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Abstract Eosinophils were previously reported to play a role in intestinal inflammation and fibrosis. Whether this is as a bystander or as an active participant is still up for debate. Moreover, data describing a causal relationship between eosinophils and intestinal fibrosis are scarce. We here aimed to elucidate the role of eosinophils in the pathogenesis of intestinal inflammation and fibrosis. Therefore, we stimulated fibroblasts with (active) eosinophils or with Eosinophil Cationic Protein (ECP), and assessed fibroblast activation via flow cytometry and immunocytochemistry. We observed decreased fibroblast activation when fibroblasts were co-cultured with active eosinophils or after stimulation with ECP in comparison to monoculture conditions, but not in case of co-culturing with inactivated eosinophils. Furthermore, eosinophil depletion in a RAG−/− chronic DSS colitis model resulted in decreased inflammation, but increased development of fibrosis. In this model, we could show increased expression of the anti-inflammatory protein IL-10 and the pro-fibrotic factors IL-1β, FGF-21 and TGF-β3 in the eosinophil-depleted mice compared to the control mice. In conclusion, our in vitro data revealed an anti-fibrotic role for eosinophils. In line, in a chronic murine colitis model, we observed a pro-inflammatory, but an anti-fibrotic, role for eosinophils. Furthermore, we identified an increased presence of anti-inflammatory and pro-fibrotic cytokines in the eosinophil depleted group.

Abstract Mantle cell lymphoma (MCL) is genetically characterized by the IG::CCND1 translocation mediated by an aberrant V(D)J rearrangement. CCND1 translocations and overexpression have been identified in occasional aggressive B-cell lymphomas with unusual features for MCL. The mechanism generating CCND1 rearrangements in these tumors and their genomic profile are not known. We have reconstructed the IG::CCND1 translocations and the genomic profile of 13 SOX11-negative aggressive B-cell lymphomas using whole genome/exome and target sequencing. The mechanism behind the translocation was an aberrant V(D)J rearrangement in three tumors and by an anomalous IGH class-switch recombination (CSR) or somatic hypermutation (SHM) mechanism in ten. The tumors with a V(D)J-mediated translocation were two blastoid MCL and one high-grade B-cell lymphoma. None of them had a mutational profile suggestive of DLBCL. The ten tumors with CSR/SHM-mediated IGH::CCND1 were mainly large B-cell lymphomas, with mutated genes commonly seen in DLBCL and BCL6 rearrangements in 6. Two cases, which transformed from marginal zone lymphomas, carried mutations in KLF2, TNFAIP3 and KMT2D. These findings expand the spectrum of tumors carrying CCND1 rearrangement that may occur as a secondary event in DLBCL mediated by aberrant CSR/SHM and associated with a mutational profile different from that of MCL.

Background: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P) 1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). It is known that non-serious treatment-emergent adverse events (TEAEs) may not lead to UC drug discontinuation but can affect treatment tolerability. Objectives: This post hoc analysis evaluated the incidence of specific, common, non-serious TEAEs reported in the etrasimod UC clinical programme and the characteristics of affected patients. Design: Data included patients from the Placebo-controlled UC cohort (phase II OASIS, and phase III ELEVATE UC 52 and ELEVATE UC 12 trials) receiving QD etrasimod (2 or 1 mg) or placebo. Methods: Proportions and incidence rates (IRs; the number of patients with a TEAE divided by the total exposure in patient-years (PYs), per 100 PY) of Headache, Pyrexia, Nausea and Dizziness TEAEs were reported. Changes in heart rate among patients with Dizziness TEAEs were also evaluated. Results: Among 943 patients (etrasimod 2 mg, N = 577 (276.7 PY); etrasimod 1 mg, N = 52 (11.4 PY); placebo, N = 314 (115.1 PY)), 48, 34, 27 and 21 patients experienced events of Headache, Pyrexia, Nausea and Dizziness, respectively. All events were non-serious; one patient treated with etrasimod was discontinued due to a Pyrexia TEAE. Numerically, IRs of Headache and Dizziness TEAEs were higher, and Nausea slightly higher, with etrasimod versus placebo (13.45 vs 8.63 per 100 PY, 6.52 vs 1.69 and 7.18 vs 5.13 per 100 PY, respectively); IRs were similar for Pyrexia. The duration of most TEAEs was 1–10 days. Conclusion: In the etrasimod UC clinical programme, all Headache, Pyrexia, Nausea and Dizziness events were non-serious. Headache and Dizziness were more frequent, and Nausea slightly more frequent, among patients receiving etrasimod versus placebo. The post hoc nature of this analysis is a limitation. These results reiterate the favourable safety profile and tolerability of etrasimod. Trial registration: ClinicalTrials.gov: NCT02447302; NCT03945188; NCT03996369.

The relevance of assessing the gingival phenotype prior to the initiation of periodontal, orthodontic, or prosthetic therapy has been clearly demonstrated. However, publications on this subject are either old or concerned with the means of assessing the gingival phenotype or the main factors likely to modify it. The main objective of this systematic review of the literature was therefore to investigate the prevalence of different gingival phenotypes in adults in good general health and with a healthy periodontium. A systematic review of the literature was performed following the guidelines of PRISMA recommendations using an electronic search strategy on four databases (PubMed, Scopus, Cochrane Library, and Embase) complemented by a manual search. Three independent authors were involved in study selection, data extraction, and bias assessment. Results: Of 807 articles, 17 of them, published between 2012 and 2023, involving 3277 subjects from 11 countries and 9766 dental sites, fulfilled the inclusion criteria. The prevalence of the gingival phenotype could not be determined at the level of an individual or a dental arch because all the publications assessed this phenotype only at the level of certain dental sectors, and were not chosen at random. The maxillary central incisors and maxillary or mandibular first molar sectors were associated with a high and thick gingival phenotype, independently of the dental morphology, gender, and age of adult subjects. Furthermore, in these regions, this gingival phenotype tended to be associated with a thick vestibular bone table. In contrast, maxillary and mandibular incisors and premolars more often had a thin gingival phenotype. For other teeth, the results were less conclusive. It is important not to rely solely on the overall appearance of the dentition but to independently assess the thickness and height of the gingiva at each dental site requiring intervention. Finally, this study highlights a key point, namely the need for further longitudinal studies to determine the prevalence in healthy adults. For practicality and feasibility reasons, these studies should be designed according to therapeutic needs, dental sector by dental sector, and within homogeneous source populations. PROSPERO registration: CRD 42023392602.

Abstract Introduction Chronic inflammatory diseases, including psoriasis, are associated with development of venous thromboembolism (VTE). The clot lysis profile (CLP) provides information on both the clotting tendency and fibrinolysis activity. We hypothesized that CLP in uncontrolled psoriasis patients is disturbed towards more clotting/less lysis compared to healthy controls (HC) and that successful psoriasis treatment could normalize the CLP. In this project, we aim to compare the CLP in patients with uncontrolled psoriasis with age- and sex-matched HC and investigate the effect of anti-inflammatory treatment on CLP. Methods Patients with uncontrolled psoriasis [psoriasis area severity index (PASI) or body surface area (BSA) > 10] (n = 87) and HC (n = 87) were recruited at a tertiary dermatology department. Samples from patients were obtained before treatment and when disease control was obtained (PASI

Background: The advent of Deep Learning initiated a new era in which neural networks relying solely on Whole-Slide Images can estimate the survival time of cancer patients. Remarkably, despite deep learning’s potential in this domain, no prior research has been conducted on image-based survival analysis specifically for peritoneal mesothelioma. Prior studies performed statistical analysis to identify disease factors impacting patients’ survival time. Methods: Therefore, we introduce MPeMSupervisedSurv, a Convolutional Neural Network designed to predict the survival time of patients diagnosed with this disease. We subsequently perform patient stratification based on factors such as their Peritoneal Cancer Index and on whether patients received chemotherapy treatment. Results: MPeMSupervisedSurv demonstrates improvements over comparable methods. Using our proposed model, we performed patient stratification to assess the impact of clinical variables on survival time. Notably, the inclusion of information regarding adjuvant chemotherapy significantly enhances the model’s predictive prowess. Conversely, repeating the process for other factors did not yield significant performance improvements. Conclusions: Overall, MPeMSupervisedSurv is an effective neural network which can predict the survival time of peritoneal mesothelioma patients. Our findings also indicate that treatment by adjuvant chemotherapy could be a factor affecting survival time.

