Operationalising Human Security in the Contemporary Operating Environment: Proposing Population Intelligence (POPINT)

Drawing upon primary research funded by the UK Defence and Security Accelerator (DASA), this article is about using data analytics and artificial intelligence (AI) for operationalising human security in the contemporary operating environment. The idea of human security has gained much traction in the international community since its introduction in a 1994 United Nations Development Programme (UNDP) report and has more recently become a military concern. Yet, the core tenets of this idea remain contested, and the military role in support of human security remains an open question. Nonetheless, the concurrent increase in Open Data and AI does give rise to new opportunities to understand the various human security concerns. In response, DASA funded Projects SOLEBAY and HAMOC to research these concerns and the possibilities of data analytics for human security. Drawing on the research findings, we propose the idea of Population Intelligence (POPINT) as a new intelligence discipline to operationalise human security

Colorectal polyp outcomes after participation in the seAFOod polyp prevention trial: Evidence of rebound elevated colorectal polyp risk after short-term aspirin use

BACKGROUND: The seAFOod polyp prevention trial was a randomised, placebo-controlled, 2 × 2 factorial trial of aspirin 300 mg and eicosapentaenoic acid (EPA) 2000 mg daily in individuals who had a screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Aspirin treatment was associated with a 20% reduction in colorectal polyp number at BCSP surveillance colonoscopy 12 months later. It is unclear what happens to colorectal polyp risk after short-term aspirin use. AIM: To investigate colorectal polyp risk according to the original trial treatment allocation, up to 6 years after trial participation. METHODS: All seAFOod trial participants were scheduled for further BCSP surveillance and provided informed consent for the collection of colonoscopy outcomes. We linked BCSP colonoscopy data to trial outcomes data. RESULTS: In total, 507 individuals underwent one or more colonoscopies after trial participation. Individuals grouped by treatment allocation were well matched for clinical characteristics, follow-up duration and number of surveillance colonoscopies. The polyp detection rate (PDR; the number of individuals who had ≥1 colorectal polyp detected) after randomization to placebo aspirin was 71.1%. The PDR was 80.1% for individuals who had received aspirin (odds ratio [OR] 1.13 [95% confidence interval 1.02, 1.24]; p = 0.02). There was no difference in colorectal polyp outcomes between individuals who had been allocated to EPA compared with its placebo (OR for PDR 1.00 [0.91, 1.10]; p = 0.92). CONCLUSION: Individuals who received aspirin in the seAFOod trial demonstrated increased colorectal polyp risk during post-trial surveillance. Rebound elevated neoplastic risk after short-term aspirin use has important implications for aspirin cessation driven by age-related bleeding risk. ISRCTN05926847

Ovarian Real-World International Consortium (ORWIC): A multicentre, real-world analysis of epithelial ovarian cancer treatment and outcomes

IntroductionMuch drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC).Methods3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved.ResultsMedian age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common.DiscussionSpecific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites

A Phase 1 Trial of MSP2-C1, a Blood-Stage Malaria Vaccine Containing 2 Isoforms of MSP2 Formulated with Montanide® ISA 720

Background: In a previous Phase 1/2b malaria vaccine trial testing the 3D7 isoform of the malaria vaccine candidate Merozoite surface protein 2 (MSP2), parasite densities in children were reduced by 62%. However, breakthrough parasitemias were disproportionately of the alternate dimorphic form of MSP2, the FC27 genotype. We therefore undertook a dose-escalating, double-blinded, placebo-controlled Phase 1 trial in healthy, malaria-naïve adults of MSP2-C1, a vaccine containing recombinant forms of the two families of msp2 alleles, 3D7 and FC27 (EcMSP2-3D7 and EcMSP2-FC27), formulated in equal amounts with Montanide® ISA 720 as a water-in-oil emulsion. Methodology/Principal Findings: The trial was designed to include three dose cohorts (10, 40, and 80 μg), each with twelve subjects receiving the vaccine and three control subjects receiving Montanide® ISA 720 adjuvant emulsion alone, in a schedule of three doses at 12-week intervals. Due to unexpected local reactogenicity and concern regarding vaccine stability, the trial was terminated after the second immunisation of the cohort receiving the 40 μg dose; no subjects received the 80 μg dose. Immunization induced significant IgG responses to both isoforms of MSP2 in the 10 μg and 40 μg dose cohorts, with antibody levels by ELISA higher in the 40 μg cohort. Vaccine-induced antibodies recognised native protein by Western blots of parasite protein extracts and by immunofluorescence microscopy. Although the induced anti-MSP2 antibodies did not directly inhibit parasite growth in vitro, IgG from the majority of individuals tested caused significant antibody-dependent cellular inhibition (ADCI) of parasite growth. Conclusions/Significance: As the majority of subjects vaccinated with MSP2-C1 developed an antibody responses to both forms of MSP2, and that these antibodies mediated ADCI provide further support for MSP2 as a malaria vaccine candidate. However, in view of the reactogenicity of this formulation, further clinical development of MSP2-C1 will require formulation of MSP2 in an alternative adjuvant. Trial Registration: Australian New Zealand Clinical Trials Registry 12607000552482

Optimal reaction coordinate as a biomarker for the dynamics of recovery from kidney transplant.

