Derivation and external validation of the SIMPLICITY score as a simple immune-based risk score to predict infection in kidney transplant recipients

Existing approaches for infection risk stratification in kidney transplant recipients are suboptimal. Here, we aimed to develop and validate a weighted score integrating non-pathogen-specific immune parameters and clinical variables to predict the occurrence of post-transplant infectious complications. To this end, we retrospectively analyzed a single-center derivation cohort of 410 patients undergoing kidney transplantation in 2008-2013 in Madrid. Peripheral blood lymphocyte subpopulations, serum immunoglobulin and complement levels were measured at one-month post-transplant. The primary and secondary outcomes were overall and bacterial infection through month six. A point score was derived from a logistic regression model and prospectively applied on a validation cohort of 522 patients undergoing kidney transplantation at 16 centers throughout Spain in 2014-2015. The SIMPLICITY score consisted of the following variables measured at month one after transplantation: C3 level, CD4+ T-cell count, CD8+ T-cell count, IgG level, glomerular filtration rate, recipient age, and infection within the first month. The discrimination capacity in the derivation and validation cohorts was good for overall (areas under the receiver operating curve of 0.774 and 0.730) and bacterial infection (0.767 and 0.734, respectively). The cumulative incidence of overall infection significantly increased across risk categories in the derivation (low-risk 13.7%; intermediate-risk, 35.9%; high-risk 77.6%) and validation datasets (10.2%, 28.9% and 50.4%, respectively). Thus, the SIMPLICITY score, based on easily available immune parameters, allows for stratification of kidney transplant recipients at month one according to their expected risk of subsequent infection

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Dietary α‐Linolenic Acid, Marine ω‐3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvención con DIeta MEDiterránea (PREDIMED) Study

Background: Epidemiological evidence suggests a cardioprotective role of α‐linolenic acid (ALA), a plant‐derived ω‐3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine ω‐3 fatty acids (long‐chain n‐3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all‐cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long‐chain n‐3 polyunsaturated fatty acids (≥500 mg/day). Methods and Results: We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable‐adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9‐y follow‐up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56–0.92) for all‐cause mortality and 0.95 (95% CI 0.58–1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long‐chain n‐3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67–1.05) for all‐cause mortality, 0.61 (95% CI 0.39–0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29–0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22–1.01) for sudden cardiac death. The highest reduction in all‐cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45–0.87]). Conclusions: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all‐cause mortality, whereas protection from cardiac mortality is limited to fish‐derived long‐chain n‐3 polyunsaturated fatty acids. Clinical Trial Registration URL: http://www.Controlled-trials.com/. Unique identifier: ISRCTN35739639

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

The essential oil of Cleonia lusitanica

The essential oil obtained from Cleonia lusitanica (L.) L. grown in Spain was analyzed by thin-layer chromatography GC and GC/MS. It was found that the major components were α-pinene (33.94–17.66%) and limonene (33.37–64.75%).Peer Reviewe

Importance of the spectral emissivity measurements at working temperature to determine the efficiency of a solar selective coating

The total emissivity of the absorbing surfaces is a critical parameter in the calculation of the radiative thermal losses in solar thermal collectors. This is because the radiative heat losses have a significant economic impact on the final cost of the electricity produced in a solar thermal plant. This paper demonstrates the need to calculate the total emissivity from spectral emissivity measurements at the working temperature of the solar thermal collector, instead of using extrapolated values from spectral emissivities measured at room temperature. Usual uncertainties produced by the estimation of the total emissivity, in which its temperature dependence is only introduced by the Planck function, are analyzed

Vegetation evolution during upper Pleistocene and Holocene in Buena Pinta archaeopaleontological site (Pinilla del Valle, Spain central mountain range)

Pollen and non-pollen palynomorphs analysis of upper Pleistocene and Holocene Buena Pinta cave sediments of the in the Calvero de la Higuera (Pinilla del Valle. Madrid) archaeopalentological site has been conducted. The results shows a vegetation dynamics from the pollen diagrams can be correlated with the vegetation progressive evolution of an open landscape as adaption to the installation of hot and dry character climatic conditions. Nivel-3 of sequence is dated by OSL is 63.451+- 5.509 years no cal.; radiocarbon dating of Carbon 14 its development, before 4.940+- 40 years BP.Peer Reviewe