Low radiographic muscle density is associated with lower overall and disease-free survival in early-stage colorectal cancer patients

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Health care use and costs of adverse drug events emerging from outpatient treatment in Germany: A modelling approach

<p>Abstract</p> <p>Background</p> <p>This study's aim was to develop a first quantification of the frequency and costs of adverse drug events (ADEs) originating in ambulatory medical practice in Germany.</p> <p>Methods</p> <p>The frequencies and costs of ADEs were quantified for a base case, building on an existing cost-of-illness model for ADEs. The model originates from the U.S. health care system, its structure of treatment probabilities linked to ADEs was transferred to Germany. Sensitivity analyses based on values determined from a literature review were used to test the postulated results.</p> <p>Results</p> <p>For Germany, the base case postulated that about 2 million adults ingesting medications have will have an ADE in 2007. Health care costs related to ADEs in this base case totalled 816 million Euros, mean costs per case were 381 Euros. About 58% of costs resulted from hospitalisations, 11% from emergency department visits and 21% from long-term care. Base case estimates of frequency and costs of ADEs were lower than all estimates of the sensitivity analyses.</p> <p>Discussion</p> <p>The postulated frequency and costs of ADEs illustrate the possible size of the health problems and economic burden related to ADEs in Germany. The validity of the U.S. treatment structure used remains to be determined for Germany. The sensitivity analysis used assumptions from different studies and thus further quantified the information gap in Germany regarding ADEs.</p> <p>Conclusions</p> <p>This study found costs of ADEs in the ambulatory setting in Germany to be significant. Due to data scarcity, results are only a rough indication.</p

Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism

Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat

Aims/hypothesis Impaired intestinal barrier function is observed in type I diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type I diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model. Methods DP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose mannitol test and ex vivo by measuring trans-epithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. heal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction-related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf-beta (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR. Results The HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered. Conclusions/interpretation Improved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect

Reproducibility of `COST Reference Microplasma Jets'

Atmospheric pressure plasmas have been ground-breaking for plasma science and technologies, due to their significant application potential in many fields, including medicinal, biological, and environmental applications. This is predominantly due to their efficient production and delivery of chemically reactive species under ambient conditions. One of the challenges in progressing the field is comparing plasma sources and results across the community and the literature. To address this a reference plasma source was established during the `Biomedical Applications of Atmospheric Pressure Plasmas' EU COST Action MP1101. It is crucial that reference sources are reproducible. Here, we present the reproducibility and variance across multiple sources through examining various characteristics, including: absolute atomic oxygen densities, absolute ozone densities, electrical characteristics, optical emission spectroscopy, temperature measurements, and bactericidal activity. The measurements demonstrate that the tested COST jets are mainly reproducible within the intrinsic uncertainty of each measurement technique

Systematic Review of Medicine-Related Problems in Adult Patients with Atrial Fibrillation on Direct Oral Anticoagulants

New oral anticoagulant agents continue to emerge on the market and their safety requires assessment to provide evidence of their suitability for clinical use. There-fore, we searched standard databases to summarize the English language literature on medicine-related problems (MRPs) of direct oral anticoagulants DOACs (dabigtran, rivaroxban, apixban, and edoxban) in the treatment of adults with atri-al fibrillation. Electronic databases including Medline, Embase, International Pharmaceutical Abstract (IPA), Scopus, CINAHL, the Web of Science and Cochrane were searched from 2008 through 2016 for original articles. Studies pub-lished in English reporting MRPs of DOACs in adult patients with AF were in-cluded. Seventeen studies were identified using standardized protocols, and two reviewers serially abstracted data from each article. Most articles were inconclusive on major safety end points including major bleeding. Data on major safety end points were combined with efficacy. Most studies inconsistently reported adverse drug reactions and not adverse events or medication error, and no definitions were consistent across studies. Some harmful drug effects were not assessed in studies and may have been overlooked. Little evidence is provided on MRPs of DOACs in patients with AF and, therefore, further studies are needed to establish the safety of DOACs in real-life clinical practice

A Genome-Scale Metabolic Reconstruction of Mycoplasma genitalium, iPS189

With a genome size of ∼580 kb and approximately 480 protein coding regions, Mycoplasma genitalium is one of the smallest known self-replicating organisms and, additionally, has extremely fastidious nutrient requirements. The reduced genomic content of M. genitalium has led researchers to suggest that the molecular assembly contained in this organism may be a close approximation to the minimal set of genes required for bacterial growth. Here, we introduce a systematic approach for the construction and curation of a genome-scale in silico metabolic model for M. genitalium. Key challenges included estimation of biomass composition, handling of enzymes with broad specificities, and the lack of a defined medium. Computational tools were subsequently employed to identify and resolve connectivity gaps in the model as well as growth prediction inconsistencies with gene essentiality experimental data. The curated model, M. genitalium iPS189 (262 reactions, 274 metabolites), is 87% accurate in recapitulating in vivo gene essentiality results for M. genitalium. Approaches and tools described herein provide a roadmap for the automated construction of in silico metabolic models of other organisms

A Functional Genomics Approach to Establish the Complement of Carbohydrate Transporters in Streptococcus pneumoniae

The aerotolerant anaerobe Streptococcus pneumoniae is part of the normal nasopharyngeal microbiota of humans and one of the most important invasive pathogens. A genomic survey allowed establishing the occurrence of twenty-one phosphotransferase systems, seven carbohydrate uptake ABC transporters, one sodium∶solute symporter and a permease, underlining an exceptionally high capacity for uptake of carbohydrate substrates. Despite high genomic variability, combined phenotypic and genomic analysis of twenty sequenced strains did assign the substrate specificity only to two uptake systems. Systematic analysis of mutants for most carbohydrate transporters enabled us to assign a phenotype and substrate specificity to twenty-three transport systems. For five putative transporters for galactose, pentoses, ribonucleosides and sulphated glycans activity was inferred, but not experimentally confirmed and only one transport system remains with an unknown substrate and lack of any functional annotation. Using a metabolic approach, 80% of the thirty-two fermentable carbon substrates were assigned to the corresponding transporter. The complexity and robustness of sugar uptake is underlined by the finding that many transporters have multiple substrates, and many sugars are transported by more than one system. The present work permits to draw a functional map of the complete arsenal of carbohydrate utilisation proteins of pneumococci, allows re-annotation of genomic data and might serve as a reference for related species. These data provide tools for specific investigation of the roles of the different carbon substrates on pneumococcal physiology in the host during carriage and invasive infection

In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention