Bridging the impactibility gap in population health management: a systematic review

Objectives Assess whether impactibility modelling is being used to refine risk stratification for preventive health interventions. Design Systematic review. Setting Primary and secondary healthcare populations. Papers Articles published from 2010 to 2020 on the use or implementation of impactibility modelling in population health management, reported with the terms a € intervenability', a € amenability', and a € propensity to succeed' (PTS) and associated with the themes a € care sensitivity', a € characteristic responders', a € needs gap', a € case finding', a € patient selection' and a € risk stratification'. Interventions Qualitative synthesis to identify themes for approaches to impactibility modelling. Results Of 1244 records identified, 20 were eligible for inclusion. Identified themes were a € health conditions amenable to care' (n=6), a € PTS modelling' (n=8) and a € comparison or combination with clinical judgement' (n=6). For the theme a € health conditions amenable to care', changes in practice did not reduce admissions, particularly for ambulatory care sensitive conditions, and sometimes increased them, with implementation noted as a possible issue. For a € PTS modelling', high costs and needs did not necessarily equate to high impactibility and targeting a larger number of individuals with disorders associated with lower costs had more potential. PTS modelling seemed to improve accuracy in care planning, estimation of cost savings, engagement and/or care quality. The a € comparison or combination with clinical judgement' theme suggested that models can reach reasonable to good discriminatory power to detect impactable patients. For instance, a model used to identify patients appropriate for proactive multimorbid care management showed good concordance with physicians (c-statistic 0.75). Another model employing electronic health record scores reached 65% concordance with nurse and physician decisions when referring elderly hospitalised patients to a readmission prevention programme. However, healthcare professionals consider much wider information that might improve or impede the likelihood of treatment impact, suggesting that complementary use of models might be optimum. Conclusions The efficiency and equity of targeted preventive care guided by risk stratification could be augmented and personalised by impactibility modelling

Impact of a malaria intervention package in schools on Plasmodium infection, anaemia and cognitive function in schoolchildren in Mali: a pragmatic cluster-randomised trial.

BACKGROUND: School-aged children are rarely targeted by malaria control programmes, yet the prevalence of Plasmodium infection in primary school children often exceeds that seen in younger children and could affect haemoglobin concentration and school performance. METHODS: A cluster-randomised trial was carried out in 80 primary schools in southern Mali to evaluate the impact of a school-based malaria intervention package. Intervention schools received two interventions sequentially: (1) teacher-led participatory malaria prevention education, combined with distribution of long-lasting insecticidal nets (LLINs), followed 7 months later at the end of the transmission season by (2) mass delivery of artesunate and sulfadoxine-pyrimethamine administered by teachers, termed intermittent parasite clearance in schools (IPCs). Control schools received LLINs as part of the national universal net distribution programme. The impact of the interventions on malaria and anaemia was evaluated over 20 months using cross-sectional surveys in a random subset of 38 schools(all classes), with a range of cognitive measures (sustained attention, visual search, numeracy, vocabulary and writing) assessed in a longitudinal cohort of children aged 9-12 years in all 80 schools. RESULTS: Delivery of a single round of IPCs was associated with dramatic reductions in malaria parasitaemia (OR 0.005, 95% CI 0.002 to 0.011, p<0.001) and gametocyte carriage (OR 0.02, 95% CI 0.00 to 0.17, p<0.001) in intervention compared with control schools. This effect was sustained for 6 months until the beginning of the next transmission season. IPCs was also associated with a significant decrease in anaemia (OR 0.56, 95% CI 0.40 to 0.78, p=0.001), and increase in sustained attention (difference +0.23, 95% CI 0.10 to 0.36, p<0.001). There was no evidence of impact on other cognitive measures. CONCLUSION: The combination of malaria prevention education, LLINs and IPCs can reduce anaemia and improve sustained attention of school children in areas of highly seasonal transmission. These findings highlight the impact of asymptomatic malaria infection on cognitive performance in schoolchildren and the benefit of IPCs in reducing this burden. Additionally, malaria control in schools can help diminish the infectious reservoir that sustains Plasmodium transmission

Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3–70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Effect of element concentration on nickel release from dental alloys using a novel ion beam method

Objectives Nickel chromium is widely used as a restorative material in dentistry but its biocompatibility is of concern as there are reports of patients suffering adverse effects caused by exposure to nickel-based restorations. The aim of this work was to quantify the amount of nickel released into solution from commercially available nickel-based alloys with varying compositions and to identify the potential use of thin films in further understanding the role of chromium in reducing nickel release. Methods Six commercially available nickel-based alloys were cast using the lost wax technique. Nickel chromium thin films were deposited onto silicon substrates by ion beam assisted physical vapor deposition. Both types of alloys were immersed into solution representative of saliva at pH 5 for 7 days. The amount of nickel released into solution was quantified by graphite-furnace atomic absorption spectrophotometry. Results The amount of nickel released from commercially available cast alloys did not correspond to the amount of nickel within the alloy. The total amount of chromium and molybdenum within the alloys proved to be of greater influence. Increasing the amount of chromium in the thin film alloys reduced the amount of nickel released but this was not linear. Significance Differences in the composition of commercial cast alloys highlighted the importance of other elements within the alloy on reducing the amount of nickel released. The use of thin film alloys can be useful in further understanding how the composition of an alloy can affect the amount of nickel released

Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention