What does not happen: quantifying embodied engagement using NIMI and self-adaptors

Previous research into the quantification of embodied intellectual and emotional engagement using non-verbal movement parameters has not yielded consistent results across different studies. Our research introduces NIMI (Non-Instrumental Movement Inhibition) as an alternative parameter. We propose that the absence of certain types of possible movements can be a more holistic proxy for cognitive engagement with media (in seated persons) than searching for the presence of other movements. Rather than analyzing total movement as an indicator of engagement, our research team distinguishes between instrumental movements (i.e. physical movement serving a direct purpose in the given situation) and non-instrumental movements, and investigates them in the context of the narrative rhythm of the stimulus. We demonstrate that NIMI occurs by showing viewers’ movement levels entrained (i.e. synchronised) to the repeating narrative rhythm of a timed computer-presented quiz. Finally, we discuss the role of objective metrics of engagement in future context-aware analysis of human behaviour in audience research, interactive media and responsive system and interface design

A time series feature of variability to detect two types of boredom from motion capture of the head and shoulders

Boredom and disengagement metrics are crucial to the correctly timed implementation of adaptive interventions in interactive systems. psychological research suggests that boredom (which other HCI teams have been able to partially quantify with pressure-sensing chair mats) is actually a composite: lethargy and restlessness. Here we present an innovative approach to the measurement and recognition of these two kinds of boredom, based on motion capture and video analysis of changes in head and shoulder positions. Discrete, three-minute, computer-presented stimuli (games, quizzes, films and music) covering a spectrum from engaging to boring/disengaging were used to elicit changes in cognitive/emotional states in seated, healthy volunteers. Interaction with the stimuli occurred with a handheld trackball instead of a mouse, so movements were assumed to be non-instrumental. Our results include a feature (standard deviation of windowed ranges) that may be more specific to boredom than mean speed of head movement, and that could be implemented in computer vision algorithms for disengagement detection

The complex relationship between empathy, engagement and boredom

In human computer interactions — especially gaming — the role of empathy has been mooted as a necessary prerequisite for higher levels of engagement and immersion. More recently other forms of engagement, including intellectual/cognitive engagement, have been proposed. In this study we present a carefully controlled dataset of human-computer interactions with a wide range of stimuli that ranged from highly engaging to boring to test these two theories. Analyzing 844 response sets to visual analogue scales (VAS) for empathy, interest, boredom, and engagement, we found that high empathy was sufficient for high engagement but is not necessary, whilst the converse was not true. We also found that empathy and boredom were incompatible with each other, but low levels of either were permissive rather than causal to the other. We conclude that there is no monotonic relationship between increasing empathy and engagement; either empathy is a sufficient (but not necessary) cause of engagement, or engagement is a necessary precursor to high empathy

Acute Renal Replacement Therapy in Children with Diarrhea-Associated Hemolytic Uremic Syndrome: A Single Center 16 Years of Experience

Acute kidney injury (AKI) is becoming more prevalent among hospitalized children, its etiologies are shifting, and new treatment modalities are evolving; however, diarrhea-associated hemolytic uremic syndrome (D+HUS) remains the most common primary disease causing AKI in young children. Little has been published about acute renal replacement therapy (ARRT) and its challenges in this population. We describe our single center's experience managing 134 pediatric patients with D+HUS out of whom 58 (43%) required ARRT over the past 16 years. In our cohort, all but one patient were started on peritoneal dialysis (PD). Most patients, 47 (81%), received acute PD on a pediatric inpatient ward. The most common recorded complications in our cohort were peritoneal fluid leaks 13 (22%), peritonitis 11 (20%), and catheter malfunction 5 (9%). Nine patients (16%) needed surgical revision of their PD catheters. There were no bleeding events related to PD despite a mean platelets count of 40.9 (±23.5) × 103/mm3 and rare use of platelets infusions. Despite its methodological limitations, this paper adds to the limited body of evidence supporting the use of acute PD as the primary ARRT modality in children with D+HUS

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Acute kidney injury (AKI) is becoming more prevalent among hospitalized children, its etiologies are shifting, and new treatment modalities are evolving; however, diarrhea-associated hemolytic uremic syndrome (D+HUS) remains the most common primary disease causing AKI in young children. Little has been published about acute renal replacement therapy (ARRT) and its challenges in this population. We describe our single center's experience managing 134 pediatric patients with D+HUS out of whom 58 (43%) required ARRT over the past 16 years. In our cohort, all but one patient were started on peritoneal dialysis (PD). Most patients, 47 (81%), received acute PD on a pediatric inpatient ward. The most common recorded complications in our cohort were peritoneal fluid leaks 13 (22%), peritonitis 11 (20%), and catheter malfunction 5 (9%). Nine patients (16%) needed surgical revision of their PD catheters. There were no bleeding events related to PD despite a mean platelets count of 40.9 (±23.5) × 10 3 /mm 3 and rare use of platelets infusions. Despite its methodological limitations, this paper adds to the limited body of evidence supporting the use of acute PD as the primary ARRT modality in children with D+HUS

Association of High-Density Lipoprotein-Cholesterol Versus Apolipoprotein A-I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer-Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women's Health Study.

BACKGROUND: The contribution of apolipoprotein A-I (apoA-I) to coronary heart disease (CHD) risk stratification over and above high-density lipoprotein cholesterol (HDL-C) is unclear. We studied the associations between plasma levels of HDL-C and apoA-I, either alone or combined, with risk of CHD events and cardiovascular risk factors among apparently healthy men and women. METHODS AND RESULTS: HDL-C and apoA-I levels were measured among 17 661 participants of the EPIC (European Prospective Investigation into Cancer)-Norfolk prospective population study. Hazard ratios for CHD events and distributions of risk factors were calculated by quartiles of HDL-C and apoA-I. Results were validated using data from the ARIC (Atherosclerosis Risk in Communities) and WHS (Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In EPIC-Norfolk, both HDL-C and apoA-I quartiles were strongly and inversely associated with CHD risk. Within HDL-C quartiles, higher apoA-I levels were not associated with lower CHD risk; in fact, CHD risk was higher within some HDL-C quartiles. ApoA-I levels were associated with higher levels of CHD risk factors: higher body mass index, HbA1c, non-HDL-C, triglycerides, apolipoprotein B, systolic blood pressure, and C-reactive protein, within fixed HDL-C quartiles. In contrast, HDL-C levels were consistently inversely associated with overall CHD risk and CHD risk factors within apoA-I quartiles (P<0.001). These findings were validated in the ARIC and WHS cohorts. CONCLUSIONS: Our findings demonstrate that apoA-I levels do not offer predictive information over and above HDL-C. In fact, within some HDL-C quartiles, higher apoA-I levels were associated with higher risk of CHD events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA-I levels. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000479

Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine

Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug-induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper-active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper-active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper-active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1-driven tumours

Assessing the causal association of glycine with risk of cardio-metabolic diseases.

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.N. G. F. and F.I. acknowledge funding from Medical Research Council Epidemiology Unit MC_UU_12015/5. N.G.F. and N. J. W. acknowledge funding from the NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). S. B. is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). J. D. is funded by the National Institute for Health Research [Senior Investigator Award]. N. J. W. and C. L. acknowledge funding from the Medical Research Council Epidemiology Unit (MC_UU_12015/1)

Association between sucrose intake and risk of overweight and obesity in a prospective sub-cohort of the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk).

