Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway. METHODS: Ninety-six individuals with ALF, 104 with cirrhosis, 31 with sepsis and 71 healthy controls (HCs) were recruited. Pathways of interest were identified by multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics. A targeted metabolomics panel was used for validation. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. Transcript-level expression of the LPA receptor (LPAR) in monocytes was investigated and the effect of LPAR antagonism was also examined in vitro. RESULTS: LPC 16:0 was highly discriminant between ALF and HC. There was an increase in ATX and LPA in individuals with ALF compared to HCs and those with sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in individuals with ALF and were associated with a poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without affecting immune checkpoints on T and NK/CD56+T cells. LPAR1 and 3 antagonism in culture reversed the effect of LPA on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPAR genes, were differentially expressed and upregulated in monocytes from individuals with ALF compared to controls. CONCLUSION: Reduced LPC levels are biomarkers of poor prognosis in individuals with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors. IMPACT AND IMPLICATIONS: We identified a metabolic signature of acute liver failure (ALF) and investigated the immunometabolic role of the lysophosphatidylcholine-autotaxin-lysophosphatidylcholinic acid pathway, with the aim of finding a mechanistic explanation for monocyte behaviour and identifying possible therapeutic targets (to modulate the systemic immune response in ALF). At present, no selective immune-based therapies exist. We were able to modulate the phenotype of monocytes in vitro and aim to extend these findings to murine models of ALF as a next step. Future therapies may be based on metabolic modulation; thus, the role of specific lipids in this pathway require elucidation and the relative merits of autotaxin inhibition, lysophosphatidylcholinic acid receptor blockade or lipid-based therapies need to be determined. Our findings begin to bridge this knowledge gap and the methods used herein could be useful in identifying therapeutic targets as part of an experimental medicine approach.

Immunometabolic analysis shows a distinct cyto-metabotype in Covid-19 compared to sepsis from other causes.

Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-É£ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-É£ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-É£ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

Bibliometric analysis of the literature relating to silicone hydrogel and daily disposable contact lenses

Purpose: Publication metrics are derived for the fields of silicone hydrogel (SH) and daily disposable (DD) contact lenses.Methods: A search of the Scopus database for papers in the fields of SH and DD contact lenses found 979 SH and 291 DD papers. Subject-specific h-indices for SH lenses (hSH-index) and DD lenses (hDD-index) were derived, in relation to five categories – authors, institutions, countries and journals – to serve as measures of impact. A short list of the most impactful entities was generated for each of the above five categories in the SH and DD fields.Results: A paper entitled “Soft contact lens polymers: An evolution” by Nicholson and Vogt was the most highly cited article (495 citations) in both SH and DD fields. The most impactful entities for the SH and DD fields were: authors – Lyndon Jones (hSH = 33) and Philip Morgan (hDD = 15); institutions – the University of Waterloo (hSH = 37) and the University of New South Wales (hDD = 15); countries – the United States (hSH = 45) and the United Kingdom (hDD = 24); and journals – Optometry and Vision Science (hSH = 33) and Contact Lens and Anterior Eye (hDD = 17). Overall, the SH field (hSH = 64) is far more impactful than the DD field (hDD = 34).Conclusions: Impactful papers, authors, institutions, countries and journals in the SH and DD fields are identified. Optometry is revealed as the leading profession in relation to SH and DD publications. (AU)

Bibliometric analysis of the literature relating to silicone hydrogel and daily disposable contact lenses.

PURPOSE: Publication metrics are derived for the fields of silicone hydrogel (SH) and daily disposable (DD) contact lenses. METHODS: A search of the Scopus database for papers in the fields of SH and DD contact lenses found 979 SH and 291 DD papers. Subject-specific h-indices for SH lenses (hSH-index) and DD lenses (hDD-index) were derived, in relation to five categories - authors, institutions, countries and journals - to serve as measures of impact. A short list of the most impactful entities was generated for each of the above five categories in the SH and DD fields. RESULTS: A paper entitled "Soft contact lens polymers: An evolution" by Nicholson and Vogt was the most highly cited article (495 citations) in both SH and DD fields. The most impactful entities for the SH and DD fields were: authors - Lyndon Jones (hSH = 33) and Philip Morgan (hDD = 15); institutions - the University of Waterloo (hSH = 37) and the University of New South Wales (hDD = 15); countries - the United States (hSH = 45) and the United Kingdom (hDD = 24); and journals - Optometry and Vision Science (hSH = 33) and Contact Lens and Anterior Eye (hDD = 17). Overall, the SH field (hSH = 64) is far more impactful than the DD field (hDD = 34). CONCLUSIONS: Impactful papers, authors, institutions, countries and journals in the SH and DD fields are identified. Optometry is revealed as the leading profession in relation to SH and DD publications.

The Influence of Donor and Recipient Complement C3 Polymorphisms on Liver Transplant Outcome.

Despite early reports of an impact of complement C3 polymorphism on liver transplant patient and graft survival, subsequent evidence has been conflicting. Our aim was to clarify the contributions of donor and recipient C3 genotype, separately and together, on patient and graft outcomes and acute rejection incidence in liver transplant recipients. Eight donor/recipient groups were analyzed according to their genotype and presence or absence of C3 F allele (FFFS, FFSS, FSFF, FSFS, FSSS, SSFF, SSFS, and SSSS) and correlated with clinical outcomes of patient survival, graft survival, and rejection. The further impact of brain death vs. circulatory death during liver donation was also considered. Over a median 5.3 y follow-up of 506 patients with clinical information and matching donor and recipient tissue, five-year patient and graft survival (95% confidence interval) were 90(81-91)% and 77(73-85)%, respectively, and 72(69-94)% were rejection-free. Early disadvantages to patient survival were associated with donor C3 F variant, especially in brain-death donors. Recipient C3 genotype was an independent determinant of graft survival by Cox proportional hazards analysis (hazard ratio 0.26, P = 0.04), and the C3 F donor variant was again associated with worse liver graft survival, particularly in brain-death donors. C3 genotype did not independently determine rejection incidence, but a greater proportion of recipient C3 F carriers were rejection-free in the circulatory death, but not the brain-death cohort. Cox proportional hazards analysis revealed significant effects of acute rejection on patient survival (hazard ratio 0.24, P = 0.018), of retransplantation on rejection risk (hazard ratio 6.3, P = 0.009), and of donor type (circulatory-death vs. brain-death) on rejection incidence (hazard ratio 4.9, P = 0.005). We conclude that both donor and recipient complement C3 genotype may influence patient and graft outcomes after liver transplantation but that the type of liver donor is additionally influential, possibly via the inflammatory environment of the transplant.

Dysregulation of the Lysophosphatidylcholine/Autotaxin/Lysophosphatidic Acid Axis in Acute-on-Chronic Liver Failure Is Associated With Mortality and Systemic Inflammation by Lysophosphatidic Acid-Dependent Monocyte Activation.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study. APPROACHES & RESULTS: Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14+ monocytes were cultured with LPC, or its autotaxin (ATX)-derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure-Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNF-α, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14+ cells without increasing phagocytic capacity. CONCLUSIONS: ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF.

Microsampling Devices for Routine Therapeutic Drug Monitoring-Are We There Yet?

BACKGROUND: The use of microsampling for therapeutic drug monitoring (TDM) is increasingly feasible as sensitive methods have become more accessible. There exists an increasing interest in the use of microsampling, and new microsampling devices and techniques can potentially improve patient convenience and care, among other features. This review provides an update on currently validated methods for measuring drugs pertinent to TDM, including data from clinical samples. METHODS: A literature record search was undertaken, including PubMed and Google Scholar. Reports that included the use of microsampling to measure concentrations of drugs associated with TDM were reviewed and included if data from patient samples were reported. The studies are described in brief, including sample preparation and analyte stability, with the most pertinent findings reported. RESULTS: Sensitive analyses and innovative designs and materials have resulted in an increasing number of reported evaluations and validations for measuring drugs using microsamples. Novel designs largely overcome common problems associated with traditional dried blood spot sampling. Although examples of patient self-sampling are rare at present, studies that evaluated feedback found it to be largely positive, revealing the feasibility of microsampling for TDM. CONCLUSIONS: Microsampling is suited to the TDM of numerous drugs in diverse situations, and it will play an increasingly important role. The issues with traditional dried blood spot samples have been largely overcome by employing novel methods to obtain volumetric samples.

Effects of an Unexpected and Expected Event on Older Adults' Autonomic Arousal and Eye Fixations During Autonomous Driving.

Driving cessation for some older adults can exacerbate physical, cognitive, and mental health challenges due to loss of independence and social isolation. Fully autonomous vehicles may offer an alternative transport solution, increasing social contact and encouraging independence. However, there are gaps in understanding the impact of older adults' passive role on safe human-vehicle interaction, and on their well-being. 37 older adults (mean age ± SD = 68.35 ± 8.49 years) participated in an experiment where they experienced fully autonomous journeys consisting of a distinct stop (an unexpected event versus an expected event). The autonomous behavior of the vehicle was achieved using the Wizard of Oz approach. Subjective ratings of trust and reliability, and driver state monitoring including visual attention strategies (fixation duration and count) and physiological arousal (skin conductance and heart rate), were captured during the journeys. Results revealed that subjective trust and reliability ratings were high after journeys for both types of events. During an unexpected stop, overt visual attention was allocated toward the event, whereas during an expected stop, visual attention was directed toward the human-machine interface (HMI) and distributed across the central and peripheral driving environment. Elevated skin conductance level reflecting increased arousal persisted only after the unexpected event. These results suggest that safety-critical events occurring during passive fully automated driving may narrow visual attention and elevate arousal mechanisms. To improve in-vehicle user experience for older adults, a driver state monitoring system could examine such psychophysiological indices to evaluate functional state and well-being. This information could then be used to make informed decisions on vehicle behavior and offer reassurance during elevated arousal during unexpected events.

The psychological wellbeing benefits of place engagement during walking in urban environments: A qualitative photo-elicitation study.

The psychological wellbeing potential of walking in urban environments has received limited attention from scholars, despite the important public health implications of identifying characteristics of urban settings that support wellbeing and encourage behaviour change. The study is the first to explore psychological wellbeing experiences of urban walking framed by theories of restorative environments and therapeutic landscape. Self-reported psychological wellbeing experiences of walking in urban settings were investigated with an innovative application of the photo-elicited interview. Fourteen adults took individual walks in Bristol city centre and photographed their journey; photographs were then discussed during the interview. Participants reported specific engagements with place related to personal connections, the identity of place, and sense of community that resulted in psychological wellbeing benefits. The findings also support the notion that non-natural elements can promote positive affective and cognitive appraisals. Building on the finding that also urban walking can support psychological wellbeing, the findings encourage future research into the health potential of different characteristics of built environments.

Effects of valent image-based secondary tasks on verbal working memory.

Two experiments examined if exposure to emotionally valent image-based secondary tasks introduced at different points of a free recall working memory (WM) task impair memory performance. Images from the International Affective Picture System (IAPS) varied in the degree of negative or positive valance (mild, moderate, strong) and were positioned at low, moderate and high WM load points with participants rating them based upon perceived valence. As predicted, and based on previous research and theory, the higher the degree of negative (Experiment 1) and positive (Experiment 2) valence and the higher the WM load when a secondary task was introduced, the greater the impairment to recall. Secondary task images with strong negative valance were more disruptive than negative images with lower valence at moderate and high WM load task points involving encoding and/or rehearsal of primary task words (Experiment 1). This was not the case for secondary tasks involving positive images (Experiment 2), although participant valence ratings for positive IAPS images classified as moderate and strong were in fact very similar. Implications are discussed in relation to research and theory on task interruption and attentional narrowing and literature concerning the effects of emotive stimuli on cognition.

Eating tasty foods to cope, enhance reward, socialize or conform: What other psychological characteristics describe each of these motives?

Psychological characteristics associated with eating motives of the Palatable Eating Motives Scale (PEMS) were identified in 192 undergraduates. Coping was characterized by greater BMI, emotion-triggered eating, and eating concern and also by binge-eating and perceived stress reactivity in females. Reward Enhancement was characterized by greater BMI, anxiety- and depression-eating in females and by anger/frustration-eating in males. Conformity was strongly characterized by binge-eating and by failure-based stress and all eating disorder traits in females and by anger/frustration- and anxiety-eating in males. The sex-divergent patterns of these traits across PEMS motives highlight the heterogeneity of hedonic eating. The traits may also be maintaining the motives, hence adresseing them should improve treatments for obesity, binge-eating, and foster healthier coping, reward, and psychosocial interactions.

Concentration Monitoring of Plasma Ribavirin: Validation of a Liquid Chromatography-Mass Spectrometric Method and Clinical Sample Collection.

BACKGROUND: A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for routine measurement of ribavirin concentrations in EDTA-anticoagulated plasma. METHODS: After protein precipitation, we used a bridged ethylene hybrid (hydrophilic interaction) chromatography column, 0.1 mmol/L ammonium formate pH 3.0, and a gradient of 85%-96% acetonitrile to achieve baseline separation of ribavirin from isobaric uridine. Quantitation was assured using both primary (m/z 245.3 > 113.0) and secondary transitions (m/z 245.3 > 96.0) of the protonated species. Chromatographic separation and column washing also negated interference from major phospholipid species. RESULTS: There was a linear relationship between concentration and response to 10 mg/L, with a minimum detectable level and a minimum level of quantitation both of 0.1 mg/L. Imprecision within the assay was <10% at 0.1 mg/L and <6% between assays for concentrations >0.4 mg/L. Bias was <4%. In clinical samples (n = 12), there was no difference in ribavirin concentrations obtained by an established liquid chromatographic assay with ultraviolet detection. Ribavirin concentrations were stable in plasma stored at room temperature for 3 days but then decreased significantly on day 7. Plasma concentrations were stable for 15 weeks at -20 °C. Concentrations in plasma separated from whole blood at room temperature fell by a median of 19.4% at 4 hours and then rose substantially (median 251% by 3 days). Dose-normalized ribavirin concentrations reached a steady state after a mean of >6 weeks treatment in 76 patients with hepatitis C. CONCLUSIONS: A hydrophilic interaction liquid chromatography-tandem mass spectrometric method to measure ribavirin in plasma was developed. Samples for ribavirin estimation should be kept at 4 °C, separated within 2 hours of collection and stored at 4 °C before analysis, with long-term storage at -20 °C. This method was applied to a study of the ribavirin therapeutic monitoring in patients with hepatitis C.

Use of a small particle solid-core packing for improved efficiency and rapid measurement of sirolimus and everolimus by LC-MS/MS.

Measurement of whole blood sirolimus and everolimus is required in order to optimize patient treatment following solid organ transplant. Assay by LC-MS/MS is increasingly preferred; however efficient use of the instrument and short turnaround times are crucial. Use of a 1.6 µm solid-core packing HPLC column (Cortecs) gave significant increases in efficiency, sensitivity and throughput compared with an existing method, following simple protein precipitation of small-volume (20 µL) whole blood samples. Sirolimus, everolimus and the stable isotopic internal standard ((13) C2 D4 - everolimus) eluted at around 0.8 min, and total analytical run time was 2.2 min, saving almost 4 min per sample compared with an existing method. Within-assay imprecision (CV) was 3.3-8.5%, and between-assay imprecision was 2.2-10.8%. Retrospective assay of external quality assurance samples and comparison of patient samples assayed in parallel showed only small differences (between +6.8 and -1.9%) in results using the Cortecs column when compared with the existing method. No significant interferences or ion suppression were observed. Copyright © 2015 John Wiley & Sons, Ltd.

Real-time sampling of reasons for hedonic food consumption: further validation of the Palatable Eating Motives Scale.

Highly palatable foods play a salient role in obesity and binge-eating, and if habitually eaten to deal with intrinsic and extrinsic factors unrelated to metabolic need, may compromise adaptive coping and interpersonal skills. This study used event sampling methodology (ESM) to examine whether individuals who report eating palatable foods primarily to cope, to enhance reward, to be social, or to conform, as measured by the Palatable Eating Motives Scale (PEMS), actually eat these foods primarily for the motive(s) they report on the PEMS. Secondly this study examined if the previously reported ability of the PEMS Coping motive to predict BMI would replicate if the real-time (ESM-reported) coping motive was used to predict BMI. A total of 1691 palatable eating events were collected from 169 college students over 4 days. Each event included the day, time, and types of tasty foods or drinks consumed followed by a survey that included an abbreviated version of the PEMS, hunger as an additional possible motive, and a question assessing general perceived stress during the eating event. Two-levels mixed modeling confirmed that ESM-reported motives correlated most strongly with their respective PEMS motives and that all were negatively associated with eating for hunger. While stress surrounding the eating event was strongly associated with the ESM-coping motive, its inclusion in the model as a predictor of this motive did not abolish the significant association between ESM and PEMS Coping scores. Regression models confirmed that scores on the ESM-coping motive predicted BMI. These findings provide ecological validity for the PEMS to identify true-to-life motives for consuming palatable foods. This further adds to the utility of the PEMS in individualizing, and hence improving, treatment strategies for obesity, binge-eating, dietary nutrition, coping, reward acquisition, and psychosocial skills.

The Kids-Palatable Eating Motives Scale: relation to BMI and binge eating traits.

INTRODUCTION: Despite high rates of obesity in adolescents, little is known about their individual motives for eating caloric foods for reasons unrelated to hunger. The goal of this study was to provide a preliminary validation of the "Kids Palatable Eating Motives Scale" (K-PEMS), a self-report survey designed to identify individual motives for eating tasty foods in adolescents. The study also sought to determine if any specific motive(s) can account for variance in BMI and binge-eating disorder (BED) traits which can exacerbate obesity. METHODS: BMIz and responses to the K-PEMS and the Children's Binge Eating Disorder Scale (C-BEDS) were obtained from inner-city low-income African American adolescents. Linear and logistic regressions were used to identify K-PEMS motives that were associated with greater BMIz and binge-eating traits. RESULTS: The K-PEMS identified eating tasty foods for Social, Conformity, Reward Enhancement, and Coping motives. Higher frequency of eating tasty foods for Social and Conformity motives and lower frequency of eating these foods for Reward Enhancement accounted for 39% of the variance in BMIz among the overweight and obese adolescents. In contrast, eating for Coping motives was related to a 3-fold increase in the amended provisional criteria for BED in children which occurred in 7% of this young minority sample. DISCUSSION: The K-PEMS can be used to identify adolescents' primary motives for eating tasty foods. These motives may provide early identification of obesity and binge-eating risk but more importantly, can be tailor-targeted to affect specific behavioral and/or cognitive changes to prevent these conditions in adulthood.

The influence of training and experience on memory strategy.

This paper investigates whether, and if so how much, prior training and experience overwrite the influence of the constraints of the task environment on strategy deployment. This evidence is relevant to the theory of soft constraints that focuses on the role of constraints in the task environment (Gray, Simms, Fu, & Schoelles, Psychological Review, 113: 461-482, 2006). The theory explains how an increase in the cost of accessing information induces a more memory-based strategy involving more encoding and planning. Experiments 1 and 3 adopt a traditional training and transfer design using the Blocks World Task in which participants were exposed to training trials involving a 2.5-s delay in accessing goal-state information before encountering transfer trials in which there was no access delay. The effect of prior training was assessed by the degree of memory-based strategy adopted in the transfer trials. Training with an access delay had a substantial carry-over effect and increased the subsequent degree of memory-based strategy adopted in the transfer environment. However, such effects do not necessarily occur if goal-state access cost in training is less costly than in transfer trials (Experiment 2). Experiment 4 used a fine-grained intra-trial design to examine the effect of experiencing access cost on one, two, or three occasions within the same trial and found that such experience on two consecutive occasions was sufficient to induce a more memory-based strategy. This paper establishes some effects of training that are relevant to the soft constraints theory and also discusses practical implications.