Single-Cell Analysis of Refractory Celiac Disease Demonstrates Inter- and Intra-Patient Aberrant Cell Heterogeneity

Background & Aims: Refractory celiac disease type II (RCDII) is a rare indolent lymphoma in the small intestine characterized by a clonally expanded intraepithelial intracellular CD3+surfaceCD3-CD7+CD56- aberrant cell population. However, RCDII pathogenesis is ill-defined. Here, we aimed at single-cell characterization of the innate and adaptive immune system in RCDII. Methods: Paired small intestinal and blood samples from 12 RCDII patients and 6 healthy controls were assessed by single-cell mass cytometry with a 39–cell surface marker antibody panel, designed to capture heterogeneity of the innate and adaptive immune system. A second single-cell mass cytometry panel that included transcription factors and immune checkpoints was used for analysis of paired samples from 5 RCDII patients. Single-cell RNA sequencing analysis was performed on duodenal samples from 2 RCDII patients. Finally, we developed a 40-marker imaging mass cytometry antibody panel to evaluate cell–cell interactions in duodenal biopsy specimens of RCDII patients. Results: We provide evidence for intertumoral and intratumoral cell heterogeneity within the duodenal and peripheral aberrant cell population present in RCDII. Phenotypic discrepancy was observed between peripheral and duodenal aberrant cells. In addition, we observed that part of the aberrant cell population proliferated and observed co-localization of aberrant cells with CD163+ antigen-presenting cells (APCs) in situ. In addition, we observed phenotypic discrepancy between peripheral and duodenal aberrant cells. Conclusions: Novel high-dimensional single-cell technologies show substantial intertumoral and intratumoral heterogeneity in the aberrant cell population in RCDII. This may underlie variability in refractory disease status between patients and responsiveness to therapy, pointing to the need for personalized therapy in RCDII based on patient-specific immune profiles

Single-Cell Analysis of Refractory Celiac Disease Demonstrates Inter- and Intra-Patient Aberrant Cell Heterogeneity

Background & Aims: Refractory celiac disease type II (RCDII) is a rare indolent lymphoma in the small intestine characterized by a clonally expanded intraepithelial intracellular CD3+surfaceCD3-CD7+CD56- aberrant cell population. However, RCDII pathogenesis is ill-defined. Here, we aimed at single-cell characterization of the innate and adaptive immune system in RCDII. Methods: Paired small intestinal and blood samples from 12 RCDII patients and 6 healthy controls were assessed by single-cell mass cytometry with a 39–cell surface marker antibody panel, designed to capture heterogeneity of the innate and adaptive immune system. A second single-cell mass cytometry panel that included transcription factors and immune checkpoints was used for analysis of paired samples from 5 RCDII patients. Single-cell RNA sequencing analysis was performed on duodenal samples from 2 RCDII patients. Finally, we developed a 40-marker imaging mass cytometry antibody panel to evaluate cell–cell interactions in duodenal biopsy specimens of RCDII patients. Results: We provide evidence for intertumoral and intratumoral cell heterogeneity within the duodenal and peripheral aberrant cell population present in RCDII. Phenotypic discrepancy was observed between peripheral and duodenal aberrant cells. In addition, we observed that part of the aberrant cell population proliferated and observed co-localization of aberrant cells with CD163+ antigen-presenting cells (APCs) in situ. In addition, we observed phenotypic discrepancy between peripheral and duodenal aberrant cells. Conclusions: Novel high-dimensional single-cell technologies show substantial intertumoral and intratumoral heterogeneity in the aberrant cell population in RCDII. This may underlie variability in refractory disease status between patients and responsiveness to therapy, pointing to the need for personalized therapy in RCDII based on patient-specific immune profiles.Pattern Recognition and Bioinformatic

Patients' Needs and Requirements for eHealth Pain Management Interventions: Qualitative Study

