Morphology, topology and dimensions of the heart and arteries of genetically normal and mutant mouse embryos at stages S21-S23.

Accurate identification of abnormalities in the mouse embryo depends not only on comparisons with appropriate, developmental stage-matched controls, but also on an appreciation of the range of anatomical variation that can be expected during normal development. Here we present a morphological, topological and metric analysis of the heart and arteries of mouse embryos harvested on embryonic day (E)14.5, based on digital volume data of whole embryos analysed by high-resolution episcopic microscopy (HREM).

Understanding and preventing type 1 diabetes through the unique working model of TrialNet.

Type 1 diabetes is an autoimmune disease arising from the destruction of pancreatic insulin-producing beta cells. The disease represents a continuum, progressing sequentially at variable rates through identifiable stages prior to the onset of symptoms, through diagnosis and into the critical periods that follow, culminating in a variable depth of beta cell depletion. The ability to identify the very earliest of these presymptomatic stages has provided a setting in which prevention strategies can be trialled, as well as furnishing an unprecedented opportunity to study disease evolution, including intrinsic and extrinsic initiators and drivers.

High-resolution Episcopic Microscopy (HREM) - Simple and Robust Protocols for Processing and Visualizing Organic Materials.

We provide simple protocols for generating digital volume data with the high-resolution episcopic microscopy (HREM) method. HREM is capable of imaging organic materials with volumes up to 5 x 5 x 7 mm in typical numeric resolutions between 1 x 1 x 1 and 5 x 5 x 5 µm. Specimens are embedded in methacrylate resin and sectioned on a microtome.

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.

Background: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.

Methods: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations.

[Morbidity Compression in Stroke: Longitudinal Analyses on Changes in the Incidence of Stroke].

Unlabelled: According to Fries, morbidity compression occurs if age at onset of disease/disability and age at death increase. Morbidity compression is also present if disease/disability rates decrease to the same or to a larger extent than standardized death rates. In all cases, healthy lifetime is gained.

Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives.

Context: Islet autoantibodies are markers of type 1 diabetes, and an increase in number of autoantibodies detected during the preclinical phase predicts progression to overt disease.

Objective: To refine the effect of age in relation to islet antibody type on progression from single to multiple autoantibodies in relatives of people with type 1 diabetes.

Research Design And Methods: We examined 994 relatives with normal glucose tolerance who were positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention.

Can Non-HLA Single Nucleotide Polymorphisms Help Stratify Risk in TrialNet Relatives at Risk for Type 1 Diabetes?

Context: Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-human leukocyte antigens (non-HLA) loci.

Objective: The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression.

Design And Setting: The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Abs) and T1D.

Late Effects of Exposure to Ionizing Radiation and Age on Human Thymus Morphology and Function.

The thymus is essential for proper development and maintenance of a T-cell repertoire that can respond to newly encountered antigens, but its function can be adversely affected by internal factors such as pregnancy and normal aging or by external stimuli such as stress, infection, chemotherapy and ionizing radiation. We have utilized a unique archive of thymus tissues, obtained from 165 individuals, exposed to the 1945 atomic bomb blast in Hiroshima, to study the long-term effects of receiving up to ∼3 Gy dose of ionizing radiation on human thymus function. A detailed morphometric analysis of thymus activity and architecture in these subjects at the time of their natural deaths was performed using bright-field immunohistochemistry and dual-color immunofluorescence and compared to a separate cohort of nonexposed control subjects.

Expansion or compression of multimorbidity? 10-year development of life years spent in multimorbidity based on health insurance claims data of Lower Saxony, Germany.

Objectives: Our study examined how life years spent in multimorbidity changed over a period of 10 years (2005-2014) and whether morbidity expansion or compression has taken place. There is a little evidence on whether life years gained due to increasing life expectancy are spent in good health, or if they are accompanied by morbidity expansion.

Methods: The analyses are based on German administrative claims data.

Intensity standardisation of 7T MR images for intensity-based segmentation of the human hypothalamus.

The high spatial resolution of 7T MRI enables us to identify subtle volume changes in brain structures, providing potential biomarkers of mental disorders. Most volumetric approaches require that similar intensity values represent similar tissue types across different persons. By applying colour-coding to T1-weighted MP2RAGE images, we found that the high measurement accuracy achieved by high-resolution imaging may be compromised by inter-individual variations in the image intensity.

Excess BMI in Childhood: A Modifiable Risk Factor for Type 1 Diabetes Development?

Objective: We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth.

Research Design And Methods: We studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index.

Change in life expectancy with type 2 diabetes: a study using claims data from lower Saxony, Germany.

Background: This study estimates life expectancy with and without type 2 diabetes for individuals in Lower Saxony, Germany in order to detect a trend in population health.

Methods: Morbidity and mortality data derived from German administrative claims data (statutory health insurance, AOK Niedersachsen, N = 2,900,065) were used covering 10 years from 2005 to 2014. Life table analysis was applied for calculating life expectancy, life expectancy free of type 2 diabetes, life expectancy with type 2 diabetes, and the proportion of life expectancy free of diabetes to total life expectancy using the Sullivan method.

A staging system for correct phenotype interpretation of mouse embryos harvested on embryonic day 14 (E14.5).

We present a simple and quick system for accurately scoring the developmental progress of mouse embryos harvested on embryonic day 14 (E14.5). Based solely on the external appearance of the maturing forelimb, we provide a convenient way to distinguish six developmental sub-stages.

Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era.

Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all- retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment.

Highly variable penetrance of abnormal phenotypes in embryonic lethal knockout mice.

Identifying genes that are essential for mouse embryonic development and survival through term is a powerful and unbiased way to discover possible genetic determinants of human developmental disorders. Characterising the changes in mouse embryos that result from ablation of lethal genes is a necessary first step towards uncovering their role in normal embryonic development and establishing any correlates amongst human congenital abnormalities. Here we present results gathered to date in the Deciphering the Mechanisms of Developmental Disorders (DMDD) programme, cataloguing the morphological defects identified from comprehensive imaging of 220 homozygous mutant and 114 wild type embryos from 42 lethal and subviable lines, analysed at E14.

Discovery and replication of microRNAs for breast cancer risk using genome-wide profiling.

Background: Genome-wide miRNA expression may be useful for predicting breast cancer risk and/or for the early detection of breast cancer.

Results: A 41-miRNA model distinguished breast cancer risk in the discovery study (accuracy of 83.3%), which was replicated in the independent study (accuracy = 63.

Long term effects of radiation exposure on telomere lengths of leukocytes and its associated biomarkers among atomic-bomb survivors.

Ionizing radiation (IR) is a major source of cellular damage and the immediate cellular response to IR has been well characterized. But the long-term impact of IR on cell function and its relationship with aging are not known. Here, we examined the IR effects on telomere length and other biomarkers 50 to 68 years post-exposure (two time points per person) in survivors of the atomic bombing at Hiroshima during WWII.

Operating lists are created by rational algorithms and use of power. What can a social scientific view offer surgeons?

Purpose: Algorithms for surgical operation planning are evidence-based. However, choices sometimes have to be made between medically equal solutions e.g.

Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503).

In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m intravenously daily for 4-5 days, every 6 weeks for eight cycles.

Increased Levels of Plasma Epstein Barr Virus DNA Identify a Poor-Risk Subset of Patients With Advanced Stage Cutaneous T-Cell Lymphoma.

Introduction: Outcomes in advanced stage (AS) cutaneous T-cell lymphomas (CTCL) are poor but with great variability. Epstein-Barr virus (EBV) is associated with a subset of non-Hodgkin lymphomas. Frequency of plasma EBV-DNA (pEBVd) detection, concordance with EBV RNA (EBER) in tumor tissue, codetection of plasma cytomegalovirus DNA (pCMVd), and prognostic effect in AS CTCL are unknown.

Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma.

Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients).

The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants.

Aims/hypothesis: The incidence of type 1 diabetes is increasing at a rate of 3-5% per year. Genetics cannot fully account for this trend, suggesting an influence of environmental factors. The accelerator hypothesis proposes an effect of metabolic factors on type 1 diabetes risk.