Identification of physical activity and sedentary behaviour dimensions that predict mortality risk in older adults: Development of a machine learning model in the Whitehall II accelerometer sub-study and external validation in the CoLaus study.

Identification of new physical activity (PA) and sedentary behaviour (SB) features relevant for health at older age is important to diversify PA targets in guidelines, as older adults rarely adhere to current recommendations focusing on total duration. We aimed to identify accelerometer-derived dimensions of movement behaviours that predict mortality risk in older populations. We used data on 21 accelerometer-derived features of daily movement behaviours in 3991 participants of the UK-based Whitehall II accelerometer sub-study (25.8% women, 60-83 years, follow-up: 2012-2013 to 2021, mean = 8.3 years). A machine-learning procedure was used to identify core PA and SB features predicting mortality risk and derive a composite score. We estimated the added predictive value of the score compared to traditional sociodemographic, behavioural, and health-related risk factors. External validation in the Switzerland-based CoLaus study (N = 1329, 56.7% women, 60-86 years, follow-up: 2014-2017 to 2021, mean = 3.8 years) was conducted. In total, 11 features related to overall activity level, intensity distribution, bouts duration, frequency, and total duration of PA and SB, were identified as predictors of mortality in older adults and included in a composite score. Both in the derivation and validation cohorts, the score was associated with mortality (hazard ratio = 1.10 (95% confidence interval = 1.05-1.15) and 1.18 (1.10-1.26), respectively) and improved the predictive value of a model including traditional risk factors (increase in C-index = 0.007 (0.002-0.014) and 0.029 (0.002-0.055), respectively). The identified accelerometer-derived PA and SB features, beyond the currently recommended total duration, might be useful for screening of older adults at higher mortality risk and for diversifying PA and SB targets in older populations whose adherence to current guidelines is low. National Institute on Aging; UK Medical Research Council; British Heart Foundation; Wellcome Trust; French National Research Agency; GlaxoSmithKline; Lausanne Faculty of Biology and Medicine; Swiss National Science Foundation

Temporal clustering analysis of endothelial cell gene expression following exposure to a conventional radiotherapy dose fraction using Gaussian process clustering

International audienceThe vascular endothelium is considered as a key cell compartment for the response to ionizing radiation of normal tissues and tumors, and as a promising target to improve the differential effect of radiotherapy in the future. Following radiation exposure, the global endothelial cell response covers a wide range of gene, miRNA, protein and metabolite expression modifications. Changes occur at the transcriptional, translational and post-translational levels and impact cell phenotype as well as the microenvironment by the production and secretion of soluble factors such as reactive oxygen species, chemokines, cytokines and growth factors. These radiation-induced dynamic modifications of molecular networks may control the endothelial cell phenotype and govern recruitment of immune cells, stressing the importance of clearly understanding the mechanisms which underlie these temporal processes. A wide variety of time series data is commonly used in bioinformatics studies, including gene expression, protein concentrations and metabolomics data. The use of clustering of these data is still an unclear problem. Here, we introduce kernels between Gaussian processes modeling time series, and subsequently introduce a spectral clustering algorithm. We apply the methods to the study of human primary endothelial cells (HUVECs) exposed to a radiotherapy dose fraction (2 Gy). Time windows of differential expressions of 301 genes involved in key cellular processes such as angiogenesis, inflammation, apoptosis, immune response and protein kinase were determined from 12 hours to 3 weeks post-irradiation. Then, 43 temporal clusters corresponding to profiles of similar expressions, including 49 genes out of 301 initially measured, were generated according to the proposed method. Forty-seven transcription factors (TFs) responsible for the expression of clusters of genes were predicted from sequence regulatory elements using the MotifMap system. Their temporal profiles of occurrences were established and clustered. Dynamic network interactions and molecular pathways of TFs and differential genes were finally explored, revealing key node genes and putative important cellular processes involved in tissue infiltration by immune cells following exposure to a radiotherapy dose fraction. © 2018 Heinonen et al

The association between accelerometer-assessed physical activity and respiratory function in older adults differs between smokers and non-smokers

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Magnetic resonance imaging changes following natalizumab discontinuation in multiple sclerosis patients with progressive multifocal leukoencephalopathy

International audienceBackground Detecting early progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) is clinically relevant. Objective Evaluating magnetic resonance imaging (MRI) changes following natalizumab (NTZ) discontinuation and preceding PML-IRIS. Methods MRIs (including diffusion-weighted imaging (DWI), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), post-contrast T1-weighted sequences) were performed every week following PML diagnosis in 11 consecutive NTZ-PML patients. PML expansion, punctate lesions, contrast-enhancement, and mass-effect/edema were evaluated on each MRI sequence, following NTZ discontinuation. Results PML-IRIS occurred from 26 to 89 days after NTZ discontinuation. MRI changes prior to early PML-IRIS appeared significantly more pronounced using DWI compared to T2-FLAIR imaging (p < 0.003). Two DWI features (marked PML expansion, punctate lesions) systematically preceded contrast-enhancement. Conclusion Subtle changes may occur on DWI preceding contrast-enhancement. © The Author(s), 2018

Repeated potassium iodide exposure during pregnancy impairs progeny’s brain development

