Challenges in implementing cardiovascular risk scores for assessment of young people with childhood-onset autoimmune rheumatic conditions

Cardio-vascular risk (CVR) stratification tools have been implemented in clinical practice to guide management decision for primary prevention of cardiovascular disease. Less is known about how we can optimally estimate the CVR in children and adolescents or about the reliability of the risk stratification tools validated in adult populations. Chronic inflammation associated with autoimmune rheumatic disease (ARD) drives an increased risk for accelerated atherosclerosis in patients of all ages. Although the research is less advanced than in adult populations, it is recognized that young people with ARDs with childhood-onset have increased CVR compared to age-matched healthy controls, as supported by studies investigating lipid biomarker profile and markers of endothelial dysfunction. Further research is needed to address the unmet need for adequate CVR identification and management strategies in young people in general, and in those with underlying chronic inflammation in particular. This perspective paper explores various challenges in adequately identifying and managing CVR in younger populations and potential directions for future research

Effect of lamotrigine on cognition in children with epilepsy

Background: Lamotrigine does not affect cognition in healthy adult volunteers or adult patients with epilepsy, but its effect on cognition in children is uncertain.// Objective: To compare the effect of lamotrigine and placebo on cognition in children with well-controlled or mild epilepsy.// Method: In a double-blind, placebo-controlled, crossover study, 61 children with well-controlled or mild epilepsy were randomly assigned to add-on therapy with either lamotrigine followed by placebo or placebo followed by lamotrigine. Each treatment phase was 9 weeks, the crossover period 5 weeks. A neuropsychological test battery was performed during EEG monitoring at baseline and at the end of placebo and drug phases. The paired Student’ t test was used for statistical analysis for neuropsychological data (two tailed) with a p value of 0.01 considered significant. Carryover and period effect were analyzed with generalized linear modeling (SPSS 10).// Results: Forty-eight children completed the study. Seizure frequency was similar during both treatment phases. No significant difference was found in continuous performance, binary choice reaction time, verbal and nonverbal recognition, computerized visual searching task, verbal and spatial delayed recognition, and verbal and nonverbal working memory between placebo and lamotrigine treatment phase. There was no significant carryover and period effect when corrected for randomization.// Conclusion: Lamotrigine exhibits no clinically significant cognitive effects in adjunctive therapy for children with epilepsy

Metabolomics defines complex patterns of dyslipidaemia in juvenile-sle patients associated with inflammation and potential cardiovascular disease risk

Cardiovascular disease (CVD) is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE) associated with atherosclerosis. The interplay between dyslipidaemia and inflammation—mechanisms that drive atherosclerosis—were investigated retro-spectively in adolescent JSLE patients using lipoprotein-based serum metabolomics in patients with active and inactive disease, compared to healthy controls (HCs). Data was analysed using machine learning, logistic regression, and linear regression. Dyslipidaemia in JSLE patients was characterised by lower levels of small atheroprotective high-density lipoprotein subsets compared to HCs. These changes were exacerbated by active disease and additionally associated with significantly higher atherogenic very-low-density lipoproteins (VLDL) compared to patients with low disease activity. Atherogenic lipoprotein subset expression correlated positively with clinical and serological markers of JSLE disease activity/inflammation and was associated with disturbed liver function, and elevated expression of T-cell and B-cell lipid rafts (cell signalling platforms mediating immune cell activa-tion). Finally, exposing VLDL/LDL from patients with active disease to HC lymphocytes induced a significant increase in lymphocyte lipid raft activation compared to VLDL/LDL from inactive patients. Thus, metabolomic analysis identified complex patterns of atherogenic dyslipidaemia in JSLE patients associated with inflammation. This could inform lipid-targeted therapies in JSLE to improve cardiovascular outcomes

Plant-based dietary changes may improve symptoms in patients with systemic lupus erythematosus

