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Background Cytomegalovirus (CMV) is an important opportunistic pathogen after transplantation. Some virological variation in transplant recipients is explained by donor and recipient CMV serostatus, but not all. Circadian variability of herpesviruses has been described, so we investigated the effect of time of day of transplantation on posttransplant CMV viremia. Methods We performed a retrospective analysis of 1517 patients receiving liver or kidney allografts at a single center from 2002 to 2018. All patients were given preemptive therapy with CMV viremia monitoring after transplantation. Circulatory arrest and reperfusion time of donor organ were categorized into 4 periods. Patients were divided into serostatus groups based on previous CMV infection in donor and recipient. CMV viremia parameters were compared between time categories for each group. Factor analysis of mixed data was used to interrogate this complex data set. Results Live-donor transplant recipients were less likely to develop viremia than recipients of deceased-donor organs (48% vs 61%; P Discussion We found no evidence for a circadian effect of transplantation on CMV viremia, but these novel results warrant confirmation by other centers.

Background Fungal coinfection is a recognized complication of respiratory virus infections, increasing morbidity and mortality, but can be readily treated if diagnosed early. An increasing number of small studies describing aspergillosis in coronavirus disease 2019 (COVID-19) patients with severe respiratory distress are being reported, but comprehensive data are lacking. The aim of this study was to determine the incidence, risk factors, and impact of invasive fungal disease in adult COVID-19 patients with severe respiratory distress. Methods An evaluation of a national, multicenter, prospective cohort evaluation of an enhanced testing strategy to diagnose invasive fungal disease in COVID-19 intensive care patients. Results were used to generate a mechanism to define aspergillosis in future COVID-19 patients. Results One-hundred and thirty-five adults (median age: 57, M/F: 2.2/1) were screened. The incidence was 26.7% (14.1% aspergillosis, 12.6% yeast infections). The overall mortality rate was 38%; 53% and 31% in patients with and without fungal disease, respectively (P = .0387). The mortality rate was reduced by the use of antifungal therapy (mortality: 38.5% in patients receiving therapy vs 90% in patients not receiving therapy (P = .008). The use of corticosteroids (P = .007) and history of chronic respiratory disease (P = .05) increased the likelihood of aspergillosis. Conclusions Fungal disease occurs frequently in critically ill, mechanically ventilated COVID-19 patients. The survival benefit observed in patients receiving antifungal therapy implies that the proposed diagnostic and defining criteria are appropriate. Screening using a strategic diagnostic approach and antifungal prophylaxis of patients with risk factors will likely enhance the management of COVID-19 patients.

Rationale: Fungal co-infection is a recognised complication of respiratory virus infections, increasing morbidity and mortality, but can be readily treated if diagnosed early. An increasing number of small studies describing aspergillosis in COVID-19 patients with severe respiratory distress are being reported, but comprehensive data is lacking. Objectives: To determine the incidence, risk factors and impact of invasive fungal disease in adult COVID-19 patients with severe respiratory distress. Methods: An evaluation of a national, multi-centre, prospective cohort evaluation of an enhanced testing strategy to diagnose invasive fungal disease in COVID-19 intensive care patients. Results were used to generate a mechanism to define aspergillosis in future COVID-19 patients. Measurements and Main Results: One-hundred and thirty-five adults (median age: 57, M/F: 2·2/1) were screened. The incidence was 25·9% (13·3% aspergillosis, 12·6% yeast infections). The overall mortality rate was 38%; 51% and 31% in patients with and without fungal disease, respectively (P: 0·0398). The mortality rate was reduced by the use of antifungal therapy (Mortality: 38·5% in patients receiving therapy versus 89% in patients not receiving therapy (P: 0·0178). The use of corticosteroids (P: 0·002) and history of chronic respiratory disease (P: 0·043) increased the likelihood of aspergillosis. Conclusions: Fungal disease occurs frequently in critically ill, mechanically ventilated COVID-19 patients. The survival benefit observed in patients receiving antifungal therapy implies that the proposed diagnostic and defining criteria are appropriate. Screening using a strategic diagnostic approach and antifungal prophylaxis of patients with risk factors will likely enhance the management of COVID-19 patients.

There is a 10% shortfall in the number of proximal colorectal cancer cases detected by the UK Bowel Cancer Screening Programme and the actual number of UK-registered proximal colorectal cancers. Sessile serrated adenomas/polyps (SSA/P) are common premalignant lesions in the proximal colon and are notoriously difficult to spot endoscopically. Missed or dismissed SSA/Ps might contribute to this UK proximal colon cancer detection disparity. In Oxfordshire, a service evaluation audit and histological review has shown a linear increase in the detection rate of these lesions over the past 4 years. This is the result of increased endoscopist and pathologist awareness of these lesions and improved interdisciplinary communication. This is the result of increased endoscopist and pathologist awareness of these lesions, together with improved interdisciplinary communication, and we predict that this will lead to a comparable detection increase nationwide. Ongoing surveillance of an increasing number of these premalignant lesions could become a significant endoscopic resource requirement once UK guidelines on serrated lesion follow up are established.

G A A b st ra ct s Conclusions: Gpsm2 controls mitotic spindle orientation in colon stem cells. Loss of Gpsm2 in normal colon causes increased apoptosis and proliferation without affecting overall tissue architecture. Future studies will determine how this affects susceptibility to injury or tumorigenesis. In human colon cancer, reduction of Gpsm2 increases the fraction of tumorigenic CD44+ cells and leads to larger tumors. Colon cancer patients whose tumors express lower levels of Gpsm2 exhibit worse clinical outcomes.

Introduction The serrated colorectal carcinogenesis pathway is increasingly recognised as a distinct and important route to CpG island methylated phenotype (CIMP) carcinomas, yet comparatively little is known about the molecular pathogenesis of these lesions. The precursor lesions - hyperplastic and serrated polyps, are initiated by BRAF or KRAS mutations which initially induce proliferation but are followed by activation of oncogene-induced senescence (OIS) pathways resulting in telomere independent cell-cycle arrest. Subversion of OIS mechanisms is thus necessary for progression of serrated lesions. We assessed (epi)genetic mutation burden and morphogen expression in different colorectal polyps and investigated the effect of disrupted morphogen balance on OIS systems Methods Colonoscopic samples of hyperplastic, serrated, conventional adenomas and neighbouring normal tissue were used. Individual crypt gene expression was measured, DNA extracted and (epi)mutation burden assessed. Epigenetic silencing of the BMP antagonist GREM2 was assessed in serrated polyps and a methylated cell-line. K-rasV12 transfection of mouse embryonic fibroblasts (MEF) was used to induce OIS and assess dynamic morphogen changes in senescing cells. shRNA knockdown of BMP4 in a cancer (HCT116) and primary immortalised (HCEC) cell-line was used to reverse the changes seen in human polyps. Results Marked BMP component changes were seen in both serrated and traditional adenomas, with fewer changes in rectal hyperplastic polyps. Only serrated polyps showed aberrant gene methylation, including epigenetic transcriptional silencing of the BMP antagonist GREM2 . Differential BMP ligand expression ( BMP2 downregulated, BMP4 upregulated) was noted in adenomas and confirmed with in situ hybridisation. KrasV12 OIS induction in MEF’s caused the reversed expression pattern of BMP ligands to that seen in polyps, a change not seen in replicative senescence of the same cells. BMP4 shRNA knockdown impeded anchorage-dependent growth of HCT116 cells and provoked a rapid cell senescence response in HCEC cells with growth arrest and up-regulation of both p21 and p16. Conclusion We hypothesise that BMP ligands are involved in mediating ( BMP2 ), or subverting ( BMP4 ) oncogene-induced senescence, and that epigenetic silencing of specific BMP pathway constituents is selected early during serrated tumourigenesis. By demonstrating the mechanistic involvement of the BMP pathway in OIS we have identified an important early tumour promoting role of morphogen dysregulation which may inform future drug development. Disclosure of Interest None Declared.

Introduction The serrated pathway of colorectal carcinogenesis is a distinct and important pathway leading to CpG island methylated phenotype (CIMP) carcinomas. These lesions are over-represented in interval cancers and may explain the failure to prevent right-sided cancer with colonoscopy. Hyperplastic polyps (HPs) in the left colon rarely transform whereas proximal serrated adenomas (SSAs) have definite malignant potential and are notoriously difficult to detect endoscopically. There is still uncertainty surrounding the diagnostic criteria and management implications of SSA’s, however as pre-malignant lesions it is vital to find, resect and diagnose them. We assessed SSA diagnosis over 4 years in a teaching hospital, and assessed the (epi)genetic mutation burden and expression profile of rectal HPs versus proximal SSAs to see if identifiable molecular differences contribute to their contrasting malignant potential. Methods We searched the pathology archives from 2009 to 2012 for the diagnosis of serrated adenomas. Cases were reviewed by 2 GI pathologists. Colonoscopic follow up for each case was assessed and compared with new American guidelines 1. 5 distal HP and proximal SSA samples were obtained endoscopically, individual crypts were dissected and morphogen gene expression analysed. Obtained DNA was assessed for BRAF and KRAS mutation and CIMP status by methylight. Results There were no serrated lesions diagnosed in 2009 - this was an unrecognised entity in our hospital at the time. Of 486 ‘hyperplastic’ polyps diagnosed in 2009, 60 proximal lesions were reassessed and 19 were confirmed as SSAs. In 2010, 40 cases of SSA were diagnosed, rising to 84 in 2011 and 130 in 2012. Follow up of SSAs was appropriate in the majority of cases but lesions aberrantly denoted as hyperplastic in 2009 did not all have follow up arranged at the time. Molecular assessment showed a significant difference in (epi)mutation burden and morphogen gene expression between distal hyperplastic polyps and proximal SSA’s. Conclusion In our hospital there was no distinction made between hyperplastic and serrated lesions prior to 2010. A 3-fold increase in SSA diagnosis in the following 3 years reflects improved endoscopic detection and pathologist recognition of these lesions. The molecular difference between distal HPs and SSAs underpins the proximal predilection of CIMP cancers, and may reflect underlying differences in colonic regional microenvironment, microbiome or morphogen balance. Improved recognition of subtle endoscopic and morphological characteristics of SSAs by gastroenterologists and pathologists will improve colonoscopic surveillance. Disclosure of Interest None Declared. Reference Rex DK et al. Am J Gastroentero l 2012; 107(9):1315–29.