International audienceProtracted radioiodine release may require repeated intake of potassium iodide (KI) to protect thyroid gland. It is well established that iodine excess inhibits transiently the thyroid function. As developing fetus depends on maternal thyroid hormones (TH) supply, more knowledge is needed about the plausible effects that repeated KI intake can cause in this sensitive population, especially that even subtle variation of maternal thyroid function may have persistent consequences on progeny brain processing. The aim of this study is to assess the consequences of repeated intake of KI during pregnancy on the progeny's thyroid function and brain development. To do so pregnant Wistar rats received KI over eight days, and then thirty days after the weaning, male progeny was subjected to behavior test. Pituitary and thyroid hormones level, anti-thyroid antibodies level, organs morphology, gene expression and global DNA methylation were assessed. Thirty days after the weaning, KI-exposed male progeny showed an uncommon hormonal status, characterized by a decrease of both thyroid-stimulating hormone (− 28%) and free thyroxine (− 7%) levels. Motor coordination was altered in KI-exposed male progeny. At the cerebellar level, we observed a decrease of mRNA expression of DCX (− 42%) and RC3 (− 85%); on the other hand, at the cortical level, mRNA expression of MBP (+ 71%), MOBP (+ 90%) and Kcna1 (+ 42%) was increased. To conclude, repeated KI prophylaxis is not adequate during pregnancy since it led to long-term irreversible neurotoxicity in the male progeny

Biokinetics and dose assessment after iodine intake in a thyroidectomised rat model

International audienceProcedures using iodine-131 represent more than 90% of all therapies in nuclear medicine in Algeria. It is important to evaluate the long-term biological effects of iodine treatment on non-target organs to improve patient radiation protection. This experimental radiotoxicology study aims to determine the biokinetic models of iodine contamination. For this purpose, two Wistar rat models, with and without a thyroid, have been used to evaluate the biological half-life of iodine and then to perform a biodistribution study of iodine activity in 15 organs and tissues. For the most relevant organs, the respective absorbed doses have been calculated using RODES software. © 2019 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved

Intracranial arteriovenous shunting Detection with arterial spin-labeling and susceptibility-weighted imaging combined

International audienceBACKGROUND AND PURPOSE Arterial spin-labeling and susceptibility-weighted imaging are 2 MR imaging techniques that do not require gadolinium. The study aimed to assess the accuracy of arterial spin-labeling and SWI combined for detecting intracranial arteriovenous shunting in comparison with conventional MR imaging. MATERIALS AND METHODS Ninety-two consecutive patients with a known (n = 24) or suspected arteriovenous shunting (n = 68) underwent digital subtraction angiography and brain MR imaging, including arterial spin-labeling/SWI and conventional angiographic MR imaging (3D TOF, 4D time-resolved, and 3D contrast-enhanced MRA). Arterial spin-labeling/SWI and conventional MR imaging were reviewed separately in a randomized order by 2 blinded radiologists who judged the presence or absence of arteriovenous shunting. The accuracy of arterial spin-labeling/SWI for the detection of arteriovenous shunting was calculated by using the area under receiver operating curve with DSA as reference standard. κ coefficients were computed to determine interobserver and intermodality agreement. RESULTS Of the 92 patients, DSA showed arteriovenous shunting in 63 (arteriovenous malformation in 53 and dural arteriovenous fistula in 10). Interobserver agreement was excellent (κ =0.83- 0.95). In 5 patients, arterial spin-labeling/SWI correctly detected arteriovenous shunting, while the conventional angiographic MR imaging did not. Compared with conventional MR imaging, arterial spin-labeling/SWI was significantly more sensitive (0.98 versus 0.90, P = .04) and equally specific (0.97) and showed significantly higher agreement with DSA (κ = 0.95 versus 0.84, P = .01) and higher area under the receiver operating curve (0.97 versus 0.93, P = .02). CONCLUSIONS Our study showed that the combined use of arterial spin-labeling and SWI may be an alternative to contrast-enhanced MRA for the detection of intracranial arteriovenous shunting

MEDIRAD formulation of science-based recommendations for medical radiation protection: a stakeholder forum survey

MEDIRAD (Implications of Medical Low Dose Radiation Exposure) is an innovative European research project funded by EURATOM which seeks to bring closer together the nuclear and medical research communities in order to advance science for radiation protection in radiotherapy, nuclear medicine, and diagnostic and interventional radiology. The project also aims to promote links between science and society, with the goal of better protecting patients and professionals, through the publication of recommendations based on MEDIRAD research findings (http://www.medirad-project.eu

Low dose of uranium induces multigenerational epigenetic effects in rat kidney

International audiencePurpose A protocol of chronic exposure to low dose of uranium was established in order to distinguish the sexual differences and the developmental process that are critical windows for epigenetic effects over generations. Methods Both male and female rats were contaminated through their drinking water with a non-toxic solution of uranyl nitrate for 9 months. The exposed generation (F0) and the following two generations (F1 and F2) were examined. Clinical monitoring, global DNA methylation profile and DNA methyltransferases (DNMTs) gene expression were analyzed in kidneys. Results While the body weight of F1 males increased, a small decrease in kidney and body weight was observed in F2 males. In addition, global DNA hypermethylation profile in kidney cells was observed in F1 and F2 males. qPCR results reveal a significant increase of methyltransferase genes expression (DNMT1 and DNMT3a) for F2 females. Conclusions In the field of public health policy and to raise attention to generational effects for the risk assessment of the environmental exposures, low doses of uranium do not imply clinical effects on adult exposed rats. However, our results confirm the importance of the developmental windows’ sensitivity in addition to the sexual dimorphisms of the offspring. © 2018, Copyright © 2018 Taylor and Francis Group LLC

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity.

PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III)