Enough is not enough: Medical students’ knowledge of early warning signs of childhood cancer

Background. The reported incidence of childhood cancer in upper-middle-income South Africa (SA) is much lower than in high-income countries, partly due to under-diagnosis and under-reporting. Documented survival rates are disturbingly low, prompting an analysis of potential factors that may be responsible.Objectives. To determine final-year medical students’ level of knowledge of early warning signs of childhood cancer and whether a correlation existed between test scores and participants’ age, gender and previous exposure to a person with cancer.Methods. A two-part questionnaire based on the Saint Siluan mnemonic, testing both recall and recognition of early warning signs of childhood cancer, was administered. The Mann-Whitney-Wilcoxon test was used to assess differences in continuous and count variables between demographic data, experience and responses, and Fisher’s exact test and Spearman’s rank correlation coefficient were used to determine correlations between demographic data, previous contact with persons with cancer and test scores. A novel equality ratio was calculated to compare the recall and recognition sections and allowed analysis of recall v. recognition.Results. The 84 participants recalled a median of six signs each (interquartile range 4 - 7) and correctly recognised a median of 70% in the recognition section, considered a pass mark. There was no correlation between participants’ age, gender, previous contact with a person with cancer and recognition scores. Students with previous exposure to a person with cancer had higher scores in the recall section, but this did not achieve statistical significance. Students were able to recognise more signs of haematological malignancies than central nervous system (CNS) malignancies.Conclusion. The study demonstrated a marked inconsistency between recall and recognition of signs of childhood cancer, with signs of CNS malignancies being least recognised. However, the majority of students could recognise enough early warning signs to meet the university pass standard. Although this study demonstrated acceptable recognition of early warning signs of childhood cancer at one university, we suggest that long-term recall in medical practitioners is poor, as reflected in the low age-standardised ratios of childhood cancer in SA. We recommend increased ongoing exposure to paediatric oncology in medical school and improved awareness programmes to increase early referrals

Kinetic temperature, electron temperature and turbulence in stellar atmospheres

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Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase

Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20–37 kg/m2). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min−1.m−2.), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR

An asymptotic preserving scheme for the Kac model of the Boltzmann equation in the diffusion limit

International audienceIn this paper we propose a numerical scheme to solve the Kac model of the Boltzmann equation for multiscale rarefied gas dynamics. This scheme is uniformly stable with respect to the Knudsen number, consistent with the fluid-diffusion limit for small Knudsen numbers, and with the Kac equation in the kinetic regime. Our approach is based on the micro-macro decomposition which leads to an equivalent formulation of the Kac model that couples a kinetic equation with macroscopic ones. This method is validated with various test cases and compared to other standard methods

Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Funding: The authors are supported by grants from the AstraZeneca SciLifeLab Research Programme, Novo Nordisk Foundation (NNF14OC0011493, and NNF17OC0030088), Swedish Diabetes Foundation (DIA2018-357), Swedish Research Council (2015-00165 and 2018-02389), the Knut and Alice Wallenberg Foundation (2018-0094), the Strategic Research Programme in Diabetes at Karolinska Institutet (2009-1068), the Stockholm County Council (SLL20170159), and the Swedish Research Council for Sport Science (P2019-0140). B.M.G. was supported by fellowships from the Novo Nordisk Foundation (NNF19OC0055072), the Wenner-Gren Foundation, an Albert Renold Travel Fellowship from the European Foundation for the Study of Diabetes, and an Eric Reid Fund for Methodology from the Biochemical Society. N.J.P. and L.S.-P. were supported by an Individual Fellowship from the Marie Skłodowska-Curie Actions (European Commission: 704978 and 675610). X.Z. and K.A.E. were supported by NIH R01AR066082. N.J.P. was supported by grants from the Sigurd och Elsa Goljes Minne and Lars Hierta Memorial Foundations (Sweden). We acknowledge the Beta Cell in-vivo Imaging/Extracellular Flux Analysis core facility supported by the Strategic Research Program in Diabetes for the usage of the Seahorse flux analyzer. Additional support was received from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation. We acknowledge the Single-Cell Omics platform at the Novo Nordisk Foundation Center for Basic Metabolic Research for technical and computational expertise and support. Schematics are created with BioRender.com.Peer reviewedPublisher PD

Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a mendelian randomisation analysis

BACKGROUND: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. METHODS AND FINDINGS: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. CONCLUSIONS: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

$\textbf{BACKGROUND}$: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. $\textbf{METHODS AND FINDINGS}$: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. $\textbf{CONCLUSIONS}$: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.MRC Epidemiology Unit, Fenland study, EPIC-InterAct study, EPIC-Norfolk case-cohort study funding: this study was funded by the United Kingdom’s Medical Research Council through grants MC_UU_12015/1, MC_UU_12015/5, MC_PC_13046, MC_PC_13048 and MR/L00002/1. We acknowledge support from the National Institute for Health Research Biomedical Research Centre. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement number 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. EPIC-InterAct Study funding: funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). MRC Human Nutrition Research funding: This research was supported by the Medical Research Council (MC_UP_A090_1006) and Cambridge Lipidomics Biomarker Research Initiative (G0800783). The SABRE study was funded at baseline by the UK Medical Research Council, Diabetes UK and the British Heart Foundation and at follow-up by a programme grant from the Wellcome Trust (WT082464) and British Heart Foundation (SP/07/001/23603); Diabetes UK funded the metabolomics analyses (13/0004774). RJOS, EN, JRZ and AK received funding from the Swedish Research Council, Stockholm County Council, Novo Nordisk Foundation and Diabetes Wellness. DBS is supported by the Wellcome Trust grant number 107064. MIM is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. IB is supported by the Wellcome Trust grant WT098051

siRNA-Mediated Reduction of Inhibitor of Nuclear Factor-κB Kinase Prevents Tumor Necrosis Factor-α–Induced Insulin Resistance in Human Skeletal Muscle

OBJECTIVE—Proinflammatory cytokines contribute to systemic low-grade inflammation and insulin resistance. Tumor necrosis factor (TNF)-α impedes insulin signaling in insulin target tissues. We determined the role of inhibitor of nuclear factor-κB kinase (IKK)β in TNF-α–induced impairments in insulin signaling and glucose metabolism in skeletal muscle