IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.

Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.

Finding value in social media: A collaborative online communication platform linking providers to education and an online tumor board across a large community of oncology practices

Background: Clinical collaboration across fragmented and often small clinic sites can be challenging. As a potential solution, OneOncology, a national community oncology network, launched OneCommunity, a secure, interactive online platform used across our network of six practices and over 130 clinic sites. One feature is a "virtual" tumor board where physicians can post complex cases at any time and obtain input from disease-specific experts from within the network. Members can also post, comment and disseminate information about policy and education updates affecting oncology. Methods: OneCommunity launched on December 15, 2019 and all 442 members of OneOncology were allowed access. We tracked numbers of membership, tumor board cases, policy updates and questions, views and responses per post, and response time for tumor board and policy posts during the study period from launch through June 11, 2020. Results: In the first six months of use, 277 providers signed up and logged into the platform. 71 individual patient cases were presented across 10 specialty tumor boards. The mean time to first response was 35 hours ( < 1 hour, 297 hours), median time was 20 hours, and 73% of postings had a response within 48 hours of original posting. The most robust tumor boards were breast, GI, and lung cancers. There was also a set of general posts that was nonspecific to patients including policy, COVID updates, and educational reviews. The average number of responses for tumor boards was significantly greater than general posts (3.5 vs. 1.8, p < 0.05). The number of views for both types of posts, however, were high (406 vs. 346, p < 0.05). Conclusions: An online communication platform is feasible and allows physicians to receive treatment suggestions for complex cases relatively quickly and across geographies. Tumor board cases received more interaction than policy and education updates. The platform lends itself to rapidly adding other aspects of cancer care such as COVID-19. Future applications include a network wide real-time molecular tumor board.

Suspected appendicitis and COVID-19, a change in investigation and management-a multicentre cohort study.

PURPOSE: The COVID-19 pandemic has reformed global healthcare delivery. On 25 March 2020, Intercollegiate guidelines were published in the UK to promote safe surgical provision during the COVID-19 outbreak advocating non-operative management or avoidance of laparoscopy when surgery is essential. The effects of this on the investigation and management of appendicitis remain unknown. METHODS: We performed a multicentre, prospective, observational study from the start of the new guidelines to the 6th of May 2020. We included all patients referred to surgical teams with suspected appendicitis. A recent historical cohort was identified for comparison. The primary outcome was the impact of the COVID-19 pandemic on the use of non-operative management in appendicitis. Secondary outcomes included imaging, negative appendicectomy rate (NAR), length of stay (LOS) and 30-day complications. RESULTS: A total of 63/164 (38%) patients compared to 79/191 (41%) were diagnosed with appendicitis before and after the guidelines were introduced (p = 0.589). CT scanning increased (71/164 vs 105/191; p = 0.033) while ultrasound scanning decreased (71/164 vs 62/191; p = 0.037). Appendicitis was more likely to be managed non-operatively (11/63 vs 51/79; p < 0.001) and, of those managed surgically, with an open approach (3/52 vs 26/28 p < 0.001). The NAR also reduced (5/52 vs 0/28; p = 0.157). LOS was shorter in non-operatively managed patients (1 day vs 3 days; p < 0.001) without a difference in complications (10/51 vs 4/28; p = 0.760). CONCLUSION: Introduction of the guidelines was associated with changes in practice. Despite these changes, short-term complications did not increase and LOS decreased. Questions remain on the longer-term complication rates in non-operatively managed patients.