Jainegelund9403

BACKGROUND Funding for human papillomavirus (HPV) vaccination in Japan began in 2010 for girls aged 12-16 years, with three-dose coverage initially reaching more than 70%. On June 14, 2013, 2 months after formal inclusion in Japan's national immunisation programme, proactive recommendations for the HPV vaccine were suspended following reports of adverse events since found to be unrelated to vaccination, but which were extensively covered in the media. Vaccine coverage subsequently dropped to less than 1% and has remained this low to date. We aimed to quantify the impact of this vaccine hesitancy crisis, and the potential health gains if coverage can be restored. METHODS In this modelling study, we used the Policy1-Cervix modelling platform. We adapted the model for Japan with use of data on HPV prevalence, screening practices and coverage, and cervical cancer incidence and mortality. We evaluated the expected number of cervical cancer cases and deaths over the lifetime of cohorts born from 1994 to 2007 in theues, 9300-10 800 preventable deaths due to cervical cancer will occur in the next 50 years (2020-69). INTERPRETATION The HPV vaccine crisis to date is estimated to result in around 5000 deaths from cervical cancer in Japan. Many of these deaths could still be prevented if vaccination coverage with extended catch-up can be rapidly restored. FUNDING National Health and Medical Research Council Australia Centre of Research Excellence in Cervical Cancer Control, Japan Society for the Promotion of Science. BACKGROUND In May, 2018, the Director-General of WHO issued a global call to eliminate cervical cancer as a public health problem, which will involve ambitious screening and vaccination coverage targets. We aimed to assess the potential for, and timing of, cervical cancer elimination in the USA and whether this could be expedited by adopting ambitious coverage targets, using two cervical cancer simulation models. METHODS In this modelling study, we used two independently-developed cervical cancer microsimulation models-Harvard and Policy1-Cervix-to estimate changes in the incidence of human papillomavirus (HPV)-induced cervical cancer over time in the USA, including herd effects from vaccination. We compared nine alternative scenarios for prophylactic HPV vaccination and cervical screening scale-up with a status quo scenario that involved no additional interventions in the context of a threshold for cervical cancer elimination of four or fewer cases per 100 000 women-years. We also estimated the number of ceras a public health problem in the next two to three decades. Time to elimination could be expedited by 10-13 years by achieving higher screening coverage. Targeting of underscreened and under-vaccinated women remains key to achieving cervical cancer elimination for all women. FUNDING US National Cancer Institute. The genotype-phenotype relationship and the physiopathology of Down Syndrome (DS) have been explored in the last 20 years with more and more relevant mouse models. From the early age of transgenesis to the new CRISPR/CAS9-derived chromosomal engineering and the transchromosomic technologies, mouse models have been key to identify homologous genes or entire regions homologous to the human chromosome 21 that are necessary or sufficient to induce DS features, to investigate the complexity of the genetic interactions that are involved in DS and to explore therapeutic strategies. In this review we report the new developments made, how genomic data and new genetic tools have deeply changed our way of making models, extended our panel of animal models, and increased our understanding of the neurobiology of the disease. But even if we have made an incredible progress which promises to make DS a curable condition, we are facing new research challenges to nurture our knowledge of DS pathophysiology as a neurodevelopmental disorder with many comorbidities during ageing. © 2020 Elsevier B.V. All rights reserved.Down Syndrome (DS) is a complex chromosomal disorder, with neurological issues, featuring among the symptoms. Primary neuronal cells and tissues are extremely useful, but limited both in supply and experimental manipulability. To better understand the cellular, molecular and pathological mechanisms involved in DS neurodevelopment and neurodegeneration, a range of different cellular models have been developed over the years including human mouse hybrid cells, transchromosomic mouse embryonic stem cells (ESCs) and human ESC and induced pluripotent stem cells derived from different sources. All of these model systems have provided useful information in the study of DS. Furthermore, different technologies to genetically modify or correct trisomy of either single genes or the whole chromosome have been developed using these cellular models. New techniques and protocols to allow better modeling of cellular mechanisms and disease processes are being developed and the use of cerebral organoids offers great promise for future research into the neural phenotypes seen in DS. © 2020 Elsevier B.V. All rights reserved.Both trisomic and non-trisomic genes may affect the incidence and severity of phenotypes associated with Down syndrome (DS). The importance of extra (trisomic) genetic material is emphasized in DS, with less emphasis to the allelic composition of candidate trisomic genes in defining the trisomic gene-phenotype relationship in DS. Allelic differences in non-trisomic genes have been shown to be important moderators of cardiac, leukemia, and developmental phenotypes associated with DS. Trisomic mouse models provide an in vivo genetic platform for examining the gene-phenotype relationship, including the influence of allelic variants, on DS-like phenotypes. DS mouse models have differing trisomic genetic makeup, and optimal development, viability and translational value of these mouse models may require a non-inbred genetic background with heterogeneity at many loci. Additionally, understanding the contribution of specific genes or regions to DS phenotypes