OBJECTIVE: The objective of the present study was to investigate associations between sugar intake and overweight using dietary biomarkers in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). DESIGN: Prospective cohort study. SETTING: EPIC-Norfolk in the UK, recruitment between 1993 and 1997. SUBJECTS: Men and women (n 1734) aged 39-77 years. Sucrose intake was assessed using 7 d diet diaries. Baseline spot urine samples were analysed for sucrose by GC-MS. Sucrose concentration adjusted by specific gravity was used as a biomarker for intake. Regression analyses were used to investigate associations between sucrose intake and risk of BMI>25·0 kg/m2 after three years of follow-up. RESULTS: After three years of follow-up, mean BMI was 26·8 kg/m2. Self-reported sucrose intake was significantly positively associated with the biomarker. Associations between the biomarker and BMI were positive (β=0·25; 95 % CI 0·08, 0·43), while they were inverse when using self-reported dietary data (β=-1·40; 95 % CI -1·81, -0·99). The age- and sex-adjusted OR for BMI>25·0 kg/m2 in participants in the fifth v. first quintile was 1·54 (95 % CI 1·12, 2·12; P trend=0·003) when using biomarker and 0·56 (95 % CI 0·40, 0·77; P trend<0·001) with self-reported dietary data. CONCLUSIONS: Our results suggest that sucrose measured by objective biomarker but not self-reported sucrose intake is positively associated with BMI. Future studies should consider the use of objective biomarkers of sucrose intake.The authors thank all EPIC-Norfolk study participants and staff for their contribution to the study. They also thank the NIHR BRC-MRC BioRepository at the Cambridge Biomedical Campus for providing infrastructure and equipment for sample preparation. Financial support: This project was supported by the Word Cancer Research Fund (WCRF), Cancer Research UK and the Medical Research Council (MRC). WCRF, Cancer Research UK and MRC had no role in the design, analysis or writing of this article. Conflict of interest: None. Authorship: The responsibilities of the authors were as follows: G.G.C.K. developed the analytical method, conducted the statistical analyses, wrote the manuscript and had primary responsibility for the final content; N.T. conducted statistical analyses and contributed to the manuscript; J.L.G., M.A.S., L.R. and S.M.A. developed the analytical method and conducted sample analyses; M.A.H.L. and A.A.M. were responsible for dietary data analysis and contributed to the manuscript; R.N.L. was responsible for follow-up and data processing; K.-T.K. (principal investigator of EPIC-Norfolk) contributed to the manuscript. All authors read and approved the final manuscript. Ethics of human subject participation: The study received ethical approval by the Norwich District Health Authority Ethics Committee and all participants gave signed informed consent.This is the final version of the article. It first appeared from Cambridge University Press via http://dx.doi.org/10.1017/S1368980015000300

Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes

Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p<4.9×10 -10 ) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such as ASNS (rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08; p=9.5×10 -30 )]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights.M.P. was supported by a fellowship from the German Research Foundation (DFG PI 1446/2-1). C.O. was founded by an early career fellowship at Homerton College, University of Cambridge. L. B. L. W. acknowledges funding by the Wellcome Trust (WT083442AIA). J.G. was supported by grants from the Medical Research Council (MC_UP_A090_1006, MC_PC_13030, MR/P011705/1 and MR/P01836X/1). Work in the Reimann/Gribble laboratories was supported by the Wellcome Trust (106262/Z/14/Z and 106263/Z/14/Z), UK Medical Research Council (MRC_MC_UU_12012/3) and PhD funding for EKB from MedImmune/AstraZeneca. Praveen Surendran is supported by a Rutherford Fund Fellowship from the Medical Research Council grant MR/S003746/1. A. W. is supported by a BHF-Turing Cardiovascular Data Science Award and by the EC-Innovative Medicines Initiative (BigData@Heart). J.D. is funded by the National Institute for Health Research [Senior Investigator Award] [*]. The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The Fenland Study is supported by the UK Medical Research Council (MC_UU_12015/1 and MC_PC_13046). Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. Nightingale Health NMR assays were funded by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233). Metabolon Metabolomics assays were funded by the NIHR 26 BioResource and the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*].The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. *The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. UK Biobank: This research has been conducted using the UK Biobank resource under Application Number 44448