Risk Model Development and Validation for Prediction of Coronary Artery Aneurysms in Kawasaki Disease in a North American Population.

Background Accurate prediction of coronary artery aneurysms ( CAAs ) in patients with Kawasaki disease remains challenging in North American cohorts. We sought to develop and validate a risk model for CAA prediction. Methods and Results A binary outcome of CAA was defined as left anterior descending or right coronary artery Z score ≥2.5 at 2 to 8 weeks after fever onset in a development cohort (n=903) and a validation cohort (n=185) of patients with Kawasaki disease. Associations of baseline clinical, laboratory, and echocardiographic variables with later CAA were assessed in the development cohort using logistic regression. Discrimination (c statistic) and calibration (Hosmer-Lemeshow) of the final model were evaluated. A practical risk score assigning points to each variable in the final model was created based on model coefficients from the development cohort. Predictors of CAAs at 2 to 8 weeks were baseline Z score of left anterior descending or right coronary artery ≥2.0, age <6 months, Asian race, and C-reactive protein ≥13 mg/ dL (c=0.82 in the development cohort, c=0.93 in the validation cohort). The CAA risk score assigned 2 points for baseline Z score of left anterior descending or right coronary artery ≥2.0 and 1 point for each of the other variables, with creation of low- (0-1), moderate- (2), and high- (3-5) risk groups. The odds of CAA s were 16-fold greater in the high- versus the low-risk groups in the development cohort (odds ratio, 16.4; 95% CI , 9.71-27.7 [ P<0.001]), and >40-fold greater in the validation cohort (odds ratio, 44.0; 95% CI, 10.8-180 [ P<0.001]). Conclusions Our risk model for CAA in Kawasaki disease consisting of baseline demographic, laboratory, and echocardiographic variables had excellent predictive utility and should undergo prospective testing

Treatment Intensification in Patients With Kawasaki Disease and Coronary Aneurysm at Diagnosis.

BackgroundCoronary artery aneurysms (CAA) are a serious complication of Kawasaki disease. Treatment with intravenous immunoglobulin (IVIg) within 10 days of fever onset reduces the risk of CAA from 25% to <5%. Corticosteroids and infliximab are often used in high-risk patients or those with CAA at diagnosis, but there are no data on their longer-term impact on CAA.MethodsRetrospective multicenter study including children who had CAA with a z score ≥2.5 and <10 at time of diagnosis and who received primary therapy with IVIg alone or in combination with either corticosteroids or infliximab within 10 days of onset of fever.ResultsOf 121 children, with a median age of 2.8 (range 0.1-15.5) years, 30 (25%) received primary therapy with corticosteroids and IVIg, 58 (48%) received primary therapy with infliximab and IVIg, and 33 (27%) received primary therapy with IVIg only. Median coronary z scores at the time of diagnosis did not differ among treatment groups (P = .39). Primary treatment intensification with either corticosteroids or infliximab were independent protective factors against progression of coronary size on follow-up (coefficient: -1.31 [95% confidence interval: -2.33 to -0.29]; coefficient: -1.07 [95% confidence interval: -1.95 to -0.19], respectively).ConclusionsAmong a high-risk group of patients with Kawasaki disease with CAA on baseline echocardiography, those treated with corticosteroids or infliximab in addition to IVIg had less progression in CAA size compared with those treated with IVIg alone. Prospective randomized trials are needed to determine the best adjunctive treatment of patients who present with CAA

A pan-cetacean MHC amplicon sequencing panel developed and evaluated in combination with genome assemblies

This study was funded by a Royal Society Research Grants for Research Fellows (RGF\R1\181014) to E.C.G. E.C.G. is funded by a Royal Society University Research Fellowship (UF160081 & URF\R\221020). F.E. is supported by a University of St Andrews School of Biology Ph.D. scholarship and a Royal Society Research Fellows Enhancement Award (RGF\EA\180213 to E.C.G). E.L.C. is funded by a Rutherford Discovery Fellowship from the Royal Society of New Zealand Te Apārangi.The major histocompatibility complex (MHC) is a highly polymorphic gene family that is crucial in immunity, and its diversity can be effectively used as a fitness marker for populations. Despite this, MHC remains poorly characterised in non-model species (e.g., cetaceans: whales, dolphins and porpoises) as high gene copy number variation, especially in the fast-evolving class I region, makes analyses of genomic sequences difficult. To date, only small sections of class I and IIa genes have been used to assess functional diversity in cetacean populations. Here, we undertook a systematic characterisation of the MHC class I and IIa regions in available cetacean genomes. We extracted full-length gene sequences to design pan-cetacean primers that amplified the complete exon2 from MHC class I and IIa genes in one combined sequencing panel. We validated this panel in 19 cetacean species and described 354 alleles for both classes. Furthermore, we identified likely assembly artefacts for many MHC class I assemblies based on the presence of class I genes in the amplicon data compared to missing genes from genomes. Finally, we investigated MHC diversity using the panel in 25 humpback and 30 southern right whales, including four paternity trios for humpback whales. This revealed copy-number variable class I haplotypes in humpback whales, which is likely a common phenomenon across cetaceans. These MHC alleles will form the basis for a cetacean branch of the Immuno-Polymorphism Database (IPD-MHC), a curated resource intended to aid in the systematic compilation of MHC alleles across several species, to support conservation initiatives.Peer reviewe

Healthy Body Healthy Mind: Trialling an exercise intervention for reducing depression in youth with major depressive disorder

Introduction: Major Depressive Disorder (MDD) has high prevalence among adolescents and young adults but evidence of any effective treatments is limited. Exercise as an effective treatment for adults has some support but studies in younger populations are lacking. MDD is associated with inflammation and exercise may contribute to reductions in inflammatory marker levels. Therefore the aim of this study was to investigate the feasibility and preliminary efficacy of brief motivational interviewing (MI) plus 12-weeks exercise training as a treatment for MDD in youth. Methods: Youth (15-25 years) with MDD were recruited to participate in a prospective trial investigating exercise as treatment for MDD. Twenty-six participants were screened (telephone then clinical psychology diagnosis) and 13 (9 females) were eligible (MDD from SCID, no psychotic illness, not pregnant, no physical barriers to exercise, not suicidal, no major eating disorder) to participate. Participants completed assessments at baseline and after 12 weeks training, which included questionnaires: the Beck Depression Inventory (BDI-II); blood samples for analysis of inflammatory biomarkers; and fitness measures: VO2max, YMCA bench press test, and a seated horizontal leg press endurance test. Prior to commencing the training program, participants engaged in a motivational interview with a psychologist to enhance engagement with the program. IL-6 was measured by ELISA. The exercise program consisted of small group trainer-led supervised exercise (resistance and endurance) training 3 times a week (1h per session) for 12 weeks, and encouragement to do at least 30min of physical activity on other days. Paired t-tests were used to determine changes from baseline and correlations used to explore relationships between changes in depression scores, training attendance and fitness levels. Results: 12 participants (mean±SD, aged 20.7±1.7 y) completed 12-week assessments; one withdrew due to family issues. Attendance at training averaged 66±25% of sessions; 3 participants completed less than 40% of training sessions. At baseline all participants met the criteria for MDD; at 12 weeks only 2 still met the criteria; depression severity (BDI-II) decreased (p\u3c0.001) from 32±9 to12±10. Aerobic fitness levels did not change with training. YMCA bench press repetitions increased (p\u3c0.001) from 20±11 to 27±11. IL-6 decreased (p\u3c0.05) from 1.39±0.78 to 0.73±0.80 pg.mL-1. Changes in depression symptom scores were significantly correlated (p\u3c0.05) with attendance (r=0.32), improvements in bench press endurance (r=0.65) and changes in IL-6 (r=0.34). Changes in IL-6 were also correlated with attendance (r=0.60) Conclusion: Exercise training is a feasible and potentially effective intervention for MDD in youth and reductions in depression severity are associated with reductions in IL-6

Effect of sink layer thickness on damping in CoMnGe (5 nm) / Ag (6 nm) / NiFe (x nm) spin valves

Poster presented at Magnetism 4 – 5 April 2016, Sheffield.In spin valve structures the damping of a ferromagnetic layer driven at resonance can be modified by the transfer of spin angular momentum into a ‘sink’ ferromagnetic layer. This effect, known as spin pumping, is interface dominated and expected to increase with increasing sink layer thickness up to a saturation absorption depth, previously reported to be 1.2 nm regardless of the sink layer’s composition [1]. Using vector network analyser ferromagnetic resonance (VNA-FMR), we have studied the variation in damping as a function of sink layer thickness in a series of CoMnGe (5 nm) / Ag (6 nm) / NiFe (x nm) spin valves. These measurements show only small variations in the CoMnGe Gilbert damping parameter for x ≤ 1.8 nm, although damping is observed to increase at x = 0.3 and 0.6 nm. Element-resolved x-ray detected ferromagnetic resonance (XFMR) [2] measurements confirm spin transfer torque due to spin pumping as the origin of the damping for x = 1.5 and 1.8 nm, with both thicknesses having the same effective spin mixing conductance, supporting the findings of Ghosh et al [1]. For thicker sink layers the source and sink FMR fields are seen to coincide, hampering the identification of spin pumping. [1] A Ghosh, et al. Physical Review Letters 109, 127202 (2012) [2] M Marcham, et al. Physical Review B 87, 180403 (2013)We thank the Advanced Light Source for access to beamlines 4.0.2 and 6.3.1 (ALS-06433, ALS-07116). The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.We thank Diamond Light Source for access to beamlines I06 and I10 (SI8782, SI11585, SI13063) that contributed to the results presented here.This work was supported by the Engineering and Physical Sciences Research Council [grant number EP/J018767/1]

Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy

Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment

PURPOSE: Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 reexpression. This study examines the role of ASS1 silencing on tumor growth and initiation and identifies a noncanonical mechanism of resistance, aiming to improve clinical responses to ADI-PEG20. EXPERIMENTAL DESIGN: Tumor initiation and growth rates were measured for a spontaneous Ass1 knockout (KO) murine sarcoma model. Tumor cell lines were generated, and resistance to arginine deprivation therapy was studied in vitro and in vivo. RESULTS: Conditional Ass1 KO affected neither tumor initiation nor growth rates in a sarcoma model, contradicting the prevalent idea that ASS1 silencing confers a proliferative advantage. Ass1 KO cells grew robustly through arginine starvation in vivo, while ADI-PEG20 remained completely lethal in vitro, evidence that pointed toward a novel mechanism of resistance mediated by the microenvironment. Coculture with Ass1-competent fibroblasts rescued growth through macropinocytosis of vesicles and/or cell fragments, followed by recycling of protein-bound arginine through autophagy/lysosomal degradation. Inhibition of either macropinocytosis or autophagy/lysosomal degradation abrogated this growth support effect in vitro and in vivo. CONCLUSIONS: Noncanonical, ASS1-independent tumor resistance to ADI-PEG20 is driven by the microenvironment. This mechanism can be targeted by either the macropinocytosis inhibitor imipramine or the autophagy inhibitor chloroquine. These safe, widely available drugs should be added to current clinical trials to overcome microenvironmental arginine support of tumors and improve patient outcomes

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations