Extracorporeal Membrane Oxygenation in the Context of the 2009 H1N1 Influenza A Pandemic

Background: Extracorporeal membrane oxygenation (ECMO) incorporates surgical techniques as adjuncts in the management of refractory respiratory dysfunction. For many years, its primary application was for support of neonatal infants in cardiorespiratory failure. As the 2009 H1N1 influenza A pandemic developed, more reports came in of severe respiratory dysfunction and even death that seemed to be occurring preferentially in younger adults. Centers with the capability began to use ECMO to salvage these patients. Results: The H1N1 virus is a subtype of influenza A. The hemagglutinin receptor binding is similar to that of the seasonal influenza virus, but 2009 H1N1 also binds to •2,3-linked receptors, which are found in the conjunctivae, distal airways, and alveolar pneumocytes. Influenza viruses elude host immune responses through drift and shift in the hemagglutinin (HA) and neuraminidase (NA) proteins. The incubation period ranges from 1-7 days. The majority of patients present with fever and cough, but a broad spectrum of clinical syndromes has been reported, and laboratory testing remains the mainstay of diagnosis. Most patients recover within a week without treatment. The H1N1 virus remains largely sensitive to the NA inhibitors but is resistant to the matrix protein-2 inhibitors. Extracorporeal membrane oxygenation provides continuous pulmonary (and sometimes cardiac) support and minimizes ventilator-induced lung injury. The potential for life-threatening complications is high. In 2009, in the Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) randomized trial of ECMO, the overall survival rate was 63% in the ECMO group compared with 47% in the control group (p = 0.03). Similar studies have been reported from Australia and New Zealand, Canada, and France. Conclusions: Supportive management is continued along with ECMO. Antiviral drugs and antimicrobial agents should be given as appropriate, as should nutritional support. Volume management should be used. Ventilator settings should be reduced as ECMO support allows, with a goal of reducing airway pressures, ventilator rate, and FiO2. Complications of ECMO are common. Bleeding, the most common, can result in death, especially if it occurs intracranially.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90458/1/sur-2E2010-2E082.pd

Prevention of Catheter-Related Blood Stream Infection: Back to Basics?

Background: Central venous catheter (CVC)-related infections are a substantial problem in the intensive care unit (ICU). Our infection control team initiated the routine use of antiseptic-coated (chlorhexidine-silver sulfadiazine; Chx-SS) CVCs in our adult ICUs to reduce catheter-associated (CA) and catheter-related (CR) blood stream infection (BSI) as we implemented other educational and best practice standardization strategies. Prior randomized studies documented that the use of Chx-SS catheters reduces microbial colonization of the catheter compared with an uncoated standard (Std) CVC but does not reduce CR-BSI. We therefore implemented the routine use of uncoated Std CVCs in our surgical ICU (SICU) and examined the impact of this change. Hypothesis: The use of uncoated Std CVCs does not increase CR-BSI rate in an SICU. Methods: Prospective evaluation of universal use of uncoated Std CVCs, implemented November 2007 in the SICU. The incidences of CA-BSI and CR-BSI were compared during November 2006-October 2007 (universal use of Chx-SS CVCs) and November 2007-October 2008 (universal use of Std CVCs) by t-test. The definitions of the U.S. Centers for Disease Control and Prevention were used for CA-BSI and CR-BSI. Patient data were collected via a dedicated Acute Physiology and Chronic Health Evaluation (APACHE) III coordinator for the SICU. Results: Annual use of CVCs increased significantly in the last six years, from 3,543 (2001) to 5,799 (2006) total days. The APACHE III scores on day 1 increased from a mean of 54.4 in 2004 to 55.6 in 2008 (p = 0.0010; 95% confidence interval [CI] 1.29-5.13). The mean age of the patients was unchanged over this period, ranging from 58.2 to 59.6 years. The Chx-SS catheters were implemented in the SICU in 2002. Data regarding the specific incidence of CR-BSI were collected beginning at the end of 2005, with mandatory catheter tip cultures when CVCs were removed. Little difference was identified in the incidence of BSI between the interval with universal Chx-SS use and that with Std CVC use. (Total BSI 0.7 vs. 0.8 per 1,000 catheter days; CA-BSI 0.5 vs. 0.8 per 1,000 catheter days; CR-BSI 0.2 vs. 0 per 1,000 catheter days.) No difference was seen in the causative pathogens of CA-BSI or CR-BSI. Conclusion: Eliminating the universal use of Chx-SS-coated CVCs in an SICU with a low background incidence of CR-BSIs did not result in an increase in the rate of CR-BSIs. This study documents the greater importance of adherence to standardization of the processes of care related to CVC placement than of coated CVC use in the reduction of CR-BSI.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90456/1/sur-2E2009-2E082.pd

Optical Propagation and Communication

Contains summary of research and reports on four research projects.National Science Foundation (Grant ECS81-20637)U.S. Navy - Office of Naval Research (Contract N00014-81-K-0662)Maryland Procurement Office (Contract MDA904-84-C-6037)U.S. Army Research Office - Durham (Contract DAAG29-80-K-0022)U.S. Army Research Office - Durham (Contract DAAG29-84-K-0095)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0941

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

RationaleThe sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.MethodsNuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.ResultsNuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.ConclusionsThe molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions

The ClinGen Epilepsy Gene Curation Expert Panel—Bridging the divide between clinical domain knowledge and formal gene curation criteria

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes

Three-dimensional, multifunctional neural interfaces for cortical spheroids and engineered assembloids.

Three-dimensional (3D), submillimeter-scale constructs of neural cells, known as cortical spheroids, are of rapidly growing importance in biological research because these systems reproduce complex features of the brain in vitro. Despite their great potential for studies of neurodevelopment and neurological disease modeling, 3D living objects cannot be studied easily using conventional approaches to neuromodulation, sensing, and manipulation. Here, we introduce classes of microfabricated 3D frameworks as compliant, multifunctional neural interfaces to spheroids and to assembloids. Electrical, optical, chemical, and thermal interfaces to cortical spheroids demonstrate some of the capabilities. Complex architectures and high-resolution features highlight the design versatility. Detailed studies of the spreading of coordinated bursting events across the surface of an isolated cortical spheroid and of the cascade of processes associated with formation and regrowth of bridging tissues across a pair of such spheroids represent two of the many opportunities in basic neuroscience research enabled by these platforms

High-Efficient Generation of Induced Pluripotent Stem Cells from Human Astrocytes

The reprogramming of human somatic cells to induced pluripotent stem (hiPS) cells enables the possibility of generating patient-specific autologous cells for regenerative medicine. A number of human somatic cell types have been reported to generate hiPS cells, including fibroblasts, keratinocytes and peripheral blood cells, with variable reprogramming efficiencies and kinetics. Here, we show that human astrocytes can also be reprogrammed into hiPS (ASThiPS) cells, with similar efficiencies to keratinocytes, which are currently reported to have one of the highest somatic reprogramming efficiencies. ASThiPS lines were indistinguishable from human embryonic stem (ES) cells based on the expression of pluripotent markers and the ability to differentiate into the three embryonic germ layers in vitro by embryoid body generation and in vivo by teratoma formation after injection into immunodeficient mice. Our data demonstrates that a human differentiated neural cell type can be reprogrammed to pluripotency and is consistent with the universality of the somatic reprogramming procedure

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment