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Background and Aims: During early phases of inflammation, activated neutrophils extrude neutrophil extracellular traps (NETs) in a PAD4-dependent manner, aggravating tissue injury and remodelling. In this study, we investigated the potential pro-fibrotic properties and signalling of NETs in Crohn's disease (CD)., Methods: NETs and activated fibroblasts were labelled on resected ileum from CD patients by multiplex immunofluorescence staining. NETs-treated human primary intestinal fibroblasts were analysed by bulk RNA-sequencing to uncover cell signalling pathways, and by high-throughput imaging to assess collagen production and migratory activity. Consequentially, TLR2/NF-kB pathway was evaluated by transfection of CCD-18Co fibroblasts with NF-kB-luciferase reporter plasmid, incorporating C29 to block TLR2 signalling. A chronic DSS mouse model was used to define the specific role of PAD4 deletion in neutrophils (MRP8-Cre, Pad4fl/fl)., Results: Immunofluorescence showed spatial co-localisation of NETs and activated fibroblasts in ileal ulcerations of CD patients. Transcriptomic analysis revealed upregulation of pro-fibrotic genes and activation of TLR-signalling pathways in NETs-treated fibroblasts. NETs treatment induced fibroblast proliferation, diminished migratory capability, and increased collagen release. Transfection experiments indicated a substantial increase in NF-kB expression with NETs, whereas C29 led to decreased expression and release of collagen. In line, a significantly reduction in collagen content was observed in the colon of MRP8-Cre, Pad4fl/fl mice subjected to chronic DSS colitis., Conclusions: NETs potentially serve as an initial stimulus for pathological activation of fibroblasts within the intestine via the TLR2/NF-kB pathway. Given their early involvement in inflammation, inhibition of PAD4 might offer a strategy to modulate both inflammation and fibrogenesis in CD., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.

Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1 + tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis., (© 2024. The Author(s).)

Plasmodium parasites cause malaria, a global health disease that is responsible for more than 200 million clinical cases and 600 000 deaths each year. Most deaths are caused by various complications, including malaria-associated acute respiratory distress syndrome (MA-ARDS). Despite the very rapid and efficient killing of parasites with antimalarial drugs, 15% of patients with complicated malaria succumb. This stresses the importance of investigating resolution mechanisms that are involved in the recovery from these complications once the parasite is killed. To study the resolution of MA-ARDS, P. berghei NK65-infected C57BL/6 mice were treated with antimalarial drugs after onset of symptoms, resulting in 80% survival. Micro-computed tomography revealed alterations of the lungs upon infection, with an increase in total and non-aerated lung volume due to edema. Whole body plethysmography confirmed a drastically altered lung ventilation, which was restored during resolution. Single-cell RNA sequencing indicated an increased inflammatory state in the lungs upon infection, which was accompanied by a drastic decrease in endothelial cells, consistent with CD8+ T cell-mediated killing. During resolution, anti-inflammatory pathways were upregulated and proliferation of endothelial cells was observed. MultiNicheNet interactome analysis identified important changes in the ligand-receptor interactions during disease resolution that warrant further exploration in order to develop new therapeutic strategies. In conclusion, our study provides insights in pro-resolving pathways that limit inflammation and promote endothelial cell proliferation in experimental MA-ARDS. This information may be useful for the design of adjunctive treatments to enhance resolution after Plasmodium parasite killing by antimalarial drugs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pollenus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus led to over 626 million infections and 6.5 million deaths worldwide and forced to cancel or postpone several sporting events. Effective control techniques are therefore urgently required to avoid COVID-19 spread at these local and global events. This narrative review addressed the healthcare and research efforts on the intersections between COVID-19 and major professional sports leagues worldwide, with special reference to the FIFA World Cup football 2022. This explained how the broader transformation of COVID-19 from being a potential risk to an urgent pandemic public health emergency, caused the world of Football to halt between February and March 2020. This review could add to the growing literature on the importance of scientific research in understanding the relationship between mass sports events and COVID-19 trajectory, concerning studies conducted globally and particularly for the recommencement of major professional football competitions. The information outlined in the article may help sports organizations understand the risks associated with sports and their settings and improve their preparedness for future events under unprecedented circumstances. There were tremendous global healthcare and research efforts to deal with this unprecedented pandemic. The successful FIFA World Cup football tournament was an indicator of the success of these efforts ., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: We sought to assess the risk of COVID-19 and seasonal flu including respiratory syncytial (RSV) and influenza viruses during the FIFA Arab Cup 2021 in Qatar with full capacity of spectators. We also, evaluated the post-event attitude toward resumption of mass football events., Methods: This was a cross-sectional study in which spectators (age ≥ 18 years) were invited for reverse-transcription PCR testing for COVID-19 and seasonal flu. At the same time, between 7 and 14 days after the event, the participants completed a self-administered questionnaire regarding their concerns during the tournament., Results: The tournament included 16 international football teams from the Arab countries. As per the study protocol, 10,000 spectators were approached and 6,475 participated. Among the participants, 4,195 (65.1%), 2,253 (34.9%) and 27 (0.4%) were vaccinated with 2 doses, vaccinated with 3 doses, and recovered from SARS-Cov-2 infection, respectively. There were 61 (0.9%), 41(0.6%) and 11(0.2%) participants who tested positive for COVID-19, RSV and influenza (A/B), respectively. The average cycle threshold (Ct) value for COVID-19 positive cases was 26.1±7.3. Among those who were electronically approached, 6,102 completed the survey whereas 373 had incomplete survey. Overall, 2069 (33.9%) participants reported symptoms that theoretically could be related to COVID-19, of them 39 had positive PCR test (1.9%). Spectators (94.3%) were optimistic about returning sport events to the pre-pandemic status., Conclusions: There was no significant increase in the daily COVID-19 cases during FIFA Arab Cup 2021 with a full capacity of spectators. Therefore, upcoming mass football events can be held safely.

