancreatic resection. Treatment algorithms are currently not standardized. Evidence regarding the role of endoscopy is scarce. METHODS: One hundred ninety-six POPF patients with (n = 132) and without (n = 64) concomitant pancreatic fluid collections (PFCs) from centers in Berlin, Kiel, and Dresden were analyzed retrospectively. Clinical resolution was used as the primary endpoint of analysis. RESULTS: Analysis was stratified by the presence or absence of a PFC because these patients differed in treatment pathway and the presence of systemic inflammation with a median C-reactive protein of 30.7 mg/dL in patients without a PFC versus 131.0 mg/dL in patients with a PFC (P = 3.4 × 10-4). In patients with PFCs, EUS-guided intervention led to resolution in a median of 8 days as compared with 25 days for percutaneous drainage and 248 days for surgery (P = 3.75 × 10-14). There was a trend toward a higher success rate of EUS-guided intervention as a primary treatment modality with 85% (P = .034), followed by percutaneous drainage (64%) and surgery (41%). When applied as a rescue intervention (n = 24), EUS led to clinical resolution in 96% of cases. In patients without PFCs, EUS-guided internalization in a novel endoscopic technique led to resolution after a median of 4 days as compared with 51 days for a remaining surgical drainage (P = 9.3 × 10-9). CONCLUSIONS: In this retrospective analysis, EUS-guided drainage of POPF led to a more rapid resolution. EUS may be considered as a viable option in the management of PFCs and POPF and should be evaluated in prospective studies.

Towards Advanced Interactive Visualization for Virtual Atlases.

An atlas is generally defined as a bound collection of tables, charts or illustrations describing a phenomenon. In an anatomical atlas for example, a collection of representative illustrations and text describes anatomy for the purpose of communicating anatomical knowledge. The atlas serves as reference frame for comparing and integrating data from different sources by spatially or semantically relating collections of drawings, imaging data, and/or text. In the field of medical image processing, atlas information is often constructed from a collection of regions of interest, which are based on medical images that are annotated by domain experts. Such an atlas may be employed, for example, for automatic segmentation of medical imaging data. The combination of interactive visualization techniques with atlas information opens up new possibilities for content creation, curation, and navigation in virtual atlases. With interactive visualization of atlas information, students are able to inspect and explore anatomical atlases in ways that were not possible with the traditional method of presenting anatomical atlases in book format, such as viewing the illustrations from other viewpoints. With advanced interaction techniques, it becomes possible to query the data that forms the basis for the atlas, thus empowering researchers to access a wealth of information in new ways. So far, atlas-based visualization has been employed mainly for medical education, as well as biological research. In this survey, we provide an overview of current digital biomedical atlas tasks and applications and summarize relevant visualization techniques. We discuss recent approaches for providing next-generation visual interfaces to navigate atlas data that go beyond common text-based search and hierarchical lists. Finally, we reflect on open challenges and opportunities for the next steps in interactive atlas visualization.

Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Mouse models of NAFLD have been used in studies of pathogenesis and treatment, and have certain features of the human disease. We performed a systematic transcriptome-wide analysis of liver tissues from patients at different stages of NAFLD progression (ranging from healthy obese individuals to those with steatosis), as well as rodent models of NAFLD, to identify those that most closely resemble human disease progression in terms of gene expression patterns. METHODS: We performed a systematic evaluation of genome-wide messenger RNA expression using liver tissues collected from mice fed a standard chow diet (controls) and 9 mouse models of NAFLD: mice on a high-fat diet (with or without fructose), mice on a Western-type diet, mice on a methionine- and choline-deficient diet, mice on a high-fat diet given streptozotocin, and mice with disruption of Pten in hepatocytes. We compared gene expression patterns with those of liver tissues from 25 patients with nonalcoholic steatohepatitis (NASH), 27 patients with NAFLD, 15 healthy obese individuals, and 39 healthy nonobese individuals (controls). Liver samples were obtained from patients undergoing liver biopsy for suspected NAFLD or NASH, or during liver or bariatric surgeries. Data sets were analyzed using the limma R-package. Overlap of functional profiles was analyzed by gene set enrichment analysis profiles. RESULTS: We found differences between human and mouse transcriptomes to be significantly larger than differences between disease stages or models. Of the 65 genes with significantly altered expression in patients with NASH and 177 genes with significantly altered expression in patients with NAFLD, compared with controls, only 1-18 of these genes also differed significantly in expression between mouse models of NAFLD and control mice. However, expression of genes that regulate pathways associated with the development of NAFLD were altered in some mouse models (such as pathways associated with lipid metabolism). On a pathway level, gene expression patterns in livers of mice on the high-fat diet were associated more closely with human fatty liver disease than other models. CONCLUSIONS: In comparing gene expression profiles between liver tissues from different mouse models of NAFLD and patients with different stages of NAFLD, we found very little overlap. Our data set is available for studies of pathways that contribute to the development of NASH and NAFLD and selection of the most applicable mouse models (http://www.nash-profiler.com).

Flexible percutaneous endoscopic retroperitoneal necrosectomy as rescue therapy for pancreatic necroses beyond the reach of endoscopic ultrasonography: A case series.

Minimally invasive or endoscopic transluminal drainage and necrosectomy are the standard of care for infected pancreatic fluid collections and necroses after pancreatitis. In an endoscopic treatment algorithm, necroses beyond the reach of safe endoscopic access are typically treated by percutaneous drainage. We aimed to evaluate percutaneous minimally invasive necrosectomy using a purely endoscopic technique in patients with extensive necrosis. In patients with necroses beyond safe transluminal reach, the percutaneous drainage canal was used for flexible endoscopic access and dilatation of the tract to 20 mm. Percutaneous endoscopic necrosectomy was carried out through this canal. We present a case series of 14 patients in whom between one and four necrosectomy (median two) sessions were done to remove solid necroses successfully in 13 out of 14 patients. There were no major complications apart from one patient with abdominal compartment syndrome secondary to delayed erosion of the splenic artery. Percutaneous flexible necrosectomy might evolve into an alternative to surgical minimally invasive necrosectomy in anatomical sites beyond transluminal endoscopic reach.

Endoscopic ultrasound-guided biliary drainage using a lumen-apposing self-expanding metal stent: a case series.

Endoscopic ultrasound-guided biliary drainage (EUS-BD) might be an alternative to percutaneous or transpapillary biliary drainage in unresectable pancreatic or biliary cancer. A lumen-apposing, fully covered, self-expanding metal stent, which creates a sealed transluminal conduit between the biliary and gastrointestinal tract may offer advantages over conventional plastic and metal stents. In this retrospective, observational, open-label case study, five patients underwent EUS-BD for obstructive jaundice in pancreatic cancer (n = 4) or distal cholangiocarcinoma (n = 1). Technical and functional success was achieved in all patients without complications. The development of specialized stent and delivery systems may render EUS-BD an effective and safe alternative to percutaneous or transpapillary approaches.

Structural basis for promiscuity and specificity during Candida glabrata invasion of host epithelia.

The human pathogenic yeast Candida glabrata harbors more than 20 surface-exposed, epithelial adhesins (Epas) for host cell adhesion. The Epa family recognizes host glycans and discriminates between target tissues by their adhesin (A) domains, but a detailed structural basis for ligand-binding specificity of Epa proteins has been lacking so far. In this study, we provide high-resolution crystal structures of the Epa1A domain in complex with different carbohydrate ligands that reveal how host cell mucin-type O-glycans are recognized and allow a structure-guided classification of the Epa family into specific subtypes. Further detailed structural and functional characterization of subtype-switched Epa1 variants shows that specificity is governed by two inner loops, CBL1 and CBL2, involved in calcium binding as well as by three outer loops, L1, L2, and L3. In summary, our study provides the structural basis for promiscuity and specificity of Epa adhesins, which might further contribute to developing anti-adhesive antimycotics and combating Candida colonization.

Interactively illustrating polymerization using three-level model fusion.

BACKGROUND: Research in cell biology is steadily contributing new knowledge about many aspects of physiological processes, both with respect to the involved molecular structures as well as their related function. Illustrations of the spatio-temporal development of such processes are not only used in biomedical education, but also can serve scientists as an additional platform for in-silico experiments. RESULTS: In this paper, we contribute a new, three-level modeling approach to illustrate physiological processes from the class of polymerization at different time scales. We integrate physical and empirical modeling, according to which approach best suits the different involved levels of detail, and we additionally enable a form of interactive steering, while the process is illustrated. We demonstrate the suitability of our approach in the context of several polymerization processes and report from a first evaluation with domain experts. CONCLUSION: We conclude that our approach provides a new, hybrid modeling approach for illustrating the process of emergence in physiology, embedded in a densely filled environment. Our approach of a complementary fusion of three systems combines the strong points from the different modeling approaches and is capable to bridge different spatial and temporal scales.

Absolute hydration free energies of blocked amino acids: implications for protein solvation and stability.

Most proteins perform their function in aqueous solution. The interactions with water determine the stability of proteins and the desolvation costs of ligand binding or membrane insertion. However, because of experimental restrictions, absolute solvation free energies of proteins or amino acids are not available. Instead, solvation free energies are estimated based on side chain analog data. This approach implies that the contributions to free energy differences are additive, and it has often been employed for estimating folding or binding free energies. However, it is not clear how much the additivity assumption affects the reliability of the resulting data. Here, we use molecular dynamics-based free energy simulations to calculate absolute hydration free energies for 15 N-acetyl-methylamide amino acids with neutral side chains. By comparing our results with solvation free energies for side chain analogs, we demonstrate that estimates of solvation free energies of full amino acids based on group-additive methods are systematically too negative and completely overestimate the hydrophobicity of glycine. The largest deviation of additive protocols using side chain analog data was 6.7 kcal/mol; on average, the deviation was 4 kcal/mol. We briefly discuss a simple way to alleviate the errors incurred by using side chain analog data and point out the implications of our findings for the field of biophysics and implicit solvent models. To support our results and conclusions, we calculate relative protein stabilities for selected point mutations, yielding a root-mean-square deviation from experimental results of 0.8 kcal/mol.

Structural basis of flocculin-mediated social behavior in yeast.

In the budding yeast Saccharomyces cerevisiae, self-recognition and the thereby promoted aggregation of thousands of cells into protective flocs is mediated by a family of cell-surface adhesins, the flocculins (Flo). Based on this social behavior FLO genes fulfill the definition of "greenbeard" genes, which direct cooperation toward other carriers of the same gene. The process of flocculation plays an eminent role in the food industry for the production of beer and wine. However, the precise mode of flocculin-mediated surface recognition and the exact structure of cognate ligands have remained elusive. Here, we present structures of the adhesion domain of a flocculin complexed to its cognate ligands derived from yeast high-mannose oligosaccharides at resolutions up to 0.95 Å. Besides a PA14-like architecture, the Flo5A domain reveals a previously undescribed lectin fold that utilizes a unique DcisD calcium-binding motif for carbohydrate binding and that is widely spread among pro- and eukaryotes. Given the high abundance of high-mannose oligosaccharides in yeast cell walls, the Flo5A structure suggests a model for recognition, where social non-self- instead of unsocial self-interactions are favored.

ScrollyVis: Interactive Visual Authoring of Guided Dynamic Narratives for Scientific Scrollytelling.

Visual stories are an effective and powerful tool to convey specific information to a diverse public. Scrollytelling is a recent visual storytelling technique extensively used on the web, where content appears or changes as users scroll up or down a page. By employing the familiar gesture of scrolling as its primary interaction mechanism, it provides users with a sense of control, exploration and discoverability while still offering a simple and intuitive interface. In this article, we present a novel approach for authoring, editing, and presenting data-driven scientific narratives using scrollytelling. Our method flexibly integrates common sources such as images, text, and video, but also supports more specialized visualization techniques such as interactive maps as well as scalar field and mesh data visualizations. We show that scrolling navigation can be used to traverse dynamic narratives and demonstrate how it can be combined with interactive parameter exploration. The resulting system consists of an extensible web-based authoring tool capable of exporting stand-alone stories that can be hosted on any web server. We demonstrate the power and utility of our approach with case studies from several diverse scientific fields and with a user study including 12 participants of diverse professional backgrounds. Furthermore, an expert in creating interactive articles assessed the usefulness of our approach and the quality of the created stories.

Changing Aesthetics in Biomolecular Graphics.

Aesthetics for the visualization of biomolecular structures have evolved over the years according to technological advances, user needs, and modes of dissemination. In this article, we explore the goals, challenges, and solutions that have shaped the current landscape of biomolecular imagery from the overlapping perspectives of computer science, structural biology, and biomedical illustration. We discuss changing approaches to rendering, color, human-computer interface, and narrative in the development and presentation of biomolecular graphics. With this historical perspective on the evolving styles and trends in each of these areas, we identify opportunities and challenges for future aesthetics in biomolecular graphics that encourage continued collaboration from multiple intersecting fields.

Considering best practices in color palettes for molecular visualizations.

Biomedical illustration and visualization techniques provide a window into complex molecular worlds that are difficult to capture through experimental means alone. Biomedical illustrators frequently employ color to help tell a molecular story, e.g., to identify key molecules in a signaling pathway. Currently, color use for molecules is largely arbitrary and often chosen based on the client, cultural factors, or personal taste. The study of molecular dynamics is relatively young, and some stakeholders argue that color use guidelines would throttle the growth of the field. Instead, content authors have ample creative freedom to choose an aesthetic that, e.g., supports the story they want to tell. However, such creative freedom comes at a price. The color design process is challenging, particularly for those without a background in color theory. The result is a semantically inconsistent color space that reduces the interpretability and effectiveness of molecular visualizations as a whole. Our contribution in this paper is threefold. We first discuss some of the factors that contribute to this array of color palettes. Second, we provide a brief sampling of color palettes used in both industry and research sectors. Lastly, we suggest considerations for developing best practices around color palettes applied to molecular visualization.

Semantic Snapping for Guided Multi-View Visualization Design.

Visual information displays are typically composed of multiple visualizations that are used to facilitate an understanding of the underlying data. A common example are dashboards, which are frequently used in domains such as finance, process monitoring and business intelligence. However, users may not be aware of existing guidelines and lack expert design knowledge when composing such multi-view visualizations. In this paper, we present semantic snapping, an approach to help non-expert users design effective multi-view visualizations from sets of pre-existing views. When a particular view is placed on a canvas, it is "aligned" with the remaining views-not with respect to its geometric layout, but based on aspects of the visual encoding itself, such as how data dimensions are mapped to channels. Our method uses an on-the-fly procedure to detect and suggest resolutions for conflicting, misleading, or ambiguous designs, as well as to provide suggestions for alternative presentations. With this approach, users can be guided to avoid common pitfalls encountered when composing visualizations. Our provided examples and case studies demonstrate the usefulness and validity of our approach.

Structure of the Yeast Cell Wall Integrity Sensor Wsc1 Reveals an Essential Role of Surface-Exposed Aromatic Clusters.

In the yeast Saccharomyces cerevisiae and other ascomycetes, the maintenance of cell wall integrity is governed by a family of plasma-membrane spanning sensors that include the Wsc-type proteins. These cell wall proteins apparently sense stress-induced mechanical forces at the cell surface and target the cell wall integrity (CWI) signaling pathway, but the structural base for their sensor function is yet unknown. Here, we solved a high-resolution crystal structure of the extracellular cysteine-rich domain (CRD) of yeast Wsc1, which shows the characteristic PAN/Apple domain fold with two of the four Wsc1 disulfide bridges being conserved in other PAN domain cores. Given the general function of PAN domains in mediating protein-protein and protein-carbohydrate interactions, this finding underpins the importance of Wsc domains in conferring sensing and localization functions. Our Wsc1 CRD structure reveals an unusually high number of surface-exposed aromatic residues that are conserved in other fungal CRDs, and can be arranged into three solvent-exposed clusters. Mutational analysis demonstrates that two of the aromatic clusters are required for conferring S. cerevisiae Wsc1-dependent resistance to the glucan synthase inhibitor caspofungin, and the chitin-binding agents Congo red and Calcofluor white. These findings suggest an essential role of surface-exposed aromatic clusters in fungal Wsc-type sensors that might include an involvement in stress-induced sensor-clustering required to elicit appropriate cellular responses via the downstream CWI pathway.

Finding haplotypic signatures in proteins.

BACKGROUND: The nonrandom distribution of alleles of common genomic variants produces haplotypes, which are fundamental in medical and population genetic studies. Consequently, protein-coding genes with different co-occurring sets of alleles can encode different amino acid sequences: protein haplotypes. These protein haplotypes are present in biological samples and detectable by mass spectrometry, but they are not accounted for in proteomic searches. Consequently, the impact of haplotypic variation on the results of proteomic searches and the discoverability of peptides specific to haplotypes remain unknown. FINDINGS: Here, we study how common genetic haplotypes influence the proteomic search space and investigate the possibility to match peptides containing multiple amino acid substitutions to a publicly available data set of mass spectra. We found that for 12.42% of the discoverable amino acid substitutions encoded by common haplotypes, 2 or more substitutions may co-occur in the same peptide after tryptic digestion of the protein haplotypes. We identified 352 spectra that matched to such multivariant peptides, and out of the 4,582 amino acid substitutions identified, 6.37% were covered by multivariant peptides. However, the evaluation of the reliability of these matches remains challenging, suggesting that refined error rate estimation procedures are needed for such complex proteomic searches. CONCLUSIONS: As these procedures become available and the ability to analyze protein haplotypes increases, we anticipate that proteomics will provide new information on the consequences of common variation, across tissues and time.