BACKGROUND: A growing body of evidence supports the potential effectiveness of electronic health (eHealth) interventions in managing chronic pain. However, research on the needs and preferences of patients with chronic pain in relation to eHealth interventions is scarce. Eliciting user input in the development of eHealth interventions may be a crucial step toward developing meaningful interventions for patients for potentially improving treatment outcomes. OBJECTIVE: This study aimed to explore the experiences of patients with chronic pain with regard to information and communication technology, understand how an eHealth intervention can support the everyday needs and challenges of patients with chronic pain, and identify possible facilitators and barriers for patients' use of an eHealth pain management intervention. METHODS: Twenty patients living with chronic pain and five spouses participated in individual interviews. Semistructured interview guides were used to explore participants' needs, experiences, and challenges in daily life as well as their information and communication technology experiences and preferences for eHealth support interventions. Spouses were recruited and interviewed to gain additional insight into the patients' needs. The study used qualitative thematic analysis. RESULTS: The participants were generally experienced technology users and reported using apps regularly. They were mainly in favor of using an eHealth self-management intervention for chronic pain and considered it a potentially acceptable way of gathering knowledge and support for pain management. The participants expressed the need for obtaining more information and knowledge, establishing a better balance in everyday life, and receiving support for improving communication and social participation. They provided suggestions for the eHealth intervention content and functionality to address these needs. Accessibility, personalization, and usability were emphasized as important elements for an eHealth support tool. The participants described an ideal eHealth intervention as one that could be used for support and distraction from pain, at any time or in any situation, regardless of varying pain intensity and concentration capacity. CONCLUSIONS: This study provides insight into user preferences for eHealth interventions aiming to address self-management for chronic pain. Participants highlighted important factors to be considered when designing and developing eHealth interventions for self-management of chronic pain, illustrating the importance and benefit of including users in the development of eHealth interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03705104; https://clinicaltrials.gov/ct2/show/NCT03705104

Patients'needs and requirements for ehealth pain management interventions: Qualitative study

Background: A growing body of evidence supports the potential effectiveness of electronic health (eHealth) interventions in managing chronic pain. However, research on the needs and preferences of patients with chronic pain in relation to eHealth interventions is scarce. Eliciting user input in the development of eHealth interventions may be a crucial step toward developing meaningful interventions for patients for potentially improving treatment outcomes. Objective: This study aimed to explore the experiences of patients with chronic pain with regard to information and communication technology, understand how an eHealth intervention can support the everyday needs and challenges of patients with chronic pain, and identify possible facilitators and barriers for patients’ use of an eHealth pain management intervention. Methods: Twenty patients living with chronic pain and five spouses participated in individual interviews. Semistructured interview guides were used to explore participants’ needs, experiences, and challenges in daily life as well as their information and communication technology experiences and preferences for eHealth support interventions. Spouses were recruited and interviewed to gain additional insight into the patients’ needs. The study used qualitative thematic analysis. Results: The participants were generally experienced technology users and reported using apps regularly. They were mainly in favor of using an eHealth self-management intervention for chronic pain and considered it a potentially acceptable way of gathering knowledge and support for pain management. The participants expressed the need for obtaining more information and knowledge, establishing a better balance in everyday life, and receiving support for improving communication and social participation. They provided suggestions for the eHealth intervention content and functionality to address these needs. Accessibility, personalization, and usability were emphasized as important elements for an eHealth support tool. The participants described an ideal eHealth intervention as one that could be used for support and distraction from pain, at any time or in any situation, regardless of varying pain intensity and concentration capacity. Conclusions: This study provides insight into user preferences for eHealth interventions aiming to address self-management for chronic pain. Participants highlighted important factors to be considered when designing and developing eHealth interventions for self-management of chronic pain, illustrating the importance and benefit of including users in the development of eHealth interventions

A user-centered approach to an evidence-based electronic health pain management intervention for people with chronic pain: design and development of EPIO

Background: Chronic pain conditions are complicated and challenging to live with. Electronic health (eHealth) interventions show promise in helping people cope with chronic illness, including pain. The success of these interventions depends not only on the technology and intervention content but also on the users’ acceptance and adherence. Involving all stakeholders (eg, patients, spouses, health care providers, designers, software developers, and researchers) and exploring their input and preferences in the design and development process is an important step toward developing meaningful interventions and possibly strengthening treatment outcomes. Objective: The aim of this study was to design and develop a user-centered, evidence-based eHealth self-management intervention for people with chronic pain. Methods: The study employed a multidisciplinary and user-centered design approach. Overall, 20 stakeholders from the project team (ie, 7 researchers, 5 editors, 7 software developers, and 1 user representative), together with 33 external stakeholders (ie, 12 health care providers, 1 health care manger, 1 eHealth research psychologist, and 17 patients with chronic pain and 2 of their spouses) participated in a user-centered development process that included workshops, intervention content development, and usability testing. Intervention content was developed and finalized based on existing evidence, stakeholder input, and user testing. Stakeholder input was examined through qualitative analyses with rapid and in-depth analysis approaches. Results: Analyses from stakeholder input identified themes including a need for reliable, trustworthy, and evidence-based content, personalization, options for feedback, behavioral tracking, and self-assessment/registration as factors to include in the intervention. Evidence-based intervention content development resulted in one face-to-face introduction session and 9 app-based educational and exercise-based modules. Usability testing provided further insight into how to optimize the design of the intervention to the user group, identifying accessibility and a simple design to be essential. Conclusions: The design and development process of eHealth interventions should strive to combine well-known evidence-based concepts with stakeholder input. This study, designing and developing the pain management intervention EPIO, illustrates how a stakeholder-centered design approach can provide essential input in the development of an eHealth self-management intervention for people with chronic pain

