Errores de medicación en pediatría

Concerns regarding patient safety affect healthcare, and medication errors are the most frequent category of medical errors and linked with severe consequences. This study discusses epidemiologic characteristics of medication errors in pediatric patients and points out prevention strategies. Approximately 8% of the studies on the subject of medication errors identified in different national and international databases are distinctively related to the pediatric population. Children are vulnerable to medication errors due to intrinsic factors, such as proper anatomic and physiological characteristics; and due to extrinsic factors, with emphasis on the lack of public health politics and changes in the pharmaceutical industry to attend children's needs. The available evidences indicate, as imperative, the implementation of strategies to prevent medication errors, contributing to promote patient safety.La seguridad del paciente es un problema de salud pública y los errores con medicamentos son los más frecuentes y más graves. Este artículo describe características epidemiológicas de errores de medicación en áreas de atención pediátrica y algunas estrategias de prevención. Aproximadamente 8% de las investigaciones sobre errores de medicación identificadas en las bases de datos nacionales e internacionales se refieren específicamente a niños. Los niños tienen mayor vulnerabilidad a la ocurrencia de errores debidos a factores intrínsecos, con destaque para características anatómicas y fisiológicas, e extrínsecos, en particular con respecto a falta de políticas sanitarias y de la industria farmacéutica orientada a la atención de tales características. Evidencias muestran la necesidad de aplicar estrategias para prevenir errores de medicación, promoviendo la seguridad del paciente.A segurança do paciente constitui problema de saúde pública, e erros com medicamentos são os mais freqüentes e graves. O artigo apresenta características epidemiológicas dos erros de medicação em diferentes áreas de atendimento pediátrico, e aponta estratégias de prevenção. Aproximadamente 8% das pesquisas sobre erros de medicação identificadas em bases de dados nacionais e internacionais referem-se à população pediátrica. Crianças apresentam maior vulnerabilidade à ocorrência de erros devido a fatores intrínsecos, destacando-se características anatômicas e fisiológicas; e extrínsecos, relativos à falta de políticas de saúde e da indústria farmacêutica voltadas ao atendimento de tais especificidades. As evidências apontam para a necessidade de implementação de estratégias de prevenção de erros de medicação, contribuindo para promover a segurança do paciente.Universidade Federal de São Paulo (UNIFESP) Departamento de EnfermagemUNIFESP, Depto. de EnfermagemSciEL

Frequent Arousal from Hibernation Linked to Severity of Infection and Mortality in Bats with White-Nose Syndrome

White-nose syndrome (WNS), an emerging infectious disease that has killed over 5.5 million hibernating bats, is named for the causative agent, a white fungus (Geomyces destructans (Gd)) that invades the skin of torpid bats. During hibernation, arousals to warm (euthermic) body temperatures are normal but deplete fat stores. Temperature-sensitive dataloggers were attached to the backs of 504 free-ranging little brown bats (Myotis lucifugus) in hibernacula located throughout the northeastern USA. Dataloggers were retrieved at the end of the hibernation season and complete profiles of skin temperature data were available from 83 bats, which were categorized as: (1) unaffected, (2) WNS-affected but alive at time of datalogger removal, or (3) WNS-affected but found dead at time of datalogger removal. Histological confirmation of WNS severity (as indexed by degree of fungal infection) as well as confirmation of presence/absence of DNA from Gd by PCR was determined for 26 animals. We demonstrated that WNS-affected bats aroused to euthermic body temperatures more frequently than unaffected bats, likely contributing to subsequent mortality. Within the subset of WNS-affected bats that were found dead at the time of datalogger removal, the number of arousal bouts since datalogger attachment significantly predicted date of death. Additionally, the severity of cutaneous Gd infection correlated with the number of arousal episodes from torpor during hibernation. Thus, increased frequency of arousal from torpor likely contributes to WNS-associated mortality, but the question of how Gd infection induces increased arousals remains unanswered

MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model

Human embryonic stem cells (hESCs) can potentially differentiate into any cell type, including dopaminergic neurons to treat Parkinson's disease (PD), but hyperproliferation and tumor formation must be avoided. Accordingly, we use myocyte enhancer factor 2C (MEF2C) as a neurogenic and anti-apoptotic transcription factor to generate neurons from hESC-derived neural stem/progenitor cells (NPCs), thus avoiding hyperproliferation. Here, we report that forced expression of constitutively active MEF2C (MEF2CA) generates significantly greater numbers of neurons with dopaminergic properties in vitro. Conversely, RNAi knockdown of MEF2C in NPCs decreases neuronal differentiation and dendritic length. When we inject MEF2CA-programmed NPCs into 6-hydroxydopamine—lesioned Parkinsonian rats in vivo, the transplanted cells survive well, differentiate into tyrosine hydroxylase-positive neurons, and improve behavioral deficits to a significantly greater degree than non-programmed cells. The enriched generation of dopaminergic neuronal lineages from hESCs by forced expression of MEF2CA in the proper context may prove valuable in cell-based therapy for CNS disorders such as PD

First proton-proton collisions at the LHC as observed with the ALICE detector: measurement of the charged-particle pseudorapidity density at root s=900 GeV

On 23rd November 2009, during the early commissioning of the CERN Large Hadron Collider (LHC), two counter-rotating proton bunches were circulated for the first time concurrently in the machine, at the LHC injection energy of 450 GeV per beam. Although the proton intensity was very low, with only one pilot bunch per beam, and no systematic attempt was made to optimize the collision optics, all LHC experiments reported a number of collision candidates. In the ALICE experiment, the collision region was centred very well in both the longitudinal and transverse directions and 284 events were recorded in coincidence with the two passing proton bunches. The events were immediately reconstructed and analyzed both online and offline. We have used these events to measure the pseudorapidity density of charged primary particles in the central region. In the range vertical bar eta vertical bar S collider. They also illustrate the excellent functioning and rapid progress of the LHC accelerator, and of both the hardware and software of the ALICE experiment, in this early start-up phase

Antisickling effects of 2,3-diphosphoglycerate depletion

Elevation of 2,3-bisphosphoglycerate (2,3-DPG) in sickle erthrocytes (SS RBCs) and concomitant acidification of the cell interior promote polymerization by decreasing the solubility (csat) of deoxyhemoglobin S. The antisickling effect of 2,3-DPG depletion was evaluated after activation of the 2,3-DPG phosphatase activity of bisphosphoglycerate mutase by glycolate-2-phosphate, leading to rapid loss of intracellular 2,3-DPG. To ensure its maximal reduction in a physiologic medium, isosmotic CO2/bicarbonate-buffered saline, pH 7.0, was used. Substitution of K+ for Na+ as the major extracellular cation suppressed K:Cl cotransport, prevented cell shrinkage, and allowed demonstration of the full antisickling effect of 2,3-DPG depletion. The modest effect on solubility per se of removing intraerythrocytic 2,3-DPG (delta Csat = 1.6 g/dL) was amplified into a much larger antisickling effect by interaction with three other cellular variables affecting solubility and polymer content (intracellular pH, O2 saturation, and mean cell hemoglobin concentration). Acting in concert, these four antisickling effects (three solubilizing, one osmotic) reduced polymer fraction of glycolate-treated SS RBCs by 32% to 63%, with a concomitant decrease in sickling of 46% to 95% at the nominal pO2 of the microcirculation (20 mm Hg). A decrement in sickling of this magnitude should significantly ameliorate the vasoocclusive severity of sickle cell disease.</jats:p

Comparing the performance of selected variant callers using synthetic data and genome segmentation

Abstract Background High-throughput sequencing has rapidly become an essential part of precision cancer medicine. But validating results obtained from analyzing and interpreting genomic data remains a rate-limiting factor. The gold standard, of course, remains manual validation by expert panels, which is not without its weaknesses, namely high costs in both funding and time as well as the necessarily selective nature of manual validation. But it may be possible to develop more economical, complementary means of validation. In this study we employed four synthetic data sets (variants with known mutations spiked into specific genomic locations) of increasing complexity to assess the sensitivity, specificity, and balanced accuracy of five open-source variant callers: FreeBayes v1.0, VarDict v11.5.1, MuTect v1.1.7, MuTect2, and MuSE v1.0rc. FreeBayes, VarDict, and MuTect were run in bcbio-next gen, and the results were integrated into a single Ensemble call set. The known mutations provided a level of “ground truth” against which we evaluated variant-caller performance. We further facilitated the comparison and evaluation by segmenting the whole genome into 10,000,000 base-pair fragments which yielded 316 segments. Results Differences among the numbers of true positives were small among the callers, but the numbers of false positives varied much more when the tools were used to analyze sets one through three. Both FreeBayes and VarDict produced strikingly more false positives than did the others, although VarDict, somewhat paradoxically also produced the highest number of true positives. The Ensemble approach yielded results characterized by higher specificity and balanced accuracy and fewer false positives than did any of the five tools used alone. Sensitivity and specificity, however, declined for all five callers as the complexity of the data sets increased, but we did not uncover anything more than limited, weak correlations between caller performance and certain DNA structural features: gene density and guanine-cytosine content. Altogether, MuTect2 performed the best among the callers tested, followed by MuSE and MuTect. Conclusions Spiking data sets with specific mutations –single-nucleotide variations (SNVs), single-nucleotide polymorphisms (SNPs), or structural variations (SVs) in this study—at known locations in the genome provides an effective and economical way to compare data analyzed by variant callers with ground truth. The method constitutes a viable alternative to the prolonged, expensive, and noncomprehensive assessment by expert panels. It should be further developed and refined, as should other comparatively “lightweight” methods of assessing accuracy. Given that the scientific community has not yet established gold standards for validating NGS-related technologies such as variant callers, developing multiple alternative means for verifying variant-caller accuracy will eventually lead to the establishment of higher-quality standards than could be achieved by prematurely limiting the range of innovative methods explored by members of the community

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study

Background: Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression. Methods and Findings: We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p Conclusions: These data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.</p