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OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Abstract Gut microbiota metabolites have been mechanistically linked to inflammatory pathway activation and atherosclerosis, which are major causes of vascular stiffness (VS). Aiming to investigate if the gut microbiome might be involved in VS development, we performed a cross-sectional study (n = 3,087), nested within the population-based European Prospective Investigations into Cancer and Nutrition (EPIC) Potsdam. We investigated the correlation of the gut microbiota (alpha diversity and taxa abundance) with 3 vascular stiffness measures: carotid-femoral (PWV), aortic augmentation index (AIX) and ankle-brachial index (ABI). Shannon index was not significantly associated with VS but the number of observed Amplicon Sequence Variants (ASV) was positively associated with PWV and AIX. We found a total of 19 ASVs significantly associated with at least one VS measure in multivariable-adjusted models. One ASV (classified as Sutterella wadsworthensis) was associated with 2 VS measures, AIX (− 0.11 ± 0.04) and PWV (-0.14 ± 0.03). Other examples of ASVs associated with VS were Collinsella aerofaciens, previously reported to be affected by diet and Bacteroides uniformis, commercially available as probiotics. In conclusion, our study suggests a potential role of individual components of the gut microbiota in the aetiology of VS.

Mitigation strategies to eliminate existing space debris, such as with Active Space Debris Removal (ASDR) missions, have become increasingly important. Among the considered ASDR approaches, one involves using a net as a capturing mechanism. A fundamental requirement for any ASDR mission is that the capture process itself should not give rise to new space debris. However, in simulations of net capturing, the potential for structural breaking is often overlooked. A discrete Multi-Spring-Damper net model was employed to simulate the impact of a 30 m × 30 m net travelling at 20 m/s onto an ESA Envisat mock-up. The Envisat was modelled as a two-rigid-body system comprised of the main body and a large solar array with a hinge connection. The analysis revealed that more than two significant substructures had a notable likelihood of breaking, prompting the recommendation of limiting the impacting velocity. The generation of secondary space debris indicates that net capturing is riskier than previously assumed in the literature.

Among lipid classes, ceramides are linked to impaired cardiometabolic health. Here the authors report the association of specific ceramides and dihydroceramides on the risk of developing type 2 diabetes and or cardiovascular disease in a prospective population cohort.

Abstract Background The high incidence of bacterial genes that confer resistance to last-resort antibiotics, such as colistin, caused by mobilized colistin resistance (mcr) genes, poses an unprecedented threat to human health. Understanding the spread, evolution, and distribution of such genes among human populations will help in the development of strategies to diminish their occurrence. To tackle this problem, we investigated the distribution and prevalence of potential mcr genes in the human gut microbiome using a set of bioinformatics tools to screen the Unified Human Gastrointestinal Genome (UHGG) collection for the presence, synteny and phylogeny of putative mcr genes, and co-located antibiotic resistance genes. Results A total of 2079 antibiotic resistance genes (ARGs) were classified as mcr genes in 2046 metagenome assembled genomes (MAGs), distributed across 1596 individuals from 41 countries, of which 215 were identified in plasmidial contigs. The genera that presented the largest number of mcr-like genes were Suterella and Parasuterella. Other potential pathogens carrying mcr genes belonged to the genus Vibrio, Escherichia and Campylobacter. Finally, we identified a total of 22,746 ARGs belonging to 21 different classes in the same 2046 MAGs, suggesting multi-resistance potential in the corresponding bacterial strains, increasing the concern of ARGs impact in the clinical settings. Conclusion This study uncovers the diversity of mcr-like genes in the human gut microbiome. We demonstrated the cosmopolitan distribution of these genes in individuals worldwide and the co-presence of other antibiotic resistance genes, including Extended-spectrum Beta-Lactamases (ESBL). Also, we described mcr-like genes fused to a PAP2-like domain in S. wadsworthensis. These novel sequences increase our knowledge about the diversity and evolution of mcr-like genes. Future research should focus on activity, genetic mobility and a potential colistin resistance in the corresponding strains to experimentally validate those findings.

