26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Anti‐β7 integrin treatment impedes the recruitment on non‐classical monocytes to the gut and delays macrophage‐mediated intestinal wound healing

Abstract Background Closing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte‐derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti‐α4β7 integrin antibody vedolizumab blocks the recruitment of non‐classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti‐β7 antibody etrolizumab on wound healing are unclear so far. Methods We analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound‐associated monocyte recruitment dynamics with multiphoton microscopy and compared the effects of etrolizumab and vedolizumab surrogate (‐s) antibodies on experimental wound healing and wound‐associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab. Results Human and mouse non‐classical monocytes expressed more αEβ7 integrin than classical monocytes and were a target of etrolizumab‐s, which blocked non‐classical monocyte adhesion to MAdCAM‐1 and E‐Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab‐s along with a reduction of peri‐lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down‐regulated on treatment with etrolizumab, but not with placebo. Conclusions Combined blockade of αEβ7 and α4β7 with etrolizumab seems to exceed the effect of anti‐α4β7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose!#!Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course.!##!Methods!#!A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed.!##!Results!#!Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients.!##!Conclusions!#!Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19