Multifunctional heterometallic Iriii-Aui probes as promising anticancer and antiangiogenic agents

A new class of emissive cyclometallated IrIII-AuI complexes with a bis(diphenylphosphino) methanide bridging ligand was successfully synthesised from the diphosphino complex [Ir(N^C)2(dppm)]+ (1). The different gold ancillary ligand, a triphenylphosphine (2), a chloride (3) or a thiocytosine (4) did not reveal any significant effect on the photophysical properties, which are mainly due to metal-to-ligand charge-transfer (3MLCT) transitions based on IrIII. However, the AuI fragment, along with the ancillary ligand, seemed crucial for the bioactivity in A549 lung carcinoma cells versus endothelial cells. Both cell types display variable sensitivities to the complexes (IC50=0.6–3.5 µM). The apoptotic pathway is activated in all cases, and paraptotic cell death seems to take place at initial stages in A549 cells. Species 2–4 showed at least dual lysosomal and mitochondrial biodistribution in A549 cells, with an initial lysosomal localisation and a possible trafficking process between both organelles with time. The bimetallic IrIII-AuI complexes disrupted the mitochondrial transmembrane potential in A549 cells and increased reactive oxygen species (ROS) generation and thioredoxin reductase (TrxR) inhibition in comparison with that displayed by the monometallic complex 1. Angiogenic activity assays performed in endothelial cells revealed the promising antimetastatic potential of 1, 2 and 4. © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH

Riesgo de mortalidad total y cardiovascular según la clasificación propuesta por las guías KDIGO en pacientes con diabetes tipo 2

Antecedentes y objetivo: El objetivo del estudio fue comprobar la validez de la clasificación de riesgo KDIGO 2012 para predecir mortalidad total (MT) y cardiovascular (MCV) en diabetes mellitus tipo 2 (DM2). Materiales y métodos: Estudio de cohortes prospectivo incluyendo pacientes con DM2. Los puntos finales clínicos fueron MT y MCV. La principal variable predictora fue la clasificación KDIGO, una variable que recoge 4 niveles de riesgo en dependencia de una combinación de la tasa de filtración glomerular y la excreción de albúmina urinaria. La evaluación del poder predictivo se realizó con el índice de mejora de discriminación integrada (IDI). Resultados: Se incluyeron 453 pacientes (39, 3% varones, edad 64, 9 [DE 9, 3] años y evolución de DM2 de 10, 4 [DE 7, 5] años). Durante una mediana de 13 años de seguimiento, hubo incremento significativo de la tasa/1000 pacientes-año de MT (26, 5 vs. 45, 1 vs. 79, 2 vs. 109, 8; p< 0, 001) y de MCV (8, 1 vs. 17, 4 vs. 24, 7 vs. 57, 5; p< 0, 001) en las sucesivas categorías de riesgo KDIGO. En análisis multivariante también hubo incremento de riesgo de MT (HR[riesgo moderado] = 1, 29; HR[riesgo alto] = 1, 83; HR[riesgo muy alto] = 2, 15; p = 0, 016) y MCV (HR[riesgo moderado] = 1, 73; HR[riesgo alto] = 2, 27; HR[riesgo muy alto] = 4, 22; p = 0, 007) en las sucesivas categorías. La clasificación KDIGO mejoró la predicción de MT (IDI = 0, 00888; p = 0, 047) y MCV (IDI = 0, 01813; p = 0, 035). Conclusiones: La clasificación de riesgo según guías KDIGO 2012 puede estratificar eficazmente el riesgo de MT y MCV en pacientes con DM2. Background and aims: Our aim was to assess the usefulness of KDIGO 2012 risk classification to predict total and cardiovascular mortality in type 2 diabetes mellitus (DM2). Material and methods: Prospective cohort study that included DM2 patients. Clinical end-points were total and cardiovascular mortality. The main predictive variable was KDIGO risk classification, which is a combination of urinary albumin excretion and glomerular filtration rate. The predictive value was evaluated by the integrated discrimination improvement (IDI) index. Results: 453 patients (39.3% males, aged 64.9 [SD 9.3] and with a mean diabetes duration of 10.4 [SD 7.5] years) were included. During a median follow-up of 13 years, mortality rates per 1000 patients/year (26.5 vs. 45.1 vs. 79, 2 vs. 109, 8; p< 0, 001) and cardiovascular mortality (8.1 vs. 17.4 vs. 24.7 vs. 57.5; p< 0, 001) were progressively increased in successive KDIGO categories. In the multivariate analysis, there was also a progressive increase of mortality risk (HR[moderate risk] = 1.29; HR[high risk]) = 1.83; HR[very high risk] = 2.15; p =.016) and cardiovascular mortality risk (HR[moderate risk] = 1.73; HR[high risk] = 2.27; HR[very high risk] = 4.22; p =.007) in the successive categories. KDIGO classification was able to improve the mortality risk prediction (IDI = 0.00888; p =.047) and cardiovascular mortality risk prediction (IDI = 0.01813; p =.035). Conclusions: KDIGO risk classification can effectively stratify total and cardiovascular mortality risk in DM2 patients

Variation in antiosteoporotic drug prescribing and spending across Spain. A population-based ecological cross-sectional study

Introduction: Evidence has shown that utilization of antiosteoporotic medications does not correspond with risk, and studies on other therapies have shown that adequacy of pharmaceutical prescribing might vary between regions. Nevertheless, very few studies have addressed the variability in osteoporotic drug consumption. We aimed to describe variations in pharmaceutical utilization and spending on osteoporotic drugs between Health Areas (HA) in Spain. Methods: Population-based cross-sectional ecological study of expenditure and utilization of the five therapeutic groups marketed for osteoporosis treatment in Spain in 2009. Small area variation analysis (SAVA) methods were used. The units of analysis were the 168 HA of 13 Spanish regions, including 7.2 million women aged 50 years and older. The main outcomes were the defined daily dose (DDD) per 1000 inhabitants and day (DDD/1000/Day) dispensed according to the pharmaceutical claims reimbursed, and the expenditure on antiosteoporotics at retail price per woman =50 years old and per year. Results: The average osteoporosis drug consumption was 116.8 DDD/1000W/Day, ranging from 78.5 to 158.7 DDD/1000W/Day between the HAs in the 5th and 95th percentiles. Seventy-five percent of the antiosteoporotics consumed was bisphosphonates, followed by raloxifene, strontium ranelate, calcitonins, and parathyroid hormones including teriparatide. Regarding variability by therapeutic groups, biphosphonates showed the lowest variation, while calcitonins and parathyroid hormones showed the highest variation. The annual expenditure on antiosteoporotics was €426.5 million, translating into an expenditure of €59.2 for each woman =50 years old and varying between €38.1 and €83.3 between HAs in the 5th and 95th percentiles. Biphosphonates, despite accounting for 79% of utilization, only represented 63% of total expenditure, while parathyroid hormones with only 1.6% of utilization accounted for 15% of the pharmaceutical spending. Conclusion: This study highlights a marked geographical variation in the prescription of antiosteoporotics, being more pronounced in the case of costly drugs such as parathyroid hormones. The differences in rates of prescribing explained almost all of the variance in drug spending, suggesting that the difference in prescription volume between territories, and not the price of the drugs, is the main source of variation in this setting. Data on geographical variation of prescription can help guide policy proposals for targeting areas with inadequate antiosteoporotic drug use

Boosting background suppression in the NEXT experiment through Richardson-Lucy deconvolution

Next-generation neutrinoless double beta decay experiments aim for half-life sensitivities of ~ 1027 yr, requiring suppressing backgrounds to &lt; 1 count/tonne/yr. For this, any extra background rejection handle, beyond excellent energy resolution and the use of extremely radiopure materials, is of utmost importance. The NEXT experiment exploits differences in the spatial ionization patterns of double beta decay and single-electron events to discriminate signal from background. While the former display two Bragg peak dense ionization regions at the opposite ends of the track, the latter typically have only one such feature. Thus, comparing the energies at the track extremes provides an additional rejection tool. The unique combination of the topology-based background discrimination and excellent energy resolution (1% FWHM at the Q-value of the decay) is the distinguishing feature of NEXT. Previous studies demonstrated a topological background rejection factor of ~ 5 when reconstructing electron-positron pairs in the 208Tl 1.6 MeV double escape peak (with Compton events as background), recorded in the NEXT-White demonstrator at the Laboratorio Subterráneo de Canfranc, with 72% signal efficiency. This was recently improved through the use of a deep convolutional neural network to yield a background rejection factor of ~ 10 with 65% signal efficiency. Here, we present a new reconstruction method, based on the Richardson-Lucy deconvolution algorithm, which allows reversing the blurring induced by electron diffusion and electroluminescence light production in the NEXT TPC. The new method yields highly refined 3D images of reconstructed events, and, as a result, significantly improves the topological background discrimination. When applied to real-data 1.6 MeV e-e+ pairs, it leads to a background rejection factor of 27 at 57% signal efficiency. [Figure not available: see fulltext.]. © 2021, The Author(s)

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020.

Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3–5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes. © 2021, The Author(s), under exclusive licence to Springer Nature Limited