often requires the utilization of genetically manipulated mice that may be established on a different inbred background than the trisomic mice. The impact of allelic differences of trisomic and background genes in human and model systems may offer insight into the variability in occurrence and severity of trisomic phenotypes. © 2020 Elsevier B.V. All rights reserved.Early intervention and environmental optimization have been central to management of Down syndrome (DS) and much of current treatment is still focused in strategies that involve early education plans. This approach has provided significant improvements for Down syndrome but it is not providing a full success. The discovery of an increasing number of genes and molecular pathways linked to intellectual disability and involving a range of synaptic and plasticity-related mechanisms has open new treatment opportunities that focus on targeted treatments boosting neural plasticity. We here discuss some of these approaches, focusing on the effects of environmental enrichment and on the discovery of pharmacological therapies showing beneficial effects even in some clinical trials in adult individuals with Down syndrome. Targeting plasticity impairments in DS is thus a promising strategy to promote cellular mechanisms involved in learning and memory within key cognitive brain region and could lead to improved connectivity. © 2020 Elsevier B.V. All rights reserved.Neurodevelopmental disorders are challenging to study in the laboratory, and despite a large investment, few novel treatments have been developed in the last decade. While animal models have been valuable in elucidating disease mechanisms and in providing insights into the function of specific genes, the predictive validity of preclinical models to test potential therapies has been questioned. In the last two decades, diverse new murine models of Down syndrome (DS) have been developed and numerous studies have demonstrated neurobiological alterations that could be responsible for the cognitive and behavioral phenotypes found in this syndrome. In many cases, similar alterations were found in murine models and in individuals with DS, although several phenotypes shown in animals have yet not been confirmed in the human condition. Some of the neurobiological alterations observed in mice have been proposed to account for their changes in cognition and behavior, and have received special attention because of being ndings in mouse models of DS and in humans, including (i) the incomplete resemble of the genetic alterations of available mouse models of DS and human trisomy 21, (ii) the lack of evidence that some of the phenotypic alterations found in mice (e.g., GABA-mediated overinhibition, and alterations in adult neurogenesis) are also present in DS individuals, and (iii) the inaccuracy and/or inadequacy of the methods used in clinical trials to detect changes in the cognitive and behavioral functions of people with DS. Despite the shortcomings of animal models, animal experimentation remains an invaluable tool in developing drugs. Thus, we will also discuss how to increase predictive validity of mouse models. selleckchem © 2020 Elsevier B.V. All rights reserved.Down syndrome (DS) is the most frequent chromosomal disorder. It is caused by the triplication of human chromosome 21, leading to increased dosage of a variety of genes including APP (Amyloid Precursor Protein). Mainly for this reason, individuals with DS are at high risk to develop Alzheimer's disease (AD). Extensive literature identified various morphological and molecular abnormalities in the endo-lysosomal pathway both in DS and AD. Most studies in this field investigated the causative role of APP (Amyloid Precursor Protein) in endo-lysosomal dysfunctions, thus linking phenotypes observed in DS and AD. In DS context, several lines of evidence and emerging hypotheses suggest that other molecular players and pathways may be implicated in these complex phenotypes. In this review, we outline the normal functioning of endosomal trafficking and summarize the research on endo-lysosomal dysfunction in DS in light of AD findings. We emphasize the role of genes of chromosome 21 implicated in endocytosis to explain endosomal abnormalities and set the limitations and perspectives of models used to explore endo-lysosomal dysfunction in DS and find new biomarkers. The review highlights the complexity of endo-lysosomal dysfunction in DS and suggests directions for future research in the field. © 2020 Elsevier B.V. All rights reserved.People who have Down syndrome are at significantly elevated risk of developing early onset Alzheimer's disease that causes dementia (AD-DS). Here we review recent progress in modeling the development of AD-DS in mouse models. These studies provide insight into mechanisms underlying Alzheimer's disease and generate new clinical research questions. In addition, they suggest potential new targets for disease prevention therapies. © 2020 Elsevier B.V. All rights reserved.Down syndrome (DS), caused by trisomy of chromosome 21 (Hsa21), results in a spectrum of phenotypes including learning and memory deficits, motor dysfunction and social constrains. The regions on Hsa21 are conserved with their synteny on mouse chromosome 10, 16 and 17. To date, a wide range of mouse models has been developed to determine genotype-phenotype relationships and identity of the causative dosage-sensitive genes. However, the comparison of behavioral results is not obvious due to the lack of consistency in the genetics background, housing conditions and behavioral protocols used. There is a growing need to standardize some of the classical behavioral test, include automated behavioral phenotyping and sophisticated analysis techniques and move through ethologically inspired tests. Here we present an overview of the status of behavioral phenotyping of DS murine models and the limitations and possibilities to improve their characterization to address genotype-phenotype relationships for understanding the pathophysiology of DS.