Abstract Background Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. Methods We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising n = 3535 participants (median age 67 years, 60% women). Advanced glycation end-products were measured as skin autofluorescence with AGE-Reader™, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index with Vascular Explorer™. A subset of 1348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Associations between skin autofluorescence and various indices of vascular stiffness were assessed by multivariable regression analyses and were adjusted for age, sex, measures of adiposity and lifestyle, blood pressure, prevalent conditions, medication use and blood biomarkers. Results Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and − 0.04 (− 0.05; − 0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (− 0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. Conclusions Our findings indicate that advanced glycation end-products measured as skin autofluorescence might be involved in vascular stiffening independent of age and other cardiometabolic risk factors not only in individuals with diabetes but also in normoglycemic and prediabetic conditions. Skin autofluorescence might prove as a rapid and non-invasive method for assessment of macrovascular disease progression across all glycemic strata.

En este artículo se analiza la intensidad y la variabilidad temporal de la isla de calor urbana (ICU) de la ciudad de Zaragoza (España) y se evalúa la acción del viento como importante factor atmosférico condicionante de la misma. A partir de los datos horarios proporcionados por la red meteorológica urbana de mesoescala de la ciudad, se calculó la diferencia de temperatura entre dos observatorios, uno urbano (Plaza Santa Marta) y otro en las afueras del área urbana (Ciudad Deportiva), en el periodo 2015-2020. Los resultados indican que la temperatura en el centro de la ciudad es, con mucha frecuencia, 1º o 2ºC más elevada que en el entorno, y en ocasiones ha llegado a superar los 8ºC. La ICU es más intensa en verano (promedios horarios de 2,5ºC) que en invierno (promedio de 2,2ºC) y es más intensa durante la noche que durante el día. El valor máximo de la ICU se alcanza en situaciones de calma atmosférica; en cambio, se debilita claramente con vientos de más de 10 km/h y llega prácticamente a desaparecer con velocidades superiores a 50 km/h.

Background: The impact of extreme changes in weather patterns on the economy and human welfare is one of the biggest challenges our civilization faces. From anthropogenic contributions to climate change, reducing the impact of farming activities is a priority since it is responsible for up to 18% of global greenhouse gas emissions. To this end, we tested whether ruminal and stool microbiome components could be used as biomarkers for methane emission and feed efficiency in bovine by studying 52 Brazilian Nelore bulls belonging to two feed intervention treatment groups, that is, conventional and by-product-based diets.Results: We identified a total of 5,693 amplicon sequence variants (ASVs) in the Nelore bulls’ microbiomes. A Differential abundance analysis with the ANCOM approach identified 30 bacterial and 15 archaeal ASVs as differentially abundant (DA) among treatment groups. An association analysis using Maaslin2 software and a linear mixed model indicated that bacterial ASVs are linked to the host’s residual methane emission (RCH4) and residual feed intake (RFI) phenotype variation, suggesting their potential as targets for interventions or biomarkers.Conclusion: The feed composition induced significant differences in both abundance and richness of ruminal and stool microbial populations in ruminants of the Nelore breed. The industrial by-product-based dietary treatment applied to our experimental groups influenced the microbiome diversity of bacteria and archaea but not of protozoa. ASVs were associated with RCH4 emission and RFI in ruminal and stool microbiomes. While ruminal ASVs were expected to influence CH4 emission and RFI, the relationship of stool taxa, such as Alistipes and Rikenellaceae (gut group RC9), with these traits was not reported before and might be associated with host health due to their link to anti-inflammatory compounds. Overall, the ASVs associated here have the potential to be used as biomarkers for these complex phenotypes.

Abstract Background The success of different species of ruminants in the colonization of a diverse range of environments is due to their ability to digest and absorb nutrients from cellulose, a complex polysaccharide found in leaves and grass. Ruminants rely on a complex and diverse microbial community, or microbiota, in a unique compartment known as the rumen to break down this polysaccharide. Changes in microbial populations of the rumen can affect the host’s development, health, and productivity. However, accessing the rumen is stressful for the animal. Therefore, the development and use of alternative sampling methods are needed if this technique is to be routinely used in cattle breeding. To this end, we tested if the fecal microbiome could be used as a proxy for the rumen microbiome due to its accessibility. We investigated the taxonomic composition, diversity and inter-relations of two different GIT compartments, rumen and feces, of 26 Nelore (Bos indicus) bulls, using Next Generation Sequencing (NGS) metabarcoding of bacteria, archaea and ciliate protozoa. Results We identified 4265 Amplicon Sequence Variants (ASVs) from bacteria, 571 from archaea, and 107 from protozoa, of which 143 (96 bacteria and 47 archaea) were found common between both microbiomes. The most prominent bacterial phyla identified were Bacteroidetes (41.48%) and Firmicutes (56.86%) in the ruminal and fecal microbiomes, respectively, with Prevotella and Ruminococcaceae UCG-005 the most relatively abundant genera identified in each microbiome. The most abundant archaeal phylum identified was Euryarchaeota, of which Methanobrevibacter gottschalkii, a methanogen, was the prevalent archaeal species identified in both microbiomes. Protozoa were found exclusively identified in the rumen with Bozasella/Triplumaria being the most frequent genus identified. Co-occurrence among ruminal and fecal ASVs reinforces the relationship of microorganisms within a biological niche. Furthermore, the co-occurrence of shared archaeal ASVs between microbiomes indicates a dependency of the predominant fecal methanogen population on the rumen population. Conclusions Co-occurring microorganisms were identified within the rumen and fecal microbiomes, which revealed a strong association and inter-dependency between bacterial, archaeal and protozoan populations of the same microbiome. The archaeal ASVs identified as co-occurring between GIT compartments corresponded to the methanogenic genera Methanobrevibacter and Methanosphaera and represented 26.34% of the overall archaeal sequencesdiversity in the rumen and 42.73% in feces. Considering that these archaeal ASVs corresponded to a significant part of the overall diversity of both microbiomes, which is much higher if one includes the interactions of these co-occurring with other rumen archaea ASVs, we suggest that fecal methanogens could be used as a proxy of ruminal methanogens.

In the northeast of the Iberian Peninsula, few studies have reconstructed drought occurrence and variability for the pre-instrumental period using documentary evidence and natural proxies. In this study, we compiled a unique dataset of rogation ceremonies – religious acts asking God for rain – from 13 cities in the northeast of Spain and investigated the annual drought variability from 1650 to 1899 CE. Three regionally different coherent areas (Mediterranean, Ebro Valley, and Mountain) were detected. Both the Barcelona and the regional Mediterranean drought indices were compared with the instrumental series of Barcelona for the overlapping period (1787–1899), where we discovered a highly significant and stable correlation with the Standardized Precipitation Index of May with a 4-month lag (r=-0.46 and r=-0.53; p, respectively). We found common periods with prolonged droughts (during the mid and late 18th century) and extreme drought years (1775, 1798, 1753, 1691, and 1817) associated with more atmospheric blocking situations. A superposed epoch analysis (SEA) was performed showing a significant decrease in drought events 1 year after the volcanic events, which might be explained by the decrease in evapotranspiration due to reduction in surface temperatures and, consequently, the higher availability of water that increases soil moisture. In addition, we discovered a common and significant drought response in the three regional drought indices 2 years after the Tambora volcanic eruption. Our study suggests that documented information on rogation ceremonies contains important independent evidence to reconstruct extreme drought events in areas and periods for which instrumental information and other proxies are scarce. However, drought index for the mountainous areas (denoted Mountain later in the text) presents various limitations and its interpretation must be treated with caution.

BackgroundSARS-CoV-2 is an RNA virus causing COVID-19. The clinical characteristics and epidemiology of COVID-19 have been extensively investigated, however, only one study so far focused on the patient’s nasopharynx microbiota. In this study we investigated the nasopharynx microbial community of patients that developed different severity levels of COVID-19. We performed 16S ribosomal DNA sequencing from nasopharyngeal swab samples obtained from SARS-CoV-2 positive (56) and negative (18) patients in the province of Alicante (Spain) in their first visit to the hospital. Positive SARS-CoV-2 patients were observed and later categorized in mild (symptomatic without hospitalization), moderate (hospitalization), and severe (admission to ICU). We compared the microbiota diversity and OTU composition among severity groups and built bacterial co-abundance networks for each group.ResultsStatistical analysis indicated differences in the nasopharyngeal microbiome of COVID19 patients. 62 OTUs were found exclusively in SARS-CoV-2 positive patients, mostly classified as members of the phylum Bacteroidota (18) and Firmicutes (25). OTUs classified as Prevotella were found to be significantly more abundant in patients that developed more severe COVID-19. Furthermore, co-abundance analysis indicated a loss of network complexity among samples from patients that later developed more severe symptoms.ConclusionOur study shows that the nasopharyngeal microbiome of COVID-19 patients showed differences in the composition of specific OTUs and complexity of co-abundance networks. Taxa with differential abundances among groups could serve as biomarkers for COVID-19 severity. Nevertheless, further studies with larger sample sizes should be conducted to validate these results.