The gut microbiota has been implicated in onset and progression of ulcerative colitis (UC). Here, we assess potential causal involvement of the microbiota and -associated fecal water (FW) metabolome in altering key functional parameters of the colonic epithelium. Fecal samples were collected from N = 51 healthy controls (HC), N = 36 patients with active UC (UC-A), and N = 41 subjects in remission N = 41 (UC-R). Using in vitro incubation experiments, the FW metabolome’s impact on butyrate oxidation rates/gene expression and cell death (cytotoxicity) of HT-29 cells, cytokine production by PBMC, and barrier integrity of Caco2 monolayers was evaluated. The FW metabolome from patients and individuals hosting the Bacteroides 2 (Bact2) enterotype (69% of UC-A, 31% of UC-R, 3% of HC), characterized by lower levels of median- and short-chain fatty acids and furan compounds, left butyrate oxidation rates unaltered but affected associated gene expression profiles. UC patients/Bact2-carriers’ FW lowered PBMC IL-8 production and increased IL-1β production. Patients’ FW increased cytotoxicity, associated with sulfide compound levels. Bact2 carriers’ FW, displaying higher levels of bile acids, lowered barrier function upon incubation of monolayers. The FW metabolome of patients and individuals hosting a dysbiotic microbiota could contribute to the disruption of functional processes of the colonic epithelium as observed in UC.

BackgroundAs the therapeutic landscape for inflammatory bowel disease (IBD) continues to expand, a need exists to understand how patients perceive and value different attributes associated with their disease as well as with current and emerging treatments. These insights can inform the development and regulation of effective interventions for IBD, benefiting various stakeholders including healthcare professionals, drug developers, regulators, Health Technology Assessment bodies, payers, and ultimately patients suffering from IBD. In response to this, the present patient preference study was developed with the aim to (1) determine the relative preference weights for IBD treatment and disease related attributes, and (2) explain how preferences may differ across patients with different characteristics (preference heterogeneity).MethodsThe patient preference study (PPS) was developed through an 8-step process, with each step being informed by an advisory board. This process included: (1) stated preference method selection, (2) attribute and level development (including a scoping literature review, focus group discussions, and advisory board meetings), (3) choice task construction, (4) sample size estimation, (5) survey implementation, (6) piloting, (7) translation, and (8) pre-testing. The resulting discrete choice experiment (DCE) survey comprises 14 attributes with between two and five varying levels. Participants will answer 15 DCE questions with a partial profile design, where each of the choice questions encompasses two hypothetical treatment profiles showing four attributes. Additionally, questions about patients' socio-demographic and clinical characteristics, as well as contextual factors are implemented. The survey is available in 15 different languages and aims to minimally recruit 700 patients globally.DiscussionThis protocol gives valuable insights toward preference researchers and decision-makers on how PPS design can be transparently reported, demonstrating solutions to remaining gaps in preference research. Results of the PPS will provide evidence regarding the disease and treatment related characteristics that are most important for IBD patients, and how these may differ across patients with different characteristics. These findings will yield valuable insights applicable to preference research, drug development, regulatory approval, and reimbursement processes, enabling decision making across the medicinal product life cycle that is aligned with the true needs of IBD patients.

Introduction Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC.Methods and analysis In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score

IntroductionSince its emergence in late 2019, the SARS-CoV-2 virus has led to a global health crisis, affecting millions and reshaping societies and economies worldwide. Investigating the determinants of SARS-CoV-2 diffusion and their spatiotemporal dynamics at high spatial resolution is critical for public health and policymaking.MethodsThis study analyses 194,682 georeferenced SARS-CoV-2 RT-PCR tests from March 2020 and April 2022 in the canton of Vaud, Switzerland. We characterized five distinct pandemic periods using metrics of spatial and temporal clustering like inverse Shannon entropy, the Hoover index, Lloyd’s index of mean crowding, and the modified space–time DBSCAN algorithm. We assessed the demographic, socioeconomic, and environmental factors contributing to cluster persistence during each period using eXtreme Gradient Boosting (XGBoost) and SHapley Additive exPlanations (SHAP), to consider non-linear and spatial effects.ResultsOur findings reveal important variations in the spatial and temporal clustering of cases. Notably, areas with flatter epidemics had higher total attack rate. Air pollution emerged as a factor showing a consistent positive association with higher cluster persistence, substantiated by both immission models and, to a lesser extent, tropospheric NO2 estimations. Factors including population density, testing rates, and geographical coordinates, also showed important positive associations with higher cluster persistence. The socioeconomic index showed no significant contribution to cluster persistence, suggesting its limited role in the observed dynamics, which warrants further research.DiscussionOverall, the determinants of cluster persistence remained across the study periods. These findings highlight the need for effective air quality management strategies to mitigate air pollution’s adverse impacts on public health, particularly in the context of respiratory viral diseases like COVID-19.

Abstract Background Reinstating inflammation resolution represents an innovative concept to regain inflammation control in diseases marked by chronic inflammation. While most therapeutics target inflammatory molecules and inflammatory effector cells and mediators, targeting macrophages to initiate inflammation resolution to control neuroinflammation has not yet been attempted. Resolution-phase macrophages are critical in the resolution process to regain tissue homeostasis, and are programmed through the presence and elimination of apoptotic leukocytes. Hence, inducing resolution-phase macrophages might represent an innovative therapeutic approach to control and terminate dysregulated neuroinflammation. Methods Here, we investigated if the factors released by in vitro induced resolution-phase macrophages (their secretome) are able to therapeutically reprogram macrophages to control neuroinflammation in the model of experimental autoimmune encephalomyelitis (EAE). Results We found that injection of the pro-resolutive secretome reduced demyelination and decreased inflammatory cell infiltration in the CNS, notably through the in vivo reprogramming of macrophages at the epigenetic level. Adoptive transfer experiments with in vivo or in vitro reprogrammed macrophages using such pro-resolutive secretome confirmed the stability and transferability of this acquired therapeutic activity. Conclusions Overall, our data confirm the therapeutic activity of a pro-resolution secretome in the treatment of ongoing CNS inflammation, via the epigenetic reprogramming of macrophages and open with that a new therapeutic avenue for diseases marked by neuroinflammation.

Introduction: As the COVID-19 pandemic becomes an endemic state, still many questions remain regarding the risks and impact of SARS-CoV-2 infection and vaccination in patients with immune-mediated inflammatory diseases (IMIDs) who were excluded from the phase 3 COVID-19 vaccination trials. Methods: The BELCOMID study collected patient data and serological samples from a large, multicentric IMID patient cohort that was prospectively followed during sequential stages of the pandemic. Patients were stratified according to vaccination status into five groups across three sampling periods. Interactions between SARS-CoV-2 infection, COVID-19 vaccination status, IMID-treatment modalities and IMID course were explored. Results: In total, 2165 patients with IBD, a dermatological or rheumatological IMID participated. SARS-CoV-2 infection rates increased over the course of the pandemic and were highest in IMID patients that had refused every vaccine. After baseline COVID-19 vaccination, serologic spike (S)-antibody responses were attenuated by particular types of immune-modulating treatment: anti-TNF, rituximab, JAKi, systemic steroids, combined biologic/immunomodulator treatment. Nonetheless, S-antibody concentration increased progressively in patients who received a booster vaccination, reaching 100% seroconversion rate in patients who had received two booster vaccines. Previous SARS-CoV-2 infection was found as a predictor of higher S-antibody response. Patients who had refused every vaccine showed the lowest rates of S-seroconversion (53.8%). Multiple logistic regression did not identify previous SARS-CoV-2 infection as a risk factor for IMID flare-up. Furthermore, no increased risk of IMID flare-up was found with booster vaccination. Conclusions: Altogether, the BELCOMID study provides evidence for the efficacy and safety of COVID-19 vaccination and confirms the importance of repeated booster vaccination in IMID patients.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Despite new treatments, the HCC rate remains important, making it necessary to develop novel therapeutic strategies. Photodynamic therapy (PDT) using a Rose-Bengal (RB) photosensitizer (RB-PDT) could be a promising approach for liver tumor treatment. However, the lack of standardization in preclinical research and the diversity of illumination parameters used make comparison difficult across studies. This work presents and characterizes a novel illumination device based on one green light-emitting diode (CELL-LED-550/3) dedicated to an in vitro RB-PDT. The device was demonstrated to deliver a low average irradiance of 0.62 mW/cm2 over the 96 wells of a multi-well plate. Thermal characterization showed that illumination does not cause cell heating and can be performed inside an incubator, allowing a more rigorous assessment of cell viability after PDT. An in vitro cytotoxic study of the RB-PDT on an HCC cell line (HepG2) demonstrated that RB-PDT induces a significant decrease in cell viability: almost all the cells died after a light dose irradiation of 0.3 J/cm2 using 75 µM of RB (

Staphylococcus aureus (S. aureus) is a pathogen associated with a wide variety of diseases, from minor to life-threatening infections. Antibiotic-resistant strains have emerged, leading to increasing concern about the control of S. aureus infections. The development of vaccines may be one way to overcome these resistant strains. However, S. aureus ability to internalize into cells – and thus to form a reservoir escaping humoral immunity – is a challenge for vaccine development. A role of T cells in the elimination of persistent S. aureus has been established in mice but it remains to be established if CD8+ T cells could display a cytotoxic activity against S. aureus infected cells. We examined in vitro the ability of CD8+ T cells to recognize and kill dendritic cells infected with S. aureus. We first evidenced that both primary mouse dendritic cells and DC2.4 cell line can be infected with S. aureus. We then generated a strain of S. aureus expressing a model CD8 epitope and transgenic F5 CD8+ T cells recognizing this model epitope were used as reporter T cells. In response to S. aureus-infected dendritic cells, F5 CD8+ T cells produced IFN-γ in an antigen-specific manner and displayed an increased ability to kill infected cells. Altogether, these results demonstrate that cells infected by S. aureus display bacteria-derived epitopes at their surface that are recognized by CD8+ T cells. This paves the way for the development of CD8+ T cell-based therapies against S. aureus.

Abstract Background The pandemic has impacted both patients infected by the SARS-CoV-2 virus and patients who seek emergency assistance due to other health issues. Changes in emergency demands are expected to have occurred during the pandemic, the objective of this investigation is to characterize the changes in ambulance emergency demands during the first year of the COVID-19 pandemic in the Vaud State of Switzerland. The goal of this research is to identify the collateral effects of the COVID-19 pandemic on emergency demands. To do so, this study quantifies the differences in health issues, level of severity, and patients’ sociodemographic characteristics (age, location, gender) prior to and during the outbreak. Method This is a retrospective, descriptive and comparative statistical analysis of all ambulance emergency missions from 2018 to 2020 (n = 107,150) in the State of Vaud in Switzerland. Variables analyzed were the number of ambulance missions, patient age and gender, health issues, severity (NACA scores), number of non-transports, mission times and locations. Variables were compared between prepandemic and pandemic situations across years and months. Comparative analysis used bivariate analysis, χ2 test, Student’s t test, and Mann‒Whitney U test. Results The pandemic has had two major impacts on the population’s emergency demands. The first appears to be due to COVID-19, with an increase in respiratory distress cases that doubled in November 2020. The second relates to the implementation of lockdown and quarantine measures for the population and the closures of restaurants and bars. These might explain the decrease in both the number of traumas and intoxications, reaching more than 25% and 28%, respectively. An increase in prehospital emergency demands by the older population, which accounted for 53% of all demands in 2020, is measured. Conclusion Collateral effects occurred during 2020 and were not only due to the pandemic but also due to protective measures deployed relative to the population. This work suggests that more targeted reflections and interventions concerning the most vulnerable group, the population of people 65 and older, should be of high priority. Gaining generalizable knowledge from the COVID-19 pandemic in prehospital settings is critical for the management of future pandemics or other unexpected disasters.

Background and Aims: Gastrointestinal (GI) endoscopy has known a great evolution in the last decades. Imaging techniques evolved from imaging with only standard white light endoscopes toward high-definition resolution endoscopes and the use of multiple color enhancement techniques, over to automated endoscopic assessment systems based on artificial intelligence. This narrative literature review aimed to provide a detailed overview on the latest evolutions within the field of advanced GI endoscopy, mainly focusing on the screening, diagnosis, and surveillance of common upper and lower GI pathology. Methods: This review comprises only literature about screening, diagnosis, and surveillance strategies using advanced endoscopic imaging techniques published in (inter)national peer-reviewed journals and written in English. Studies with only adult patients included were selected. A search was performed using MESH terms: dye-based chromoendoscopy, virtual chromoendoscopy, video enhancement technique, upper GI tract, lower GI tract, Barrett’s esophagus, esophageal squamous cell carcinoma, gastric cancer, colorectal polyps, inflammatory bowel disease, artificial intelligence. This review does not elaborate on the therapeutic application or impact of advanced GI endoscopy. Conclusions: Focusing on current and future applications and evolutions in the field of both upper and lower GI advanced endoscopy, this overview is a practical but detailed projection of the latest developments. Within this review, an active leap toward artificial intelligence and its recent developments in GI endoscopy was made. Additionally, the literature is weighted against the current international guidelines and assessed for its potential positive future impact.

Abstract The early detection of tissue and organ damage associated with autoimmune diseases (AID) has been identified as key to improve long-term survival, but non-invasive biomarkers are lacking. Elevated cell-free DNA (cfDNA) levels have been observed in AID and inflammatory bowel disease (IBD), prompting interest to use cfDNA as a potential non-invasive diagnostic and prognostic biomarker. Despite these known disease-related changes in concentration, it remains impossible to identify AID and IBD patients through cfDNA analysis alone. By using unsupervised clustering on large sets of shallow whole-genome sequencing (sWGS) cfDNA data, we uncover AID- and IBD-specific genome-wide patterns in plasma cfDNA in both the obstetric and general AID and IBD populations. We demonstrate that pregnant women with AID and IBD have higher odds of receiving inconclusive non-invasive prenatal screening (NIPS) results. Supervised learning of the genome-wide patterns allows AID prediction with 50% sensitivity at 95% specificity. Importantly, the method has the potential to identify pregnant women with AID during routine NIPS. Since AID pregnancies have an increased risk of severe complications, early recognition or detection of new-onset AID can redirect pregnancy management and limit potential adverse events. This method opens up new avenues for screening, diagnosis and monitoring of AID and IBD.

Background: Since not all Crohn’s disease (CD) patients respond adequately to ustekinumab therapy, biomarkers could aid to monitor treatment response and optimize therapeutic outcomes. Objectives: To explore the dynamics of serum biomarker concentrations to monitor the response to ustekinumab treatment in CD patients. Design: Retrospective, exploratory study to evaluate concentrations of serum cytokines and acute phase proteins and their relation to endoscopic remission in CD patients during ustekinumab treatment. Methods: Serum concentrations of 16 proteins including cytokines and acute phase proteins were measured using the Mesoscale Discovery Platform in serum of healthy controls ( n = 13), and CD patients ( n = 61) at baseline (week 0), week 8 and week 24 during ustekinumab treatment. Endoscopic remission was defined as simple endoscopic score for CD (SES-CD)

Meeting the increasing consumer and market expectations for sustainably produced beef requires measurement and demonstration of the producers’ sustainability practices. Typically, demonstration of sustainable production relies on time consuming and costly on-ground audits. Online tools using combinations of remotely sensed data and other information sources could offer a cost-effective alternative. However, there are also concerns about the merits and risks of such tools. This paper presents a case of the development process of an online platform for Australian beef producers to demonstrate their sustainable production practices, connected with learning opportunities for continual improvement of their sustainability performance. The project is led by an innovative cross-sectoral collaboration of beef industry, non-government organisation and university partners. Our approach combines producer and market perspectives; focusing on the “value proposition” of the proposed technology for producers, and value chains’ priorities in sustainability markets and in having the ability to demonstrate sustainability in a cost-effective manner. The development process adopted co-design at three levels: (1) the “Consortium” of project partners (2) collaborative co-design through small online groups with producers and value chain representatives; and (3) consultative co-design through producer testing of the platform as it is built by software developers. The design process focused on five themes: tree cover, ground cover, biodiversity stewardship, carbon balance, and drought resilience. We present the main platform design characteristics sought by the co-design groups, and the indicators and measures they considered important for each of the five themes. We then discuss a set of key issues and their implications for technology development, according to a framework expressing interactions between people and their properties, processes and technology. This case shows the importance of taking a “demand-led” rather than a “supply-driven” approach, for the best possible fit of new technology to its users. Since co-design is more often consultative than treating users as equals or leaders in a technology design process, our case highlights the desirability of a fully collaborative approach to co-design.

Objective To infer potential mechanisms driving disease subtypes among patients with inflammatory bowel disease (IBD), we profiled the transcriptome of purified circulating monocytes and CD4 T-cells.Design RNA extracted from purified monocytes and CD4 T-cells derived from the peripheral blood of 125 endoscopically active patients with IBD was sequenced using Illumina HiSeq 4000NGS. We used complementary supervised and unsupervised analytical methods to infer gene expression signatures associated with demographic/clinical features. Expression differences and specificity were validated by comparison with publicly available single cell datasets, tissue-specific expression and meta-analyses. Drug target information, druggability and adverse reaction records were used to prioritise disease subtype-specific therapeutic targets.Results Unsupervised/supervised methods identified significant differences in the expression profiles of CD4 T-cells between patients with ileal Crohn’s disease (CD) and ulcerative colitis (UC). Following a pathway-based classification (Area Under Receiver Operating Characteristic - AUROC=86%) between ileal-CD and UC patients, we identified MAPK and FOXO pathways to be downregulated in UC. Coexpression module/regulatory network analysis using systems-biology approaches revealed mediatory core transcription factors. We independently confirmed that a subset of the disease location-associated signature is characterised by T-cell-specific and location-specific expression. Integration of drug-target information resulted in the discovery of several new (BCL6, GPR183, TNFAIP3) and repurposable drug targets (TUBB2A, PRKCQ) for ileal CD as well as novel targets (NAPEPLD, SLC35A1) for UC.Conclusions Transcriptomic profiling of circulating CD4 T-cells in patients with IBD demonstrated marked molecular differences between the IBD-spectrum extremities (UC and predominantly ileal CD, sandwiching colonic CD), which could help in prioritising particular drug targets for IBD subtypes.

Circulating antibody-secreting cells are present in the peripheral blood of healthy individuals reflecting the continued activity of the humoral immune system. Antibody-secreting cells typically express CD27. Here we describe and characterize a small population of antibody-secreting class switched CD19+CD43+ B cells that lack expression of CD27 in the peripheral blood of healthy subjects. In this study, we characterized CD27-CD43+ cells. We demonstrate that class-switched CD27-CD43+ B cells possess characteristics of conventional plasmablasts as they spontaneously secrete antibodies, are morphologically similar to antibody-secreting cells, show downregulation of B cell differentiation markers, and have a gene expression profile related to conventional plasmablasts. Despite these similarities, we observed differences in IgA and IgG subclass distribution, expression of homing markers, replication history, frequency of somatic hypermutation, immunoglobulin repertoire, gene expression related to Toll-like receptors, cytokines, and cytokine receptors, and antibody response to vaccination. Their frequency is altered in immune-mediated disorders.Conclusionwe characterized CD27-CD43+ cells as antibody-secreting cells with differences in function and homing potential as compared to conventional CD27+ antibody-secreting cells.

Spike-based COVID-19 vaccines induce potent neutralizing antibodies but their efficacy against SARS-CoV-2 variants decreases. OVX033 is a recombinant protein composed of the full-length nucleocapsid (N) protein of SARS-CoV-2 genetically fused to oligoDOM®, a self-assembling domain which improves antigen immunogenicity. OVX033 including N as an antigenic target is proposed as new vaccine candidate providing broad-spectrum protection against sarbecoviruses. OVX033 demonstrated its ability to trigger cross-reactive T cell responses and cross-protection against three variants of SARS-CoV-2 (B.1 Europe, Delta B.1.617.2, and Omicron B.1.1.529) in a hamster challenge model, as evidenced by lower weight loss, lower lung viral loads, and reduced lung histopathological lesions.

Abstract Infliximab dosage de‐escalation without prior knowledge of drug concentrations may put patients at risk for underexposure and trigger the loss of response. A single‐model approach for model‐informed precision dosing during infliximab maintenance therapy has proven its clinical benefit in patients with inflammatory bowel diseases. We evaluated the predictive performances of two multi‐model approaches, a model selection algorithm and a model averaging algorithm, using 18 published population pharmacokinetic models of infliximab for guiding dosage de‐escalation. Data of 54 patients with Crohn’s disease and ulcerative colitis who underwent infliximab dosage de‐escalation after an earlier escalation were used. A priori prediction (based solely on covariate data) and maximum a posteriori prediction (based on covariate data and trough concentrations) were compared using accuracy and precision metrics and the classification accuracy at the trough concentration target of 5.0 mg/L. A priori prediction was inaccurate and imprecise, with the lowest classification accuracies irrespective of the approach (median 59%, interquartile range 59%–63%). Using the maximum a posteriori prediction, the model averaging algorithm had systematically better predictive performance than the model selection algorithm or the single‐model approach with any model, regardless of the number of concentration data. Only a single trough concentration (preferably at the point of care) sufficed for accurate and precise prediction. Predictive performance of both single‐ and multi‐model approaches was robust to the lack of covariate data. Model averaging using four models demonstrated similar predictive performance with a five‐fold shorter computation time. This model averaging algorithm was implemented in the TDMx software tool to guide infliximab dosage de‐escalation in the forthcoming prospective MODIFI study (NCT04982172).

BackgroundThe risks and impact of COVID19 disease and vaccination in patients with Immune Mediated Inflammatory Diseases (IMID) remain incompletely understood. IMID patients and particularly patients receiving immunosuppressive treatment were excluded from the original, registrational phase-3 COVID19 vaccination efficacy and safety trials. Real-world observational data can help to fill this gap in knowledge. The BELCOMID study aims to explore the interaction between IMIDs, immune-modulating treatment modalities and SARS-CoV-2 infection and vaccination in a real-life patient cohort.MethodsA multidisciplinary, prospective, observational cohort study was set up. Consecutive patients with IMIDs of the gut, joints and skin followed at two high-volume referral centers were invited. Both patients under conventional treatment or targeted immune modulating therapies were included. Patient data and serological samples were collected at 3 predefined periods (before COVID19 vaccination, before booster vaccination, after booster vaccination). Primary endpoints were positive PCR-test and SARS-CoV-2 serology reflecting previous SARS-CoV-2 infection or vaccination. Associations with IMID treatment modality and IMID disease activity were assessed. Results of the first two inclusion periods (before booster vaccination) are reported.ResultsAt the first inclusion period data was assessed of 2165 IMID-patients before COVID19 vaccination. At the second inclusion period, data of 2065 patients was collected of whom 1547 had received complete baseline COVID19 vaccination and 222 were partially vaccinated. SARS-CoV-2 infection rate remained low in both groups. No significant increase in IMID flare-up rate was noted in patients with prior SARS-CoV-2 infection. Multiple logistic regression analyses did not show a significant influence of IMID-treatment modality or IMID activity on SARS-CoV-2 infection risk (based on PCR positivity or N-serology). Patients treated with conventional immunomodulators, systemic steroids, and patients on advanced therapies such as biologics or small molecules, had reduced S-antibody seroconversion. S-antibody response was also lower in patients without prior SARS-CoV-2 infection and in active smokers. A subset of patients (4.1%) had no S- nor N-antibody seroconversion following complete baseline vaccination.ConclusionThe BELCOMID study results confirm the benign course of COVID19 infection and vaccination in a large real-life IMID-population. However, our results underscore the need for repeated vaccination and smoking cessation in patients with IMIDs treated with immune-modulating therapies or systemic steroids during the pandemic.

Single Nucleotide Polymorphisms (SNPs) affect cellular regulatory networks, and SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Here the authors introduce iSNP, a precision medicine pipeline that combines genomics and network biology approaches to uncover patient specific pathways affected in complex diseases.

Convivial conservation requires a deep structural shift in research methods and methodology. Although convivial conservation calls for moving beyond the dichotomy of the human and the non-human, this dichotomy is often reproduced in the research methods and methodologies that are used. Most (conservation) researchers have been trained to investigate what non-humans might 'mean' to humans, thereby inevitably silencing the voices of non-humans. This research article identifies a number of threshold concepts and methodologies by turning to multi-species work in nature conservation and challenges the historical anthropocentric framings in this field. It critically challenges the convivial conservation concept by questioning who or what is counted as a research participant from this perspective. Additionally, the article outlines different multi-species research methods and methodology and puts forward the need for threshold and promiscuous methods developed with collaboration between social and natural scientists and non-humans to bring about transformative change in conservation as envisaged by the proponents of convivial conservation. It concludes by offering ways to promote greater conviviality in nature conservation research through a more expansive sense of research participants, recognition of their inter-subjectivities, and multi-sensory communication of their situated knowledges.

Objectives: The subjectivity of the Physician Global Assessment (PGA) is a limitation of the Mayo score in assessing severity of ulcerative colitis (UC). We compared treatment efficacy using endpoint definitions based on modified Mayo (mMayo) score, versus those based on Mayo score, using data from the tofacitinib OCTAVE program. Design: This post hoc analysis included data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain). Methods: Remission and clinical response [with nonresponder imputation (NRI)] were assessed using mMayo (without PGA) and Mayo scores, and further stratified by prior tumor necrosis factor inhibitor (TNFi) failure status. Results: At week 8 of OCTAVE Induction 1 and 2, remission rates with placebo and tofacitinib 10 mg twice daily (BID), respectively, were 7.7% and 24.8% (mMayo) and 6.0% and 17.6% (Mayo). At week 52 of OCTAVE Sustain, remission rates with placebo, tofacitinib 5 and 10 mg BID, respectively, were 12.1%, 35.9%, and 42.1% (mMayo) and 11.1%, 34.3%, and 40.6% (Mayo). A statistically significant ( p

BackgroundThe need for effective public health surveillance systems to track virus spread for targeted interventions was highlighted during the COVID-19 pandemic. It spurred an interest in the use of spatiotemporal clustering and genomic analyses to identify high-risk areas and track the spread of the SARS-CoV-2 virus. However, these two approaches are rarely combined in surveillance systems to complement each one's limitations; spatiotemporal clustering approaches usually consider only one source of virus transmission (i.e., the residential setting) to detect case clusters, while genomic studies require significant resources and processing time that can delay decision-making. Here, we clarify the differences and possible synergies of these two approaches in the context of infectious disease surveillance systems by investigating to what extent geographically-defined clusters are confirmed as transmission clusters based on genome sequences, and how genomic-based analyses can improve the epidemiological investigations associated with spatiotemporal cluster detection.MethodsFor this purpose, we sequenced the SARS-CoV-2 genomes of 172 cases that were part of a collection of spatiotemporal clusters found in a Swiss state (Vaud) during the first epidemic wave. We subsequently examined intra-cluster genetic similarities and spatiotemporal distributions across virus genotypes.ResultsOur results suggest that the congruence between the two approaches might depend on geographic features of the area (rural/urban) and epidemic context (e.g., lockdown). We also identified two potential superspreading events that started from cases in the main urban area of the state, leading to smaller spreading events in neighboring regions, as well as a large spreading in a geographically-isolated area. These superspreading events were characterized by specific mutations assumed to originate from Mulhouse and Milan, respectively. Our analyses propose synergistic benefits of using two complementary approaches in public health surveillance, saving resources and improving surveillance efficiency.

Microbial dysbiosis is an established finding in patients with inflammatory bowel disease (IBD), but host-microbial interactions are poorly understood. We aimed to unravel the effect of microbiota exposure on intestinal epithelial cells. Confluent Transwell® organoid monolayers of eight UC patients and eight non-IBD controls were co-cultured for six hours with microbiota (3x108 cells) of UC patients or a healthy volunteer (HV), in the presence or absence of an inflammatory cytokine mix. Transepithelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran measurements, and RNA sequencing were performed on epithelial cells, and 16S rRNA sequencing on microbiota samples before and after co-culture. Transcriptomic response following microbiota exposure was not different between epithelial cells from UC patients or non-IBD controls. Following UC microbiota exposure, but not HV microbiota, a strong decrease in epithelial barrier integrity was observed in both UC and HV epithelial cells by TEER and FITC dextran measurements. Exposure of inflamed epithelium to UC microbiota induced transcriptomic stress pathways including activation of EGR1, MAPK and JAK/STAT signaling, as well as AP-1 family and FOSL transcripts. Stress responses after HV microbiota stimulation were milder. We conclude that not the epithelial cell origin (UC versus non-IBD) but the microbial donor drives transcriptomic responses, as exposure to UC microbiota was sufficient to induce stress responses in all epithelial cells. Further research on therapies to restore the microbial balance, to remove the constant trigger of dysbiosis, is required.

Here, the authors report quantitative daily gut microbiome variation of individual gut bacterial abundances in healthy individuals, linked to changes in transit time and diet, highlighting the potential need for multiple samplings for microbiome target identification and the development and application of reliable microbiome diagnostics.

Abstract Background New minimally invasive treatments are vital to delay joint replacement surgery in patients with knee osteoarthritis. This study was designed to select the most effective among three formulations of an enhanced protein solution containing clonidine, hyaluronic acid, and human plasma (JTA-004), and compare the safety and efficacy of intra-articular administration of the selected formulation with a reference treatment (hyaluronic acid) in symptomatic knee osteoarthritis patients. Methods In this two-stage, double-blind, phase II/III study conducted in 12 Belgian centers, 50–79-year-old patients with primary knee osteoarthritis were randomized (1:1:1:1) to receive one dose of one of three JTA-004 formulations (differing in clonidine concentration [50 or 100 μg/ml] and volume [2 or 4 ml]) or the reference treatment (hylan G-F 20). Patients were evaluated using Western Ontario McMaster Universities (WOMAC®) Scores and the Short-Form health survey up to 6 months post-injection (Month 6). Drug consumption and safety were evaluated. Results Among 164 treated patients, 147 completed the study. The JTA-004 formulation containing 200 μg clonidine and 20 mg hyaluronic acid in 2 ml (JTA-200/2) was selected based on interim results at Month 6. The difference in adjusted mean change in WOMAC Pain Subscale Score from baseline (JTA-200/2 minus reference group) at Month 6 was − 9.49 mm; statistical superiority of JTA-200/2 over the reference was not demonstrated. No statistically significant differences in adjusted mean changes from baseline between JTA-200/2 and reference groups were observed for Pain, Physical Function and Stiffness Subscales WOMAC Scores, Total WOMAC Score, and Well-being Score at any timepoint, although JTA-200/2 induced larger improvements in WOMAC Scores than the reference. Statistically significantly larger improvements in WOMAC Pain Subscale Scores for JTA-004 versus the reference were observed in post-hoc analyses on pooled data from all JTA-004 formulations at Month 6 (p = 0.030) and Month 3 (p = 0.014). All JTA-004 formulations had clinically acceptable safety profiles. Conclusions This study provided preliminary evidence of the safety of intra-articular injection of JTA-004 in knee osteoarthritis patients. Phase III randomized controlled trials with larger sample sizes are needed to evaluate the efficacy of JTA-004 in knee osteoarthritis. Trial registration Clinicaltrials.gov/identifier NCT02740231; clinicaltrialsregister.eu/identifier 2015–002117-30. Retrospectively registered 13/4/2016.

Immune mediated inflammatory diseases (IMIDs) are a heterogeneous group of debilitating, multifactorial and unrelated conditions featured by a dysregulated immune response leading to destructive chronic inflammation. The immune dysregulation can affect various organ systems: gut (e.g., inflammatory bowel disease), joints (e.g., rheumatoid arthritis), skin (e.g., psoriasis, atopic dermatitis), resulting in significant morbidity, reduced quality of life, increased risk for comorbidities, and premature death. As there are no reliable disease progression and therapy response biomarkers currently available, it is very hard to predict how the disease will develop and which treatments will be effective in a given patient. In addition, a considerable proportion of patients do not respond sufficiently to the treatment. ImmUniverse is a large collaborative consortium of 27 partners funded by the Innovative Medicine Initiative (IMI), which is sponsored by the European Union (Horizon 2020) and in-kind contributions of participating pharmaceutical companies within the European Federation of Pharmaceutical Industries and Associations (EFPIA). ImmUniverse aims to advance our understanding of the molecular mechanisms underlying two immune-mediated diseases, ulcerative colitis (UC) and atopic dermatitis (AD), by pursuing an integrative multi-omics approach. As a consequence of the heterogeneity among IMIDs patients, a comprehensive, evidence-based identification of novel biomarkers is necessary to enable appropriate patient stratification that would account for the inter-individual differences in disease severity, drug efficacy, side effects or prognosis. This would guide clinicians in the management of patients and represent a major step towards personalized medicine. ImmUniverse will combine the existing and novel advanced technologies, including multi-omics, to characterize both the tissue microenvironment and blood. This comprehensive, systems biology-oriented approach will allow for identification and validation of tissue and circulating biomarker signatures as well as mechanistic principles, which will provide information about disease severity and future disease progression. This truly makes the ImmUniverse Consortium an unparalleled approach.

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) with the involvement of immune cells and molecules, including cytokines, chemokines and proteases. A previous extensive review about the molecular biology of matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs), related to intestinal barrier destruction and restoration functions in IBD, is here complemented with the literature from the last five years. We also compare IBD as a prototypic mucosal inflammation of an epithelial barrier against microorganisms with inflammatory retinopathy as a disease with a barrier dysfunction at the level of blood vessels. Multiple reasons are at the basis of halting clinical trials with monoclonal antibodies against MMP-9 for IBD treatment. These include (i) the absence of a causative role of MMP-9 in the pathology in animal models of IBD, (ii) the fact that endotoxins, crossing the intestinal barrier, induce massive local release of both neutrophil collagenase (MMP-8) and gelatinase B (MMP-9), (iii) insufficient recognition that MMPs modify the activities of cytokines, chemokines and their receptors, (iv) ignorance that MMPs exist as mixtures of proteoforms with different posttranslational modifications and with different specific activities and (v) the fact that MMPs and TIMPs act in an interactive network, possibly having also beneficial effects on IBD evolution. Nevertheless, inhibition of MMPs may be a useful therapeutic approach during specific IBD disease phases or in specific sub-phenotypes. This temporary “window of opportunity” for MMP-9 inhibition may be complemented by a locoregional one, provided that the pharmacological agents are targeted in time to affected tissues, as is achieved in ophthalmological inflammation. Thus, in order to discover spatial and temporal windows of opportunity for MMP inhibition as treatment of IBD, more preclinical work including well controlled animal studies will be further needed. In this respect, MMP-9/NGAL complex analysis in various body compartments is helpful for better stratification of IBD patients who may benefit from anti-MMP-9.

Abstract Background Population ageing and increased prevalence of chronic diseases result in the emergence of new demands in prehospital care. The prehospital system is facing an increase of cases without acute threat to life (so-called “non-urgent”), which generates tension due to a higher number of admissions to emergency departments and a greater use of prehospital resources. Our aim is to understand this transition in prehospital activities and to delineate the primary missions performed by paramedics in 2018 with a focus on the population concerned, the severity of cases encountered and the typology of health issues. Method The study is retrospective, and descriptive, using a statistical description of 35,188 primary missions realized in 2018 in the State of Vaud (Switzerland). The characteristics taken into consideration are the age and gender of patients, as well as the health issue, the severity of cases based on National Advisory Committee for Aeronautics score (NACA score), and the time and place of intervention. Results The results describe the primary missions in the State of Vaud in 2018 and show that 87% of missions concern “non-urgent” situations (without acute threat to life). Over half of patients are 65 or older, the highest proportion of health issues, 49%, are medical and only 23% of missions are for traumas. Mission related to mental health issues reach 7% and those for intoxication 6%. Most missions take place between 7:00 am and 6:00 pm (67%), and around 12% of missions lead to the non-transport of the patient. Conclusion The prehospital sector is confronted with a major transition in terms of patient care. An increase of non-urgent cases is observed, associated with the care of persons aged 65 or more. Our results question the adequacy between the needs in terms of prehospital care and the paramedic profession as it is currently defined, as well as the place of this profession within the health network. Reflecting upon the role of paramedics with respect to the socio-demographic evolution of populations appears necessary, to analyse the adequacy of the paramedics’ skills to respond to the current needs.

Abstract Background Tick-borne diseases (TBDs) are a serious threat to humans, wildlife and livestock, and cause severe economic losses in many tropical drylands. The effective control of TBDs has been constrained by limited understanding of what determines tick loads in animals. We tested interactive effects of several biological factors (sex, age and body condition), one environmental factor (rainfall) and one human factor (management type) on tick loads in animals. Methods We collected ticks on animals at four sampling sites in the semi-arid savanna area of Laikipia County, Kenya, of which two are commercial ranches and the other two are open pastoral grazing areas. From 2017 to 2019, we collected a total of 2038 ticks from 619 domestic animals from various cattle and camel herds and from 79 tranquilised wild animals. Results Generally, wild herbivores (zebras, rhinos and elephants) had higher tick loads than domestic animals. As 83% of the tick samples were taken from Boran cattle, we analysed tick load in these cattle in more detail. Boran cattle had high tick loads in the wet season, especially those animals in poor condition. No differences were found between female and male cattle, regardless of season. The calves had high tick loads during both the wet and dry seasons, whereas the sub-adult and adult cattle had less ticks during the dry season. Cattle on the intensively managed ranches had lower tick load than those in the transhumant management system. Conclusion These findings highlight the importance of establishing effective control of ticks on domestic animals in transhumant management systems as tick loads were high on these animals in both the wet and dry season. Graphic abstract

Abstract Background The mechanism of gingival growth that may occur during fixed orthodontic treatment is not yet fully understood and the amount of dental plaque is often incriminated. The objective of this study was to evaluate the prevalence of gingival growth during multi-attachment orthodontic treatment and to prioritize its predicting factors, especially the quantity of biofilm. Methods This comprehensive cross-sectional descriptive study was conducted on orthodontic patients aged 9 to 30 years, in good health, treated by a fixed appliance. Periodontal clinical parameters such as plaque index, gingival index, probing pocket depth, periodontal phenotype and gingival enhancement index were recorded. Likewise, the brushing habits and the date of the last scaling were noted. The orthodontic parameters studied were the duration of the treatment, the type of bracket, the alloys used for the arches and the type of ligatures. Descriptive statistics were carried out, and variables presenting p value

Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), affect several million people worldwide. CD and UC are characterized by periods of clinical remission and relapse. Although IBD patients present chronic alterations of the gut microbiome, called dysbiosis, little attention has been devoted to the relapse-related microbiome. To address this gap, we generated shotgun metagenomic data from the stools of two European cohorts—134 Spanish (followed up for one year) and 49 Belgian (followed up for 6 months) subjects—to characterize the microbial taxonomic and metabolic profiles present. To assess the predictive value of microbiome data, we added the taxonomic profiles generated from a previous study of 130 Americans. Our results revealed that CD was more dysbiotic than UC compared to healthy controls (HC) and that strategies for energy extraction and propionate production were different in CD compared to UC and HC. Remarkably, CD and UC relapses were not associated with alpha- or beta-diversity, or with a dysbiotic score. However, CD relapse was linked to alterations at the species and metabolic pathway levels, including those involved in propionate production. The random forest method using taxonomic profiles allowed the prediction of CD vs. non-CD with an AUC = 0.938, UC vs. HC with an AUC = 0.646, and CD relapse vs. remission with an AUC = 0.769. Our study validates previous taxonomic findings, points to different relapse-related growth and defence mechanisms in CD compared to UC and HC and provides biomarkers to discriminate IBD subtypes and predict disease activity.

AbstractBackground Psoriasis is a chronic inflammatory skin disease associated with numerous comorbidities. Psoriasis has been linked to an increased risk of metabolic syndrome and atherosclerotic arterial disease. Inflammatory conditions are known to increase the risk of venous thromboembolism (VTE), a frequent cause of morbidity and mortality. However, the relationship between psoriasis and VTE has received little attention and existing studies have shown conflicting results.Objectives This systematic review aims to perform a meta-analysis on VTE in psoriasis patients.Methods We conducted a systematic electronic search of the incidence of VTE (pulmonary embolism [PE], deep venous thrombosis [DVT] and/or retinal vein occlusion [RVO]) in psoriasis patients on PubMed, Web of Science, Embase and Cochrane (specifics: see Appendix 1 in Supporting information). Only English literature and full manuscripts were included; abstracts were excluded. Pooled risk ratio and 95% confidence interval were calculated using Review Manager.Results Seven articles were included. Each study separately indicated a correlation between psoriasis and VTE after adjustment for several clinical parameters. The confounders included in the adjustment differed between studies, but all included adjustment for age, gender and comorbidities. A meta-analysis of the unadjusted data of the five studies that reported raw data on number of VTE events and patient follow-up (person-years) showed a pooled risk ratio for VTE and psoriasis of 1.29 (95% CI: 0.92–1.81). The statistical heterogeneity was high with I2 of 97%.Conclusions Published data adjusted for key confounders demonstrate in general a significantly increased prevalence of VTE in psoriasis patients. Both psoriasis severity and number of confounders assessed seem to have an impact on this correlation. In this review, we pooled unadjusted data of the studies and we found a non-significant increased risk for VTE in psoriasis patients compared to healthy controls. This discrepancy suggests that psoriasis severity, age, gender or comorbidities may influence the risk of VTE in subgroups of the psoriasis population. Future research to identify subgroups at risk for VTE is warranted.Key messagesThe included studies reported an increased risk of VTE, DVT, PE and RVO in psoriasis patients.A meta-analysis was performed on five studies that reported raw data and showed that the pooled risk ratio for VTE in psoriasis patients overall was increased, however not significantly, compared to healthy controls.Further research to pinpoint psoriasis subgroups at risk (e.g. severe psoriasis patients, younger age, associated comorbidities) of developing VTE is warranted.

Summary: Inflammatory responses of the intestinal epithelial barrier in patients with Crohn’s disease (CD), a chronic inflammatory bowel disease (IBD), are associated with gut microbial alterations. At a community level, there is scarce mechanistic evidence on the effects of gut microbial alterations on host mucosal barrier responses. We used a computational microbe-host interaction prediction framework based on network diffusion and systems biology to integrate publicly available paired gut microbial and intestinal gene expression datasets. The ileal signaling network potentially modulated by the microbiota was enriched with immune-related pathways such as those associated with IL-4, IL-2, IL-13, NFkB, and toll-like receptors. We identified bacterial proteins eliciting post-translational modifications on host receptors, resulting in the de-repression of pro-inflammatory cytokines via critical hub proteins such as NFkB. The signaling networks were over-represented with CD associated genes and CD drug targets. Using datasets generated from our validation cohorts, we confirmed some of the results.

Abstract Background The clinical decisions of emergency department triage nurses need to be of the highest accuracy. However, studies have found repeatedly that these nurses over- or underestimate the severity of patient health conditions. This has major consequences for patient safety and patient flow management. Workplace distractors such as noise and task interruptions have been pointed to as factors that might explain this inaccuracy. The use of a serious game reproducing the work environment during triage affords the opportunity to explore the impact of these distractors on nurse emergency triage accuracy, in a safe setting. Methods/design A pilot study with a factorial design will be carried out to test the acceptability and feasibility of a serious game developed specifically to simulate the triage process in emergency departments and to explore the primary effects of distractors on nurse emergency triage accuracy. Eighty emergency nurses will be randomized into four groups: three groups exposed to different distractors (A, noise; B, task interruptions; C, noise and task interruptions) and one control group. All nurses will have to complete 20 clinical vignettes within 2 h. For each vignette, a gold standard assessment will be determined by experts. Pre-tests will be conducted with clinicians and certified emergency nurses to evaluate the appeal of the serious game. Discussion Study results will inform the design of large-scale investigations and will help identify teaching, training, and research areas that require further development.

