New Concepts in Pacemaker Syndrome

After implantation of a permanent pacemaker, patients may experience severe symptoms of dyspnea, palpitations, malaise, and syncope resulting from pacemaker syndrome. Although pacemaker syndrome is most often ascribed to the loss of atrioventricular (A-V) synchrony, more recent data may also implicate left ventricular dysynchrony caused by right ventricular pacing. Previous studies have not shown reductions in mortality or stroke with rate-modulated dual-chamber (DDDR) pacing as compared to ventricular-based (VVI) pacing. The benefits in A-V sequential pacing with the DDDR mode are likely mitigated by the interventricular (V-V) dysynchrony imposed by the high percentage of ventricular pacing commonly seen in the DDDR mode. Programming DDDR pacemakers to encourage intrinsic A-V conduction and reduce right ventricular pacing will likely decrease heart failure and pacemaker syndrome. Studies are currently ongoing to address these questions

Misdiagnosis, Mistreatment, and Harm - When Medical Care Ignores Social Forces.

The Case Studies in Social Medicine demonstrate that when physicians use only biologic or individual behavioral interventions to treat diseases that stem from or are exacerbated by social factors, we risk harming the patients we seek to serve

Phytophthora functional genomics database (PFGD): functional genomics of phytophthora–plant interactions

The Phytophthora Functional Genomics Database (PFGD; ), developed by the National Center for Genome Resources in collaboration with The Ohio State University-Ohio Agricultural Research and Development Center (OSU-OARDC), is a publicly accessible information resource for Phytophthora–plant interaction research. PFGD contains transcript, genomic, gene expression and functional assay data for Phytophthora infestans, which causes late blight of potato, and Phytophthora sojae, which affects soybeans. Automated analyses are performed on all sequence data, including consensus sequences derived from clustered and assembled expressed sequence tags. The PFGD search filter interface allows intuitive navigation of transcript and genomic data organized by library and derived queries using modifiers, annotation keywords or sequence names. BLAST services are provided for libraries built from the transcript and genomic sequences. Transcript data visualization tools include Quality Screening, Multiple Sequence Alignment and Features and Annotations viewers. A genomic browser that supports comparative analysis via novel dynamic functional annotation comparisons is also provided. PFGD is integrated with the Solanaceae Genomics Database (SolGD; ) to help provide insight into the mechanisms of infection and resistance, specifically as they relate to the genus Phytophthora pathogens and their plant hosts

The Legume Information System (LIS): an integrated information resource for comparative legume biology

The Legume Information System (LIS) (http://www.comparative-legumes.org), developed by the National Center for Genome Resources in cooperation with the USDA Agricultural Research Service (ARS), is a comparative legume resource that integrates genetic and molecular data from multiple legume species enabling cross-species genomic and transcript comparisons. The LIS virtual plant interface allows simplified and intuitive navigation of transcript data from Medicago truncatula, Lotus japonicus, Glycine max and Arabidopsis thaliana. Transcript libraries are represented as images of plant organs in different developmental stages, which are selected to query the analyzed and annotated data. Complex queries can be accomplished by adding modifiers, keywords and sequence names. The LIS also contains annotated genomic data featuring transcript alignments to validate gene predictions as well as motif and similarity analyses. The genomic browser supports comparative analysis via novel dynamic functional annotation comparisons. CMap, developed as part of the GMOD project (http://www.gmod.org/cmap/index.shtml), has been incorporated to support comparative analyses of community linkage and physical map data. LIS is being expanded to incorporate gene expression and biochemical pathways which will be seamlessly integrated forming a knowledge discovery framework

The treatment of severe child aggression (TOSCA) study: Design challenges

<p>Abstract</p> <p>Background</p> <p>Polypharmacy (the concurrent use of more than one psychoactive drug) and other combination interventions are increasingly common for treatment of severe psychiatric problems only partly responsive to monotherapy. This practice and research on it raise scientific, clinical, and ethical issues such as additive side effects, interactions, threshold for adding second drug, appropriate target measures, and (for studies) timing of randomization. One challenging area for treatment is severe child aggression. Commonly-used medications, often in combination, include psychostimulants, antipsychotics, mood stabilizers, and alpha-2 agonists, which vary considerably in terms of perceived safety and efficacy.</p> <p>Results</p> <p>In designing our NIMH-funded trial of polypharmacy, we focused attention on the added benefit of a second drug (risperidone) to the effect of the first (stimulant). We selected these two drugs because their associated adverse events might neutralize each other (e.g., sleep delay and appetite decrease from stimulant versus sedation and appetite increase from antipsychotic). Moreover, there was considerable evidence of efficacy for each drug individually for the management of ADHD and child aggression. The study sample comprised children (ages 6-12 years) with both diagnosed ADHD and disruptive behavior disorder (oppositional-defiant or conduct disorder) accompanied by severe physical aggression. In a staged sequence, the medication with the least problematic adverse effects (stimulant) was openly titrated in 3 weeks to optimal effect. Participants whose behavioral symptoms were not normalized received additional double-blind medication, either risperidone or placebo, by random assignment. Thus children whose behavioral symptoms were normalized with stimulant medication were not exposed to an antipsychotic. All families participated in an empirically-supported parent training program for disruptive behavior, so that the actual comparison was stimulant+parent training versus stimulant+antipsychotic+parent training.</p> <p>Conclusions</p> <p>We hope that the resolutions of the challenges presented here will be useful to other investigators and facilitate much-needed research on child psychiatric polypharmacy.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00796302">NCT00796302</a></p

Re-presenting para-sport bodies: Disability and the cultural legacy of the Paralympic Games

This report provides data and recommendations drawn from the rst funded academic project to examine the implications of the rapid commercialisation of the Paralympic Games and the increasing visibility of disa- bility in the media; in uenced by the success of Channel 4’s entry as the United Kingdom’s o cial Paralympic broadcaster in 2012. Through an integrated methodological approach, we provide a joined-up evidence base that captures the intentions and practices of Channel 4’s (C4) broadcasting of the Rio 2016 Paralympics; the in uence of this on the content of Paralympic coverage and mediated forms of disability representation; and the wider impact on public attitudes toward disability. This approach allowed us to examine the important and in uential relationship between Paralympic production practices, progressive social change and cultural legacies

Bioactivation of isoxazole-containing bromodomain and extra-terminal domain (BET) inhibitors

The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 for more in-depth analysis. OXFBD\u27s bioactivations were evenly split between traditional quinones and novel extended quinone-methides involving the isoxazole yet strongly favored the latter quinones. Subsequent experimental studies confirmed the formation of both types of quinones for OXFBD molecules, yet traditional quinones were the dominant reactive metabolites. Modeled I-BET151 bioactivations led to extended quinone-methides, which were not verified experimentally. The differences in observed and predicted bioactivations reflected the need to improve overall bioactivation scaling. Nevertheless, our coupled modeling approach predicted BET inhibitor bioactivations including novel extended quinone methides, and we experimentally verified those pathways highlighting potential concerns for toxicity in the development of these new drug leads

Ring opening metathesis polymerisation of a new bio-derived monomer from itaconic anhydride and furfuryl alcohol

A new oxa-norbornene bio-based lactone obtained from the 100% atom economic reaction of furfuryl alcohol and itaconic anhydride via a tandem Diels-Alder addition and lactonisation is presented. Esterification of the resulting acid gives a monomer for the production of a bio-based polymer with low polydispersity and well controlled molecular weight via ring-opening metathesis polymerisation (ROMP)

Early and efficient detection of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures.

Early, efficient and inexpensive methods for the detection of pulmonary tuberculosis are urgently needed for effective patient management as well as to interrupt transmission. These methods to detect M. tuberculosis in a timely and affordable way are not yet widely available in resource-limited settings. In a developing-country setting, we prospectively evaluated two methods for culturing and detecting M. tuberculosis in sputum. Sputum samples were cultured in liquid assay (micro broth culture) in microplate wells and growth was detected by microscopic observation, or in Löwenstein-Jensen (LJ) solid media where growth was detected by visual inspection for colonies. Sputum samples were collected from 321 tuberculosis (TB) suspects attending Bugando Medical Centre, in Mwanza, Tanzania, and were cultured in parallel. Pulmonary tuberculosis cases were diagnosed using the American Thoracic Society diagnostic standards. There were a total of 200 (62.3%) pulmonary tuberculosis cases. Liquid assay with microscopic detection detected a significantly higher proportion of cases than LJ solid culture: 89.0% (95% confidence interval [CI], 84.7% to 93.3%) versus 77.0% (95% CI, 71.2% to 82.8%) (p = 0.0007). The median turn around time to diagnose tuberculosis was significantly shorter for micro broth culture than for the LJ solid culture, 9 days (interquartile range [IQR] 7-13), versus 21 days (IQR 14-28) (p<0.0001). The cost for micro broth culture (labor inclusive) in our study was US $4.56 per sample, versus US$11.35 per sample for the LJ solid culture. The liquid assay (micro broth culture) is an early, feasible, and inexpensive method for detection of pulmonary tuberculosis in resource limited settings