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Introduction Older adults with cancer suffer from the combined effects of ageing, cancer disease and treatment side effects. The main treatment for patients with haematological malignancies is chemotherapy, associated with significant toxicities. Chemotherapy can alter patients’ physical function and quality of life which are often already diminished in older patients due to ageing and comorbidities. It therefore seems essential to develop and to evaluate interventions capable of preventing physical and psychosocial decline and its consequences. Promoting physical activity is a promising approach to improve physical function and quality of life in older adults with cancer, but there are limited data on the feasibility of such interventions among older patients with haematological malignancies, concomitant to chemotherapy.Methods and analysis OCAPI (OnCogeriatric and Individualized Physical Activity) is a single-arm, interdisciplinary, prospective, interventional, feasibility study. It is intended to include 40 patients (20 patients with acute myeloid leukaemia and 20 patients with non-Hodgkin’s lymphoma) over 65 years in an individualised 6-month physical activity programme. The programme consists of individually supervised exercise sessions with an increasing volume of physical activity either at home and/or in a laminar airflow room (depending on the disease and treatment regimen) followed by unsupervised sessions and phone follow-ups. Patients will receive an activity tracker during the 6 months of the programme. Evaluations will take place at inclusion and at 3, 6 and 12 months to assess the feasibility of the programme and to explore potential changes in physical, psychosocial and clinical outcomes. The results will generate preliminary data to implement a larger randomised controlled trial.Ethics and dissemination The study protocol was approved by the French ethics committee (Comité de protection des personnes Est I, N°ID-RCB 2019-A01231-56, 12 July 2019). All participants will have to sign and date an informed consent form. The findings will be disseminated in peer-reviewed journals and academic conferences.Trial registration number NCT04052126.

Background/Objectives: Intensive training of the more affected upper extremity (UE) has been shown to be effective for children with unilateral spastic cerebral palsy (USCP). Two types of UE training have been particularly successful: Constraint-Induced Movement Therapy (CIMT) and Bimanual training. Reorganization of the corticospinal tract (CST) early during development often occurs in USCP. Prior studies have suggested that children with an ipsilateral CST controlling the affected UE may improve less following CIMT than children with a contralateral CST. We tested the hypothesis that improvements in UE function after intensive training depend on CST laterality.Study Participants and Setting: Eighty-two children with USCP, age 5 years 10 months to 17 years, University laboratory setting.Materials/Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to determine each child's CST connectivity pattern. Children were stratified by age, sex, baseline hand function and CST connectivity pattern, and randomized to receive either CIMT or Bimanual training, each of which were provided in a day-camp setting (90 h). Hand function was tested before, immediately and 6 months after the intervention with the Jebsen-Taylor Test of Hand Function, the Assisting Hand Assessment, the Box and Block Test, and ABILHAND-Kids. The Canadian Occupational Performance Measure was used to track goal achievement and the Pediatric Evaluation of Disability Inventory was used to assess functioning in daily living activities at home.Results: In contrast to our hypothesis, participants had statistically similar improvements for both CIMT and Bimanual training for all measures independent of their CST connectivity pattern (contralateral, ipsilateral, or bilateral) (p < 0.05 in all cases).Conclusions/Significance: The efficacy of CIMT and Bimanual training is independent of CST connectivity pattern. Children with an ipsilateral CST, previously thought to be maladaptive, have the capacity to improve as well as children with a contralateral or bilateral CST following intensive CIMT or Bimanual training.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02918890.

Human herpesvirus 6A and 6B are two closely related viruses that infect almost all humans. In contrast to most herpesviruses, HHV-6A/B can integrate their genomes into the telomeres during the infection process. Both viruses can also integrate in germ cells and subsequently be inherited in children. How HHV-6A/B integrate into host telomeres and the consequences of this remain a subject of active research. Here, we developed a method to measure telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. This method was validated using a panel of HeLa cells having short or long telomeres. These cell lines were infected with HHV-6A, revealing that the virus could efficiently integrate into telomeres independent of their length. Furthermore, we assessed the telomere lengths after HHV-6A integration and found that the virus-containing telomeres display a variety of lengths, suggesting that either telomere length is restored after integration or telomeres are not shortened by integration. Our results highlight new aspects of HHV-6A/B biology and the role of telomere length on virus integration.

