Increase In Absolute Number Research Articles

Does an agroecological approach impact the nematode biological and functional diversity in intensive protected production systems?

ABSTRACT Food production systems in protected conditions are probably the most intensive agricultural systems causing biodiversity loss. Experimental sites in different European areas were established to investigate whether an agroecological approach to organic greenhouse production allows preserving or increasing biodiversity. Soil nematode communities were characterized by DNA-metabarcoding, and some biodiversity indices were calculated. A general increase in absolute number of genera indicates that the innovative treatments potentially positively influence biodiversity. A multidimensional analysis revealed that the change in nematode community compositions is caused more by country and sampling year than by the farming system. However, regionally, some shifts in biodiversity are obvious and the impact by a farming practice likely. This study is the first indication that the implementation of some agroecological measures in European protected cropping systems is feasible as at least they did not worsen (nor improve) soil biodiversity.

Immunological profiling for short-term predictive analysis in PD-1/PD-L1 therapy for lung cancer

BackgroundImmune checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1) and PD-1 ligand-1 (PD-L1) antibodies, have achieved breakthrough results in improving long-term survival rates in lung cancer. Although high levels of PD-L1 expression and tumor mutational burden have emerged as pivotal biomarkers, not all patients derive lasting benefits, and resistance to immune checkpoint blockade remains a prevalent issue. Comprehending the immunological intricacies of lung cancer is crucial for uncovering the mechanisms that govern responses and resistance to immunomodulatory treatments. This study aimed to explore the potential of peripheral immune markers in predicting treatment efficiency among lung cancer patients undergoing PD-1/PD-L1 checkpoint inhibitors.MethodsThis study enrolled 71 lung cancer patients undergoing PD-1/PD-L1 inhibitor therapy and 20 healthy controls. Immune cell subsets (CD4 + T cells, CD8 + T cells, B cells, NK cells, and NKT cells), phenotypic analysis of T cells and B cells, and PMA/Ionomycin-stimulated lymphocyte function assay were conducted.ResultsLung cancer patients exhibited significant alterations in immune cell subsets, notably an increased percentage of Treg cells. Post-treatment, there were substantial increases in absolute numbers of CD3 + T cells, CD8 + T cells, and NKT cells, along with heightened HLA-DR expression on CD3 + T and CD8 + T cells. Comparison between complete remission and non-complete remission (NCR) groups showed higher Treg cell percentages and HLA-DR + CD4 + T cells in the NCR group.ConclusionThe study findings suggest potential predictive roles for immune cell subsets and phenotypes, particularly Treg cells, HLA-DR + CD4 + T cells, and naïve CD4 + T cells, in evaluating short-term PD-1/PD-L1 therapy efficacy for lung cancer patients. These insights offer valuable prospects for personalized treatment strategies and underscore the importance of immune profiling in lung cancer immunotherapy.

The projected increase of vertebral osteomyelitis in Germany implies a demanding challenge for future healthcare management of aging populations.

Since an increase in the occurrence of native vertebral osteomyelitis (VO) is expected and reliable projections are missing, it is urgent to provide a reliable forecast model and make it a part of future health care considerations. Comprehensive nationwide data provided by the Federal Statistical Office of Germany were used to forecast total numbers and incidence rates (IR) of VO as a function of age and gender until 2040. Projections were done using autoregressive integrated moving average model on historical data from 2005 to 2019 in relation to official population projections from 2020 to 2040. The IR of VO is expected to increase from 12.4 in 2019 to 21.5 per 100,000 inhabitants [95% CI 20.9-22.1] in 2040. The highest increase is predicted in patients over 75years of age for both men and women leading to a steep increase in absolute numbers, which is fourfold higher compared to patients younger than 75years. While the IR per age group will not increase any further after 2035, the subsequent increase is due to a higher number of individuals aged 75years or older. Our data suggest that increasing IR of VO will seriously challenge healthcare systems, particularly due to demographic change and increasing proportions of populations turning 75years and older. With respect to globally fast aging populations, future health care policies need to address this burden by anticipating limitations in financial and human resources and developing high-level evidence-based guidelines for prevention and interdisciplinary treatment.