Background: Methods to study gastric emptying in rodents are time consuming or terminal, preventing repetitive assessment in the same animal. Magnetic resonance imaging (MRI) is a non-invasive technique increasingly used to investigate gastrointestinal function devoid of these shortcomings. Here, we evaluated MRI to measure gastric emptying in control animals and in two different models of gastroparesis., Methods: Mice were scanned using a 9.4 Tesla MR scanner. Gastric volume was measured by delineating the stomach lumen area. Control mice were scanned every 30 min after ingestion of a 0.2 g meal and stomach volume was quantified. The ability of MRI to detect delayed gastric emptying was evaluated in models of morphine-induced gastroparesis and streptozotocin-induced diabetes., Key Results: Magnetic resonance imaging reproducibly detected increased gastric volume following ingestion of a standard meal and progressively decreased with a half emptying time of 59 ± 5 min. Morphine significantly increased gastric volume measured at t = 120 min (saline: 20 ± 2 vs morphine: 34 ± 5 mm 3 ; n = 8-10; p < 0.001) and increased half emptying time using the breath test (saline: 85 ± 22 vs morphine: 161 ± 46 min; n = 10; p < 0.001). In diabetic mice, gastric volume assessed by MRI at t = 60 min (control: 23 ± 2 mm 3 ; n = 14 vs diabetic: 26 ± 5 mm 3 ; n = 18; p = 0.014) but not at t = 120 min (control: 21 ± 3 mm 3 ; n = 13 vs diabetic: 18 ± 5 mm 3 ; n = 18; p = 0.115) was significantly increased compared to nondiabetic mice., Conclusions and Inferences: Our data indicate that MRI is a reliable and reproducible tool to assess gastric emptying in mice and represents a useful technique to study gastroparesis in disease models or for evaluation of pharmacological compounds., (© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background and Aims: To describe the COVID-19 positivity rate among football players, team staff, and local organizing committee members participated in the Asian Football Confederation (AFC) Champions League (West) tournament organized with the Bio-secure bubble protocol in place., Methods: A retrospective observational study was carried out to include a total of 2184 participants during the AFC-West tournament in Qatar, which was a 3-week event (September 14-October 3, 2020). This event was undertaken under the Bio-secure bubble protocol, which was developed and implemented for sports events in Qatar during the pandemic. Within 72 h of departure and upon arrival in Qatar, all participants underwent reverse-transcriptase polymerase chain reaction testing (RT-PCR) to diagnose COVID-19. The test was considered positive based on the cycle threshold (cT) value which was <30, whereas, reactive if cT value was ≥30 and <40, and negative (cT > 40)., Results: Of the 2184 participants (528 players, 388 team staff, and 1268 local staff), 916 international participants were tested for COVID-19 PCR upon arrival at the Hamad International Airport, whereas the local staff ( n  = 1268) were tested 2 days before entering the bubble. The mean age of the players was 27.5 ± 9.8. Fifteen teams participated and as many as 60 matches were played over 3 weeks. Most participants tested negative (95.3%) and 3.9% tests were inconclusive. During the entire tournament, the positivity rate was 2.7% among all participants. Of the total positive cases, 0.8% were positive before entering the bubble system. The remaining (1.9%) tested positive during the tournament phase (19 players, 16 team officials, and 8 organizing committee staff)., Conclusion: Bio-secure bubble protocol operated in a controlled environment presents a minimal risk of COVID-19 infection for hosting international football events. This framework could be benchmarked to resume professional football competitions under unprecedented pandemic situations., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Background: Elite professional sports events involving mass gatherings carry a high risk of viral transmission during the coronavirus disease of 2019 (COVID-19) pandemic. We describe the potential impact of resuming professional football leagues involving international participants adhering to a strict Bio-secure bubble protocol and investigate the consequences of spectators/fan attendance at such mass events during the ongoing COVID-19 pandemic in Qatar., Methods: We conducted a descriptive cohort study involving football players, referees, match officials, local organizing committee (LOC) members, hotel and security staff working in close coordination, and over 10,000 spectators from the Asian Football Confederation (AFC) Champions League (East) and the final match. The study covered almost four weeks of the event (November 19 to December 19, 2020) under a robust Bio-secure bubble protocol. It included extensive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RT-PCR (reverse transcription-polymerase chain reaction) every 3-6 days and clinical symptom monitoring on and off the field. Target variables included positive RT-PCR results and clinical symptom monitoring among participants, and rapid antigen testing for fan attendance to examine their safe return to the stadiums., Results: A total of 12,250 RT-PCR tests involving 3158 individuals in the Bio-secure bubble were done over one month for all the AFC (East) matches, including the final match. Overall, 44 matches involving 16 teams were played. During the championship, only five individuals (three LOC members and two match officials) returned positive for COVID-19 infections. Four individuals (three team staff/officials and one person outside the Bio-secure bubble) had reactive results. None of the players tested positive for COVID-19 infection. All individuals testing positive were asymptomatic or had mild symptoms, with no one requiring hospitalization other than symptomatic treatment. The overall positivity rate was 0.15% for the entire duration of the AFC (East) Champions League. For the final match, a total of 10,320 rapid antigen tests were done for spectators, of which only one test was positive for COVID-19., Conclusions: This report shows a very low incidence rate of COVID-19 infections during mass gathering events at the international level. For the resumption of football with spectators, careful mitigation strategies should be considered to reduce the risk of transmission to a sufficiently safe level. This may require proper coordination and measures (i.e., physical distancing, testing, entry, and exit routes in the stadium, and seating arrangement inside the stadium with limited attendance). Based on this, during the ongoing COVID-19 pandemic, the supervised and controlled resumption of football matches with spectators can be done safely provided that a strict Bio-secure bubble protocol has been implemented., (© 2022 Al Musleh, Khan, Abdurahiman, Asim, El-Menyar, Penney, Al-Thani, licensee HBKU Press.)