Human herpesvirus -6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes. Viral integration can occur in several cell types, including germinal cells, resulting in individuals that harbor the viral genome in every cell of their body. The integrated genome is efficiently silenced but can sporadically reactivate resulting in various clinical symptoms. To date, the integration mechanism and the subsequent silencing of HHV-6A/B genes remains poorly understood. Here we investigate the genome-wide chromatin contacts of the integrated HHV-6A in latently-infected cells. We show that HHV-6A becomes transcriptionally silent upon infection of these cells over the course of seven days. In addition, we established an HHV-6–specific 4C-seq approach, revealing that the HHV-6A 3D interactome is associated with quiescent chromatin states in cells harboring integrated virus. Furthermore, we observed that the majority of virus chromatin interactions occur toward the distal ends of specific human chromosomes. Exploiting this finding, we established a 4C-seq method that accurately detects the chromosomal integration sites. We further implement long-read minION sequencing in the 4C-seq assay and developed a method to identify HHV-6A/B integration sites in clinical samples.

Background: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking.Methods: We developed and evaluated a rapid language test for PPA (“PARIS”) assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients (N = 36), typical amnesic Alzheimer's disease (AD) patients (N = 24) and healthy controls (N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia (“LAST”, “ART”).Results: The application duration of the “PARIS” was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the “PARIS” reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the “LAST” and “ART,” the “PARIS” also had the highest sensitivity for detecting language decline.Conclusions: The “PARIS” is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing.

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

The recent claim by an atypical project owner of a strong commitment to environmental issues appears to exhibit an alternative response to the traditional methods applied to social housing. In this article, we will study the case of Foncière Chênelet, a social landlord which describes itself as a societal project developer that pursues a holistic approach to the issues of sustainability in the sector. We will examine how this positioning takes shape in the operational field, and explore its impact on the architectural, urban and landscape forms, as well as on building-related professions and ways of living. We will also focus on the housing model developed by Foncière Chênelet, and in particular on one specific project that illustrates this approach.

Since the beginning of the year, the world's attention has rightly been focused on the spread of the Coronavirus Disease 2019 (COVID-19) pandemic and the implementation of drastic mitigation strategies to limit disease transmission. However, public health information campaigns tailored to children are very rare. Now more than ever, at a time when some governments are taking populations out of lockdown and youth are returning to schools, children around the world need to fully grasp the modes of transmission of the disease, the health risks, the scientific notions of the immune system, the value of barrier measures, and the progress of scientific research. In the context of the COVID-19 pandemic, comics can be very useful for communicating quickly and effectively abstract and important information to children who might be under the influence of a large amount of sometimes contradictory information. Conveying precise, reliable, and accessible information to children is key in a world overwhelmingly impacted by the outbreak. This should be the role and the responsibility of world health official leaders and governments in compliance with the United Nations Convention on the Rights of the Child. In partnership with mainstream medias, consortia of scientists, communication experts, and education specialists, it is urgent that world leaders engage children in this worldwide public health fight.

Partial hepatectomy (PH) is the main treatment for early-stage hepatocellular carcinoma (HCC). Yet, a significant number of patients undergo recursion of the disease that could be linked to the fate of innate immune cells during the liver regeneration process. In this study, using a murine model, we investigated the impact of PH on HCC development by bioluminescence imaging and flow cytometry. While non-resected mice were able to control and reject orthotopic implanted Hepa1-6 hepatocarcinoma cells, resected liver underwent an increased tumoral proliferation. This phenomenon was associated with a PH-induced reduction in the number of liver-resident macrophages, i.e., Kupffer cells (KC). Using a conditional ablation model, KC were proved to participate in Hepa1-6 rejection. We demonstrated that in the absence of Hepa1-6, PH-induced KC number reduction was dependent on tumor necrosis factor-alpha (TNF-α), receptor-interacting protein kinase (RIPK) 3, and caspase-8 activation, whereas interleukin (IL)-6 acted as a KC pro-survival signal. In mice with previous Hepa1-6 encounter, the KC reduction switched toward a TNF-α-RIPK3–caspase-1 activation. Moreover, KC disappearance associated with caspase-1 activity induced the recruitment of monocyte-derived cells that are beneficial for tumor growth, while caspase-8-dependent reduction did not. In conclusion, our study highlights the importance of the TNF-α-dependent death pathway induced in liver macrophages following partial hepatectomy in regulating the antitumoral immune responses.

A key question in the field of animal cognition is how animals comprehend their physical world. Object permanence is one of the fundamental features of physical cognition. It is the ability to reason about hidden objects and to mentally reconstruct their invisible displacements. This cognitive skill has been studied in a wide range of species but never directly in the horse (Equus caballus). In this study, we therefore assessed the understanding of visible and invisible displacements in adult Welsh mares in two complementary experiments, using different horses. In experiment 1, visible displacement was investigated using two tasks adapted from the Uzgiris and Hunt scale 1. Invisible displacement was assessed using a transposition task, in which food was first hidden in one of two containers and the location of the containers was then switched. In experiment 2, we further investigated horses’ understanding of visible and invisible displacements using an easier procedure designed to avoid potentially confounding factors. In both experiments, horses successfully completed the tasks involving visible displacement with two or three possible hiding places. However, in both experiments, horses failed the transposition tasks, suggesting that they may not be able to track the displacement of an object that is not directly perceived (i.e., invisible displacement). These results bring new insights into object permanence in horses and how they represent their physical world.

BackgroundThe World Health Organization (WHO) proposed guidelines on dengue clinical classification in 1997 and more recently in 2009 for the clinical management of patients. The WHO 1997 classification defines three categories of dengue infection according to severity: dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Alternative WHO 2009 guidelines provide a cross-sectional classification aiming to discriminate dengue fever from dengue with warning signs (DWWS) and severe dengue (SD). The primary objective of this study was to perform a comparison of two dengue classifications. The secondary objective was to describe the changes of hematological and biochemical parameters occurring in patients presenting with different degrees of severity during the course of the disease, since progression to more severe clinical forms is unpredictable.Methodology/principal findingsWe performed a prospective, monocentric, cross-sectional study of hospitalized children in Cambodia, aged from 2 to 15 years old with severe and non-severe dengue. We enrolled 243 patients with acute dengue-like illness: 71.2% were dengue infections confirmed using quantitative reverse transcription PCR or NS1 antigen capture ELISA, of which 87.2% and 9.0% of DF cases were respectively classified DWWS and SD, and 35.9% of DHF were designated SD using an adapted WHO 2009 classification for SD case definition. Systematic use of ultrasound at patient admission was crucial for detecting plasma leakage. No difference was observed in the concentration of secreted NS1 protein between different dengue severity groups. Lipid profiles were different between DWWS and SD at admission, characterized by a decrease in total cholesterol, HDL cholesterol, and LDL cholesterol, in SD.Conclusions/significanceOur results show discrepancies between the two classifications, including misclassification of severe dengue cases as mild cases by the WHO 1997 classification. Using an adapted WHO 2009 classification, SD more precisely defines the group of patients requiring careful clinical care at a given time during hospitalization.

Human herpesvirus 6B (HHV-6B) is a betaherpesvirus capable of integrating its genome into the telomeres of host chromosomes. Until now, the cellular and/or viral proteins facilitating HHV-6B integration have remained elusive. Here we show that a cellular protein, the promyelocytic leukemia protein (PML) that forms nuclear bodies (PML-NBs), associates with the HHV-6B immediate early 1 (IE1) protein at telomeres. We report enhanced levels of SUMOylated IE1 in the presence of PML and have identified a putative SUMO Interacting Motif (SIM) within IE1, essential for its nuclear distribution, overall SUMOylation and association with PML to nuclear bodies. Furthermore, using PML knockout cell lines we made the original observation that PML is required for efficient HHV-6B integration into host chromosomes. Taken together, we could demonstrate that PML-NBs are important for IE1 multiSUMOylation and that PML plays an important role in HHV-6B integration into chromosomes, a strategy developed by this virus to maintain its genome in its host over long periods of time.

Grapevine trunk diseases (GTDs) are one of the most economically important diseases of grapevines, causing yield reductions and limiting vineyard lifespans. Fungal pathogens responsible for GTDs primarily infect grapevines through pruning wounds. The lack of systemic fungicides to stop the advance of fungi in vine vascular systems makes the use of pruning wound protection with either synthetic chemicals or biological control agents (BCAs) the main available GTD control strategy. Demands for sustainable grape production and increasing limitations on pesticide usage have raised interest in potential use of BCAs as pruning wound protectants against GTDs. The objectives of this study were to characterize 16 Trichoderma isolates from southern Italy using molecular methods, and to evaluate their potential activity as BCAs in vitro against the GTD canker-causing fungi Diplodia seriata, Eutypa lata and Neofusicoccum parvum. Molecular studies along with phylogenetic analyses identified eight species, including Trichoderma atroviride, T. guizhouense, T. harzianum, T. koningiopsis, T. longibrachiatum, T. paratroviride, T. paraviridescens, T. spirale, and one unidentified Trichoderma sp. All these species had optimum mycelium growth between 25 and 35°C. In vitro dual culture experiments assessed antagonistic capabilities of all the Trichoderma isolates against D. seriata, E. lata and N. parvum, and showed that the isolates inhibited mycelial growth of the pathogens by up to 70%. The most inhibitory isolates were tested in planta for capability to protect pruning wounds against D. seriata and N. parvum in a detached cane assay. All the selected Trichoderma isolates gave >80% control of D. seriata and 60% control of N. parvum, and protected pruning wounds for up to 21 d after treatment.

Obesity is associated with altered N-acylethanolamine levels (NAE). Here the authors show that deletion of the gene encoding N-acylphosphatidylethanolamine phospholipase D, a key enzyme for NAE synthesis, in intestinal cells of mice leads to the development of obesity and hepatic steatosis via a mechanism involving the gut-brain axis.

Human herpesviruses 6A and 6B (HHV-6A/B) are unique among human herpesviruses in their ability to integrate their genome into host chromosomes. Viral integration occurs at the ends of chromosomes within the host telomeres. The ends of the HHV-6A/B genomes contain telomeric repeats that facilitate the integration process. Here, we report that productive infections are associated with a massive increase in telomeric sequences of viral origin. The majority of the viral telomeric signals can be detected within viral replication compartments (VRC) that contain the viral DNA processivity factor p41 and the viral immediate-early 2 (IE2) protein. Components of the shelterin protein complex present at telomeres, including TRF1 and TRF2 are also recruited to VRC during infection. Biochemical, immunofluorescence coupled with in situ hybridization and chromatin immunoprecipitation demonstrated the binding of TRF2 to the HHV-6A/B telomeric repeats. In addition, approximately 60% of the viral IE2 protein localize at cellular telomeres during infection. Transient knockdown of TRF2 resulted in greatly reduced (13%) localization of IE2 at cellular telomeres (p

Con el propósito de desarrollar políticas públicas basadas en evidencia, este artículo se ocupa de comparar las maneras en que se evaluaba la política educativa antes y después de la reforma educativa de 2013. Nos concentramos en tres temas cruciales en la evaluación: logro en aprendizajes, evaluación a docentes y programas federales de educación. El análisis comparado rastrea los cambios clave que experimentó la evaluación en cuatro rubros: la toma de decisiones, los actores, los objetos específicos de la evaluación y los métodos. Concluimos que la información que generó el Sistema Nacional de Evaluación Educativa (SNEE) no contribuyó a decisiones que promovieran la calidad de la educación y revelamos la influencia persistente de la Secretaría de Educación Pública (SEP), así como la creciente participación de los gobiernos estatales en el SNEE.

BACKGROUND:A recent study in French Guiana suggested that populations living in precarious neighborhoods were more at risk for Chikungunya CHIKV than those living in more privileged areas. The objective of the present study was to test the hypothesis that Zika virus (ZIKV) infection was more frequent in precarious pregnant women than in non-precarious pregnant women, as reflected by their health insurance status. METHODS:A multicentric cross-sectional study was conducted in Cayenne hospital including ZIKV pregnant women with serological or molecular proof of ZIKV during their pregnancy between January and December 2016. Health insurance information was recorded at delivery, which allowed separating women in: undocumented foreigners, precarious but with residence permit, and non-precarious. RESULTS:A total of 6654 women were included. Among them 1509 (22,7%) had confirmed ZIKV infection. Most women were precarious (2275/3439) but the proportion of precarious women was significantly greater in ZIKV-confirmed 728/906 (80.4%) than the ZIKV-negatives 1747/2533 (69.0%), p

Psoriasis is an inflammatory skin disease mainly associated with an epidermal disorder. However, the involvement of the dermal extracellular matrix (ECM) composition in psoriasis is still poorly understood. This study aimed to investigate the expression of ECM components in psoriatic skin substitutes (PS−) compared with healthy skin substitutes (HS−), as well as the effect of an n-3 polyunsaturated fatty acid, namely α-linolenic acid (ALA), on the psoriatic dermal compartment (PSALA+). Liquid chromatography tandem mass spectrometry analyses revealed that the lipidome of PS− contained higher amounts of n-6 derived prostaglandins (PGE2) and lipoxygenase products (9-HODE and 15-HETE). ALA supplementation increased the levels of PGE3, 13-HOTrE, 15-HEPE, and 18-HEPE, and decreased the levels of PGE2, 15-HETE, and 9-HOPE compared with PS−, indicating that ALA modulates the dermal lipidome of psoriatic skin substitutes. Gene expression profiling showed that several genes encoding for different ECM proteins were overexpressed in PS− compared with HS−, namely COL1A1 (4.2-fold), COL1A2 (3-fold), COL3A1 (4.4-fold), COL4A1 (2.3-fold), COL4A2 (6.3-fold), COL5A1 (3.3-fold), COL5A2 (5.2-fold), and COL5A3 (4.6-fold). Moreover, the expression of collagen IV (Col IV), collagen VII (Col VII), and laminin was found to be increased in PS− compared with HS−, and to be restored with ALA (PSALA+) according to immunofluorescence staining, while only the collagen I to collagen III ratio was altered according to dot blot analyses. Linear regression analysis revealed several positive correlations, including Col III with 14-HDHA levels, fibronectin with 12-HETE and 15-HETE levels, the dermo-epidermal junction Col IV with PGF2α, 9-HODE, and 13-HODE levels, and laminin with levels of PGF2α, 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE. These results suggest that the ECM plays an underestimated role in the pathogenesis of psoriasis and that ALA supplementation can regulate the ECM composition.

Background: Stroke is a high burden illness and the second leading cause of worldwide disability with generally poor recovery rates. Robust benefits of hippotherapy, a novel neurorehabilitation approach, in functional recovery following various severe neurological disabling conditions has been shown. In the present study, we will analyze the effect of a hippotherapy program on the outcome of post-stroke patients in the first year post-stroke. Method: A randomized controlled clinical trial on the effectiveness of hippotherapy (4 weeks/18 weeks hippotherapy/conventional neurorehabilitation) versus conventional neurorehabilitation alone (22 weeks) will be conducted over 48 weeks. In the treated group, one-hour daily hippotherapy sessions will be exclusively conducted during the hippotherapy’s cycles, alternated with periods of conventional neurorehabilitation. A test battery will measure both the functional and psychological outcomes. The primary endpoint will be the patient’s functional independence. The secondary endpoints will measure the sensorimotor function, autonomy, and quality of life, as well as the caregivers’ quality of life. Results and conclusion: Individual brain connectome, life history and personality construct influence the brain’s functional connectivity and are central to developing optimal tailored neurorehabilitation strategies. According to our current practice, hippotherapy allows the enhancement of substantial neuroplastic changes in the injured brain with significant neurological recovery. The protocol aims to confirm those issues. Trial registration in ClinicalTrials.gov NCT04759326 accessed on 19 February 2021.

Botryosphaeria dieback (BD) is a grapevine trunk disease (GTD) causing significant yield losses and limiting the lifespan of vineyards worldwide. Fungi responsible for BD infect grapevines primarily through pruning wounds, and thus pruning wound protection, using either synthetic chemicals or biological control agents (BCAs), is the main available management strategy. However, no products to control GTDs are currently registered in Canada. With a focus on more sustainable grapevine production, there is an increasing demand for alternatives to chemical products to manage GTDs. Accordingly, the objective of this study was to identify Trichoderma species from grapevines in British Columbia (BC) and evaluate their potential biocontrol activity against BD fungi Diplodia seriata and Neofusicoccum parvum. Phylogenetic analyses identified seven species, including T. asperelloides, T. atroviride, T. harzianum, T. koningii, T. tomentosum, and two novel species, T. canadense and T. viticola. In vitro dual culture antagonistic assays showed several isolates to inhibit fungal pathogen mycelial growth by up to 75%. In planta detached cane assays under controlled greenhouse conditions identified T. asperelloides, T. atroviride and T. canadense isolates from BC as providing 70% to 100% pruning wound protection against BD fungi for up to 21 days after treatment. In addition, these isolates were shown to provide similar or better control when compared against commercial chemical and biocontrol products. This study demonstrates the potential that locally sourced Trichoderma species can have for pruning wound protection against BD fungi, and further supports the evaluation of these isolates under natural field conditions.