Clinical management of cUTI, cIAI, and HABP/VABP attributable to carbapenem-resistant Gram-negative infections in Spain

Introduction. Carbapenem-resistant Gram-negative (CRGN) infections are a major public health problem in Spain, often implicated in complicated, healthcare-associated infections that require the use of potentially toxic antibacterial agents of last resort. The objective of this study was to assess the clinical management of complicated infections caused by CRGN bacteria in Spanish hospitals. Methods. The study included: 1) a survey assessing the GN infection and antibacterial susceptibility profile in five participating Spanish hospitals and 2) a non-interventional, retrospective single cohort chart review of 100 patients with complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/ VABP) attributable to CRGN pathogens. Results. In the participating hospitals CRGN prevalence was 9.3% amongst complicated infections. In the retrospective cohort, 92% of infections were healthcare-associated, and Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common pathogens. OXA was the most frequently detected carbapenemase type (71.4%). We found that carbap enems were frequently used to treat cUTI, cIAI, HABP/VABP caused by CRGN pathogens. Carbapenem use, particularly in combination with other agents, persisted after confirmation of carbapenem resistance. Clinical cure was 66.0%, mortality during hospitalization 35.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%. Conclusion. Our results reflect the high burden and un met needs associated with the management of complicated infections attributable to CRGN pathogens in Spain and highlight the urgent need for enhanced clinical management of these difficult-to-treat infections.Funding: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

A Genome-Wide Association Study of Attention Function in a Population-Based Sample of Children

BACKGROUND: Attention function filters and selects behaviorally relevant information. This capacity is impaired in some psychiatric disorders and has been proposed as an endophenotype for Attention-Deficit/Hyperactivity Disorder; however, its genetic basis remains largely unknown. This study aimed to identify single nucleotide polymorphism (SNPs) associated with attention function. MATERIALS AND METHODS: The discovery sample included 1655 children (7-12 years) and the replication sample included 546 children (5-8 years). Five attention outcomes were assessed using the computerized Attentional Network Test (ANT): alerting, orienting, executive attention, Hit Reaction time (HRT) and the standard error of HRT (HRTSE). A Genome-wide Association Study was conducted for each outcome. Gene set enrichment analyses were performed to detect biological pathways associated with attention outcomes. Additional neuroimaging analyses were conducted to test neural effects of detected SNPs of interest. RESULTS: Thirteen loci showed suggestive evidence of association with attention function (P<10-5) in the discovery sample. One of them, the rs4321351 located in the PID1 gene, was nominally significant in the replication sample although it did not survive multiple testing correction. Neuroimaging analysis revealed a significant association between this SNP and brain structure and function involving the frontal-basal ganglia circuits. The mTOR signaling and Alzheimer disease-amyloid secretase pathways were significantly enriched for alerting, orienting and HRT respectively (FDR<5%). CONCLUSION: These results suggest for the first time the involvement of the PID1 gene, mTOR signaling and Alzheimer disease-amyloid secretase pathways, in attention function during childhood. These genes and pathways have been proposed to play a role in neuronal plasticity, memory and neurodegenerative disease

Airborne copper exposure in school environments associated with poorer motor performance and altered basal ganglia

Children are more vulnerable to the effects of environmental elements. A variety of air pollutants are among the identified factors causing neural damage at toxic concentrations. It is not obvious, however, to what extent the tolerated high levels of air pollutants are able to alter brain development. We have specifically investigated the neurotoxic effects of airborne copper exposure in school environments. Speed and consistency of motor response were assessed in 2836 children aged from 8 to 12 years. Anatomical , diffusion tensor imaging, and functional were used to directly test the brain repercussions in a subgroup of 263 children. Higher copper exposure was associated with poorer motor performance and altered structure of the basal ganglia. Specifically, the architecture of the caudate nucleus region was less complete in terms of both tissue composition and neural track water diffusion. Functional consistently showed a reciprocal connectivity reduction between the caudate nucleus and the frontal cortex. The results establish an association between environmental copper exposure in children and alterations of basal ganglia structure and function

The influence of selected genetic and environmental factors on white matter pathway structure measured with diffusion tensor imaging