Background: With the global spread of COVID-19 infection caused by the severe acute respiratory syndrome coronavirus-2 virus (SARS-CoV-2), all the national and international sports events were ceased early in 2020. The sport activities have been reinstated since then, albeit without spectators. However, several governments have established a variety of risk-mitigation measures to gradually reintroduce the spectators to stadiums., Objectives: We aimed to evaluate the implementation of a strict health protocol to ensure the resumption of professional football with spectators and to access its effectiveness in limiting the spread of COVID-19 infections within the community., Methods: This was a retrospective, observational study involving football players, match officials, local organizing committee members, working in close coordination, and over 16,000 spectators in the state of Qatar. We examined data from the Amir Cup final (December 18th, 2020), which was played under a strict protocol that included extensive reverse transcription-Polymerase chain reaction (RT-PCR) testing for players and match officials, as well as the utility of COVID-19 rapid antigen and antibody testings as screening tools for spectators to ensure their safe return to the stadiums. In addition, we reviewed the guidelines and protocols that were put in place to organize Qatar's Amir Cup Football Final, which drew over 16,000 spectators in the stadium., Results: A total of 16,171 spectators undertook rapid antigen and antibody tests for the Amir cup final (from December16-December18, 2020). Fifteen Spectators (n = 15) returned with a positive result for COVID-19 infection during the final event (positivity rate = 0.12%). All players underwent RT-PCR testing 48 h before the match. None of the players tested positive for COVID-19 infections. 1311 individuals reported having symptoms related to COVID-19 post final of Amir Cup. These spectators were tested for COVID-19 RT-PCR with an overall positivity rate (positive/reactive) to be 0.42% (69/16171)., Conclusion: This report shows a meagre incidence rate of COVID-19 infections during and post-Amir Cup football final. Based on the low infectivity rate reported during and post the Amir Cup, we propose that supervised and controlled resumption of football matches with spectators can be carried out safely following a strict testing and tracing protocol. Similar infection control policies can be replicated with a higher number of spectators., (© 2022. The Author(s).)

Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c + monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206 + MhcII hi and Timp2 + MhcII lo Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206 + Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206 + Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation., (© 2022. The Author(s).)