436 research outputs found

    Identifying critically important cardiovascular outcomes for trials in hemodialysis: an international survey with patients, caregivers and health professionals

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    BACKGROUND: Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in people on hemodialysis (HD). Cardiovascular outcomes are reported infrequently and inconsistently across trials in HD. This study aimed to identify the priorities of patients/caregivers and health professionals (HPs) for CVD outcomes to be incorporated into a core outcome set reported in all HD trials. METHODS: In an international online survey, participants rated the absolute importance of 10 cardiovascular outcomes (derived from a systematic review) on a 9-point Likert scale, with 7-9 being critically important. The relative importance was determined using a best-worst scale. Likert means, medians and proportions and best-worst preference scores were calculated for each outcome. Comments were thematically analyzed. RESULTS: Participants included 127 (19%) patients/caregivers and 549 (81%) HPs from 53 countries, of whom 530 (78%) completed the survey in English and 146 (22%) in Chinese. All but one cardiovascular outcome ('valve replacement') was rated as critically important (Likert 7-9) by all participants; 'sudden cardiac death', 'heart attack', 'stroke' and 'heart failure' were all rated at the top by patients/caregivers (median Likert score 9). Patients/caregivers ranked the same four outcomes as the most important outcomes with mean preference scores of 6.2 (95% confidence interval 4.8-7.5), 5.9 (4.6-7.2), 5.3 (4.0-6.6) and 4.9 (3.6-6.3), respectively. The same four outcomes were ranked most highly by HPs. We identified five themes underpinning the prioritization of outcomes: 'clinical equipoise and potential for intervention', 'specific or attributable to HD', 'severity or impact on the quality of life', 'strengthen knowledge and education', and 'inextricably linked burden and risk'. CONCLUSIONS: Patients and HPs believe that all cardiovascular outcomes are of critical importance but consistently identify sudden cardiac death, myocardial infarction, stroke and heart failure as the most important outcomes to be measured in all HD trials

    Standardized Outcomes in Nephrology-Transplantation: A Global Initiative to Develop a Core Outcome Set for Trials in Kidney Transplantation.

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    BACKGROUND: Although advances in treatment have dramatically improved short-term graft survival and acute rejection in kidney transplant recipients, long-term graft outcomes have not substantially improved. Transplant recipients also have a considerably increased risk of cancer, cardiovascular disease, diabetes, and infection, which all contribute to appreciable morbidity and premature mortality. Many trials in kidney transplantation are short-term, frequently use unvalidated surrogate endpoints, outcomes of uncertain relevance to patients and clinicians, and do not consistently measure and report key outcomes like death, graft loss, graft function, and adverse effects of therapy. This diminishes the value of trials in supporting treatment decisions that require individual-level multiple tradeoffs between graft survival and the risk of side effects, adverse events, and mortality. The Standardized Outcomes in Nephrology-Transplantation initiative aims to develop a core outcome set for trials in kidney transplantation that is based on the shared priorities of all stakeholders. METHODS: This will include a systematic review to identify outcomes reported in randomized trials, a Delphi survey with an international multistakeholder panel (patients, caregivers, clinicians, researchers, policy makers, members from industry) to develop a consensus-based prioritized list of outcome domains and a consensus workshop to review and finalize the core outcome set for trials in kidney transplantation. CONCLUSIONS: Developing and implementing a core outcome set to be reported, at a minimum, in all kidney transplantation trials will improve the transparency, quality, and relevance of research; to enable kidney transplant recipients and their clinicians to make better-informed treatment decisions for improved patient outcomes

    Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models

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    INTRODUCTION: The experiments reported here address the question of whether a short-term hormone treatment can prevent mammary tumorigenesis in two different genetically engineered mouse models. METHODS: Two mouse models, the p53-null mammary epithelial transplant and the c-neu mouse, were exposed to estrogen and progesterone for 2 and 3 weeks, respectively, and followed for development of mammary tumors. RESULTS: In the p53-null mammary transplant model, a 2-week exposure to estrogen and progesterone during the immediate post-pubertal stage (2 to 4 weeks after transplantation) of mammary development decreased mammary tumorigenesis by 70 to 88%. At 45 weeks after transplantation, analysis of whole mounts of the mammary outgrowths demonstrated the presence of premalignant hyperplasias in both control and hormone-treated glands, indicating that the hormone treatment strongly affects the rate of premalignant progression. One possible mechanism for the decrease in mammary tumorigenesis may be an altered proliferation activity as the bromodeoxyuridine labeling index was decreased by 85% in the mammary glands of hormone-treated mice. The same short-term exposure administered to mature mice at a time of premalignant development also decreased mammary tumorigenesis by 60%. A role for stroma and/or systemic mediated changes induced by the short-term hormone (estrogen/progesterone) treatment was demonstrated by an experiment in which the p53-null mammary epithelial cells were transplanted into the cleared mammary fat pads of previously treated mice. In such mice, the tumor-producing capabilities of the mammary cells were also decreased by 60% compared with the same cells transplanted into unexposed mice. In the second set of experiments using the activated Her-2/neu transgenic mouse model, short-term estradiol or estradiol plus progesterone treatment decreased mammary tumor incidence by 67% and 63%, and tumor multiplicity by 91% and 88%, respectively. The growth rate of tumors arising in the hormone-treated activated Her-2/neu mice was significantly lower than tumors arising in non-hormone treated mice. CONCLUSION: Because these experiments were performed in model systems that mimic many essential elements of human breast cancer, the results strengthen the rationale for translating this prevention strategy to humans at high risk for developing breast cancer

    Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

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    The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

    Cognitive impairment in patients with a schizoaffective disorder: a comparison with bipolar patients in euthymia

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    OBJECTIVES: Several studies have shown persistent neurocognitive impairment in patients with a bipolar affective disorder (BD) even in euthymia as well as in patients with a schizoaffective disorder (SAD). The aim of our study was to compare the neuropsychological performance between these two groups. Confounding variables were controlled to enhance our understanding of cognitive dysfunction in both BD and SAD. METHODS: Several domains of neurocognitive function, executive function, memory, attention, concentration and perceptuomotor function were examined in 28 euthymic SAD patients and 32 BD patients by using a neuropsychological test battery. The Hamilton Depression Rating Scale (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) were used to evaluate the patients' clinical status. Data analysis was performed by using a multivariate analysis of covariance (ANCOVA/MANCOVA). RESULTS: Euthymic SAD patients showed greater cognitive impairment than euthymic BD patients in the tested domains including declarative memory and attention. Putative significant group differences concerning cognitive flexibility vanished when controlled for demographic and clinical variables. Age and medication were robust predictors to cognitive performance of both SAD and BD patients. CONCLUSIONS: Our results point out the worse cognitive outcome of SAD compared to BD patients in remission. Remarkably, the variance is higher for some of the test results between the groups than within each group, this being discussed in light of the contradictive concept of SAD

    A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R

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    BACKGROUND: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. CASE PRESENTATION: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. CONCLUSIONS: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism

    Targeted Ablation of Oligodendrocytes Triggers Axonal Damage

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    Glial dysfunction has been implicated in a number of neurodegenerative diseases. In this study we investigated the consequences of glial and oligodendrocyte ablation on neuronal integrity and survival in Drosophila and adult mice, respectively. Targeted genetic ablation of glia was achieved in the adult Drosophila nervous system using the GAL80-GAL4 system. In mice, oligodendrocytes were depleted by the injection of diphtheria toxin in MOGi-Cre/iDTR double transgenic animals. Acute depletion of oligodendrocytes induced axonal injury, but did not cause neuronal cell death in mice. Ablation of glia in adult flies triggered neuronal apoptosis and resulted in a marked reduction in motor performance and lifespan. Our study shows that the targeted depletion of glia triggers secondary neurotoxicity and underscores the central contribution of glia to neuronal homeostasis. The models used in this study provide valuable systems for the investigation of therapeutic strategies to prevent axonal or neuronal damage
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