[ENG] The present doctoral thesis is focused on describing the effects that different environmental and genetic modulators have on white matter pathways and its consequences measured with diffusion tensor imaging. We chose to focus on two examples of each type of modulators. Firstly, we selected as environment modulating factors: pollutants and video games. On one side, pollution as an external factor that enters passively the brain and may influence developmental trajectories. And on the other hand, we used video games as a good example of active behavior that can modify white matter tracts through practice. Secondly, Down syndrome and Prader-Willi syndrome were selected as representative genetic syndromes that may interfere on white matter growth because, although Down syndrome has higher incidence rate than Prader-Willi syndrome, both show behavioral and cognitive alterations, indicating an abnormal brain development. The results of this doctoral thesis lead to the conclusion that white matter pathways development is not an immutable process and it can be modified by diverse modulators. In the same way, diffusion tensor imaging is a good-quality technique to capture and identify those white matter changes through life.[spa] La presente tesis doctoral se centra en describir los efectos que diferentes moduladores ambientales y genéticos tienen sobre las vías de la sustancia blanca y sus consecuencias a través de imágenes de tensor de difusión. Decidimos centrarnos dos ejemplos de cada tipo de moduladores. En primer lugar, se seleccionó como factores de modulación ambiental: contaminantes y videojuegos. Por un lado, la contaminación es un factor externo que penetra pasivamente el cerebro y puede influir en las trayectorias del desarrollo. Y por otro lado, los videojuegos son un buen ejemplo de comportamiento activo que puede modificar los tractos de la materia blanca a través de la práctica. En segundo lugar, se seleccionaron el síndrome de Down y síndrome de Prader-Willi como síndromes genéticos representativos que pueden interferir en el crecimiento de la materia blanca ya que, aunque el síndrome de Down tiene una tasa de incidencia superior al síndrome de Prader-Willi, ambos muestran alteraciones cognitivas y conductuales fruto de un subdesarrollo de las vías de sustancia blanca. Los resultados de esta tesis doctoral nos llevan a la conclusión de que el desarrollo de vías de sustancia blanca no es un proceso inmutable y puede ser modificado por diversos moduladores. De la misma manera, el tensor de difusión es una técnica adecuada para capturar e identificar los cambios en la sustancia blanca que acontecen a lo largo de la vid

Moda infantil "Molate" colección 2009: Tú eliges

Realización de una colección de camisetas infantiles interactivas con el niño, ya que ayudan a su desarrollo cognitivo mediante la combinación de formas y colores. El objetivo es que el niño aprenda de una forma divertida y al mismo tiempo tome partido en su indumentaria para que cree él mismo sus propios diseños exclusivos. La colección va destinada a niños de entre cuatro y diez años, niños y niñas indistintamente ya que los diseños en su mayoría son unisex.Ayala Fenoll, RT. (2008). Moda infantil "Molate" colección 2009: Tú eliges. http://hdl.handle.net/10251/18256.Archivo delegad

Evolution of Clonal and Susceptibility Profiles of Serotype 19A Streptococcus pneumoniae among Invasive Isolates from Children in Spain, 1990 to 2008▿

The genetic structure and antibiotic nonsusceptibility of all serotype 19A Streptococcus pneumoniae pediatric pneumococcal isolates received at the Spanish Pneumococcal Reference Laboratory (1990 to 2008) were analyzed. Of them, 410 (79.8%) isolates belonged to 14 sequence types (STs) with >10 isolates each, and 104 to 73 STs (with 21 new STs, ST5141 to ST5161, with one isolate each). Time trends in 2000 to 2008 (n = 471) were explored by lineal regression. Serotype 19A increased from 5.7% in 2000 to 16.8% in 2008 (R2 = 0.872; P = 0.001). Decreasing trends (P < 0.03) were found for ST202 (R2 = 0.774) and ST81 (R2 = 0.559), and increasing trends (P < 0.03) for ST878 (R2 = 0.544) and ST320 (R2 = 0.530), both belonging to the clonal complex (CC) Denmark14-32 and first detected in 2003 and 2007, respectively, and ST2013 (R2 = 0.704) and ST4461 (R2 = 0.707), both appearing in 2004. Penicillin nonsusceptibility was clustered in ST81, ST276, ST320, ST878, ST2013, and ST4461 (>90% nonsusceptibility), and amoxicillin and cefotaxime nonsusceptibility in ST320: 87% amoxicillin (MIC50/MIC90 = 8/8 μg/ml) and 43.5% cefotaxime (MIC50/MIC90 = 1/2 μg/ml) nonsusceptibility. No trends were found for erythromycin nonsusceptibility (ranging from 38.5% to 66.7%) and cefotaxime nonsusceptibility (ranging from 0.0% to 7.8%), but increasing trends (P < 0.02) were found for oral penicillin (from 16.7% in 2000 to 56.3% in 2008; R2 = 0.628) and amoxicillin (from 0.0% before 2007 to 13.8% in 2008; R2 = 0.628) nonsusceptibility. This study warns about the emergence of serotype 19A STs associated with high-level antibiotic nonsusceptibility, with a role for ST320 and ST878 occupying the niche left by some pneumococcal 7-valent conjugate vaccine (PCV7)-related resistant STs. The rapid expansion of serotype 19A and STs related to antibiotic resistance indicates that vaccines covering serotype 19A present advantages in countering invasive disease

A longitudinal study of brain anatomy changes preceding dementia in Down syndrome

We longitudinally assessed Down syndrome individuals at the age of risk of developing dementia to measure changes in brain anatomy and their relationship to cognitive impairment progression. Forty-two Down syndrome individuals were initially included, of whom 27 (mean age 46.8 years) were evaluable on the basis of completing the 2-year follow-up and success in obtaining good quality MRI exams. Voxel-based morphometry was used to estimate regional brain volumes at baseline and follow-up on 3D anatomical images. Longitudinal volume changes for the group and their relationship with change in general cognitive status and specific cognitive domains were mapped. As a group, significant volume reduction was identified in the substantia innominata region of the basal forebrain, hippocampus, lateral temporal cortex and left arcuate fasciculus. Volume reduction in the substantia innominata and hippocampus was more prominent in individuals whose clinical status changed from cognitively stable to mild cognitive impairment or dementia during the follow-up. Relevantly, longitudinal memory score change was specifically associated with volume change in the hippocampus, prospective memory with prefrontal lobe and verbal comprehension with language-related brain areas. Results are notably concordant with the well-established anatomical changes signaling the progression to dementia in Alzheimer's disease, despite the dense baseline pathology that developmentally accumulates in Down syndrome. This commonality supports the potential value of Down syndrome as a genetic model of Alzheimer's neurodegeneration and may serve to further support the view that Down syndrome patients are best candidates to benefit from treatment research in Alzheimer's disease

Disease Isolates of <em>Streptococcus pseudopneumoniae</em> and Non-Typeable <em>S. pneumoniae</em> Presumptively Identified as Atypical <em>S. pneumoniae</em> in Spain

<div><p>We aimed to obtain insights on the nature of a collection of isolates presumptively identified as atypical <i>Streptococcus pneumoniae</i> recovered from invasive and non-invasive infections in Spain. One-hundred and thirty-two isolates were characterized by: optochin susceptibility in ambient and CO₂-enriched atmosphere; bile solubility; PCR-based assays targeting pneumococcal genes <i>lyt</i>A, <i>ply</i>, <i>psp</i>A, <i>cps</i>A, <i>Spn</i>9802, <i>ali</i>B-like ORF2, and a specific 16S rRNA region; multilocus sequence analysis; and antimicrobial susceptibility. By multilocus sequence analysis, 61 isolates were <i>S. pseudopneumoniae</i>, 34 were pneumococci, 13 were <i>S. mitis</i>, and 24 remained unclassified as non-pneumococci. Among <i>S. pseudopneumoniae</i> isolates, 51 (83.6%) were collected from respiratory tract samples; eight isolates were obtained from sterile sources. High frequency of non-susceptibility to penicillin (60.7%) and erythromycin (42.6%) was found. Only 50.8% of the <i>S. pseudopneumoniae</i> isolates displayed the typical optochin phenotype originally described for this species. None harbored the <i>cps</i>A gene or the pneumococcal typical <i>lyt</i>A restriction fragment length polymorphism. The <i>Spn</i>9802 and the specific 16S rRNA regions were detected among the majority of the <i>S. pseudopneumoniae</i> isolates (n = 59 and n = 49, respectively). The <i>ply</i> and <i>psp</i>A genes were rarely found. A high genetic diversity was found and 59 profiles were identified. Among the <i>S. pneumoniae</i>, 23 were capsulated and 11 were non-typeable. Three non-typeable isolates, associated to international non-capsulated lineages, were recovered from invasive disease sources. In conclusion, half of the atypical pneumococcal clinical isolates were, in fact, <i>S. pseudopneumoniae</i> and one-fourth were other streptococci. We identified <i>S. pseudopneumoniae</i> and non-typeable pneumococci as cause of disease in Spain including invasive disease.</p> </div

Properties of <i>S. pneumoniae</i> clinical isolates.

a<p>Novel STs and alleles found in this study are represented in bold.</p>b<p>PEN, penicillin; CTX, cefotaxime; ERY, erythromycin; CLI, clindamycin; TET, tetracycline; CHL, chloramphenicol, SXT, trimethoprim-sulfamethoxazole non-susceptible; CIP, ciprofloxacin; LEV, levofloxacin.</p>c<p>International clones of PMEN; SLV, Single Locus Variant; DLV, Double Locus Variant.</p