The evolution of disease or the progress of recovery of a patient is a complex process, which depends on many factors. A quantitative description of this process in real-time by a single, clinically measurable parameter (biomarker) would be helpful for early, informed and targeted treatment. Organ transplantation is an eminent case in which the evolution of the post-operative clinical condition is highly dependent on the individual case. The quality of management and monitoring of patients after kidney transplant often determines the long-term outcome of the graft. Using NMR spectra of blood samples, taken at different time points from just before to a week after surgery, we have shown that a biomarker can be found that quantitatively monitors the evolution of a clinical condition. We demonstrate that this is possible if the dynamics of the process is considered explicitly: the biomarker is defined and determined as an optimal reaction coordinate that provides a quantitatively accurate description of the stochastic recovery dynamics. The method, originally developed for the analysis of protein folding dynamics, is rigorous, robust and general, i.e., it can be applied in principle to analyze any type of biological dynamics. Such predictive biomarkers will promote improvement of long-term graft survival after renal transplantation, and have potentially unlimited applications as diagnostic tools

NMR-based metabolomic studies in transplantation

Acute rejection is one of the most common forms of graft damage following solid organ transplantation and recurrent episodes can have deleterious effects on long term graft survival. Episodes can vary from severe to sub-clinical and definitive diagnosis can only be carried out using an invasive biopsy, which can not only cause damage to the graft, but can allow detection of an acute rejection episode to be delayed, allowing further immunological damage to the graft. For this reason, l H-NMR spectroscopy and pattern recognition techniques were applied to sample. from those undergoing either kidney or liver transplantation in an attempt to elucidate a biornarker of acute rejection. In the case of kidney transplantation. lower level of ether phospholipids (p = 0.010). ethanolamine phospholipid (p == 0.010) and diacyl glycerophospholipids (p = 0.020 were found in the lipidic component of erythrocyte extracts from those patients undergoing an acute rejection episode compared to those who did not. Specific fatty acids were also reduced including linoleic acid (p = 0.0 I 0), arachidonic, eicosapentaenoic and related fatty acid (p = 0.0 13) and the degree of unsaturation of the fatty acid chains was reduced in rejecting patients (p = 0.038). This is indicative of increased oxidative stress in the erythrocyte of rejecting patients. The aqueous component of the erythrocytes yielded creatinine at the most influential marker, alongside ketones, organic acids amino acids and adenine nucleotide. Subsequent dynamic modeling allowed the time-dependent trends in creatinine throughout the seven day study period to be related to the transplant outcome. Analysis of both the low molecular weight and macromolecular components of the plasma of liver transplant patients did not allow identification of an acute rejection marker but did allow visualisation of the Changes occurring to the metabolic profile following transplantation. Increases in low density lipoprotein (LDL) and very low density lipoprotein (VLDL) were observed over the seven day post-transplant. corresponding with a recovery of liver function. Increased levels of glycoprotein were also observed, which may occur as a result of a reaction to the trauma caused by surgery. A reduction in choline phospholipids was also observed, which has also been observed following major surgery. These NMR studies have provided useful insights on acute rejection and the transplant process.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Unsupervised optimization.

<p>a) NMR spectra for blood extracts of a single patient, collected over nine time points. b) Patients trajectories projected on the first principal component do not show any feature enabling us to separate the trajectories according to the clinical assessment of the patients. The color indicates the final clinical classification of the patient: primary function patients are shown in black, delayed graft function in red, and acute rejection in blue. c) Patients trajectories projected on the optimal reaction coordinate. d) Leave-one-out cross-validation: every trajectory is projected on the optimal reaction coordinate constructed without that specific trajectory.</p

Supervised optimisation.

<p><b>a)</b> PF versus AR and DGF with binning interval of 0.32 ppm: the results are similar to the unsupervised analysis <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003685#pcbi-1003685-g001" target="_blank">Fig. 1C</a>. <b>b)</b> AR versus PF and DGF with binning interval of 0.32 ppm: no clear separation between the classes. <b>c)</b> AR versus PF and DGF with binning interval of 0.1 ppm: AR is separated from PF and DGF. <b>d)</b> leave one out cross validation of panel <b>c</b>: small binning interval of 0.1 ppm leads to overfitting.</p

Linear coefficients of the optimal reaction coordinate , where <i>I_k</i> is the logarithm of the intensity of NMR spectra in bin k.

<p>Linear coefficients of the optimal reaction coordinate , where <i>I_k</i> is the logarithm of the intensity of NMR spectra in bin k.</p

Complex Patient Navigation by Veteran Patients in the Veterans Health Administration (VHA) for Chronic Headache Disease: A Qualitative Study

Patients living with headache diseases often have difficulty accessing evidence-based care. Authors conducted a qualitative research study with 20 patients receiving headache care at seven Headache Centers of Excellence within the Veterans Health Administration to examine their experiences navigating headache care. This study employed thematic qualitative analysis and conducted cross-case comparisons. Several key findings emerged. 1) Most patients saw multiple healthcare providers over numerous years before reaching a headache specialist to manage chronic headaches. 2) Receipt of high-quality and comprehensive headache specialty care was associated with high satisfaction. 3) Patients with headache diseases reported oftentimes they experienced an arduous journey across multiple healthcare systems and between several healthcare providers before receiving evidence-based headache treatment that they found acceptable. Results demonstrate that most patients were satisfied with their current specialty headache care in the Veterans Health Administration. Authors discuss implications for future studies and highlight ways to improve patient satisfaction and timely access to appropriate headache care