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Objectives To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection. Methods One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on β-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays. Results Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC β-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility. Conclusions We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new β-lactam/β-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.

Liver involvement during infectious mononucleosis is common, but jaundice is considered rare. This study aimed to investigate serum bilirubin concentrations in patients with infectious mononucleosis and immune abnormalities associated with jaundice.We report on an adult patient with monoclonal B lymphocytosis and IgM-lambda gammopathy who developed a severe icteric hepatitis during infectious mononucleosis. We then reviewed the clinical records of 389 patients admitted to the hospital with infectious mononucleosis between 1995 and 2018 (51.7% male patients; median age, 19 years; range, 15-87 years) with focus on liver abnormalities and associated factors.Fifty-nine patients (15.1%) had serum bilirubin concentrations between 1.5 and 3 mg/dL, and 47 patients (12.0%) had serum bilirubin3 mg/dL. Patients with increased bilirubin concentrations had a distinct clinical presentation, with more frequent abdominal pain, nausea and vomiting, and less frequent sore throat than patients with normal bilirubin. Age and sex were not significantly different for the patients with increased and normal serum bilirubin concentrations. The patients with increased serum bilirubin concentrations showed higher levels of immune activation markers than the patients with normal bilirubin, including blood lymphocyte counts, serum IgM, and βTransient hyperbilirubinemia is common during severe (in-hospital) infectious mononucleosis in adult patients. Patients with hyperbilirubinemia have less frequent pharyngitis symptoms and more frequent abdominal symptoms. Hyperbilirubinemia during infectious mononucleosis is associated with immune activation markers.

Assessing the Nature-Based Solutions (NBS) contribution to urban resilience, along with developing tools capable of demonstrating their long-term value, comprises a most needed step forward. Nevertheless, the NBS contribution to urban resilience has been yet slightly explored. Given the urban resilience complexity and multiple NBS capabilities, specific needs for a robust assessment should be investigated. This paper identifies the requirements for a comprehensive assessment of the NBS contribution to urban resilience and analyses the main assessment frameworks focused on resilience and NBS for urban drainage. First, the evolution of the resilience concept and relevant resilience assessment frameworks (RAF) are presented. Secondly, NBS challenges to enhance resilience and NBS assessment proposals are analysed. Thirdly, the attributes for assessing urban resilience and aspects to assess the NBS contribution are analysed. To conclude, a critical analysis of the assessment approaches is presented. Important challenges across the RAF have been identified, especially regarding their feasibility of application. Based on the performed analysis, most RAFs are not feasible for city benchmarking and assessing the resilience evolution over time, neither for assessing comprehensively the NBS contribution. Regarding specifically the NBS assessment proposals, just one focused on urban resilience was developed to date, which allows evaluating their contribution over time, between cities, or between different NBS.

Objectives To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants. Methods The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies. Results For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes. Conclusions Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.

In the present study, mercury (Hg), cadmium (Cd), lead (Pb), selenium (Se), and arsenic (As) were measured in liver, kidney, and feathers of adult, juvenile, and chick seagulls (Larus michahellis) collected from the northwest of Spain. Age, sex, and the geographical location of samples were considered variables that can influence metal bioaccumulation, for which concentrations were determined by means of ICP-MS. The mean concentrations (dry weight) found in seagulls were 7.01 ± 0.37 mg Hg/kg, 22.82 ± 2.83 mg Cd/kg, 7.36 ± 1.36 mg Pb/kg, 18.64 ± 0.63 mg Se/kg, and 10.64 ± 0.59 mg As/kg. Regarding the different factors analyzed, Hg was the only metal showing sex-related differences, being significantly higher (p p p p p p L. michahellis can reveal local contamination around the foraging and breeding sites and can be a very useful monitoring instrument for assessing heavy metal contamination and sentinel species of environmental health.

Plastic crystals are supramolecular materials that possess a unique high entropy mesophase at elevated temperatures, where a long-range structural symmetry coexists with a local molecular orientational disorder. The transition to mesophase can involve a large entropy change useful for thermal energy storage and influences the temperature range of ferroelectric and piezoelectric properties, important for sensor applications. Synchrotron X-ray diffraction and pair distribution function analysis were used to study the structure, while calorimetry, dielectric, leakage current measurements, and density functional theory were used to investigate the influence of the organic cation on the structure and properties of tetraethylammonium bromotrichloroferrate(III) [(C2H5)4N][FeBrCl3] and tetramethylammonium bromotrichloroferrate [(CH3)4N][FeBrCl3]. The [(C2H5)4N][FeBrCl3] mesophase transition had an entropy change of 151.5 J·K–1·kg–1, while [(CH3)4N][FeBrCl3] had only 49 J·K–1·kg–1. This was explained by the [(C2H5)4N][FeBrCl3] mesophase having less long-range structural symmetry and more local orientational disorder, of both the cations and anions, compared to [(CH3)4N][FeBrCl3]. Both materials exhibited at least two conductive mechanisms below the transition, vacancy-mediated ionic and electronic conduction. The introduction of anion orientational freedom, as opposed to cation orientational freedom, at the mesophase transition was most influential for the electrical properties.

MALDI-TOF MS is considered to be an important tool for the future development of rapid microbiological techniques. We propose the application of MALDI-TOF MS as a dual technique for the identification of bacteria and the detection of resistance, with no extra hands-on procedures.

Emergence of cefiderocol resistance among carbapenemase-producing Enterobacterales, particularly those in the Enterobacter cloacae complex (ECC), is becoming of alarming concern; however, the mechanistic basis of this phenomenon remains poorly understood.

In the present study, livers, kidneys and adipose tissue of Yellow-legged Gull (Larus michahellis) were collected. Samples were used to determine relationships between heavy metals/metalloids in liver and kidneys (Hg, Cd, Pb, Se and As) or persistent organic pollutants in adipose tissue (7 PCBs and 11 organochlorine pesticides) with biomarkers of oxidative stress (CAT, GPx, GR, GSH, GST, MDA) analysed in both internal organs. Three possible influencing variables have been studied: age, sex and sampling area. As a result, statistically significant differences (P, The work was funded by the Consejería de Economía e Infraestructuras of Junta de Extremadura (Convocatoria de Proyectos de investigación en los centros públicos de I + D + i de la Comunidad Autónoma de Extremadura, 2016; Ref. IB16112); project code: 2017/00206/001.

Supplementary Data from Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma

Supplementary Figure from Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL.Significance:Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival.This article is highlighted in the In This Issue feature, p. 85

In this study we describe the finding of a Cephenemyia stimulator larva in the brain of a roe deer (Capreolus capreolus) after performing a computed tomography (CT) scan of its head. Despite this anatomical location of oestrid larvae could be relatively frequent in other genera, such as Oestrus, to our knowledge, this is the first reported case involving the genus Cephenemyia. Concretely, a second-instar C. stimulator larva was found in the basis of the cranium. The location of a macroscopic hemorrhagic lesion involving the brain parenchyma peripheral to the location of the larva suggests that tissue colonization occurred before the animal was hunted. Since no detectable alterations or damage to the cranial bones were observed, we suggest a possible larval migration route drilling the skull bones. Finally, we propose the use of the term “neuromyiasis” to be referred to the invasion of the central nervous system by dipteran larvae, particularly oestrids.

Introduction: The olfactory system in most mammals is divided into several subsystems based on the anatomical locations of the neuroreceptor cells involved and the receptor families that are expressed. In addition to the main olfactory system and the vomeronasal system, a range of olfactory subsystems converge onto the transition zone located between the main olfactory bulb (MOB) and the accessory olfactory bulb (AOB), which has been termed the olfactory limbus (OL). The OL contains specialized glomeruli that receive noncanonical sensory afferences and which interact with the MOB and AOB. Little is known regarding the olfactory subsystems of mammals other than laboratory rodents.Methods: We have focused on characterizing the OL in the red fox by performing general and specific histological stainings on serial sections, using both single and double immunohistochemical and lectin-histochemical labeling techniques.Results: As a result, we have been able to determine that the OL of the red fox (Vulpes vulpes) displays an uncommonly high degree of development and complexity.Discussion: This makes this species a novel mammalian model, the study of which could improve our understanding of the noncanonical pathways involved in the processing of chemosensory cues.

19 pags., 16 figs., 8 tabs., We present the design, prototype developments and test results of the new time-of-flight detector (ToFD) which is part of the R3B experimental setup at GSI and FAIR, Darmstadt, Germany. The ToFD detector is able to detect heavy-ion residues of all charges at relativistic energies with a relative energy precision σΔE/ ΔE of up to 1% and a time precision of up to 14 ps (sigma). Together with an elaborate particle-tracking system, the full identification of relativistic ions from hydrogen up to uranium in mass and nuclear charge is possible., This work received support from BMBF (05P19RFFN1, 05P15RDFN1, 05P19RDFN1) and HIC for FAIR. J.P. has been supported by the Institute for Basic Science (IBS-R031-D1). E.C. has been supported by the Ministry of Science and Innovation in Spain (PGC2018-099746-B-C22). J.L.R.S. thanks the support from the Regional Government of Galicia under the program of postdoctoral fellowships ED481B-2017-002 and ED481D-2021-018. O.T. has been supported by AEI/FEDER, UE project No. PID2019-104390GB-I00. G.B., A.H., H.T.J., B.J. and T.N. have been supported by the Swedish Research Council under contract 2017-03839. This work was supported by the Royal Society and UK STFC awards ST/L005727/1, ST/P003885/1.

La Neonatología define un neonato al recién nacido (RN) desde el momento del nacimiento hasta completar veinte y ocho días después del parto. Esta contribución centra su atención en el campo de las Redes Neuronales Artificiales (RNA), y específicamente supervisadas. Busca que, a través de estas redes, se pueda discriminar entre un RN sano y uno patológico a partir de su llanto en el período neonatal, siendo su objetivo implementar una RNA supervisada Back-Propagation (BP) para clasificar el llanto en neonatos con Hipoxia a partir de parámetros acústicos. Para su elaboración se concibió una metodología basada en los métodos teóricos que integró, entre otros, el método análisis-síntesis para analizar disímiles propiedades que engloban la dinámica de las RNA. Como resultado se obtuvo el clasificador de llanto (normal-patológico) implementado con RNA. Con este resultado obtenido se comprueba las potencialidades de las RNA y su uso práctico en diferentes áreas del conocimiento.

The mammalian olfactory systems can be divided into several subsystems based on the anatomical location of their neuroreceptor cells and the family of receptors they express. The more in depth studied systems are the main olfactory system and the vomeronasal system, whose first integrative enters are the main and the accessory olfactory bulb, respectively. In addition, there is a range of olfactory subsystems which converge to the transition zone located between the main olfactory bulb and the accessory olfactory bulb., which has been termed as olfactory limbus (OL) and includes specialized glomeruli which receive uncanonical sensory afferences and interact with the MOB and AOB. Beyond the laboratory rodents, there is a lack of information regarding the olfactory subsystems of carnivores. We have focused on the specific study of the olfactory limbus of the fox, performing serial histological sections, general and specific histological stainings, including both double and simple immunohistochemical and lectin-histochemical labeling techniques. As a result, we have been able to determine that the OL of the fox shows an uncommon development with a high degree of development and complexity. This makes this species a novel mammalian model that could provide a wider understanding of non-canonical pathways involved in the processing of chemosensory cues.

Purpose to compare group B Streptococcus (GBS) infection incidence in HIV-exposed uninfected (HEU) and HIV-unexposed (HU) infants in a Spanish cohort. Methods retrospective study in 5 hospitals in Madrid (Spain). Infants ≤ 90 days of life with a GBS infection were included from January 2008 to December 2017. Incidence of GBS infection in HEU and HU children was compared. Results HEU infants presented a 7-fold greater risk of GBS infection and a 29-fold greater risk of GBS meningitis comparing to HU, with statistical signification. Early-onset infection was 10-fold more frequent in HEU children, with statistical signification, and late-onset infection was almost 5-fold more frequent in the HUE infants’ group, without statistical significance. Conclusions HEU infants presented an increased risk of GBS infection and meningitis. One in each 500 HEU infants of our cohort had a central nervous system infection and 1 in each 200, a GBS infection. Although etiological causes are not well understood, this should be taken into account by physicians when attending this population.

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUG [Abstract] In this work, “breathing-caloric” effect is introduced as a new term to define very large thermal changes that arise from the combination of structural changes and gas adsorption processes occurring during breathing transitions. In regard to cooling and heating applications, this innovative caloric effect appears under very low working pressures and in a wide operating temperature range. This phenomenon, whose origin is analyzed in depth, is observed and reported here for the first time in the porous hybrid organic–inorganic MIL-53(Al) material. This MOF compound exhibits colossal thermal changes of ΔS ∼ 311 J K–1 kg–1 and ΔH ∼ 93 kJ kg–1 at room temperature (298 K) and under only 16 bar, pressure which is similar to that of common gas refrigerants at the same operating temperature (for instance, p(CO2) ∼ 64 bar and p(R134a) ∼ 6 bar) and noticeably lower than p > 1000 bar of most solid barocaloric materials. Furthermore, MIL-53(Al) can operate in a very wide temperature range from 333 K down to 254 K, matching the operating requirements of most HVAC systems. Therefore, these findings offer new eco-friendly alternatives to the current refrigeration systems that can be easily adapted to existing technologies and open the door to the innovation of future cooling systems yet to be developed. This work was financially supported by Ministerio de Economía y Competitividad MINECO and EU-FEDER (projects MAT2017-86453-R and PDC2021-121076-I00), Xunta de Galicia and IACOBUS Programme. Funding for open access fee was provided by Universidade da Coruña/CISUG

Pseudomonas aeruginosa, a major cause of nosocomial infections, is considered a paradigm of antimicrobial resistance, largely due to hyperproduction of chromosomal cephalosporinase AmpC. Here, we explore the ability of 6-pyridylmethylidene penicillin-based sulfones 1-3 to inactivate the AmpC β-lactamase and thus rescue the activity of the antipseudomonal ceftazidime. These compounds increased the susceptibility to ceftazidime in a collection of clinical isolates and PAO1 mutant strains with different ampC expression levels and also improved the inhibition kinetics relative to avibactam, displaying a slow deacylation rate and involving the formation of an indolizine adduct. Bromide 2 was the inhibitor with the lowest KI (15.6 nM) and the highest inhibitory efficiency (kinact/KI). Computational studies using diverse AmpC enzymes revealed that the aromatic moiety in 1-3 targets a tunnel-like site adjacent to the catalytic serine and induces the folding of the H10 helix, indicating the potential value of this not-always-evident pocket in drug design.

Las sociedades hispánicas medievales compartieron un amplio y variado caudal de principios y valores comunes en el terreno político, social, cultural y espiritual. Aunque existían elementos propios y exclusivos de cada reino, hubo una sólida base común que permitía una rápida adaptación de los personajes que emigraban a otros territorios vecinos. Las respectivas sociedades cortesanas fueron capaces de entenderse a partir de los rasgos culturales, artísticos, literarios y espirituales que todas tenían en común, y aprovecharon los contactos políticos, familiares e institucionales para enriquecerlos. Un estudio comparado de algunos de estos intercambios permite entender la fisonomía de lo hispánico durante la Baja Edad Media, una época caracterizada por la definición progresiva de los poderes del Estado. Los ejemplos que ofrecen los especialistas que escriben en este volumen nos muestran un variado panorama cultural que combina la especialidad temática con el contexto general de la época.

We present a temperature-dependent Raman scattering study of a [(CH

The purpose of this study is to compare group B Streptococcus (GBS) infection incidence in HIV-exposed uninfected (HEU) and HIV-unexposed (HU) infants in a Spanish cohort. We conducted a retrospective study in 5 hospitals in Madrid (Spain). Infants ≤ 90 days of life with a GBS infection were included from January 2008 to December 2017. Incidence of GBS infection in HEU and HU children was compared. HEU infants presented a sevenfold greater risk of GBS infection and a 29-fold greater risk of GBS meningitis compared to HU, with statistical significance. Early-onset infection was tenfold more frequent in HEU children, with statistical significance, and late-onset infection was almost fivefold more frequent in the HUE infants' group, without statistical significance.HEU infants presented an increased risk of GBS sepsis and meningitis. One in each 500 HEU infants of our cohort had a central nervous system infection and 1 in each 200, a GBS infection. Although etiological causes are not well understood, this should be taken into account by physicians when attending this population.• HIV-exposed uninfected infants are at higher risk of severe infections. • An increased susceptibility of these infants to group B Streptococcus infections has been described in low- and high-income countries, including a higher risk of meningitis in a South African cohort.• Group B Streptococcal meningitis is more frequent in HIV-exposed uninfected infants also in high-income countries. • Physicians should be aware of this increased risk when attending these infants.

Cardiopulmonary nematodes are highly pathogenic parasites affecting domestic and wild canids. As the result of conservation programs, the Iberian wolf (

Cancer is a major cause of morbidity and mortality. Tobacco use, unhealthy diet, and physical inactivity are some of the lifestyle risk factors that have led to an increase in cancer. This article updates the evidence and includes recommendations for prevention strategies for each of the cancers with the highest incidence. These are based on the reduction of risk factors (primary prevention) and early diagnosis of cancer through screening and early detection of signs and symptoms, in medium-risk and high-risk populations. This update of the 2022 PAPPS has taken into account the vision of the National Health System Cancer Strategy, an update approved by the Interterritorial Council of the National Health System on January 2021 and the European Strategy (Europe's Beating Cancer Plan) presented on 4 February 2021.

Specific identification of oestrid larvae is usually problematic not only when using morphobiometric features, but also when applying molecular criteria, since very few molecular markers have been described for this group of flies. New molecular markers for oestrid are needed for more reliable species identification, diagnostic purposes, and epidemiological surveys; moreover, they can help in phylogenetic reconstruction. Here, we report the characterization of COI, 28S rDNA, ITS1, and ITS2 in Cephenemyia stimulator from roe deer and in Cephenemyia auribarbis and Pharyngomyia picta from red deer. The COI and 28S rDNA are very uniform in length, while the ITSs sequences are highly variable at both intraspecific and interspecific levels. The described ITSs sequences were longer than those described for other dipteran species by the presence of simple repeats and tandem repeat sequences. In C. auribarbis both ITS1 and ITS2 appeared as two variants, one short and the other long. In general, the analyzed markers present low intraspecific genetic variation and high interspecific variation. ITSs showed the greatest amount of intraspecific and interspecific variation. Phylogenetic analysis demonstrated that the characterized sequences differentiate the species and genera of Oestridae.

Zinc, cadmium, and lead in livers, kidneys, and feathers of 48 young and adult Atlantic puffins found dead or dying off the coast of Galicia (Northwest Spain) were determined. The most abundant bet...

BackgroundPseudomonas aeruginosa may develop resistance to novel cephalosporin/β-lactamase inhibitor combinations during therapy through the acquisition of structural mutations in AmpC.ObjectivesTo describe the molecular and biochemical mechanisms involved in the development of resistance to ceftolozane/tazobactam in vivo through the selection and overproduction of a novel AmpC variant, designated PDC-315.MethodsPaired susceptible/resistant isolates obtained before and during ceftolozane/tazobactam treatment were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. Characterization of the novel PDC-315 variant was performed through genotypic and biochemical studies. The effects at the molecular level of the Asp245Asn change were analysed by molecular dynamics simulations using Amber.ResultsWGS identified mutations leading to modification (Asp245Asn) and overproduction of AmpC. Susceptibility testing revealed that PAOΔC producing PDC-315 displayed increased MICs of ceftolozane/tazobactam, decreased MICs of piperacillin/tazobactam and imipenem and similar susceptibility to ceftazidime/avibactam compared with WT PDCs. The catalytic efficiency of PDC-315 for ceftolozane was 10-fold higher in relation to the WT PDCs, but 3.5- and 5-fold lower for piperacillin and imipenem. IC50 values indicated strong inhibition of PDC-315 by avibactam, but resistance to cloxacillin inhibition. Analysis at the atomic level explained that the particular behaviour of PDC-315 is linked to conformational changes in the H10 helix that favour the approximation of key catalytic residues to the active site.ConclusionsWe deciphered the precise mechanisms that led to the in vivo emergence of resistance to ceftolozane/tazobactam in P. aeruginosa through the selection of the novel PDC-315 enzyme. The characterization of this new variant expands our knowledge about AmpC-mediated resistance to cephalosporin/β-lactamase inhibitors in P. aeruginosa.

A model is proposed to fit differential scanning calorimetry (DSC) isothermal crystallization curves obtained from the molten state at different temperatures. A commercial 3D printing polylactic acid (PLA) sample is used to test the method. All DSC curves are fitted by a mixture of two simultaneous functions, one of them being a time derivative generalized logistic accounting for the exothermic effect and the other, a generalized logistic, accounting for the baseline. There is a rate parameter, which is allowed to vary across different temperatures. The rate parameter values obtained at different temperatures were jointly explained as a result of three crystallization processes, each one defined by a characteristic crystallization time, a characteristic temperature, and a dispersion or width factor. Apart from the very good fittings obtained at all temperatures, the results agree with the existence of a few crystal forms of PLA, which were demonstrated by other authors. Thus, the main significance of this work consists in providing a new approach in order to mathematically describe the isothermal crystallization kinetics of a polymer from the melt. Such a kinetic description is needed in order to predict the extent of a crystallization process as a function of time at any isothermal temperature. The approach used here allows to understand the overall crystallization of the PLA used in this work as the sum of three crystallization processes, each of them corresponding to a different crystal form. Each experimental crystallization exotherm, which may include more than one crystal form, can be reproduced by a generalized logistic function. The overall rate factor at a given temperature is the weighted sum of the rate factors of the different crystal structures at that temperature. The rate factor of each of these three processes is described by a Gaussian function whose parameters are a crystallization time, a characteristic temperature and a temperature dispersion factor. Therefore, the crystallization rate for each crystal form can be interpreted as a relative likelihood to crystallize at a given temperature. On the other hand, the characteristic crystallization time parameter refers to the time needed for a given crystal structure to be formed at the temperature at which the relative likelihood to crystallize of that form is highest.

The vomeronasal system (VNS) has been extensively studied within specific animal families, such as Rodentia. However, the study of the VNS in other families, such as Canidae, has long been neglected. Among canids, the vomeronasal organ (VNO) has only been studied in detail in the dog, and no studies have examined the morphofunctional or immunohistochemical characteristics of the VNS in wild canids, which is surprising, given the well‐known importance of chemical senses for the dog and fox and the likelihood that the VNS plays roles in the socio‐reproductive physiology and behaviours of these species. In addition, characterising the fox VNS could contribute to a better understanding of the domestication process that occurred in the dog, as the fox would represent the first wild canid to be studied in depth. Therefore, the aim of this study was to analyze the morphological and immunohistochemical characteristics of the fox VNO. Tissue dissection and microdissection techniques were employed, followed by general and specific histological staining techniques, including with immunohistochemical and lectin‐histochemical labelling strategies, using antibodies against olfactory marker protein (OMP), growth‐associated protein 43 (GAP‐43), calbindin (CB), calretinin (CR), α‐tubulin, Gαo, and Gαi2 proteins, to highlight the specific features of the VNO in the fox. This study found significant differences in the VNS between the fox and the dog, particularly concerning the expression of Gαi2 and Gαo proteins, which were associated with the expression of the type 1 vomeronasal receptors (V1R) and type 2 vomeronasal receptors (V2R), respectively, in the vomeronasal epithelium. Both are immunopositive in foxes, as opposed to the dog, which only expresses Gαi2. This finding suggests that the fox possesses a well‐developed VNO and supports the hypothesis that a profound transformation in the VNS is associated with domestication in the canid family. Furthermore, the unique features identified in the fox VNO confirm the necessity of studying the VNS system in different species to better comprehend specific phylogenetic aspects of the VNS.

Introduction: There is not much information about the care of infants with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) in Spain. This includes whether protocols are routinely used, the type of neuro-monitoring performed, and how information on the neurological prognosis is presented to families. The answers to these would allow to detect and implement areas of improvement. Method: A cross-sectional analysis was performed on the responses to structured questionnaires sent to all the Spanish neonatal units that were performing TH in June 2015. Questions were divided into 5 sections: (1) the availability of protocols and technological resources, (2) the use of neuro-monitoring tools, (3) the knowledge and training of the professionals; (4) the prognostic information given to the parents; and (5) the discharge report and the follow-up plan. Results: Most centres (95%) use servo controlled whole-body cooling methods and have specific management protocols. Sedation is used in 70% of centres, and in 68% of them the onset of enteral feeding is delayed until the end of the cooling period. Amplitude-integrated electroencephalography monitoring is used in more than 80% of the centres, although only in 50% are nurses able to interpret it. Cerebral oxygen saturation is not often monitored (16%). As regards diagnostic-prognostic studies, neuroimaging is universal, but brain damage biomarkers are hardly used (29%). Prognostic information is offered within the first 72 posnatal hours in 21% of the centres, and is given without the presence of the nurse in 70% of the centres. Follow-up is performed by a neuro-paediatrician (84%), with an uneven duration between centres. Conclusions: The care of infants with HIE treated with TH in Spain is generally adequate, although there are areas for improvement in neuromonitoring, sedation, prognostic information, teamwork, and duration of follow-up. Resumen: Introducción: Apenas conocemos cómo es la asistencia de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI) en hipotermia terapéutica (HT), especialmente si existen protocolos asistenciales, la neuromonitorización que se realiza o cómo es la aproximación al pronóstico neurológico. Este conocimiento permite detectar e implementar áreas de mejora asistencial. Método: Estudio transversal de los 57 hospitales españoles que realizaban HT en 2015, mediante cuestionario sobre: 1) la disponibilidad de protocolos y de recursos tecnológicos; 2) el uso de herramientas de neuromonitorización; 3) los conocimientos de los profesionales; 4) la información pronóstica que se da los padres, y 5) el informe al alta y del plan de seguimiento. Resultados: El 95% utiliza enfriamiento corporal-total servocontrolado y dispone de protocolos específicos de actuación. El 70% utiliza sedación y el 68% deja al paciente a dieta absoluta. La monitorización con electroencefalografía integrada por amplitud se utiliza en más del 80% de los centros, aunque solo en el 50% la enfermera es capaz de interpretarlo. La saturación de oxígeno cerebral es escasamente monitorizada (16%). Entre los estudios diagnóstico-pronósticos, la neuroimagen es universal, pero los neurobiomarcadores apenas se utilizan (29%). Solo el 21% ofrece información pronóstica antes de las 72 h de vida; sin presencia de la enfermera en el 70%. El seguimiento lo realiza el neuropediatra (84%), con una duración desigual entre centros. Conclusiones: La asistencia del RN con EHI en España es adecuada, con áreas de mejora en: neuromonitorización, sedación, marco temporal de la información pronóstica, trabajo en equipo y estandarización de la duración del seguimiento.

Resumen: Introducción: Apenas conocemos cómo es la asistencia de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI) en hipotermia terapéutica (HT), especialmente si existen protocolos asistenciales, la neuromonitorización que se realiza o cómo es la aproximación al pronóstico neurológico. Este conocimiento permite detectar e implementar áreas de mejora asistencial. Método: Estudio transversal de los 57 hospitales españoles que realizaban HT en 2015, mediante cuestionario sobre: 1) la disponibilidad de protocolos y de recursos tecnológicos; 2) el uso de herramientas de neuromonitorización; 3) los conocimientos de los profesionales; 4) la información pronóstica que se da los padres, y 5) el informe al alta y del plan de seguimiento. Resultados: El 95% utiliza enfriamiento corporal-total servocontrolado y dispone de protocolos específicos de actuación. El 70% utiliza sedación y el 68% deja al paciente a dieta absoluta. La monitorización con electroencefalografía integrada por amplitud se utiliza en más del 80% de los centros, aunque solo en el 50% la enfermera es capaz de interpretarlo. La saturación de oxígeno cerebral es escasamente monitorizada (16%). Entre los estudios diagnóstico-pronósticos, la neuroimagen es universal, pero los neurobiomarcadores apenas se utilizan (29%). Solo el 21% ofrece información pronóstica antes de las 72 h de vida; sin presencia de la enfermera en el 70%. El seguimiento lo realiza el neuropediatra (84%), con una duración desigual entre centros. Conclusiones: La asistencia del RN con EHI en España es adecuada, con áreas de mejora en: neuromonitorización, sedación, marco temporal de la información pronóstica, trabajo en equipo y estandarización de la duración del seguimiento. Abstract: Introduction: There is not much information about the care of infants with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) in Spain. This includes whether protocols are routinely used, the type of neuro-monitoring performed, and how information on the neurological prognosis is presented to families. The answers to these would allow to detect and implement areas of improvement. Method: A cross-sectional analysis was performed on the responses to structured questionnaires sent to all the Spanish neonatal units that were performing TH in June 2015. Questions were divided into 5 sections: 1) the availability of protocols and technological resources, 2) the use of neuro-monitoring tools, 3) the knowledge and training of the professionals; 4) the prognostic information given to the parents; and 5) the discharge report and the follow-up plan. Results: Most centres (95%) use servo controlled whole-body cooling methods and have specific management protocols. Sedation is used in 70% of centres, and in 68% of them the onset of enteral feeding is delayed until the end of the cooling period. Amplitude-integrated electroencephalography monitoring is used in more than 80% of the centres, although only in 50% are nurses able to interpret it. Cerebral oxygen saturation is not often monitored (16%). As regards diagnostic-prognostic studies, neuroimaging is universal, but brain damage biomarkers are hardly used (29%). Prognostic information is offered within the first 72 posnatal hours in 21% of the centres, and is given without the presence of the nurse in 70% of the centres. Follow-up is performed by a neuro-paediatrician (84%), with an uneven duration between centres. Conclusions: The care of infants with HIE treated with TH in Spain is generally adequate, although there are areas for improvement in neuromonitoring, sedation, prognostic information, teamwork, and duration of follow-up.

The global distribution of carbapenemases such as KPC, OXA-48, and metallo-β-lactamases (MBLs) gives cause for concern, as these enzymes are not inhibited by classical β-lactamase inhibitors (BLIs). The current development of new inhibitors is one of the most promising highlights for the treatment of multidrug-resistant bacteria. The activity of cefepime in combination with the novel BLIs zidebactam, taniborbactam, and enmetazobactam was studied in a collection of 400 carbapenemase-producing

Three new diterpene alkaloids, (+)-8-epiagelasine T (

HIV infection continues to be a worldwide public health problem. After the introduction of effective preventive measures, perinatal transmission dramatically decreased. Our aim was to assess the sociodemographic changes in pregnant women living with HIV infection and trends in perinatal transmission rates over time.The Madrid cohort of HIV-infected mother-infant pairs is a multicenter, prospective, observational, and cohort study that collects information on HIV-infected pregnant women and their children.Information on clinical-epidemiological characteristics of HIV-infected pregnant women until delivery and their children from 9 public hospitals was included. Data were collected from a standardized questionnaire from medical records. The results were classified in 3 periods: period 1 (P1) 2000-2006, period 2 (P2) 2007-2013, and period 3 (P3) 2014-2020.A total of 1521 women living with HIV and 1548 newborns were included. In P1, most mothers (75.8%) were Spanish, whereas in P2 and P3 there was a predominance of foreign origin [62.8% and 70.5% respectively ( P0.01)]. The percentage of women with antiretroviral treatment before pregnancy increased significantly in P3 ( P0.01). The proportion of Caesarean sections decreased over time ( P0.01): 66.2% (n = 472) in P1, 54.9% (n = 245) in P2, and 46.7% (n = 141) in P3. The percentage of preterm and low birth weight newborns showed a statistically significant decrease. Even though there were no statistically significant differences ( P = 0.154), a decrease in cases of perinatal infection was observed (1.6% in P1, 1.3% in P2 and 0.3% in P3).The epidemiologic characteristics of pregnant women with HIV infection have changed over time in our setting, with an increase of non-Caucasian, heterosexual, and perinatally infected mothers. Although there are still perinatal infections, especially in vulnerable populations such as immigrant women, transmission rate has markedly decreased in recent years and is still of major concern. Prevention measures should be reinforced in the most socially disadvantaged groups.

This work demonstrates that, despite the existence of a significant number of works on PLA crystallization, there is still a relatively simple way, different from those already described, in which its complex kinetics can be observed. The X-ray diffraction (XRD) results presented here confirm that the PLLA under study crystallizes mostly in the α and α′ forms. An interesting observation is that at any temperature in the studied range of the patterns, the X-ray reflections stabilize with a given shape and at a given angle, different for each temperature. That means that both α and α′ forms coexist and are stable at the same temperatures so that the shape of each pattern results from both structures. However, the patterns obtained at each temperature are different because the predominance of one crystal form over the other depends on temperature. Thus, a two-component kinetic model is proposed to account for both crystal forms. The method involves the deconvolution of the exothermic DSC peaks using two logistic derivative functions. The existence of the rigid amorphous fraction (RAF) in addition to the two crystal forms increases the complexity of the whole crystallization process. However, the results presented here show that a two-component kinetic model can reproduce the overall crystallization process fairly well over a broad range of temperatures. The method used here for PLLA may be useful for describing the isothermal crystallization processes of other polymers.