Gerald A. Higgins

Virtual reality simulation for the operating room: proficiency-based training as a paradigm shift in surgical skills training.

Summary Background Data:To inform surgeons about the practical issues to be considered for successful integration of virtual reality simulation into a surgical training program. The learning and practice of minimally invasive surgery (MIS) makes unique demands on surgical training programs. A decade ago Satava proposed virtual reality (VR) surgical simulation as a solution for this problem. Only recently have robust scientific studies supported that vision Methods:A review of the surgical education, human-factor, and psychology literature to identify important factors which will impinge on the successful integration of VR training into a surgical training program. Results:VR is more likely to be successful if it is systematically integrated into a well-thought-out education and training program which objectively assesses technical skills improvement proximate to the learning experience. Validated performance metrics should be relevant to the surgical task being trained but in general will require trainees to reach an objectively determined proficiency criterion, based on tightly defined metrics and perform at this level consistently. VR training is more likely to be successful if the training schedule takes place on an interval basis rather than massed into a short period of extensive practice. High-fidelity VR simulations will confer the greatest skills transfer to the in vivo surgical situation, but less expensive VR trainers will also lead to considerably improved skills generalizations. Conclusions:VR for improved performance of MIS is now a reality. However, VR is only a training tool that must be thoughtfully introduced into a surgical training curriculum for it to successfully improve surgical technical skills.

New simulation technologies for surgical training and certification: Current status and future projections

Computer-based virtual reality technology has evolved to the point at which medical simulation can be incorporated into medical education and into the eventual objective evaluation of surgical competence. Flight simulation provides a model for examining the role of computer-based simulation in medical training and certification. The plan by which medical simulators are being designed and validated for surgical training is presented, as is a description of the current state of medical simulation and the limitations of the technology. A realistic argument for adoption is suggested that takes into account lower price constraints, technological limitations, and professional barriers to the implementation of simulator-based training and accreditation.1

A glutamatergic network mediates lithium response in bipolar disorder as defined by epigenome pathway analysis

AIM A regulatory network in the human brain mediating lithium response in bipolar patients was revealed by analysis of functional SNPs from genome-wide association studies (GWAS) and published gene association studies, followed by epigenome mapping. METHODS An initial set of 23,312 SNPs in linkage disequilibrium with lead SNPs, and sub-threshold GWAS SNPs rescued by pathway analysis, were studied in the same populations. These were assessed using our workflow and annotation by the epigenome roadmap consortium. RESULTS Twenty-seven percent of 802 SNPs that were associated with lithium response (13 published studies gene association studies and two GWAS) were shared in common with 1281 SNPs from 18 GWAS examining psychiatric disorders and adverse events associated with lithium treatment. Nineteen SNPs were annotated as active regulatory elements such as enhancers and promoters in a tissue-specific manner. They were located within noncoding regions of ten genes: ANK3, ARNTL, CACNA1C, CACNG2, CDKN1A, CREB1, GRIA2, GSK3B, NR1D1 and SLC1A2. Following gene set enrichment and pathway analysis, these genes were found to be significantly associated (p = 10(-27); Fisher exact test) with an AMPA2 glutamate receptor network in human brain. Our workflow results showed concordance with annotation of regulatory elements from the epigenome roadmap. Analysis of cognate mRNA and enhancer RNA exhibited patterns consistent with an integrated pathway in human brain. CONCLUSION This pharmacoepigenomic regulatory pathway is located in the same brain regions that exhibit tissue volume loss in bipolar disorder. Although in silico analysis requires biological validation, the approach provides value for identification of candidate variants that may be used in pharmacogenomic testing to identify bipolar patients likely to respond to lithium.

Stress and glucocorticoid receptor transcriptional programming in time and space: Implications for the brain-gut axis

Chronic psychological stress is associated with enhanced abdominal pain and altered intestinal barrier function that may result from a perturbation in the hypothalamic–pituitary–adrenal (HPA) axis. The glucocorticoid receptor (GR) exploits diverse mechanisms to activate or suppress congeneric gene expression, with regulatory variation associated with stress‐related disorders in psychiatry and gastroenterology.

Network Reconstruction Reveals that Valproic Acid Activates Neurogenic Transcriptional Programs in Adult Brain Following Traumatic Injury

ObjectivesTo determine the mechanism of action of valproic acid (VPA) in the adult central nervous system (CNS) following traumatic brain injury (TBI) and hemorrhagic shock (HS).MethodsData were analyzed from different sources, including experiments in a porcine model, data from postmortem human brain, published studies, public and commercial databases.ResultsThe transcriptional program in the CNS following TBI, HS, and VPA treatment includes activation of regulatory pathways that enhance neurogenesis and suppress gliogenesis. Genes which encode the transcription factors (TFs) that specify neuronal cell fate, including MEF2D, MYT1L, NEUROD1, PAX6 and TBR1, and their target genes, are induced by VPA. VPA represses genes responsible for oligodendrogenesis, maintenance of white matter, T-cell activation, angiogenesis, and endothelial cell proliferation, adhesion and chemotaxis. NEUROD1 has regulatory interactions with 38% of the genes regulated by VPA in a swine model of TBI and HS in adult brain. Hi-C spatial mapping of a VPA pharmacogenomic SNP in the GRIN2B gene shows it is part of a transcriptional hub that contacts 12 genes that mediate chromatin-mediated neurogenesis and neuroplasticity.ConclusionsFollowing TBI and HS, this study shows that VPA administration acts in the adult brain through differential activation of TFs responsible for neurogenesis, genes responsible for neuroplasticity, and repression of TFs that specify oligodendrocyte cell fate, endothelial cell chemotaxis and angiogenesis.Short title: Mechanism of action of valproic acid in traumatic brain injury

Alterations in the human proteome following administration of valproic acid.

BACKGROUND High doses of the histone deacetylase inhibitor valproic acid (VPA, 150–400 mg/kg) improve outcomes in animal models of lethal insults. We are conducting a US Food and Drug Administration–approved Phase I, double-blind, placebo-controlled trial to evaluate the safety and tolerability of ascending doses of VPA in human volunteers. We hypothesized that VPA would induce significant changes in the proteome of healthy humans when given at doses lower than those used in prior animal studies. METHODS Peripheral blood mononuclear cells were obtained from three healthy subjects randomized to receive VPA (120 mg/kg over 1 hour) at baseline and at 4 and 8 hours following infusion. Detailed proteomic analysis was performed using 1D gel electrophoresis, liquid chromatography, and mass spectrometry. Proteins with differential expression were chosen for functional annotation and pathway analysis using Ingenuity Pathway Analysis (Qiagen GmbH, Hilden, Germany) and Panther Gene Ontology. RESULTS A total of 3,074 unique proteins were identified. The average number of proteins identified per sample was 1,716 ± 459. There were a total of 140 unique differentially expressed proteins (p < 0.05). There was a minor and inconsistent increase in histone and nonhistone protein acetylation. Functional annotation showed significant enrichment of apoptosis (p = 3.5E−43), cell death (p = 9.9E−72), proliferation of cells (p = 1.6E−40), dementia (p = 9.6E−40), amyloidosis (p = 6.3E−38), fatty acid metabolism (p = 4.6E−76), quantity of steroid (p = 4.2E−75), and cell movement (p = 1.9E−64). CONCLUSIONS Valproic acid induces significant changes to the proteome of healthy humans when given at a dose of 120 mg/kg. It alters the expression of key proteins and pathways, including those related to cell survival, without significant modification of protein acetylation. In the next part of the ongoing Phase I trial, we will study the effects of VPA on trauma patients in hemorrhagic shock. LEVEL OF EVIDENCE Therapeutic study, level V.

The epigenome, 4D nucleome and next-generation neuropsychiatric pharmacogenomics

The 4D nucleome has the potential to render challenges in neuropsychiatric pharmacogenomics more tractable. The epigenome roadmap consortium has demonstrated the critical role that noncoding regions of the human genome play in determination of human phenotype. Chromosome conformation capture methods have revealed the 4D organization of the nucleus, bringing interactions between distant regulatory elements into close spatial proximity in a periodic manner. These functional interactions have the potential to elucidate mechanisms of CNS drug response and side effects that previously have been unrecognized. This perspective assesses recent advances likely to reveal novel pharmacodynamic regulatory pathways in human brain, charting a future new avenue of pharmacogenomics research, using the spatial and temporal architecture of the human epigenome as its foundation.

Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways

The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS.

Teleostm: Development of a software toolkit for authoring virtual medical environments

Virtual reality simulations in medicine present a variety of technical challenges that differ from those associated with flight, space, and battlefield simulations. One imposing barrier to the widespread adoption of medical simulators is the lack of software tools that could enable medical content developers to author simulations in their respective disciplines. Our experience in developing custom standalone virtual reality applications in medicine has provided the basis for the development of Teleos™, a software toolkit for authoring interactive simulations in medicine.

3D Cell Nuclear Morphology: Microscopy Imaging Dataset and Voxel-Based Morphometry Classification Results

Cell deformation is regulated by complex underlying biological mechanisms associated with spatial and temporal morphological changes in the nucleus that are related to cell differentiation, development, proliferation, and disease. Thus, quantitative analysis of changes in size and shape of nuclear structures in 3D microscopic images is important not only for investigating nuclear organization, but also for detecting and treating pathological conditions such as cancer. While many efforts have been made to develop cell and nuclear shape characteristics in 2D or pseudo-3D, several studies have suggested that 3D morphometric measures provide better results for nuclear shape description and discrimination. A few methods have been proposed to classify cell and nuclear morphological phenotypes in 3D, however, there is a lack of publicly available 3D data for the evaluation and comparison of such algorithms. This limitation becomes of great importance when the ability to evaluate different approaches on benchmark data is needed for better dissemination of the current state of the art methods for bioimage analysis. To address this problem, we present a dataset containing two different cell collections, including original 3D microscopic images of cell nuclei and nucleoli. In addition, we perform a baseline evaluation of a number of popular classification algorithms using 2D and 3D voxel-based morphometric measures. To account for batch effects, while enabling calculations of AUROC and AUPR performance metrics, we propose a specific cross-validation scheme that we compare with commonly used k-fold cross-validation. Original and derived imaging data are made publicly available on the project web-page: http://www.socr.umich.edu/projects/3d-cell-morphometry/data.html.