Incorporating Genomic Analysis In The Clinical Practice Of Hepatology

In the past two decades, whole-exome sequencing has been successfully demonstrated as an indispensable instrument in uncovering the genetic etiology underlying numerous types of unexplained liver disease. Characterization of these illnesses into distinct molecular disease entities has revolutionized understanding of pathophysiology and has translated into improved guidance on management, treatment and prognosis for patients. However, hepatologists have been slow to welcome the technology into their mainstream clinical practice, largely due to inadequate training in genomic medicine. There thus remains a pressing need to create various forums through which clinicians can gain better appreciation for the value of genetic analysis in the field of hepatology and amass the knowledge and confidence to incorporate genetic analysis into their own clinical practice. To address this need, we aimed to facilitate the dissemination of new information on liver disease with an underlying genetic etiology through a two-pronged approach: (1) the generation of an online database housing genotype-phenotype correlation information for diseases affecting the liver, and (2) the promotion of a multidisciplinary Hepatology Genome Rounds series. In this Thesis, we detail the creation of a comprehensive database focused on genetic liver diseases, reflecting the genotypic and phenotypic profiles of more than 7,500 individuals with genetic variants across 269 genes. This newly developed database will provide clinicians and researchers a centralized source for information on genotype-phenotype correlation to aid in diagnosis and education. In addition, we demonstrate that the Hepatology Genome Rounds series, which is an interdisciplinary forum highlighting hepatology cases of clinical interest and educational value, is an important venue for the distribution of genomic knowledge within the field of hepatology and for providing ongoing education to providers and trainees in genomic medicine. We describe our single-center experience, which has led to the reconsideration of diagnoses in two patients and an improved understanding of genotype-phenotype correlations across all cases. As the value of genetic analysis continues to emerge in understanding human disease and pathophysiology, we foresee similar approaches being adopted at other institutions and in additional specialties in coming years for further propagation of genomics in clinical medicine

An Integrated Analysis of the Physiological Effects of Space Flight: Executive Summary

A large array of models were applied in a unified manner to solve problems in space flight physiology. Mathematical simulation was used as an alternative way of looking at physiological systems and maximizing the yield from previous space flight experiments. A medical data analysis system was created which consist of an automated data base, a computerized biostatistical and data analysis system, and a set of simulation models of physiological systems. Five basic models were employed: (1) a pulsatile cardiovascular model; (2) a respiratory model; (3) a thermoregulatory model; (4) a circulatory, fluid, and electrolyte balance model; and (5) an erythropoiesis regulatory model. Algorithms were provided to perform routine statistical tests, multivariate analysis, nonlinear regression analysis, and autocorrelation analysis. Special purpose programs were prepared for rank correlation, factor analysis, and the integration of the metabolic balance data

CT Scanning

Since its introduction in 1972, X-ray computed tomography (CT) has evolved into an essential diagnostic imaging tool for a continually increasing variety of clinical applications. The goal of this book was not simply to summarize currently available CT imaging techniques but also to provide clinical perspectives, advances in hybrid technologies, new applications other than medicine and an outlook on future developments. Major experts in this growing field contributed to this book, which is geared to radiologists, orthopedic surgeons, engineers, and clinical and basic researchers. We believe that CT scanning is an effective and essential tools in treatment planning, basic understanding of physiology, and and tackling the ever-increasing challenge of diagnosis in our society

A novel diffusion tensor imaging-based computer-aided diagnostic system for early diagnosis of autism.

Autism spectrum disorders (ASDs) denote a significant growing public health concern. Currently, one in 68 children has been diagnosed with ASDs in the United States, and most children are diagnosed after the age of four, despite the fact that ASDs can be identified as early as age two. The ultimate goal of this thesis is to develop a computer-aided diagnosis (CAD) system for the accurate and early diagnosis of ASDs using diffusion tensor imaging (DTI). This CAD system consists of three main steps. First, the brain tissues are segmented based on three image descriptors: a visual appearance model that has the ability to model a large dimensional feature space, a shape model that is adapted during the segmentation process using first- and second-order visual appearance features, and a spatially invariant second-order homogeneity descriptor. Secondly, discriminatory features are extracted from the segmented brains. Cortex shape variability is assessed using shape construction methods, and white matter integrity is further examined through connectivity analysis. Finally, the diagnostic capabilities of these extracted features are investigated. The accuracy of the presented CAD system has been tested on 25 infants with a high risk of developing ASDs. The preliminary diagnostic results are promising in identifying autistic from control patients

Personalized Medicine: the Future of Health Care

BACKGROUND: Most medical treatments have been designed for the “average patients”. As a result of this “one-size-fits-all-approach”, treatments can be very successful for some patients but not for others. The issue is shifting by the new innovation approach in diseases treatment and prevention, precision medicine, which takes into account individual differences in people\u27s genes, environments, and lifestyles. This review was aimed to describe a new approach of healthcare performance strategy based on individual genetic variants.CONTENT: Researchers have discovered hundreds of genes that harbor variations contributing to human illness, identified genetic variability in patients\u27 responses to different of treatments, and from there begun to target the genes as molecular causes of diseases. In addition, scientists are developing and using diagnostic tests based on genetics or other molecular mechanisms to better predict patients\u27 responses to targeted therapy.SUMMARY: Personalized medicine seeks to use advances in knowledge about genetic factors and biological mechanisms of disease coupled with unique considerations of an individual\u27s patient care needs to make health care more safe and effective. As a result of these contributions to improvement in the quality of care, personalized medicine represents a key strategy of healthcare reform

Multi-Scale Peripheral Vasculopathy with Metabolic Syndrome

The combination of cardiovascular and metabolic risk factors including obesity, dyslipidemia, hypertension, and insulin resistance, in combination with a prothrombotic and proinflammatory state, is a condition termed Metabolic Syndrome (METS). Twenty percent of the adult population is afflicted with METS which increases the risk of type-2 diabetes mellitus and cardiovascular disease. Further, the presence of peripheral vascular disease (PVD) is tightly coupled with METS which is a perfusion-demand mismatch of blood supply to active skeletal muscle resulting in painful claudication and a late-stage potential for amputation. The underlying contributors of METS associated micro-vasculopathies in the skeletal muscle, their impact on impaired perfusion, and the potential for reversibility remain unclear. Owing its hyperphagia to leptin signaling resistance, the obese Zucker rat (OZR) is a translationally relevant model for human METS and the associated micro-vasculopathies. The overall purpose of this thesis is to utilize a multi-scale approach, particularly intravital microscopy and isolate vessels, to garner a greater understanding of the observed OZR vasculopathies and to investigate the potential of therapeutic interventions for their reversibility. Project 1: The purpose was to identify any alterations in postcapillary and collecting venule function in the OZR compared to healthy controls. The OZR presented with impaired dilator reactivity and elevation in thromboxane A2 constrictor responses for both postcapillary and collecting venules. Project 2: The purpose was to identify the possible contributors of a disconnect for in-situ and ex-vivo vascular studies utilizing the OZR model. Using a multi-scale approach, Project 2 provides insight to this disconnect and reveals a heterogenous adrenergic response in the OZR, giving rise to new potential avenues of study. Project 3: The purpose was to determine the potential for reversibility or restoration of established PVD using the chronic ingestion of an HMG-CoA inhibitor, atorvastatin, and/or the implementation of regular exercise. Following a seven-week intervention, the intervention groups revealed vascular improvements with the combination group having the greatest capacity for reversibility (in specific indices). Significance: Therefore, this thesis further advances the understanding of METS associated PVD as well as potential modes for improvement following its establishment

The effect of therapeutic and non-therapeutic interventions on the health trajectory of individuals with cystic fibrosis

Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), resulting in a build-up of viscous mucus and multi-organ dysfunction. Advances in treatment have decreased the burden of CF and increased survival age. However, clinicians and researchers must continue to look for areas that contribute to improved quantity and quality of life for individuals with CF. The aim of this thesis was to explore the effects of nutritional status, aerobic capacity, and modulator therapy on clinical outcomes within CF patients. Study 1 demonstrated the minimal effective dose of exercise needed to elicit change in aerobic capacity. Safety and efficacy of this protocol was evidenced with increases in aerobic capacity akin to that seen in the general population. Study 2 observed the longitudinal effect nutritional status had on pulmonary function. Female pulmonary function evidenced an increased sensitivity to change in body mass index when compared to males. Study 3 evaluated the lived experience of CFTR treatment, highlighting despite clinically relevant benefits, benefits do not come in the absence of negative physical and psychological challenges. Study 4 demonstrated increased incidence of overweight/obesity following implementation of CFTR treatment Introduction of CFTR treatment has rapidly changed the outlook of CF care. As landscape of the disease changes there is a need to adapt to new individual needs in what is a familiar disease with a new face. Whilst diet and exercise represented significant cornerstones of care in the past 30 years, as disease burden decreases, there is a need to view diet and exercise as means of enhancing physical and psychological health, rather than tools to manage the symptoms of the disease. Whilst this thesis is unable to quantify the effect of CFTR therapy on health, the future has never looked brighter for CF patients

Numerical and Experimental Analysis of Injection and Mixture Formation in High-Performance CNG Engines

L'abstract è presente nell'allegato / the abstract is in the attachmen