Purpose Pleural effusion (PEs) may complicate diffuse large B-cell lymphomas (DLBCL). However, their real prevalence and prognostic significance have seldom been approached systematically. Methods Retrospective single-center evaluation of consecutive patients with DLBCL was conducted. Baseline characteristics, PEs on CT imaging, pleural fluid analyses, and outcome until death or censoring date were collected. Results Of 185 DLBCL patients, 55 (30%) had PEs, of which 27 (49%) were analyzed. Most tapped PEs were malignant (n = 24) and cytological and/or flow cytometric analyses provided the diagnosis in about 70% of the cases. Malignant PEs were exudates with adenosine deaminase levels > 35 U/L in 35% of the cases. More than one-third of lymphomatous PEs required definitive pleural procedures for symptomatic relief. PEs greater than 200 mL on CT scans were an independent predictor of poor survival in Cox regression modeling (hazard ratio 1.9). Conclusions PEs are common in DLBCL and foreshadow a poor prognosis., Author(s): José M. Porcel [sup.1] , Irene Cuadrat [sup.1] , Tomás García-Cerecedo [sup.2] , Marina Pardina [sup.3] , Silvia Bielsa [sup.1] Author Affiliations: (Aff1) 0000 0004 1765 7340, grid.411443.7, Pleural [...]

El siglo XVII conoció en España varios periodos de crisis agrarias que provocaron escasez de productos de primera necesidad y un aumento del precio de los cereales. Las fluctuaciones de los precios del trigo, cebada y centeno están relativamente bien documentadas en muchas zonas del país; sin embargo, el conocimiento de la influencia que sobre estas variaciones pudieron tener factores climáticos y ambientales es aún muy limitado. En este trabajo se presentan los registros históricos del coste de los cereales de cuatro ciudades de diferentes entornos geográficos del Nordeste de la península Ibérica durante el periodo 1630-1660 y se comparan con los índices de sequía reconstruidos a partir de fuentes proxy documentales y dendroclimáticas. Se observa que las variaciones de los precios coinciden con anomalías regionales en la sequía de primavera-verano. Las correlaciones directas entre ambos son bajas, apenas superan r = 0,19; sin embargo, si el análisis se centra en los valores extremos, la influencia del clima aumenta: los precios son altos durante los periodos más secos y descienden durante los periodos considerados normales o húmedos; aunque con respuestas espacialmente variables. Esta correspondencia es mayor en los años anteriores y posteriores a la Guerra dels Segadors, lo cual indica que el intercambio de bienes y la coherencia de los datos estaban controlados tanto por factores sociopolíticos como ambientales, siendo estos últimos más influyentes en tiempos de paz.

Previously, we reported that immunomodulatory lactobacilli, nasally administered, beneficially regulated the lung antiviral innate immune response induced by Toll-like receptor 3 (TLR3) activation and improved protection against the respiratory pathogens, influenza virus and respiratory syncytial virus in mice. Here, we assessed the immunomodulatory effects of viable and non-viable Lactiplantibacillus plantarum strains in human respiratory epithelial cells (Calu-3 cells) and the capacity of these immunobiotic lactobacilli to reduce their susceptibility to the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immunobiotic L. plantarum MPL16 and CRL1506 differentially modulated IFN-β, IL-6, CXCL8, CCL5 and CXCL10 production and IFNAR2, DDX58, Mx1 and OAS1 expression in Calu-3 cells stimulated with the TLR3 agonist poly(I:C). Furthermore, the MPL16 and CRL1506 strains increased the resistance of Calu-3 cells to the challenge with SARS-CoV-2. L. plantarum MPL16 induced these beneficial effects more efficiently than the CRL1506 strain. Of note, neither non-viable MPL16 and CRL1506 strains nor the non-immunomodulatory strains L. plantarum CRL1905 and MPL18 could modify the resistance of Calu-3 cells to SARS-CoV-2 infection or the immune response to poly(I:C) challenge. To date, the potential beneficial effects of immunomodulatory probiotics on SARS-CoV-2 infection and COVID-19 outcome have been extrapolated from studies carried out in the context of other viral pathogens. To the best of our knowledge, this is the first demonstration of the ability of immunomodulatory lactobacilli to positively influence the replication of the new coronavirus. Further mechanistic studies and in vivo experiments in animal models of SARS-CoV-2 infection are necessary to identify specific strains of beneficial immunobiotic lactobacilli like L. plantarum MPL16 or CRL1506 for the prevention or treatment of the COVID-19.

Tree rings are an important proxy to understand the natural drivers of climate variability in the Mediterranean Basin and hence to improve future climate scenarios in a vulnerable region. Here, we compile 316 tree-ring width series from 11 conifer sites in the western Iberian Range. We apply a new standardization method based on the trunk basal area instead of the tree cambial age to develop a regional chronology which preserves high- to low-frequency variability. A new reconstruction for the 1602–2012 period correlates at −0.78 with observational September temperatures with a cumulative mean of the 21 previous months over the 1945–2012 calibration period. The new IR2Tmax reconstruction is spatially representative for the Iberian Peninsula and captures the full range of past Iberian Range temperature variability. Reconstructed long-term temperature variations match reasonably well with solar irradiance changes since warm and cold phases correspond with high and low solar activity, respectively. In addition, some annual temperature downturns coincide with volcanic eruptions with a 3-year lag.

Mountain systems within the Mediterranean region, e.g., the Pyrenees, are very sensitive to climate change. In the present study, we quantified the magnitude of extreme precipitation events and the number of days with torrential precipitation (daily precipitation ≥ 100 mm) in all the rain gauges available in the Pyrenees for the 1981–2015 period, analyzing the contribution of the synoptic scale in this type of event. The easternmost (under Mediterranean influence) and north-westernmost (under Atlantic influence) areas of the Pyrenees registered the highest number of torrential events. The heaviest events are expected in the eastern part, i.e., 400 mm day−1 for a return period of 200 years. Northerly advections over the Iberian Peninsula, which present a low zonal index, i.e., implying a stronger meridional component, give rise to torrential events over the western Pyrenees; and easterly advections favour extreme precipitation over the eastern Pyrenees. The air mass travels a long way, from the east coast of North America, bringing heavy rainfall to the western Pyrenees. In the case of the torrential events over the eastern Pyrenees, the trajectory of the air mass causing the events in these areas is very short and originates in the Mediterranean Basin. The North Atlantic Oscillation (NAO) index has no influence upon the occurrence of torrential events in the Pyrenees, but these events are closely related to certain Mediterranean teleconnections such as the Western Mediterranean Oscillation (WeMO).

In a previous work, we demonstrated that nasally administered Dolosigranulum pigrum 040417 beneficially modulated the respiratory innate immune response triggered by the activation of Toll-like receptor 3 (TLR3) and improved protection against Respiratory Syncytial Virus (RSV) in mice. In this work, we aimed to evaluate the immunomodulatory effects of D. pigrum 040417 in human respiratory epithelial cells and the potential ability of this immunobiotic bacterium to increase the protection against Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The respiratory commensal bacterium D. pigrum 040417 differentially modulated the production of IFN-β, IL-6, CXCL8, CCL5 and CXCL10 in the culture supernatants of Calu-3 cells stimulated with poly(I:C) or challenged with SARS-CoV-2. The differential cytokine profile induced by the 040417 strain was associated with a significant reduction in viral replication and cellular damage after coronavirus infection. Of note, D. pigrum 030918 was not able to modify the resistance of Calu-3 cells to SARS-CoV-2 infection, indicating a strain-specific immunomodulatory effect for respiratory commensal bacteria. The findings of this work improve our understanding of the immunological mechanisms involved in the modulation of respiratory immunity induced by respiratory commensal bacteria, by demonstrating their specific effect on respiratory epithelial cells. In addition, the results suggest that particular strains such as D. pigrum 040417 could be used as a promising alternative for combating SARS-CoV-2 and reducing the severity of COVID-19.