A User-Centered Approach to an Evidence-Based Electronic Health Pain Management Intervention for People With Chronic Pain: Design and Development of EPIO

Background Chronic pain conditions are complicated and challenging to live with. Electronic health (eHealth) interventions show promise in helping people cope with chronic illness, including pain. The success of these interventions depends not only on the technology and intervention content but also on the users’ acceptance and adherence. Involving all stakeholders (eg, patients, spouses, health care providers, designers, software developers, and researchers) and exploring their input and preferences in the design and development process is an important step toward developing meaningful interventions and possibly strengthening treatment outcomes. Objective The aim of this study was to design and develop a user-centered, evidence-based eHealth self-management intervention for people with chronic pain. Methods The study employed a multidisciplinary and user-centered design approach. Overall, 20 stakeholders from the project team (ie, 7 researchers, 5 editors, 7 software developers, and 1 user representative), together with 33 external stakeholders (ie, 12 health care providers, 1 health care manger, 1 eHealth research psychologist, and 17 patients with chronic pain and 2 of their spouses) participated in a user-centered development process that included workshops, intervention content development, and usability testing. Intervention content was developed and finalized based on existing evidence, stakeholder input, and user testing. Stakeholder input was examined through qualitative analyses with rapid and in-depth analysis approaches. Results Analyses from stakeholder input identified themes including a need for reliable, trustworthy, and evidence-based content, personalization, options for feedback, behavioral tracking, and self-assessment/registration as factors to include in the intervention. Evidence-based intervention content development resulted in one face-to-face introduction session and 9 app-based educational and exercise-based modules. Usability testing provided further insight into how to optimize the design of the intervention to the user group, identifying accessibility and a simple design to be essential. Conclusions The design and development process of eHealth interventions should strive to combine well-known evidence-based concepts with stakeholder input. This study, designing and developing the pain management intervention EPIO, illustrates how a stakeholder-centered design approach can provide essential input in the development of an eHealth self-management intervention for people with chronic pain. Trial Registration ClinicalTrials.gov NCT03705104; https://clinicaltrials.gov/ct2/show/NCT0370510

A User-Centered Approach to an Evidence-Based Electronic Health Pain Management Intervention for People With Chronic Pain: Design and Development of EPIO

Background: Chronic pain conditions are complicated and challenging to live with. Electronic health (eHealth) interventions show promise in helping people cope with chronic illness, including pain. The success of these interventions depends not only on the technology and intervention content but also on the users’ acceptance and adherence. Involving all stakeholders (eg, patients, spouses, health care providers, designers, software developers, and researchers) and exploring their input and preferences in the design and development process is an important step toward developing meaningful interventions and possibly strengthening treatment outcomes. Objective: The aim of this study was to design and develop a user-centered, evidence-based eHealth self-management intervention for people with chronic pain. Methods: The study employed a multidisciplinary and user-centered design approach. Overall, 20 stakeholders from the project team (ie, 7 researchers, 5 editors, 7 software developers, and 1 user representative), together with 33 external stakeholders (ie, 12 health care providers, 1 health care manger, 1 eHealth research psychologist, and 17 patients with chronic pain and 2 of their spouses) participated in a user-centered development process that included workshops, intervention content development, and usability testing. Intervention content was developed and finalized based on existing evidence, stakeholder input, and user testing. Stakeholder input was examined through qualitative analyses with rapid and in-depth analysis approaches

Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease

Chronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR+CD38+ EM CD4+ T cells, T regulatory-like cells, PD1+ EM CD8+ T cells, neutrophils, CD27+ TCRγδ cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4+ T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4+ T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD.Pattern Recognition and BioinformaticsComp Graphics & Visualisatio

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally