Predictors of response and disease course in patients with inflammatory bowel disease treated with biological therapy-the Danish IBD Biobank Project:protocol for a multicentre prospective cohort study

IntroductionInflammatory bowel diseases (IBDs) are chronic diseases of unknown cause characterised by a progressive and unpredictable disease course. In the last decade, biological treatment has become a cornerstone in the treatment of IBD. However, one-in-three-to-four patients do not respond to first-line biological agents and another third of patients see their response diminish over time. This highlights an unmet need for optimising the use of biologicals and the prediction of treatment response. Considering the multifaceted nature of IBD, we hypothesise that multiomics profiling of sequential samples from single patients could facilitate the discovery of predictive biomarkers of response to biological therapy and disease course.MethodsThis is a multicentre prospective cohort study which will enrol 840 biological-naïve patients with IBD who initiate biological therapy in a 3-year period. Primary outcomes are the occurrence of primary non-response (evaluated at weeks 14–16) and loss of response (evaluated during entire follow-up in patients who obtain partial or full response after induction period). Each patient will be followed up for their clinical data for at least 1 year or till the end of study period (up to 4 years). Blood and stool samples will be collected sequentially during the first year of biological treatment. Intestinal tissue will be sampled after 1 year of treatment and whenever an endoscopy is performed. Samples will undergo transcriptomic, proteomic and microbial DNA analyses. Omics data will be integrated with clinical data to identify a panel of predictive biomarkers of response to biological therapy and disease behaviour in patients with IBD.Ethics and disseminationEthical approval has been obtained from the Danish Ethics Committee (H-18064178). Inclusion is ongoing at three study centres and will be initiated in two additional centres. Both positive and negative study results will be disseminated through peer-reviewed journals according to Strengthening the Reporting of Observational Studies in Epidemiology guidelines, as well as presented at international conferences

Welfare effects of environmental hypercapnia quantified by indicators based on morphology and allostatic load in Atlantic salmon (Salmo salar)

Water supply is a limited resource in most salmon hatcheries, which is compensated by reduced water flow and oxygenation. However, reduced water exchange can lead to accumulation of CO2, resulting in environmental hypercapnia, which may have negative impacts on fish welfare. Thus, environmental hypercapnia can be a common welfare problem for salmon in hatcheries, and particularly in recirculating systems (RAS). In this experiment, Atlantic salmon were exposed to chronic environmental hypercapnia during the last 68 days of the freshwater phase, whereupon effects on physiological stress coping mechanisms and morphological welfare indicators were investigated. Effects on stress coping mechanisms were quantified by measuring changes in brain serotonergic chemistry and plasma cortisol at basal levels and in response to a standardized acute stress test. The results show that exposure to elevated CO2 saturation in the water compromised stress responsiveness of brainstem serotonergic activity, altered osmotic homeostasis, and suppressed growth indicating that fish experience allostatic overload. However, no effects on morphological welfare indicators were observed. This accentuates the need for physiological measures, including physiological responses to controlled challenges to activate the stress axis, when investigating the welfare status of fish reared in systems with potential high CO2.publishedVersio

The Citrullinated and MMP-degraded Vimentin Biomarker (VICM) Predicts Early Response to Anti-TNF alpha Treatment in Crohn's Disease

Background: In Crohn's disease (CD), 10% to 40% of patients do not respond to anti-tumor necrosis factor- (TNF) treatment. Currently, there are no biomarkers with adequate sensitivity to separate responders from nonresponders at an early stage. Aim: The aim of this study was to investigated whether early changes in the VICM (citrullinated and matrix metalloproteinase-degraded vimentin) biomarker were associated with response to anti-TNF treatment in patients with CD. Methods: Serum VICM levels were measured by ELISA in 2 independent cohorts of CD patients (n=42) treated with anti-TNF (infliximab or adalimumab). Response was determined by achieving clinical remission (Harvey Bradshaw Index<5). Results: Compared with baseline, VICM serum levels were reduced by anti-TNF in the infliximab cohort (week 6 and 14) and in the adalimumab cohort (week 8). VICM was lower in the responders compared with the nonresponders [infliximab: Week 6, P<0.05; area under the curve (AUC)=0.90; adalimumab: Week 1, P<0.01 (AUC=0.91), and week 8, P<0.05 (AUC=0.86)], and were able to predict response to treatment after 1 week of treatment with an odds ratio of 42.5. Conclusions: The VICM biomarker was time dependently reduced in CD patients responding to anti-TNF treatment. We suggest that VICM may be used as a marker for monitoring early response to anti-TNF in patients with CD

Infliximab Induces Clonal Expansion of γδ-T Cells in Crohn's Disease: A Predictor of Lymphoma Risk?

BACKGROUND: Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion. METHODOLOGY/PRINCIPAL FINDINGS: We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n=20) or adalimumab (Humira®; n=26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5-15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells. CONCLUSION/SIGNIFICANCE: CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents

A comparative study on quality, shelf life and sensory attributes of Atlantic salmon slaughtered on board slaughter vessels against traditional land-based facilities

The purpose of this study was to investigate the shelf life and quality of Atlantic salmon (Salmo salar) slaughtered onboard vessels and shipped to Denmark in −0.8 °C refrigerated seawater (RSW) as compared to traditional land-based slaughtering facilities having fish on ice. The quality and shelf life were measured on fresh and smoked fillets including blood spot counting, fillet gaping, texture hardness, microbiological counts, Quality Index Method (QIM) and sensory analysis. Blood spot counting and fillet gaping were measured on smoked fillets. Fresh fish slaughtered onboard the vessel had significantly lower fillet gaping scores as compared to those slaughtered at the facility, while no difference was found on smoked fillets. There were no significant differences in blood spots counts nor texture hardness between any of the groups. Salmon slaughtered on the vessel had a significant lower QIM score. The total mesophilic count and H2S producing bacteria for fish slaughtered onboard vessels were significant lower at the end of storage (21d). Sensory analysis after 18 days of storage revealed minimal differences between the groups, whereas fish from the vessel had lower protein precipitation. We conclude that fish slaughtered onboard vessels and transported in superchilled RSW onboard a slaughter vessel presents good quality and improves shelf life over time.publishedVersio

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)

Purpose Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4–46.1) had thrombocytopenia; 23.4% (20–26) had thrombocytopenia at ICU admission, and 19.8% (17.6–22.2) developed thrombocytopenia during their ICU stay. Non-AIDS-, non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19–2.42). Conclusion Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.publishedVersio

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)

Purpose: Thrombocytopenia (platelet count &lt; 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods: We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results: We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4–46.1) had thrombocytopenia; 23.4% (20–26) had thrombocytopenia at ICU admission, and 19.8% (17.6–22.2) developed thrombocytopenia during their ICU stay. Absence of acquired immune deficiency syndrome (AIDS), non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19–2.42). Conclusion: Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic

Platelet aggregation during targeted temperature management after out-of-hospital cardiac arrest: A randomised clinical trial

Some studies conclude that mild hypothermia causes platelet dysfunction leading to an increased bleeding risk, whereas others state that platelet aggregation is enhanced during mild hypothermia. Therefore, the aim of this study was to clarify whether standard or prolonged duration of targeted temperature management affected platelet aggregation. We randomised 82 comatose patients resuscitated after out-of-hospital cardiac arrest to either 24 hours (standard group) or 48 hours (prolonged group) of targeted temperature management at 33±1°C. Blood samples were collected 22 hours, 46 hours and 70 hours after reaching target temperature. Platelet aggregation was assessed by impedance aggregometry employing a Multiplate®Analyser, using the COLtest®, TRAPtest®, ADPtest® and ASPItest® as agonists, and with the results reported as area under the curve (AUC, AU*min). The platelet aggregation was below the normal range in all blood samples. No differences were observed between the standard group and the prolonged group in either of the blood samples (all p ≥ 0.11), except for a 24% decreased aggregation (95% confidence interval (CI) (10%;37%), p = 0.002) when using the COLtest® in the 46-hour sample. Comparing the 22-hour sample with the 46-hour sample in the prolonged group separately, we found no differences when employing the COLtest®, the ASPItest® or the ADPtest® in patients without the use of adenosine diphosphate receptor inhibitors (all p values ≥0.21), but aggregation induced by the TRAPtest® decreased by 14% (95% CI −8%;−20%), p < 0.001). We concluded that the platelet aggregation post cardiac arrest was below the normal range independent of the core temperature. Moreover, no substantial difference was found in platelet aggregation between standard and prolonged targeted temperature management