Measures of fragmentation of rest activity patterns: mathematical properties and interpretability based on accelerometer real life data.

Accelerometers, devices that measure body movements, have become valuable tools for studying the fragmentation of rest-activity patterns, a core circadian rhythm dimension, using metrics such as inter-daily stability (IS), intradaily variability (IV), transition probability (TP), and self-similarity parameter (named α ). However, their use remains mainly empirical. Therefore, we investigated the mathematical properties and interpretability of rest-activity fragmentation metrics by providing mathematical proofs for the ranges of IS and IV, proposing maximum likelihood and Bayesian estimators for TP, introducing the activity balance index (ABI) metric, a transformation of α , and describing distributions of these metrics in real-life setting. Analysis of accelerometer data from 2,859 individuals (age=60-83 years, 21.1% women) from the Whitehall II cohort (UK) shows modest correlations between the metrics, except for ABI and α . Sociodemographic (age, sex, education, employment status) and clinical (body mass index (BMI), and number of morbidities) factors were associated with these metrics, with differences observed according to metrics. For example, a difference of 5 units in BMI was associated with all metrics (differences ranging between -0.261 (95% CI -0.302, -0.220) to 0.228 (0.18, 0.268) for standardised TP rest to activity during the awake period and TP activity to rest during the awake period, respectively). These results reinforce the value of these rest-activity fragmentation metrics in epidemiological and clinical studies to examine their role for health. This paper expands on a set of methods that have previously demonstrated empirical value, improves the theoretical foundation for these methods, and evaluates their empirical use in a large dataset.

3-T MR neurography of lumbo-sacral plexus in hereditary transthyretin-related amyloidosis with polyneuropathy.

OBJECTIVES: Our aim was to evaluate the ability of magnetic resonance neurography (MRN) of the lumbo-sacral plexus (LSP) to distinguish patients with hereditary transthyretin-related amyloidosis with polyneuropathy (ATTRv-PN) from asymptomatic variant carriers (AVC) and healthy controls and to assess its prognostic value. METHODS: Three-Tesla MRN was performed in 25 consecutive ATTRv-PN patients, 18 AVC, and 10 controls including T2-w DIXON and DWI MR sequences. Two blinded readers independently assessed LSP root diameter and intraneural signal on the MRN images of each subject. MRN findings were compared between groups and correlated with clinical impairment scored on the Neuropathy Impairment Score (NIS) and the modified Polyneuropathy Disability score (mPND). RESULTS: The agreement between readers on MRN images was excellent (Cohen's kappa = 0.82). LSP root enlargement was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 4.38, p = 0.038). Increased LSP root intraneural signal on T2-w images was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 3.4, p = 0.016). In contrast, there were no MRN abnormalities in controls. In ATTRv-PN patients, LSP root enlargement was associated with higher mPND scores (p = 0.03) and increased intraneural signal on T2-w images was associated with significantly higher NIS and mPND scores (p = 0.004 and 0.02, respectively). CONCLUSIONS: MRN of the LSP can help differentiate ATTRv-PN patients from AVC. LSP root enlargement and increased intraneural signal are significantly associated with clinical impairment, suggesting potential implications for patient care. KEY POINTS: • ATTRv-PN patients showed abnormal LSP changes on MRN. • MRN of the LSP can help to differentiate ATTRv-PN patients from AVC and healthy controls. • LSP root enlargement and increased intraneural signal were significantly associated with clinical impairment in ATTRv-PN patients.

Protection and safety of a repeated dosage of KI for iodine thyroid blocking during pregnancy.

In case of nuclear power plant accidents resulting in the release of radioactive iodine (131I) in large amounts, a single intake of stable iodine is recommended in order to prevent131I fixation to the thyroid gland. However, in situations of prolonged exposure to131I (e.g. Fukushima-Daiichi natural and nuclear disaster), repetitive administration of iodine may be necessary to ensure adequate protection, with acceptable safety in vulnerable populations including pregnant women. Here we conducted toxicological studies on adult rats progeny following prolonged exposure to potassium iodide (KI)in utero. Pregnant Wistar rats were treated with 1 mg kg d-1KI or saline water for 2 or 4 d either between gestation days gestational day (GD) GD 9-12, or GD13-16. Plasma samples from the progeny were tested 30 d post-weaning for clinical biochemistry, thyroid hormones, and anti-thyroid antibody levels. Thyroid and brain were collected for gene expression analysis. The hormonal status was similar for the mothers in all experimental conditions. In the offspring, while thyroid-stimulating hormone and anti-thyroid peroxidase (anti-TPO) antibody levels were similar in all groups, a significant increase of FT3 and FT4 levels was observed in GD9-GD10 and in GD13-GD14 animals treated for 2 d, respectively. In addition, FT4 levels were mildly decreased in 4 d treated GD13-16 individuals. Moreover, a significant decrease in the expression level of thyroid genes involved in iodide metabolism, TPO and apical iodide transporter, was observed in GD13-GD14 animals treated for 2 d. We conclude that repeated KI administration for 2-4 d during gestation did not induce strong thyroid toxicity.

Five-year mortality of severely malnourished patients with chronic anorexia nervosa admitted to a medical unit.

OBJECTIVE: Anorexia nervosa (AN) is associated with one of the highest mortality rates of any psychiatric disorder but limited mortality data were reported for those with extremely severe malnutrition. This study aimed to estimate standardized mortality ratio (SMR), investigate predictive factors of mortality and causes of death among a sample of patients with AN admitted to a specialized clinical nutrition unit (CNU) because of extremely severe malnutrition. METHODS: Between 11/27/1997 and 01/15/2014, vital status was determined for 384 patients admitted for AN at the first time in the CNU. Sociodemographic, anamnestic, and clinical data were collected. We calculated the SMR. Univariate and multivariate Cox regression analyses were performed to identify mortality predictors. RESULTS: Crude mortality rate was 11.5%. (44 deaths) and SMR 15.9 [CI 95% (11.6-21.4)], 5.2 years post inpatient treatment. Mortality predictors at the time of hospitalization were as follows: older age, occurrence of an in-hospital suicide attempt, transfer to medical intensive care unit and the following somatic complications: frank anemia, dysnatremia, infectious and cardiac complications. Other predictors of mortality were: past or present history of discharge against medical advice, hematological comorbidities (not related to AN). A longer inpatient length of stay was a protective factor. CONCLUSION: Very severely malnourished patients with AN hospitalized in a medical unit because of extremely severe somatic issues have a medium-term mortality rate higher than the general population and even higher than patients in tertiary specialized ED units. This study highlights predictive factors of mortality that will help clinicians in recognizing and managing patients at risk of death.

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

Procedures 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.

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

BACKGROUND: 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.

Clinical Relevance of the Feces Sign in Small-Bowel Obstruction Due to Adhesions Depends on Its Location.

OBJECTIVE: The objective of our study was to evaluate if the feces sign can be used to predict successful nonoperative treatment or progression to ischemia in patients with small-bowel obstruction (SBO) due to adhesions. MATERIALS AND METHODS: For this single-center retrospective observational study involving a blinded independent review by two radiologists of 237 consecutive CT examinations of 216 patients with SBO due to adhesions (age: mean, 70.9 years; median, 74 years; interquartile range, 62-84 years), the location of the transition zone (TZ), number of TZs, and presence and location of the feces sign relative to the TZ were recorded. The reference standard for diagnosing ischemia was surgical and pathologic findings (n = 108 CT examinations) or, when treatment was nonoperative (n = 129 CT examinations), clinical outcome. Factors associated with successful nonoperative treatment and ischemia were identified by univariate and multivariate analyses. RESULTS: A feces sign was seen in 88 of 237 CT examinations (37.1%). The feces sign was at the TZ, which we refer to as the "TZ feces" sign, in 82 of 88 (93.2%) patients; between two TZs, which we refer to as the "trapped feces" sign, in 14 (15.9%) patients; and in both locations in eight (9.1%) patients. By univariate analysis, an isolated TZ feces sign was associated positively with successful nonoperative treatment (odds ratio [OR], 3.37; 95% CI, 1.71-6.66; p < 0.001) and negatively with ischemia (OR, 0.33; 95% CI, 0.13-0.85; p = 0.02). Combined TZ and trapped feces signs were associated with ischemia (OR, 24.16; 95% CI, 2.86-203.89; p = 0.003). By multivariate analysis, regardless of the location of the feces sign, the feces sign was not significantly associated with successful nonoperative treatment or progression to ischemia. CONCLUSION: The feces sign is common and helps to identify the TZ. Among the CT signs of SBO, the feces sign does not independently help to predict successful nonoperative treatment or progression to ischemia.

Altered signal intensity of active enhancing inflammatory lesions using post-contrast double inversion recovery MR sequence.

OBJECTIVES: We aimed at establishing the impact upon gadolinium administration on the conspicuity of active enhancing multiple sclerosis (MS) lesions using double inversion recovery (DIR) at 3T. METHODS: 15 consecutive patients with MS (n=8) or a clinically isolated syndrome (n=7) underwent pre and post-contrast DIR in addition to T2-weighted, FLAIR, pre and post-contrast T1-weighted sequences. First, two neuroradiologists located and marked all the enhancing MS lesions visible in consensus. Second, two other neuroradiologists, blinded to other sequences than DIR, independently assessed the SI changes from pre to post-contrast DIR images for each enhancing lesion, according to a 4-point-scale: increased SI (grade 1), absence of change (grade 2), lesion being partially (grade 3) or completely masked on post-contrast DIR images (grade 4). RESULTS: 246 MS lesions were detected including 26 enhancing on post-contrast T1-weighted images in 9 patients. The two blinded readers concluded to a decreased signal-intensity on post-contrast DIR images for all the 26 enhancing MS lesions (14 of grade 3 and 12 of grade 4). Inter-observer agreement was excellent, Kappa=0.85 (0.75 - 0.94). Using DIR post-contrast leads to altered signal-intensity of enhancing active MS lesions, ranging from partial to complete signal-loss. CONCLUSION: Our study strongly suggests the use of DIR before gadolinium administration. KEY POINTS: • DIR has gained widespread use in MS. • MRI protocols for MS patients usually contain several post-contrast sequences. • Signal-intensity of enhancing MS lesions is altered using DIR post-contrast. • Our study strongly suggests the use of DIR before gadolinium administration.

Asymptomatic Progressive Multifocal Leukoencephalopathy Associated with Natalizumab: Diagnostic Precision with MR Imaging.

PURPOSE: To determine diagnostic precision with magnetic resonance (MR) imaging of the brain, the most predictive MR imaging features, and the added value of comparison with previous data for the diagnosis of asymptomatic progressive multifocal leukoencephalopathy (PML) associated with natalizumab (NTZ). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and written informed consent was obtained. Eleven consecutive patients with multiple sclerosis (MS) who had received a definitive diagnosis of asymptomatic NTZ-associated PML (NTZ PML, 18 brain lesions) underwent 3-T MR imaging. The control group included 40 patients with MS but without PML who were treated with NTZ. Three readers independently performed blinded analysis of MR images. First, the readers were asked to detect NTZ PML lesions without comparing current images with previously obtained MR imaging data by evaluating MR images for the following features: U fiber and/or cortex involvement, lesion signal intensity and borders, and occurrence of punctate lesions. Second, they reassessed NTZ PML lesions with all the previous MR imaging data available. Diagnostic precision with MR imaging was assessed with and without comparison with previously obtained data. Logistic regression analyses were performed to identify the association of MR imaging features with NTZ PML. RESULTS: Overall interobserver agreement was good (κ = 0.76; 95% confidence interval [CI]: 0.71, 0.81). Hyperintensity on diffusion-weighted images and involvement of U fibers were the most predictive features (odds ratio, 33.7; 95% CI: 4.9, 229.7 [P < .0001] and odds ratio, 8.7; 95% CI: 1.2, 61.4 [P = .03], respectively), while punctate lesions were exclusively observed in patients with NTZ PML. Comparison with previous MR imaging data improved specificity of MR imaging for the detection of NTZ PML lesions (from 88% to 100%, P = .05). CONCLUSION: Recognition of the most predictive imaging features and comparison with previous MR imaging data may facilitate the detection of asymptomatic NTZ PML.

Comparison of 3D double inversion recovery and 2D STIR FLAIR MR sequences for the imaging of optic neuritis: pilot study.

OBJECTIVES: We compared the three-dimensional (3D) double inversion recovery (DIR) magnetic resonance imaging (MRI) sequence with the coronal two-dimensional (2D) short tau inversion recovery (STIR) fluid-attenuated inversion recovery (FLAIR) for the detection of optic nerve signal abnormality in patients with optic neuritis (ON). METHODS: The study group consisted of 31 patients with ON (44 pathological nerves) confirmed by visual-evoked potentials used as the reference. MRI examinations included 2D coronal STIR FLAIR and 3D DIR with 3-mm coronal reformats to match with STIR FLAIR. Image artefacts were graded for each portion of the optic nerves. Each set of MR images (2D STIR FLAIR, DIR reformats and multiplanar 3D DIR) was examined independently and separately for the detection of signal abnormality. RESULTS: Cisternal portion of optic nerves was better delineated with DIR (p < 0.001), while artefacts impaired analysis in four patients with STIR FLAIR. Inter-observer agreement was significantly improved (p < 0.001) on 3D DIR (κ = 0.96) compared with STIR FLAIR images (κ = 0.60). Multiplanar DIR images reached the best performance for the diagnosis of ON (95% sensitive and 94% specific). CONCLUSIONS: Our study showed a high sensitivity and specificity of 3D DIR compared with STIR FLAIR for the detection of ON. These findings suggest that the 3D DIR sequence may be more useful in patients suspected of ON. KEY POINTS: 3D DIR is increasingly used in neuroradiology. Compared with STIR FLAIR, 3D DIR improves detection of optic neuritis. Multiplanar analysis had the best diagnostic performance for optic nerve signal abnormalities. Sensitivity was 95% and specificity 94%. Findings support the use of 3D DIR instead of 2D sequences.

3D mapping of cerebrospinal fluid local volume changes in patients with hydrocephalus treated by surgery: preliminary study.

OBJECTIVE: To develop automated deformation modelling for the assessment of cerebrospinal fluid (CSF) local volume changes in patients with hydrocephalus treated by surgery. METHODS: Ventricular and subarachnoid CSF volume changes were mapped by calculating the Jacobian determinant of the deformation fields obtained after non-linear registration of pre- and postoperative images. A total of 31 consecutive patients, 15 with communicating hydrocephalus (CH) and 16 with non-communicating hydrocephalus (NCH), were investigated before and after surgery using a 3D SPACE (sampling perfection with application optimised contrast using different flip-angle evolution) sequence. Two readers assessed CSF volume changes using 3D colour-encoded maps. The Evans index and postoperative volume changes of the lateral ventricles and sylvian fissures were quantified and statistically compared. RESULTS: Before surgery, sylvian fissure and brain ventricle volume differed significantly between CH and NCH (P = 0.001 and P = 0.025, respectively). After surgery, 3D colour-encoded maps allowed for the visual recognition of the CSF volume changes in all patients. The amounts of ventricle volume loss of CH and NCH patients were not significantly different (P = 0.30), whereas readjustment of the sylvian fissure volume was conflicting in CH and NCH patients (P < 0.001). The Evans index correlated with ventricle volume in NCH patients. CONCLUSION: 3D mapping of CSF volume changes is feasible providing a quantitative follow-up of patients with hydrocephalus. KEY POINTS: • MRI can provide helpful information about cerebrospinal fluid volumes. • 3D CSF mapping allows quantitative follow-up in communicating and non-communicating hydrocephalus. • Following intervention, fissures and cisterns readjust in both forms of hydrocephalus. • These findings support the hypothesis of suprasylvian block in communicating hydrocephalus. • 3D mapping may improve shunt dysfunction detection and guide valve pressure settings.

Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment.

Bone sarcoma as a second malignancy is rare but highly fatal. The present knowledge about radiation-absorbed organ dose-response is insufficient to predict the risks induced by radiation therapy techniques. The objective of the present study was to assess the treatment-induced risk for bone sarcoma following a childhood cancer and particularly the related risk of radiotherapy. Therefore, a retrospective cohort of 4,171 survivors of a solid childhood cancer treated between 1942 and 1986 in France and Britain has been followed prospectively. We collected detailed information on treatments received during childhood cancer. Additionally, an innovative methodology has been developed to evaluate the dose-response relationship between bone sarcoma and radiation dose throughout this cohort. The median follow-up was 26 years, and 39 patients had developed bone sarcoma. It was found that the overall incidence was 45-fold higher [standardized incidence ratio 44.8, 95 % confidence interval (CI) 31.0-59.8] than expected from the general population, and the absolute excess risk was 35.1 per 100,000 person-years (95 % CI 24.0-47.1). The risk of bone sarcoma increased slowly up to a cumulative radiation organ absorbed dose of 15 Gy [hazard ratio (HR) = 8.2, 95 % CI 1.6-42.9] and then strongly increased for higher radiation doses (HR for 30 Gy or more 117.9, 95 % CI 36.5-380.6), compared with patients not treated with radiotherapy. A linear model with an excess relative risk per Gy of 1.77 (95 % CI 0.6213-5.935) provided a close fit to the data. These findings have important therapeutic implications: Lowering the radiation dose to the bones should reduce the incidence of secondary bone sarcomas. Other therapeutic solutions should be preferred to radiotherapy in bone sarcoma-sensitive areas.

[Micro-RNAs as biomarkers of radiation-induced injuries]. / Les micro-ARN comme biomarqueurs des lésions radio-induites.

In the event of a radiological or nuclear emergency following an accident or malicious act, potentially involving many victims, medical care requires the identification and diagnosis of individuals exposed to high doses of ionizing radiation as quickly as possible. While an initial screening can be carried out directly in the field, additional biological in-lab analyses are required to refine the diagnosis and optimize the therapeutic management of victims. The fast and simultaneous management of many patients is limited by currently established techniques. To overcome these constraints, the use of new biomarkers to predict the risk and severity of radiation-induced injuries is under investigation. This synthesis summarizes the latest scientific advances demonstrating the potential of microRNAs as biomarkers of radiationinduced injuries, highlighting their relevance for human health care and radioprotection.

Title: Les micro-ARN comme biomarqueurs des lésions radio-induites. Abstract: En cas d'urgence radiologique ou nucléaire résultant d'un accident ou d'un acte de malveillance, la prise en charge médicale requiert l'identification et le diagnostic des individus exposés à de fortes doses de rayonnements ionisants le plus rapidement possible. Bien qu'un triage préliminaire puisse être effectué directement sur le terrain, une analyse complémentaire en laboratoire est nécessaire pour affiner le diagnostic. Les techniques actuellement utilisées limitent la prise en charge rapide et simultanée de nombreux patients. Afin de pallier ces contraintes, l'utilisation de nouveaux biomarqueurs pour prédire le risque et la gravité des lésions radio-induites est à l'étude. Dans cette revue, nous abordons le potentiel des micro-ARN comme biomarqueurs pour le pronostic des lésions radio-induites et leur pertinence pour une utilisation en radioprotection chez l'homme.

MR compatible detectors assessment for a 0.35 T MR-linac commissioning.

PURPOSE: To assess a large panel of MR compatible detectors on the full range of measurements required for a 0.35 T MR-linac commissioning by using a specific statistical method represented as a continuum of comparison with the Monte Carlo (MC) TPS calculations. This study also describes the commissioning tests and the secondary MC dose calculation validation. MATERIAL AND METHODS: Plans were created on the Viewray TPS to generate MC reference data. Absolute dose points, PDD, profiles and output factors were extracted and compared to measurements performed with ten different detectors: PTW 31010, 31021, 31022, Markus 34045 and Exradin A28 MR ionization chambers, SN Edge shielded diode, PTW 60019 microdiamond, PTW 60023 unshielded diode, EBT3 radiochromic films and LiF µcubes. Three commissioning steps consisted in comparison between calculated and measured dose: the beam model validation, the output calibration verification in four different phantoms and the commissioning tests recommended by the IAEA-TECDOC-1583. MAIN RESULTS: The symmetry for the high resolution detectors was higher than the TPS data of about 1%. The angular responses of the PTW 60023 and the SN Edge were - 6.6 and - 11.9% compared to the PTW 31010 at 60°. The X/Y-left and the Y-right penumbras measured by the high resolution detectors were in good agreement with the TPS values except for the PTW 60023 for large field sizes. For the 0.84 × 0.83 cm2 field size, the mean deviation to the TPS of the uncorrected OF was - 1.7 ± 1.6% against - 4.0 ± 0.6% for the corrected OF whereas we found - 4.8 ± 0.8% for passive dosimeters. The mean absolute dose deviations to the TPS in different phantoms were 0 ± 0.4%, - 1.2 ± 0.6% and 0.5 ± 1.1% for the PTW 31010, PTW 31021 and Exradin A28 MR respectively. CONCLUSIONS: The magnetic field effects on the measurements are considerably reduced at low magnetic field. The PTW 31010 ionization chamber can be used with confidence in different phantoms for commissioning and QA tests requiring absolute dose verifications. For relative measurements, the PTW 60019 presented the best agreement for the full range of field size. For the profile assessment, shielded diodes had a behaviour similar to the PTW 60019 and 60023 while the ionization chambers were the most suitable detectors for the symmetry. The output correction factors published by the IAEA TRS 483 seem to be applicable at low magnetic field pending the publication of new MR specific values.

Evidence of Alveolar Macrophage Metabolic Shift Following Stereotactic Body Radiation Therapy -Induced Lung Fibrosis in Mice.

PURPOSE: Radiation-induced pneumopathy is the main dose-limiting factor in cases of chest radiation therapy. Macrophage infiltration is frequently observed in irradiated lung tissues and may participate in lung damage development. Radiation-induced lung fibrosis can be reproduced in rodent models using whole thorax irradiation but suffers from limits concerning the role played by unexposed lung volumes in damage development. METHODS AND MATERIALS: Here, we used an accurate stereotactic body radiation therapy preclinical model irradiating 4% of the mouse lung. Tissue damage development and macrophage populations were followed by histology, flow cytometry, and single-cell RNA sequencing. Wild-type and CCR2 KO mice, in which monocyte recruitment is abrogated, were exposed to single doses of radiation, inducing progressive (60 Gy) or rapid (80 Gy) lung fibrosis. RESULTS: Numerous clusters of macrophages were observed around the injured area, during progressive as well as rapid fibrosis. The results indicate that probably CCR2-independent recruitment and/or in situ proliferation may be responsible for macrophage invasion. Alveolar macrophages experience a metabolic shift from fatty acid metabolism to cholesterol biosynthesis, directing them through a possible profibrotic phenotype. Depicted data revealed that the origin and phenotype of macrophages present in the injured area may differ from what has been previously described in preclinical models exposing large lung volumes, representing a potentially interesting trail in the deciphering of radiation-induced lung damage processes. CONCLUSIONS: Our study brings new possible clues to the understanding of macrophage implications in radiation-induced lung damage, representing an interesting area for exploration in future studies.

Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade.

The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5-2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

microRNA blood signature for localized radiation injury.

A radiological accident, whether from industrial, medical, or malicious origin, may result in localized exposure to high doses of ionizing radiations, leading to the development of local radiation injury (LRI), that may evolve toward deep ulceration and necrosis of the skin and underlying tissues. Early diagnosis is therefore crucial to facilitate identification and management of LRI victims. Circulating microRNAs (miRNA) have been studied as potential diagnostic biomarkers of several diseases including hematological defects following whole-body irradiation (WBI). This study aims to identify a blood miRNA signature associated with LRI in a preclinical C57BL/6J mouse model of hindlimb irradiation using different 10-MV X-ray doses that lead to injuries of different severities. To this end, we first performed broad-spectrum plasma miRNA profiling, followed by a targeted validation step, on two independent animal cohorts. Using a multivariate sparse partial least square discriminant analysis, we identified a panel of eight circulating miRNAs able to segregate mice according to LRI severity. Interestingly, these miRNAs were previously associated with WBI (miR-150-5p, miR-342-3p, miR-146a-5p), inflammation (miR-18a-5p, miR-148b-3p, miR-532-5p) and skin diseases (miR-139-5p, miR-195-5p). Our results suggest the use of circulating miRNAs as suitable molecular biomarkers for LRI prognosis and diagnosis.

Inflammatory cells dynamics control neovascularization and tissue healing after localized radiation induced injury in mice.

Local overexposure to ionizing radiation leads to chronic inflammation, vascular damage and cachexia. Here we investigate the kinetics of inflammatory cells from day (D)1 to D180 after mouse hindlimb irradiation and analyze the role of monocyte (Mo) subsets in tissue revascularization. At D1, we find that Mo and T cells are mobilized from spleen and bone marrow to the blood. New vessel formation during early phase, as demonstrated by ~1.4- and 2-fold increased angiographic score and capillary density, respectively, correlates with an increase of circulating T cells, and Mohi and type 1-like macrophages in irradiated muscle. At D90 vascular rarefaction and cachexia are observed, associated with decreased numbers of circulating Molo and Type 2-like macrophages in irradiated tissue. Moreover, CCR2- and CX3CR1-deficency negatively influences neovascularization. However adoptive transfer of Mohi enhances vessel growth. Our data demonstrate the radiation-induced dynamic inflammatory waves and the major role of inflammatory cells in neovascularization.

Biodose Tools: an R shiny application for biological dosimetry.

INTRODUCTION: In the event of a radiological accident or incident, the aim of biological dosimetry is to convert the yield of a specific biomarker of exposure to ionizing radiation into an absorbed dose. Since the 1980s, various tools have been used to deal with the statistical procedures needed for biological dosimetry, and in general those who made several calculations for different biomarkers were based on closed source software. Here we present a new open source program, Biodose Tools, that has been developed under the umbrella of RENEB (Running the European Network of Biological and retrospective Physical dosimetry). MATERIALS AND METHODS: The application has been developed using the R programming language and the shiny package as a framework to create a user-friendly online solution. Since no unique method exists for the different mathematical processes, several meetings and periodic correspondence were held in order to reach a consensus on the solutions to be implemented. RESULTS: The current version 3.6.1 supports dose-effect fitting for dicentric and translocation assay. For dose estimation Biodose Tools implements those methods indicated in international guidelines and a specific method to assess heterogeneous exposures. The app can include information on the irradiation conditions to generate the calibration curve. Also, in the dose estimate, information about the accident can be included as well as the explanation of the results obtained. Because the app allows generating a report in various formats, it allows traceability of each biological dosimetry study carried out. The app has been used globally in different exercises and training, which has made it possible to find errors and improve the app itself. There are some features that still need consensus, such as curve fitting and dose estimation using micronucleus analysis. It is also planned to include a package dedicated to interlaboratory comparisons and the incorporation of Bayesian methods for dose estimation. CONCLUSION: Biodose Tools provides an open-source solution for biological dosimetry laboratories. The consensus reached helps to harmonize the way in which uncertainties are calculated. In addition, because each laboratory can download and customize the app's source code, it offers a platform to integrate new features.

Measures of fragmentation of rest activity patterns: mathematical properties and interpretability based on accelerometer real life data.

Accelerometers, devices that measure body movements, have become valuable tools for studying the fragmentation of rest-activity patterns, a core circadian rhythm dimension, using metrics such as inter-daily stability (IS), intradaily variability (IV), transition probability (TP), and self-similarity parameter (named α). However, their use remains mainly empirical. Therefore, we investigated the mathematical properties and interpretability of rest-activity fragmentation metrics by providing mathematical proofs for the ranges of IS and IV, proposing maximum likelihood and Bayesian estimators for TP, introducing the activity balance index metric, an adaptation of α, and describing distributions of these metrics in real-life setting. Analysis of accelerometer data from 2,859 individuals (age=60-83 years, 21.1% women) from the Whitehall II cohort (UK) shows modest correlations between the metrics, except for ABI and α. Sociodemographic (age, sex, education, employment status) and clinical (body mass index (BMI), and number of morbidities) factors were associated with these metrics, with differences observed according to metrics. For example, a difference of 5 units in BMI was associated with all metrics (differences ranging between -0.261 (95% CI -0.302, -0.220) to 0.228 (0.18, 0.268) for standardised TP rest to activity during the awake period and TP activity to rest during the awake period, respectively). These results reinforce the value of these rest-activity fragmentation metrics in epidemiological and clinical studies to examine their role for health. This paper expands on a set of methods that have previously demonstrated empirical value, improves the theoretical foundation for these methods, and evaluates their empirical worth in a large dataset.