Abstract 6655: Oncolytic adenovirus dually expressing interferon beta and membrane-stable CD40 ligand increases polyfunctional CD8+T cells associated with antitumor activity

Abstract MEM-288 is a dual-transgene armed oncolytic adenovirus in phase 1 clinical development as a standalone agent and in combination with immune checkpoint inhibitors (ICI). It encodes two potent immune agonists: IFNβ and a recombinant membrane-stable chimeric form of CD40L (MEM40). We previously demonstrated this agonist combination is better than either agonist individually to activate conventional dendritic cells type 1 (cDC1) crucial for CD8+ T cell cross-priming, and to increase tumor-antigen reactive CD8+ T cells. Furthermore, first-in-human Phase 1 clinical trial (NCT05076760) results of MEM-288 for advanced non-small cell lung cancer (NSCLC) and other solid tumors showed MEM-288 tumor shrinkage was associated with systemic antitumor T cell immunity as demonstrated by cytokine, T cell clonotype, and tumor neoantigen analysis. Here, we investigated the precise nature of the localized and systemic T cell response induced by MEM40 + IFNβ in preclinical tumor models. Single-cell RNA sequencing of tumor infiltrating T lymphocytes (TILs) revealed that MEM40 + IFNβ elicited a strong increase in T cells expressing Granzyme B and PRF1, key effector cytokines and cytotoxicity mediators. We tracked the CD8+ T cell response in CD45.1 C57BL/6 mice implanted with syngeneic B16 tumor expressing the model antigen OVA. Interestingly, intratumoral treatment with adenovirus encoding MEM40 + IFNβ did not cause an appreciable increase in absolute numbers of antigen-reactive CD8+ T cells, despite tumor growth inhibition. However, MEM40 + IFNβ compared to control unarmed adenovirus induced a significant (p < 0.005) 5-fold increase in polyfunctional IFNγ+TNFα+PRF1+ and IFNγ+TNFα+Granzyme B+ CD8+ T cells. Polyfunctional CD8+ T cells have the capacity to simultaneously produce effector cytokines and cytotoxicity mediators and are known to be strongly associated with antitumor T cell activity. The robust polyfunctional CD8+ T cell response in these studies is consistent with T cell-driven antitumor activity found in both our preclinical tumor experiments and our clinical studies in advanced NSCLC patients responding to MEM-288. Overall, our findings suggest MEM40 + IFNβ generates a strong polyfunctional CD8+ T cell response in the TME that warrants continued evaluation to understand the pleiotropic mechanisms of this cancer immunotherapy. Citation Format: Mark J. Cantwell, Andreas N. Saltos, Hong Zheng, Dana Foresman, Amer A. Beg. Oncolytic adenovirus dually expressing interferon beta and membrane-stable CD40 ligand increases polyfunctional CD8+T cells associated with antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6655.

#4731 THE CHANGING HAEMODIALYSIS POPULATION IN A SINGLE UK CENTRE: A POST PANDEMIC PHENOMENON?

Abstract Background and Aims Following the Covid-19 pandemic, UK dialysis centres have seen a sharp increase in numbers of patients requiring renal replacement therapy (RRT) particularly haemodialysis (HD). This has resulted in pressures on dialysis capacity and staffing. There may also have been negative effects on other aspects of quality of care, such as a fall in the proportion of patients dialysing via an Arterio-venous fistula (AVF) or worsening anaemia. To study this further, we conducted a retrospective observational study to describe the incident and prevalent HD populations in the post-Covid pandemic period and compare these against pre-pandemic patterns, in a single UK dialysis centre. Method We reviewed data on prevalent HD patient numbers across our service. We specifically collected data from all patients commencing HD between January 2021 and December 2022 using electronic medical records. We collected information on time known to renal prior to starting dialysis, clinic data including which types of clinic attended, documentation of pre-dialysis decisions about modality as well as vascular access referrals, vascular access clinics and vascular access surgery as well as haemoglobin (Hb) at first dialysis. We compared figures with published pre-pandemic data from the 23rd annual UK Renal Registry report on data collected to December 2019 for our centre. We defined a planned start to dialysis as patients who were known to renal >90 days. This aligns with the registry definition. We compared proportional data using the chi square test. Results Comparing prevalent data in Dec. 2022 with Dec 2019, there was a 17% increase in the prevalent HD population from 298 to 349. The proportion of patients dialysing via an AVF fell from 88% to 80% (p = 0.006). The spread across different types of HD in Dec.2022 remained static at 71% In-Centre HD (72% in Dec 2019), 11% Satellite HD (9% in 2019) and 17% HHD (18% 2019) with overall numbers rising across all HD modalities (p for trend = 0.37). PD numbers also rose from 58 to 71 keeping the total percentage on home therapies stable at 31% in our unit. From Jan. 2021- Dec. 2022 inclusive 147 people commenced HD of whom 115 (78%) had planned starts. This compares to 58 starting HD in 2019 and 79% planned (p = 0.85). There was a significant fall in the proportion of planned start HD patients who commenced dialysis with an AVF/AVG, from 81% in 2019 to 56% in 2021-22 (p = 0.003). Themes emerged n planned starters who did not start HD with an AVF/AVG and are detailed in Figure 1. Median Hb level of planned starts on HD was lower at only 94 for 2021-22 and 99 in 2019. Looking in detail at those missing appointments in clinics, 33% had prior documented evidence of fear of Covid-19. Delays in AVF surgery consisted of delayed and cancelled theatre dates, failed AVF requiring re-do or AVF awaiting further intervention at time of dialysis initiation. In the group with a last minute change in decision sighted reasons included: worsening eyesight, development of dementia in partner, reducing mobility. Others changed their mind after further input from the PD team. Despite attending the Advanced Kidney Clinic (AKC) there were still a number of patients with no decision at all. Cancellation of group sessions for dialysis education persisted in our centre until mid-2022 and may have contributed to reduced timely decision making as well as late modality switches. All those with an early failure of PD (defined as < 90 days) had chosen PD prior to the Covid-19 pandemic with intervening remote visits in AKC. Conclusion Following the Covid-19 pandemic, unexpected and unprecedented changes in the HD incident population have been observed, resulting in pressures on dialysis services. In particular, we report an increase in absolute number of dialysis patients, a significant fall in the proportion of patients initiating dialysis with definitive vascular access and a rise in those starting anaemic. This was not related to a change in the proportion of patients with planned starts but may be related to delayed shared decision making as a result of remote consultations and greater delays in vascular access surgery. We have identified a number of areas for service improvement.

