An Intelligent Online System for Enhanced Recruitment of Patients for Clinical Research

Computational Infrastructure and Informatics Poster SessionThe recruitment and retention of subjects for clinical research has been identified as one of the bottlenecks in the development of new drugs and treatments by the healthcare industry. The Kansas City Area Life Sciences Institute has been instrumental in bringing together the Midwest Psychiatric Research Group and researchers from the School of Computing and Engineering at the University of Missouri-Kansas City to address this important problem. The resulting academic-corporate partnership has been funded by a 2-year Small Business Innovation Research Grant of $518,298 awarded by the National Institute of Mental Health at the National Institutes of Health. The project is based on developing and employing a novel internet-based system to enhance the voluntary enrollment of research subjects for studies conducted by Clinical Research Organizations. This will proactively engage patients and their caregivers who desire to be informed about clinical trials that might be relevant for their specific diagnoses, disease states and other characteristics. An important goal of the project is to facilitate accurate matches between the requirements of a clinical research study and the profile of research volunteers. To achieve this, state of the art knowledge representation and search techniques are being employed. Phase I of the project is focused on the development of a system for recruitment for clinical research trials on “Generalized Anxiety Disorder,” with eventual expansion to the inclusion of volunteers for studies on other mental health disorders

Ontology-based methods for disease similarity estimation and drug repositioning

Title from PDF of title page, viewed on October 2, 2012Dissertation advisor: Deendayal DinakarpandianVitaIncludes bibliographic references (p. 174-181)Thesis (Ph.D.)--School of Computing and Engineering and Dept. of Mathematics and Statistics. University of Missouri--Kansas City, 2012Human genome sequencing and new biological data generation techniques have provided an opportunity to uncover mechanisms in human disease. Using gene-disease data, recent research has increasingly shown that many seemingly dissimilar diseases have similar/common molecular mechanisms. Understanding similarity between diseases aids in early disease diagnosis and development of new drugs. The growing collection of gene-function and gene-disease data has instituted a need for formal knowledge representation in order to extract information. Ontologies have been successfully applied to represent such knowledge, and data mining techniques have been applied on them to extract information. Informatics methods can be used with ontologies to find similarity between diseases which can yield insight into how they are caused. This can lead to therapies which can actually cure diseases rather than merely treating symptoms. Estimating disease similarity solely on the basis of shared genes can be misleading as variable combinations of genes may be associated with similar diseases, especially for complex diseases. This deficiency can be potentially overcome by looking for common or similar biological processes rather than only explicit gene matches between diseases. The use of semantic similarity between biological processes to estimate disease similarity could enhance the identification and characterization of disease similarity besides indentifying novel biological processes involved in the diseases. Also, if diseases have similar molecular mechanisms, then drugs that are currently being used could potentially be used against diseases beyond their original indication. This can greatly benefit patients with diseases that do not have adequate therapies especially people with rare diseases. This can also drastically reduce healthcare costs as development of new drugs is far more expensive than re-using existing ones. In this research we present functions to measure similarity between terms in an ontology, and between entities annotated with terms drawn from the ontology, based on both co-occurrence and information content. The new similarity measure is shown to outperform existing methods using biological pathways. The similarity measure is then used to estimate similarity among diseases using the biological processes involved in them and is evaluated using a manually curated and external datasets with known disease similarities. Further, we use ontologies to encode diseases, drugs and biological processes and demonstrate a method that uses a network-based algorithm to combine biological data about diseases with drug information to find new uses for existing drugs. The effectiveness of the method is demonstrated by comparing the predicted new disease-drug pairs with existing drug-related clinical trials.Introduction and motivation -- Ontologies in biomedical domain -- Methods to compute ontological similarity -- Proposed approach for ontological term similarity -- Augmentation of vocabulary and annotation in ontologies -- Estimation of disease similarity -- Use of ontologies for drug repositioning -- Future directions-perspective from pharmaceutical industry -- Appendix 1. Table for the ontological similarity scores -- Appendix 2. Test set of 200 records for evaluating mapping of disease text to Disease Ontology -- Appendix 3. Curated set of disease similarities used as the benchmark set -- Appendix 4. F-scores for different combinations of Score-Pvalues and GO-Process-Pvalues for PSB estimates of disease similarity -- Appendix 5. Test set formed from opinions of medical residents http://rxinformatics.umn.edu/SemanticRelatednessResources.html -- Appendix 6. Drug repositioning candidate

Surgical Anatomy of Acetabulum and Biomechanics

Both column acetabular fractures are challenging articular injuries. Majority of them are treated operatively. The concept of “secondary congruence” was introduced by Letournel. Despite this, biomechanical data on secondary congruence indicate that nonoperative treatment leads to an increase in peak pressures in the supra-acetabular region with the potential risk of developing posttraumatic degenerative osteoarthritis. Operative management is therefore justified. A cohort of 10 patients having both column (anterior and posterior) acetabular fractures managed using bicolumnar plating between Jan 2016 and Dec 2017 were enrolled in the study and were analyzed during follow-up period. Eighty percent of the patients had excellent to good result. Average postoperative score was 85.7. Assessment was done using Modified Harris Hip score

Sex-dimorphic gene expression and ineffective dosage compensation of Z-linked genes in gastrulating chicken embryos

<p>Abstract</p> <p>Background</p> <p>Considerable progress has been made in our understanding of sex determination and dosage compensation mechanisms in model organisms such as <it>C. elegans</it>, <it>Drosophila </it>and <it>M. musculus</it>. Strikingly, the mechanism involved in sex determination and dosage compensation are very different among these three model organisms. Birds present yet another situation where the heterogametic sex is the female. Sex determination is still poorly understood in birds and few key determinants have so far been identified. In contrast to most other species, dosage compensation of bird sex chromosomal genes appears rather ineffective.</p> <p>Results</p> <p>By comparing microarrays from microdissected primitive streak from single chicken embryos, we identified a large number of genes differentially expressed between male and female embryos at a very early stage (Hamburger and Hamilton stage 4), long before any sexual differentiation occurs. Most of these genes are located on the Z chromosome, which indicates that dosage compensation is ineffective in early chicken embryos. Gene ontology analyses, using an enhanced annotation tool for Affymetrix probesets of the chicken genome developed in our laboratory (called Manteia), show that among these male-biased genes found on the Z chromosome, more than 20 genes play a role in sex differentiation.</p> <p>Conclusions</p> <p>These results corroborate previous studies demonstrating the rather inefficient dosage compensation for Z chromosome in birds and show that this sexual dimorphism in gene regulation is observed long before the onset of sexual differentiation. These data also suggest a potential role of non-compensated Z-linked genes in somatic sex differentiation in birds.</p

RETRACTED ARTICLE: Release-Active Dilutions of Diclofenac Enhance Anti-inflammatory Effect of Diclofenac in Carrageenan-Induced Rat Paw Edema Model

The study was aimed to investigate the effect of technologically treated diclofenac (release-active dilutions of diclofenac (RAD of diclofenac)) on anti-inflammatory activity of diclofenac in carrageenan-induced rat paw edema model. Ninety male Wistar albino rats (6–8 weeks) divided into nine groups (n = 10) were used. Anti-inflammatory activity was assessed at 1, 2, 3, 4, and 6 h after subplantar injection of carrageenan (0.1 ml of a 1 % solution in normal saline). Diclofenac alone was studied at 5 and 20 mg/kg, RAD of diclofenac alone at 7.5 ml/kg and their combination at 5 and 7.5 ml/kg, respectively. Diclofenac reduced (p < 0.05 at least) paw edema at all time points. RAD of diclofenac enhanced (p < 0.05) anti-inflammatory effect of diclofenac (5 mg/kg) at 2, 4, and 6 h on concurrent and at 2 and 4 h on sequential administration. Moreover at 2 h, anti-inflammatory effect of combination treatment reached values comparable to those of diclofenac (20 mg/kg). In conclusion, RAD of diclofenac enhanced anti-inflammatory effect of diclofenac

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Comprehensive mutations analyses of FTO (fat mass and obesity-associated gene) and their effects on FTO’s substrate binding implicated in obesity

An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity (FTO) gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the FTO gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the FTO gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders

Versuche uber Immunisierung von dem Konjunktivalsack aus mit Berucksichtigung des Einflusses der Ultraviolettbestrahlung auf den Immunisierungsvorgang

1) In Vorversuchen hat der Verfasser eingehend einerseits den direkten Einfluss der Ultraviolettstrahlen auf die beabsichtigte Antigene, ihre Suspensions-bzw. Losungs-medien so wie auf die in Immunserum anwesenden Antikorper festgestellt, anderseits die lokale und allgemeine Einwirkung auf den Tierkorper der U. V. Bestrahlung des Kaninchenauges sichergestellt. Im allgemeinen hat die U. V. Bestrahlung auf lebende Bakterien verschiedener Rassen bakterizide Wirkung entfaltet. Die Wirkungskraft war bei verschiedenen Bakterienarten, in verschiedenen Suspensionsmedien und je nach der Bestrahlungsweise verschieden. Auf das Auge selbst hat die U. V. Bestrahlung, vorausgesetzt, dass sie zweck-massig durchgefuhrt wird, keinen ublen Einfluss. Die Keime des Konjunktivalsackes nehmen als Folge der Bestrahlung an ihrer Zahl ab. Als allgemeiner Einfluss auf den Tierkorper kann der Aufstieg der Korpertem-peratur nach der Bestrahlung und die Korpergewichtzunahme erwahnt werden. Uber-massiges Bestrahlen fuhrt zur Gewichtsabnahme. Im Gegenteil zu der Wirkung im immuisierten Korper verliert das direkt bestr-ahlte Immunserum an seinem Antikorpergehalt. 2) Durch Agglutinationsproben wurde der Immunisierungsvorgang verfolgt und die Moglichkeit der Immunisierung vom Konjumktivalsack aus festgestellt. Es kamen die folgenden Bakterien in Frage; B. typhi B. prodigiosus, Staphylokokken, Gonoko-kken, Pneumokokken, V. Metschnikoffi. Als Aufschwemmungsmedium der bakteriellen Antigene wurde Kochsalzlosung, Dionin-, NaHCO3-, und verdunnte HCl- losung gebraucht. Diese Immunisierungsversuche wurden teilweise mit, teilweise ohne U. V. Bestrahlung durchgefuhrt, wodurch die Tatsache festgestellt wurde, dass die Bestr-ahlung auf die Agglutininbildung einen gunstigen Einfluss ausubt. 3) Ahnlich wie mit den verschiedenen Bakterien wurden auch Immunisierungs-versuche mit Diphterietoxin angestellt. Es ist zwar gelungen im Blute der auf die in Frage stehende Weise behandelten Versuchstiere das spezifische Antitoxin nachzuweisen, aber es lag kein Beweis a