Limerick City Profile (NIRSA) Working Paper Series. No. 13

The purpose of this profile is to provide a comprehensive account of the present state of the city, in order to assist the City Development Board in the preparation of its strategy for economic, social and cultural development over the next ten years

Cross-sectional study of the provision of interventional oncology services in the UK

Objective: To map out the current provision of interventional oncology (IO) services in the UK. Design: Cross-sectional multicentre study. Setting: All National Health Service (NHS) trusts in England and Scottish, Welsh and Northern Ireland health boards. Participants: Interventional radiology (IR) departments in all NHS trusts/health boards in the UK. Results: A total of 179 NHS trusts/health boards were contacted. We received a 100% response rate. Only 19 (11%) institutions had an IO lead. 144 trusts (80%) provided IO services or had a formal pathway of referral in place for patients to a recipient trust. 21 trusts (12%) had plans to provide an IO service or formal referral pathway in the next 12 months only. 14 trusts (8%) did not have a pathway of referral and no plans to implement one. 70 trusts (39%) offered supportive and disease-modifying procedures. One trust had a formal referral pathway for supportive procedures. 73 trusts (41%) provided only supportive procedures (diagnostic or therapeutic). Of these, 43 (59%) had a referral pathway for disease-modifying IO procedures, either from a regional cancer network or through IR networks and 30 trusts (41%) did not have a referral pathway for disease-modifying procedures. Conclusion: The provision of IO services in the UK is promising; however, collaborative networks are necessary to ensure disease-modifying IO procedures are made accessible to all patients and to facilitate larger registry data for research with commissioning of new services

United Kingdom Fund Managers and Institutional Investors’ Attitudes Toward Japanese Equities

This article explores UK fund managers and institutional investors' attitudes toward Japanese equities. We find a declining home bias of UK pension funds vis-à-vis Japanese equities since the early 1990s. However, for the most part, this decrease is a reflection of Japan's decreasing equity market and gross domestic product weights. Only in the 2000s did UK pension funds increase their Japanese equity holdings slightly. While our informants showed a comparatively high degree of variance in opinions about market factors, certain macro and institutional factors—namely, economic growth, deflation, demographics, and corporate governance—were rated high as explanatory factors for an overall low enthusiasm in Japanese equities. Our discussion confirms that these factors appear to make investments in Japan comparatively less attractive

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Limerick City Profile (NIRSA) Working Paper Series. No. 13

The purpose of this profile is to provide a comprehensive account of the present state of the city, in order to assist the City Development Board in the preparation of its strategy for economic, social and cultural development over the next ten years

Limerick City Profile (NIRSA) Working Paper Series. No. 13

The purpose of this profile is to provide a comprehensive account of the present state of the city, in order to assist the City Development Board in the preparation of its strategy for economic, social and cultural development over the next ten years

Limerick City Profile (NIRSA) Working Paper Series. No. 13

The purpose of this profile is to provide a comprehensive account of the present state of the city, in order to assist the City Development Board in the preparation of its strategy for economic, social and cultural development over the next ten years