Abstract Introduction Insight in the pathogenesis of intestinal fibrosis is an unmet medical need in inflammatory bowel diseases. Studies in murine models and human organ fibrosis point to a potential role of innate lymphoid cells (ILC) in chronic intestinal inflammation and fibrosis. Materials and Methods Dextran sodium sulfate (DSS) in drinking water was used to induce chronic colitis and remodeling in C57Bl/6 wild type (WT), RAG‐deficient, RAG−/− common γ chain deficient and anti‐CD90.2 monoclonal antibody treated RAG−/− mice. Inflammation was scored by macroscopic and histological examination and fibrosis was evaluated by hydroxyproline quantification and histology. Results In RAG−/− mice (which have a normal ILC population but no adaptive immunity), chronic intestinal inflammation and fibrosis developed similarly as in WT mice, with a relative increase in ILC2 during repeated DSS exposure. Chronic colitis could also be induced in the absence of ILC (RAG−/−γc−/− or anti‐CD90.2 treated RAG−/− mice) with no attenuation of fibrosis. Importantly, clinical recovery based on weight gain after stopping DSS exposure was impaired in ILC‐deficient or ILC‐depleted mice. Conclusion These data argue against a profibrotic effect of ILC in chronic colitis, but rather suggest that ILC have a protective and recovery‐enhancing effect after repeated intestinal injury.

Australia has managed well through the COVID-19 pandemic, compared to many other developed nations. Through its first and second waves it was relatively successful in terms of control of outbreaks. Nevertheless, like everywhere, the shock to national systems has been profound, and adjustment remains complex and volatile. Food is a critical human need, and the food industry is recognised as a vital economic sector. We present an examination of some of the adaptive responses of Australia's food systems during the early stages of the COVID-19 pandemic, from January 2020 to October 2020, with a focus on three case studies (seafood exports, consumer behaviour and food sector employment). These case studies provide observations of specific stresses experienced, as well as insights into the adaptation strategies carried out by various actors within the nation's food systems. The shock was experienced differently in different parts of given food systems, and the opportunities for adaptation varied. Some supply chains lost business, others had to adapt to rapidly increased demands, and surges. Our analysis reveals features of Australia's food systems, and their relationships to other systems, that have facilitated resilience, and features that have impeded it. We found that international supply chains are highly vulnerable to global shocks, that insecure employment conditions throughout the food system reduce the resilience of the system overall, and that consumers are not fully confident in supply chains. We observed the importance of agency and adaptive behaviour throughout the food systems as actors worked to build their own resilience, with consequences for other parts of the system. Our findings suggest that food system resilience can be enhanced by ensuring that the goals and priorities of those most vulnerable in society are recognised and addressed within decision making processes throughout the system.

The French Society of Pathology (SFP) organized its first data challenge in 2020 with the help of the Health Data Hub (HDH). The organization of this event first consisted of recruiting nearly 5000 cervical biopsy slides obtained from 20 pathology centers. After ensuring that patients did not refuse to include their slides in the project, the slides were anonymized, digitized, and annotated by expert pathologists, and finally uploaded to a data challenge platform for competitors from around the world. Competing teams had to develop algorithms that could distinguish 4 diagnostic classes in cervical epithelial lesions. Among the many submissions from competitors, the best algorithms achieved an overall score close to 95%. The final part of the competition lasted only 6 weeks, and the goal of SFP and HDH is now to allow for the collection to be published in open access for the scientific community. In this report, we have performed a “post-competition analysis” of the results. We first described the algorithmic pipelines of 3 top competitors. We then analyzed several difficult cases that even the top competitors could not predict correctly. A medical committee of several expert pathologists looked for possible explanations for these erroneous results by reviewing the images, and we present their findings here targeted for a large audience of pathologists and data scientists in the field of digital pathology.

The past decades witnessed a significant stride in deciphering the pathophysiology of inflammatory bowel disease, which further advanced drug development adding several new biologicals and small molecules to the arsenal of available therapies. Surprisingly, this wealth in therapeutic options did not yield the aspired high durable response rates. In addition, the increase in therapeutic availabilities ignited an increase in research toward biomarkers that could help assign therapies to patients with the highest probability of response. Luckily, major steps have been undertaken in this domain which resulted in the discovery of some interesting biomarkers that are still under validation. However, the pace in which this domain is progressing, the discordance between short-term endpoints in biomarker discovery studies and the ambition of the disease community in modifying disease course, and the uncertainties about the validity of discovered biomarkers highlight the need for a critical appraisal of research conduct in this domain. In this review, we shed light on areas of improvement in biomarker discovery studies that will help optimize the use of available therapies and break the current therapeutic ceiling.

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-β, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.

Eosinophils are leukocytes which reside in the gastrointestinal tract under homeostatic conditions, except for the esophagus which is normally devoid of eosinophils. Research on eosinophils has primarily focused on anti-helminth responses and type 2 immune disorders. In contrast, the search for a role of eosinophils in chronic intestinal inflammation and fibrosis has been limited. With a shift in research focus from adaptive to innate immunity and the fact that the eosinophilic granules are filled with inflammatory mediators, eosinophils are becoming a point of interest in inflammatory bowel diseases. In the current review we summarize eosinophil characteristics and recruitment as well as the current knowledge on presence, inflammatory and pro-fibrotic functions of eosinophils in inflammatory bowel disease and other chronic inflammatory conditions, and we identify research gaps which should be covered in the future.

Tumor-released extracellular vesicles (EVs) contain tumor-specific cargo distinguishing them from healthy EVs, and making them eligible as circulating biomarkers. Glypican 1 (GPC1)-positive exosome relevance as liquid biopsy elements is still debated. We carried out a prospective study to quantify GPC1-positive exosomes in sera from pancreatic ductal adenocarcinoma (PDAC) patients undergoing up-front surgery, as compared to controls including patients without cancer history and patients displaying pancreatic preneoplasic lesions. Sera were enriched in EVs, and exosomes were pulled down with anti-CD63 coupled magnetic beads. GPC1-positive bead percentages determined by flow cytometry were significantly higher in PDAC than in the control group. Diagnosis accuracy reached 78% (sensitivity 64% and specificity 90%), when results from peripheral and portal blood were combined. In association with echo-guided-ultrasound-fine-needle-aspiration (EUS-FNA) negative predictive value was 80% as compared to 33% for EUS-FNA only. This approach is clinically relevant as a companion test to the already available diagnostic tools, since patients with GPC1-positive exosomes in peripheral blood showed decreased tumor free survival.

Abstract Background Therapeutic drug monitoring involves therapeutic modifications based on the measurement of drug levels and antidrug antibodies. The viability of therapeutic drug monitoring in vedolizumab-treated patients with inflammatory bowel disease remains questioned. Main body Accumulating evidence from clinical trials and real-world data suggests that an exposure–efficacy relationship may exist for vedolizumab in inflammatory bowel disease, but results are not as straightforward as they are for anti-tumour necrosis factor-α therapy. Robust target vedolizumab trough levels are currently missing, since available data are heterogenous and prospective, interventional pharmacokinetic–pharmacodynamic studies are lacking. The positioning of vedolizumab drug monitoring in therapeutic algorithms is yet to be defined. Conclusion Therapeutic drug monitoring has the potential to improve the outcome parameters of vedolizumab-treated patients with inflammatory bowel disease. Before the therapeutic drug monitoring of vedolizumab can be implemented in a widespread fashion, prospective studies are needed to evaluate the effect of vedolizumab dose optimisation. These studies should focus on objective disease markers and vedolizumab drug levels, and define thresholds for optimal drug exposure.