IMMU-06. SYSTEMIC MRNA VACCINES RESET IMMUNOGENICITY AGAINST DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND DIPG remains a uniformly fatal disease in dire need of new therapies. There are currently no systemic therapies with proven efficacy against these tumors. To overcome these barriers, we developed a systemic mRNA lipid particle (LP) vaccine that localizes to tumors and reticuloendothelial (RE) organs to modulate both innate and adaptive immunity against poorly immunogenic tumors like DIPG. OBJECTIVE We sought to assess whether RNA-LPs encoding for model antigens (e.g. H3K27M) would reprogram innate immunity and simultaneously elicit sustained adaptive immunity against diffuse midline glioma (DMG). RESULTS RNA-LP encoding for model antigens elicit massive recruitment of nearly all monocytes and lymphocytes to RE organs secondary to a danger response mediated by release of orchestrated cytokines (IL-12, TNF-α, IFN-α) and chemokines (CCL2, CCL4, CXCL9-10). This corresponds to increases in absolute numbers of activated DCs and T cells in the RE organs of mice and reprogramming the glioma tumor microenvironment in canines (pet dogs with spontaneous disease). In neonatal mice inoculated midline with established murine K2 gliomas, we observed that RNA-LP vaccines encoding for H3K27M (beginning at ~day 30) elicit significant long-term survivorship, which appears curative in the bulk of animals treated. While H3K27M specific constructs appeared superior, we observed improved survivorship with irrelevant mRNA species (i.e. pp65 and GFP) suggesting these tumors to be particularly sensitive to innate immune modulation. In mice with DMGs, we observed clinical symptomatology of edema/hydrocephalus followed by improvement in many animals suggesting pseudoprogression from intratumoral inflammation and remodeling. CONCLUSION RNA-LPs reprogram the tumor microenvironment of poorly immunogenic tumors in effect making them ‘hot.’ Treatment responses in murine models of advanced DMGs are encouraging. We are advancing a final RNA-LP formulation for FDA-IND submission and early phase clinical trials for DIPG through multi-institutional consortia.

The global, regional, and national burden of stomach cancer among adolescents and young adults in 204 countries and territories, 1990-2019: A population-based study.

Stomach cancer is a significant health problem in many countries. But healthcare needs of adolescents and young adults (AYAs) stomach cancer patients have been historically neglected. An accurate appraisal of the burden of AYA stomach cancer is crucial to formulating effective preventive strategies. In this study, we report the most recent estimates of AYA stomach cancer burden concerning socio-demographic index (SDI) in 204 countries and territories between 1990 and 2019. Estimates from the Global Burden of Disease study 2019 were used to analyze incidence, mortality, and disability-adjusted life years (DALYs) due to AYA stomach cancer at global, regional, and national levels. Association between AYA stomach cancer burden and SDI were investigated. All estimates are reported as absolute numbers and age-standardized rates, which were standardized to the GBD world population and reported per 100,000 population. In 2019, there were 49,000 incident cases, 27,895 deaths, and 1.57 million DALYs due to AYA stomach cancer globally. The highest age-standardized incidence rate occurred in East Asia [2.42 (women) and 4.71 (men) per 100,000 person-years] and high-income Asia Pacific [3.16 (women) and 2.61 (men) per 100,000 person-years]. Age-standardized death [1.53 (women) and 2.65 (men) per 100,000 person-years] and DALY [150.96 (women) and 87.13 (men) per 100,000 person-years] rates were highest in Oceania. Compared with 1990, in 2019 more than 1,075 more incident cases of AYA stomach cancer were estimated with a decrease of 7,784 deaths. Despite the increase in absolute number of incident cases, the worldwide age-standardized rates of AYA stomach cancer (incidence, deaths, and DALYs) have declined since 1990. The drop in the disease burden was associated with an improved SDI. Globally, 24.41% of the age-standardized DALYs were attributable to a high-sodium diet in both sexes combined, and 0.57% of the age-standardized DALYs were attributable to smoking in men. The global burden of AYA stomach cancer is substantial, especially in developing regions. Capacity-building activities for AYA stomach cancer will benefit the younger generation and population health worldwide.

P096 Characterization of suppressive immune cell subsets in mouse models of colitis-associated colorectal cancer

Abstract Background Chronic colonic inflammation in inflammatory bowel disease (IBD) patients increases the risk of colitis-associated cancer (CAC). Cancer development in CAC is different from that observed in sporadic colorectal cancer (CRC). Most studies have focused on the role of pro-inflammatory immune cell subsets in CAC, yet it is becoming increasingly clear that immunosuppression may also drive cancer progression. We hypothesize that emergence of immunosuppressive cell subsets as a result of chronic intestinal inflammation, dampens anti-tumor immune responses and accelerates the development of CAC. Methods To simulate cancer formation in the background of chronic inflammation, mice were treated with azoxymethane (AOM) followed by three cycles of dextran sodium sulphate (DSS). Apc Min/+ mice treated with AOM were used to model sporadic CRC. After 10 weeks, immune cells from the proximal and distal colonic lamina propria, mesenteric lymph nodes (MLNs) and tumors were obtained for microscopy analyses and processed to obtain single cell suspensions for flow cytometry. Immune cell populations were studied by conventional flow cytometry and immunofluorescence. Results We observed a significant increase in absolute numbers of PD1+CTLA4+TIM3+ ‘exhausted’ CD4+ T cells in the lamina propria from proximal colons in CAC mice as compared to sporadic CRC mice. Interestingly, these numbers showed a positive correlation with the inflammation score in AOM/DSS, demonstrating that chronic inflammation is associated with the emergence of ‘exhausted’ T cells. In addition, we observed a trend to higher numbers of M2-like (MHCII-CD206+) suppressive macrophages and CD4+FoxP3+ regulatory T cells (Tregs) in tumors from CAC mice compared to sporadic CRC. When analysing T cell immune responses in the MLNs, we found a significant decrease in the ratio IFNγ/IL10-producing CD8+ T cells in CAC mice as compared to CRC mice, suggesting a shift towards an anti-inflammatory T cell response in CAC. Conclusion In summary, suppressive immune cell subsets were increased in colonic mucosa and tumors from CAC mice as a result of chronic inflammation, which may be associated with the development of dysplasia. Further functional studies are necessary to prove the role of suppressive immune subsets in IBD-associated dysplasia- and carcinoma progression.

Revisiting Papillomavirus Taxonomy: A Proposal for Updating the Current Classification in Line with Evolutionary Evidence.

Papillomaviruses infect a wide array of animal hosts and are responsible for roughly 5% of all human cancers. Comparative genomics between different virus types belonging to specific taxonomic groupings (e.g., species, and genera) has the potential to illuminate physiological differences between viruses with different biological outcomes. Likewise, extrapolation of features between related viruses can be very powerful but requires a solid foundation supporting the evolutionary relationships between viruses. The current papillomavirus classification system is based on pairwise sequence identity. However, with the advent of metagenomics as facilitated by high-throughput sequencing and molecular tools of enriching circular DNA molecules using rolling circle amplification, there has been a dramatic increase in the described diversity of this viral family. Not surprisingly, this resulted in a dramatic increase in absolute number of viral types (i.e., sequences sharing <90% L1 gene pairwise identity). Many of these novel viruses are the sole member of a novel species within a novel genus (i.e., singletons), highlighting that we have only scratched the surface of papillomavirus diversity. I will discuss how this increase in observed sequence diversity complicates papillomavirus classification. I will propose a potential solution to these issues by explicitly basing the species and genera classification on the evolutionary history of these viruses based on the core viral proteins (E1, E2, and L1) of papillomaviruses. This strategy means that it is possible that a virus identified as the closest neighbor based on the E1, E2, L1 phylogenetic tree, is not the closest neighbor based on L1 nucleotide identity. In this case, I propose that a virus would be considered a novel type if it shares less than 90% identity with its closest neighbors in the E1, E2, L1 phylogenetic tree.

341.12: Sharing Under KAS – What Is the Impact According to KDPI?

Purpose: The Kidney Allocation System (KAS) implemented in 2014 changed prioritization of highly sensitized patients and other groups impacting sharing. We sought to determine effects on sharing according to Kidney Donor Profile Index (KDPI) across pre- and post-KAS eras. Methods: Using UNOS data, we compared local, regional, and national utilization for deceased donor kidney transplants (DDKT) alone according to KDPI group and KAS era: Era 1 (2010-2011, pre-KDPI), Era 2 (2012-2013, pre-KAS), Era 3 (2014-2015, early post-KAS), Era 4 (2016-2017), and Era 5 (2018-2020). Results: Since KAS, sharing has increased across all KDPI groups, and is more pronounced with increasing KDPI. Regional utilization more than doubled for KDPI >85% kidneys while local use decreased 30% from Era 1 to 5 (Table 1). However, a 60% increase in absolute numbers of DDKT across eras resulted in higher local DDKT volume in Era 5 despite increased sharing. Sharing for calculated panel reactive antibody (cPRA) 99-100% patients increased post-KAS across all groups, but the effect was less pronounced for KDPI >85% (32% increase compared with 71-89% increase for the other 3 KDPI groups). Sharing for high cPRA patients accounted for only 23% of shared kidneys and 8% of DDKT in Era 5. Conclusion: KAS increased sharing across all KDPI groups with the largest change occurring in regional use of KDPI >85% organs. Higher DDKT volumes over time offset any changes in sharing such that local volumes for all KDPI groups increased. Increased sharing for cPRA 99-100% occurred across all KDPI groups, but represents a minority of kidneys shared.

Outcomes After Major Surgical Procedures in Octogenarians: A Nationwide Cohort Study

IntroductionAging of the worldwide population has been observed, and postoperative outcomes could be worse in elderly patients. This nationwide study assessed trends in number of surgical resections in octogenarians regarding various major surgical procedures and associated postoperative outcomes.MethodsAll patients who underwent surgery between 2014 and 2018 were included from Dutch nationwide quality registries regarding esophageal, stomach, pancreas, colorectal liver metastases, colorectal cancer, lung cancer and abdominal aortic aneurysms (AAA). For each quality registry, the number of patients who were 80 years or older (octogenarians) was calculated per year. Postoperative outcomes were length of stay (LOS), 30 day major morbidity and 30 day mortality between octogenarians and younger patients.ResultsNo increase in absolute number and proportion of octogenarians that underwent surgery was observed. Median LOS was higher in octogenarians who underwent surgery for colorectal cancer, colorectal liver metastases, lung cancer, pancreatic disease and esophageal cancer. 30 day major morbidity was higher in octogenarians who underwent surgery for colon cancer, esophageal cancer and elective AAA-repair. 30 day mortality was higher in octogenarians who underwent surgery for colorectal cancer, lung cancer, stomach cancer, pancreatic disease, esophageal cancer and elective AAA-repair. Median LOS decreased between 2014 and 2018 in octogenarians who underwent surgery for stomach cancer and colorectal cancer. 30 day major morbidity decreased between 2014 and 2018 in octogenarians who underwent surgery for colon cancer. No trends were observed in octogenarians regarding 30 day mortality between 2014 and 2018.ConclusionNo increase over time in absolute number and proportion of octogenarians that underwent major surgery was observed in the Netherlands. Postoperative outcomes were worse in octogenarians.

Non-ischemic neurovascular emergencies at a supra-regional medical center during the SARS-CoV2-pandemia

ObjectiveTo assess the impact of the lockdown in Germany due to the SARS-CoV2-pandemic on the incidence and the outcome of neurovascular emergencies at a tertiary medical center. MethodsFrom March 16th, 2020 (first lockdown in Germany) to January 31st, 2021, all neurosurgical emergencies were included and compared to a longitudinal case-cohort. Cases were descriptively recorded and retrospectively analyzed with respect to incidence and outcome. ResultsAll emergencies referred to our tertiary medical center decreased by 10% during the pandemic, whereas, neurosurgical emergencies increased by 18.4% (764 vs. 905 cases). Number of specific non-ischemic neurovascular emergencies increased by 29% (95 vs. 123 cases). The difference was not statistically significant (p = 0.53). Mortality rate increased dramatically by 40% during the pandemic throughout all neurovascular cases. As all included patients were negative PCR-tested for SARS-CoV2 the observed increase is unrelated to the virus infection. ConclusionUnexpectedly, according to our data neurovascular emergencies raised in number and severity during the pandemic in Germany at our tertiary referral center. Furthermore, the case fatality increased. Even though our data lack proof of evidence for these findings, we might suggest two possible explanations for the absolute increase in numbers: firstly, patients might have refused to seek medical help while suffering only mild symptoms. Furthermore, as numerous lower-level medical centers restricted admissions, the referral times of patients in need of neurosurgical attention increased. We, therefore, suggest that even in a pandemic situation like the SARS-CoV2/COVID-19, it seems of utmost importance to retain dedicated neurovascular competence in designated centers to care for these emergencies.

Circulating Interleukin-6 and CD16 positive monocytes increase following angioplasty of an arteriovenous fistula

Arteriovenous fistulas are the ideal form of vascular access that allows provision of haemodialysis. Stenotic lesions caused by neointimal hyperplasia commonly occur resulting in patients requiring a fistuloplasty. This is effective but there is a high recurrence rate. We sought to investigate the effects of a fistuloplasty on monocyte populations. Blood samples were taken from patients before and after their fistuloplasty procedure. Samples were analysed using flow cytometry, ELISA and Luminex assays. Univariate cox regression was carried out to investigate associations with post fistuloplasty patency. At 1–2 days post fistuloplasty, the proportion of classical (CD14++CD16−) monocytes decreased (p < 0.001), whilst intermediate (CD14++CD16+) and non-classical (CD14+CD16+) monocytes increased (both p < 0.01) in a cohort of 20 patients. A time course study carried out in 5 patients showed that this was due to an increase in absolute numbers of non-classical and intermediate monocytes. Higher levels of non-classical monocytes pre-fistuloplasty were associated with an increased risk for patency loss (p < 0.05). We measured 41 soluble factors in plasma samples taken before a fistuloplasty in 54 patients, with paired post-fistuloplasty samples (1–2 days) available in 30 patients. After correcting for false discovery, the only factor with a significant change in level was IL-6 (P = 0.0003, q = 0.0124). In a further time-course study in 6 patients, peak level of IL-6 occurred 2–3 h post fistuloplasty. This study demonstrates that there is a systemic inflammatory response to the fistuloplasty procedure and that monocyte subsets and IL-6 may be important in the pathophysiology of restenosis.

Age and Ageing journal 50th anniversary commentary seriesHealthcare for older people in Asia.

Populations in Asian developed economies are rapidly ageing, such that, currently, Hong Kong and Japan have the longest life expectancy at birth for both men and women. However, extended lifespan is not necessarily accompanied by prolongation of health span, such that there is increasing prevalence of frailty and dependency, which translates into increase in complex health and social needs as well as increase in absolute numbers of older adults that require such needs. Consideration of social determinants of healthy ageing would be important in the design of equitable health and social care systems. There is a trend towards development of integrated medical social care in the community in Asian countries. Long-term care insurance and also philanthropic support play a role in the financing of such care models.

Invasive serogroup B meningococci in England following three years of 4CMenB vaccination – First real-world data

ObjectivesIn 2015 the UK became the first country to implement the meningococcal B (MenB) vaccine, 4CMenB, into the national infant program. 4CMenB is expected to cover meningococci expressing sufficient levels of cross-reactive proteins. This study presents clonal complex, 4CMenB antigen genotyping, and 4CMenB coverage data for all English invasive MenB isolates from 2014/15 (1 year pre-vaccine) through 2017/18 and compares data from vaccinated and unvaccinated ≤3 year olds. MethodsVaccine coverage of all invasive MenB isolates from 2014/15 to 2017/18 (n = 784) was analysed using the Meningococcal Antigen Typing System. Genotyping utilised the Meningococcus Genome Library. ResultsAmong ≤3 year olds, proportionally fewer cases in vaccinees (1, 2 or 3 doses) were associated with well-covered strains e.g. cc41/44 (20.5% versus 36.4%; P<0.01) and antigens e.g. PorA P1.4 (7.2% versus 17.3%; P = 0.02) or fHbp variant 1 peptides (44.6% vs 69.1%; P<0.01). Conversely, proportionally more cases in vaccinees were associated with poorly-covered strains e.g. cc213 (22.9% versus 9.6%; P<0.01) and antigens e.g. variant 2 or 3 fHbp peptides (54.2% versus 30.9%; P<0.01). Conclusions4CMenB reduces disease due to strains with cross-reactive antigen variants. No increase in absolute numbers of cases due to poorly covered strains was observed in the study period.

EP.WE.351Changes in social behaviour during the COVID-19 pandemic and consequences on hospital admissions from acute alcoholic related pancreatitis

BackgroundShifts in social behaviours as a consequence of the COVID-19 pandemic may make people more prone to alcohol use as a coping mechanism. This study aims to investigate whether there was an impact on acute alcohol-related pancreatitis cases given potential changes in alcohol consumption during the first COVID-19 lockdown period in the United Kingdom. It considers the time period since social establishments re-opened in July 2020, to evaluate whether increase alcoholic pancreatitis cases, as a proxy for altered drinking habits, persisted.MethodsAll codes relating to pancreatitis were used to identify cases between March to September (2016 to 2020). Inclusion criteria: acute alcohol-related pancreatitis only. These cases were screened by a group of independent medical juniors and analysed using Excel.ResultsA total of 1905 patients with pancreatitis were identified in the initial search, of which 136 were admitted with acute alcoholic pancreatitis. There was an increase in absolute number of new cases in 2020 compared to previous years (27 compared to a mean of 16 in the previous 4 years). When shops and pubs reopened, cases reduced by 37.5%.ConclusionThis study highlights the issue of increased admission with acute pancreatitis relating to alcohol in the COVID-19 lock down period. During which, this group of patients are likely socially isolated with a lack of support. This calls for an increase in community support for such patients with emphasis on admission avoidance. This is especially important in an era when there is increased hospital admission due to COVID-19.

