In silico identification and experimental validation of hits active against KPC-2 \u3b2-lactamase

Bacterial resistance has become a worldwide concern, particularly after the emergence of resistant strains overproducing carbapenemases. Among these, the KPC-2 carbapenemase represents a significant clinical challenge, being characterized by a broad substrate spectrum that includes aminothiazoleoxime and cephalosporins such as cefotaxime. Moreover, strains harboring KPC-type \u3b2-lactamases are often reported as resistant to available \u3b2-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam). Therefore, the identification of novel non \u3b2-lactam KPC-2 inhibitors is strongly necessary to maintain treatment options. This study explored novel, non-covalent inhibitors active against KPC-2, as putative hit candidates. We performed a structure-based in silico screening of commercially available compounds for non-\u3b2-lactam KPC-2 inhibitors. Thirty-two commercially available high-scoring, fragment-like hits were selected for in vitro validation and their activity and mechanism of action vs the target was experimentally evaluated using recombinant KPC-2. N-(3-(1H-tetrazol-5-yl)phenyl)-3-fluorobenzamide (11a), in light of its ligand efficiency (LE = 0.28 kcal/mol/non-hydrogen atom) and chemistry, was selected as hit to be directed to chemical optimization to improve potency vs the enzyme and explore structural requirement for inhibition in KPC-2 binding site. Further, the compounds were evaluated against clinical strains overexpressing KPC-2 and the most promising compound reduced the MIC of the \u3b2-lactam antibiotic meropenem by four fold

Velocity Dispersions and Stellar Populations of the Most Compact and Msssive early-Type Galaxies at Redshift similar to 1

We present Gran-Telescopio-Canarias/OSIRIS optical spectra of four of the most compact and massive early-type galaxies (ETGs) in the Groth Strip Survey at redshift z similar to 1, with effective radii R-e = 0.5-2.4 kpc and photometric stellarmasses M-star = (1.2-4) x 10(11)M(circle dot). We find that these galaxies have velocity dispersions sigma = 156-236 km s(-1). The spectra are well fitted by single stellar population models with approximately 1 Gyr of age and solar metallicity. We find that (1) the dynamical masses of these galaxies are systematically smaller by a factor of similar to 6 than the published stellarmasses using BRIJK photometry, and (2) when estimating stellarmasses as 0.7xM(dyn), a combination of passive luminosity fading with mass/size growth due to minor mergers can plausibly evolve our objects to match the properties of the local population of ETGs

Elderly People With Drug-Related Problems Identified in the Emergency Department : Impact of Therapeutic Complexity on Consultations to the Health System

Different scales have been validated to assess the medication regimen complexity. However, the effect of this complexity on the risk of health care center consultations in patients with drug-related problems is unknown. This study's objective is to evaluate the association between the Medication Regimen Complexity Index (MCRI) and the number of drugs prescribed and new consultations to the health care system in patients who visit an emergency service due to drug-related problems. This is a retrospective observational study. We included patients >65 years who attended in an emergency service for drug-related problems. To identify variables associated with health care center reconsultation, a multivariate analysis was performed, including demographic and comorbidity variables, number of drugs prescribed, and MCRI value. Two hundred and one patients were included. A significant association was found between the prescription of more than five drugs (odds ratio [OR] = 2.50, 95% confidence interval [CI] = [1.08, 5.79]), an MCRI > 20 (2.98 [1.46-6.09]), and an increase in the number of drugs prescribed (2.87 [1.57-5.21]) and its MCRI (2.06 [1.13-3.77]) at discharge and a new visit to the emergency department. An association was found between the prescription of more than five drugs, an MCRI > 20, an increase in the number of drugs, and in MCRI value at discharge and a new visit to any other health care center. The number of prescribed drugs and the medication complexity of patients who visit the emergency department for drug-related problems was associated with an increase in the number of revisits to the emergency department and to other health care centers

Multidrug-resistant Mycobacterium tuberculosis, Bangui, Central African Republic

We investigated multidrug-resistant (MDR) Mycobacterium tuberculosis strains in Bangui, Central African Republic. We found 39.6% with the same spoligotype and synonymous single nucleotide polymorphism in the mutT1 gene. However, strains had different rpoB mutations responsible for rifampin resistance. MDR strains in Bangui may emerge preferentially from a single, MDR-prone family

Salud Mental y Salud Pública en España: Vigilancia epidemiológica

La desigual trayectoria histórica de la EM frente a otras enfermedades ha justificado movimientos profesionales y sociales que abrieron grandes expectativas, pero cosecharon escasos resultados en términos de salud para los pacientes y de mejoras en su frágil entorno. No es de extrañar que el enfoque estructuralista del siglo XX desembocara en una nueva forma de abordar la salud mental que revolucionó la Europa Occidental y también España en las décadas de los 70 y 80 (Basaglia, 2013). La reforma psiquiátrica fue la punta del iceberg que facilitó una atención más personalizada y adecuada a la cultura de bienestar y de derechos de la Europa occidental y una mayor efectividad en el ámbito bio-psico-social. Los esfuerzos por la normalización del paciente mental y su integración en la atención sanitaria común cosecharon mayores frutos en el ámbito de la clínica que en el de la salud pública. La vinculación entre salud física y salud mental avanzaron especialmente en el ámbito de las patologías de mayor morbimortalidad (cardiovasculares, cáncer, y otras), recomendándose con frecuencia atención especializada para abordar sus consecuencias emocionales y su potencial asociación con trastornos mentales (Páez y cols., 2007; Gil Moncayo y cols., 2008). Otro buen ejemplo fue la incorporación progresiva de nuevas opciones terapéuticas para pacientes mentales (pisos de acogida, hospitales de día, etc). A pesar de estos grandes avances en el abordaje multidimensional del binomio salud/enfermedad mental, la tradicional división entre salud física y salud mental sigue siendo una barrera para abordar los trastornos mentales y su prevención de una forma integral, de acuerdo con las definiciones de salud y bienestar al uso (Giner y cols., 2014). En sus informes de 2004 y 2005 sobre la salud en el mundo, la OMS insiste en que «la salud mental es más que la ausencia de enfermedad, o su presencia está íntimamente conectada con la salud física».SALUD PÚBLICA Y SALUD MENTAL: CÓMO AFRONTAR CON EFICACIA LA VIGILANCIA PARA UNA ACCIÓN SANITARIA MÁS. MARCO GENERAL PARA LA PREVENCIÓN DE ENFERMEDADES MENTALES SEGÚN LA ORGANIZACIÓN MUNDIAL DE LA SALUD. HACIA UNA VIGILANCIA DE LA SALUD PÚBLICA EN SALUD MENTAL. INDICADORES DE SALUD MENTAL EN LOS SISTEMAS DE INFORMACIÓN. SISTEMAS DE INFORMACIÓN DE SALUD MENTAL EN PAÍSES EUROPEOS. LA EVALUACIÓN DE LA SALUD MENTAL EN LA ENCUESTA NACIONAL DE SALUD DE ESPAÑA. EL SISTEMA DE INFORMACIÓN EN SALUD MENTAL Y ADICCIONES EN CATALUNYA. EL SISTEMA DE INFORMACIÓN EN SALUD MENTAL EN GALICIA. NECESIDADES DE INFORMACIÓN EN SALUD MENTAL DESDE UNA PERSPECTIVA ASISTENCIAL. TRASTORNOS MENTALES EN LOS DIAGNÓSTICOS HOSPITALARIOS EN ESPAÑA: 2004-2013. ASOCIACIÓN E IMPACTO DE LA SALUD MENTAL EN LA DISCAPACIDAD GRAVE EN PERSONAS DE EDAD MEDIA Y AVANZADA EN. CARGA DE ENFERMEDAD DE LOS TRASTORNOS MENTALES Y DEL COMPORTAMIENTO. MORTALIDAD POR SUICIDIO.N

Associations between chronic conditions, body functions, activity limitations and participation restrictions: a cross-sectional approach in Spanish non-clinical populations

OBJECTIVES: To analyse the relationships between chronic conditions, body functions, activity limitations and participation restrictions in the International Classification of Functioning, Disability and Health (ICF) framework. DESIGN: A cross-sectional study. SETTING: 2 geographical areas in the Autonomous Region of Aragon, Spain, namely, a rural area, Cinco Villas, and an urban area in the city of Zaragoza. PARTICIPANTS: 864 individuals selected by simple random sampling from the register of Social Security card holders, aged 50 years and over, positive to disability screening. MAIN OUTCOME MEASURES: ICF Checklist-body function domains, WHO Disability Assessment Schedule 2.0 (WHODAS 2.0, 36-item (WHODAS-36)) global scores and medical diagnoses (chronic conditions) from primary care records. RESULTS: Mild disability (WHODAS-36 level 5-24%) was present in 51.5% of the sample. In the adjusted ordinal regression model with WHODAS-36 as the dependent variable, disability was substantially associated with moderate-to-complete impairment in the following functions: mental, OR 212.8 (95% CI 72 to 628.9); neuromusculoskeletal, OR 44.8 (24.2 to 82.8); and sensory and pain, OR 6.3 (3.5 to 11.2). In the relationship between health conditions and body function impairments, the strongest links were seen for: dementia with mental functions, OR 50.6 (25.1 to 102.1); cerebrovascular disease with neuromusculoskeletal function, OR 5.8 (3.5 to 9.7); and chronic renal failure with sensory function and pain, OR 3.0 (1.49 to 6.4). Dementia, OR 8.1 (4.4 to 14.7) and cerebrovascular disease, OR 4.1 (2.7 to 6.4) were associated with WHODAS-36 scores. CONCLUSIONS: Body functions are heterogeneously linked to limitations in activities and restrictions on participation, with the highest impact being due to mental and musculoskeletal functions. This may be relevant for disability assessment and intervention design, particularly if defined on a body function basis. Control of specific health conditions, such as dementia and cerebrovascular disease, appears to be paramount in reducing disability among persons aged 50 years and over.This study was funded by the Carlos III Institute of Health (EPI projects 1637/06 and 1530/07; Health Research Fund grants PI06/1098 and PI07/90206), Convenio Marco IMSERSO-ISCIII reference number STVI 1282/ 15, Consortium for Biomedical Research in Neurodegenerative Diseases (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED), Zaragoza Regional Authority and Farasdués Foundation.S

The X-shooter Spectral Library (XSL): Data Release 3

We present the third data release (DR3) of the X-shooter Spectral Library (XSL). This moderate-to-high resolution, near-ultraviolet-to-near-infrared ($350-2480$ nm, R $\sim$ 10 000) spectral library is composed of 830 stellar spectra of 683 stars. DR3 improves upon the previous data release by providing the combined de-reddened spectra of the three X-shooter segments over the full $350-2480$ nm wavelength range. It also includes additional 20 M-dwarf spectra from the ESO archive. We provide detailed comparisons between this library and Gaia EDR3, MILES, NGSL, CaT library, and (E-)IRTF. The normalised rms deviation is better than $D=0.05$ or 5$\%$ for the majority of spectra in common between MILES (144 spectra of 180), NGSL (112$/$116), and (E-)IRTF (55$/$77) libraries. Comparing synthetic colours of those spectra reveals only negligible offsets and small rms scatter, such as the median offset(rms) 0.001$\pm$0.040 mag in the (box1-box2) colour of the UVB arm,-0.004$\pm$0.028 mag in (box3-box4) of the VIS arm, and -0.001$\pm$0.045 mag in (box2-box3) colour between the UVB and VIS arms, when comparing stars in common with MILES. We also find an excellent agreement between the Gaia published (BP-RP) colours and those measured from the XSL DR3 spectra, with a zero median offset and an rms scatter of 0.037 mag for 449 non-variable stars. The unmatched characteristics of this library, which combine a relatively high resolution, a large number of stars, and an extended wavelength coverage, will help us to bridge the gap between the optical and the near-IR studies of intermediate and old stellar populations, and to probe low-mass stellar systems.Comment: 26 pages, 25 figures, accepted to Astronomy & Astrophysics. The data are available at the CDS via anonymous ftp to cdsarc.u-strasbg.fr(130.79.128.5) or via http://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/ or on the XSL web-page http://xsl.astro.unistra.f

Mutations in Putative Mutator Genes of Mycobacterium tuberculosis Strains of the W-Beijing Family

Alterations in genes involved in the repair of DNA mutations (mut genes) result in an increased mutation frequency and better adaptability of the bacterium to stressful conditions. W-Beijing genotype strains displayed unique missense alterations in three putative mut genes, including two of the mutT type (Rv3908 and mutT2) and ogt. These polymorphisms were found to be characteristic and unique to W-Beijing phylogenetic lineage. Analysis of the mut genes in 55 representative W-Beijing isolates suggests a sequential acquisition of the mutations, elucidating a plausible pathway of the molecular evolution of this clonal family. The acquisition of mut genes may explain in part the ability of the isolates of W-Beijing type to rapidly adapt to their environment

The ESO Distant Cluster Sample: galaxy evolution and environment out to z=1

The ESO Distant Cluster Survey (EDisCS, P.I. Simon D.M. White, LP 166.A-0162) is an ESO large programme aimed at studying clusters and cluster galaxies at z=0.4-1. How different is the evolution of the star formation activity in clusters, in groups and in the field? Does it depend on cluster mass and/or the local galaxy density? How relevant are starburst and post-starburst galaxies in the different environments? Is there an evolution in the galaxies' structures, and if so, is this related to the changes in their star formation activity? These are some of the main questions that have been investigated using the EDisCS dataset.Comment: to appear in The Messenger, issue June 200

SALMANTICOR study. Rationale and design of a population-based study to identify structural heart disease abnormalities: a spatial and machine learning analysis

[EN]Introduction: This study aims to obtain data on the prevalence and incidence of structural heart disease in a population setting and, to analyse and present those data on the application of spatial and machine learning methods that, although known to geography and statistics, need to become used for healthcare research and for political commitment to obtain resources and support effective public health programme implementation. Methods and analysis: We will perform a cross-sectional survey of randomly selected residents of Salamanca (Spain). 2400 individuals stratified by age and sex and by place of residence (rural and urban) will be studied. The variables to analyse will be obtained from the clinical history, different surveys including social status, Mediterranean diet, functional capacity, ECG, echocardiogram, VASERA and biochemical as well as genetic analysis. Ethics and dissemination: The study has been approved by the ethical committee of the healthcare community. All study participants will sign an informed consent for participation in the study. The results of this study will allow the understanding of the relationship between the different influencing factors and their relative importance weights in the development of structural heart disease