INTRODUCTION: Previous studies have reported that patients affected by systemic lupus erythematosus (SLE) are interested in using diet to treat fatigue, cardiovascular disease and other symptoms. However, to date, there is insufficient information regarding the ways for patients to modify their diet to improve SLE symptoms. We investigated the relationship between the eating patterns of SLE patients and their self-reported disease symptoms and general aspects of health. METHODS: A UK-based, online survey was developed, in which patients with SLE were asked about their attitudes and experiences regarding their SLE symptoms and diet. RESULTS: The majority (>80%) of respondents that undertook new eating patterns with increased vegetable intake and/or decreased intake of processed food, sugar, gluten, dairy and carbohydrates reported benefiting from their dietary change. Symptom severity ratings after these dietary changes were significantly lower than before (21.3% decrease, p<0.0001). The greatest decreases in symptom severity were provided by low/no dairy (27.1% decrease), low/no processed foods (26.6% decrease) and vegan (26% decrease) eating patterns (p<0.0001). Weight loss, fatigue, joint/muscle pain and mood were the most cited symptoms that improved with dietary change. CONCLUSION: SLE patients who changed their eating patterns to incorporate more plant-based foods while limiting processed foods and animal products reported improvements in their disease symptoms. Thus, our findings show promises in using nutrition interventions for the management of SLE symptoms, setting the scene for future clinical trials in this area. Randomised studies are needed to further test whether certain dietary changes are effective for improving specific symptoms of SLE

Sex hormones drive changes in lipoprotein metabolism

Summary Women have a reduced cardiovascular disease (CVD) risk compared to men which could be partially driven by sex hormones influencing lipid levels post-puberty. The interrelationship between sex hormones and lipids was explored in pre-pubertal children, young post-pubertal cis-men/women, and transgender individuals on cross-sex-hormone treatment (trans-men/women) using serum metabolomics assessing 149 lipids. High-density lipoproteins (HDL, typically atheroprotective) were significantly increased and very-low- and low-density lipoproteins (typically atherogenic) were significantly decreased in post-pubertal cis-women compared to cis-men. These differences were not observed pre-puberty and were induced appropriately by cross-sex-hormone treatment in transgender individuals, supporting that sex hormones regulate lipid metabolism in vivo. Only atheroprotective apolipoprotein (Apo)A1 expressing lipoproteins (HDL) were differentially expressed between all hormonally unique comparisons. Thus, oestradiol drives a typically atheroprotective lipid profile through upregulation of HDL/ApoA1 which could contribute to the sexual dimorphism observed in CVD risk post-puberty. Together, this could inform sex-specific therapeutic strategies for CVD management

An Advanced Calibration Method for Image Analysis in Laboratory-Scale Seawater Intrusion Problems

existing methods of converting image light intensity to concentration can be labour intensive and time consuming. The new approach proposed in this study utilises the Random Forest machine learning technique to build a calibration model to replace the requirement for unique calibrations of each test aquifer. Calibration images from a previous experimental study were used to train the Random Forest model and the output was compared to the results from a high resolution pixel-wise methodology. The Random Forest model provided a trade-off in accuracy with increased efficiency and reduced sensitivity to image desynchronisation when compared to the pixel-wise method. The reduced accuracy was attributed in part to non-linear lighting distribution across the sandbox, which could be corrected by orientating the backlights effectively. Time savings of around 35% were achieved for this experimental study and this is expected to increase for larger scale studies. The new calibration approach exhibits some promising features in terms of its robustness to experimental error and its ability to process efficiently large-scale experiments in a shorter time fram

Plankton community respiration and bacterial metabolism in a North Atlantic Shelf Sea during spring bloom development (April 2015)

Spring phytoplankton blooms are important events in Shelf Sea pelagic systems as the increase in carbon production results in increased food availability for higher trophic levels and the export of carbon to deeper waters and the sea-floor. It is usually accepted that the increase in phytoplankton abundance and production is followed by an increase in plankton respiration. However, this expectation is derived from field studies with a low temporal sampling resolution (5–15 days). In this study we have measured the time course of plankton abundance, gross primary production, plankton community respiration, respiration of the plankton size classes (> 0.8 μm and 0.2–0.8 μm) and bacterial production at ≤5 day intervals during April 2015 in order to examine the phasing of plankton autotrophic and heterotrophic processes. Euphotic depth-integrated plankton community respiration increased five-fold (from 22 ± 4 mmol O2m−2 d−1 on 4th April to 119 ± 4 mmol O2m−2 d−1 on 15th April) at the same time as gross primary production also increased five-fold, (from 114 ± 5 to 613 ± 28 mmol Cm−2 d−1). Bacterial production began to increase during the development of the bloom, but did not reach its maximum until 5 days after the peak in primary production and plankton respiration. The increase in plankton community respiration was driven by an increase in the respiration attributable to the> 0.8 μm size fraction of the plankton community (which would include phytoplankton, microzooplankton and particle attached bacteria). Euphotic depth-integrated respiration of the 0.2–0.8 μm size fraction (predominantly free living bacteria) decreased and then remained relatively constant (16 ± 3 – 11 ± 1 mmol O2m−2 d−1) between the first day of sampling (4th April) and the days following the peak in chlorophyll-a (20th and 25th April). Recent locally synthesized organic carbon was more than sufficient to fulfil the bacterial carbon requirement in the euphotic zone during this productive period. Changes in bacterial growth efficiencies (BGE, the ratio of bacterial production to bacterial carbon demand) were driven by changes in bacterial production rates increasing from<30 ± 14% on 4th April to 51 ± 11% on 25th of April. This study therefore shows a concurrent rather than a phased increase in primary production and community respiration attributable to cells>0.8 μm during the development of the spring bloom, followed 5 days later by a peak in bacterial production. In addition, the size fractionated respiration rates and high growth efficiencies suggest that free living bacteria are not the major producers of CO2 before, during and a few days after this shelf sea spring phytoplankton bloom

Alloactivation of naïve CD4⁺ CD8⁻ CD25⁺T regulatory cells: Expression of CD8α identifies potent suppressor cells that can promote transplant tolerance induction

Therapy with alloantigen-specific CD4+ CD25+ T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are not alloantigen-specific and are weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells in the presence of rIL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rβ2) and are more potent alloantigen-specific regulators that we call Ts1 cells. This study examined additional markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4+ CD25+ Foxp3+ Treg. After culture of naïve DA CD4+ CD8− CD25+ T cells with rIL-2 and PVG alloantigen, or rIL-2 without alloantigen, CD8α was expressed on 10–20% and CD8β on <5% of these cells. These cells expressed ifngr and Il12rb2. CD8α+ cells had increased Ifngr that characterizes Ts1 cells as well was Irf4, a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4+ CD8α+ CD25+ Treg consistent with the CD8α+ cells expressing IL-12R. In MLC, the CD8α+ fraction suppressed responses against allogeneic stimulators more than the mixed Ts1 population, whereas the CD4+ CD8− CD25+ T cells were less potent. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8α+ cells were much less effective. This study demonstrated that expression of CD8α by rIL-2 and alloantigen activation of CD4+ CD8− CD25+ Foxp3+ T cells was a marker of activated and potent Treg that included alloantigen-specific Treg

Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE

Background: Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE. Methods: Serum metabolomic analysis (including >200 lipoprotein measures) was performed on a discovery (n=31, median age 19) and validation (n=31, median age 19) cohort of JSLE patients. Data was analysed using cluster, receiver operating characteristic analysis and logistic regression. RNA-sequencing assessed gene expression in matched patient samples. Findings: Hierarchical clustering of lipoprotein measures identified and validated two unique JSLE groups. Group-1 had an atherogenic and Group-2 had an atheroprotective lipoprotien profile. Apolipoprotein(Apo)B:ApoA1 distinguished the two groups with high specificity (96.2%) and sensitivity (96.7%). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively. Finally, baseline ApoB:ApoA1 ratio correlated positively with SLE disease activity index (r=0.43, p=0.0009) and negatively with Lupus Low Disease Activity State (r=-0.43, p=0.0009) over 5-year follow-up. Interpretation: Multi-omic analysis identified high ApoB:ApoA1 as a potential biomarker of increased cardiometabolic risk and worse clinical outcomes in JSLE. ApoB:ApoA1 could help identify patients that require increased disease monitoring, lipid modification or lifestyle changes. Funding: Lupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis