Analysis of the roles of kisspeptins and the tachykinin receptor, Tacr2, in the control of Reproduction: novel interactive pathways, regulatory mechanisms and metabolic implications

For sake of clarity, this Doctoral Thesis has been divided in 3 main experimental sets: In the Experimental Set 1, a comprehensive series of phenotypical, pharmacological, behavioral and histological analyses were conducted in a novel mouse line with congenital ablation of Tacr2, namely, the Tacr2 KO mouse, to unravel the physiological role of neurokinin 2 receptor (NK2R) signaling, and its eventual interplay with kisspeptins, in the control of the HPG axis. Our initial pharmacological studies documented the capacity of the agonist of NK2R to evoke acute LH responses after icv administration in control mice, which was comparable with those elicited by the other TAC agonists as well as kisspeptin (Kp-10). Similar pharmacological studies in Tacr2 KO mice revealed that the LH responses to the NK1R and NK3R receptor agonists and Kp-10 were not affected by Tacr2 ablation. On the contrary, the LH response to a NK2R agonist was sexually dimorphic, so that Tacr2 KO female mice displayed an attenuated LH response while, despite effective ablation of NK2R, Tacr2 KO male mice displayed a grossly conserved LH responsiveness to NK2R agonist, which, nonetheless, was abrogated after blockade of NK3R. Next, we carried out a thorough reproductive characterization of Tacr2 null mice of both sexes, which documented that the congenital lack of NK2R signaling does not compromise the timing of puberty onset or the fertility either in males or females. Yet, a trend for increased breeding intervals together with partially alteration in LH pulsatility were observed in Tacr2 KO female mice in adulthood; the latter consisting in the suppression of basal LH levels, but no changes in the number of LH pulses. On the other hand, histological analyses suggested the existence of a defective function of Sertoli cells in their interaction with spermatids in adult Tacr2 KO male, but no gross morphological alterations in the ovary or the uterus of females KO mice. In addition, Tacr2 KO female mice failed to display a significant increase of LH levels at 2 days after ovariectomy (OVX), although no differences were detected at later periods, nor did OVX Tacr2 KO female mice showed differences in terms of tail skin temperature as compared with littermate controls. On the other hand, LH levels in Tacr2 KO mice subjected to conditions of energy deficit caused by 24-h fasting were significantly lower than in controls. A three-chamber social sex preference and female urine sniffing tests were also applied to adult male and female null mice and their controls. Yet, no differences in any of the behavioral parameters explored, including velocity, distance moved and time spent in the vicinity of the same or opposite-sex mouse, were noted between control and KO mice. Additionally, to assess the impact of the lack of NK2R signaling on key metabolic parameters, we monitored body weight gain in both adult female and male Tacr2 KO mice, which was similar to that of control littermates. Likewise, body composition analyses demonstrated similar fat and lean mass in Tacr2 KO and control mice; energy expenditure and respiratory quotient, total and nocturnal locomotor activity, and the day/night feeding patterns during 24 hours were also similar in control and Tacr2 KO mice. Moreover, measurement of blood pressure demonstrated that Tacr2 KO mice display values of systolic blood pressure similar to their control littermates. Finally, metabolic analyses addressing glucose homeostasis after challenge mice with an obesogenic diet revealed a significant increase in the basal glucose levels in Tacr2 KO males. In the Experimental Set 2, a series of proteomic, molecular and immunohistochemical analyses were implemented using genetically modified mouse lines to explore novel targets mediating kisspeptins actions. We performed a first proteomic analysis in samples from the preoptic area (POA) of Kiss1 KO male mice icv injected with Kp-10, which pointed out a set of 30 differentially-expressed proteins involved in cellular metabolism and energy balance, cell signaling, protein folding and synaptic plasticity; the later revealed that glial fibrillary acidic protein (GFAP), an astrocyte marker, was modified in response to Kp-10. In a second proteomic analysis using a next-generation technology, we found that astrocyte markers including GFAP were again modified in response to Kp-10; a finding that was also confirmed by RT-qPCR and western blot analyses. These findings led us to analyze and demonstrate for the first time the expression of Gpr54 and the presence of functional kisspeptin receptors in astrocytes. On the latter, we found in both primary astrocyte cultures from neonatal rats and mice the activation of downstream signaling pathways in response to kisspeptin. Our data also demonstrated the co-expression of Gpr54 in GFAP-positive cells in mouse brain tissue, with a substantial enrichment in the % of co-location in the hypothalamic regions of the vascular organ of lamina terminalis (VOLT) and anteroventral periventricular nucleus (AVPV). In addition, in two models of congenital ablation of Gpr54, we observed changes in astrocytic GFAP labelling by immunohistochemistry in the arcuate nucleus (ARC) of these mouse models, although immunoreactivity of S100 calcium binding protein B (S100β), another astrocytic marker protein, was not affected. Finally, in the Experimental Set 3, a series of phenotypic and pharmacological analyses were conducted in a novel mouse line with selective ablation of Gpr54 in GFAP-positive cells, namely, the G-KiRKO mouse (for GFAP cell-specific Kisspeptin Receptor KO), to evaluate the physiological role of kisspeptin signaling in astrocytes in the control of the reproductive axis. First, we carried out a set of molecular and immunohistochemical analyses that involved the use of a reporter mouse line and primary astrocyte cultures for the validation of our GKiRKO model. These analyses confirmed effective ablation of Gpr54 in astrocytes. However, despite the effective disruption of kisspeptin signaling in astrocytes, characterization of GKiRKO mice revealed normal pubertal timing, and preserved LH levels and estrous cyclicity in the adulthood of G-KiRKO mice. Yet, challenging of G-KiRKO mice with icv injection of Kp-10 demonstrated an enhancement of LH responses, suggesting a repressive role of astrocyte signaling in mediating kisspeptin actions in terms of gonadotropin secretion. The measurement of the metabolic parameters (i.e., body weight gain and body composition analysis) did not show differences in G-KiRKO vs. control mice. Nevertheless, the glucose tolerance test (GTT) revealed a subtle improvement of the response to a glucose bolus in GKiRKO mice, without showing alterations in insulin sensitivity. On the other hand, obesogenic conditions defined by chronic exposure to HFD evidenced a delay in the vaginal opening (VO), external marker of puberty in female rodents, in HFD-fed G-KiRKO mice in comparison to HFD-fed control mice. In contrast, no differences were detected in term of first estrus, indirect marker of first ovulation, neither in the age of balano-preputial separation (BSP), external marker of puberty in male rodents, in HFD-fed KO mice versus controls. In adulthood, only HFD-fed G-KiRKO female mice displayed the LH hyper-response to Kp-10, as observed in lean conditions. In addition, high-fat diet exposure induced estrous cycle irregularities in GKiRKO female mice, as evidenced by longer cycle length and a higher number of days in diestrus and reduced number of days in estrus. The metabolic parameters, such as body weight gain and body composition remained unaltered in G-KiRKO mice. In HFD-fed G-KiRKO males, the levels of glucose during the GTT were lower than those observed for control mice, as already registered in conditions of normal feeding. In contrast, no differences in terms of insulin sensitivity (assessed by ITT) were detected. In the case of HFD-fed G-KiRKO female mice, no differences in basal glucose levels, neither in the response to glucose or insulin boluses, were detected. Finally, GFAP immunoreactivity was not different in the ARC nucleus of G-KiRKO male mice fed HFD in comparison to their controls. By contrast, GFAP immunoreactivity responses to acute exposure to HFD were significantly lower in the ARC of G-KiRKO male mice.Esta Tesis Doctoral se ha dividido en tres bloques experimentales principales: En el Bloque Experimental 1, se ha realizado una caracterización fenotípica, farmacológica y comportamental exhaustiva, incluyéndose también análisis histológicos, del modelo de ratón con ablación congénita de Tacr2, denominado Tacr2 KO, para desvelar la implicación de la señalización por NK2R, y su interacción con kisspeptinas, en el control de la función reproductiva. Los estudios farmacológicos iniciales documentaron la capacidad del agonista de NK2R para evocar una respuesta en términos de secreción de LH tras su administración icv en ratones control, en la misma medida que lo hacen los otros agonistas de taquiquininas y la kisspeptina (Kp-10). Estudios farmacológicos similares en el modelo Tacr2 KO no mostraron alteraciones en la respuesta de LH a los agonistas de NK1R y NK3R así como de Kp-10. No obstante, en la respuesta de LH al agonista de NK2R se observó un dimorfismo sexual; esto es, mientras que en hembras la respuesta apareció parcialmente atenuada, en los machos Tacr2 KO esta respuesta estuvo prácticamente conservada, siendo esta última suprimida tras el bloqueo de la señalización por NK3R. La caracterización reproductiva de este modelo reveló que el inicio de la pubertad y la fertilidad no están comprometidas por la ausencia de señalización por NK2R, aunque sí se detectó una tendencia al incremento en el intervalo de cría, así como un deterioro en la función en las células de Sertoli en su interacción con las espermátides en los ratones macho adultos Tacr2 KO, aunque ninguna alteración en ovario ni útero en el caso de las hembras KO. Por otro lado, los ratones hembra Tacr2 KO presentaron niveles basales de secreción pulsátil de LH significativamente bajos, sin cambios aparentes en el número de pulsos de LH. Además, en las hembras Tacr2 KO, no se observó el incremento de los niveles de LH tras dos días después de la ovariectomía (OVX) que sí es detectado en las hembras controles. En estas mismas hembras Tacr2 KO ovariectomizadas, el perfil de temperatura de la cola monitorizado no reveló diferencias con respecto a los controles. En el caso de los machos Tacr2 KO, en condiciones de déficit energético consecuencia de un ayudo de 24 horas de duración, se registraron niveles de LH significativamente más bajos que los de los controles. Por otro lado, los estudios de comportamiento de preferencia por el sexo opuesto y de orina de hembras, en los que se incluye la monitorización de la velocidad y distancia recorrida durante el test, no mostraron ninguna respuesta diferencial entre los ratones KO y los controles. Adicionalmente, se analizaron indicadores metabólicos para valorar el impacto de la ausencia de señalización por NK2R sobre la homeostasis metabólica. Entre ellos la ganancia de peso corporal fue similar entre ratones Tacr2 KO y sus controles. Del mismo modo, los análisis de composición corporal indicaron que no había diferencias en el porcentaje de masa grasa y magra entre KO y controles, ni tampoco en el gasto energético, coeficiente respiratorio, actividad locomotora total y nocturna, ni en los patrones de ingesta durante el día y la noche registrados durante 24 horas. La medida de la presión sanguínea tampoco evidenció diferencias entre animales controles y KO. Finalmente, se observaron niveles basales de glucosa significativamente más elevados en los ratones macho Tacr2 KO tras la exposición crónica de estos a una dieta obesogénica. En el Bloque Experimental 2, se llevaron a cabo una serie de análisis proteómicos, moleculares e inmunohistoquímicos en modelos de ratón modificados genéticamente dirigidos a identificar nuevas dianas de acción de las kisspeptinas. En el primer estudio proteómico realizado en muestras del área preóptica del hipotálamo de ratones deficientes para kisspeptina, Kiss1 KO, inyectados intracerebroventriculamente (icv) con Kp-10, se observó la expresión diferencial de 30 proteínas implicadas en el metabolismo celular y balance energético, señalización celular, plegamiento de proteínas y plasticidad sináptica; identificándose en esta última categoría a la proteína acídica fibrilar glial (GFAP), marcador de astrocitos. En el segundo estudio proteómico, en el que se empleó una tecnología de nueva generación, se detectó de nuevo que la expresión de GFAP y otros indicadores de astrocitos eran modificados en respuesta a la administración de kisspeptina; efecto que fue confirmado también por análisis de RT-qPCR y western blot. A partir de estas evidencias, implementamos una serie de análisis que permitieron demostrar por primera vez en cultivos primarios de astrocitos de rata y ratón la expresión del receptor de kisspeptina, Gpr54. Además, se comprobó que la señalización por kisspeptinas era funcional en estas células. In vivo se detectó la co-expresión de Gpr54 y GFAP en cerebro de ratón, registrándose un enriquecimiento del porcentaje de co-localización Gpr54- GFAP en las áreas hipotalámicas del órgano vascular de la lámina terminal (VOLT) y del área anteroventral periventricular (AVPV). Por último, mediante análisis por inmunohistoquímica se observaron cambios en el marcaje de GFAP en el núcleo arcuato (ARC) en dos modelos de ratón con eliminación congénita de Gpr54, si bien dichos cambios no fueron extensibles a la proteína S100B de unión a calcio, otro marcador de astrocitos. Finalmente, en el Bloque Experimental 3, se llevaron a cabo una serie de estudios fenotípicos y farmacológicos en un modelo novedoso de ratón con deleción selectiva del receptor Gpr54 en células GFAP-positivas, modelo de ratón denominado como G-KiRKO (del inglés GFAP cell-specific Kisspeptin Receptor KO), a fin de caracterizar el papel fisiológico de la señalización por kisspeptinas en astrocitos en el control de la función reproductiva. Primero, se validó el modelo mediante análisis moleculares e inmunohistoquímicos empleando una línea reportera de ratón y cultivos primarios de astrocitos; análisis que confirmaron la eficiente eliminación de Gpr54 de astrocitos. Sin embargo, la eliminación efectiva de la señalización de kisspeptina en astrocitos en el modelo G-KiRKO, no afectó la edad de llegada a la pubertad, ni modificó la secreción de LH ni alteró el ciclo estral en la edad adulta. En cambio, los ratones G-KiRKO presentaron respuestas significativamente aumentadas de LH tras la administración icv de Kp-10. Por otro lado, los ratones G-KiRKO tampoco presentaron alteraciones en parámetros metabólicos como son el peso y composición corporal, pero sí se registró una respuesta glucémica mejorada en el test de sobrecarga de glucosa, sin verse afectada la respuesta a insulina. A su vez, los ratones hembra G-KiRKO mostraron una atenuación del efecto de una dieta obesogénica (HFD) sobre el adelanto de la edad de apertura vaginal, marcador externo de llegada a la pubertad en roedores hembra. No obstante, no se afectó la edad de primer estro, indicador de la primera ovulación en roedores, ni tampoco la edad de la separación balanoprepucial en el caso de los ratones macho. En la edad adulta, solo en el caso de las hembras GKiRKO se detectó un aumento excesivo de la respuesta de LH tras la administración con Kp- 10, que previamente se había observado en condicionales basales. Además, con la exposición a la dieta rica en grasas, el ciclo estral en hembras KO se vio comprometido, registrándose ciclos más largos, con un mayor número de días en la fase de diestro y menos en estro. Por otro lado, los valores de parámetros metabólicos como el peso y la composición corporal en los ratones G-KiRKO fueron comparables a los de los controles. Bajo esta condición de estrés metabólico, solo los machos G-KiRKO mostraron una respuesta glucémica mejorada, similar a la observada en condiciones fisiológicas, sin alteraciones en la respuesta a insulina, y sin diferencias en la respuesta de glucosa ni de insulina entre las hembras controles y G-KiRKO. Por otro lado, los ratones macho G-KiRKO presentaron una respuesta disminuida en términos de inmunoreactividad de GFAP en el ARC tras exposición aguda a HFD

La libre competencia y su regulación en la comunidad andina: un aporte jurídico para la eficiencia en los mercados y el bienestar de los consumidores en Colombia

This reflection article is the product of the investigation "Free Competition and its regulation in Decision of of the Andean Community", and is framed in the disciplinary that handles Competition Law both in Colombian internal law, and in the community law that is applied in the CAN and in the interdisciplinary, because there is talk of the globalization of law in Latin America, which proposes to materialize the impulse of the integration of the diverse economies that exists within the States, which materialize the international trade in commercial practice establishing strips of territory, of free foreign trade, with rates and taxes common to markets and international economic societies that are asking for the support of international law, to reduce conflicts in the transit and flow of goods in the transnational markets. It is for the foregoing that the issue of Andean community integration has contrasted dissimilar conflicts throughout its history, due to political discrepancies between the States parties, a situation that shows that the objectives determined in the Cartagena Agreement are fulfilled in party and that on several decisive issues there is no common position by the signing parties of the agreement in question, which is why it is necessary to review the regulation in the Andean Community of free competition, for market efficiency and well-being of consumers in Colombia. This research is pure legal for the law, it is qualitative from the scientific research approach, and the applied method is analytical, since a documentary-type investigation was carried out in electronic databases, which allowed the structuring of a systematic exploration. search by keywords on the words and key concepts of the research to later carry out a content analysis of the information collected in bibliographic records. Este artículo de reflexión es producto de la estancia en el postdoctorado Públicas para Regular la Pobreza Urbana en el Distrito de Cartagena”, y se enmarca en lo disciplinario que maneja el Derecho de la Competencia tanto en el derecho interno colombiano, como en el derecho comunitario que se aplica en la CAN y en lo interdisciplinario, porque se habla de la globalización del derecho en américa latina, lo cual plantea materializar el impulso de la integración de las economías diversas que existe al interior de los Estados, que materializan el comercio internacional en la práctica comercial estableciendo franjas del territorio, de libre comercio exterior, con tasas e impuestos comunes a los mercados y sociedades económicas internacionales que van pidiendo el apoyo del derecho internacional, para aminorar los conflictos en el tránsito y flujo de mercancías en los mercados transnacionales. Es por lo anterior que el tema de la integración comunitaria andina ha contrapuesto disímiles conflictos a lo largo de su historia, debido a discrepancias de carácter político entre los Estados parte, situación que evidencia que los objetivos determinados en el Acuerdo de Cartagena se vean cumplido en parte y que en varios temas decisivos no exista una postura común por las partes firmantes del acuerdo en mención, es por ello por lo que se requiere revisar la regulación en la Comunidad Andina de la libre competencia, para la eficiencia en los mercados y el bienestar de los consumidores en Colombia. Esta investigación es jurídica pura para el derecho, es cualitativa desde el enfoque de la investigación científica, y el método aplicado es el analítico, ya que se efectuó una indagación de tipo documental en bases de datos electrónicas, que permitió la estructuración de una exploración sistemática de averiguación por palabras clave sobre las palabras y conceptos claves de la investigación para posteriormente realizar un análisis de contenido de la información recabada en fichas bibliográficas.Globalización en América Latina y de la investigación “Efectividad de las Política

Deregulation of miR-324/KISS1/kisspeptin in early ectopic pregnancy: mechanistic findings with clinical and diagnostic implications

[Abstract] BACKGROUND: Ectopic pregnancy is a life-threatening condition for which novel screening tools that would enable early accurate diagnosis would improve clinical outcomes. Kisspeptins, encoded by KISS1, play an essential role in human reproduction, at least partially by regulating placental function and possibly embryo implantation. Kisspeptin levels are elevated massively in normal pregnancy and reportedly altered in various gestational pathologic diseases. Yet, the pathophysiologic role of KISS1/kisspeptin in ectopic pregnancy has not been investigated previously. OBJECTIVE: The purpose of this study was to evaluate changes of KISS1/kisspeptin levels in ectopic pregnancy and their underlaying molecular mechanisms and to ascertain the diagnostic implications of these changes. STUDY DESIGN: A total of 122 women with normal pregnancy who underwent voluntary termination of pregnancy and 84 patients who experienced tubal ectopic pregnancy were recruited. Measurements of plasma kisspeptins and KISS1 expression analyses in human embryonic/placental tissue were conducted in ectopic pregnancy and voluntary termination of pregnancy control subjects during the early gestational window (<12 weeks). Putative microRNA regulators of KISS1 were predicted in silico, followed by expression analyses of selected microRNAs and validation of repressive interactions in vitro. Circulating levels of these microRNAs were also assayed in ectopic pregnancy vs voluntary termination of pregnancy. RESULTS: Circulating kisspeptins gradually increased during the first trimester of normal pregnancy but were reduced markedly in ectopic pregnancy. This profile correlated with the expression levels of KISS1 in human embryonic/placental tissue, which increased in voluntary termination of pregnancy but remained suppressed in ectopic pregnancy. Bioinformatic predictions and expression analyses identified miR-27b-3p and miR-324-3p as putative repressors of KISS1 in human embryonic/placental tissue at <12 weeks gestation, when expression of microRNAs was low in voluntary termination of pregnancy control subjects but significantly increased in ectopic pregnancy. Yet, a significant repressive interaction was documented only for miR-324-3p, occurring at the predicted 3'-UTR of KISS1. Interestingly, circulating levels of miR-324-3p, but not of miR-27b-3p, were suppressed distinctly in ectopic pregnancy, despite elevated tissue expression of the pre-microRNA. A decision-tree model that used kisspeptin and miR-324-3p levels was successful in discriminating ectopic pregnancy vs voluntary termination of pregnancy, with a receiver-operating characteristic area under the curve of 0.95±0.02 (95% confidence interval). CONCLUSION: Our results document a significant down-regulation of KISS1/kisspeptins in early stages of ectopic pregnancy via, at least partially, a repressive interaction with miR-324-3p. Our data identify circulating kisspeptins and miR-324-3p as putative biomarkers for accurate screening of ectopic pregnancy at early gestational ages.Ministerio de E$conomía y Competitividad (España); BFU2014-57581-PMinisterio de Economía y Competitividad ; BFU2017-83934-PInstituto de Salud Carlos III; PIE-00005Junta de Andalucía; P08-CVI-03788Junta de Andalucía; P12-FQM-0194

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3

ObjectivesCARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain.MethodsIn total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC &gt; 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis.ResultsIn total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5).ConclusionThis study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3

Critical aspects in the handling of reactive silica in cementitious materials: Effectiveness of rice husk ash vs nano-silica in mortar dosage

Nano-silica addition improves mechanical and durability behavior in mortars. However, nanomaterial handling requires use of occupational risk prevention measures as Individual Protection Equipment for the workers. Moreover, the high agglomeration of nanomaterials produces uncertainty in the expected mortar performance. Rice husk ash as a source of reactive silica in cement compositions is compared with nano-silica. The use of rice husk ash provides similar physical-chemical cementitious materials than other commercial nano-silica providing relevant differences during the composition. Near 50% wt of volatility is found for the silica nanoparticles during the handling dosage. Thus, the rice husk ash presents a reduced volatility, ~12% wt and it allows ensuring high content with adequate workability. Mortars with addition of rice husk ash reach higher compressive strength and resistivity in correlation with lower porosity. For that, the use of rice husk ash is viable as safer alternative material than nano-silica in the cementitious compositions. In addition, as the rice husk ash comes from agricultural waste resources their use as secondary raw material will contributes to circularity in the economy by reducing engineered nanomaterials consumptionThis work was supported by the Spanish Ministry of Economy and Competitiveness through the Project MAT-2017-86450-C4-1-R, Spanish National Research Council under Project NANOMIND 201560E068 and H2020 project FISSAC grant 642154. Dr. M. Torres-Carrasco is also indebted to MINECO for a postdoctoral fellowship “Juan de la Cierva-Formación” (ref: FJCI-2016-28488).Publicad

Índice de Impacto de las Revistas Españolas de Ciencias Sociales[Comunicación]

An analysis of impact factor of social science spanish scientific journals is presented