Resource implications following expansion of computed tomography coronary angiography: An Australian experience.

To determine the downstream utilisation of Computed Tomography Coronary Angiography (CTCA) in a single Australian tertiary centre. A single-centre retrospective study analysed 1460 patients undergoing CTCA between 1st January 2015 to 31st December 2018 at a tertiary hospital in Victoria, Australia, with a catchment area of 500,000 people. The coronary stenosis grading, plaque characteristics and coronary calcium score were identified. The downstream impact was assessed by measuring the number of stress echocardiograms, myocardial perfusion scans (MPS), invasive coronary angiograms and subsequent revascularisations. The number of CTCA's performed steadily increased from 59 in 2015 to 395, 461 and 545 in 2016, 2017 and 2018 respectively. Seven hundred and fifty-seven (52%) were females, and 703 (48%) males with 724 (50%) normal CTCA studies. The number of downstream stress echocardiogram performed each year was 2, 60, 46 and 16, respectively, accompanied by MPS numbers of 0, 21, 29, and 18. There were 9, 37, 57 and 64 invasive coronary angiograms with 1, 13, 19 and 22 corresponding revascularisations. Despite small increases in absolute numbers of patients presenting with chest pain (from 2678 in 2015 to 3660 in 2018), there was a significant increase in downstream further testing from 11 in 2015 to 98 in 2018. The use of CTCA expansion has resulted in an increase in downstream testing. Therefore, resource planning with regards to CTCA expansion will have to account for increased rates of functional testing, invasive angiography and revascularisation.

The Level of Circulating Myeloma Cells at Diagnosis Correlates with a Plasma Cell Leukemia-like Phenotype of the Corresponding Myeloma Cells in Bone Marrow

Background The pathogenesis of multiple myeloma (MM) is typically initiated by the acquisition of either an IgH translocation or hyperdiploidy in a postgerminal center B cell, followed by the accumulation of so-called secondary events. These events lead to disease progression from monoclonal gammopathy of undeterminate significance (MGUS) to MM, which eventually can transform into a plasma cell leukemia (PCL). In contrast with MM cells, PCL cells are independent of the bone marrow (BM) microenvironment, have a more plasmablast-like morphology, are associated with higher β2-microglobulin (β2M) serum levels, have a higher prevalence of MYC aberrations and deletion of chromosome 17p (del17p), and mostly lack CD56 expression. Disease progression from MGUS to PCL is also characterized by a clear increase in absolute number of circulating tumor cells (CTCs) in the peripheral blood (PB). Both its prognostic significance (e.g. Gonsalves et al. - Leukemia 2014) and the potential to be used as minimally invasive liquid biopsy (Lohr et al. - Sci Transl Med 2016 & Mishima et al. - Cell Rep 2017) have made CTCs an active area of investigation in MM. Despite this, the relation between MM tumor biology and CTC levels is still largely unknown. Since CTC levels are correlated with disease stage and the presence of a high CTC load confers a similar prognosis to PCL patients, we hypothesized that CTC levels are related to a more PCL-like biology of BM MM cells. Methods At baseline, we collected PB and BM from newly diagnosed MM (NDMM) patients, who had been included in the IFM 2015-01/HOVON 131 MM (Cassiopeia) trial (NCT02541383). BM was enriched for CD138+ MM cells, on which FISH was performed on all samples for t(4;14) and del17p. Serum β2M and albumin were measured at the same time point as well. On samples with a flowcytometric MM purity of ≥80%, also gene-expression profiling (GEP) was performed, with the HG U133 Plus 2.0 array (Affymetrix), followed by calculation of the SKY92 high-risk (HR-SKY92) score and differential gene expression analysis. For normalization, MAS5 was used; expressed probe sets were selected based on present calls (affy and panp packages, Bioconductor). Differential gene expression analysis was performed by comparing patients with the top 20% highest CTC scores (CTC high) versus the remaining patients (CTC normal) (Limma package, Bioconductor). For pathway analysis, gene set enrichment analysis (GSEA) (Broad Institute) was performed, using a list of differentially expressed genes via the pre-ranked analysis option, with the gene set library c2.all.v6.0.symbols. The CTC level was generally determined within one day after sampling. Absolute levels of CTCs (number per µL) were determined in PB samples that were processed according to the standardized Next Generation Flow MRD (NGF-MRD) protocol (EuroFlow) (Flores-Montero et al. - Leukemia 2017), using two 8-color MM-MRD tubes and Euroflow Standard Operating Procedures, allowing a sensitivity of at least 10-5 in all samples. Results CTCs could be detected in 119/140 (85%) patients. GEP was performed in 83/140 (59%) patient samples, with 20/83 (24%) being HR-SKY92. The absolute level of CTCs was positively correlated with serum β2M levels (p Among the most significantly upregulated pathways were CHEK2 and ATM, which both positively regulate p53 activity and thereby may confer a selective pressure to inactivate p53 (e.g. by loss of one copy, del17p). Of note, two MYC-related pathways were represented among the 15 most upregulated pathways. Conclusions To our knowledge, we are the first to describe a differential GEP between BM MM samples with a high CTC load versus normal CTC load. NDMM tumors with a high CTC load show multiple features of advanced disease, including an increased ISS stage, serum β2M levels, HR-SKY92 prevalence, MYC activity and plasmablast-like GEP. These findings suggest that MM tumors with a high CTC load may be in a transitional phase between MM and PCL. Disclosures Kuiper: SkylineDx: Employment. Delforge: Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees. van Vliet: SkylineDx: Employment. van de Donk: Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees; BMS: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Moreau: Onyx Pharmaceutical: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity9s Board of Directors or advisory committees. Sonneveld: Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding.

Age-dependent differences in the immune response to human metapneumovirus

Abstract Objective: Human metapneumovirus (HMPV) is a leading cause of serious respiratory infection in older adults, but pathophysiology in this population is incompletely understood. Methods: We developed an elderly mouse model of HMPV using 72-week-old mice. Aged mice and 6-week-old mice were infected intratracheally with HMPV and euthanized at different time points to measure viral titer and cellular immune response. We also infected young v. aged macrophages in vitro to determine cytokine response. Results: Aged HMPV-infected mice demonstrated increased weight loss, higher clinical disease scores, increased lung histopathology, and delayed viral clearance with virus persisting in the lung through day 9 post-infection while 6-week young mice cleared infection completely by day 7. Aged mice showed a significant increase in absolute number of CD8+ T cells in bronchoalveolar lavage (BAL) and lung; however, CD8+ T cells in aged mice exhibited fewer HMPV-specific tetramer+ CD8+ cells in both BAL and lung. Most aged cells expressed two or more impairment receptors (PD1, LAG3, or TIM3). Luminex analysis of lung homogenate and BAL revealed increased Th2 and inflammatory cytokine expression in aged mice. Aged HMPV-infected peritoneal macrophages in vitro had significantly increased expression of IFNb and decreased IFNg, while bone marrow-derived macrophages had decreased IFNl expression. Conclusions: These findings suggest that aged mice have a dysregulated CD8+ T cell response to HMPV, increasing disease but delaying viral clearance. Altered cytokine production by aged macrophages may skew CD8+ T cell response. Future studies will investigate the specific mechanisms surrounding impaired immune response in the aged host.

Access to HIV services and viral load suppression among children during the 90-90-90 strategy implementation in South Africa: A time series analysis.

BackgroundDuring the era of the Millennium Development Goals (MDG), children were shown to have less access to human immunodeficiency virus (HIV) services than their adult counterparts; hence the call to prioritise children in the implementation of the Sustainable Development Goals (SDGs). However, South African (SA) national data in 2019 indicated that almost 3 years into the implementation of the 90-90-90 strategy, only 59% of children living with HIV had been tested for HIV compared to 90% of adults.ObjectivesTo evaluate the access of children to HIV services and record the viral load (VL) suppression rates during the implementation of the 90-90-90 strategy in the City of Johannesburg (COJ), South Africa.MethodsThis study applied a quasi-experimental interrupted time-series (ITS) design using the monthly District Health Information System (DHIS) and National Health Laboratory Services (NHLS) databases spanning the period from 2015 to 2020, that is, before and after the implementation and roll-out of the 90-90-90 strategy. Data were extracted from these databases into MS Excel 2010 spreadsheets and analysed with Stata 15 software from Stata Corp using a two-tailed t-test at a 5% level of significance.ResultsOverall, a significant increase was observed in the number of individuals tested for HIV, n = 757, p = 0.0086, and retained in care n = 2523, p = 0.001 over the whole period of analysis beginning in April 2015. Adult HIV testing, antiretroviral treatment (ART) initiation and retention in care had been decreasing in absolute numbers over a 10-month period before the intervention. An increase in these three data elements was observed following the implementation of the 90-90-90 program. On the other hand, children aged 0–15 years had demonstrated a significant increase in absolute numbers tested for HIV, n = 171, p = 0.001, but an insignificant increase in number of ART initiations, n = 14.33, p = 0.252, before implementation but a decrease after this. The overall VL suppression rates for children were lower than those of adults.ConclusionAlthough the COJ has recorded progress in adult HIV testing, ART initiation and retention, children living with HIV aged 0–15 years continue to experience less access to HIV services and lower VL suppression than youths and adults of ≥ 15 years. Therefore, to ensure that the 90-90-90 targets are achieved across different age groups, children must be prioritised so that they can equally access these services with adults.